pituitrin and Shock--Septic

Vasopressors and fluids are the cornerstones for the treatment of shock. The current international guidelines on shock recommend norepinephrine as the first-line vasopressor and vasopressin as the second-line vasopressor. In clinical practice, due to drug availability, local practice variations, special settings, and ongoing research, several alternative vasoconstrictors and adjuncts are used in the absence of precise equivalent doses. Norepinephrine equivalence (NEE) is frequently used in clinical trials to overcome this heterogeneity and describe vasopressor support in a standardized manner. NEE quantifies the total amount of vasopressors, considering the potency of each such agent, which typically includes catecholamines, derivatives, and vasopressin. Intensive care studies use NEE as an eligibility criterion and also an outcome measure. On the other hand, NEE has several pitfalls which clinicians should know, important the lack of conversion of novel vasopressors such as angiotensin II and also adjuncts such as methylene blue, including a lack of high-quality data to support the equation and validate its predictive performance in all types of critical care practice. This review describes the history of NEE and suggests an updated formula incorporating novel vasopressors and adjuncts.

Topics: Critical Care; Humans; Norepinephrine; Shock; Shock, Septic; Vasoconstrictor Agents; Vasopressins

During hemorrhagic shock, blood loss causes a fall in blood pressure, decreases cardiac output, and, consequently, O

Topics: Hemodynamics; Humans; Kidney; Norepinephrine; Shock, Hemorrhagic; Shock, Septic; Vasoconstrictor Agents; Vasopressins

This review discusses the rationale for vasopressin use, summarizes the results of clinical trials evaluating vasopressin, and focuses on the timing of vasopressin initiation to provide clinicians guidance for optimal adjunctive vasopressin initiation in patients with septic shock.. Patients with septic shock require vasoactive agents to restore adequate tissue perfusion. After norepinephrine, vasopressin is the suggested second-line adjunctive agent in patients with persistent inadequate mean arterial pressure. Vasopressin use in practice is heterogeneous likely because of inconsistent clinical trial findings, the lack of specific recommendations for when it should be used, and the high drug acquisition cost. Despite these limitations, vasopressin has demonstrated price inelastic demand, and its use in the United States has continued to increase. However, questions remain regarding optimal vasopressin use in patients with septic shock, particularly regarding patient selection and the timing of vasopressin initiation.. Experimental studies evaluating the initiation timing of vasopressin in patients with septic shock are limited, and recent observational studies have revealed an association between vasopressin initiation at lower norepinephrine-equivalent doses or lower lactate concentrations and lower mortality.

Topics: Arterial Pressure; Humans; Norepinephrine; Shock, Septic; United States; Vasoconstrictor Agents; Vasopressins

Septic and vasoplegic shock are common types of vasodilatory shock (VS) with high mortality. After fluid resuscitation and the use of catecholamine-mediated vasopressors (CMV), vasopressin, angiotensin II, methylene blue (MB), and hydroxocobalamin can be added to maintain blood pressure.. VS treatment utilizes a phased approach with secondary vasopressors added to vasopressor agents to maintain an acceptable mean arterial pressure (MAP). This review covers additional vasopressors and adjunctive therapies used when fluid and catecholamine-mediated vasopressors fail to maintain target MAP.. Evidence supporting additional vasopressor agents in catecholamine-resistant VS is limited to case reports, series, and a few randomized control trials (RCTs) to guide recommendations. Vasopressin is the most common agent added next when MAPs are not adequately supported with CMV. VS patients failing fluids and vasopressors with cardiomyopathy may have cardiotonic agents such as dobutamine or milrinone added before or after vasopressin. Angiotensin II, another class of vasopressor, is used in VS to maintain adequate MAP. MB and/or hydroxocobalamin, vitamin C, thiamine, and corticosteroids are adjunctive therapies used in refractory VS. More RCTs are needed to confirm the utility of these drugs, at what doses, which combinations and in what order they should be given.

Topics: Angiotensin II; Ascorbic Acid; Cardiotonic Agents; Catecholamines; Cytomegalovirus Infections; Dobutamine; Humans; Hydroxocobalamin; Methylene Blue; Milrinone; Shock; Shock, Septic; Thiamine; Vasoconstrictor Agents; Vasopressins

Vasodilatory shock is a serious medical condition that increases the morbidity and mortality of perioperative and critically ill patients. Norepinephrine is an established first-line therapy for this condition, but at high doses, it may lead to diminishing returns. Oftentimes, secondary noncatecholamine agents are required in those whose hypotension persists. Angiotensin II and vasopressin are both noncatecholamine agents available for the treatment of hypotension in vasodilatory shock. They have distinct modes of action and unique pharmacologic properties when compared to norepinephrine. Angiotensin II and vasopressin have shown promise in certain subsets of the population, such as those with acute kidney injury, high Acute Physiology and Chronic Health Evaluation II scores, or those receiving cardiac surgery. Any benefit from these drugs must be weighed against the risks, as overall mortality has not been shown to decrease mortality in the general population. The aims of this narrative review are to provide insight into the historical use of noncatecholamine vasopressors and to compare and contrast their unique modes of action, physiologic rationale for administration, efficacy, and safety profiles.

Topics: Angiotensin II; Catecholamines; Humans; Hypotension; Shock, Septic; Vasoconstrictor Agents; Vasodilation; Vasopressins

Sepsis is defined as a potentially fatal organ dysfunction caused by a dysregulated host response to infection. Despite tremendous progress in the medical sciences, sepsis remains one of the leading causes of morbidity and mortality worldwide. The host response to sepsis and septic shock involves changes in the immune, autonomic, and neuroendocrine systems. Regarding neuroendocrine changes, studies show an increase in plasma vasopressin (AVP) concentrations followed by a decline, which may be correlated with septic shock. AVP is a peptide hormone derived from a larger precursor (preprohormone), along with two peptides, neurophysin II and copeptin. AVP is synthesized in the hypothalamus, stored and released from the neurohypophysis into the bloodstream by a wide range of stimuli. The measurement of AVP has limitations due to its plasma instability and short half-life. Copeptin is a more stable peptide than AVP, and its immunoassay is feasible. The blood concentrations of copeptin mirror those of AVP in many physiological states; paradoxically, during sepsis-related organ dysfunction, an uncoupling between copeptin and AVP blood levels appears to happen. In this review, we focus on clinical and experimental studies that analyzed AVP and copeptin blood concentrations over time in sepsis. The findings suggest that AVP and copeptin behave similarly in the early stages of sepsis; however, we did not find a proportional decrease in copeptin concentrations as seen with AVP during septic shock. Copeptin levels were higher in nonsurvivors than in survivors, suggesting that copeptin may work as a marker of severity or sepsis-related organ dysfunction.

Topics: Glycopeptides; Humans; Neurosecretory Systems; Peptide Hormones; Sepsis; Shock, Septic; Vasopressins

The effect of early vasopressin initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early start of vasopressin support within 6 h after the diagnosis on clinical outcomes in septic shock patients.. We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of February 2021. We included studies involving adult patients (> 16 years)with septic shock. All authors reported our primary outcome of short-term mortality and in the experimental group patients in the studies receiving vasopressin infusion within 6 h after diagnosis of septic shock and in the control group patients in the studies receiving no vasopressin infusion or vasopressin infusion 6 h after diagnosis of septic shock, clearly comparing with clinically relevant secondary outcomes(use of renal replacement therapy(RRT),new onset arrhythmias, ICU length of stay and length of hospitalization). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI).. Five studies including 788 patients were included. The primary outcome of this meta-analysis showed that short-term mortality between the two groups was no difference (odds ratio [OR] = 1.09; 95% CI, 0.8 to 1.48; P = 0.6; χ2 = 0.83; I2 = 0%). Secondary outcomes demonstrated that the use of RRT was less in the experimental group than that of the control group (OR = 0.63; 95% CI, 0.44 to 0.88; P = 0.007; χ2 = 3.15; I2 = 36%).The new onset arrhythmias between the two groups was no statistically significant difference (OR = 0.59; 95% CI, 0.31 to 1.1; P = 0.10; χ2 = 4.7; I2 = 36%). There was no statistically significant difference in the ICU length of stay(mean difference = 0.16; 95% CI, - 0.91 to 1.22; P = 0.77; χ2 = 6.08; I2 = 34%) and length of hospitalization (mean difference = -2.41; 95% CI, -6.61 to 1.78; P = 0.26; χ2 = 8.57; I2 = 53%) between the two groups.. Early initiation of vasopressin in patients within 6 h of septic shock onset was not associated with decreased short-term mortality, new onset arrhythmias, shorter ICU length of stay and length of hospitalization, but can reduce the use of RRT. Further large-scale RCTs are still needed to evaluate the benefit of starting vasopressin in the early phase of septic shock.

Topics: Acute Kidney Injury; Arrhythmias, Cardiac; Early Medical Intervention; Humans; Intensive Care Units; Length of Stay; Mortality; Renal Replacement Therapy; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Norepinephrine is the first line vasopressor used in patients with septic shock. However, norepinephrine doses above 1 µg/kg/min are associated with mortality rates of over 80%, suggesting a need to implement adjunctive strategies prior to reaching this dosage. The present study therefore sought to review the existing and emergent vasopressor agents for patients with refractory septic shock. This paper summarizes the use of vasoactive drugs that may be considered in the context of refractory shock. The clinical application of present and future therapies and the related outcome are discussed. A review of the available literature indicated that vasopressin may be a good first option in patients with refractory septic shock, but evidence remains somewhat sparse. Although the use of vasopressin in these circumstances is likely preferable to the use of terlipressin, a pro-drug with an extended half-life, the use of selepressin, a pure V1 agonist, should be further assessed in future studies. Angiotensin II is another emerging option that uses a different signaling pathway. However, nitric oxide synthase inhibitors and methylene blue do not appear to be appropriate in the management of patients with refractory septic shock. In conclusion, the use of different adjunctive agents in combination with the use of norepinephrine may be useful in patients with refractory septic shock, but care must be taken to avoid excessive vasoconstriction.

Topics: Humans; Norepinephrine; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

The Canadian Critical Care Society performed a meta- analysis to assess the benefits and risks of the application of vasopressin and vasopressin- analogues in distributive shock. Their results were formulated as a Guideline in 2019. In the meta- analysis mainly included were studies with patients suffering from sepsis causing the distributive shock. The recommendations of the Surviving Sepsis Campaign 2016 concerning catecholamine therapy clearly prefer norepinephrin as the first- choice vasopressor, the use of vasopressin as an additionally administered drug is rated more tentative. Also the Canadian guideline now, implicating recently published studies, argues for the use of vasopressin or vasopressin- analogues in addition to an existing norepinephrine therapy, even though the level of evidence remains still low and there's no simple therapeutic algorithm formulated. This is based on a lowered incidence of newly- diagnosed atrial fibrillation and decreased mortality rate while administration remains safe.

Topics: Atrial Fibrillation; Canada; Catecholamines; Guidelines as Topic; Humans; Meta-Analysis as Topic; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Shock is a serious acute circulatory failure leading to inadequate oxygen delivery to the cells. Its treatment is mainly based on circulating fluid optimization, and vasopressors to provide an adequate mean arterial pressure and microcirculatory flow. Norepinephrine is the drug of choice, but high dosages may be responsible for several side effects, including increased myocardial oxygen consumption, dysrhythmias, and peripheral and organ ischemia. Moreover, some patients are "non-responders" to first-line norepinephrine treatment. Hence, other drugs have been proposed to reach and maintain the hemodynamic target. In general, they are described as catecholamine-sparing agents. Among others, the most used are vasopressin, corticosteroids, and angiotensin II. Methylene blue (MB) represents a further option, even though its use is still a topic of controversy. This review article tries to summarize what is known and unknown about the actions of MB in patients in shock. It reduces excessive production of nitric oxide via blockade of guanylate cyclase in shock states. At present, it appears the MB provides positive results in septic shock, if administered early. Further randomized controlled trials are warranted regarding its use to provide more precise indications to physicians involved in the treatment of such patients.

Topics: Adult; Aged; Aged, 80 and over; Hemodynamics; Humans; Male; Methylene Blue; Microcirculation; Middle Aged; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Patients with septic shock in whom norepinephrine (NE) infusion alone is insufficient to raise blood pressure require the concomitant administration of vasopressin (VP). However, current guidelines do not advise clinicians as to which vasoactive agent to discontinue first once the patient's septic shock begins to resolve. Moreover, there is controversial data guiding clinicians on how to discontinue vasopressors for septic shock patients who are receiving a combination therapy of NE and VP.. The PubMed, EMBASE, and Cochrane Central Register databases were searched from the database inception until October 18, 2018. Studies were limited to adult patients with septic shock who received concomitant NE and VP treatment, that included different orders of vasopressor discontinuation. The primary outcome was the incidence of hypotension. Overall mortality, ICU mortality, and length of stay (LOS) in the ICU were secondary outcomes. Sensitivity and subgroup analyses as well as trial sequential analysis were performed.. One prospective randomized controlled trial and seven retrospective cohort studies were included in present meta-analysis. Compared with discontinuing VP first, the incidence of hypotension was significantly lower when NE was discontinued first (odds ratio, OR 0.3, 95% confidence interval, CI 0.10 to 0.86, P = 0.02; I = 91%). No significant difference was detected in either overall mortality (OR 1.28, 95% CI 0.77 to 2.10, P = 0.34) or ICU mortality (OR 0.99, 95% CI 0.74 to 1.34, P = 0.96) between these two groups. Furthermore, ICU LOS was also evaluated in five studies, and no statistical significance was observed between the two groups with different orders in weaning vasopressors (mean difference 1.35, 95% CI -2.05 to 4.74, P = 0.44). The subgroup analyses suggested a significant association between hypotension and the practice of discontinuing VP first specifically in patients with a low usage rate of corticosteroids (odds ratio, OR 0.18, 95% confidence interval, CI 0.04 to 0.78, P = 0.02). The trial sequential analysis indicated a lack of sufficient evidence to draw conclusions from the current results (required information size  = 11 821).. In adults with septic shock treated with concomitant VP and NE therapy, discontinuing VP first may lead to a higher incidence of hypotension but is not associated with mortality or ICU LOS. Further prospective studies with larger sample sizes are warranted.

Topics: Adrenal Cortex Hormones; Humans; Length of Stay; Norepinephrine; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Shock, Septic; Vasopressins

The metabolic and circulatory disturbances in patients with septic shock results in a high mortality rate. There is a lack of high-level evidence on the optimal approach. We present a meta-analysis elucidating the outcomes of regimes with only noradrenaline versus a combination of noradrenaline and vasopressin in managing septic shock.. A literature search of studies comparing the use of noradrenaline and vasopressin in septic shock was conducted, using MEDLINE and EMBASE databases. The primary outcome evaluated was mortality rate. Subgroup analysis of secondary measures was also conducted using Review Manager 5.3 software.. Four RCTs of 1039 patients were included. There is good evidence supporting a comparable mortality rate (RR: 0.92, 95% CI: 0.78, 1.08, p = .32, I. The two regimes have equivalent outcomes, but vasopressin has a role in selected patients experiencing less severe septic shock beyond a 36-h period. Further work will make definitive clinical recommendations for optimal strategy of vasopressin or noradrenaline usage.

Topics: Humans; Norepinephrine; Shock, Septic; Sympathomimetics; Vasoconstrictor Agents; Vasopressins

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Catecholamines; Drug Therapy, Combination; Humans; Length of Stay; Myocardial Ischemia; Randomized Controlled Trials as Topic; Renal Replacement Therapy; Shock, Septic; Stroke; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Vasodilatory shock is the final common pathway for all forms of severe shock, with sepsis the most common primary etiology and the leading cause of critical illness-related mortality. The pathophysiology of this condition remains incompletely elucidated. Deficiency of the neuropeptide hormone vasopressin seems to play a significant role. The physiology of vasopressin and its interaction with the pathophysiology of vasodilatory shock are described in this review. A brief review of the major randomized controlled trials assessing the efficacy and safety of vasopressin and its analogs in this complex patient cohort is also provided.

Topics: Humans; Shock, Septic; Vasoconstrictor Agents; Vasodilation; Vasoplegia; Vasopressins

The aim of this study was to evaluate the effects and safety of vasopressin receptor agonists in patients with septic shock.. PubMed, EMBASE, and Cochrane library were searched for randomized controlled trials evaluating the effects of vasopressin receptor agonists in septic shock patients. Two reviewers performed literature selection, data extraction, and quality evaluation independently. The primary outcome was mortality. And secondary outcomes included intensive care unit (ICU) length of stay, duration of mechanical ventilation, and incidence of adverse events. In addition, a trial sequential analysis (TSA) was performed.. The use of vasopressin might result in reduced mortality in patients with septic shock. An increased risk of digital ischemia must be taken into account.

Topics: Hospital Mortality; Humans; Length of Stay; Patient Safety; Receptors, Vasopressin; Shock, Septic; Vasopressins

The impact of vasopressin and norepinephrine discontinuation order in the recovery phase of septic shock remains controversial. This systematic review and patient-level meta-analysis were performed to determine the impact of vasopressin and norepinephrine discontinuation order on clinically significant outcomes in the recovery phase of septic shock.. Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, and ClinicalTrials.gov were searched from inception through November 2018 for studies comparing outcomes after the discontinuation of vasopressin or norepinephrine in septic shock. Individual patient-level data were obtained from included studies and combined using a two-stage meta-analysis.. Six studies of low or moderate risk of bias with 957 patients were included. Clinically significant hypotension occurred more frequently when vasopressin was discontinued first compared to norepinephrine (60.7% versus 43.3%, respectively). First discontinuation of norepinephrine compared to vasopressin had lower pooled odds of developing clinically significant hypotension (odds ratio [OR] 0.22, 95% confidence interval [CI] 0.07-0.68, I. Discontinuation of norepinephrine prior to vasopressin during the recovery phase of septic shock resulted in less clinically significant hypotension but no difference in mortality or lengths of stay. Larger, prospective studies evaluating the impact of relative vasopressin deficiency and norepinephrine and vasopressin discontinuation order and timing on patient-centered outcomes are needed.

Topics: Drug Administration Schedule; Drug Therapy, Combination; Humans; Hypotension; Incidence; Norepinephrine; Shock, Septic; Vasopressins

We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups.. Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses.. Four trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86-1.12] or serious adverse events (RR 1.02, 95% CI 0.82-1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%-3.2%] but fewer arrhythmias (ARD - 2.8%, 95% CI - 0.2% to - 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74-0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion).. Vasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.

Topics: Aged; APACHE; Female; Humans; Length of Stay; Male; Middle Aged; Randomized Controlled Trials as Topic; Shock, Septic; Survivors; Vasoconstrictor Agents; Vasopressins

Catecholamines, especially norepinephrine, are the most frequently used vasopressors for treating patients with septic shock. During the recent decades, terlipressin, vasopressin V1A agonist, and even Ca. Relevant randomized controlled trials were identified by searching PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials updated to February 22, 2018. A network meta-analysis was performed to evaluate the effect of different types of vasoactive medications. The primary outcome was 28-day mortality. Intensive care unit (ICU) mortality, hospital and ICU length of stay (LOS), and adverse events were also assessed.. A total of 43 trials with 5767 patients assessing 17 treatment modalities were included. Treatments ranking based on surface under the cumulative ranking curve values from largest to smallest were NE/DB 85.9%, TP 75.1%, NE/EP 74.6%, PI 74.1%, EP 72.5%, VP 66.1%, NE 59.8%, PE 53.0%, DA 42.1%, DX 38.2%, SP 27.0%, PA 24.3%, EX 22.8%, LE 21.5%, and DB 13.3% for 28-day mortality. Treatments ranking for ICU mortality were TP/NE 86.4%, TP 80.3%, TP/DB/NE 65.7%, VP/NE 62.8%, NE 57.4%, VP 56.5%, PE 48.4%, DA 33.0%, PA 27.5%, LE 22.1%, and DB 9.9%. The incidence of myocardial infarction was reported with NE/EP 3.33% (n = 1 of 30), followed by EP 3.11% (n = 5 of 161), and then VP 3.10% (n = 19 of 613), NE 3.03% (n = 43 of 1417), DA 2.21% (n = 19 of 858), NE/DB 2.01% (n = 4 of 199), LE 1.16% (n = 3 of 258), and PA 0.39% (n = 1 of 257). The incidence of arrhythmia was reported with DA 26.01% (n = 258 of 992), followed by EP 22.98% (n = 37 of 161), and then NE/DB 20.60% (n = 41 of 199), NE/EP 20.0% (n = 6 of 30), NE 8.33% (n = 127 of 1525), LE 5.81% (n = 15 of 258), PA 2.33% (n = 6 of 257), and VP 1.67% (n = 10 of 600).. The use of norepinephrine plus dobutamine was associated with lower 28-day mortality for septic shock, especially among patients with lower cardiac output.

Topics: Catecholamines; Dopamine; Humans; Mortality; Norepinephrine; Odds Ratio; Randomized Controlled Trials as Topic; Shock, Septic; Terlipressin; Vasopressins

Septic shock is a serious stage of sepsis with a hospital mortality rate of more than 40%. The pathophysiology of septic shock is vasodilation and increased permeability. Fluid resuscitation, vasopressor drugs are usually used to maintain the perfusion pressure of the main organs. However, infectious patients usually have the irresponsive vessel to catecholamines and may lead to obvious side effects using high doses of norepinephrine or dopamine. Recent studies have shown that vasopressin (AVP) improves hemodynamics, increases tissue perfusion, and synergizes with norepinephrine in patients with septic shock, showing extent application prospects in the treatment of septic shock. The practice of AVP in septic shock is reviewed in this article in order to provide a reference for clinicians.

Topics: Humans; Shock, Septic; Treatment Outcome; Vasopressins

Septic shock remains one of the major causes of morbidity and mortality in the critically ill. Despite early goal therapy and administration of cathecholaminergic agents, up to 30% of patients succumb to the disease. In this manuscript, we first summarize the standard of care of patients with septic shock and current guidelines. We review the physiologic role of vasopressin and its role in septic shock management. We then review the most up-to-date evidence on the potential role of V1a receptor agonists such as Selepressin, in septic shock. Exciting new trials are being completed in order to elucidate the role of V1a receptor agonists as potential first-line vasopressor alternatives in the therapy of circulatory shock in septic patients.

Topics: Critical Illness; Humans; Receptors, Vasopressin; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Inotropes and vasopressors are cornerstone of therapy in septic shock, but search for the best agent is ongoing. We aimed to determine which vasoactive drug is associated with the best survival.. PubMed, BioMedCentral, Embase, and the Cochrane Central Register were searched. Randomized trials performed in septic patients with at least 1 group allocated to an inotrope/vasopressor were included. Network meta-analysis with a frequentist approach was performed.. The 33 included studies randomized 3470 patients to 16 different comparators. As compared with placebo, levosimendan (odds ratio [OR], 0.17, 95%; confidence interval [CI], 0.05-0.60), dobutamine (OR, 0.30; 95% CI, 0.09-0.99), epinephrine (OR, 0.35; 95% CI, 0.13-0.96), vasopressin (OR, 0.37; 95% CI, 0.16-0.89), and norepinephrine plus dobutamine (OR, 0.4; 95% CI, 0.11-0.96) were significantly associated with survival. Norepinephrine improved survival compared with dopamine (OR, 0.81; 95% CI, 0.66-1.00). Rank analysis showed that levosimendan had the highest probability of being the best treatment.. Among several regimens for pharmacological cardiovascular support in septic patients, regimens based on inodilators have the highest probability of improve survival.

Topics: Arginine Vasopressin; Cardiotonic Agents; Dobutamine; Dopamine; Epinephrine; Humans; Hydrazones; Network Meta-Analysis; Norepinephrine; Odds Ratio; Pyridazines; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic; Simendan; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Septic shock is a leading cause of mortality in intensive care units throughout the world. While this disease state represents a highly complex pathophysiology involving numerous organ systems, the early approach to care includes adequate hemodynamic support traditionally achieved via infusions of vasoactive medications after adequate fluid resuscitation. Relative adrenal and vasopressin deficiencies are a common feature of septic shock that contribute to impaired hemodynamics. Hydrocortisone and vasopressin are endocrine system hormone analogues that target the acute neuroendocrine imbalance associated with septic shock. This clinically focused annotated review describes the pathophysiological mechanisms behind their use and explores the potential clinical roles of early administration and synergy when combined.

Topics: Adrenal Insufficiency; Animals; Hemodynamics; Humans; Resuscitation; Shock, Septic; Vasopressins

Vasopressin has gained wide support as an adjunct vasopressor in patients with septic shock. This agent exerts its vasoconstriction effects through smooth muscle V1 receptors and also has antidiuretic activity via renal V2 receptors. This interaction with the renal V2 receptors results in the integration of aquaporin 2 channels in the apical membrane of the renal collecting duct leading to free water reabsorption. Thus, water intoxication with subsequent hyponatremia, although rare, is a potentially serious side effect of exogenous vasopressin administration. We present 2 patients who developed hyponatremia within hours of initiation of vasopressin infusion. Extensive diuresis followed its discontinuation with subsequent normalization of serum sodium. One of the patients required the use of hypertonic saline for more rapid normalization of serum sodium due to concerns for potential seizure activity. A review of the literature relevant to the incidence of vasopressin-induced hyponatremia is provided as well as discussion on additional factors relevant to septic shock that should be considered when determining the relative risk of hyponatremia in patients receiving vasopressin.

Topics: Adrenal Cortex Hormones; Diuresis; Female; Humans; Hyponatremia; Male; Receptors, Vasopressin; Shock, Septic; Sodium; Vasoconstrictor Agents; Vasopressins; Water Intoxication; Young Adult

Arginine-vasopressin (AVP) is an important hormone in the regulation of plasma osmolality and blood volume/pressure. In clinical practice it is frequently used in the treatment of septic shock and decompensated cirrhosis. In this review the physiology of AVP and its analogues is presented. In addition the use of AVP in cirrhosis and sepsis is reviewed.

Topics: Arginine Vasopressin; Humans; Liver Circulation; Liver Cirrhosis; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Shock, Septic; Vasopressins

International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock.. Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled.. Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels.. Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock.

Topics: Epinephrine; Hemodynamics; Humans; Lypressin; Norepinephrine; Phenylephrine; Shock, Septic; Terlipressin; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

The choice of vasopressor in septic shock has been a matter of debate. The purpose of this study was to systematically review overall evidence of vasopressor and inotropic agents in septic shock using a Bayesian network meta-analysis.. Databases, including Medline, Scopus, CINAHL, and Google Scholar were searched to identify relevant studies. Eligible studies were randomized controlled trials that reported mortality rates on the use of vasopressors and inotropes in patients with septic shock. We chose to use 28-day mortality as the outcome assessment criterion.. Fourteen studies with a total of 2811 patients were included in the analysis. Norepinephrine (NE) and NE + low-dose vasopressin but not epinephrine (EPI) were associated with significantly reduced mortality compared with dopamine. (Odds ratio, 0.80 [95% credibility interval, 0.65-0.99], 0.69 [0.48-0.98], and 0.56 [0.26-1.18], respectively). The addition of an inotropic agent such as dobutamine or dopexamine did not reduce mortality compared with EPI or NE alone.. Our results support the use of NE with or without low-dose vasopressin as the first-line vasopressor therapy in septic shock. No concrete evidence exists to support the use of EPI over dopamine as the second-line agent or the addition of an inotropic agent.

Topics: Arginine Vasopressin; Bayes Theorem; Cardiotonic Agents; Dobutamine; Dopamine; Epinephrine; Humans; Norepinephrine; Randomized Controlled Trials as Topic; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Severe sepsis is a major cause of mortality among critically ill patients. Early recognition accompanied by early initiation of broad-spectrum antibiotics with source control and fluid resuscitation improves outcomes. Hemodynamic resuscitation starts with fluid therapy followed by vasopressors if necessary. Cases refractory to first-line vasopressors (norepinephrine) will require second-line vasopressors (epinephrine or vasopressin) and low-dose steroid therapy. Resuscitation goals should include optimization of central venous oxygenation and serum lactate.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Epinephrine; Female; Fluid Therapy; Humans; Norepinephrine; Pregnancy; Pregnancy Complications, Infectious; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin and its analogue terlipressin are potent vasopressors which have been recently proposed in the treatment of catecholamine-resistant septic shock. We review the physiology, metabolism and pharmacology of vasopressin and terlipressin, as well as the available data on their efficacy and safety in neonates and children with septic shock. In adults, vasopressin deficiency can contribute to refractory shock states associated with sepsis. Differently, in children with septic shock vasopressin levels may be normal or even augmented. Nevertheless, low doses of vasopressin and terlipressin seem to have the potential to restore vasomotor tone in conditions refractory to catecholamines, improving organ perfusion with preservation of renal blood flow, while decreasing catecholamine requirements. Vasopressin and terlipressin produce vasoconstriction via stimulation of V1-receptors. In particular, terlipressin has a higher selectivity for V1-receptors and a longer half-life when compared to vasopressin, allowing for intermittent bolus doses. However, the pharmacology of vasopressin/terlipressin in newborns and children has not been sufficiently investigated and data on potential short and long-term adverse effects are still lacking. Further clinical, pharmacokinetic and pharmacodynamic studies are needed to better define the role of vasopressin and terlipressin in septic shock, as well as to prove their effectiveness and safety in infants and children.

Topics: Child; Humans; Infant, Newborn; Lypressin; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

Topics: Drug Therapy, Combination; Humans; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The vasoconstrictive and antidiuretic physiologic properties of vasopressin (antidiuretic hormone) have long been known. Until recently however, vasopressin was mostly used for diabetes insipidus and noctournal enuresis. This review summarizes the growing body of evidence regarding the perioperative use of vasopressin and its analogues in the management of certain forms of cardiovascular collapse. Physiologically, vasopressin is involved in regulating osmotic, volemic, and cardiovascular homeostasis. It acts via several specific vasopressin receptors that are variably distributed in the heart, kidneys and vasculature etc. Under normal conditions, its antidiuretic effect predominates and vasopressin only induces vasoconstriction at high concentrations. Regarding catecholamine-resistant vasodilatory shock, current evidence suggests that with adequate volume resuscitation, exogenous vasopressin in low "physiologic" doses (0.01-0.04 units/min) safely supports mean arterial pressure without adversely affecting myocardial function and splanchnic circulation. One possible explanation is that metabolic acidosis impairs the function of alpha-adrenergic (but not vasopressin) receptors, thus diminishing the response to catecholamines. Although there is yet no clear cut mortality benefit, vasopressin is now recommended as a second-line agent in septic shock for its catecholamine-sparing effect and as an alternative to epinephrine in cardiopulmonary resuscitation. It has also demonstrated efficacy in ameliorating vasoplegia after cardiopulmonary bypass as well as perioperative hypotension in patients on renin-angiotensin system antagionists preoperatively. In summary, accumulating clinical experience and formal studies indicate that vasopressin has a role in restoring vascular tone in refractory vasodilatory shock states with minimal adverse effects provided that euvolemia is assured.

Topics: Anesthesia; Animals; Antidiuretic Agents; Critical Care; Heart Arrest; Hemodynamics; Humans; Perioperative Care; Shock; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

For many years, basic research with relatively straightforward pathophysiologic approaches has driven clinical trials using molecules that supposedly interfere positively with inflammatory processes. However, most of these trials have failed to demonstrate any outcome benefit. Indeed, we need to revisit current paradigms and to think about the possibility that outcome may be predetermined in severe sepsis or septic shock. In addition, an early diagnosis of sepsis prior to the onset of clinical decline is also of particular interest to health practitioners because this information increases the possibilities for early and specific treatment of this life threatening condition. Indeed, the time to initiate therapy is thought to be crucial and the major determent factor in surviving sepsis. Despite substantial progress in sepsis therapy, the gap between the discovery of new effective medical molecules and their implementation in the daily clinical practice of the intensive care unit remains a major hurdle. Fortunately, ongoing research continues to provide new information on the management of sepsis, in particular, severe sepsis or septic shock. High quality and effective management tools are necessary to bring evidence-based therapy to the bedside. On this basis, new therapies could be tested to reduce mortality rates with respect to recently published studies.

Topics: Adrenal Cortex Hormones; Animals; Humans; Hydroxyethyl Starch Derivatives; NF-kappa B; Sepsis; Shock, Septic; Vasopressins

This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 μg/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care--or septic shock--and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroid

Topics: Hemostatics; Humans; Intensive Care Units; Randomized Controlled Trials as Topic; Shock, Septic; Vasopressins

The hemodynamics of septic shock is characterized by a primary reduction of vascular tone, which defines vasoplegia. Septic vasoplegia is due to reduced endogenous production of vasopressin, as well as to the overproduction of vasodilating molecules (nitric oxide, prostacyclin, peroxynitrite and kynurenine) and the opening of ATP-sensitive potassium channels. Treatment is supportive and includes primarily alpha-adrenergic catecholamines. Vasopressin may also be useful, although its place is still controversial. Further agents can improve the vascular responsiveness to catecholamines, most notably low doses hydrocortisone, and, to a lesser extent, activated protein C. Further, innovative therapies, based on recent understanding of pathophysiological mechanisms, might become useful agents to treat septic vasoplegia in the future.

Topics: Catecholamines; Humans; Hydrocortisone; KATP Channels; Models, Biological; Nitric Oxide; Peroxynitrous Acid; Prostaglandins I; Protein C; Shock, Septic; Signal Transduction; Vasoplegia; Vasopressins

Vasopressin and terlipressin, a long-acting V1a analogue, are increasingly used in intensive care. The main clinical indications are the treatment of patients with septic shock and of patients with cirrhosis, who develop variceal bleeding, the hepatorenal syndrome or both. In this review, we summarize the effects of these drugs on splanchnic hemodynamics and organ function.. A recent systematic meta-analysis of randomized trials suggests that terlipressin may improve renal function in hepatorenal syndrome and thereby reduce mortality by 34%. Moreover, a recent study reported that association of terlipressin and albumin was more effective than terlipressin alone. In patients with variceal bleeding, the bleeding control is significantly improved by early administration of terlipressin. The place of vasopressin in the treatment of patients with septic shock is still discussed, but compared with norepinephrine, vasopressin showed at least an equal efficacy.. The use of vasopressin and its synthetic analogues has shown beneficial effects in the management of patients with cirrhosis, especially in the context of variceal bleeding, the hepatorenal syndrome or both. In both cases, the use of terlipressin improved survival. Therefore, in these clinical indications, terlipressin is a part of recommendations. The role of vasopressin in patients with septic shock remains to be precisely evaluated.

Topics: Critical Care; Critical Illness; Hemodynamics; Hepatorenal Syndrome; Humans; Intensive Care Units; Liver; Liver Cirrhosis; Lypressin; Risk Factors; Shock, Septic; Terlipressin; Varicose Veins; Vasoconstrictor Agents; Vasopressins

The definition of septic shock includes sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of organ perfusion abnormalities, and ultimately cell dysfunction. To restore adequate organ perfusion and cell homeostasis, cardiac output should be restored with volume infusion plus vasopressor agents as indicated. Appropriate arterial pressure for each individual patient and proper arterial oxygen content are key elements to restoring perfusion. Tissue perfusion can be monitored by markers of organ and mitochondrial function, namely urine output, level of consciousness, peripheral skin perfusion, central or mixed venous oxygen saturation, and lactate. The hemodynamic effects of the different vasopressor agents depend on the relative affinity to adrenergic receptors. Those with predominant alpha-agonist activity produce more vasoconstriction (inoconstrictors) while those with predominant beta-agonist stimulation increase cardiac performance (inodilators). The debate about whether one vasopressor agent is superior to another is still ongoing. The Surviving Sepsis Campaign guidelines refer to either norepinephrine or dopamine as the first-choice vasopressor agent to correct hypotension in septic shock. However, recent data from observational and controlled trials have challenged these recommendations concerning different adrenergic agents. As a result, our view on the prescription of vasopressors has changed from a probably oversimplified "one-size-fits-all" approach to a multimodal approach in vasopressor selection.

Topics: Adrenergic Agents; Algorithms; Blood Flow Velocity; Blood Pressure; Cardiotonic Agents; Decision Trees; Dobutamine; Dopamine; Epinephrine; Fluid Therapy; Humans; Lypressin; Monitoring, Physiologic; Norepinephrine; Patient Selection; Practice Guidelines as Topic; Resuscitation; Shock, Septic; Terlipressin; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Septic shock is characterized by vasodilation and hypotension despite increased vasoconstrictors. While nitric oxide is known to be responsible for vasodilation, failure of vascular smooth muscle to constrict may be due in part to low plasma levels of vasopressin, a neurohypophyseal hormone. In the initial phase of septic shock, vasopressin concentration usually increases but then decreases to a significantly lower concentration after onset of septic shock. In this review, we discuss the neural mechanisms for the regulation of vasopressin secretion during septic shock.

Topics: Animals; Humans; Muscle, Smooth, Vascular; Pituitary Gland, Posterior; Shock, Septic; Vasodilation; Vasopressins

Vasopressin is a stress hormone. However, vasopressin levels are inappropriately low in septic shock. Vasopressin stimulates AVPR1a, AVPR1b, AVPR2 and purinergic receptors. Vasopressin increases blood pressure by occupying AVPR1a receptors on vascular smooth muscle. An increase in ventricular afterload due to vasopressor administration limits ventricular systolic ejection, an effect that becomes increasingly important as systolic contractility is decreased. Stimulation of AVPR1a receptors may also decrease edemagenesis. Stimulation of AVPR1b by vasopressin releases ACTH and cortisol. AVPR2 stimulation increases retention of water by increasing cyclic AMP. Yet, vasopressin infusion may increase urine output, creatinine clearance and improve renal function in septic shock. Vasopressin has many effects on immune function such as altering cytokines, neuroimmunity, prostaglandins, humoral immunity and immune cells. For example, vasopressin decreases sepsis-induced pulmonary inflammation, could have renal anti-inflammatory effects and may decrease prostaglandin levels in a dose-dependent manner. Vasopressin may also modulate responses to stress by expression and release from immune cells. Interestingly, there are vasopressin receptors on immune cells. Many small clinical studies of vasopressin infusion in septic shock have shown that vasopressin infusion increases blood pressure, decreases requirements for norepinephrine and improves renal function. However, vasopressin could decrease coronary, cerebral and mesenteric perfusion. A multicenter trial of vasopressin versus norepinephrine in septic shock found no overall difference in mortality. Vasopressin may decrease mortality in patients with less severe septic shock. Vasopressin plus corticosteroid treatment may decrease mortality compared to corticosteroids plus norepinephrine. Potential mechanisms are that vasopressin plus corticosteroids beneficially alter immunity in septic shock.

Topics: Animals; Humans; Mice; Models, Molecular; Norepinephrine; Randomized Controlled Trials as Topic; Rats; Receptors, Vasopressin; Shock, Septic; Treatment Outcome; Vasopressins

When fluid administration fails to restore an adequate arterial pressure and organ perfusion in patients with septic shock, therapy with vasoactive agents should be initiated. The ultimate goals of such therapy in shock are to restore effective tissue perfusion and to normalize cellular metabolism. The efficacy of hemodynamic therapy in sepsis should be assessed by monitoring a combination of clinical and hemodynamic parameters. Although specific end points for therapy are debatable, and therapies will inevitably evolve as new information becomes available, the idea that clinicians should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis remains a fundamental principle.

Topics: Adrenergic Agents; Adrenergic alpha-Agonists; Animals; Cardiac Output; Cardiotonic Agents; Dopamine; Epinephrine; Hemodynamics; Humans; Phenylephrine; Regional Blood Flow; Resuscitation; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Trauma with resultant hypovolemic shock remains both prevalent and difficult to treat. Standard strategies using volume resuscitation and catecholamine support have historically yielded poor results. Vasopressin has emerged as a possible pharmacologic adjunct, particularly in patients with shock refractory to the administration of fluids and catecholamines. Much of the data regarding vasopressin is extrapolated from its usefulness in cases of nonhypovolemic human shock, which are supported by convincing animal studies. It is true that humans show a deficiency in vasopressin minutes after significant hemorrhage that can respond to administration of exogenous vasopressin. When given in physiological dosing regimens, vasopressin appears to be a safe adjunct to other therapy. Definite recommendations regarding indications for use, recommended dose, and long-term outcome in patients with hemorrhagic shock await a much needed prospective, randomized, controlled trial.

Topics: Animals; Hemostatics; Humans; Receptors, Vasopressin; Shock, Hemorrhagic; Shock, Septic; Vasopressins

Sepsis remains a common problem in critically ill patients.. Considerable advances have been made in our understanding of the pathophysiology of sepsis and recent years have seen a surge of potential new therapeutic agents for sepsis. Definitions have been rethought and strategies proposed to better characterise patients with sepsis as the importance of individually targeted treatment packages has been realised. Current management aims to control infection, to achieve haemodynamic stabilisation, to modulate the immune response and to provide metabolic and organ support. As new therapies are introduced, treatment recommendations will need to be adapted accordingly.

Topics: Anti-Infective Agents; Bacteriological Techniques; Biomarkers; Blood Glucose; Blood Transfusion; Critical Illness; Fluid Therapy; Hemodynamics; Hospital Mortality; Humans; Hydrocortisone; Immunologic Factors; Inflammation Mediators; Intensive Care Units; Oxygen; Prognosis; Protein C; Recombinant Proteins; Resuscitation; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasodilatory septic shock is characterized by profound vasodilation of the peripheral circulation, relative refractoriness to catecholamines and a relative deficiency of the posterior pituitary hormone, vasopressin. Arginine vasopressin is effective in restoring vascular tone in vasodilatory septic shock and may be associated with decreased mortality in less severe septic shock as well as improved mortality and decreased renal failure in septic shock patients at risk for renal failure.

Topics: Animals; Arginine Vasopressin; Clinical Trials as Topic; Humans; Shock, Septic; Vasoconstrictor Agents; Vasodilation; Vasopressins

Terlipressin, a long-acting vasopressinergic V1 agonist, is increasingly used to increase mean arterial blood pressure in the common setting of catecholamine-refractory septic shock. Traditionally, terlipressin has been used as drug of last resort and administered as intermittent high-dose bolus infusion (1-2 mg every 4 to 6 hours). Recent experimental and clinical evidence, however, suggests that terlipressin may also be used as a low-dose continuous infusion (1-2 microg kg(-1) h(-1)) in the early course of the disease. This approach may sufficiently increase systemic blood pressure and thereby prevent unwanted side effects, such as exaggerating increases in peripheral resistance or rebound hypotension. Small-scale clinical studies suggest that low-dose terlipressin, when given as a first-line vasopressor agent, is safe. Randomised, clinical multicenter trials are now needed to investigate whether or not early institution of low-dose continuous terlipressin infusion improves overall outcome of patients suffering from vasodilatory shock states.

Topics: Animals; Humans; Lypressin; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

The present paper is aimed at reviewing new findings on the use of terlipressin in children with septic shock. The level of evidence based on the data available in the literature is very low. Three series of cases and four isolated cases report on the use of terlipressin in children with catecholamine-refractory septic shock. The aggregated population represents 39 children. The dosages of boli vary from 7 microg/kg twice a day to 2 microg/kg every 4 hours. Low-dose continuous infusion has also been described. Terlipressin injection is associated with an approximately 30% increase in blood pressure. Mortality of these children with catecholamine refractory septic shock is 54%. The paucity of most reports does not make it possible to conclude on the global and microcirculatory effects of this treatment. Future studies are required before any recommendations on the use of terlipressin in children with septic shock can be made.

Topics: Animals; Catecholamines; Drug Resistance; Humans; Infant; Infant, Newborn; Lypressin; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

Sepsis is the systemic inflammatory response syndrome secondary to a local infection. Septic shock, the severe complication of sepsis associated with refractory hypotension, is frequently a near-fatal condition requiring prompt diagnosis and management. Although the recent years have been associated with considerable improvements in the knowledge of the pathophysiology of the disease and remarkable advances have been achieved in sepsis treatment, the morbidity and mortality of this disease are still unacceptably high. In this review, we will briefly discuss the ongoing standard treatment of septic shock and describe novel potential therapies, aiming to improve hemodynamic support and/or control inflammatory response in sepsis. These therapies were associated with benefits in experimental studies and have been tested or are currently under testing in randomized controlled studies with septic patients.

Topics: Animals; Clinical Trials as Topic; Hemofiltration; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunoglobulins; Inflammation; Models, Biological; Sepsis; Shock, Septic; Treatment Outcome; Vasopressins

This is a review of the management of septic shock that suggests an approach to treatment (ABCDEF: Airway, Breathing, Circulation, Drugs, Evaluate the source of sepsis, Fix the source of sepsis) for clinicians. The incidence of septic shock is increasing and mortality ranges from 30% to 70%. The commonest sources of infection are lung (25%), abdomen (25%), and other sources. Septic shock occurs because of highly complex interactions between the infecting microorganism(s) and the responses of the human host. The innate immune response is rapidly followed by the more specific adaptive immune response. Septic shock is characterized by alterations in the coagulant/anticoagulant balance such that there is a more pro-coagulant phenotype. Lung protective ventilation (which means the use of relatively low tidal volumes of 4 -6 mL/kg ideal body weight) is recommended for treatment of patients who have septic shock. Rivers early goal-directed therapy is recommended because it showed a significant increase in survival. Surviving Sepsis guidelines recommend resuscitation of septic shock with either crystalloid or colloid. Patients who have septic shock should be treated with intravenous broad-spectrum antibiotics as rapidly as possible and certainly within one hour. Activated protein C (APC) is a vitamin K dependent serine protease that is an anticoagulant and is also cytoprotective and anti-inflammatory. APC (24 mg/kg/hour infusion for 96 hours) decreased mortality (APC 25% vs placebo 31%, relative risk 0.81P=0.005) and improved organ dysfunction in patients at high risk of death (e.g. APACHE II >25 [APC 31% vs placebo 44%]). APC is not recommended to treat surgical patients who have one organ system dysfunction. In 2006, the European regulatory authority indicated that there must be another randomized placebo-controlled trial of APC to further establish efficacy as assessed by mortality reduction. Vasopressin is a key stress hormone in response to hypotension. The VASST study was a randomized trial of vasopressin versus norepinephrine in septic shock. There was no difference in mortality between vasopressin versus norepinephrine-treated patients (35% versus 39% respectively). In patients who had less severe septic shock, patients treated with vasopressin may have lowered mortality compared with norepinephrine (26% vs 36%). Annane et al. found that hydrocortisone plus fludrocortisone (compared to placebo) was associated with lower mortality in patients who had an in

Topics: Adrenal Cortex Hormones; Anemia; Anti-Bacterial Agents; Anticoagulants; Blood Coagulation; Fluid Therapy; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Protein C; Renal Insufficiency; Shock, Septic; Vasopressins

Vasopressin is a 9-amino acid peptide synthesized by magnocellular neurons of the hypothalamus and released from posterior pituitary gland. The primary physiological role of vasopressin is the maintenance of fluid homeostasis. In this review, the classification of vasopressin receptors, namely V1 vascular, V2 renal, V3 pituitary, oxytocin receptors, and purinergic receptors, and the effects of vasopressin on vascular smooth muscles, the heart, and the kidneys are discussed. Mortality rates of vasodilatory (or distributive), for example septic shock, are high. The use of vasopressin is an alternative therapy for vasodilatory shock with better outcome. Vasopressin is effective in resuscitation of adults after ventricular fibrillation or pulseless tachycardia, when epinephrine is not effective.

Topics: Adult; Clinical Trials as Topic; Dilatation, Pathologic; Heart; Heart Arrest; Homeostasis; Humans; Intensive Care Units; Kidney; Muscle, Smooth, Vascular; Receptors, Vasopressin; Resuscitation; Shock; Shock, Septic; Survival Analysis; Tachycardia; Time Factors; Treatment Outcome; Vasoconstrictor Agents; Vasodilation; Vasopressins; Ventricular Fibrillation

This article reviews new findings on the use of vasopressor agents in septic shock.. Several recent large randomized clinical trials have compared vasopressor agents in patients with septic shock. Briefly, the survival of patients treated with norepinephrine alone or a combination of norepinephrine and dobutamine did not significantly differ from that of patients treated with epinephrine. In observational studies, dopamine use was associated with poor outcome. The results of a clinical trial comparing dopamine and norepinephrine as a first-line agent in septic shock are pending. The addition of low-dose vasopressin to norepinephrine did not significantly improve the survival of patients with septic shock. A positive effect on survival was observed in a predetermined (norepinephrine dose <15 microg/kg/min) subgroup of patients with moderate shock. There is no large randomized clinical trial on the use of terlipressin. In contrast, nitric oxide inhibitors were associated with increased mortality in patients with septic shock.. The use of norepinephrine or epinephrine can be left to the discretion of the treating physician. Low-dose vasopressin administration remains an option for catecholamine-refractory septic shock. The potential benefit of early use in combination with a moderate dose of norepinephrine remains to be determined.

Topics: Humans; Resuscitation; Shock, Septic; Sympathetic Nervous System; Vasoconstrictor Agents; Vasopressins

Vasopressin is essential for cardiovascular homeostasis, acting via the kidney to regulate water resorption, on the vasculature to regulate smooth muscle tone, and as a central neurotransmitter, modulating brainstem autonomic function. Although it is released in response to stress or shock states, a relative deficiency of vasopressin has been found in prolonged vasodilatory shock, such as is seen in severe sepsis. In this circumstance, exogenous vasopressin has marked vasopressor effects, even at doses that would not affect blood pressure in healthy individuals. These two findings provide the rationale for the use of vasopressin in the treatment of septic shock. However, despite considerable research attention, the mechanisms for vasopressin deficiency and hypersensitivity in vasodilatory shock remain unclear.. To summarize vasopressin's synthesis, physiologic roles, and regulation and then review the literature describing its vascular receptors and downstream signaling pathways. A discussion of potential mechanisms underlying vasopressin hypersensitivity in septic shock follows, with reference to relevant clinical, in vivo, and in vitro experimental evidence.. Search of the PubMed database (keywords: vasopressin and receptors and/or sepsis or septic shock) for articles published in English before May 2006 and manual review of article bibliographies.. The pathophysiologic mechanism underlying vasopressin hypersensitivity in septic shock is probably multifactorial. It is doubtful that this phenomenon is merely the consequence of replacing a deficiency. Changes in vascular receptors or their signaling and/or interactions between vasopressin, nitric oxide, and adenosine triphosphate-dependent potassium channels are likely to be relevant. Further translational research is required to improve our understanding and direct appropriate educated clinical use of vasopressin.

Topics: Antidiuretic Agents; Autonomic Nervous System Diseases; Calcium Signaling; Catecholamines; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Intracellular Fluid; Kidney; Muscle, Smooth, Vascular; Nitric Oxide; Pituitary-Adrenal System; Receptors, Oxytocin; Receptors, Vasopressin; Shock, Septic; Sodium-Potassium-Exchanging ATPase; Vasoconstrictor Agents; Vasopressins; Water-Electrolyte Balance

The aim of this article is to review mechanisms of action of vasopressin and clinical studies of vasopressin in septic shock.. Arginine vasopressin is an important stress hormone that has both vasoactive and antidiuretic properties. The vasoactive properties of vasopressin have been more applicable clinically because of the discovery by Landry and colleagues that there is a deficiency of vasopressin in septic shock and that infusion of relatively low doses of vasopressin improves responsiveness to infused catecholamines (such as norepinephrine). There are at least 16 clinical studies of infusion of vasopressin in patients who have septic shock. The majority of studies found that vasopressin infusion increased blood pressure and urine output, and decreased the dose requirement of norepinephrine. Several studies showed that vasopressin infusion increased urine output. Both vasopressin and norepinephrine have important adverse effects including decreased cardiac output, decreased heart rate, arrhythmias, myocardial ischemia, mesenteric ischemia, and digital ischemia.. It is still unclear whether there is net benefit from low dose vasopressin infusion in patients who have septic shock. There may be certain patients who benefit but there are few studies of a prolonged vasopressin infusion to determine which patients benefit.

Topics: Humans; Norepinephrine; Receptors, Vasopressin; Shock, Septic; Vasodilation; Vasopressins

Topics: Animals; Clinical Trials as Topic; Humans; Norepinephrine; Receptors, Vasopressin; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is a neuropeptide hormone which has been used clinically for more than 50 years and plays a major role in circulatory homeostasis and in the regulation of serum osmolality. Recent work has emphasized its role in the treatment of septic shock. This paper reviews the physiology of this neurohormone and the available evidence in favor of its use as a vasodilator for children in shock.. MEDLINE, using the terms vasopressin, vasodilation, shock and septic shock, plus synonyms and related terms. Classic publications on the topic were also reviewed and selected depending on their relevance to the study objectives.. Vasopressin is synthesized in the neurohypophysis and released in response to a decrease in plasma volume or an increase in serum osmolality. The action of vasopressin is mediated by the activation of oxytocin receptors and of several G protein-coupled receptors, which are classified according to their location and intracellular transmission routes as V1 receptors (or V1b), V2 and V3 receptors (or V1b). The main role of vasopressin is to induce vasoconstriction. However, in certain organs, it can also induce selective vasodilation. Several clinical studies in adults and children have reported that the effects of vasopressin for the treatment of vasodilatory septic shock, due to a variety of causes, are both beneficial and safe.. The evidence is restricted. Most studies are retrospective and include a small number of patients. Nevertheless, there is significant experience concerning the use of vasopressin in Pediatrics. Vasopressin has a beneficial clinical effect in children and can be indicated in the treatment of refractory vasodilatory shock, after adequate volume resuscitation and when high doses of other vasopressors are not effective.

Topics: Adult; Animals; Blood Pressure; Child; Critical Illness; Evidence-Based Medicine; Hemodynamics; Humans; Infusions, Intravenous; Randomized Controlled Trials as Topic; Retrospective Studies; Shock, Septic; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Vasopressins

In critical care medicine, catecholamines are most widely used to reverse circulatory dysfunction and thus to restore tissue perfusion. However, catecholamines not only influence systemic and regional hemodynamics, but also exert a variety of significant metabolic, endocrine, and immunologic effects. Arginine vasopressin is a vasomodulatory hormone with potency to restore vascular tone in vasodilatory hypotension. Although the evidence supporting the use of low doses of vasopressin or its analogs in vasodilatory shock is increasing, lack of data regarding mortality and morbidity prevent their implementation in critical care protocols.

Topics: Catecholamines; Critical Illness; Hemodynamics; Humans; Immune System; Neurosecretory Systems; Receptors, Vasopressin; Regional Blood Flow; Shock; Shock, Septic; Splanchnic Circulation; Stress, Physiological; Vasodilation; Vasopressins

Clinical reports and experimental studies support the beneficial effects of low-dose vasopressin infusions in vasodilatory shock. Before we can recommend vasopressin for routine clinical use in vasodilatory shock, and particularly septic shock, we must await the results of currently ongoing and recently completed randomized clinical trials to ensure that vasopressin does indeed have beneficial effects on organ function and outcome.

Topics: Animals; Humans; Hypotension; Randomized Controlled Trials as Topic; Renal Circulation; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Despite significant advances in the understanding of the pathophysiology of sepsis, severe sepsis and septic shock continue to be associated with high morbidity and mortality. Eradication of infection, with appropriate antibiotics and source control, remains the cornerstone of sepsis management, but does not ensure survival. Aggressive supportive care, such as fluid resuscitation, vasoactive agents or mechanical ventilation, is often required. With the exception of drotrecogin alfa, attempts to modulate the inflammatory response in sepsis have generally been unsuccessful. Early goal-directed therapy targeting adequate central venous oxygen saturation appears to improve outcome. Recently, there has been renewed interest in the use of corticosteroids, not as anti-inflammatory agents, but as replacement therapy. There is also some evidence to suggest that tight glucose control may improve outcome in these patients.

Topics: Adrenal Cortex Hormones; Blood Glucose; Humans; Protein C; Resuscitation; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Septic shock is a major cause of death following trauma and a persistent problem in surgical patients. It is a challenge to the critical care medicine specialist and carries an unacceptably high mortality rate, despite adequate antibiotic and vasopressor therapy. The prevalent hypothesis regarding its mechanism is that the syndrome is caused by an excessive defensive and inflammatory response. During the acute phase some signalling mechanisms are activated, particularly hormone release, which function to restore the host homeostasis that has been disturbed by the infection. Since the neuroendocrine and immune systems are functionally related, so the exposure to antigens induces a synchronized response, which allows the organism to successfully endure immunology changes. An important characteristic of this communication includes the appearance of proteins released into the circulation by activated immune cells. These proteins, called cytokines can enter the circulation and reach neuroendocrine organs, where they act either themselves or through the release of intermediates such as prostaglandin, catecholamines and nitric oxide. The synthesis of nitric oxide may be induced in brain as a consequence of infection and may alter the function of the hypothalamic-pituitary axis. In this review we discuss the physiologic roles of the nitric oxide in central nervous system controlling the regulation of vasopressin and oxytocin during the pathophysiology of sepsis.

Topics: Animals; Female; Humans; Male; Nitric Oxide; Oxytocin; Shock, Septic; Vasopressins

Vasopressin, synthesized in the hypothalamus, is released by increased plasma osmolality, decreased arterial pressure, and reductions in cardiac volume. Three subtypes of vasopressin receptors, V1, V2, and V3, have been identified, mediating vasoconstriction, water reabsorption, and central nervous system effects, respectively. Vasopressin and its analogs have been studied intensively for the treatment of states of "relative vasopressin deficiency," such as sepsis, vasodilatory shock, intraoperative hypotension, and cardiopulmonary resuscitation. Infusion of vasopressin (0.01-0.04 U/min) decreases catecholamine requirements in patients with sepsis and other types of vasodilatory shock. Bolus application of 1 mg terlipressin, the V1 agonist, reverses refractory hypotension in anesthetized patients and has been studied in patients with septic shock and chronic liver failure. During cardiopulmonary resuscitation, a 40-U bolus dose of vasopressin may be considered to replace the first or second bolus of epinephrine regardless of the initial rhythm. The side effects of vasopressin and its analogs must be further characterized.

Topics: Adrenocorticotropic Hormone; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Pressure; Cardiopulmonary Resuscitation; Hemostasis; Humans; Hypertension; Hypertension, Portal; Neuroendocrine Tumors; Shock, Septic; Vasopressins; Water-Electrolyte Balance

This article summarizes the effects of catecholamines and vasopressin on the cardiovascular system, focusing on their metabolic and immunologic properties. Particular attention is dedicated to the septic shock condition.

Topics: Catecholamines; Critical Care; Critical Illness; Humans; Shock, Septic; Vasopressins

To review and assess available literature on chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, and dosing and administration of terlipressin in septic shock.. A literature search of MEDLINE (1966-September 2006), International Pharmaceutical Abstracts (1970-September 2006), and Cochrane database (third quarter 2006) was conducted, using key terms of terlipressin, lypressin, triglycyl-lysine vasopressin, hemodynamic support, septic shock, vasopressor, and V1 receptor agonist. Bibliographies of relevant articles were reviewed for additional references.. Available English-language literature, including abstracts, animal studies, preclinical studies, clinical trials, and review articles, were examined.. Because of potentially favorable pharmacokinetics versus vasopressin and limited availability of vasopressin in some countries, the effects of terlipressin, a vasopressin analog, have been studied recently for the treatment of septic shock. When administered as a 1-2 mg intravenous dose in patients with septic shock, terlipressin increases mean arterial pressure, urine output, systemic vascular resistance index, pulmonary vascular resistance index, and left and right ventricular stroke work index while decreasing heart rate, cardiac output, lactate, and oxygen delivery and consumption index. It is unclear whether lower doses of terlipressin would produce a similar vasopressor response with fewer cardiopulmonary effects and whether the effects of the drug on oxygen transport indices are detrimental.. Terlipressin is a promising investigational medication for treatment of septic shock. Small trials have shown terlipressin to have favorable effects on hemodynamics in patients with septic shock refractory to conventional vasopressor treatment. It should be used with extreme caution in patients with underlying cardiac or pulmonary dysfunction. Further studies are needed to verify safety, efficacy, and dosing of terlipressin in patients with septic shock, and its use cannot be recommended in lieu of vasopressin at this time.

Topics: Animals; Humans; Lypressin; Receptors, Vasopressin; Shock, Septic; Terlipressin; Vasopressins

Vasopressin is a nonapeptide synthesised in the hypothalamus and released upon stimulations such as hyperosmolality, hypotension and hypovolaemia. In acute shock states serum vasopressin levels increase rapidly and decrease in prolonged septic shock. The administration of vasopressin in healthy subjects has little effect, whereas in vasodilatory shock it increases the mean arterial pressure through V1 receptors and decreases the cardiac output. Vasopressin stimulates the V2 receptors in the kidney leading to reabsorption of water through aquaporin 2. However, in vasodilatory shock the antidiuretic effects are overcome by the effect vasopressin has on the kidneys: improvement of renal blood flow leading to water excretion. Twenty-four studies on the use of vasopressin in patients with vasodilatory shock are reviewed. They show that vasopressin potentiates norepinephrine effects, increases blood pressure significantly in patients with vasodilatory shock and may improve renal function. Side effects ranging from ischaemic skin lesions to possible intestinal ischaemia should not be underestimated. Above a dose of 0.04 U/min it may lead to cardiac arrest. Effects on mortality cannot be interpreted from these studies. Broad clinical use should await controlled trials to clarify its effects on clinical outcomes such as organ failure and mortality.

Topics: Animals; Hemodynamics; Humans; Kidney; Norepinephrine; Shock; Shock, Septic; Vasodilation; Vasopressins; Water-Electrolyte Balance

Vasopressin (antidiuretic hormone) is emerging as a potentially major advance in the treatment of septic shock. Terlipressin (tricyl-lysine-vasopressin) is the synthetic, long-acting analogue of vasopressin, and has comparable pharmacodynamic but different pharmacokinetic properties. Vasopressin mediates vasoconstriction via V1 receptor activation on vascular smooth muscle. Septic shock first causes a transient early increase in blood vasopressin concentrations; these concentrations subsequently decrease to very low levels as compared with those observed with other causes of hypotension. Infusions of 0.01-0.04 U/min vasopressin in septic shock patients increase plasma vasopressin concentrations. This increase is associated with reduced need for other vasopressors. Vasopressin has been shown to result in greater blood flow diversion from nonvital to vital organ beds compared with adrenaline (epinephrine). Of concern is a constant decrease in cardiac output and oxygen delivery, the consequences of which in terms of development of multiple organ failure are not yet known. Terlipressin (one or two boluses of 1 mg) has similar effects, but this drug has been used in far fewer patients. Large randomized clinical trials should be conducted to establish the utility of these drugs as therapeutic agents in patients with septic shock.

Topics: Adult; Animals; Antidiuretic Agents; Cardiac Output; Child; Diuresis; Drug Therapy, Combination; Epinephrine; Humans; Infusions, Parenteral; Intensive Care Units; Kidney; Lypressin; Multiple Organ Failure; Randomized Controlled Trials as Topic; Sheep; Shock, Septic; Swine; Terlipressin; Vasoconstrictor Agents; Vasopressins

Sepsis remains a significant problem and cause of morbidity and mortality in intensive care. Vasopressin infusions are currently used as rescue therapy for the treatment of vasodilatory, catecholamine-resistant septic shock. At present, there are no large randomised, controlled trials in the literature investigating vasopressin in this role, although two such studies are currently ongoing in Canada. This review outlines the pathophysiology of sepsis and that of vasopressin in sepsis and reviews the available evidence for the use of vasopressin in sepsis and septic shock. A review of the safety data for vasopressin in this indication is included. Recommendations for the use of vasopressin in septic shock, along with suggestions for the direction of further work in the field are presented.

Topics: Clinical Trials as Topic; Drug Costs; Hemostatics; Humans; Sepsis; Shock, Septic; Vasopressins

Topics: Anaphylaxis; Child; Crystalloid Solutions; Fluid Therapy; Hemodynamics; Humans; Isotonic Solutions; Shock; Shock, Cardiogenic; Shock, Septic; Vasopressins

Vasopressin is emerging as a rational therapy for vasodilatory shock states. In part 1 of the review we discussed the structure and function of the various vasopressin receptors. In part 2 we discuss vascular smooth muscle contraction pathways with an emphasis on the effects of vasopressin on ATP-sensitive K+ channels, nitric oxide pathways, and interaction with adrenergic agents. We explore the complex and contradictory studies of vasopressin on cardiac inotropy and coronary vascular tone. Finally, we summarize the clinical studies of vasopressin in shock states, which to date have been relatively small and have focused on physiologic outcomes. Because of potential adverse effects of vasopressin, clinical use of vasopressin in vasodilatory shock should await a randomized controlled trial of the effect of vasopressin's effect on outcomes such as organ failure and mortality.

Topics: Animals; Cardiovascular Physiological Phenomena; Clinical Trials as Topic; Humans; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Contraction; Potassium Channels; Receptors, Vasopressin; Shock, Septic; Vasodilator Agents; Vasopressins

Many advances have improved the care of critically ill patients, but only a few have been through the use of pharmaceutical agents. Recently, the US Food and Drug Administration (FDA) approved drotrecogin alfa (activated), or recombinant human activated protein C, for the treatment of patients with a high risk of death from severe sepsis. Drotrecogin alfa (activated) has antiinflammatory, antithrombotic and fibrinolytic properties. When given as a continuous intravenous infusion, recombinant human activated protein C decreases absolute mortality of severely septic patients by 6.1%, resulting in a 19.4% relative reduction in mortality. The absolute reduction in mortality increases to 13% if the population treated is restricted to patients with an APACHE II score greater than 24, as suggested by the FDA. The most frequent and serious side effect is bleeding. Severe bleeds increased from 2% in patients given placebo to 3.5% in patients receiving drotrecogin alfa (activated). The risk of bleeding was only increased during the actual infusion time of the drug, and the bleeding risk returned to placebo levels 24 hours after the infusion was discontinued. Patients treated in the intensive care unit frequently develop anemia, usually severe enough to require at least one transfusion of red blood cells. With the recent discovery of the harmful effects of allogeneic red blood cell transfusions and the increasing shortage of available red blood cell products, emphasis has been placed on minimizing transfusions. Patients who receive exogenous recombinant human erythropoietin maintain higher hemoglobin levels, in spite of requiring fewer transfusions during their stay in the intensive care unit. Recombinant human erythropoietin appears to be effective whether it is given as 300 units/kg of body weight subcutaneously every other day or as 40,000 units subcutaneously every week. Differences in hemoglobin values were not apparent until at least one week of therapy, but they continued to diverge after that initial week. Furthermore, the incidence of adverse events was similar to that of patients receiving placebo and there was no difference in mortality, suggesting that avoidance of blood transfusions did not translate into increased survival. Thus, recombinant human erythropoietin appears to be both safe and effective in treating the anemia found in critically ill patients, but it is less clear that such treatment is cost effective, especially in the higher dose regimens

Topics: Critical Care; Critical Illness; Epoetin Alfa; Erythropoietin; Humans; Protein C; Recombinant Proteins; Shock, Septic; Vasopressins

Vasopressin is a potent vasopressor for improving organ perfusion during septic shock. The rationale for the use of vasopressin is its relative deficiency of plasma levels and hypersensitivity to its vasopressor effects during septic shock. Growing evidence suggests that low-dose (<0.04 U/min) vasopressin is safe and effective for the treatment of vasodilatory shock. Although it is being used more frequently, there are no randomized clinical trials comparing vasopressin as a first-line agent to commonly used vasopressors. However, vasopressin causes arterial smooth muscle cell contraction through a non-catecholamine receptor pathway, thus it represents an attractive adjunct to the management of septic shock, especially when catecholamines are ineffective.

Topics: Amino Acid Sequence; Blood Circulation; Blood Pressure; Dose-Response Relationship, Drug; Humans; Lypressin; Models, Biological; Osmolar Concentration; Pulmonary Circulation; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

Hemodynamic support during the circulatory failure with vasodilation, most frequently during the septic shock, is based on volume recovery and administration of inotropic drugs. If such therapy is not sufficient, vasoconstriction drugs are subsequently or parallel added to maintain the perfusion pressure. As a standard therapy, norepinephrine or other catecholamines with alpha-adrenergic effect are used in rising doses. Some patients do not respond to such therapy with desired hemodynamic changes--they develop catecholamine resistant shock. Because of serious side effects of high doses of catecholamines, alternative vasopressors are necessary. Vasopressin, antidiuretic hormone, has in physiological conditions only minimal effect of the vascular tone. During hypovolemia its concentration rises and it may significantly contribute to the maintenance of arterial pressure by vasoconstriction. Contrary to it, during septic shock the levels of vasopressine are very low and vasodilation clinically dominates. At the same time, the septic shock is accompanied by an increased sensitivity to vasopressin administration. In a critical shock a serious deficit of endogenous vasopressin is expected. At present several pilot studies with vasopressine administration in septic shock exist in literature describing beneficial effect of vasopressin on hemodynamic parameters. Such comparatively low doses have no side effects on perfusion and function of body organs. Terlipressin, which is available in Czech Republic, is a synthetic analogue of vasopressin with extended effect. Its intermittent administration is used for the treatment of portal hypertension complications. Terlipressin in animal model of septic shock has similarly beneficial effects as vasopressin. High doses of Terlipressin have, similarly to vasopressin, adverse effects on pulmonary circulation and other systems. Till present, only casuistic experience has been published with low doses of Terlipressin in the treatment of septic shock resistant to catecholamines, which has shown similar effects to vasopressin. In shock states with the deficit of endogenous vasopressin, which are resistant to high doses of catecholamines, administration of vasopressin analogues represents a new perspective therapy. The treatment should be studied from the point of morbidity and mortality. A careful approach has to be used in septic patients with pre-existing obliterative vassal disease.

Topics: Animals; Humans; Lypressin; Shock; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasodilation; Vasopressins

Septic shock that requires therapy with adrenergic agents is associated with high rates of mortality. Inappropriately normal or low serum concentrations of vasopressin contribute to the development of hypotension during sepsis. We critically evaluated the role of administering exogenous vasopressin to patients with septic shock. A computerized search of MEDLINE from January 1966--December 2003 and a manual search of relevant journals for abstracts were conducted. Eleven retrospective, six prospective cohort, and four prospective randomized studies were identified. Most studies evaluated short-term infusions of vasopressin at 0.08 U/minute or less as add-on therapy in patients requiring adrenergic agents. The results show that starting vasopressin in patients with septic shock increases systemic vascular resistance and arterial blood pressure, thus reducing the dosage requirements of adrenergic agents. These effects are rapid and sustained. Substantial enhancement of urine production, likely due to increased glomerular filtration rate, was shown in several studies. A few studies demonstrated clinically significant reduced cardiac output or cardiac index after vasopressin was begun, necessitating cautious use in patients with cardiac dysfunction. Vasopressin was associated with ischemia of the mesenteric mucosa, skin, and myocardium; elevated hepatic transaminase and bilirubin concentrations; hyponatremia; and thrombocytopenia. Limiting the dosage to 0.03 U/minut or less may minimize the development of these adverse effects. Vasopressin 0.03 U/minute or less should be considered if response to one or two adrenergic agents is inadequate or as a method to reduce the dosage of adrenergic agents. At present, vasopressin therapy should not be started as first-line therapy. Additional studies are needed to determine the optimum dosage, duration, and place in therapy of vasopressin relative to adrenergic agents. A multicenter, comparative study of vasopressin 0.03 U/minute as add-on therapy is under way and should provide mortality data.

Topics: Adult; Blood Pressure; Critical Care; Humans; Randomized Controlled Trials as Topic; Retrospective Studies; Shock, Septic; Skin Diseases; Vasoconstrictor Agents; Vasopressins

Vasopressin is one of the most important endogenously released stress hormones during shock. In this review, studies published in the past year that add to our understanding of the use of vasopressin in the ICU are discussed.. Endogenous vasopressin levels are inappropriately low in adults with severe sepsis but not in children with meningococcal septic shock. Vasopressin but not norepinephrine improved renal blood flow and oxygen delivery and prolonged survival in animal models of septic shock. In human vasodilatory shock, the combination of low-dose vasopressin and norepinephrine was found to be safe and effective. In humans, vasopressin can cause gastrointestinal hypoperfusion and ischemic skin lesions. In hypodynamic animal models of sepsis vasopressin compromised oxygen delivery and decreased systemic and gut blood flow.High-dose bolus vasopressin appeared promising in animal studies of hemorrhagic shock and cardiopulmonary arrest and in a large, randomized clinical trial of vasopressin versus epinephrine in human cardiopulmonary arrest with asystole. However, poor neurologic outcomes raised controversy in introducing vasopressin into CPR guidelines.. There is growing evidence that vasopressin infusion in septic shock is safe and effective. Several studies published this year support the hypothesis that vasopressin should be used as a continuous low-dose infusion (between 0.01 and 0.04 U/min in adults) and not titrated as a single vasopressor agent. However, multiple studies highlight the clinical equipoise that exists regarding the use of vasopressin in vasodilatory shock. Guidelines on management of septic shock recommend "cautious use of vasopressin pending further studies."

Topics: Animals; Heart Arrest; Humans; Intensive Care Units; Shock, Hemorrhagic; Shock, Septic; Time Factors; Vasoconstrictor Agents; Vasopressins

Topics: Algorithms; Anti-Inflammatory Agents; Bicarbonates; Cardiotonic Agents; Cardiovascular System; Critical Care; Decision Trees; Fluid Therapy; Humans; Incidence; Monitoring, Physiologic; Oxygen Consumption; Protein C; Resuscitation; Shock, Septic; Steroids; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Vasopressin (antidiuretic hormone) is emerging as a potentially major advancement in the treatment of septic shock. Vasopressin is both a vasopressor and an antidiuretic hormone. It also has haemostatic, gastrointestinal, and thermoregulatory effects. This article reviews the physiology of vasopressin and all the relevant clinical literature on its use in the treatment of septic shock.. Extraction from Pubmed database of French and English articles on the physiology and clinical use of vasopressin. The following key words were selected: vasodilatory shock, vasopressin, septic shock, catecholamines, norepinephrine, renal function, diuresis, mesenteric haemodynamic. The collected articles were reviewed and selected according to their quality and originality.. Vasopressin mediates vasoconstriction via V1-receptor activation on vascular smooth muscle. Septic shock causes first a transient early increase in blood vasopressin concentrations that decreases later to very low concentrations compared to other causes of hypotension. Vasopressin infusion of 0.01-0.04 U min(-1) in septic shock patients increases plasma vasopressin concentrations. This increase is associated with a lesser need for other vasopressors. Vasopressin has been shown to produce greater blood flow diversion from non-vital to vital organ beds than does adrenaline. A large randomized clinical trial should be performed to assess its place as a therapeutic agent of septic shock patient.

Topics: Clinical Trials as Topic; Diuretics; Humans; Shock, Septic; Vasoconstrictor Agents; Vasodilation; Vasopressins

Topics: Blood Pressure; Clinical Trials as Topic; Humans; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The clinical spectrum of sepsis, severe sepsis, and septic shock is responsible for a growing number of deaths and excessive health care expenditures. Until recently, despite multiple clinical trials, no intervention provided a beneficial outcome in septic patients. Within the last 2 years, studies that involved drotrecogin alfa (activated), corticosteroid therapy, and early goal-directed therapy showed efficacy in those with severe sepsis and septic shock. These results have provided optimism for reducing sepsis-related mortality.

Topics: Adrenal Cortex Hormones; Clinical Protocols; Critical Care; Critical Illness; Dopamine; Fibrinolytic Agents; Hemodynamics; Hemostatics; Heparin; Humans; Insulin; Multiple Organ Failure; Protein C; Recombinant Proteins; Respiration, Artificial; Respiratory Distress Syndrome; Sepsis; Shock, Septic; Vasopressins

Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. Treatment of hemodynamics in septic shock consists of appropriate fluid therapy guided by invasive monitoring combined with vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output. The drug of choice for low vascular resistance is norepinephrine, while insufficient myocardial contractility is commonly treated with dobutamine. The use of norepinephrine seems to be associated with better prognosis as compared to results from the use of dopamine or epinephrine. In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.

Topics: Adrenal Cortex Hormones; Dobutamine; Fibrinolytic Agents; Fluid Therapy; Humans; Myocardial Contraction; Myocardium; Norepinephrine; Perfusion; Resuscitation; Shock, Septic; Vasopressins

Topics: Blood Pressure; Hemodynamics; Humans; Shock, Septic; Survival Analysis; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Topics: Anti-Inflammatory Agents; Catecholamines; Drug Therapy; Humans; Hydrocortisone; Receptors, Catecholamine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Infection is problematic because it affects many patients (adults and children), is a major cause of death in intensive care units (ICU) worldwide, and uses a large amount of hospital resources. The mortality rate among patients with septic shock varies but approximates 40% in infected patients admitted to ICUs. Because of the large number of adults dying of sepsis, many resources are expended. Children are physiologically different from adults, but nonetheless, many similarities exist with respect to the response to septic shock.

Topics: Animals; Blood Transfusion; Cardiopulmonary Resuscitation; Diagnosis, Differential; Hemodynamics; Humans; Monitoring, Physiologic; Respiration, Artificial; Shock, Septic; Steroids; Vasoconstrictor Agents; Vasopressins

Epinephrine during cardiopulmonary resuscitation (CPR) is being discussed controversially due to its beta-receptor mediated adverse effects such as increased myocardial oxygen consumption, ventricular arrhythmias, ventilation-perfusion defect, postresuscitation myocardial dysfunction, ventricular arrhythmias and cardiac failure. In the CPR laboratory simulating adult pigs with ventricular fibrillation or postcountershock pulseless electrical activity, vasopressin improved vital organ blood flow, cerebral oxygen delivery, resuscitability, and neurological recovery better than did epinephrine. In paediatric preparations with asphyxia, epinephrine was superior to vasopressin, whereas in both paediatric pigs with ventricular fibrillation, and adult porcine models with asphyxia, combinations of vasopressin and epinephrine proved to be highly effective. This may suggest that a different efficiency of vasopressors in paediatric vs. adult preparations; and different effects of dysrhythmic vs. asphyxial cardiac arrest on vasopressor efficiency may be of significant importance. Whether these theories can be extrapolated to humans is unknown at this point in time. In patients with out-of-hospital ventricular fibrillation, a larger proportion of patients treated with vasopressin survived 24 h compared with patients treated with epinephrine; during in-hospital CPR, comparable short-term survival was found in groups treated with either vasopressin or epinephrine. Currently, a large trial of out-of-hospital cardiac arrest patients being treated with vasopressin vs. epinephrine is ongoing in Germany, Austria and Switzerland. The new CPR guidelines of both the American Heart Association, and European Resuscitation Council recommend 40 U vasopressin intravenously, and 1 mg epinephrine intravenously as equally effective for the treatment of adult patients in ventricular fibrillation; however, no recommendation for vasopressin was made to date for adult patients with asystole and pulseless electrical activity, and paediatrics due to lack of clinical data. When adrenergic vasopressors were unable to maintain arterial blood pressure in patients with vasodilatory shock, continuous infusions of vasopressin ( approximately 0.04 to approximately 0.1 U/min) stabilised cardiocirculatory parameters, and even ensured weaning from catecholamines.

Topics: Animals; Cardiopulmonary Resuscitation; Heart Arrest; Humans; Shock, Septic; Swine; Vasoconstrictor Agents; Vasopressins

Vasopressin is emerging as a rational therapy for the hemodynamic support of septic shock and vasodilatory shock due to systemic inflammatory response syndrome. The goal of this review is to understand the physiology of vasopressin relevant to septic shock in order to maximize its safety and efficacy in clinical trials and in subsequent therapeutic use. Vasopressin is both a vasopressor and an antidiuretic hormone. It also has hemostatic, GI, and thermoregulatory effects, and is an adrenocorticotropic hormone secretagogue. Vasopressin is released from the axonal terminals of magnocellular neurons in the hypothalamus. Vasopressin mediates vasoconstriction via V1-receptor activation on vascular smooth muscle and mediates its antidiuretic effect via V2-receptor activation in the renal collecting duct system. In addition, vasopressin, at low plasma concentrations, mediates vasodilation in coronary, cerebral, and pulmonary arterial circulations. Septic shock causes first a transient early increase in blood vasopressin concentrations that decrease later in septic shock to very low levels compared to other causes of hypotension. Vasopressin infusion of 0.01 to 0.04 U/min in patients with septic shock increases plasma vasopressin levels to those observed in patients with hypotension from other causes, such as cardiogenic shock. Increased vasopressin levels are associated with a lesser need for other vasopressors. Urinary output may increase, and pulmonary vascular resistance may decrease. Infusions of > 0.04 U/min may lead to adverse, likely vasoconstriction-mediated events. Because clinical studies have been relatively small, focused on physiologic end points, and because of potential adverse effects of vasopressin, clinical use of vasopressin should await a randomized controlled trial of its effects on clinical outcomes such as organ failure and mortality.

Topics: Animals; Humans; Kidney; Osmosis; Shock, Hemorrhagic; Shock, Septic; Systemic Inflammatory Response Syndrome; Vasoconstriction; Vasodilation; Vasopressins

Vasopressin (antidiuretic hormone) is emerging as a potentially major advance in the treatment of a variety of shock states. Increasing interest in the clinical use of vasopressin has resulted from the recognition of its importance in the endogenous response to shock and from advances in understanding of its mechanism of action. From animal models of shock, vasopressin has been shown to produce greater blood flow diversion from non-vital to vital organ beds (particularly the brain) than does adrenaline. Although vasopressin has similar direct actions to the catecholamines, it may uniquely also inhibit some of the pathologic vasodilator processes that occur in shock states. There is current interest in the use of vasopressin in the treatment of shock due to ventricular fibrillation, hypovolaemia, sepsis and cardiopulmonary bypass. This article reviews the physiology and pharmacology of vasopressin and all of the relevant animal and human clinical literature on its use in the treatment of shock following a MEDLINE (1966-2000) search.

Topics: Advanced Cardiac Life Support; Animals; Cardiopulmonary Bypass; Humans; Shock; Shock, Septic; Vasopressins

Topics: Humans; Hypotension; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Blood Pressure; Humans; Shock, Cardiogenic; Shock, Septic; Vasodilation; Vasopressins

Topics: Animals; Bradykinin; Catecholamines; Endorphins; Histamine; Histamine Release; Kallikreins; Kinins; Prostaglandins; Serotonin; Shock, Septic; Thromboxanes; Vasoactive Intestinal Peptide; Vasopressins

In the present review, an attempt has been made to describe the modern concept of circulatory shock (Part I). The shock inducing insults (low circulatory volume/vascular capacity equation, heart failure, or disturbance of cellular metabolism induce physiological defense mechanisms, which result in peripheral vasoconstriction in order to maintain adequate blood pressure and perfusion of vital organs (compensatory phase). However, when the insult is too aggressive or too prolonged, deterioration of the cardiovascular system and cellular function ensues as a result of anaerobic metabolism, loss of vascular tone, reperfusion injury, depression of the reticuloendothelial system, disseminated intravascular coagulation, and myocardial failure (decompensatory phase). This leads to widespread cellular destruction, autodigestion, and finally death of the patient. Recent features of shock therapy will be discussed in part II of this review.

Topics: Animals; Carbohydrate Metabolism; Cardiomyopathy, Dilated; Disseminated Intravascular Coagulation; Energy Metabolism; Hemodynamics; Lipid Metabolism; Mononuclear Phagocyte System; Neurotransmitter Agents; Oxygen Consumption; Proteins; Shock; Shock, Septic; Vasopressins

Topics: Addison Disease; Adrenal Cortex Hormones; Adrenal Glands; Adrenocorticotropic Hormone; Anti-Inflammatory Agents; Asthma; Corticotropin-Releasing Hormone; Facial Paralysis; Glucocorticoids; Granulomatosis with Polyangiitis; Hepatitis; Humans; Hypothalamus; Melanocyte-Stimulating Hormones; Myasthenia Gravis; Pituitary Gland; Pulmonary Edema; Retroperitoneal Fibrosis; Shock, Septic; Vasopressins

Refractory septic shock in neonates is still associated with high mortality, necessitating an alternative therapy, despite all currently available treatments. This study aims to assess the vasopressor effect of methylene blue (MB) in comparison to terlipressin (TP) as adjuvant therapy for refractory septic shock in the preterm neonate.. A double-blinded randomized controlled trial was conducted in the Neonatal Intensive Care Units at Ain Shams University, Egypt. Thirty preterm neonates with refractory septic shock were randomized to receive either MB or TP as an adjuvant to conventional therapy. Both MB and TP were administered as an intravenous loading dose followed by continuous intravenous infusion. The hemodynamic variables, functional echocardiographic variables, and oxidant stress marker were assessed over a 24 h period together with the side effects of MB.. MB causes significant improvement in mean arterial blood pressure with a significant decrease of the norepinephrine requirements (1.15±0.21μm/kg/min at baseline vs. 0.55±0.15μm/kg/min at 24 h). MB infusion causes an increase of the pulmonary pressure (44.73±8.53 mmHg at baseline vs. 47.27±7.91 mmHg after 24 h) without affecting the cardiac output. Serum malonaldehyde decreased from 5.45±1.30 nmol/mL at baseline to 4.40±0.90 nmol/mL at 24 h in the MB group.. Administration of MB to preterm infants with refractory septic shock showed rapid increases in systemic vascular resistance and arterial blood pressure with minimal side effects.

Topics: Hemodynamics; Humans; Infant; Infant, Newborn; Infant, Premature; Methylene Blue; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

Hemodynamic stabilization is a core component in the resuscitation of septic shock. However, the optimal target blood pressure remains debatable. Previous randomized controlled trials suggested that uniformly adopting a target mean arterial pressure (MAP) higher than 65 mmHg for all adult septic shock patients would not be beneficial; however, it has also been proposed that higher target MAP may be beneficial for elderly patients, especially those with arteriosclerosis.. A multicenter, pragmatic single-blind randomized controlled trial will be conducted to compare target MAP of 80-85 mmHg (high-target) and 65-70 mmHg (control) in the resuscitation of septic shock patients admitted to 28 hospitals in Japan. Patients with septic shock aged ≥65 years are randomly assigned to the high-target or control groups. The target MAP shall be maintained for 72 h after randomization or until vasopressors are no longer needed to improve patients' condition. To minimize the adverse effects related to catecholamines, if norepinephrine dose of ≥ 0.1 μg/kg/min is needed to maintain the target MAP, vasopressin will be initiated. Other therapeutic approaches, including fluid administration, hydrocortisone use, and antibiotic choice, will be determined by the physician in charge based on the latest clinical guidelines. The primary outcome is all-cause mortality at 90 days after randomization.. The result of this trial will provide great insight on the resuscitation strategy for septic shock in the era of global aged society. Also, it will provide the better understanding on the importance of individualized treatment strategy in hemodynamic management in critically ill patients.. UMIN Clinical Trials Registry; UMIN000041775. Registered 13 September 2020.

Topics: Adult; Aged; Anti-Bacterial Agents; Blood Pressure; Catecholamines; Humans; Hydrocortisone; Multicenter Studies as Topic; Norepinephrine; Randomized Controlled Trials as Topic; Shock, Septic; Single-Blind Method; Vasoconstrictor Agents; Vasopressins

We previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A.. Secondary analysis of publicly available transcriptomic data.. Multiple adult ICUs.. Adults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50).. Randomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms.. Endotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05).. This exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.

Topics: Adrenal Cortex Hormones; Aged; Female; Gene Expression Profiling; Humans; Hydrocortisone; Male; Middle Aged; Norepinephrine; Shock, Septic; Vasopressins

Although dopamine and norepinephrine are recommended as first-line agents in the treatment of shock, it is unclear which is the optimal vasoactive inotropic agent (VIA) to manage postcardiotomy circulatory shock. This single-center, randomized clinical trial aimed to investigate the efficacy and safety of dopamine versus norepinephrine in postcardiotomy circulatory shock.. We randomly assigned the patients with postcardiotomy circulatory shock to receive either dopamine or norepinephrine. When shock persisted despite the dose of 20 μg/kg/min of dopamine or the dose of 0.2 μg/kg/min of norepinephrine, epinephrine or vasopressin could be added. The primary endpoint was new-onset tachyarrhythmic event during drug infusion. Secondary endpoints included requirement of additional VIAs, postoperative complications, and all-cause mortality within 30 days of drug initiation.. At the planned interim analysis of 100 patients, the boundary for the benefit of norepinephrine has been crossed, and the study was stopped early. Excluding two patients withdrawing a consent, 48 patients were assigned to dopamine and 50 patients to norepinephrine. New-onset tachyarrhythmic event occurred in 12 (25%) patients in the dopamine and one (2%) patient in the norepinephrine group (p = .009). The requirement for additional VIAs was more common in the dopamine group (p < .001). Other secondary endpoints were similar between groups.. Despite the limited study subjects with early determination, in patients with postcardiotomy circulatory shock, dopamine as a first-line vasopressor was associated with higher tachyarrhythmic events and greater need for additional VIAs compared with norepinephrine.

Topics: Cardiac Surgical Procedures; Dopamine; Humans; Norepinephrine; Shock; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The study objective was to analyze the association between low plasma vasopressin and progression of sepsis to septic shock in neonates < 34 weeks gestation. Septic neonates of < 34 weeks gestation were consecutively enrolled; moribund neonates and those with major malformations were excluded. Subjects were monitored for progression of sepsis to septic shock over the first 7 days from enrolment. Plasma vasopressin levels and inducible nitric oxide synthase levels were measured at the onset of sepsis (T0), severe sepsis (T1), and septic shock (T2). Primary outcome was plasma vasopressin levels at the point of sepsis in those who progressed to septic shock in comparison with matched nested controls in the non-progression group. Forty-nine (47%) enrolled subjects developed severe sepsis or septic shock. Plasma vasopressin levels (pg/ml) at the onset of sepsis were significantly low in those who progressed to septic shock (median (IQR), 31 (2.5-80) versus 100 (12-156); p = 0.02). After adjusting for confounders, vasopressin levels were independently associated with progression to septic shock (adjusted OR (95% CI), 0.97 (0.96, 0.99); p = 0.01).Conclusion: Preterm septic neonates who progressed to septic shock had suppressed vasopressin levels before the onset of shock. Low vasopressin levels were independently associated with progression to septic shock.What is known:• In animal sepsis models and adult septic patients, exuberant production of nitric oxide metabolites and low vasopressin levels have been reportedly associated with progression to septic shock.• Vasopressin levels have been variably reported as low as well as elevated in children with septic shock.What is New:• Preterm neonates who progressed from sepsis to septic shock had significantly lower levels of vasopressin before the onset of shock in comparison with those who did not progress.• Low vasopressin levels independently predicted the progression from sepsis to septic shock in this population.

Topics: Biomarkers; Disease Progression; Early Diagnosis; Female; Humans; Infant, Newborn; Male; Neonatal Sepsis; Prospective Studies; ROC Curve; Shock, Septic; Vasopressins

Topics: Aldosterone; Glycopeptides; Humans; Kinetics; Renin; Shock, Septic; Vasopressins

Previous trials suggest that vasopressin may improve outcomes in patients with vasodilatory shock. The aim of this study was to evaluate whether vasopressin could be superior to norepinephrine to improve outcomes in cancer patients with septic shock.. Single-center, randomized, double-blind clinical trial, and meta-analysis of randomized trials.. ICU of a tertiary care hospital.. Two-hundred fifty patients 18 years old or older with cancer and septic shock.. Patients were assigned to either vasopressin or norepinephrine as first-line vasopressor therapy. An updated meta-analysis was also conducted including randomized trials published until October 2018.. The primary outcome was all-cause mortality at 28 days after randomization. Prespecified secondary outcomes included 90-days all-cause mortality rate; number of days alive and free of advanced organ support at day 28; and Sequential Organ Failure Assessment score 24 hours and 96 hours after randomization. We also measure the prevalence of adverse effects in 28 days. A total of 250 patients were randomized. The primary outcome was observed in 71 patients (56.8%) in the vasopressin group and 66 patients (52.8%) in the norepinephrine group (p = 0.52). There were no significant differences in 90-day mortality (90 patients [72.0%] and 94 patients [75.2%], respectively; p = 0.56), number of days alive and free of advanced organ support, adverse events, or Sequential Organ Failure Assessment score.. In cancer patients with septic shock, vasopressin as first-line vasopressor therapy was not superior to norepinephrine in reducing 28-day mortality rate.

Topics: Double-Blind Method; Female; Humans; Male; Middle Aged; Neoplasms; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent.. We aimed to categorize patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock.. A post hoc analysis was performed of a double-blind, randomized clinical trial in septic shock (VANISH [Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock]). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined by a previously established model using seven discriminant genes.. Samples were available from 176 patients: 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (P = 0.50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (P = 0.02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (odds ratio = 7.9; 95% confidence interval = 1.6-39.9).. Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immunocompetent SRS2 endotype had significantly higher mortality when given corticosteroids compared with placebo. Clinical trial registered with www.clinicaltrials.gov (ISRCTN 20769191).

Topics: Aged; Double-Blind Method; Female; Gene Expression Profiling; Humans; Hydrocortisone; Immunocompetence; Kaplan-Meier Estimate; Male; Middle Aged; Norepinephrine; Phenotype; Sepsis; Shock, Septic; Survival Analysis; Transcriptome; Vasopressins

Topics: Adult; Clinical Protocols; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Hypotension; Infusions, Intravenous; Male; Receptors, Vasopressin; Research Design; Risk Assessment; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Delays in achieving target mean arterial pressure (MAP) are associated with increased morbidity and mortality in patients with septic shock. This trial was conducted to test the hypothesis that early concomitant treatment with vasopressin and norepinephrine reduces the time to achieve and maintain target MAP compared with initial norepinephrine monotherapy.. A single-center prospective open-label trial was conducted in patients with septic shock between November 2015 and June 2016 at a medical intensive care unit in an academic medical center. Initial norepinephrine monotherapy was initiated between November 2015 and February 2016. Between March and June 2016, vasopressin was initiated within 4 hours of norepinephrine. The primary outcome was time to achieving and maintaining MAP of 65 mm Hg for at least 4 hours that was compared between groups using the Student t test and examined using the Kaplan-Meier curve (Clinical Trials registration: NCT02454348).. Eighty-two patients were included (41 in each group). Patients treated with early concomitant vasopressin and norepinephrine more frequently had a positive culture (59% vs 37%, p=0.05) and grew nonlactose fermenting gram-negative bacilli (34% vs 10%, p=0.01) compared with patients treated with norepinephrine monotherapy, respectively. The median time to achieve and maintain MAP occurred faster in the early concomitant vasopressin and norepinephrine group, at 5.7 hours (interquartile range [IQR] 1.7-10.3 hrs), compared with 7.6 hours (IQR 3.6-16.7 hrs, p=0.058) in the norepinephrine group. Durations of therapy for norepinephrine or vasopressin, amount of norepinephrine received in the first 24 hours, norepinephrine dosage when MAP was achieved and maintained, maximum norepinephrine dosage, and mortality were similar between groups.. Patients treated with early concomitant vasopressin and norepinephrine achieved and maintained MAP of 65 mm Hg faster than those receiving initial norepinephrine monotherapy, suggesting that overcoming vasopressin deficiency sooner may reduce the time patients spend in the early phase of septic shock.

Topics: Academic Medical Centers; Aged; Arterial Pressure; Drug Therapy, Combination; Female; Humans; Intensive Care Units; Male; Middle Aged; Norepinephrine; Prospective Studies; Shock, Septic; Time Factors; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

The Septic Shock 3.0 definition could alter treatment comparisons in randomized controlled trials in septic shock. Our first hypothesis was that the vasopressin versus norepinephrine comparison and 28-day mortality of patients with Septic Shock 3.0 definition (lactate > 2 mmol/L) differ from vasopressin versus norepinephrine and mortality in Vasopressin and Septic Shock Trial. Our second hypothesis was that there are differences in plasma cytokine levels in Vasopressin and Septic Shock Trial for lactate less than or equal to 2 versus greater than 2 mmol/L.. Retrospective analysis of randomized controlled trial.. Multicenter ICUs.. We compared vasopressin-to-norepinephrine group 28- and 90-day mortality in Vasopressin and Septic Shock Trial in lactate subgroups. We measured 39 cytokines to compare patients with lactate less than or equal to 2 versus greater than 2 mmol/L.. Patients with septic shock with lactate greater than 2 mmol/L or less than or equal to 2 mmol/L, randomized to vasopressin or norepinephrine.. Concealed vasopressin (0.03 U/min.) or norepinephrine infusions.. The Septic Shock 3.0 definition would have decreased sample size by about half. The 28- and 90-day mortality rates were 10-12 % higher than the original Vasopressin and Septic Shock Trial mortality. There was a significantly (p = 0.028) lower mortality with vasopressin versus norepinephrine in lactate less than or equal to 2 mmol/L but no difference between treatment groups in lactate greater than 2 mmol/L. Nearly all cytokine levels were significantly higher in patients with lactate greater than 2 versus less than or equal to 2 mmol/L.. The Septic Shock 3.0 definition decreased sample size by half and increased 28-day mortality rates by about 10%. Vasopressin lowered mortality versus norepinephrine if lactate was less than or equal to 2 mmol/L. Patients had higher plasma cytokines in lactate greater than 2 versus less than or equal to 2 mmol/L, a brisker cytokine response to infection. The Septic Shock 3.0 definition and our findings have important implications for trial design in septic shock.

Topics: Biomarkers; Cytokines; Humans; Intensive Care Units; Kaplan-Meier Estimate; Lactic Acid; Norepinephrine; Research Design; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V. This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety.. A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group.. In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation.. ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.

Topics: Adolescent; Adult; Aged; Belgium; Child; Denmark; Double-Blind Method; Female; Humans; Hypotension; Male; Middle Aged; Norepinephrine; Placebos; Receptors, Vasopressin; Shock, Septic; United States; Vasoconstrictor Agents; Vasopressins

To assess the impact of vasopressin on the microcirculation and to develop a predictive model to estimate the probability of microcirculatory recruitment in patients with septic shock.. This prospective interventional study included patients with septic shock receiving noradrenaline for less than 48 hours. We infused vasopressin at 0.04 U/min for one hour. Hemodynamic measurements, including sidestream dark-field imaging, were obtained immediately before vasopressin infusion, 1 hour after vasopressin infusion and 1 hour after vasopressin withdrawal. We defined patients with more than a 10% increase in total vascular density and perfused vascular density as responders. ClinicalTrials.gov: NCT02053675.. Eighteen patients were included, and nine (50%) showed improved microcirculation after infusion of vasopressin. The noradrenaline dose was significantly reduced after vasopressin (p=0.001) and was higher both at baseline and during vasopressin infusion in the responders than in the non-responders. The strongest predictor for a favorable microcirculatory response was the dose of noradrenaline at baseline (OR=4.5; 95% CI: 1.2-17.0; p=0.027). For patients using a noradrenaline dose higher than 0.38 mcg/kg/min, the probability that microcirculatory perfusion would be improved with vasopressin was 53% (sensitivity 78%, specificity 77%).. In patients with septic shock for no longer than 48 h, administration of vasopressin is likely to result in an improvement in microcirculation when the baseline noradrenaline dose is higher than 0.38 mcg/kg/min.

Topics: Drug Therapy, Combination; Female; Humans; Male; Microcirculation; Middle Aged; Norepinephrine; Prospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Arginine vasopressin as a supplementary vasopressor in septic shock restores vascular tone and mean arterial pressure, meanwhile decreases dose and exposure time to catecholamines. The objective of this study was to evaluate the effect of vasopressin on lactate and lactate clearance as markers of tissue perfusion during septic shock. In this prospective, randomized, controlled trial, 30 patients with septic shock were enrolled in two groups. One group received norepinephrine infusion (titrated to reach the target MAP of ≥65 mm Hg) and the other group in addition to norepinephrine, received vasopressin at a constant rate of 0.03 u/min. Serum lactate levels were assessed at baseline, 24 and 48 hours after randomization. Lactate clearance was estimated for each patient at 24 and 48 hours. Venous lactate was measured in both groups. Despite a tendency toward higher venous lactate at 24 and 48 hours in the norepinephrine group (3.1 vs. 2.5, P=0.67 and 1.7 vs. 1.1, P=0.47), the conflict was not statistically significant among them. While lactate clearance after 24 hours was significantly higher in vasopressin treatment group (46% vs. 20%, respectively; P=0.048), the 48-hour lactate clearance did not differ from statistic viewpoints despite their clinical values (66% vs. 40%, P=0.17). Although lactate levels did not significantly differ between treatment groups, lactate clearance at 24 hours was significantly higher in vasopressin group. This may be the effect of vasopressin effect on microcirculation and tissue hypoperfusion or its catecholamine sparing effect.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Lactic Acid; Male; Microcirculation; Middle Aged; Norepinephrine; Prospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

To investigate if plasma cytokine concentrations predict a beneficial response to corticosteroid treatment in septic shock patients.. A cohort of septic shock patients in whom a panel of 39 cytokines had been measured at baseline (n = 363) was included. Patients who received corticosteroids were propensity score matched to non-corticosteroid-treated patients. An optimal threshold to identify responders to corticosteroid treatment for each cytokine was defined as the concentration above which the odds ratio for 28-day survival between corticosteroid- and non-corticosteroid-treated patients was highest.. Propensity score matching partitioned 165 patients into 61 sets; each set contained matched corticosteroid- and non-corticosteroid-treated patients. For 13 plasma cytokines threshold concentrations were found where the odds ratio for survival between corticosteroid- and non-corticosteroid-treated patients was significant (P < 0.05). CD40 ligand was associated with the highest odds ratio and identified 21 % of the patients in the propensity score matched cohort as responders to corticosteroid treatment. Combinations of triplets of cytokines with a significant odds ratio, using the thresholds identified above, were tested to find a higher proportion of responders. IL3, IL6, and CCL4 identified 50 % of the patients in the propensity score matched cohort as responders to corticosteroid treatment. The odds ratio for 28-day survival was 19 (95 % CI 3.5-140, P = 0.02) with a concentration above threshold for a least one of these cytokines.. Plasma concentration of selected cytokines is a potential predictive biomarker to identify septic shock patients that may benefit from treatment with corticosteroids.

Topics: Adrenal Cortex Hormones; Aged; Biomarkers; Case-Control Studies; Cytokines; Female; Humans; Male; Middle Aged; Odds Ratio; Respiration, Artificial; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative.. To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock.. A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock.. Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103).. The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes.. A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]).. Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further.. clinicaltrials.gov Identifier: ISRCTN 20769191.

Topics: Adult; Aged; Aged, 80 and over; Critical Care; Double-Blind Method; Drug Administration Schedule; Female; Fluid Therapy; Humans; Hydrocortisone; Intensive Care Units; Male; Middle Aged; Norepinephrine; Renal Insufficiency; Renal Replacement Therapy; Shock, Septic; Treatment Outcome; United Kingdom; Vasoconstrictor Agents; Vasopressins

Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock.. Prospective open-label randomized controlled pilot trial.. Four adult ICUs in London teaching hospitals.. Sixty-one adult patients who had septic shock.. Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6-12 and 24-36 hours after hydrocortisone/placebo administration.. Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1-5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32-0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, -32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups.. Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.

Topics: Aged; Anti-Inflammatory Agents; Drug Interactions; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Organ Dysfunction Scores; Pilot Projects; Prospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids.. This is a multicentre, factorial (2×2), randomised, double-blind, placebo-controlled trial. 412 patients will be recruited from multiple UK intensive care units and randomised to receive vasopressin (0-0.06 U/min) or noradrenaline (0-12 µg/min) as a continuous intravenous infusion as initial vasopressor therapy. If maximum infusion rates of this first study drug are reached, the patient will be treated with either hydrocortisone (initially 50 mg intravenous bolus six-hourly) or placebo, before additional open-label catecholamine vasopressors are prescribed. The primary outcome of the trial will be the difference in renal failure-free days between treatment groups. Secondary outcomes include need for renal replacement therapy, survival rates, other organ failures and resource utilisation.. The trial protocol and information sheets have received a favourable opinion from the Oxford A Research Ethics Committee (12/SC/0014). There is an independent Data Monitoring and Ethics Committee and independent membership of the Trial Steering Committee including patient and public involvement. The trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.. ISRCTN 20769191 and EudraCT 2011-005363-24.

Topics: Double-Blind Method; Humans; Norepinephrine; Prospective Studies; Research Design; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Cardiac troponins are sensitive and specific biomarkers of myocardial necrosis. We evaluated troponin, CK, and ECG abnormalities in patients with septic shock and compared the effect of vasopressin (VP) versus norepinephrine (NE) on troponin, CK, and ECGs.. This was a prospective substudy of a randomized trial. Adults with septic shock randomly received, blinded, a low-dose infusion of VP (0.01 to 0.03 U/min) or NE (5 to 15 μg/min) in addition to open-label vasopressors, titrated to maintain a mean blood pressure of 65 to 75 mm Hg. Troponin I/T, CK, and CK-MB were measured, and 12-lead ECGs were recorded before study drug, and 6 hours, 2 days, and 4 days after study-drug initiation. Two physician readers, blinded to patient data and drug, independently interpreted ECGs.. We enrolled 121 patients (median age, 63.9 years (interquartile range (IQR), 51.1 to 75.3), mean APACHE II 28.6 (SD 7.7)): 65 in the VP group and 56 in the NE group. At the four time points, 26%, 36%, 32%, and 21% of patients had troponin elevations, respectively. Baseline characteristics and outcomes were similar between patients with positive versus negative troponin levels. Troponin and CK levels and rates of ischemic ECG changes were similar in the VP and the NE groups. In multivariable analysis, only APACHE II was associated with 28-day mortality (OR, 1.07; 95% CI, 1.01 to 1.14; P=0.033).. Troponin elevation is common in adults with septic shock. We observed no significant differences in troponin, CK, and ECGs in patients treated with vasopressin and norepinephrine. Troponin elevation was not an independent predictor of mortality.. Controlled-trials.com ISRCTN94845869.

Topics: Adult; Aged; Biomarkers; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Norepinephrine; Prospective Studies; Shock, Septic; Troponin T; Vasopressins

Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change plasma cytokine levels in early septic shock.. Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and norepinephrine on plasma cytokine levels in septic shock.. We studied 394 patients in a randomized, controlled trial of vasopressin versus norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus norepinephrine-induced changes in cytokine levels over 24 hours.. A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P < 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with norepinephrine (P = 0.037). In less severe septic shock, the difference in plasma cytokine reduction over 24 hours between survivors and nonsurvivors was less pronounced than that seen in more severe septic shock. Furthermore, vasopressin decreased interferon-inducible protein 10 and granulocyte colony-stimulating factor more than did norepinephrine in less severe septic shock, whereas vasopressin decreased granulocyte-macrophage colony-stimulating factor in patients who had more severe shock.. Survivors of septic shock had greater decreases of cytokines, chemokines and growth factors in early septic shock. Vasopressin decreased 24-hour plasma cytokine levels more than did norepinephrine. The vasopressin-associated decrease of cytokines differed according to severity of shock. Clinical trial registered with www.controlled-trials.com (ISRCTN94845869).

Topics: Adolescent; Adrenergic alpha-Agonists; Adult; Aged; Aged, 80 and over; Biomarkers; Cytokines; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Norepinephrine; Shock, Septic; Survival Rate; Treatment Outcome; United States; Vasoconstrictor Agents; Vasopressins; Young Adult

Vasopressin is known to be an effective vasopressor in the treatment of septic shock, but uncertainty remains about its effect on other hemodynamic parameters.. We examined the cardiopulmonary effects of vasopressin compared with norepinephrine in 779 adult patients with septic shock recruited to the Vasopressin and Septic Shock Trial. More detailed cardiac output data were analyzed for a subset of 241 patients managed with a pulmonary artery catheter, and data were collected for the first 96 h after randomization. We compared the effects of vasopressin vs norepinephrine in all patients and according to severity of shock (< 15 or ≥ 15 μg/min of norepinephrine) and cardiac output at baseline.. Equal BPs were maintained in both treatment groups, with a significant reduction in norepinephrine requirements in the patients treated with vasopressin. The major hemodynamic difference between the two groups was a significant reduction in heart rate in the patients treated with vasopressin (P <.0001), and this was most pronounced in the less severe shock stratum (treatment × shock stratum interaction, P =.03). There were no other major cardiopulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between patients treated with vasopressin and those treated with norepinephrine. There was significantly greater use of inotropic drugs in the vasopressin group than in the norepinephrine group.. Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion.. ISRCTN Register; No.: ISRCTN94845869; URL: www.isrctn.org

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Cardiovascular System; Double-Blind Method; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Severity of Illness Index; Shock, Septic; Stroke Volume; Vasoconstrictor Agents; Vasopressins

We hypothesized that lactate levels even within the normal range are prognostic and that low lactate levels predict a beneficial response to vasopressin infusion in septic shock. We conducted a retrospective analysis using the Vasopressin in Septic Shock Trial (VASST) as a derivation cohort (n = 665), then validated using another single-center septic shock cohort, St Paul's Hospital (SPH) cohort (n = 469). Lactate levels were divided into quartiles. The primary outcome variable was 28-day mortality in both cohorts. We used receiver operating characteristic (ROC) curve analysis to compare the prognostic value of lactate concentrations versus Acute Physiology and Chronic Health Evaluation II scores. We then explored whether lactate concentrations might predict beneficial response to vasopressin compared with noradrenaline in VASST. Normal lactate range is less than 2.3 mmol/L. At enrollment, patients in the second quartile (1.4 < lactate < 2.3 mmol/L) had significantly increased mortality and organ dysfunction compared with patients who had lactate ≤ 1.4 mmol/L (quartile 1) (P < 0.0001). Quartile 2 outcomes were as severe as quartile 3 (2.3 ≤ lactate < 4.4 mmol/L) outcomes. Baseline lactate values (ar ea under the ROC curve = 0.63, 0.66; VASST, SPH) were as good as Acute Physiology and Chronic Health Evaluation II scores (area under the ROC curve = 0.66, 0.73; VASST, SPH) as prognostic indicators of 28-day mortality. Lactate concentrations of 1.4 mmol/L or less predicted a beneficial response in those randomized to vasopressin compared with noradrenaline in VASST (P < 0.05). Lactate concentrations within the "normal" range can be a useful prognostic indicator in septic shock. Furthermore, patients whose lactate level is less than or equal to 1.4 mmol/L may benefit from vasopressin infusion.

Topics: Aged; Biomarkers; Epidemiologic Methods; Female; Humans; Lactic Acid; Male; Middle Aged; Norepinephrine; Predictive Value of Tests; Prognosis; Reference Values; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

To compare the effects of vasopressin versus norepinephrine infusion on the outcome of kidney injury in septic shock.. Post-hoc analysis of the multi-center double-blind randomized controlled trial of vasopressin versus norepinephrine in adult patients who had septic shock (VASST).. Seven hundred seventy-eight patients were randomized to receive a blinded infusion of either low-dose vasopressin (0.01-0.03 U/min) or norepinephrine infusion (5-15 microg/min) in addition to open-label vasopressors and were included in the outcome analysis. All vasopressors were titrated and weaned to maintain a target blood pressure.. RIFLE criteria for acute kidney injury were used to compare the effects of vasopressin versus norepinephrine. In view of multiple simultaneous comparisons, a p value of 0.01 was considered statistically significant. Kidney injury was present in 464 patients (59.6%) at study entry. In patients in the RIFLE "Risk" category (n = 106), vasopressin as compared with norepinephrine was associated with a trend to a lower rate of progression to renal "Failure" or "Loss" categories (20.8 vs. 39.6%, respectively, p = 0.03), and a lower rate of use of renal replacement therapy (17.0 vs. 37.7%, p = 0.02). Mortality rates in the "Risk" category patients treated with vasopressin compared to norepinephrine were 30.8 versus 54.7%, p = 0.01, but this did not reach significance in a multiple logistic regression analysis (OR = 0.33, 99% CI 0.10-1.09, p = 0.02). The interaction of treatment group and RIFLE category was significant in predicting mortality.. Vasopressin may reduce progression to renal failure and mortality in patients at risk of kidney injury who have septic shock.

Topics: Acute Kidney Injury; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The CysGlyGln haplotype of the beta(2)-adrenergic receptor gene (ADRB2) is functional and associated with altered responses to adrenergic agonists in patients with asthma. Whether this functional haplotype alters outcome in patients receiving adrenergic agonists in septic shock is unknown.. To determine whether genetic variation of ADRB2 influences outcome in septic shock.. Two cohorts of patients with septic shock were studied: a single center (St. Paul's Hospital [SPH]) cohort (n = 589) and the Vasopressin and Septic Shock Trial (VASST) cohort (n = 616). The A allele of the rs1042717 G/A polymorphism is in complete linkage disequilibrium with the CysGlyGln haplotype of ADRB2; therefore, rs1042717 was genotyped. Modulation by norepinephrine and salbutamol of IL-6 production by stimulated in vitro lymphoblastoid cells was measured by genotype.. Patients who had the AA genotype of rs1042717 displayed increased 28-day mortality in SPH (adjusted hazard ratio, 2.23; 95% confidence interval, 1.33-3.72; P = 0.0022), and this result was replicated in VASST (adjusted hazard ratio 2.82; 95% confidence interval, 1.56-5.09; P = 0.0006). This genotypic effect was eliminated in patients treated with acute low-dose corticosteroids. In all patients, the AA genotype was associated with more organ dysfunction. Patients with the AA genotype had a higher heart rate (SPH; P < 0.05; VASST; P < 0.05) and required a higher norepinephrine dose over Days 1 through 3 (VASST; P < 0.05). The AA genotype was associated with decreased norepinephrine and salbutamol inhibition of IL-6 production by stimulated lymphoblastoid cells in vitro (P < 0.05).. The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

Topics: Adrenergic alpha-Agonists; Adult; Aged; Alleles; British Columbia; Cells, Cultured; Child; Cohort Studies; Double-Blind Method; Gene Frequency; Genotype; Haplotypes; Humans; Infant; Interleukin-6; Linkage Disequilibrium; Middle Aged; Norepinephrine; Phenotype; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-2; Risk Factors; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The optimum septic shock vasopressor support strategy is currently debated. This study was performed to evaluate the efficacy and safety of norepinephrine (NE) and dopamine (DA) as the initial vasopressor in septic shock patients who were managed with a specific treatment protocol. A prospective, randomized, open-label, clinical trial was used in a medical intensive care unit comparing DA with NE as the initial vasopressor in fluid-resuscitated 252 adult patients with septic shock. If the maximum dose of the initial vasopressor was unable to maintain the hemodynamic goal, then fixed-dose vasopressin was added to each regimen. If additional vasopressor support was needed to achieve the hemodynamic goal, then phenylephrine was added. The primary efficacy end point was all-cause 28-day mortality. Secondary end points included organ dysfunction, hospital and intensive care unit length of stay, and safety (primarily occurrence of arrhythmias). The 28-day mortality rate was 50% (67/134) with DA as the initial vasopressor compared with 43% (51/118) for NE treatment (P = 0.282). There was a significantly greater incidence of sinus tachycardia with DA (24.6%; 33/134) than NE (5.9%; 7/118) and arrhythmias noted with DA treatment (19.4%; 26/134) compared with NE treatment (3.4%; 4/118; P < 0.0001), respectively. Logistic regression analysis identified Acute Physiologic and Chronic Health Evaluation II score (P < 0.0001) and arrhythmia (P < 0.015) as significant predictors of outcome. In this protocol-directed vasopressor support strategy for septic shock, DA and NE were equally effective as initial agents as judged by 28-day mortality rates. However, there were significantly more cardiac arrhythmias with DA treatment. Patients receiving DA should be monitored for the development of cardiac arrhythmias (NCT00604019).

Topics: Adult; Arrhythmias, Cardiac; Dopamine; Female; Humans; Male; Norepinephrine; Shock, Septic; Tachycardia, Sinus; Vasoconstrictor Agents; Vasopressins

Vasopressin and corticosteroids are often added to support cardiovascular dysfunction in patients who have septic shock that is nonresponsive to fluid resuscitation and norepinephrine infusion. However, it is unknown whether vasopressin treatment interacts with corticosteroid treatment.. Post hoc substudy of a multicenter randomized blinded controlled trial of vasopressin vs. norepinephrine in septic shock.. Twenty-seven Intensive Care Units in Canada, Australia, and the United States.. : Seven hundred and seventy-nine patients who had septic shock and were ongoing hypotension requiring at least 5 microg/min of norepinephrine infusion for 6 hours.. Patients were randomized to blinded vasopressin (0.01-0.03 units/min) or norepinephrine (5-15 microg/min) infusion added to open-label vasopressors. Corticosteroids were given according to clinical judgment at any time in the 28-day postrandomization period.. The primary end point was 28-day mortality. We tested for interaction between vasopressin treatment and corticosteroid treatment using logistic regression. Secondary end points were organ dysfunction, use of open-label vasopressors and vasopressin levels.. There was a statistically significant interaction between vasopressin infusion and corticosteroid treatment (p = 0.008). In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively, p = 0.03). In contrast, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p = 0.06). In patients who received vasopressin infusion, use of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours (p = 0.006) to 67% at 24 hours (p = 0.025) compared with patients who did not receive corticosteroids.. There is a statistically significant interaction between vasopressin and corticosteroids. The combination of low-dose vasopressin and corticosteroids was associated with decreased mortality and organ dysfunction compared with norepinephrine and corticosteroids.

Topics: Adrenal Cortex Hormones; Drug Synergism; Female; Humans; Hydrocortisone; Male; Middle Aged; Norepinephrine; Shock, Septic; Single-Blind Method; Vasopressins

Septic shock is associated with vasopressin deficiency and hypersensitivity to its exogenous administration. The aim of this study is to review the 28-day survival rate, hemodynamic and renal effects of vasopressin therapy in refractory septic shock Japanese patients.. 55 Japanese patients experiencing catecholamine-resistant septic shock were treated with vasopressin. Hemodynamic alterations and the serum concentrations of aspartate aminotransferase, total bilirubin and creatinine clearance were evaluated following vasopressin treatment.. In both, survivors and non-surviving patients, treatment with vasopressin resulted in a significantly increase in mean arterial pressure, hourly urine output, and a significant decrease in heart rate and total pressor dosage requirements. Creatinine clearance was significantly increased only in survivors. There were no significant changes in the serum concentrations of aspartate aminotransferase and total bilirubin. The 28-day survival rate was 45% (25 patients).. In Japanese septic shock patients, vasopressin infusion improved hemodynamic status and reduced catecholamine requirement, and 28-day survival rate was 45%.

Topics: Blood Pressure; Cardiotonic Agents; Dopamine; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Follow-Up Studies; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infusions, Intravenous; Japan; Middle Aged; Norepinephrine; Prospective Studies; Shock, Septic; Survival Rate; Time Factors; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Recent clinical data suggest that early administration of vasopressin analogues may be advantageous compared to a last resort therapy. However, it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in septic shock. The aim of the present prospective, randomized, controlled pilot trial study was, therefore, to compare the impact of continuous infusions of either vasopressin or terlipressin, when given as first-line therapy in septic shock patients, on open-label norepinephrine requirements.. We enrolled septic shock patients (n = 45) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomized to receive continuous infusions of either terlipressin (1.3 microg.kg-1.h-1), vasopressin (.03 U.min-1) or norepinephrine (15 microg.min-1; n = 15 per group). In all groups, open-label norepinephrine was added to achieve a mean arterial pressure between 65 and 75 mmHg, if necessary. Data from right heart and thermo-dye dilution catheterization, gastric tonometry, as well as laboratory variables of organ function were obtained at baseline, 12, 24, 36 and 48 hours after randomization. Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors. Time-independent variables were compared with one-way ANOVA.. There were no differences among groups in terms of systemic and regional hemodynamics. Compared with infusion of .03 U of vasopressin or 15 microg.min-1 of norepinephrine, 1.3 microg.kg-1.h-1 of terlipressin allowed a marked reduction in catecholamine requirements (0.8 +/- 1.3 and 1.2 +/- 1.4 vs. 0.2 +/- 0.4 microg.kg-1.min-1 at 48 hours; each P < 0.05) and was associated with less rebound hypotension (P < 0.05). At the end of the 48-hour intervention period, bilirubin concentrations were higher in the vasopressin and norepinephrine groups as compared with the terlipressin group (2.3 +/- 2.8 and 2.8 +/- 2.5 vs. 0.9 +/- 0.3 mg.dL-1; each P < 0.05). A time-dependent decrease in platelet count was only observed in the terlipressin group (P < 0.001 48 hours vs. BL).. The present study provides evidence that continuous infusion of low-dose terlipressin--when given as first-line vasopressor agent in septic shock--is effective in reversing sepsis-induced arterial hypotension and in reducing norepinephrine requirements.

Topics: Acid-Base Equilibrium; Aged; Dobutamine; Female; Hemodynamics; Homeostasis; Humans; Lypressin; Male; Middle Aged; Norepinephrine; Oxygen; Pilot Projects; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors.. In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 microg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 microg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions.. A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10).. Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors. (Current Controlled Trials number, ISRCTN94845869 [controlled-trials.com].).

Topics: Adult; Aged; Blood Pressure; Catecholamines; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Norepinephrine; Severity of Illness Index; Shock, Septic; Treatment Failure; Vasoconstrictor Agents; Vasopressins

To identify predictors of 28-day mortality among patients with refractory septic shock treated with norepinephrine with or without vasopressin.. Prospective observational cohort study.. A 1,200-bed academic medical center.. One hundred thirty-seven patients with septic shock treated with norepinephrine with or without vasopressin.. None.. The 28-day mortality rate was 37.2% (n = 51). By multivariate analysis, significant predictors of death were norepinephrine plus vasopressin administration (adjusted odds ratio [AOR], 13.96; 95% confidence interval [CI] 6.47, 30.08; p = 0.001), lack of goal-directed fluid administration during initial resuscitation (AOR 15.82; 95% CI 6.16, 40.61; p = 0.003), inappropriate initial antimicrobial therapy (AOR 8.95; 95% CI 2.93, 27.33; p = 0.05), and higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (AOR 1.14; 95% CI 1.07, 1.21; p = 0.033). Patients who received norepinephrine plus vasopressin (n = 68) had a significantly higher mortality rate than patients managed with norepinephrine alone (n = 69) 28 days after the initiation of vasopressors (54.4% vs. 20.3%; p < 0.001). This finding was confirmed in patients matched optimally across treatment groups.. Our study found an association between the use of norepinephrine plus vasopressin and 28-day mortality in refractory septic shock. In view of its known mechanism of action, vasopressin contributed to this excess mortality. Further recommendations regarding the use of vasopressin await the results of large randomized trials evaluating its efficacy and safety for septic shock.

Topics: Adult; Aged; APACHE; Drug Combinations; Female; Humans; Intensive Care Units; Kaplan-Meier Estimate; Male; Middle Aged; Missouri; Norepinephrine; Odds Ratio; Prospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

To compare the effects of arginine-vasopressin (AVP) and norepinephrine (NE) on hemodynamic variables, organ dysfunction, and adverse events in early hyperdynamic septic shock.. Randomized, controlled, open-label trial.. Twenty-three patients with early (12h) hyperdynamic septic shock in two teaching hospitals.. AVP (0.04-0.20 Umin(-1), n=13) as a single agent or NE (0.1-2.8microg kg(-1)min(-1), n=10) infusion for 48[Symbol: see text]h to achieve mean arterial pressure at or above 70mmHg.. Hemodynamic parameters and Sequential Organ Failure Assessment (SOFA) score were measured. AVP and NE equally increased mean arterial pressure over 48h, but NE was required in 36% of AVP patients at 48h. Compared to baseline, AVP increased systemic vascular resistance, decreased exposure to NE, decreased cardiac output by decreasing heart rate, increased creatinine clearance, and improved SOFA score. The PrCO(2) - PaCO(2) difference remained stable throughout the study. One AVP patient developed acute coronary syndrome with dose-dependent ECG changes. Three patients in both groups died during their ICU stay.. In early hyperdynamic septic shock, the administration of high-dose AVP as a single agent fails to increase mean arterial pressure in the first hour but maintains it above 70mmHg in two-thirds of patients at 48h. AVP decreases NE exposure, has no effect on the PrCO(2) - PaCO(2 )difference, and improves renal function and SOFA score.

Topics: Arginine; Drug Combinations; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Multiple Organ Failure; Norepinephrine; Prospective Studies; Shock, Septic; Survival Analysis; Vasoconstrictor Agents; Vasopressins

To evaluate if low plasma vasopressin and high norepinephrine concentrations predict grave prognosis of sepsis, a prospective sample of consecutive patients visiting the emergency department of a university teaching hospital who met the American College of Chest Physicians criteria of sepsis or severe sepsis was enrolled. Besides septic workup, we measured serum vasopressin and norepinephrine concentrations to correlate the impending outcome. One hundred eighty-two patients aged 27 to 99 years met the inclusive criteria and were classified as those with septic shock (n = 72), severe sepsis (n = 56), and those with sepsis only (n = 54) according to the outcome within 6 hours. Thirty healthy subjects were included as control. The plasma vasopressin level at baseline was significantly lower for those who finally developed septic shock (septic shock group, 3.6 +/- 2.5 pg/mL; 95% confidence interval [CI], 3.0-4.2 pg/mL; severe sepsis group, 21.8 +/- 4.1 pg/mL, 95% CI, 20.7-22.9 pg/mL; sepsis group, 10.6 +/- 6.5 pg/mL, 95% CI, 8.8-12.4 pg/mL, P < .001), whereas the norepinephrine level was highest for the same group (septic shock group, 3650 +/- 980 pg/mL, 95% CI, 3420-3880 pg/mL; severe sepsis group, 3600 +/- 1000 pg/mL, 95% CI, 3330-3870 pg/mL; sepsis group, 1720 +/- 320 pg/mL, 95% CI, 1630-1810 pg/mL). The vasopressin/norepinephrine ratio was significantly lower for the patients with final diagnosis of septic shock (P < .001). The mean interval between the time of samples drawn and the time of the most severe occurring sequelae was 2.4 +/- 0.8 hours. Receiver operating characteristic analysis revealed that the vasopressin/norepinephrine ratio 1 x 10(-3) had a sensitivity of 97% (95% CI, 90%-99%) and a specificity of 85% (95% CI, 78%-91%) for detecting impending septic shock. Low serum vasopressin/norepinephrine ratio can predict impending septic shock.

Topics: Adult; Aged; Aged, 80 and over; Clinical Protocols; Emergency Medicine; Female; Humans; Male; Middle Aged; Norepinephrine; Odds Ratio; Predictive Value of Tests; Prospective Studies; ROC Curve; Shock, Septic; Vasopressins

To study the effect of continuous infusion of vasopressin on the splanchnic circulation in patients with severe septic shock.. Prospective clinical study.. ICU in a teaching hospital.. Eleven consecutive patients with documented septic shock who remained hypotensive despite norepinephrine infusion at a rate > or =0.2 microg/kg/min.. Insertion of a gastric tonometry catheter, and continuous infusion of vasopressin 0.04 U/min during 4 h.. Difference between gastric and arterial CO(2) partial pressure (P[g-a]CO(2) gap), mean arterial pressure, and cardiac index were recorded at baseline and after 15 min, 30 min, 60 min, 120 min, and 240 min.. The median P(g-a)CO(2) gap increased from 5 mm Hg at baseline to 19 mm Hg after 4 h (p = 0.022). Mean arterial pressure increased from 61 +/- 13 mm Hg at baseline to 68 +/- 9 mm Hg after 4 h (p = 0.055). No significant changes in cardiac index were noted.. In norepinephrine-dependent patients in septic shock, continuous infusion of low-dose vasopressin results in a significant increase of the P(g-a)CO(2) gap compatible with GI hypoperfusion.

Topics: Adult; Aged; APACHE; Blood Pressure; Critical Care; Female; Humans; Hypotension; Male; Manometry; Middle Aged; Norepinephrine; Pneumonia; Prospective Studies; Shock, Septic; Splanchnic Circulation; Vasoconstrictor Agents; Vasopressins

Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether short-term vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion.. Patients experiencing septic shock that required high-dose vasopressor support were randomized to a double-blinded 4-h infusion of either norepinephrine (n = 11) or vasopressin (n = 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured.. Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 microg/min to a blinded infusion of 17.0 mug/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 microg/min to 5.3 microg/min at 4 h (P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h; P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group.. The authors conclude that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock.

Topics: Aged; Blood Pressure; Carbon Dioxide; Cardiac Output; Creatinine; Double-Blind Method; Electrocardiography; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Natriuresis; Norepinephrine; Regional Blood Flow; Shock, Septic; Urodynamics; Vascular Resistance; Vasoconstrictor Agents; Vasopressins

To investigate the physiologic effects of exogenous vasopressin as a potential alternative to traditional high-dose catecholamine therapy for septic patients with vascular hyporeactivity to catecholamines.. Prospective, case-controlled study.. Intensive care unit of a university hospital.. Vasopressin was infused in 16 critically ill septic patients who remained persistently hypotensive despite infusions of pharmacologic doses of catecholamines.. Continuous intravenous infusion of vasopressin at 0.04 units/min for 16 hrs, in place of escalating the amount of catecholamines being infused.. After administration of vasopressin, systemic vascular resistance and mean arterial pressure were immediately and significantly increased in comparison with the values obtained just before vasopressin. When the vasopressin infusions were discontinued, mean arterial pressure decreased immediately and dramatically. We did not detect any obvious adverse cardiac effects during the vasopressin infusions. Vasopressin had no effect on other hemodynamic parameters or any of the metabolic parameters studied, including measures of oxygenation, plasma glucose, or electrolytes. Urine output increased significantly during the administration of vasopressin, although this effect may be nonspecific. Lactate concentrations decreased, particularly in the survival group, but the decreases were not significant. Overall survival was 56%.. Low-dose vasopressin infusions increased mean arterial pressure, systemic vascular resistance, and urine output in patients with vasodilatory septic shock and hyporesponsiveness to catecholamines. The data indicate that low-dose vasopressin infusions may be useful in treating hypotension in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Blood Gas Analysis; Blood Glucose; Critical Illness; Drug Monitoring; Electrolytes; Female; Hemodynamics; Humans; Infusions, Intravenous; Lactic Acid; Male; Middle Aged; Prospective Studies; Renin; Shock, Septic; Survival Analysis; Time Factors; Vasoconstrictor Agents; Vasopressins

Despite appropriate therapy, refractory hypotension often occurs in septic shock. A double-blinded placebo controlled clinical trial was performed to assess the role of low-dose vasopressin (VP) as a pressor agent in septic shock.. Patients admitted to a trauma intensive care unit with vasodilatory septic shock were randomized to receive either VP at 0.04 U/min (n = 5) or placebo (n = 5). Vasodilatory septic shock was defined as a need for catecholamine agents to maintain a mean arterial pressure more than or equal to 70 mm Hg, despite a cardiac index more than 2.5 L/min and a minimal pulmonary artery wedge pressure more than 12 mm Hg. After 1 hour of initiation of the study drug, attempts to discontinue norepinephrine, phenylephrine, and/or dopamine, in respective order, were undertaken provided that the mean arterial pressure remained more than or equal to 70 mm Hg.. A vasopressin infusion increased systolic arterial pressure (98 +/- 5 to 125 +/- 8 mm Hg, p < 0.008) because of peripheral vasoconstriction (systemic vascular resistance increased from 878 +/- 218 to 1,190 +/- 213 dynes/s per cm(-5) p < 0.05). Arterial pressure and systemic vascular resistance were statistically unaffected in the placebo group. Before study termination, measured at 24 hours after drug initiation, two patients in the placebo group died of refractory hypotension. However, all patients receiving VP survived the 24-hour study period and had all other catecholamine pressors withdrawn and blood pressure maintained solely with a low-dose VP infusion.. A VP infusion improved arterial pressure and permitted the withdrawal of catecholamine vasopressors. VP is a useful agent in the treatment of refractory septic shock.

Topics: Blood Pressure; Cardiac Output; Cardiotonic Agents; Dopamine; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Phenylephrine; Pulmonary Wedge Pressure; Shock, Septic; Survival Analysis; Vascular Resistance; Vasoconstrictor Agents; Vasopressins

Topics: Aged; Drug Synergism; Fatal Outcome; Female; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Cohort Studies; Humans; Hypotension; Incidence; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Current guidelines recommend norepinephrine as the first-line vasopressor in septic shock followed by addition of vasopressin to achieve a goal mean arterial pressure. Limited evidence exists evaluating how the timing of vasopressin addition affects clinical outcomes in septic shock.. The objective of this study was to determine whether the timing of the addition of vasopressin to norepinephrine affects shock resolution.. This was a multi-site, single system, retrospective cohort, institutional review board (IRB)-approved study examining adult patients with septic shock who received norepinephrine and vasopressin. Patients were divided and statistically analyzed in two subgroups: early vasopressin addition (<3 hours) and late vasopressin addition (≥3 hours). The primary outcome was time to shock resolution, defined as vasopressor free for at least 24 hours. Secondary outcomes included norepinephrine dose at 3 hours after initiation of vasopressin, in-hospital mortality, and intensive care unit length of stay.. A total of 243 patients were included in this study. A statistically significant decrease in time to shock resolution was observed in the early vasopressin addition group compared to the late vasopressin addition group (37.6 hours vs 60.7 hours; adjusted hazard ratio [HR]: 2.07 [1.48-2.89;. Addition of vasopressin to norepinephrine within 3 hours was associated with a faster time to shock resolution. These findings suggest a potential for improved clinical outcomes with earlier vasopressin addition.

Topics: Addiction Medicine; Adult; Humans; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

In septic shock, vasopressors aim to improve tissue perfusion and prevent persistent organ dysfunction, a characteristic of chronic critical illness (CCI). Adjunctive vasopressin is often used to decrease catecholamine dosage, but the association of vasopressin response with subsequent patient outcomes is unclear. We hypothesized vasopressin response is associated with favorable clinical trajectory.. We included patients with septic shock receiving vasopressin as a catecholamine adjunct in this retrospective cohort study. We defined vasopressin response as a lowering of the catecholamine dose required to maintain mean arterial pressure ≥65 mm Hg, 6 h after vasopressin initiation. Clinical trajectories were adjudicated as early death (ED; death before day 14), CCI (ICU stay ≥14 days with persistent organ dysfunction), or rapid recovery (RR; not meeting ED or CCI criteria). Trajectories were placed on an ordinal scale with ED the worst outcome, CCI next, and RR the best outcome. The association of vasopressin response with clinical trajectory was assessed with multivariable ordinal logistic regression.. In total 938 patients were included; 426 (45.4%) were vasopressin responders. The most frequent trajectory was ED (49.8%), 29.7% developed CCI, and 20.5% had rapid recovery. In survivors to ICU day 14 (those without ED), 59.2% had CCI and 40.8% experienced RR. Compared with vasopressin non-responders, vasopressin responders less frequently experienced ED (42.5% vs. 55.9%) and more frequently experienced RR (24.6% vs. 17.0%;. Vasopressin responsive status was associated with improved clinical trajectory in septic shock patients. Early vasopressin response is a potential novel prognostic marker for short-term clinical trajectory.

Topics: Catecholamines; Critical Illness; Humans; Multiple Organ Failure; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Critical Illness; Humans; Norepinephrine; Phenylephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Critical Illness; Humans; Norepinephrine; Phenylephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

To determine the number of patients retrieved by aeromedical teams for septic shock requiring vasopressor support who meet criteria for vasopressin therapy under the Surviving Sepsis Campaign 2021 guidelines.. Retrospective chart review of patients transferred by LifeFlight Retrieval Medicine on vasopressors over 2 years.. One thousand one hundred and fifty-eight patients were retrieved on vasopressor therapy, with 428 requiring infusions for septic shock. One hundred and fifteen of these met criteria for administration of vasopressin under Surviving Sepsis Campaign guidelines.. A sufficient percentage of patients on vasopressors for septic shock require vasopressin therapy to meet current best treatment guidelines, and the inclusion of vasopressin in retrieval drug kits should be considered by Australian aeromedical services.

Topics: Air Ambulances; Australia; Humans; Retrospective Studies; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Critical Illness; Humans; Norepinephrine; Phenylephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Critical Illness; Humans; Norepinephrine; Phenylephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Acute Kidney Injury; Humans; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

vasopressin is commonly used as a second-line vasopressor for patients with septic shock, but the optimal timing of initiation is uncertain. This study was designed to investigate when vasopressin initiation may be beneficial for 28-day mortality in septic shock patients.. This was a retrospective observational cohort study from the MIMIC-III v1.4 and MIMIC-IV v2.0 databases. All adults diagnosed with septic shock according to Sepsis-3 criteria were included. Patients were stratified into two groups based on norepinephrine (NE) dose at the time of vasopressin initiation, defined as the low doses of NE group (NE<0.25 µg/kg/min) and the high doses of NE group (NE ≥ 0.25 µg/kg/min). The primary end-point was 28-day mortality after diagnosis of septic shock. The analysis involved propensity score matching (PSM), multivariable logistic regression, doubly robust estimation, the gradient boosted model, and an inverse probability-weighting model.. A total of 1817 eligible patients were included in our original cohort (613 in the low doses of NE group and 1204 in the high doses of NE group). After 1:1 PSM, 535 patients from each group with no difference in disease severity were included in the analysis. The results showed that vasopressin initiation at low doses of NE was associated with reduced 28-day mortality (odds ratio [OR] 0.660, 95% confidence interval [CI] 0.518-0.840, p < 0.001). Compared with patients in the high doses of NE group, patients in the low doses of NE group received significantly shorter duration of NE, with less intravenous fluid volume on the first day after initiation of vasopressin, more urine on the second day, and longer mechanical ventilation-free days and CRRT-free days. Nevertheless, there were no significant differences in hemodynamic response to vasopressin, duration of vasopressin, and ICU or hospital length of stay.. Among adults with septic shock, vasopressin initiation when low-dose NE was used was associated with an improvement in 28-day mortality.

Topics: Adult; Cohort Studies; Humans; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin, used as a catecholamine adjunct, is a vasoconstrictor that may be detrimental in some hemodynamic profiles, particularly left ventricular (LV) systolic dysfunction. This study tested the hypothesis that echocardiographic parameters differ between patients with a hemodynamic response after vasopressin initiation and those without a response.. This retrospective, single-center, cross-sectional study included adults with septic shock receiving catecholamines and vasopressin with an echocardiogram performed after shock onset but before vasopressin initiation. Patients were grouped by hemodynamic response, defined as decreased catecholamine dosage with mean arterial pressure ≥ 65 mmHg six hours after vasopressin initiation, with echocardiographic parameters compared. LV systolic dysfunction was defined as LV ejection fraction (LVEF) <45%.. Of 129 included patients, 72 (56%) were hemodynamic responders. Hemodynamic responders, versus non-responders, had higher LVEF (61% [55%,68%] vs. 55% [40%,65%]; p = 0.02) and less-frequent LV systolic dysfunction (absolute difference  -16%; 95% CI -30%,-2%). Higher LVEF was associated with higher odds of hemodynamic response (for each LVEF 10%, response OR 1.32; 95% CI 1.04-1.68). Patients with LV systolic dysfunction, versus without LV systolic dysfunction, had higher mortality risk (HR(t) = e. Pre-drug echocardiographic profiles differed in hemodynamic responders after vasopressin initiation versus non-responders.

Topics: Adult; Catecholamines; Cross-Sectional Studies; Echocardiography; Hemodynamics; Humans; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins; Ventricular Dysfunction, Left

Significant practice variation exists when selecting between hydrocortisone and vasopressin as second line agents in patients with septic shock in need of escalating doses of norepinephrine. The goal of this study was to assess differences in clinical outcomes between these two agents.. Multicenter, retrospective, observational study.. Ten Ascension Health hospitals.. Adult patients with presumed septic shock receiving norepinephrine prior to study drug initiation between December 2015 and August 2021.. Vasopressin (0.03-0.04 units/min) or hydrocortisone (200-300 mg/day).. A total of 768 patients were included with a median (interquartile range) SOFA score of 10 (8-13), norepinephrine dose of 0.3 mcg/kg/min (0.1-0.5 mcg/kg/min), and lactate of 3.8 mmol/L (2.4-7.0 mmol/L) at initiation of the study drug. A significant difference in 28-day mortality was noted favoring hydrocortisone as an adjunct to norepinephrine after controlling for potential confounding factors (OR 0.46 [95% CI, 0.32-0.66]); similar results were seen following propensity score matching. Compared to vasopressin, hydrocortisone initiation was also associated with a higher rate of hemodynamic responsiveness (91.9% vs. 68.2%, p < 0.01), improved resolution of shock (68.8% vs. 31.5%, p < 0.01), and reduced recurrence of shock within 72 h (8.7% vs. 20.7%, p < 0.01).. Addition of hydrocortisone to norepinephrine was associated with a lower 28-day mortality in patients with septic shock, compared to the addition of vasopressin.

Topics: Adult; Humans; Hydrocortisone; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Septic shock is a leading cause of death in intensive care units (ICUs), with short-term mortality rates of 35-40%. Vasopressin (AVP) is a second-line vasoactive agent for septic shock, and recent studies suggest that early AVP use can be beneficial. However, differences between early initiation of AVP combined with norepinephrine (NE) and nonearly AVP with NE are unclear. A retrospective cohort research was designed to explore the effects of early AVP initiation versus nonearly AVP initiation.. This retrospective single-center cohort study included adult patients with septic shock from the MIMIC (Medical Information Mart for Intensive Care)-IV database. According to whether AVP was used early in the ICU (intensive care unit), patients were assigned to the early- (within 6 h of septic shock onset) and non-early-AVP (at least 6 h after septic shock onset) groups. The primary outcome was 28-day mortality. The secondary outcomes were ICU and hospital mortality, the numbers of vasopressor-free and ventilation-free days at 28 days, ICU length of stay (LOS), hospital LOS, sequential organ failure assessment (SOFA) score on days 2 and 3, and renal replacement therapy (RRT) use on days 2 and 3. Univariate and multivariate cox proportional-hazards regression, propensity-score matching were used to analyze the differences between the groups.. The study included 531 patients with septic shock: 331 (62.5%) in the early-AVP group and 200 (37.5%) in the non-early-AVP group. For 1:1 matching, 158 patients in the early-AVP group were matched with the same number of patients with nonearly AVP. Regarding the primary outcome, there was no significant difference between the early- and non-early-AVP groups in 28-day mortality (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.68-1.24). For the secondary outcomes, there were no differences between the early- and non-early-AVP groups in ICU mortality (HR = 0.95, 95% CI = 0.67-1.35), hospital mortality (HR = 0.95, 95% CI = 0.69-1.31), the numbers of vasopressor-free and ventilation-free days at 28 days, ICU LOS, hospital LOS, SOFA score on days 2 and 3, and RRT use on days 2 and 3.. There was no difference in short-term mortality between early AVP combined with NE and nonearly AVP with NE in septic shock.

Topics: Adult; Cohort Studies; Humans; Intensive Care Units; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is a second-line vasoactive agent for refractory septic shock. Vasopressin loading is not generally performed because of the lack of evidence for its effects and safety. However, based on our previous findings, we hypothesized it can predict the responsibility to vasopressin infusion with safety, and prospectively examined it in the present study.. Vasopressin loading was performed via the intravenous administration of a bolus of 1 U, followed by its continuous infusion at 1U/h in patients with septic shock treated with ≥ 0.2 μg/kg/min noradrenaline. An arterial pressure wave analysis was conducted, and endocrinological tests were performed immediately prior to vasopressin loading. We classified patients into responders/non-responders based on mean arterial pressure (MAP) changes after vasopressin loading. Based on our previous findings, the lower tertile of MAP changes was selected as the cut-off. The change in the catecholamine index (CAI) after 6 h was assigned as the primary outcome. Digital ischemia, mesenteric ischemia, and myocardial ischemia during the admission period were prospectively and systematically recorded as adverse events.. Ninety-two patients were registered during the study period and examined. Sixty-two patients with a MAP change > 22 mmHg were assigned as responders and the others as non-responders. Blood adrenocorticotropic hormone levels were significantly higher in non-responders. Stroke volume variations were higher in responders before loading, while stroke volume and dP/dt. Vasopressin loading may be safely introduced for septic shock. Vasopressin loading may be used to predict responses to its continuous infusion and select appropriate strategies to increase blood pressure.

Topics: Administration, Intravenous; Catecholamines; Humans; Norepinephrine; Shock, Septic; Vasopressins

Topics: Humans; Prospective Studies; Shock; Shock, Septic; Vasopressins

Topics: Adult; Humans; Hydrocortisone; Norepinephrine; Retrospective Studies; Shock, Septic; Vasopressins

Topics: Adult; Humans; Hydrocortisone; Norepinephrine; Retrospective Studies; Shock, Septic; Vasopressins

To determine the association of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality.. Retrospective, observational study using segmented and multivariable logistic regression to evaluate the associations of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality.. Multiple hospitals within the Cleveland Clinic Health System.. Adult patients who met criteria for septic shock based on the U.S. Centers for Disease Control and Prevention Adult Sepsis Event definition.. All patients received continuous infusion vasopressin as an adjunct to catecholamine vasopressors.. In total, 1,610 patients were included with a mean Acute Physiology and Chronic Health Evaluation III 109.0 ± 35.1 and Sequential Organ Failure Assessment 14.0 ± 3.5; 41% of patients survived the hospital admission. At the time of vasopressin initiation, patients had median (interquartile range) lactate concentration 3.9 mmol/L (2.3-7.2 mmol/L), norepinephrine-equivalent dose 25 µg/min (18-40 µg/min), and 5.3 hours (2.1-12.2 hr) elapsed since shock onset. The odds of in-hospital mortality increased 20.7% for every 10 µg/min increase in norepinephrine-equivalent dose up to 60 µg/min at the time of vasopressin initiation (adjusted odds ratio, 1.21 [95% CI, 1.09-1.34]), but no association was detected when the norepinephrine-equivalent dose exceeded 60 µg/min (adjusted odds ratio, 0.96 [95% CI, 0.84-1.10]). There was a significant interaction between timing of vasopressin initiation and lactate concentration (p = 0.02) for the association with in-hospital mortality. A linear association between increasing in-hospital mortality was detected for increasing lactate concentration at the time of vasopressin initiation, but no association was detected for time elapsed from shock onset.. Higher norepinephrine-equivalent dose at vasopressin initiation and higher lactate concentration at vasopressin initiation were each associated higher in-hospital mortality in patients with septic shock who received vasopressin.

Topics: Adult; Catecholamines; Humans; Lactic Acid; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is suggested as an adjunct to norepinephrine in patients with septic shock. However, after vasopressin was rebranded in November 2014, its cost exponentially increased. Utilization patterns of vasopressin after its rebranding are unclear. The objective of this study was to determine if there is an association between the rebranding of vasopressin in November 2014 and its utilization in vasopressor-dependent patients with severe sepsis or septic shock.. Retrospective, multicenter, database study between January 2010 and March 2017.. Premier Healthcare Database hospitals.. Adult patients admitted to an ICU with severe sepsis or septic shock, who received at least one vasoactive agent for two or more calendar days were included.. The proportion of patients who received vasopressin and vasopressin cost was assessed before and after rebranding, and evaluated with segmented regression.. Among 294,733 patients (mean age, 66 ± 15 yr), 27.8% received vasopressin, and ICU mortality was 26.5%. The proportion of patients receiving vasopressin was higher after rebranding (31.2% postrebranding vs 25.8% prerebranding). Before vasopressin rebranding, the quarterly proportion of patients who received vasopressin had an increasing slope (prerebranding slope 0.41% [95% CI, 0.35-0.46%]), with no difference in slope detected after vasopressin rebranding (postrebranding slope, 0.47% [95% CI, 0.29-0.64%]). After vasopressin rebranding, mean vasopressin cost per patient was higher ($527 ± 1,130 vs $77 ± 160), and the quarterly slope of vasopressin cost was higher (change in slope $77.18 [95% CI, $75.73-78.61]). Total vasopressin billed cost postrebranding continually increased by ~$294,276 per quarter from less than $500,000 in Q4 2014 to over $3,000,000 in Q1 2017.. After vasopressin rebranding, utilization continued to increase quarterly despite a significant increase in vasopressin cost. Vasopressin appeared to have price inelastic demand in septic shock.

Topics: Aged; Aged, 80 and over; Humans; Middle Aged; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The objective of this study was to develop and externally validate a model to predict adjunctive vasopressin response in patients with septic shock being treated with norepinephrine for bedside use in the intensive care unit.. This was a retrospective analysis of two adult tertiary intensive care unit septic shock populations.. Barnes-Jewish Hospital (BJH) from 2010 to 2017 and Beth Israel Deaconess Medical Center (BIDMC) from 2001 to 2012.. Two septic shock populations (548 BJH patients and 464 BIDMC patients) that received vasopressin as second-line vasopressor.. Patients who were vasopressin responsive were compared with those who were nonresponsive. Vasopressin response was defined as survival with at least a 20% decrease in maximum daily norepinephrine requirements by one calendar day after vasopressin initiation, without a third-line vasopressor.. Two supervised machine learning models (gradient-boosting machine [XGBoost] and elastic net penalized logistic regression [EN]) were trained in 1000 bootstrap replications of the BJH data and externally validated in the BIDMC data to predict vasopressin responsiveness.. Vasopressin responsiveness was similar among each cohort (BJH 45% and BIDMC 39%). Mortality was lower for vasopressin responders compared with nonresponders in the BJH (51% vs. 73%) and BIDMC (45% vs. 83%) cohorts, respectively. Both models demonstrated modest discrimination in the training (XGBoost area under receiver operator curve [AUROC] 0.61 [95% confidence interval (CI) 0.61-0.61], EN 0.59 [95% CI 0.58-0.59]) and external validation (XGBoost 0.68 [95% CI 0.63-0.73], EN 0.64 [95% CI 0.59-0.69]) datasets.. Vasopressin nonresponsiveness is common and associated with increased mortality. The models' modest performances highlight the complexity of septic shock and indicate that more research will be required before clinical decision support tools can aid in anticipating patient-specific responsiveness to vasopressin.

Topics: Adult; Humans; Machine Learning; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressors increase arterial pressure but they may have deleterious effects on mesenteric blood flow. We aimed to evaluate the response of gut biomarkers and superior mesenteric blood flow to different vasopressors with and without dobutamine.. Thirty New Zealand rabbits were included and randomly allocated to 5 groups: group A - sham group; group B - norepinephrine; group C - norepinephrine plus dobutamine; group D - vasopressin; and group E - vasopressin plus dobutamine. Mean arterial pressure (MAP) target was greater than 60 mmHg. Endotoxic shock was induced by intra-venous injection of lipopolysaccharide (LPS) in four of the five groups. Aortic blood flow (Qao), superior mesenteric artery flow (QSMA) and lactate were measured after LPS injection. Enterocyte damage was evaluated by measurements of serum citrulline and intestinal fatty acid-binding protein (I-FABP) after 4 h.. The largest reduction in Qao occurred in group D (64 ± 17.3 to 38 ± 7.5 mL min-1; P = 0.04). QSMA also declined significantly in groups D and E and remained lower than in the other groups over 4 h (group D - baseline: 65 ± 31; 1 h: 37 ± 10; 2 h: 38 ± 10; 3 h: 46 ± 26; and 4 h: 48 ± 15 mL min-1; P < 0.005; group E - baseline: 73 ± 14; 1 h: 28 ± 4.0; 2 h: 37 ± 6.4; 3 h: 40 ± 11; and 4 h: 48 ± 11; P < 0.005; all in mL min-1). Serum citrulline was significantly lower in groups D (P = 0.014) and E (P = 0.019) in comparison to group A. The fluid administration regimen was similar in all groups.. Vasopressin seems to negatively impact gut enterocyte function during endotoxic shock despite the association of an inodilator and adequate fluid replacement.

Topics: Animals; Citrulline; Dobutamine; Hemodynamics; Humans; Lipopolysaccharides; Norepinephrine; Rabbits; Shock, Septic; Vasoconstrictor Agents; Vasopressins

To evaluate the outcomes of patients with septic shock treated with a combination of norepinephrine with phenylephrine compared to norepinephrine with vasopressin.. This was a retrospective cohort study including adults admitted between 2002 and 2017 with septic shock according to the Sepsis 3 criteria. We compared outcomes of patients treated with norepinephrine with phenylephrine to those treated with norepinephrine with vasopressin. Multivariate analysis was carried out to evaluate the association of norepinephrine with phenylephrine compared to norepinephrine with vasopressin with in-hospital mortality.. During the study period, 158 patients with septic shock were treated with norepinephrine with phenylephrine and 129 with norepinephrine with vasopressin. Crude in-hospital mortality was not different between the two groups [91/158 (57.6%) versus 80/129 (62.5%), p = 0.40]. There was also no difference in ICU length of stay or hospital length of stay. Multivariate analysis demonstrated no significant association of norepinephrine with phenylephrine with in-hospital mortality compared to norepinephrine with vasopressin (OR 0.62 (95% confidence interval 0.31, 1.23, p = 0.17).. Phenylephrine used as a second-line vasoactive agent combined with norepinephrine may be a reasonable option compared to vasopressin. However, this finding needs to be validated in a randomized controlled trial.

Topics: Adult; Critical Illness; Humans; Norepinephrine; Phenylephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Purpose : The aim of the study is to determine whether initiating vasopressin earlier in septic shock reduces organ dysfunction and in-hospital all-cause mortality. Methods : This multicenter, retrospective, cohort study evaluated patients admitted to the medical intensive care unit between October 2011 and August 2018 with septic shock who received vasopressin within 48 hours of shock onset. The primary composite outcome was the proportion of patients with a change in the Sequential Organ Failure Assessment score greater than 3 from baseline to 72 hours after initiation of vasopressin and/or in-hospital all-cause mortality. Secondary outcomes included time to hemodynamic stability, acute kidney injury, and intensive care unit length of stay. Results : A total of 385 patients included in the final evaluation with a mean Acute Physiology and Chronic Health Evaluation II score of 31 and a mean baseline Sequential Organ Failure Assessment score of 13. Median time to initiation of vasopressin after norepinephrine was 7.3 hours. The primary composite outcome was significantly reduced in patients who had vasopressin initiated earlier in septic shock (odds ratio = 1.08, 95% confidence interval = 1.03-1.13, P < 0.001). After controlling for baseline data in a multivariable regression model the primary outcome remained statistically significant (odds ratio = 1.04, 95% confidence interval = 1.02-1.07, P = 0.001). Conclusions : Early initiation of vasopressin in septic shock may reduce the risk of in-hospital all-cause mortality and/or organ dysfunction.

Topics: Cohort Studies; Humans; Multiple Organ Failure; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Lactic Acid; Shock, Septic; Vasopressins

Arginine vasopressin (AVP) is suggested as an adjunct to norepinephrine in patients with septic shock. Guidelines recommend an AVP dosage up to 0.03 units/min, but 0.04 units/min is commonly used in practice based on initial studies. This study was designed to compare the incidence of hemodynamic response between initial fixed-dosage AVP 0.03 units/min and AVP 0.04 units/min.. This retrospective, multi-hospital health system, cohort study included adult patients with septic shock receiving AVP as an adjunct to catecholamine vasopressors. Patients were excluded if they received an initial dosage other than 0.03 units/min or 0.04 units/min, or AVP was titrated within the first 6 hours of therapy. The primary outcome was hemodynamic response, defined as a mean arterial pressure ≥65 mm Hg and a decrease in catecholamine dosage at 6 hours after AVP initiation. Inverse probability of treatment weighting (IPTW) based on the propensity score for initial AVP dosage receipt was utilized to estimate adjusted exposure effects.. Of the 1536 patients included in the observed data, there was a nearly even split between initial AVP dosage of 0.03 units/min (n = 842 [54.8%]) and 0.04 units/min (n = 694 [45.2%]). Observed patients receiving AVP 0.03 units/min were more frequently treated at the main campus academic medical center (96.3% vs. 52.2%, p < 0.01) and in a medical intensive care unit (87.4% vs. 39.8%, p < 0.01). The IPTW analysis included 1379 patients with achievement of baseline covariate balance. There was no evidence for a difference between groups in the incidence of hemodynamic response (0.03 units/min 50.0% vs. 0.04 units/min 53.1%, adjusted relative risk 1.06 [95% CI 0.94, 1.20]).. Initial AVP dosing varied by hospital and unit type. Although commonly used, an initial AVP dosage of 0.04 units/min was not associated with a higher incidence of early hemodynamic response to AVP in patients with septic shock.

Topics: Adult; Hemodynamics; Humans; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The optimal vasopressor management for septic patients with left ventricular (LV) dysfunction has not been well established, and current evidence is conflicting regarding the optimal vasopressor discontinuation order.. The objective was to evaluate the impact of LV dysfunction on the hemodynamic management of septic shock by assessing the incidence of clinically significant hypotension after vasopressor discontinuation.. In this single-center, retrospective cohort study, adult patients were included if they met the Sepsis-3 definition of septic shock, had LV dysfunction (defined as an ejection fraction ≤40%), and received norepinephrine and vasopressin as the last vasopressors discontinued. The primary outcome was the incidence of clinically significant hypotension following discontinuation of vasopressin or norepinephrine. Clinically significant hypotension was defined as a MAP less than 60 mmHg and the need for either: 1) the reinstitution of the previously discontinued agent at any dosage, 2) the receipt of at least 500 mL of a crystalloid at a rate of at least 500 mL/hour, 3) or the receipt of at least 25 grams of albumin 5% at a rate of at least 25 gram/hour. Secondary outcomes included intensive care unit (ICU) and hospital lengths of stay, and ICU and hospital mortality.. A total of 78 patients met inclusion criteria, with 37 patients having vasopressin discontinued first and 41 having norepinephrine discontinued first. Clinically significant hypotension occurred in 28 patients (76%) following the discontinuation of vasopressin, compared to 28 patients (81%) following the discontinuation of norepinephrine (p = 0.61). ICU length of stay was 9 days in the vasopressin discontinued first cohort, compared to 15 days in the norepinephrine discontinued first cohort (p = 0.01). There was no statistically significant difference in mortality observed.. The discontinuation order of norepinephrine and vasopressin did not impact the incidence of clinically significant hypotension in patients with septic shock and LV dysfunction, but may influence ICU length of stay, although other factors may have impacted this finding.

Topics: Adult; Humans; Hypotension; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins; Ventricular Function, Left

After fluid administration for vasodilatory shock, vasopressors are commonly infused. Causes of vasodilatory shock include septic shock, post-cardiovascular surgery, post-acute myocardial infarction, postsurgery, other causes of an intense systemic inflammatory response, and drug -associated anaphylaxis. Therapeutic vasopressors are hormones that activate receptors-adrenergic: α1, α2, β1, β2; angiotensin II: AG1, AG2; vasopressin: AVPR1a, AVPR1B, AVPR2; dopamine: DA1, DA2. Vasopressor choice and dose vary widely because of patient and physician practice heterogeneity. Vasopressor adverse effects are excessive vasoconstriction causing organ ischemia/infarction, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. To date, no randomized controlled trial (RCT) of vasopressors has shown a decreased 28-day mortality rate. There is a need for evidence regarding alternative vasopressors as first-line vasopressors. We emphasize that vasopressors should be administered simultaneously with fluid replacement to prevent and decrease duration of hypotension in shock with vasodilation. Norepinephrine is the first-choice vasopressor in septic and vasodilatory shock. Interventions that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality significantly. In patients not responsive to norepinephrine, vasopressin or epinephrine may be added. Angiotensin II may be useful for rapid resuscitation of profoundly hypotensive patients. Inotropic agent(s) (e.g., dobutamine) may be needed if vasopressors decrease ventricular contractility. Dopamine has fallen to almost no-use recommendation because of adverse effects; angiotensin II is available clinically; there are potent vasopressors with scant literature (e.g., methylene blue); and the novel V1a agonist selepressin missed on its pivotal RCT primary outcome. In pediatric septic shock, vasopressors, epinephrine, and norepinephrine are recommended equally because there is no clear evidence that supports the use of one vasoactive agent. Dopamine is recommended when epinephrine or norepinephrine is not available. New strategies include perhaps patients will be

Topics: Angiotensin II; Dopamine; Epinephrine; Humans; Intensive Care Units; Norepinephrine; Shock; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Shock, Septic; Vasopressins

Topics: Humans; Shock, Septic; Vasopressins

No clear association between standard vasopressin doses and body mass index exists, despite potential pharmacokinetic and pharmacodynamic variability among patients with septic shock. It is unknown if higher doses may alter hemodynamic response.. The purpose of this study was to evaluate the effect of vasopressin dose on hemodynamic response in obese patients with septic shock.. A single-center, retrospective cohort study was conducted in adult, obese patients with septic shock receiving catecholamine vasopressors and vasopressin. Patients were analyzed according to vasopressin dose received: standard dose (≤0.04 U/min) and high dose (>0.04 U/min). The primary outcome was percentage change in norepinephrine equivalent (NEQ) dose.. A total of 182 patients were included in the analysis, with 136 in the standard-dose vasopressin group and 46 in the high-dose vasopressin group. There was no difference in percentage change in NEQ dose at 6 hours after standard- or high-dose vasopressin attainment (-28.6% vs -19.1%;. This represents the first analysis comparing standard and higher doses of vasopressin in obese patients with septic shock. Receipt of high-dose vasopressin was not associated with a difference in catecholamine requirement or improved outcomes. Further studies are warranted to provide guidance on the use of high-dose vasopressin in septic shock.

Topics: Adult; Hemodynamics; Humans; Norepinephrine; Obesity; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Adrenergic beta-Antagonists; Amputation, Surgical; Cefepime; Child; Clindamycin; Debridement; Diagnosis, Differential; Epinephrine; Fasciotomy; Female; Fluid Therapy; Humans; Hypertension; Ischemia; Leg; Norepinephrine; Propranolol; Shock, Septic; Tachycardia; Therapeutic Irrigation; Treatment Outcome; Vasopressins

Topics: Adult; Blood Pressure; Cohort Studies; Creatinine; Female; Heart Rate; Humans; Intensive Care Units; Lactic Acid; Length of Stay; Male; Middle Aged; Norepinephrine; Proportional Hazards Models; Retrospective Studies; Shock, Hemorrhagic; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Positive hemodynamic response to vasopressin after 6 hours of infusion was independently associated with lower mortality in a previous retrospective study of patients with septic shock. However, factors previously associated with higher plasma vasopressin concentration were not associated with response, and the relationship between plasma vasopressin concentration and hemodynamic response has not been evaluated.. This cross-sectional study compared plasma vasopressin concentrations in hemodynamic responders and nonresponders to vasopressin in patients with septic shock to evaluate plasma vasopressin concentration as a therapeutic target for hemodynamic response to vasopressin.. Adult patients with septic shock were included if they were treated with fixed-dose vasopressin as an adjunct to catecholamines for at least 3 hours. Patients were assigned to groups based on vasopressin response.. Ten hemodynamic responders to vasopressin and eight nonresponders were included. Blood samples for plasma vasopressin concentration were collected 3-6 hours after vasopressin initiation. Baseline characteristics were similar between groups. No difference was detected in plasma vasopressin concentrations between hemodynamic responders and nonresponders (median 88.6 pg/ml [interquartile range (IQR) 84.4-107.5 pg/ml] vs 89.9 pg/ml [IQR 67.5-157.4 pg/ml], p=0.79, respectively). We also did not detect a difference between groups after correcting for vasopressin dose; median vasopressin plasma concentration per 0.01 units/minute of vasopressin infusion for responders was 25.9 pg/ml (IQR 21.8-31.8 pg/ml) versus 29.5 pg/ml (IQR 23.0-57.5 pg/ml, p=0.48) for nonresponders. No difference in clinical outcomes was detected between groups. The findings were robust to multiple sensitivity analyses.. This study does not support the use of plasma vasopressin concentrations as a therapeutic target to predict hemodynamic response to exogenous vasopressin in septic shock.

Topics: Case-Control Studies; Cross-Sectional Studies; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

To determine the cost-effectiveness of escalating doses of norepinephrine or norepinephrine plus the adjunctive use of vasopressin or angiotensin II as a second-line vasopressor for septic shock.. Decision tree analysis was performed to compare costs and outcomes associated with norepinephrine monotherapy or the two adjunctive second-line vasopressors. Short- and long-term outcomes modeled included ICU survival and lifetime quality-adjusted-life-years (QALY) gained. Costs were modeled from a payer's perspective, with a willingness-to-pay threshold set at $100,000/unit gained. One-way (tornado diagrams) and probabilistic sensitivity analyses were performed.. Adjunctive vasopressin was the most cost-effective therapy, and dominated both norepinephrine monotherapy and adjunctive angiotensin II by producing higher ICU survival at less cost. For the lifetime horizon, while norepinephrine monotherapy was least expensive, adjunctive vasopressin was the most cost-effective with an incremental cost-effectiveness ratio of $19,762 / QALY gained. Although adjunctive angiotensin II produced more QALYs compared to norepinephrine monotherapy, it was dominated in the long-term evaluation by second-line vasopressin. Sensitivity analyses demonstrated model robustness and medication costs were not significant drivers of model results.. Vasopressin is the most cost-effective second-line vasopressor in both the short- and long-term evaluations. Vasopressor price is a minor contributor to overall cost.

Topics: Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Norepinephrine; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Shock, Septic; United States; Vasoconstrictor Agents; Vasopressins

Mortality rate for septic shock, despite advancements in knowledge and treatment, remains high. Treatment includes administration of broad-spectrum antibiotics and stabilization of the mean arterial pressure (MAP) with intravenous fluid resuscitation. Fluid-refractory shock warrants vasopressor initiation. There is a paucity of evidence regarding the timing of vasopressor initiation and its effect on patient outcomes.. This retrospective, single-centered, cohort study included patients with septic shock from January 2017 to July 2017. Time from initial hypotension to vasopressor initiation was measured for each patient. The primary outcome was 30-day mortality.. Of 530 patients screened,119 patients were included. There were no differences in baseline patient characteristics. Thirty-day mortality was higher in patients who received vasopressors after 6 h (51.1% vs 25%, p < .01). Patients who received vasopressors within the first 6 h had more vasopressor-free hours at 72 h (34.5 h vs 13.1, p = .03) and shorter time to MAP of 65 mmHg (1.5 h vs 3.0, p < .01).. Vasopressor initiation after 6 h from shock recognition is associated with a significant increase in 30-day mortality. Vasopressor administration within 6 h was associated with shorter time to achievement of MAP goals and higher vasopressor-free hours within the first 72 h.

Topics: Aged; Arterial Pressure; Cost-Benefit Analysis; Fluid Therapy; Health Care Costs; Humans; Hypotension; Norepinephrine; Quality-Adjusted Life Years; Resuscitation; Retrospective Studies; Shock, Septic; Time-to-Treatment; Vasoconstrictor Agents; Vasopressins

Topics: Angiotensin II; Humans; Shock; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Peri-intubation cardiac arrest and hypotension in patients with septic shock occur often in the emergency department (ED) and ultimately lead to worse clinical outcomes. In recent years, the use of push-dose, or bolus-dose, vasopressors in the ED have become common practice for transient hypotension and bridging to continuous infusion vasopressors. Push-dose epinephrine and phenylephrine are the agents used most frequently in this scenario.. A 63-year-old woman who was apneic and pulseless presented to our ED. After 4 min of cardiopulmonary resuscitation, spontaneous circulation was achieved, and the patient was intubated for airway protection. She became hypotensive with a blood pressure of 55/36 mm Hg. After receiving a 1-L bolus of lactated Ringer solution, she remained hypotensive with blood pressure of 80/51 mm Hg and a pulse of 129 beats/min. One unit of intravenous vasopressin push bolus was administered. Within 1 min, her hemodynamics improved to a blood pressure of 141/102 mm Hg and pulse of 120 beats/min. Over the next 2 h, her mean arterial pressure slowly and progressively declined from 120 to 80. No further vasoactive medications were required for approximately 120 min until norepinephrine and vasopressin was initiated for septic shock. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case report discusses the use of push-dose vasopressin as an alternate vasoactive medication to improve hemodynamics in a patient with vasodilatory septic shock.

Topics: Drug Therapy, Combination; Emergency Service, Hospital; Female; Humans; Hypotension; Middle Aged; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Epinephrine; Humans; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Neoplasms; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Neoplasms; Norepinephrine; Shock, Septic; Vasopressins

Guidance for the discontinuation of vasopressors in the recovery phase of septic shock is limited. Norepinephrine is more easily titrated; however, septic shock is a vasopressin deficient state, which exogenous vasopressin endeavors to resolve. Discontinuation of vasopressin before norepinephrine may result in clinically significant hypotension.. This retrospective, cohort study compared discontinuation of norepinephrine and vasopressin in medically, critically ill patients in the recovery phase of septic shock from May 2014 to June 2016. Difference in clinically significant hypotension after norepinephrine or vasopressin discontinuation was evaluated with χ. Vasopressin was discontinued first or last in 62 and 92 patients, respectively. Sequential Organ Failure Assessment scores at 72 hours (7.9 vs 7.6,. Adult patients receiving norepinephrine and vasopressin in the resolving phase of septic shock may be less likely to develop clinically significant hypotension if vasopressin is the final vasopressor discontinued.

Topics: Aged; Critical Care; Drug Administration Schedule; Female; Humans; Intensive Care Units; Male; Middle Aged; Norepinephrine; Organ Dysfunction Scores; Retrospective Studies; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Vasopressors such as norepinephrine are first line for support of mean arterial pressure (MAP) in the management of septic shock. Their use, however, is commonly associated with many adverse events. These detriments frequently trigger the use of alternative, noncatecholamine therapies, including vasopressin. Vasopressin deficiency is a known physiologic consequence of septic shock, and while guidelines recommend vasopressin in addition to norepinephrine, no consensus exists on the duration of deficiency or ideal time of cessation. Studies have suggested that vasopressin discontinuation prior to other vasopressors may lead to hypotension; however, data are limited. This study evaluates the optimal sequence for the discontinuation of vasopressin therapy in septic shock.. This was a 1-year retrospective study of 152 patients admitted to the medical intensive care unit (ICU) with septic shock who received concurrent norepinephrine and vasopressin for vasoactive support. Patients were excluded if death occurred on vasopressors, within 24 hours after discontinuation of vasopressors, or within 48 hours of ICU admission. The primary outcome of hemodynamic instability included incidence of hypotension after vasopressor discontinuation (2 consecutive MAPs < 60 mm Hg), fluid bolus administration, greater than 0.05 μg/kg/min increase in norepinephrine requirements, or addition of an alternative vasopressor. Secondary outcomes included time to hypotension, total vasopressor duration, arrhythmias, mortality, and length of stay.. Ninety-one patients met exclusion criteria, resulting in 61 patients for evaluation. Vasopressin was the first vasoactive therapy to be discontinued in 19 patients and last in 42 patients. Baseline characteristics and the use of potentially confounding treatments known to effect MAP were similar between groups. Discontinuation of vasopressin first was associated with a significant increase in hemodynamic instability (74% vs 16.7%,. Vasopressin discontinuation prior to cessation of norepinephrine infusion was associated with an increased risk of hemodynamic instability.

Topics: Critical Care; Female; Hemodynamics; Humans; Hypotension; Male; Middle Aged; Norepinephrine; Outcome and Process Assessment, Health Care; Retrospective Studies; Shock, Septic; United States; Vasoconstrictor Agents; Vasopressins; Withholding Treatment

Despite international guidelines, regional differences in treatment of vasodilatory shock remain. We characterized these differences using data from Angiotensin II in High Output Shock (ATHOS-3) trial.. The 321 patients treated in the ATHOS-3 trial were included. Baseline and hour-48 data were analyzed for differences in demographics, clinical characteristics, and treatment patterns, and grouped into four geographical areas: United States, Canada, Europe, and Australasia. Differences were analyzed by Kruskal-Wallis tests for continuous, and chi-square tests for categorical data. Temporal analysis compared changes in the treatment of shock during the treatment period.. Differences in baseline characteristics across geographic areas were noted in BMI, albumin, CVP, MELD score, APACHE II score, and total SOFA score. Baseline norepinephrine and norepinephrine equivalent doses (NED) were higher (p < .0001 and p = .0494, respectively), and vasopressin use was lower (p < .0001) in Europe. Baseline steroids were utilized more in the US and Canada (p = .0011).. Management of vasodilatory shock differs globally with respect to utilization of steroids and vasopressors. This practice heterogeneity may influence shock trials interpretation and patient outcomes, though more definitive evidence would require larger prospective intervention data.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Angiotensin II; Australia; Canada; Chi-Square Distribution; Europe; Female; Humans; Male; Middle Aged; Neurophysins; Norepinephrine; Prospective Studies; Protein Precursors; Retrospective Studies; Shock; Shock, Septic; United States; Vasoconstrictor Agents; Vasopressins; Young Adult

Topics: Hemodynamics; Humans; Infusions, Intravenous; Shock, Septic; Substance Withdrawal Syndrome; Vasoconstrictor Agents; Vasopressins

Topics: Cohort Studies; Epinephrine; Female; Humans; Male; Middle Aged; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Catheter-Related Infections; Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The specific norepinephrine dose at which epinephrine should be added in septic shock is unclear. This study sought to determine the norepinephrine-equivalent dose at epinephrine initiation that correlated with hemodynamic stability.. Septic shock patients receiving both norepinephrine and epinephrine were included in this study. Classification and regression tree analysis was conducted to determine breakpoints in norepinephrine-equivalent dose predicting hemodynamic stability, with two cohorts identified. The primary outcome was hemodynamic stability, and secondary outcomes were shock-free survival, time to achieve hemodynamic stability, and change in SOFA score.. Optimal dose group was identified as initiating epinephrine when norepinephrine-equivalent dose was between 37 and 133 μg/min. A total of 138 and 61 patients were classified in optimal and non-optimal dose groups, respectively. Baseline characteristics were similar between groups except vasopressin use was more frequent in the optimal dose group. More patients in optimal dose group versus non-optimal dose group achieved hemodynamic stability (40 [29%] vs. 9 [14.8%]), absolute risk difference 14.2% [95% CI 2.5-25.9%]; p = .03). On multivariable analysis, initiating epinephrine within the optimal norepinephrine-equivalent dose range was independently associated with higher odds of hemodynamic response (OR 3.06 [95% CI 1.2-7.6]; p = .02). No differences were observed in other secondary outcomes.. Initiation of epinephrine when patients were receiving norepinephrine-equivalent doses of 37-133 μg/min was associated with a higher rate of hemodynamic stability.

Topics: Aged; Drug Therapy, Combination; Epinephrine; Female; Hemodynamics; Humans; Male; Middle Aged; Neurophysins; Norepinephrine; Protein Precursors; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is commonly used as an adjunct vasopressor in shock. However, response to vasopressin varies among critically ill patients.. To identify patient-specific factors that are associated with vasopressin responsiveness in critically ill adults.. This retrospective, multicenter study included adult patients who were admitted to an intensive care unit (ICU) and received vasopressin for shock. Patients were excluded if they received vasopressin for less than 30 minutes, if vasopressin was initiated prior to ICU arrival, or if an additional vasopressor was initiated within 30 minutes of starting vasopressin. Responsiveness was defined as an increase in mean arterial pressure of ≥10 mm Hg or the ability to taper a concurrent catecholamine vasopressor. Patient-specific factors evaluated in a multivariate analysis included age, gender, ethnicity, body mass index, type of shock, serum pH, Sequential Organ Failure Assessment (SOFA) score, and use of stress-dose steroids. These variables were also evaluated in a subgroup analysis of patients with septic shock.. Of 1619 patients screened, 400 patients were included, with 231 identified as vasopressin responsive and 169 as nonresponsive. Vasopressin used as an adjunct vasopressor, as opposed to first line, during shock was the only variable associated with vasopressin responsiveness (odds ratio [OR] = 1.71; 95% CI = 1.10 to 2.65). Among the subgroup of patients with septic shock, female patients had a higher odds of responding than male patients (OR = 2.10; 95% CI = 1.12 to 3.95).. Vasopressin initiated as an adjunct vasopressor, as opposed to first-line therapy, was associated with response.

Topics: Aged; Arterial Pressure; Critical Illness; Female; Humans; Intensive Care Units; Male; Middle Aged; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Despite widespread use of vasopressin for the treatment of septic shock, few cases of diabetes insipidus (DI) following its discontinuation have been reported.. A 54-year-old man presented with pneumonia progressing to septic shock, requiring norepinephrine and vasopressin for refractory hypotension. After clinical improvement, the patient on 3 separate occasions developed polyuria and severe hypernatremia upon discontinuation of vasopressin, with prompt recovery upon its resumption.. Occurrence of DI upon discontinuation of vasopressin infusion appears to be rare, but incidence may be underestimated due to a paucity of published reports. Actual incidence and underlying mechanism of this phenomenon remain to be elucidated.

Topics: Diabetes Insipidus; Humans; Male; Middle Aged; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Norepinephrine; Shock; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The effect of patient weight and body mass index (BMI) on hemodynamic response to vasoactive medications is not fully understood. In titratable vasopressors, this effect is less likely a concern due to the ability to titrate dose to response; however, with the use of fixed-dose vasopressin, patient weight and BMI may impact response.. This was a single-center, retrospective cohort of patients who received fixed-dose vasopressin for septic shock for at least 6 h with concomitant catecholamines in the medical, surgical, or neurosciences intensive care unit (ICU) at a tertiary care center. The association of weight- and BMI-adjusted vasopressin dose with change in catecholamine dose and change in mean arterial pressure (MAP) were evaluated using Spearman's correlation. Patients were further stratified by World Health Organization BMI categories to evaluate secondary outcomes.. There were 938 patients included with a median weight of 86.3 (70.6-106.6) kg and BMI of 29.5 (24.9-36.2) kg/m. There was no correlation between weight-adjusted vasopressin dose and change in catecholamine dose (r = -0.05, P = 0.13) or change in MAP (r = 0.04, P = 0.31) 2 h after initiation of vasopressin. Similarly, no correlation was found when evaluating change in catecholamine dose or MAP at 6 and 12 h after vasopressin initiation (all P values >0.05). Comparable findings were observed when evaluating correlations between BMI-adjusted vasopressin dose with change in MAP and catecholamine dose at all time points (all P values >0.05). BMI groupings were balanced with 238 patients (25.4%) having a BMI less than 25, 254 patients (27.1%) having BMI 25 to 30, 182 patients (19.4%) having BMI 30 to 35, and 264 patients (28.1%) having BMI more than 35. The median duration of mechanical ventilation and ICU free days were 3.99 (1.50-5.07) and 0 (0-1.6) days, respectively, with no differences observed when stratified by BMI (P = 0.59 and P = 0.83, respectively). In-hospital mortality was 64.8% and there was no difference among BMI groups (P = 0.35).. In this large cohort of septic shock patients, adjusting vasopressin dose for weight and BMI did not impact changes in catecholamine doses or MAP. Duration of mechanical ventilation, ICU free days, and mortality after vasopressin initiation were not affected by BMI.

Topics: Aged; Body Mass Index; Catecholamines; Female; Hemodynamics; Hospital Mortality; Humans; Male; Middle Aged; Retrospective Studies; Shock, Septic; Vasopressins

Patients with septic shock often require vasoactive agents for hemodynamic support; however, the optimal approach to discontinuing these agents once patients reach the recovery phase is currently unknown. The objective of this evaluation was to compare the incidence of hypotension within 24 hours based on the discontinuation order of norepinephrine (NE) and vasopressin (AVP) in patients in the recovery phase of septic shock.. Retrospective cohort study.. The medical, surgical, and neurosciences intensive care units (ICUs) at a large tertiary care academic medical center.. A total of 585 adults in the recovery phase of septic shock who received fixed-dose AVP for at least 6 hours as an adjunct to NE between September 2011 and August 2015 were included. Of these patients, 155 had AVP discontinued first, and 430 had NE discontinued first.. Hypotension was evaluated during the 24-hour period after discontinuation of the first vasoactive agent and was defined as mean arterial pressure less than 60 mm Hg with one or more of the following interventions: increased remaining vasoactive agent dose by 25%, reinstitution of the discontinued agent, or administration of at least 1 L of fluid bolus. Time to hypotension was evaluated with survival analysis, and risk of hypotension was evaluated with multivariable Cox proportional hazards regression. No significant difference between groups was noted in the incidence of hypotension within 24 hours (55% in the AVP discontinued first group vs 50% in the NE discontinued first group, p=0.28) or ICU mortality (45.2% vs 40.0%, p=0.26). After adjustment for baseline factors with multivariable Cox proportional hazards regression, having AVP discontinued first was independently associated with an increased risk of hypotension with a time-varying effect that decreased over time (HR(t) = e. In patients recovering from septic shock treated with concomitant AVP and NE, no significant difference was noted in the incidence of hypotension based on discontinuation order of these agents.

Topics: Academic Medical Centers; Aged; Cohort Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypotension; Incidence; Intensive Care Units; Male; Middle Aged; Norepinephrine; Proportional Hazards Models; Retrospective Studies; Shock, Septic; Time Factors; Vasoconstrictor Agents; Vasopressins

Postoperative vasoplegic shock after cardiac surgery seems to be a frequent complication with poor outcomes. We hypothesized that vasopressin may increase the risk of poor outcomes in patients with preoperative Left Ventricular Dysfunction (pLVD) rather than norepinephrine. The aim of this study was to assess whether vasopressin is superior to norepinephrine to improve outcomes in patients with pLVD after cardiac surgery.. This retrospective cohort study included 1,156 patients with postoperative vasoplegic shock (mean arterial pressure <65 mmHg resistant to fluid challenge and cardiac index >2.20 L/min m) and pLVD (left ventricular ejection fraction ≤35%, left ventricular end-diastolic diameter ≥60 mm, New York Heart Association ≥III) from 2007 to 2017. To address any indicated biases, we derived a propensity score predicting the functions of vasopressin (0.02-0.07 U/min) and norepinephrine (10-60 μg/min) on postoperative vasoplegic shock. The primary outcomes were 30-day mortality, mechanical ventilation more than 48 h, cardiac reoperation, extracorporeal membrane oxygenation, stroke, and acute kidney injury, whereas the secondary outcomes included infection, septic shock, atrial fibrillation and ventricular arrhythmias.. There were 338 patients (169 vasopressin and169 norepinephrine) with a similar risk profile in propensity score-matched cohort. In propensity-matched patients, the primary outcomes of vasopressin and norepinephrine showed no significant difference (50.89% vs. 58.58%, P = 0.155). However, compared with norepinephrine, secondary outcomes of vasopressin were increased due to the high rate of atrial fibrillation (11.83% vs. 20.12%, P = 0.038) and ventricular arrhythmias (14.20% vs. 24.85%, P = 0.014).. Compared with norepinephrine, vasopressin could not improve the postoperative outcomes in patients with pLVD after cardiac surgery. Vasopressin should be cautious to be used as a first-line vasopressor agent in postcardiac vasoplegic shock.

Topics: Aged; Cardiac Surgical Procedures; Female; Humans; Male; Middle Aged; Norepinephrine; Propensity Score; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins; Ventricular Dysfunction, Left

There is little data guiding clinicians on how to discontinue vasopressors among septic shock patients on concomitant norepinephrine (NE) and vasopressin (VP).. To determine the incidence of hypotension within 24 hours of discontinuing NE (NE DC first) versus VP (VP DC first) first in septic shock patients.. This retrospective study evaluated septic shock patients admitted to the medical intensive care unit (MICU) and surgical ICU (SICU) receiving concomitant NE and VP. Receipt of additional vasopressors, mixed shock states, expired or care withdrawn, and NE and VP discontinued simultaneously were exclusion criteria. The primary outcome was incidence of hypotension within 24 hours of first vasopressor discontinuation. Secondary outcomes included time to hypotension, hospital length of stay (LOS), ICU LOS, and ICU mortality.. A total of 80 patients were included (NE DC first [n = 35]; VP DC first [n = 45]), with a median age of 73 years and median modified Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores of 21 and 7, respectively. More patients in the NE DC first group were in the SICU (42.9% vs 20.0%; P = 0.048) with more intra-abdominal infections (40.0% vs 15.6%; P = 0.021) and fewer appropriate empirical antibiotics (62.9% vs 86.7%; P = 0.018). Hypotension within 24 hours of first agent discontinuation was higher in the VP DC first group (28.6% vs 62.2%; P = 0.004), with similar hospital LOS and ICU mortality. Multivariate analysis identified VP DC first as an independent predictor of hypotension (odds ratio = 7.2; CI = 2.3-22.7).. Among septic shock patients on concomitant NE and VP, discontinuation of VP first was associated with an increased incidence of hypotension; future prospective control trials are warranted.

Topics: Aged; Aged, 80 and over; Drug Therapy, Combination; Female; Humans; Hypotension; Incidence; Intensive Care Units; Male; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The Surviving Sepsis Guidelines suggest the use of vasopressin in case of catecholamine-refractory septic shock. Terlipressin (TP) as a V

Topics: Animals; Catecholamines; Hemodynamics; Kidney; Norepinephrine; Peritoneal Lavage; Sheep, Domestic; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

RCTs in septic shock negative for mortality may show organ dysfunction benefits. We hypothesized that RCTs in septic shock show significant differences between treatment groups in organ support despite no mortality differences.. RCTs of epinephrine vs. norepinephrine plus dobutamine, norepinephrine vs. dopamine and vasopressin vs. norepinephrine reported days alive and free ("DAF") of vasopressors, ventilation and RRT, by subtracting days with support from the lesser of 28 or days to death. We also assigned zero DAF to non-survivors ("DAF and Mortality") and calculated the composite "DAF vasopressors, ventilation and RRT".. Using "DAF", norepinephrine was better than dopamine for vasopressors. In contrast, using "DAF and Mortality", norepinephrine was better than dopamine for vasopressors, ventilation and RRT; norepinephrine + dobutamine was better than epinephrine for ventilation. Using the novel composite "DAF vasopressors, ventilation and RRT", norepinephrine + dobutamine was better than epinephrine (p = 0.033), norepinephrine better than dopamine (p = 0.03), and vasopressin better than norepinephrine in less severe shock (p = 0.03).. Differences between treatment groups in organ dysfunction in RCTs in septic shock occur despite lack of mortality differences depending on calculation method. If standardized and validated further, DAF could become the primary endpoint of RCTs in septic shock.

Topics: Clinical Trials as Topic; Dobutamine; Dopamine; Epinephrine; Humans; Neurophysins; Norepinephrine; Protein Precursors; Randomized Controlled Trials as Topic; Shock; Shock, Septic; Time Factors; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Low-dose steroids may reduce the mortality of severely ill patients with septic shock. We sought to determine whether exposure to stress-dose steroids during and/or after cardiopulmonary resuscitation is associated with reduced risk of death due to postresuscitation septic shock.. We analyzed pooled, individual patient data from two prior, randomized clinical trials (RCTs). RCTs evaluated vasopressin, steroids, and epinephrine (VSE) during resuscitation and stress-dose steroids after resuscitation in vasopressor-requiring, in-hospital cardiac arrest. In the second RCT, 15 control group patients received open-label, stress-dose steroids. Patients with postresuscitation shock were assigned to a Steroids (n = 118) or No Steroids (n = 73) group according to an "as-treated" principle. We used cumulative incidence competing risks Cox regression to determine cause-specific hazard ratios (CSHRs) for pre-specified predictors of lethal septic shock (primary outcome). In sensitivity analyses, data were analyzed according to the intention-to-treat (ITT) principle (VSE group, n = 103; control group, n = 88).. Lethal septic shock was less likely in Steroids versus No Steroids group, CSHR, 0.40, 95% confidence interval (CI), 0.20-0.82; p = 0.012. ITT analysis yielded similar results: VSE versus Control, CSHR, 0.44, 95% CI, 0.23-0.87; p = 0.019. Adjustment for significant, between-group baseline differences in composite cardiac arrest causes such as "hypotension and/or myocardial ischemia" did not appreciably affect the aforementioned CSHRs.. In this reanalysis, exposure to stress-dose steroids (primarily in the context of a combined VSE intervention) was associated with lower risk of postresuscitation lethal septic shock.

Topics: Aged; Cardiopulmonary Resuscitation; Drug Combinations; Epinephrine; Female; Heart Arrest; Humans; Male; Middle Aged; Patient Admission; Protective Factors; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Shock, Septic; Steroids; Time Factors; Treatment Outcome; Vasopressins

Topics: Humans; Shock, Septic; Vasopressins

The objective of this study was to evaluate the short-term hemodynamic effects as well as vasopressor requirements with concomitant vasopressin (AVP) and hydrocortisone (HCT) compared to either agent alone in refractory septic shock.. This was a retrospective, cohort study conducted in adult septic shock patients. Patients received continuous infusion AVP at 0.04units/min and/or HCT 200-300mg intravenous daily in divided doses for refractory septic shock. Refractory septic shock was defined as systolic or mean blood pressure (MAP) of <90mmHg or <70mmHg, respectively, despite fluid resuscitation and requiring norepinephrine.. A total of 300 patients were evaluated. The rate of achieving a "response" (norepinephrine dose reduction by ≥50% without any decrease in MAP) at 4h from baseline was significantly higher in patients receiving concomitant AVP/HCT (88.5%) compared to HCT alone (62.3%) or AVP alone (72.9%) (p=0.0005). The AVP/HCT group had higher "response" rates over the HCT and AVP monotherapy groups at 12 (p=0.052) and 24h (p=0.036). Multivariate regression showed combination therapy to be independently associated with response at 4h.. Concomitant AVP and HCT was associated with an immediate, additive catecholamine-sparing effect over either agent alone in patients with refractory septic shock.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hydrocortisone; Male; Middle Aged; Retrospective Studies; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

To compare the hemodynamic response in septic shock patients receiving vasopressin who were on chronic renin-angiotensin-aldosterone system inhibitor therapy with those who were not.. Single-center, retrospective cohort study.. Medical and surgical ICUs at a 1,100-bed academic medical center.. Medical and surgical ICU patients with septic shock who received vasopressin infusion added to at least one concomitant vasopressor agent between January 2014 and December 2015, then divided into two cohorts: 1) patients who were on chronic renin-angiotensin-aldosterone system inhibitor therapy as outpatients and 2) patients who were not on chronic renin-angiotensin-aldosterone system inhibitor therapy as outpatients.. None.. Mean arterial pressure at 6 hours was 72.2 mm Hg in the renin-angiotensin-aldosterone system inhibitor group versus 69.7 mm Hg in the non-renin-angiotensin-aldosterone system inhibitor group (p = 0.298). There was no difference in mean arterial pressure at 1, 24, or 48 hours between groups. Total concomitant vasopressor requirements, based on norepinephrine equivalents excluding vasopressin, were significantly lower at 24 hours in the renin-angiotensin-aldosterone system inhibitor group versus the non-renin-angiotensin-aldosterone system inhibitor group (10.7 vs 18.1 µg/min, respectively; p = 0.007), but no significant differences were seen at the other time points assessed. There were no significant differences in ICU or hospital length of stay or mortality.. There was no significant difference in the primary outcome of 6-hour mean arterial pressure in septic shock patients receiving vasopressin who were on chronic renin-angiotensin-aldosterone system inhibitor therapy versus those receiving vasopressin who were not on chronic renin-angiotensin-aldosterone system inhibitor therapy. Renin-angiotensin-aldosterone system inhibitor patients had lower total concomitant vasopressor requirements at 24 hours compared with non-renin-angiotensin-aldosterone system inhibitor patients.

Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Agents; Dose-Response Relationship, Drug; Female; Hospital Mortality; Humans; Infusions, Intravenous; Length of Stay; Male; Middle Aged; Renin-Angiotensin System; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

In this article, we present a clinical case of refractory septic shock resulting from intestinal perforation treated with high doses of vasopressin and hydrocortisone during emergency surgery. The use of such high doses of vasopressin for this type of shock is not described in the literature.. A 49-year-old white woman with grade III obesity, Crohn's disease, and an intestinal perforation presented with refractory septic shock. Initially, a low dose of vasopressin was used. Then, the dosage was increased to 0.4 U/minute; in the literature, this is defined as "salvage therapy." This therapy consists of an initial load followed by a continuous infusion of hydrocortisone.. The significant increase in her cardiac index and stroke volume index resulted in an improvement in peripheral resistance, gas exchange, and urine output and a decrease in her heart rate, interleukin-6 level, and tumor necrosis factor-α level. The administration of high doses of vasopressin and corticosteroids was demonstrated to be safe for the immune system, to reduce the systemic inflammatory response, and to have direct cardiovascular effects. Further studies are required to examine the use of vasopressin as an initial vasopressor as well as its use in high dosages and in combination with corticosteroids.

Topics: Acute Disease; Anti-Inflammatory Agents; Crohn Disease; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Ileocecal Valve; Intestinal Perforation; Middle Aged; Obesity, Morbid; Shock, Septic; Tomography, X-Ray Computed; Vasoconstrictor Agents; Vasopressins

We aim to identify the appropriate vasoactive agent in patients with septic shock who are refractory to optimal doses of norepinephrine.. In this retrospective observational cohort study over a 4-year period, patients who received norepinephrine within 24 hours of ICU admission and a second agent within 48 hours were enrolled.. Among 2640 patients screened, 234 patients were enrolled, aged 60.8 ± 17.8 years, Acute Physiology and Chronic Health Evaluation IV 98.3 ± 27.5, 81.6% mechanically ventilated, and 65.8% in-hospital mortality. Within 96 hours, 2.8 ± 1.0 vasoactive agents were administered. Fifty, 50, 66, and 68 patients received dobutamine, dopamine, phenylephrine, and vasopressin as the second agent, with crude in-hospital mortality 40.0%, 66.0%, 74.2%, and 76.5%, respectively, P < .001. Survival analysis showed a statistically significant difference in survival time by second vasoactive agent, P < .001. After adjusting for confounding variables, dobutamine showed significant decreased odds ratio (OR) for mortality compared to vasopressin: OR 0.34 (95% confidence interval 0.14-0.84, P = .04). The relative risk of dying was 55.8% lower in patients receiving dobutamine versus vasopressin, P < .01.. Dobutamine is associated with decreased mortality compared to other second vasoactive agents in septic shock when norepinephrine is not sufficient. A prospective randomized trial examining the outcome impact of the second vasoactive agent is needed.

Topics: Aged; Comparative Effectiveness Research; Dobutamine; Dopamine; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Male; Middle Aged; Norepinephrine; Phenylephrine; Retrospective Studies; Shock, Septic; Survival Analysis; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

In septic shock, the dose of norepinephrine (NE) at which vasopressin (AVP) should be added is unknown. Following an increase in AVP price, our medical intensive care unit (MICU) revised its vasopressor guidelines to reserve AVP for patients requiring greater than 50 µg/min of NE.. The purpose of this study is to compare efficacy and safety outcomes for patients admitted before the guideline revision with those for patients admitted after the revision.. This was a single-center, retrospective cohort study of patients admitted to Vanderbilt University Medical Center from November 1, 2014, to November 30, 2015. Before June 1, 2015, the vasopressor guidelines recommended initiation of AVP for patients requiring 10 µg/min of NE or greater. After June 1, 2015, the guidelines recommended initiation of AVP at a NE dose of 50 µg/min or greater.. Time to achieve goal mean arterial pressure (MAP) was shorter in the postintervention group (2.0 vs 1.3 hours; P = 0.03) in univariate analysis but not after adjusting for prespecified confounders. Incidence of new arrhythmias was similar between the 2 groups (14.9% vs 10.9%; P = 0.567). In multivariable analysis accounting for baseline severity of illness, admission after the revision was associated with decreased 28-day mortality (odds ratio = 0.34; 95% CI = 0.16-0.71; P = 0.004).. Use of a vasopressor guideline restricting AVP initiation in septic patients to those on at least 50 µg/min of NE appeared to be safe and did not affect the time to reach goal MAP.

Topics: Aged; Arrhythmias, Cardiac; Arterial Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Incidence; Intensive Care Units; Male; Middle Aged; Norepinephrine; Practice Guidelines as Topic; Retrospective Studies; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Takayasu arteritis, also known as "pulseless disease," causes proximal occlusion of the lumen of large arteries of the neck and arm, leading to impalpable pulses and "pseudohypotension." This may misdirect the management plan for a patient in the emergency setting if the presence of vascular occlusion is not previously known.. We describe a young woman who presented to the emergency department (ED) with fever. On evaluation, she had shock, which was not responsive to a fluid bolus. Bedside Rapid Diagnostic Test was positive for Plasmodium vivax, and a diagnosis of severe vivax malaria was made. She was started on intravenous artesunate and vasopressors in view of her persistent hypotension in the face of a normal central venous pressure. A thorough examination at that time revealed palpable lower limb pulses with feeble upper limb pulses. Vasopressors were tapered while monitoring lower limb blood pressure. Computed tomographic angiogram confirmed the diagnosis of Takayasu arteritis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Hypotension and shock are regularly encountered in the ED. Occlusive arterial disease involving upper limbs can mimic refractory shock, leading to potentially harmful and unnecessary interventions. Emergency physicians should be aware of this possibility. A simple routine of quickly checking all peripheral pulses would help them avoid this pitfall.

Topics: Adult; Anti-Bacterial Agents; Antimalarials; Artemisinins; Artesunate; Ceftriaxone; Drug Combinations; Female; Humans; Malaria, Vivax; Norepinephrine; Plasmodium vivax; Primaquine; Pyrimethamine; Shock, Septic; Sulfadoxine; Takayasu Arteritis; Vasoconstrictor Agents; Vasopressins

Topics: Arginine Vasopressin; Humans; Norepinephrine; Shock; Shock, Septic; Vasoconstrictor Agents; Vasodilation; Vasopressins

Selective vasopressin V(1A) receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V(1A) receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model.. Randomized animal study.. University hospital animal research laboratory.. Forty-six adult female sheep.. Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 μg]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70-80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours.. In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals.. In this clinically relevant model, selepressin, a selective V(1A) receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early.

Topics: Animals; Arginine Vasopressin; Female; Norepinephrine; Random Allocation; Receptors, Vasopressin; Sheep; Sheep Diseases; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Arginine Vasopressin; Female; Norepinephrine; Receptors, Vasopressin; Sheep Diseases; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Fixed-dose vasopressin is an adjunctive therapy to norepinephrine (NE) to raise mean arterial pressure (MAP) and decrease NE requirements in patients with septic shock. It is unknown if weight affects hemodynamic response to vasopressin or if a weight-based vasopressin strategy is superior to fixed dosing.. The primary objective was to evaluate effect of body weight on response to vasopressin as measured by change in MAP 1 hour post-vasopressin initiation.. A single-center, retrospective study was performed in patients with septic shock. Baseline characteristics, catecholamine and vasopressin requirement, response to therapy, and adverse events were collected.. Forty patients were included who received a fixed-dose vasopressin in addition to catecholamine infusions. No correlation was found in the primary outcome of change in MAP at 1 hour after vasopressin initiation compared with vasopressin dose relative to patient weight or body mass index (BMI). Change in MAP at 6 and 12 hours was not significant. In the obese population (n = 9), there was a significant negative correlation between BMI and change in MAP at 6 hours (correlation coefficient r = -0.951; P = 0.0009). Linear regression analysis confirmed that vasopressin dose relative toweight was independently associated with change in MAP at 1, 6, and 12 hours, whereas changes in NE dosing were not.. Increasing weight-based dosing of vasopressin did not correlate with change in MAP when used with catecholamine vasopressors in septic shock. However, fixed-dose vasopressin may not be sufficient in obese septic shock patients with a BMI ≥30 kg/m(2).

Topics: Arterial Pressure; Body Mass Index; Body Weight; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Obesity; Regression Analysis; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Septic shock is a major cause of death worldwide and a considerable healthcare burden in the twenty-first century. Attention has shifted from damaging effects of the proinflammatory response to the detrimental role of antiinflammation, a phenomenon known as sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis may render patients vulnerable to secondary infections and is associated with impaired outcome. The immunoparalysis hypothesis compels us to reevaluate the current management of septic shock and to assess whether we are inadvertently compromising or altering the host immune response. In this perspective, we discuss the potential detrimental role of norepinephrine, the cornerstone treatment for septic shock, in sepsis-induced immunoparalysis. We provide a short overview of the current understanding of the immunologic pathophysiology of sepsis, followed by a detailed description of the immunomodulatory effects of norepinephrine and alternative vasopressors. We conclude that although the development of novel therapies aimed at reversing immunoparalysis is underway, the use of norepinephrine may aggravate the development, extent, and duration of sepsis-induced immunoparalysis. Current in vitro and animal data indicate that norepinephrine treatment exerts immunosuppressive and bacterial growth-promoting effects and may increase susceptibility toward infections. However, evidence in humans is circumstantial, as immunologic effects of norepinephrine have not been investigated properly in experimental or clinical studies. Alternatives such as vasopressin/selepressin, angiotensin II, and phenylephrine could have a fundamental advantage over norepinephrine with respect to their immunologic properties. However, also for these agents, in vivo immunologic data in humans are largely lacking. As such, human studies on the immunomodulatory properties of norepinephrine and viable alternatives are highly warranted.

Topics: Adjuvants, Immunologic; Humans; Immune System Diseases; Immunocompromised Host; Immunomodulation; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin may be used to treat vasodilatory hypotension in septic shock, but it is not recommended by guidelines as a first- or second-line agent. Little is known about how often the drug is used currently in septic shock.. We conducted this study to describe patterns of vasopressin use in a large cohort of U.S. adults with septic shock and to identify patient and hospital characteristics associated with vasopressin use.. This was a retrospective cohort study of adults admitted to U.S. hospitals with septic shock in the Premier healthcare database (July 2008 to June 2013). We performed multilevel mixed-effects logistic regression with hospitals as a random effect to identify factors associated with use of vasopressin alone or in combination with other vasopressors on at least 1 day of hospital admission. We calculated quotients of Akaike Information Criteria (AIC) to determine relative contributions of patient and hospital characteristics to observed variation.. Among 584,421 patients with septic shock in 532 hospitals, 100,923 (17.2%) received vasopressin. A total of 6.1% of patients receiving vasopressin received vasopressin alone, and 93.9% received vasopressin in combination with other vasopressors (up to five vasopressors in 15 different combinations). The mean monthly rate of vasopressin use increased from 14.5 to 19.6% over the study period, representing an average annual relative increase of 8% (P < 0.001). The median hospital rate of vasopressin use for septic shock was 11.7% (range, 0-69.7%). Patient demographic and clinical characteristics, including patient age (adjusted odds ratio, 0.71 for age > 85 yr compared with the reference group of age < 50 yr; 95% confidence interval, 0.69-0.74) and acute respiratory dysfunction (adjusted odds ratio, 3.25; 95% confidence interval, 3.20-3.31), were responsible for the majority of observed variation in vasopressin use (quotient of AICs, 0.56). However, hospital of admission also contributed substantially to observed variation (quotient of AICs, 0.37).. Approximately one-fifth of patients with septic shock received vasopressin, but rarely as a single vasopressor. The use of vasopressin has increased over time. The likelihood of receiving vasopressin was strongly associated with the specific hospital to which each patient was admitted.

Topics: Aged; Databases, Factual; Drug Therapy, Combination; Drug Utilization; Female; Hospitals; Humans; Hypotension; Logistic Models; Male; Middle Aged; Odds Ratio; Retrospective Studies; Shock, Septic; United States; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Norepinephrine; Renal Insufficiency; Sepsis; Shock, Septic; Vasopressins

Septic shock features a high hospital mortality. Improving our ability to risk stratify these patients at admission may help better define management strategies and design studies. The primary objective of this study was to determine if patients dead or with sustained vasopressor need at day 7 had a relative arginine vasopressin (AVP) deficiency as compared with vasopressor-free patients at day 7. Another objective was to explore if plasma CT-proAVP (C terminal part of preprovasopressin) measured within 24 h of sepsis onset could predict patient severity.. This was a prospective observational study in a medical and surgical intensive care unit. One hundred thirteen patients were included in this analysis: 102 patients with severe sepsis or septic shock and 11 nonseptic controls. The CT-proAVP was measured at three time points within the first week after sepsis onset.. The CT-proAVP measured within 24 h of sepsis onset failed to predict vasopressor need. More importantly, CT-proAVP plasma levels in patients with a sustained need of vasopressors did not differ from vasopressor-free patients at days 1 and 2. The CT-proAVP was more elevated in septic shock as compared with severe sepsis or nonseptic patients. When analyzing 28-day mortality, nonsurvivors featured higher levels of the CT-proAVP compared with survivors.. Patients with septic shock and sustained need of vasopressors do not seem to present a relative AVP deficiency. In sepsis, the subgroup of patients that may benefit from AVP supplementation still needs to be identified. Our study further confirms previous data on the ability of the CT-proAVP to predict patient severity in severe sepsis and septic shock.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Comorbidity; Female; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Prognosis; Prospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Female; Humans; Male; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The objective of this study was to compare the incidence of severe adverse events of vasopressin vs hydrocortisone for endocrine support therapy in patients with septic shock.. This was a retrospective, propensity-matched cohort of patients admitted to the medical intensive care unit with septic shock between February 2012 and February 2015. Patients were included if vasopressin or hydrocortisone was administered for hemodynamic support secondary to norepinephrine.. In the unmatched cohort of 124 patients, vasopressin was associated with a significant decrease in the number of severe adverse events (P=.03). In the matched cohort, severe adverse events occurred 3 times as often in patients receiving hydrocortisone; however, this difference was not statistically significant. (odds ratio, 3.33; 95% confidence interval, 0.92-12.11; P=.06). In the matched cohort, vasopressin was associated with a faster time to hemodynamic stability (P<.05) and discontinuation of hemodynamic support (P<.01) with an increased requirement for third-line therapy (P<.01). No statistical differences were seen in length of stay (intensive care unit and hospital), length of mechanical ventilation, and in-hospital mortality.. Given the lower incidence of adverse events and faster time to hemodynamic stability, vasopressin appears to be the most advantageous endocrine agent for hemodynamic support in septic shock.

Topics: Adrenal Cortex Hormones; Aged; Arginine Vasopressin; Critical Care; Endocrine System; Female; Hemodynamics; Hospital Mortality; Humans; Hydrocortisone; Incidence; Intensive Care Units; Male; Middle Aged; Norepinephrine; Retrospective Studies; Shock, Septic; Vasopressins

Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine β-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock.

Topics: Arginine Vasopressin; Ascorbic Acid; Hemodynamics; Humans; Norepinephrine; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The objective of this study was to determine the effect of early vs late vasopressin therapy on catecholamine dose and duration.. We conducted a single-center, retrospective chart review of adult patients admitted to the medical intensive care unit between January 2010 and December 2011 with septic shock requiring catecholamine and vasopressin therapy. Patients were included in the early group if vasopressin was initiated within 6 hours and the late group if vasopressin was initiated between 6 and 48 hours of catecholamine(s).. Duration of catecholamine and vasopressin therapy was similar between the 35 patients in the early group and the 36 in the late group. Vasopressin therapy was associated with a decrease in catecholamine requirements in both groups. Early vasopressin was associated with fewer new onset arrhythmias (37.1% vs 62.9%, P<.001). There was no difference in mortality, hospital, or intensive care unit length of stay between the early and late group vasopressin groups (88.6% vs 88.9%, P=1; 14 vs 10 days, P=.48; 9 vs 7 days, P=.71, respectively).. Early initiation of vasopressin therapy in adult critically ill patients with septic shock was associated with no difference in total catecholamine requirements but decreased incidence of new onset arrhythmias.

Topics: Aged; Arginine Vasopressin; Arrhythmias, Cardiac; Catecholamines; Critical Illness; Drug Administration Schedule; Female; Hospital Mortality; Humans; Incidence; Intensive Care Units; Male; Middle Aged; Retrospective Studies; Shock, Septic; Vasopressins

Topics: Anti-Inflammatory Agents; Female; Humans; Hydrocortisone; Male; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Restoration of adequate tissue perfusion is the goal of resuscitation in septic shock. A growing understanding of microcirculatory dysfunction in sepsis led to a change in resuscitation practice away from targeting arterial and central venous pressures and towards tissue perfusion-guided protocols. This change in the approach to resuscitation was accompanied by a change in the role of vasoconstrictors. This review summarizes the pathophysiological and therapeutic mainstays of septic shock resuscitation and attempts to critically evaluate the scientific evidence on the use of vasopressin as a non-adrenergic vasoconstrictor in septic shock. Based on the published study results vasopressin appears to be of potential benefit in adult patients with moderate septic shock (norepinephrine requirements < 15 μg/min) and lacking signs of systemic hypoperfusion (e.g. normal arterial lactate levels). A vasopressin infusion with the sole target to increase arterial blood pressure despite the presence of systemic hypoperfusion is dangerous and can result in a critical deterioration of tissue perfusion.

Topics: Aged; Hemodynamics; Humans; Male; Microcirculation; Norepinephrine; Regional Blood Flow; Resuscitation; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The frequency, risk factors, and mortality rates of serious adverse events associated with the use of vasopressin and norepinephrine are not clear. The objectives of this study were to determine frequency, risk factors (including candidate gene polymorphisms), and outcomes of serious adverse events in septic shock patients.. Retrospective cohort study using multicenter discovery and single-center validation cohorts.. ICUs at academic teaching centers.. Five hundred ninety-seven patients with septic shock in discovery (Vasopressin and Septic Shock trial) and 533 patients in validation (St. Paul's Hospital) cohorts.. Vasopressin and norepinephrine for septic shock.. The primary outcome variable was 90-day mortality rates of patients with and without serious adverse events. Secondary outcome variables were the association between vasopressor genotype pathway polymorphisms, plasma vasopressin levels, and serious adverse events. Plasma vasopressin concentrations were measured at baseline, 6 hours, 24 hours, 72 hours, and 7 days after vasopressor infusion. Patients with septic shock were genotyped for 268 vasopressor pathway tag single-nucleotide polymorphisms. Serious adverse events occurred in 10.5% and 9.7% of patients in Vasopressin and Septic Shock trial and St. Paul's Hospital cohorts, respectively. Patients who had serious adverse events had higher mortality (p < 0.01) than patients without serious adverse events (adjusted for age, serum lactate, Acute Physiology and Chronic Health Evaluation II, and maximum dose of norepinephrine day 1) (hazard ratio, 2.97; 95% CI, 2.20-4.00; p < 0.001 and hazard ratio, 1.89; 95% CI, 1.26-2.85; p = 0.002 in Vasopressin and Septic Shock trial and St. Paul's Hospital, respectively). There was no difference in the area under the plasma vasopressin concentration curve between patients with and without serious adverse events (p = 0.1). The AA genotype of rs28418396 single-nucleotide polymorphism (near the arginine vasopressin receptor 1b gene) was significantly associated with serious adverse events in discovery and validation cohorts (p = 0.001 and p = 0.04, respectively).. Serious adverse events associated with vasopressin and norepinephrine in patients who have septic shock are associated with increased mortality and morbidity. AA genotype of rs28418396 single-nucleotide polymorphism near the arginine vasopressin receptor 1b gene is associated with serious adverse events. The mechanism of this association requires investigation.

Topics: Aged; Area Under Curve; Cohort Studies; Female; Genotype; Humans; Male; Middle Aged; Norepinephrine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Vasopressin; Retrospective Studies; Risk Factors; Shock, Septic; Survival Rate; Vasoconstrictor Agents; Vasopressins

This research is aimed to discover the influence and underling mechanism of combined infusion of arginine vasopressin with levosimendan on acute lung injury in rat septic shock with norepinephrine supplemented. The traditional fecal peritonitis-induced septic shock model was undergone in rats for study. It is observed that the combined infusion supplemented with norepinephrine brought about a lower mean pulmonary artery pressure; lower high-mobility group box 1 levels, pulmonary levels of interleukin-6, and arterial total nitrate/nitrite; lower apoptotic cells scores and total histological scores; but higher pulmonary gas exchange when compared with the separate infusion group and norepinephrine group. This therapy shows potential clinical beneficial assistance in sepsis-induced acute lung injury. The results suggest the mechanism of such effect is through abating pulmonary artery pressure, and more importantly suppressing inflammatory responses in lung when compared with norepinephrine infusion group and the separate infusion of levosimendan or vasopressin alone.

Topics: Acute Lung Injury; Animals; Blood Gas Analysis; Cardiovascular Agents; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Female; HMGB1 Protein; Hydrazones; Lung; Nitrogen Oxides; Norepinephrine; Pyridazines; Rats; Shock, Septic; Simendan; Vasopressins

Topics: Female; Humans; Male; Norepinephrine; Polymorphism, Single Nucleotide; Receptors, Vasopressin; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Adult; Aged; Humans; Middle Aged; Norepinephrine; Organ Dysfunction Scores; Shock, Septic; Vasopressins

To investigate the prognostic value of decreased vasopressin (VP) modulation in the late-phase of septic shock.. A prospective study was conducted. Fifty-five septic shock patients hospitalized in intensive care unit (ICU) of the First Hospital of Hebei Medical University from January 2012 to February 2014 were enrolled. All patients received 3% hypertonic saline solution infusion. Serum concentrations of sodium and VP were measured before and after hypertonic saline solution infusion. Patients with ratio of difference in sodium and VP before and after infusion of 3% hypertonic saline (ΔVP/ΔNa)≤0.5 pg/mmol were defined as non-responders, and who >0.5 pg/mmol were defined as responders. The levels of lactic acid, C-reactive protein (CRP), and vasoactive drug [dopamine (DA) and norepinephrine (NE)] usage between the two groups were compared. The 28-day mortality, live time in the dead, and ICU day in survivors were analyzed between the two groups. The receiver operating characteristic curve (ROC curve) was drawn to assess prognostic value of VP.. There were 30 cases (54.5%) in non-responsive group, and 25 (45.5%) in responsive group. There were no significant differences in the age, acute physiology and chronic health evaluation II (APACHEII) score, central venous pressure (CVP), blood pressure, plasma albumin level, sodium level before and after hypertonic saline solution infusion between the two groups. The baseline level of VP in the non-responsive group was markedly lower than that of the responsive group (ng/L: 10.66 ± 1.57 vs. 17.13 ± 5.12, t=6.091, P<0.001). After hypertonic saline solution infusion, the VP level was also significantly decreased compared with that in the responsive group (ng/L: 11.65 ± 1.74 vs. 22.50 ± 5.31, t=9.758, P<0.001). The non-responders showed higher lactic acid (mmol/L: 3.04 ± 0.55 vs. 2.28 ± 0.38, t=-5.881, P<0.001) and CRP (mg/L: 117.9 ± 23.0 vs. 94.9 ± 17.0, t=-4.143, P<0.001), and received larger dosage of vasoactive drugs [DA (μg × kg⁻¹ × min⁻¹): 14.8 ± 3.9 vs. 8.9 ± 1.6, t=-5.725, P<0.001; NE (μg × kg⁻¹ × min⁻¹): 0.96 ± 0.42 vs. 0.40 ± 0.09, t=-5.625, P<0.001] for maintaining blood pressure compared with those in responders. The non-responsive group showed higher 28-day mortality (66.7% vs. 40.0%, χ² =3.911, P=0.048) and longer ICU day (days: 9.9 ± 2.3 vs. 6.7 ± 1.7, t=-4.044, P<0.001), but the live time in the dead showed no difference between non-responsive group and responsive group (days: 5.8 ± 1.9 vs. 6.1 ± 2.3, t=0.384, P=0.704). ROC curve showed that the area under ROC curve (AUC) for ΔVP/ΔNa predicting the outcome was 0.828, and the ΔVP/ΔNa threshold value of 0.5 pg/mmol had the sensitivity of 66.7% and specificity of 64.0% for prediction of the outcome (95% confidence interval: 0.722-0.934).. Osmotic pressure-regulated VP secretion was impaired and decreased in the late-phase of septic shock, and made the sense in prognosis.

Topics: C-Reactive Protein; Central Venous Pressure; Humans; Intensive Care Units; Lactic Acid; Norepinephrine; Osmotic Pressure; Predictive Value of Tests; Prognosis; Prospective Studies; Saline Solution, Hypertonic; Shock, Septic; Time Factors; Vasopressins

Early goal-directed therapy is a time-sensitive therapeutic algorithm with a tiered approach to target hypoperfusion and cardiovascular collapse within the first 6 hours of septic shock. The Surviving Sepsis Campaign guidelines recommend norepinephrine or dopamine as the initial vasoactive agent for resuscitation in septic shock, reserving the administration of vasopressin as adjunctive therapy.. To determine whether vasopressin was noninferior to norepinephrine as the initial vasopressor to achieve a mean arterial pressure (MAP) goal in the first 6 hours of shock onset.. This retrospective cohort study evaluated adults who received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy for the management of septic shock. Patients were excluded if the treatment arm was not monotherapy, if they were admitted to a cardiology or cardiothoracic surgery service, or if they lacked a comparator-based 1:1 frequency matching.. A total of 130 patients were included, 65 in each treatment arm. The proportion of patients who achieved a goal MAP in the vasopressin group was 63% (95% CI 51%-75%) and was 67.7% (95% CI 56%-79%) in the norepinephrine group. This observed difference between goal MAP attainment did not exceed the predefined noninferiority margin of -25% (CI for 4.7% difference -21.2% to 12%), suggesting noninferiority of vasopressin. No significant difference was identified between vasopressin and norepinephrine for final mean (SD) MAP achieved (75 [9.6] and 76.0 [8.2] mm Hg, respectively; p = 0.06) or the mean total change from baseline MAP to goal (14.1 [8.4] and 15.1 [9.1] mm Hg, respectively; p = 0.6).. Vasopressin was noninferior to norepinephrine for the achievement of a MAP goal in the first 6 hours from onset of septic shock. Further prospective analysis is warranted; however, the results are useful for consideration of alternative vasopressors in the setting of drug shortages.

Topics: Adult; Aged; Arterial Pressure; Female; Humans; Male; Middle Aged; Norepinephrine; Resuscitation; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

To define some of the most common characteristics of vascular hyporesponsiveness to catecholamines during septic shock and outline current therapeutic approaches and future perspectives.. Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents.. NO and peroxynitrite are mainly responsible for vasoplegia and vascular hyporeactivity while COX 2 enzyme is responsible for the increase in PGI2, which also contributes to hyporeactivity. Moreover, K+ATP and BKCa channels are over-activated during septic shock and participate in hypotension. Finally, other mechanisms are involved in vascular hyporesponsiveness such as critical illness-related corticosteroid insufficiency, vasopressin depletion, dysfunction and desensitization of adrenoreceptors as well as inactivation of catecholamines by oxidation.. In animal models, several therapeutic approaches, targeted on one particular compound have proven their efficacy in preventing or reversing vascular hyporesponsiveness to catecholamines. Unfortunately, none have been successfully tested in clinical trials. Nevertheless, very high doses of catecholamines ( > 5 μg/kg/min), hydrocortisone, terlipressin or vasopressin could represent an alternative for the treatment of refractory septic shock.

Topics: Animals; Catecholamines; History, 20th Century; History, 21st Century; Humans; Nitric Oxide; Potassium Channels; Shock, Septic; Vasoconstrictor Agents; Vasopressins

One of the rationales for the use of vasopressin in septic shock has been its potential cardioprotective mechanisms. Lower heart rates, higher arterial pressures, and fewer norepinephrine doses during vasopressin therapy were hypothesized to protect the heart from myocardial ischemia. In a prospective sub-study of the VASST (Vasopressin in Septic Shock Trial) project, Mehta and colleagues specifically evaluated this hypothesis but failed to find lower cardiac biomarkers or fewer ischemic electrocardiogram changes in patients receiving vasopressin compared with subjects receiving norepinephrine alone. After recent evidence of a lacking survival benefit, the present study results further challenge the future role of vasopressin as a vasopressor in septic shock.

Topics: Female; Humans; Male; Myocardial Ischemia; Norepinephrine; Shock, Septic; Vasopressins

Vasopressin (AVP) secretion during an osmotic challenge is frequently altered in the immediate post-acute phase of septic shock. We sought to determine if this response is still altered in patients recovering from septic shock.. Prospective interventional study.. Intensive care unit (ICU) at Raymond Poincaré and Etampes Hospitals.. Normonatremic patients at least 5 days post discontinuation of catecholamines given for a septic shock.. Osmotic challenge involved infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 minutes.. Plasma AVP levels were measured 15 minutes before the infusion and then every 30 minutes for two hours. Non-responders were defined as those with a slope of the relation between AVP and plasma sodium levels less than < 0.5 ng/mEq. Among the 30 included patients, 18 (60%) were non-responders. Blood pressure and plasma sodium and brain natriuretic peptide levels were similar in both responders and non-responders during the course of the test. Critical illness severity, hemodynamic alteration, electrolyte disturbances, treatment and outcome did not differ between the two groups. Responders had more severe gas exchange abnormality. Thirst perception was significantly diminished in non-responders. The osmotic challenge was repeated in 4 non-responders several months after discharge and the abnormal response persisted.. More than half of patients recovering from septic shock have an alteration of osmoregulation characterised by a dramatic decrease in vasopressin secretion and thirst perception during osmotic challenge. The mechanisms of this alteration but also of the relationship between haematosis and normal response remain to be elucidated.

Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Osmoregulation; Prospective Studies; Shock, Septic; Thirst; Vasopressins

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency has been reported in patients with sepsis but its clinical relevance and pathophysiology remain unclear. Our objectives were to assess the clinical significance, prognostic value and pathophysiology of ADAMTS13 deficiency in patients with septic shock with and without disseminated intravascular coagulation (DIC).. This was a prospective monocenter cohort study of patients with septic shock. Von Willebrand Factor, ADAMTS13-related parameters and plasma IL-6 concentration were measured at inclusion to the study. Patients were categorized into three groups according to the presence of ADAMT13 deficiency (<30%) or DIC.. This study included 72 patients with a median age of 59 years (interquartile range (IQR) 50 to 71). Each of the included patients received vasopressors; 55 (76%) were under mechanical ventilation and 22 (33%) underwent renal replacement therapy. Overall, 19 patients (26%) had DIC, and 36 patients had ADMTS13 deficiency (50%). Patients with DIC, ADAMTS13 deficiency or both were more severe at ICU admission. Mortality was higher in septic shock patients from group one. By multivariate analysis, Simplified Acute Physiology Score 2 (SAPS2) score (odds ratio (OR) 1.11/point; 95% CI 1.01 to 1.24) and ADAMTS13 activity <30% (OR 11.86; 95% CI 1.36 to 103.52) were independently associated with hospital mortality. There was no correlation between ADAMTS13 activity and the International Society for Thrombosis and Haemostasis (ISTH) score (rs = -0.97, P = 0.41) suggesting that ADAMTS13 functional deficiency and DIC were independent parameters. IL-6 level was higher in patients with ADAMTS13 activity <30% [895 (IQR 330 to 1843) pg/mL versus 83 (IQR 43 to 118), P = 0.0003).. Septic shock was associated with a functional deficiency of ADAMTS13, independently of DIC. ADAMTS13 functional deficiency is then a prognostic factor for mortality in septic shock patients, independently of DIC.

Topics: ADAM Proteins; ADAMTS13 Protein; Aged; APACHE; Biomarkers; Disseminated Intravascular Coagulation; Female; France; Humans; Interleukin-6; Male; Middle Aged; Multivariate Analysis; Organ Dysfunction Scores; Prognosis; Prospective Studies; Renal Replacement Therapy; Respiration, Artificial; Shock, Septic; Survival Analysis; Vasoconstrictor Agents; Vasopressins; von Willebrand Factor

Septic shock is a serious condition with a consequent drop in blood pressure and inadequate tissue perfusion. Small-volume resuscitation with hypertonic saline (HS) has been proposed to restore physiological haemodynamics during haemorrhagic and endotoxic shock. In the present study, we sought to determine the effects produced by an HS infusion in rats subjected to caecal ligation and perforation (CLP). Male Wistar rats were randomly grouped and submitted to either CLP or sham surgery. Either HS (7.5% NaCl, 4 ml kg(-1) i.v.) or isotonic saline (IS; 0.9% NaCl, 4 ml kg(-1) i.v.) was administered 6 h after CLP. Recordings of mean arterial pressure and heart rate were made during this protocol. Moreover, measurements of electrolyte, vasopressin and oxytocin secretion were analysed after either the HS or the IS treatment. Six hours after CLP, we observed a characteristic decrease in mean arterial pressure that occurs after CLP. The HS infusion in these rats produced a transient elevation of the plasma sodium concentration and osmolality and increased plasma vasopressin and oxytocin levels. Moreover, the HS infusion could restore the mean arterial pressure after CLP, which was completely blunted by the previous injection of the vasopressin but not the oxytocin antagonist. The present study demonstrated that rats subjected to CLP and an infusion of hypertonic saline respond with secretion of neurohypophyseal hormones and a transient increase in blood pressure mediated by the V(1) receptor.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arterial Pressure; Disease Models, Animal; Fluid Therapy; Heart Rate; Homeostasis; Hormone Antagonists; Infusions, Intravenous; Male; Osmolar Concentration; Oxytocin; Pituitary Gland, Posterior; Rats; Rats, Wistar; Receptors, Oxytocin; Receptors, Vasopressin; Saline Solution, Hypertonic; Shock, Septic; Sodium; Time Factors; Vasopressins; Water-Electrolyte Balance

Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.

Topics: Animals; Aorta; Blood Pressure; Cholecystokinin; Drug Evaluation, Preclinical; Endotoxemia; Heart Rate; Hypotension; Inflammation Mediators; Interleukin-10; Lactic Acid; Lipopolysaccharides; Liver; Macrophages, Peritoneal; Male; Nitric Oxide Synthase Type II; Proglumide; Rats; Rats, Wistar; Shock, Septic; Tumor Necrosis Factor-alpha; Vasopressins

Vasopressin and direct hemoperfusion with an immobilized polymyxin B column (PMX) have emerged recently as treatments for septic shock. This study assessed the impact of these two treatments on the survival of patients with septic shock.. A retrospective, matched cohort study was performed to compare patients who had septic shock and were treated with PMX or vasopressin. The primary endpoint was the 90-day mortality rate. 30 patients receiving PMX were matched to 30 treated with vasopressin.. The 90-day survival rate was significantly higher in the vasopressin group than the PMX group (83% vs. 53%; p = 0.008). In the PMX group, the subgroup with gastrointestinal surgery had a significantly higher survival rate than the subgroup without surgery (76.9% vs. 52.9%; p = 0.01). Cox multivariate analysis showed that vasopressin therapy (versus PMX; HR = 0.27; p < 0.01). The estimated hazard ratio for the SOFA score was 1.44 (p < 0.01), and total pressor dosage an baseline was 1.26 (p = 0.01).. We found a significant reduction of the mortality rate in septic shock patients who received vasopressin compared with PMX. In the PMX group, the subgroup with gastrointestinal surgery had a significantly higher survival rate than the subgroup without such surgery.

Topics: Aged; Anti-Bacterial Agents; Case-Control Studies; Cohort Studies; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hemoperfusion; Humans; Male; Middle Aged; Polymyxin B; Retrospective Studies; Shock, Septic; Survival Analysis; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Levels of vasopressin and its precursor copeptin in pediatric sepsis and septic shock are not well defined. The main aim of this study is to compare the serum levels of vasopressin and copeptin in children with septic shock or sepsis and in healthy children. We hypothesized that vasopressin and copeptin levels are elevated in early and late stages of pediatric septic shock.. Three groups were included: healthy children, children with clinical diagnosis of sepsis, and children admitted to the pediatric intensive care unit (PICU) with diagnosis of sepsis shock. Blood samples were drawn from children in all groups within 24 h of admission. For the septic shock group, additional samples at 24-h intervals were drawn up to 120 h after PICU admission. We used competitive immunoassays to determine vasopressin and copeptin levels.. There were 70 children in the control group, 53 children in the sepsis group, and 13 in the septic shock group. At baseline, there was a difference in median vasopressin levels [60.9 (Interquartile range: 32.3, 138.0) vs. 141.1 (45.2, 542) vs. 326 (55.6, 399) pg/mL, p < 0.05], but there was no difference in copeptin levels [1.2 (0.8, 1.8) vs. 1.5 (1.0, 2.2) vs. 0.9 (0.8, 1.2) ng/mL, p = 0.14] between the three groups. There was no difference in vasopressin and copeptin levels in early and late stages of pediatric septic shock.. Baseline vasopressin levels were different between the three groups. In pediatric septic shock, vasopressin and copeptin levels are not robust markers for severity and clinical outcomes.

Topics: Biomarkers; Child; Child, Preschool; Female; Glycopeptides; Humans; Infant; Intensive Care Units, Pediatric; Male; Prospective Studies; Sepsis; Shock, Septic; Singapore; Vasopressins

Vasopressors used for the management of septic shock are often dosed according to body weight. Use of vasopressin for physiologic replacement in patients with septic shock is usually administered as a standard non-weight-based dose. We hypothesized that the efficacy of vasopressin may be influenced by body weight.. The primary objective was to determine if the effects of vasopressin on other vasopressor dosing requirements is related to body weight. Secondary objectives included evaluation of blood pressure and heart rate after the start of vasopressin infusion.. A retrospective, cohort study in a large academic health center was conducted. Sixty-four adult inpatients with septic shock (26 medical intensive care unit and 38 surgical intensive care unit) who required vasopressor administration including vasopressin therapy were included. Dosing requirements of vasopressors were captured 1 hour before and during the hour of vasopressin initiation and 2 and 4 hours later. Other information collected during the study period included blood pressure, mean arterial pressure, and heart rate.. Most of the patients (n = 61) received vasopressin at a dose of 0.04 U/min. Changes in vasopressor dosing were significantly correlated with weight-adjusted vasopressin at 2 hours (correlation coefficient = -0.36, P = .03) and 4 hours (correlation coefficient = -0.46, P < .001). Use of vasopressin was associated with significant increases in systolic blood pressure, diastolic blood pressure, and mean arterial pressure at each time point compared with baseline.. Effects of vasopressin on catecholamine dosing requirements in the setting of septic shock may be influenced by body weight. Prospective studies are needed to examine weight-based dosing of vasopressin in this setting.

Topics: Blood Pressure; Body Weight; Drug Dosage Calculations; Drug Therapy, Combination; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Norepinephrine; Retrospective Studies; Shock, Septic; Statistics, Nonparametric; Vasoconstrictor Agents; Vasopressins

To compare the effects on von Willebrand factor release of the mixed vasopressin type 1a and type 2 receptor agonist arginine vasopressin and the selective vasopressin type 1a receptor agonist FE 202158, [Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin, at doses required for the treatment of septic shock.. Prospective, randomized, controlled laboratory experiment.. University animal research facility.. Twenty-four chronically instrumented sheep.. After a 5-day recovery from instrumentation, sheep were randomly assigned to receive a single intravenous bolus of the selective vasopressin type 2 receptor agonist desmopressin (1 nmol·kg(-1)) or continuous intravenous infusions of arginine vasopressin (3 pmol·kg(-1)·min(-1)), the selective vasopressin type 1a receptor agonist FE 202158 (10 pmol·kg(-1)·min(-1)), or vehicle (0.9% NaCl) (n = 6 each).. The von Willebrand factor antigen activity relative to hemoglobin concentration (vWF:Ag/Hb ratio) was measured at different time points during the 120-min study period. Maximal vWF:Ag/Hb ratio expressed as percentage of baseline level was significantly increased compared to vehicle-infused animals (3 ± 2%) in the desmopressin (40 ± 6%, p < .001) and arginine vasopressin groups (25 ± 4%, p < .001). The ratio for the FE 202158 group was not statistically different from the sham group (9 ± 2%, p = .208). Notably, maximal vWF:Ag/Hb ratio was lower in the FE 202158 than the arginine vasopressin group (p < .005).. Unlike the mixed vasopressin type 1a receptor/vasopressin type 2 receptor agonist arginine vasopressin, the selective vasopressin type 1a receptor agonist FE 202158 does not release von Willebrand factor. Because von Willebrand factor is involved in coagulatory and inflammatory pathways during septic shock, future studies should clarify the role of the vasopressin type 2 receptor-mediated von Willebrand factor increase by arginine vasopressin and the potential benefit of selective vasopressin type 1a receptor-agonists like FE 202158.

Topics: Animals; Arginine Vasopressin; Blood Coagulation; Female; Prospective Studies; Random Allocation; Receptors, Vasopressin; Sheep; Shock, Septic; Vasopressins; von Willebrand Factor

Topics: Adrenal Cortex Hormones; Data Collection; Humans; Physician's Role; Shock, Septic; Survival Rate; Vasopressins

Dobutamine (DB) has been recommended in combination with vasopressor therapy in septic shock, given its reported ability to improve mesenteric and microcirculatory perfusion. Vasopressin (VP) is typically reserved as a second-line agent due to the concern of ischemia. The purpose of our study was to determine whether combination DB and VP therapy improved microcirculatory blood flow in severe endotoxic shock.. Septic shock was induced in 20 anesthetized piglets with injection of E. coli endotoxin. DB (10 μg/kg/min, n = 5) and VP (0.04 units/min, n = 10) were administered alone and in combination (n = 15). Measurements were compared at baseline, following endotoxin administration, and following treatment. Microcirculatory blood flow was determined via the injection of colored microspheres.. VP completely reversed endotoxin-mediated hypotension with a mean arterial pressure (MAP) of 85 ± 4.5 mm Hg, which was not significantly altered with the addition of DB (77 ± 4.9 mm Hg). Endotoxin uniformly depressed cardiac output (CO) from baseline (227 ± 10.7 versus 174 ± 12.4 mL/min/kg) despite treatment with VP alone or in combination with DB. The addition of DB did not improve the CO in this severe septic shock model. VP was found to shunt microcirculatory flow from the skin and GI tract to vital organs such as the brain, liver, and kidneys, which was not altered with the addition of DB.. Results indicate that DB is ineffective in increasing CO or improving mesenteric blood flow when used with physiologic replacement doses of VP. In combination, DB is unable to overcome the blood flow distribution achieved with VP administration alone in severe endotoxic shock.

Topics: Acid-Base Equilibrium; Animals; Cardiotonic Agents; Disease Models, Animal; Dobutamine; Drug Therapy, Combination; Heart Rate; Microcirculation; Severity of Illness Index; Shock, Septic; Stroke Volume; Sus scrofa; Vasoconstrictor Agents; Vasopressins

Relative vasopressin deficiency, a contributor to vasodilatory septic shock, also may be a cause of the vasodilatory state in liver disease. This study assessed endogenous vasopressin levels in patients with liver disease and their hemodynamic response to exogenous vasopressin.. A prospective, observational study.. A single-center, tertiary hospital.. Human subjects undergoing liver transplantation or major surgery.. Vasopressin levels were measured in 28 patients with liver disease undergoing liver transplantation and 7 control patients with normal liver function. Additionally, intravenous vasopressin was administered to 20 liver transplant recipients, and the hemodynamic response was observed.. Patients with liver disease had significantly lower baseline vasopressin levels than controls (19.3 ± 27.1 pg/mL v 50.9 ± 36.7 pg/mL, p = 0.015). Patients with low vasopressin levels (≤20 pg/mL) were more likely to have lower baseline mean blood pressure (≤80 mmHg) than patients with high vasopressin levels (11/16 v 0/4, p = 0.013). Systemic vascular resistance increased by 33% 3 minutes after intravenous vasopressin. Thirteen of 16 patients with low vasopressin levels compared with 1 of 4 patients with high vasopressin levels responded to exogenous vasopressin, with an increase of mean blood pressure by more than 20% (p = 0.028).. Patients with liver disease have lower vasopressin levels than controls and respond with a brisk vasoconstrictor response to exogenous vasopressin. Therefore, relative endogenous vasopressin deficiency may contribute to vasodilatory shock in liver disease similar to what has been observed in septic shock.

Topics: Adult; Aged; End Stage Liver Disease; Female; Humans; Liver Transplantation; Male; Middle Aged; Prospective Studies; Shock, Septic; Vascular Resistance; Vasodilation; Vasopressins

We tested the hypothesis that single nucleotide polymorphisms (SNPs) within genes of the NF-κB pathway are associated with altered clinical outcome of septic shock patients. We genotyped 59 SNPs in the NF-κB pathway in a discovery cohort of septic shock patients (St. Paul's Hospital [SPH], N = 589), which identified the C allele of rs7222094 T/C within MAP3K14 (NF-κB inducing kinase; NIK) associated with increased 28-d mortality (uncorrected p = 0.00024, Bonferroni corrected p = 0.014). This result was replicated in a second cohort of septic shock patients (Vasopressin and Septic Shock Trial [VASST; N = 616]) in which the CC genotype of rs7222094 was associated with increased 28-d mortality (Cox regression: SPH cohort hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.12-1.64; p = 0.002 Caucasian only; and VASST cohort HR, 1.24; 95% CI, 1.00-1.52; p = 0.048 Caucasian only). Patients having the CC genotype of rs7222094 in SPH experienced more renal and hematological dysfunction (p = 0.003 and p = 0.011), while patients of the VASST cohort with the rs7222094 CC genotype showed the same trend toward more renal dysfunction. In lymphoblastoid cell lines, we found the rs7222094 genotype most strongly associated with mRNA expression of CXCL10, a chemokine regulated by NF-κB. Accordingly, we measured CXCL10 protein levels and found that the CC genotype of rs7222094 was associated with significantly lower levels than those of the TT genotype in lymphoblastoid cell lines (p < 0.05) and in septic shock patients (p = 0.017). This suggests that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients, perhaps due to altered regulation of NF-κB pathway genes, including CXCL10.

Topics: Cell Line, Transformed; Chemokine CXCL10; Cohort Studies; Double-Blind Method; Genotype; Humans; Multicenter Studies as Topic; NF-kappaB-Inducing Kinase; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Randomized Controlled Trials as Topic; Shock, Septic; Signal Transduction; Vasopressins

The ultimate goals of hemodynamic therapy in shock are to restore effective tissue perfusion and to normalize cellular metabolism. In sepsis, both global and regional perfusion must be considered. In addition, mediators of sepsis can perturb cellular metabolism, leading to inadequate use of oxygen and other nutrients despite adequate perfusion; one would not expect organ dysfunction mediated by such abnormalities to be corrected by hemodynamic therapy. Despite the complex pathophysiology of sepsis, an underlying approach to its hemodynamic support can be formulated that is particularly pertinent with respect to vasoactive agents. Both arterial pressure and tissue perfusion must be taken into account when choosing therapeutic interventions and the efficacy of hemodynamic therapy should be assessed by monitoring a combination of clinical and hemodynamic parameters. It is relatively easy to raise blood pressure, but somewhat harder to raise cardiac output in septic patients. How to optimize regional blood and microcirculatory blood flow remains uncertain. Specific end points for therapy are debatable and are likely to evolve. Nonetheless, the idea that clinicians should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis remains a fundamental principle. The practice parameters were intended to emphasize the importance of such an approach so as to provide a foundation for the rational choice of vasoactive agents in the context of evolving monitoring techniques and therapeutic approaches.

Topics: Blood Pressure; Cardiac Output; Cardiotonic Agents; Dopamine; Epinephrine; Fluid Therapy; Hemodynamics; Humans; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is an essential peptide hormone regulating cardiovascular homeostasis and an adjunctive vasopressor therapy for septic shock.. We tested for association between single nucleotide polymorphisms (SNPs) in vasopressin pathway genes and altered outcome in derivation (n = 589) and replication (n = 616) cohorts of patients with septic shock. The primary outcome was 28-day mortality and the secondary outcome was vasopressin clearance. In a third cardiac surgical cohort (n = 977), we tested for locus-specific heritability of serum sodium concentrations.. Of 17 tested tag SNPs in five vasopressin pathway genes (arginine vasopressin [AVP], arginine vasopressin receptor 1A and 1B [AVPR1A, AVPR1B], leucyl/cystinyl aminopeptidase [LNPEP], and oxytocin receptor [OXTR]), rs18059 in LNPEP (also known as vasopressinase) was associated with 28-day mortality in the derivation cohort (P = .037). Therefore, we resequenced the 160-kb haplotype block encompassing the LNPEP gene, including rs18059, and genotyped the 230 identified SNPs in the derivation cohort. The strongest signal was found for LNPEP rs4869317 (adjusted P = .044). The rs4869317 TT genotype was associated with increased 28-day mortality in the derivation cohort (51.0% [TT] vs 34.5% [AA/AT]; adjusted hazard ratio [HR], 1.58; 95% CI, 1.21-2.06; P = .00073) and the replication cohort (38.6% vs 29.6%; HR, 1.36; 95% CI, 1.03-1.80; P = .030). We found that the TT genotype was associated with increased plasma vasopressin clearance (P = .028), and the rs4869317 genotype accounted for 80% of the variance of serum sodium concentrations (locus-specific heritability) in cardiac surgical patients.. The genetic variation in LNPEP (vasopressinase) is associated with 28-day mortality in septic shock and is associated with biologic effects on vasopressin clearance and serum sodium regulation. Further confirmation in additional cohorts is required.

Topics: Aged; Cardiac Surgical Procedures; Cystinyl Aminopeptidase; Female; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Shock, Septic; Sodium; Vasopressins

Topics: Adrenal Insufficiency; Adult; Amputation, Surgical; Anti-Bacterial Agents; Disseminated Intravascular Coagulation; Epoprostenol; Escherichia coli; Escherichia coli Infections; Female; Gangrene; Humans; Hydrocortisone; Hypotension; Kidney Calculi; Leg; Metatarsus; Pain; Platelet Aggregation Inhibitors; Purpura Fulminans; Shock, Septic; Vasopressins

The reliability of electrocardiogram interpretation to diagnose myocardial ischemia in critically ill patients is unclear. In adults with septic shock, we assessed intra- and inter-rater agreement of electrocardiogram interpretation, and the effect of knowledge of troponin values on these interpretations.. Prospective substudy of a randomized trial of vasopressin vs. norepinephrine in septic shock.. Nine Canadian intensive care units.. Adults with septic shock requiring at least 5 μg/min of norepinephrine for 6 hrs.. Twelve-lead electrocardiograms were recorded before study drug, and 6 hrs, 2 days, and 4 days after study drug initiation.. Two physician readers, blinded to patient data and group, independently interpreted electrocardiograms on three occasions (first two readings were blinded to patient data; third reading was unblinded to troponin). To calibrate and refine definitions, both readers initially reviewed 25 trial electrocardiograms representing normal to abnormal. Cohen's Kappa and the φ statistic were used to analyze intra- and inter-rater agreement.. One hundred twenty-one patients (62.2 ± 16.5 yrs, Acute Physiology and Chronic Health Evaluation II 28.6 ± 7.7) had 373 electrocardiograms. Blinded to troponin, readers 1 and 2 interpreted 46.4% and 30.0% of electrocardiograms as normal, and 15.3% and 12.3% as ischemic, respectively. Intrarater agreement was moderate for overall ischemia (κ 0.54 and 0.58), moderate/good for "normal" (κ 0.69 and 0.55), fair to good for specific signs of ischemia (ST elevation, T inversion, and Q waves, reader 1 κ 0.40 to 0.69; reader 2 κ 0.56 to 0.70); and good/very good for atrial arrhythmias (κ 0.84 and 0.79) and bundle branch block (κ 0.88 and 0.79). Inter-rater agreement was fair for ischemia (κ 0.29), moderate for ST elevation (κ 0.48), T inversion (κ 0.52), and Q waves (κ 0.44), good for bundle branch block (κ 0.78), and very good for atrial arrhythmias (κ 0.83). Inter-rater agreement for ischemia improved from fair to moderate (κ 0.52, p = .028) when unblinded to troponin.. In patients with septic shock, inter-rater agreement of electrocardiogram interpretation for myocardial ischemia was fair, and improved with troponin knowledge.

Topics: Biomarkers; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Norepinephrine; Observer Variation; Prospective Studies; Shock, Septic; Time Factors; Troponin; Vasoconstrictor Agents; Vasopressins

Topics: Child, Preschool; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Hypotension; Mediastinitis; Shock, Septic; Staphylococcal Infections; Surgical Wound Infection; Vascular Resistance; Vasoconstrictor Agents; Vasopressins

There are little data regarding the discontinuation of vasoactive medications in patients recovering from septic shock. We designed this retrospective cohort study to evaluate the incidence of hypotension based on the order of removal of norepinephrine (NE) and vasopressin (AVP) in patients receiving concomitant NE and AVP infusions for the treatment of septic shock.. Consecutive patients receiving concomitant NE and AVP infusions for septic shock admitted to the intensive care units of a tertiary care academic medical center were evaluated.. Of 50 included patients, the first vasoactive medication discontinued was NE in 32 patients and AVP in 18 patients. The groups had similar Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores at shock onset and at the time of discontinuation of the first agent. Five patients who had NE discontinued first (16%) versus 10 patients who had AVP discontinued first (56%) developed hypotension within 24 hours (unadjusted relative risk, 3.6; 95% confidence interval, 1.5-4.5; P = .008). In a multivariate analysis, only discontinuation of AVP first was independently associated with hypotension (adjusted relative risk, 5.9; 95% confidence interval, 1.7-21.0; P = .006).. Discontinuation of AVP before NE may lead to a higher incidence of hypotension in patients recovering from septic shock receiving concomitant AVP and NE.

Topics: APACHE; Cohort Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypotension; Incidence; Male; Middle Aged; Multivariate Analysis; Norepinephrine; Retrospective Studies; Shock, Septic; Treatment Outcome; Vasopressins

Topics: Adrenal Cortex Hormones; Clinical Trials as Topic; Critical Care; Drug Interactions; Drug Therapy, Combination; Female; Humans; Intensive Care Units; Male; Prognosis; Risk Assessment; Shock, Septic; Survival Analysis; Vasopressins

The purpose of this study was to compare the effects of norepinephrine (NE) and vasopressin on systemic hemodynamics, renal and mesenteric artery blood flow, inflammatory response and inducible nitric oxide synthase (iNOS) activity during endotoxin shock in streptozotocin-induced diabetic rats.. The study was designed to include three sets of experiments: (1) measurement of changes in systemic hemodynamics and mesenteric and renal artery blood flow; (2) measurement of biochemical variables; and (3) measurement of iNOS activity in the mesenteric artery. Systemic hemodynamics, regional artery blood flow changes and biochemical variables were assessed before treatment and 1, 2 and 3 h after treatment.. Vasopressin, but not NE, prevented the decreases in aortic blood flow, but did not restore mesenteric artery blood flow. In addition, vasopressin partially restored renal artery blood flow in diabetic rats. Plasma nitrite levels and iNOS activity in the mesenteric artery were elevated after intravenous LPS in diabetic rats. Endotoxin-induced decreases in mesenteric arterial blood flow were partially restored by vasopressin with nonselective NOS inhibitor, N G-nitro-l-arginine methyl ester (l-NAME), in diabetic rats. Moreover, l-NAME prevented increases in plasma nitrite levels and iNOS activity in the mesenteric artery. In contrast, endotoxin-induced decreases in renal arterial blood flow were partially restored by vasopressin with l-NAME, but not by NE in diabetic rats.. Nitric oxide may be one possible contributor to reduced sensitivity of the mesenteric and renal arteries to vasopressin during septic shock in streptozotocin-induced diabetic rats.

Topics: Animals; Diabetes Mellitus, Experimental; Hemodynamics; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Rats; Rats, Wistar; Renal Circulation; Shock, Septic; Splanchnic Circulation; Streptozocin; Vasopressins

Capnocytophaga canimorsus is a gram-negative rod that is a normal inhabitant of the oral flora of most dogs, cats and other animals. Clinically significant infections of humans by this common organism are extremely rare. We present a case of an 87-year-old woman who presented with septic shock and multiorgan system failure. Blood cultures were positive for a gram-negative rod that five days after admission was identified as C. canimorsus. She was treated aggressively with intravenous fluid resuscitation, vasopressors and parenteral antibiotics and recovered. The epidemiology, virulence factors, and treatment options for C. canimorsus are discussed.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Antidiuretic Agents; Capnocytophaga; Female; Fluid Therapy; Gram-Negative Bacterial Infections; Humans; Multiple Organ Failure; Penicillanic Acid; Piperacillin; Risk Factors; Shock, Septic; Tazobactam; Vancomycin; Vasopressins

Topics: Cardiotonic Agents; Female; Humans; Hypotension; Middle Aged; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Adrenal Cortex Hormones; Drug Synergism; Drug Therapy, Combination; Humans; Hydrocortisone; Shock, Septic; Vasopressins

Topics: Arginine Vasopressin; Clinical Trials as Topic; Glycopeptides; Humans; Sepsis; Shock, Septic; Vasopressins

Topics: Adrenomedullin; Biomarkers; Glycopeptides; Hospital Mortality; Humans; Predictive Value of Tests; Prognosis; Protein Precursors; Shock, Septic; Up-Regulation; Vasopressins

To investigate the effects of fluid resuscitation administration on vasopressin secretion and its association with pressor response in endotoxic shock during a period of inappropriately low vasopressin secretion.. Prospective, controlled experiment.. Animal basic science laboratory.. Male Wistar rats, weighing 250 to 300 grams.. Rats received lipopolysaccharide (2 mg/kg, intravenous) and had their mean arterial pressure monitored during the next 4 hrs. Subsequently, the animals were assigned randomly to one of seven groups (n = 6 per group) that differed in the composition or volume of the resuscitation fluid administered: control group (no fluid administered); isotonic saline solution (0.9% NaCl; 4 mL/kg); hypertonic saline solution (7.5% NaCl; 4 mL/kg); 0.9% NaCl in 6% hydroxyethyl starch 450/0.7 (4, 8, or 16 mL/kg); or 7.5% NaCl in 6% hydroxyethyl starch 450/0.7 (4 mL/kg).. Blood pressure was lower in the lipopolysaccharide-treated group. Administration of 0.9% NaCl in 6% hydroxyethyl starch 450/0.7 did not change mean arterial pressure, but reduced vasopressin plasma levels at a dose of 16 mL/kg. Hypertonic saline solution or 7.5% NaCl in 6% hydroxyethyl starch 450/0.7 administration was followed by an immediate recovery of blood pressure and also by an increase in plasma vasopressin levels when compared to isotonic saline solution. The vasopressin V1 receptor antagonist (10 microg/kg, intravenous, 5 min before infusion) completely blunted the increase in mean arterial pressure induced by hypertonic saline solution or 7.5% NaCl in 6% hydroxyethyl starch 450/0.7 in endotoxemic rats.. Isotonic blood volume expansion reduced vasopressin plasma levels. Furthermore, the subsequent release of vasopressin is essential for the pressor response caused by hypertonic fluid infusion during endotoxic shock.

Topics: Animals; Blood Pressure; Endotoxins; Fluid Therapy; Hydroxyethyl Starch Derivatives; Isotonic Solutions; Lipopolysaccharides; Male; Plasma Substitutes; Random Allocation; Rats; Rats, Wistar; Resuscitation; Saline Solution, Hypertonic; Shock, Septic; Sodium Chloride; Vasopressins

Topics: Animals; Blood Pressure; Blood Volume; Fluid Therapy; Hydroxyethyl Starch Derivatives; Isotonic Solutions; Osmolar Concentration; Plasma Substitutes; Rats; Resuscitation; Saline Solution, Hypertonic; Shock, Septic; Sodium Chloride; Vasopressins

Topics: Humans; Severity of Illness Index; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Topics: Drug Therapy, Combination; Humans; Norepinephrine; Severity of Illness Index; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Drug Therapy, Combination; Humans; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Algorithms; Humans; Hyponatremia; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Child; Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Arginine Vasopressin; Critical Illness; Humans; Receptors, Vasopressin; Shock, Septic; Vasoconstrictor Agents; Vasopressins

A systemic inflammatory response to infection characterizes sepsis which associated to refractory hypotension, turns into severe sepsis. Our aim was to evaluate hormonal and cardiovascular alterations after experimental sepsis induced by cecal ligation and puncture (CLP). Male Wistar rats (200-250 g) were submitted to CLP or sham operation. The animals were decapitated at 0, 2, 4, 6 and 8 h after surgery for collection of blood samples for plasma osmolality, sodium and vasopressin (AVP) measurements. The mean arterial pressure (MAP) and heart rate (HR) were recorded 1 h before and to each 1 h during 5hs after surgery. The spontaneous baroreflex sensitivity and spectral analysis of HR and MAP variability were analyzed after recording. The plasma osmolality and sodium did not show any alterations compared to the sham group. MAP decreased from 3 h (85 vs.103 mm Hg, P<0.05) to 5 h in the CLP group (76 vs.106 mm Hg, P<0.05). This was accompanied by an increase in HR. The AVP plasma level was elevated at 4 h (6.0+/-1.1 vs. 1.1+/-0.2 pg/mL, P<0.05) and returned to basal levels at 8 h after CLP (2.3+/-0.5 vs. 1.9+/-0.2 pg/mL, P>0.05). A reduction in baroreflex sensitivity occurred 1 h after injury. The CLP group showed a reduction in overall variability, low-frequency power, and low/high-frequency ratio of HR and low-frequency power of MAP. The data suggest an impairment of autonomic control of the heart and vessels during polymicrobial sepsis. This reduction in autonomic nervous system activity causes the impairment of baroreflex that in turn may contribute to the reduction of vasopressin plasma levels in the late phase of severe sepsis.

Topics: Animals; Autonomic Nervous System; Autonomic Nervous System Diseases; Baroreflex; Blood Pressure; Cecum; Disease Models, Animal; Heart Rate; Hypotension; Ligation; Male; Osmolar Concentration; Peritonitis; Rats; Rats, Wistar; Sepsis; Shock, Septic; Sodium; Time Factors; Up-Regulation; Vasopressins

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Endotoxemia; Glucocorticoids; Hormones; Humans; Inflammation Mediators; Neurophysins; Prednisolone; Protein Precursors; Shock, Septic; Vasopressins

Patients with septic shock are haemodynamically unstable and suffer from vasodilation. Studying the human forearm vascular bed in patients with septic shock, we tested the hypothesis that the responses to regionally infused endothelium-(in)dependent vasodilators and vasoconstrictors are uniformly impaired. Forearm blood flow (FBF, venous occlusion plethysmography) and brachial arterial pressure were determined to calculate forearm vascular resistance (FVR) in eight consecutive sedated, mechanically ventilated patients with septic shock (APACHE II Score range 21-34, SOFA Score 11-16) and 11 healthy volunteers. Despite increased baseline FBF in patients with septic shock (6.1 (SD 1.5) ml x min(-1) x (100 ml of tissue)(-1) compared to 4.7 (1.4) in volunteers) the significant decreases in FVR seen in response to exogenous nitric oxide (nitroprusside) and acetylcholine did not differ between groups. However, compared to volunteers, mitigation of endogenous nitric oxide production by a low dose of N(G)-methyl-L-arginine acetate (L-NMMA) caused a significant increase (+6.7 mmHg x min x ml(-1)) in septic patients. Regional vasoconstriction in response to phenylephrine (FVR: +9.9 vs +30.7 mmHg x min x ml(-1) in controls) and angiotensin II (FVR: +9.0 vs +67.4 mmHg x min x ml(-1)) was markedly impaired. In contrast, vasopressin, in dosages evoking no vasoconstriction in volunteers, induced a significant increase in FVR in septic patients (+10.0 mmHg x min x ml(-1)). In the forearm of patients with septic shock, vasoconstriction by alpha1- and angiotensin II receptor agonists is selectively impaired, whereas the vasoconstrictor response to vasopressin is exaggerated. These findings exclude a generalised impairment of vasomotor activity in patients with septic shock and provide a rationale for vasopressin administration.

Topics: Adult; Aged; Endothelium, Vascular; Forearm; Humans; Middle Aged; Plethysmography; Shock, Septic; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins

The present study was designed to assess the hypothesis that dexamethasone (DEX) through the control of nitric oxide (NO) synthesis could regulate the release of vasopressin (AVP), which plays an important role in the regulation of arterial pressure and plasma osmolality. Endotoxemic shock was induced by intravenous (i.v.) injection of 1.5 mg/kg lipopolisaccharide (LPS) in male Wistar rats weighing 250-300 g. After LPS administration, a group of animals were treated with DEX (1.0 mg/kg of body weight), whereas saline-injected rats served as controls. The LPS administration induced a significant decrease in mean arterial pressure (MAP) with a concomitant increase in heart rate (HR) (Delta VMAP: -16.1+/-4.2 mm Hg; Delta VHR: 47.3+/-8.1 bpm). An increase in plasma AVP concentration occurred and was present for 2 h after LPS administration (11.1+/-0.9 pg/mL) returning close to basal levels thereafter and remaining unchanged until the end of the experiment. When LPS was combined with i.v. administration of a low dose of DEX, we observed an attenuation in the drop of MAP (Delta VMAP: -2.2+/-1.9 mm Hg) and a decrease in NO plasma concentration [NO] after LPS administration (1098.1+/-68.1 microM) compared to [NO] after DEX administration (523.4+/-75.2 microM). However, this attenuation in the drop of MAP was accompanied by a decrease in AVP plasma concentration (3.7+/-0.4 pg/mL). These data suggest that AVP does not participate in the recovery of MAP when DEX is administered in this endotoxemic shock model.

Topics: Animals; Blood Pressure; Dexamethasone; Glucocorticoids; Lipopolysaccharides; Male; Nitric Oxide; Rats; Rats, Wistar; Shock, Septic; Vasopressins

Topics: Blood Pressure; Catecholamines; Drug Therapy, Combination; Humans; Norepinephrine; Shock, Septic; Time Factors; Vasoconstrictor Agents; Vasopressins

The choice of inotropic agent, particularly in catecholamine-resistant septic shock, remains an area of debate. Here we discuss a recent trial examining the use of vasopressin in a carefully controlled trial setting. Yet more data on the use of drotrecogin alfa (activated) in septic shock are described, as are novel but as yet experimental approaches to the treatment of sepsis. Finally, it is important not to forget to read the latest surviving sepsis guidelines.

Topics: Anti-Infective Agents; Clinical Trials as Topic; Humans; Incidence; Norepinephrine; Practice Guidelines as Topic; Protein C; Recombinant Proteins; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Drug Therapy, Combination; Humans; Norepinephrine; Shock, Septic; Survival Analysis; Vasoconstrictor Agents; Vasopressins

The administration of lipopolysaccharide (LPS) to experimental animals results in a septic shock-like syndrome characterized by hypotension, and the hemodynamic management includes the restoration of adequate tissue perfusion by administration of resuscitation fluids to achieve an effective circulating volume. In the present study, we sought to investigate the effects of hypertonic saline solution administration on vasopressin secretion and mean arterial pressure in endotoxic shock. The pressor response to isotonic saline solution (0.9% sodium chloride) or hypertonic saline (7.5% sodium chloride, 4 mL/kg i.v.) was evaluated 4 h after LPS (1.5 mg/kg) administration. At this moment, plasma vasopressin did not differ from control; however, the blood pressure was lower in the LPS-treated group. The hypertonic saline administration was followed by an immediate recovery of blood pressure and also by an increase in plasma vasopressin levels compared with isotonic saline solution. The vasopressin V1 receptor antagonist (10 microg/kg, i.v., 5 min before infusion) blocked the pressor response to hypertonic saline solution. These data suggest that the recovery of blood pressure after hypertonic saline solution administration during endotoxic shock is mediated by vasopressin secretion.

Topics: Animals; Blood Pressure; Male; Rats; Rats, Wistar; Saline Solution, Hypertonic; Shock, Septic; Vasopressins

Vasopressin increases arterial pressure in septic shock even when alpha-adrenergic agonists fail. The authors studied the effects of vasopressin on microcirculatory blood flow in the entire gastrointestinal tract in anesthetized pigs during early septic shock.. Thirty-two pigs were intravenously anesthetized, mechanically ventilated, and randomly assigned to one of four groups (n=8 in each; full factorial design). Group S (sepsis) and group SV (sepsis-vasopressin) were made septic by fecal peritonitis. Group C and group V were nonseptic control groups. After 300 min, group V and group SV received intravenous infusion of 0.06 U.kg.h vasopressin. In all groups, cardiac index and superior mesenteric artery flow were measured. Microcirculatory blood flow was recorded with laser Doppler flowmetry in both mucosa and muscularis of the stomach, jejunum, and colon.. While vasopressin significantly increased arterial pressure in group SV (P<0.05), superior mesenteric artery flow decreased by 51+/-16% (P<0.05). Systemic and mesenteric oxygen delivery and consumption decreased and oxygen extraction increased in the SV group. Effects on the microcirculation were very heterogeneous; flow decreased in the stomach mucosa (by 23+/-10%; P<0.05), in the stomach muscularis (by 48+/-16%; P<0.05), and in the jejunal mucosa (by 27+/-9%; P<0.05), whereas no significant changes were seen in the colon.. Vasopressin decreased regional flow in the superior mesenteric artery and microcirculatory blood flow in the upper gastrointestinal tract. This reduction in flow and a concomitant increase in the jejunal mucosa-to-arterial carbon dioxide gap suggest compromised mucosal blood flow in the upper gastrointestinal tract in septic pigs receiving low-dose vasopressin.

Topics: Animals; Blood Pressure; Gastrointestinal Tract; Heart Rate; Microcirculation; Shock, Septic; Splanchnic Circulation; Swine; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Biomedical Research; Humans; Shock, Septic; Time Factors; Vasopressins

There is escalating interest in the therapeutic use of vasopressin in septic shock. However, little attention has focused on mechanisms underlying its pressor hypersensitivity, which contrasts with the vascular hyporesponsiveness to catecholamines. We investigated whether a long-term rodent model of sepsis would produce changes in endogenous levels and pressor reactivity to exogenous norepinephrine and vasopressin comparable with those seen in septic patients.. In vivo and ex vivo animal study.. University research laboratory.. Male adult Wistar rats.. Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Biochemical and hormonal profiles were measured at time points up to 48 hrs. Pressor responses to intravenous norepinephrine, vasopressin, and F-180, a selective V1 receptor agonist, were measured at 24 hrs. Contractile responses to these drugs were assessed in mesenteric arteries taken from animals at 24 hrs using wire myography. Comparisons were made against sham operation controls.. Septic rats became unwell and hypotensive, with a mortality of 64% at 48 hrs (0% in controls). Plasma norepinephrine levels were elevated in septic animals at 24 hrs (1968 +/- 490 vs. 492 +/- 90 pg/mL in controls, p = .003), whereas vasopressin levels were similar in the two groups (4.5 +/- 0.8 vs. 3.0 +/- 0.5 pg/mL, p = not significant). In vivo, the pressor response to norepinephrine was markedly reduced in the septic animals, but responses to vasopressin and F-180 were relatively preserved. In arteries from septic animals, norepinephrine contractions were decreased (efficacy as measured by maximum contractile response, Emax: 3.0 +/- 0.3 vs. 4.7 +/- 0.2 mN, p < .001). In contrast, the potency of vasopressin (expressed as the negative log of the concentration required to produce 50% of the maximum tension, pD2: 9.1 +/- 0.04 vs. 8.7 +/- 0.05, p < .001) and F-180 (pD2 8.2 +/- 0.04 vs. 7.6 +/- 0.02, p < .001) was enhanced (n > or = 6 for all groups).. This long-term animal model demonstrates changes in circulating vasoactive hormones similar to prolonged human sepsis, and decreased pressor sensitivity to norepinephrine. Ex vivo sensitivity to vasopressin agonists was heightened. This model is therefore appropriate for the further investigation of mechanisms underlying vasopressin hypersensitivity, which may include receptor or calcium-handling alterations within the vasculature.

Topics: Animals; Disease Models, Animal; Norepinephrine; Rats; Rats, Wistar; Shock, Septic; Time Factors; Vasoconstrictor Agents; Vasomotor System; Vasopressins

Vasopressin has been shown to increase blood pressure in catecholamine-resistant septic shock. The aim of this study was to measure the effects of low-dose vasopressin on regional (hepato-splanchnic and renal) and microcirculatory (liver, pancreas, and kidney) blood flow in septic shock.. Thirty-two pigs were anesthetized, mechanically ventilated, and randomly assigned to one of four groups (n = 8 in each). Group S (sepsis) and group SV (sepsis/vasopressin) were exposed to fecal peritonitis. Group C and group V were non-septic controls. After 240 minutes, both septic groups were resuscitated with intravenous fluids. After 300 minutes, groups V and SV received intravenous vasopressin 0.06 IU/kg per hour. Regional blood flow was measured in the hepatic and renal arteries, the portal vein, and the celiac trunk by means of ultrasonic transit time flowmetry. Microcirculatory blood flow was measured in the liver, kidney, and pancreas by means of laser Doppler flowmetry.. In septic shock, vasopressin markedly decreased blood flow in the portal vein, by 58% after 1 hour and by 45% after 3 hours (p < 0.01), whereas flow remained virtually unchanged in the hepatic artery and increased in the celiac trunk. Microcirculatory blood flow decreased in the pancreas by 45% (p < 0.01) and in the kidney by 16% (p < 0.01) but remained unchanged in the liver.. Vasopressin caused marked redistribution of splanchnic regional and microcirculatory blood flow, including a significant decrease in portal, pancreatic, and renal blood flows, whereas hepatic artery flow remained virtually unchanged. This study also showed that increased urine output does not necessarily reflect increased renal blood flow.

Topics: Animals; Kidney; Liver; Liver Circulation; Pancreas; Regional Blood Flow; Renal Circulation; Shock, Septic; Splanchnic Circulation; Swine; Vasopressins

Topics: Case-Control Studies; Critical Care; Female; Hemodynamics; Humans; Male; Shock, Septic; Vasopressins

To determine the effect of vasodilatory septic shock-like conditions on vasoconstricting responses to vasopressin and norepinephrine in isolated resistance arteries.. Prospective, randomized animal study.. University research laboratory.. Male adult Sprague-Dawley rats.. Small mesenteric arteries (outside diameter, 50-150 microm) were cannulated and studied in vitro under physiologic conditions. A vasodilatory septic shock-like state was produced by treatment with the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP), and the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Vasoconstricting concentration-response relationships were determined for norepinephrine and vasopressin before and after application of SNAP or SNAP+ IBMX. Synergism between low-dose vasopressin and norepinephrine and between low-dose norepinephrine and vasopressin was determined before and after SNAP or SNAP+IBMX.. Norepinephrine and vasopressin produced concentration-dependent contractions (half-maximal effective concentration [EC(50)] = 2.5 microM and 3.9 nM, respectively) that were significantly inhibited by 1 microM SNAP (EC(50) = 3.6 microM and 8.1 nM, respectively) or 100 microM SNAP + 10 microM IBMX (EC(50) = 10 microM and 8.2 nM, respectively). Low-dose vasopressin significantly increased the responsiveness to norepinephrine (EC50 = 0.5 microM) just as a low-dose norepinephrine significantly enhanced the vasopressin response (EC(50) = 2.3 nM). The synergistic effects of low-dose vasopressin and norepinephrine, or low-dose norepinephrine and vasopressin, were also significantly inhibited by 1 microM SNAP (EC(50) = 2.5 microM and 4.2 nM, respectively) or 100 microM SNAP + 10 microM IBMX (EC(50) = 9 microM and 8.4 nM, respectively).. Vasoconstriction produced by vasopressin or norepinephrine, and the synergistic vasoconstriction produced by the combinations, was inhibited in vasodilatory septic shock-like conditions. Thus, in addition to the well-described vasopressin deficiency in vasodilatory septic shock, these studies indicate that decreased vasopressin responsiveness further contributes to a state of relative vasopressin insufficiency in this condition.

Topics: Animals; Male; Norepinephrine; Rats; Rats, Long-Evans; Shock, Septic; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasopressins

Topics: Catheterization, Peripheral; Female; Humans; Infusions, Intravenous; Middle Aged; Necrosis; Shock, Septic; Skin Diseases; Vasoconstrictor Agents; Vasopressins

The mortality induced by severe sepsis and septic shock remains very elevated despite progress in diagnosis and treatment. All the experts in the field consider that further progress is possible with better and more prompt use of the treatments now available. The "Surviving Sepsis" campaign reviews the diverse treatments that can be used and the best ways to prescribe them. It also proposes two bundles of objectives to be completed systematically for all patients: the first within the first 6 hours, the second between the sixth and 24th hour. Encouraging results show that applying these therapeutic principles can reduce mortality by 30% (relative percentage) compared with a treatment without specific objectives.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Humans; Hydrotherapy; Hypovolemia; Practice Guidelines as Topic; Sepsis; Shock, Septic; Survivors; Vasopressins

Septic shock is an important cause of death in pediatric intensive care units. Initial evaluations have shown that vasopressin may have a role in catecholamine refractory shock in adults. It is important to determine whether children with septic shock have deficiency of vasopressin. This will help in defining the role of vasopressin in septic shock.. Prospective cohort study.. Pediatric intensive care unit of a tertiary care hospital in north India.. Patients were children with septic shock, and controls were children with sepsis but no shock.. Vasopressin levels in plasma were determined by enzyme-linked immunosorbent assay for children with septic shock at diagnosis (baseline) and thereafter at 24, 48, and 96 hrs to determine the time trends. The baseline vasopressin values for children with septic shock were compared with those for children without shock.. The median (95% confidence interval) vasopressin level at baseline in children with septic shock was 116 (63.3-130.7) pg/mL, and in children with sepsis but no shock it was 106 (61.7-131.77) pg/mL. The median value for survivors was 76 (44.6-130.9) pg/mL, and for nonsurvivors, 118 (81.7-259) pg/mL (p = .16). The serial values also did not show any significant changes; the values at 24 hrs (n = 17), 48 hrs (n = 16), and 96 hrs (n = 15) were 105 (76.1-125.9), 105 (41.4-155.5), and 109.5 (54.9-154.8) pg/mL, respectively.. The results of our study suggest that vasopressin levels are elevated in children with septic shock and that serial values up to 96 hrs do not show any decline.

Topics: Chi-Square Distribution; Child; Child, Preschool; Female; Humans; Infant; Male; Prospective Studies; Shock, Septic; Statistics, Nonparametric; Vasopressins

Topics: Child; Child, Preschool; Female; Humans; Infant; Male; Shock, Septic; Vasopressins

Topics: Antidiuretic Agents; Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

This study examined whether electrolytic ablation of the periventricular anteroventral third ventricle (AV3V) region would affect the hypothalamic activation and the increase of hypophysial hormone secretion induced by systemic injection of lipopolysaccharide (LPS) in rats. LPS significantly increased the number of cells showing Fos immunoreactivity in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus (P<0.05) and also increased plasma levels of vasopressin, oxytocin, adrenocorticotropin and corticosterone (P<0.05). AV3V lesion significantly reduced LPS-induced Fos immunoreactivity (P<0.05) and vasopressin and oxytocin secretion (P<0.05). Elevations in adrenocorticotropin but not in plasma corticosterone after LPS were affected by prior AV3V lesions. These findings demonstrate that LPS-induced Fos expression in the PVN and SON, and hypophysial hormone secretion is dependent on the integrity of the AV3V region.

Topics: Adrenocorticotropic Hormone; Animals; Cardiovascular Physiological Phenomena; Disease Models, Animal; Hypothalamo-Hypophyseal System; Hypothalamus; Inflammation Mediators; Lipopolysaccharides; Male; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Pituitary Hormones; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Shock, Septic; Stress, Physiological; Supraoptic Nucleus; Third Ventricle; Vasopressins; Water-Electrolyte Balance

To evaluate vasopressin as a rescue therapy in catecholamine-refractory septic and cardiogenic shock in very-low-birthweight (VLBW) infants.. Prospective assessment of vasopressin therapy in three VLBW infants with catecholamine-refractory septic shock (24 + 6 wk, 600 g) and cardiogenic shock (26 + 1 wk, 890 g; 26 + 1 wk, 880 g) at a university hospital.. Adequate systemic arterial blood pressure could only be restored after vasopressin administration as a continuous infusion over a 36-h period in the preterm suffering from septic shock; in the two neonates with cardiogenic shock, only a transient stabilization in mean arterial pressure was observed, which did not impact on the poor prognosis.. Although vasopressin appears to be a suitable rescue therapy in catecholamine-resistant septic shock in VLBW infants, further evaluation in controlled clinical trials is warranted.

Topics: Diseases in Twins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Norepinephrine; Shock, Cardiogenic; Shock, Septic; Treatment Failure; Vasoconstrictor Agents; Vasopressins

The septic shock is characterized by decrease in median arterial pressure; many researchers have been related a deficiency in vasopressin release during the septic shock. Lipopolysaccharide administration is used to induce septic shock model in animals. We investigated the heme-oxygenase (HO) inhibition during the endotoxemic shock-like conditions. The LPS administration induced a significant decrease in MAP (-15.4 +/- 1.2 mmHg at second hour, -25.8 +/- 8.7 mmHg at fourth hour, and -22.3 +/- 8.6 mmHg at sixth hour) with a concomitant increase in heart rate (486.3 +/- 55.0, 531.8 +/- 53.8, and 510.0 +/- 55.3 bpm, respectively), a significant decrease in diuresis (from 1.1 +/- 0.7 to 0.4 +/- 0.3/100g body weight at fourth hour), and a transitory decrease in body temperature (from 37.0 +/- 0.5 to 35.4 +/- 0.8 degrees C at second hour). An increase in plasma arginine vasopressin (AVP) concentration (from 3.2 +/- 0.9 to 19.0 +/- 5.7 pg/mL at the first hour) occurred in these animals and was present for 2 h after LPS administration, returning close to basal levels thereafter and remaining unchanged until the end of the experiment. When LPS was combined with the i.c.v. administration of HO inhibitor, we observed a sustained increase in plasma AVP concentration, attenuation in the drop of MAP, and increase in antidiuresis induced by LPS treatment. These data suggest that central HO pathway may activate a control mechanism that attenuates AVP secretion during endotoxemia and may consequently regulate the MAP and diuretic output.

Topics: Animals; Arginine Vasopressin; Blood Pressure; Deuteroporphyrins; Diuresis; Enzyme Inhibitors; Heart Rate; Heme Oxygenase (Decyclizing); Hypotension; Lipopolysaccharides; Male; Rats; Rats, Wistar; Shock, Septic; Vasopressins

Topics: Adult; Blood Pressure; Cardiac Output; Child, Preschool; Dobutamine; Dopamine; Heart Rate; Humans; Norepinephrine; Resuscitation; Shock, Septic; Vasoconstrictor Agents; Vasopressins

We reported anesthetic management of a patient complicated with septic shock. Catecolamines were not effective to improve severe hypotension. Therefore, vasopressin was used and this improved the severe hypotension. Vasopressin may be useful for a patient complicated with septic shock and severe hypotension.

Topics: Abdomen, Acute; Aged; Anesthesia, General; Humans; Hypotension; Male; Shock, Septic; Vasoconstrictor Agents; Vasopressins

This is a report on a case of severe skin necrosis in a vasodilatory septic shock patient after the infusion of low-dose vasopressin through a central venous catheter. An 84-year-old male was hospitalized for edema on both legs at Asan Medical Center, Seoul, Korea. On hospital day 8, the patient began to complain of dyspnea and he subsequently developed severe septic shock caused by E. coli. After being transferred to the medical intensive care unit, his hypotension, which was refractory to norepinephrine, was controlled by an infusion of low-dose vasopressin (0.02 unit/min) through a central venous catheter into the right subclavian vein. After the infusion of low-dose vasopressin, severe skin necrosis with bullous changes developed, necessitating discontinuation of the low-dose vasopressin infusion. The patient expired from refractory septic shock. Although low-dose vasopressin can control hypotension in septic shock patients, low-dose vasopressin must be used with caution because ischemic complications such as skin necrosis can develop even with administration through a central venous catheter.

Topics: Aged, 80 and over; Catheterization, Central Venous; Dose-Response Relationship, Drug; Fatal Outcome; Humans; Infusions, Intravenous; Male; Necrosis; Shock, Septic; Skin; Vasoconstrictor Agents; Vasopressins

Vasopressin is one of the key regulators of the body's water and solute balance. When this balance is pathologically disturbed, determination of serum vasopressin concentrations might be a helpful tool for guiding therapy. However, due to its instability and considerable association to platelets, reliable measurement of circulating vasopressin is difficult to achieve, if at all. In search of a more robust way for quantifying vasopressin release, we identified copeptin, a glycopeptide with unknown function, as an alternative diagnostic target. Since copeptin is derived from the same precursor peptide as vasopressin, released amounts of copeptin should mirror those of vasopressin. With a newly developed sensitive sandwich immunoassay, we detected strongly elevated concentrations of fully processed copeptin in serum of septic shock patients. The magnitude of elevation and the high stability of copeptin in serum and plasma indicate that copeptin measurement is not affected by the problems, which are associated with the direct measurement of vasopressin, and thus is apparently suitable to indirectly determine the release of vasopressin.

Topics: Enzyme-Linked Immunosorbent Assay; Female; Glycopeptides; Humans; Male; Protein Precursors; Shock, Septic; Vasopressins

To describe use of vasopressin infusion for catecholamine-refractory septic shock in children.. We report successful use of vasopressin infusion in three children with septic shock, in whom hypotension and poor perfusion persisted despite use of multiple infusions of vasopressors and inotropes.. All three had a rapid improvement in hypotension and perfusion after starting vasopressin infusion, allowing tapering of other infusions. Two children recovered completely.. Vasopressin appears to be useful in treatment of catecholamine-refractory septic shock in children.

Topics: Adolescent; Catecholamines; Child, Preschool; Female; Humans; Infant; Shock, Septic; Treatment Failure; Vasoconstrictor Agents; Vasopressins

A 64-year-old female patient was admitted to a general intensive care unit with sustained hypotension resulting from severe sepsis. Her admission plasma B-type natriuretic peptide was elevated (407 pg/ml), and echocardiogram displayed normal ventricular dimensions and function. The right ventricular end-diastolic diameter increased with acute fluid loading, and this coincided with a parallel increase in B-type natriuretic peptide. Subsequent fluid depletion was accompanied by a reduction in both right ventricular end-diastolic diameter and B-type natriuretic peptide. The present case indicates that acute fluid loading may alter plasma B-type natriuretic peptide levels, and highlights the importance of taking the clinical context into account when interpreting these levels.

Topics: Creatinine; Electrocardiography; Fatal Outcome; Female; Fluid Therapy; Heart Atria; Heart Ventricles; Hemofiltration; Humans; Hypotension; Intubation, Intratracheal; Middle Aged; Multiple Organ Failure; Natriuretic Peptides; Norepinephrine; Positive-Pressure Respiration; Sepsis; Shock, Septic; Ultrasonography; Vasoconstrictor Agents; Vasopressins

Recent studies demonstrate that vasopressin is useful when treating hemorrhagic and septic shock. The effect of vasopressin on systemic anaphylaxis has not been investigated except in clinical case reports. Vasopressin increases blood pressure because of vasoconstriction through the V1 receptor. Thus, we evaluated the effect of vasopressin on circulatory depression and bronchoconstriction provoked by systemic anaphylaxis and survival rates in rabbits. In the first set of experiments, 15 nonsensitized rabbits received normal saline (control) and vasopressin at 0.8 or 0.08 U/kg. In the second set, 40 sensitized rabbits received horse serum to induce anaphylaxis, and then received the same drugs as in the first set. In the first set, mean arterial pressure (MAP) in vasopressin groups increased by 18% to 24% compared with the control. Vasopressin at 0.8 U/kg decreased MAP insignificantly before the increases of MAP occurred. In the second set, vasopressin at 0.08 U/kg improved the survival rate. At 45 min after antigen challenge, 69% of the rabbits that received vasopressin at 0.08 U/kg were alive, whereas 29% of the control rabbits and 23% of the rabbits that received vasopressin at 0.8 U/kg were alive. Vasopressin increased MAP by 36% to 109% compared with the control within 5 min, however, at 2 min, vasopressin at 0.8 U/kg had no effect on MAP. Pulmonary dynamics were similar. In conclusion, vasopressin at 0.08 U/kg improved survival rates and severe hypotension provoked by systemic anaphylaxis, suggesting that this agent may be useful in the treatment of systemic anaphylaxis.

Topics: Anaphylaxis; Animals; Blood Pressure; Electrocardiography; Female; Hemodynamics; Hypotension; Male; Rabbits; Shock, Septic; Temperature; Time Factors; Treatment Outcome; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

Topics: Blood Pressure; Heart Rate; Humans; Infusions, Intravenous; Shock, Septic; Time Factors; Vasoconstrictor Agents; Vasopressins

Topics: Dose-Response Relationship, Drug; Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Biomarkers; Critical Care; Critical Illness; Female; Humans; Male; Prognosis; Reference Values; Severity of Illness Index; Shock, Septic; Vasopressins

Topics: Adenosine Triphosphate; Blood Pressure; Brain Ischemia; Calcium Channels; Hemostatics; Humans; Hypotension; Muscle, Smooth, Vascular; Shock; Shock, Cardiogenic; Shock, Septic; Vasoconstrictor Agents; Vasodilation; Vasopressins

Norepinephrine (NE), a standard of care, AVP, an alternative candidate, and L-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased ( approximately 35%) but aortic blood flow increased during endotoxin infusion (P < 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio (P < 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance ( approximately 3- to 4-fold), whereas AVP or LC attenuated this drop (P < 0.05 vs. control). In contrast, NE did not improve endotoxin-induced renal dysfunction. Endotoxin induced gut and lung hyperpermeability (P < 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE ( approximately 2-fold increase) but not AVP infusion (P < 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P ( approximately 2- and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function.

Topics: Acid-Base Equilibrium; Adenosine Triphosphate; Animals; Canavanine; Energy Metabolism; Enzyme Inhibitors; Hemodynamics; Intestinal Mucosa; Kidney; Lactic Acid; Lung; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Norepinephrine; Permeability; Phosphocreatine; Pyruvic Acid; Rats; Rats, Wistar; Renal Agents; Shock, Septic; Vasoconstrictor Agents; Vasopressins

1. Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2. In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3 nmol x kg(-1)) increased the diastolic blood pressure (DBP) by about 30 mmHg. Administration of LPS (0.4 and 4 mg x kg(-1)) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3. The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB(1) receptor antagonist SR 141716A (0.1 micromol x kg(-1)), but not by the CB(2) receptor antagonist SR 144528 (3 micromol x kg(-1)), the vanilloid VR1 receptor antagonist capsazepine (1 micromol x kg(-1)) or the histamine H(3) receptor antagonist clobenpropit (0.1 micromol x kg(-1)). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4. We conclude that in the initial phase of septic shock, the activation of presynaptic CB(1) receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response.

Topics: Animals; Autonomic Fibers, Postganglionic; Autonomic Fibers, Preganglionic; Blood Pressure; Camphanes; Capsaicin; Decerebrate State; Disease Models, Animal; Electric Stimulation; Germany; Imidazoles; Infusions, Intravenous; Lipopolysaccharides; Male; Norepinephrine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Presynaptic; Rimonabant; Shock, Septic; Solvents; Thiourea; Vagotomy; Vasomotor System; Vasopressins

To determine whether pressor doses of vasopressin impair organ blood flow in endotoxic shock.. Graded doses of vasopressin or phenylephrine, starting at the clinically recommended doses for pressure support in septic shock, were intravenously infused during endotoxic shock.. University hospital surgical research laboratory.. Twelve random-bred female Yorkshire pigs.. We measured mean arterial pressure, cardiac output, heart rate, pulmonary artery occlusion pressure, and carotid, mesenteric, renal, and iliac blood flows.. Low doses of vasopressin (typically used in the clinical management of septic shock) raised arterial pressure by increasing systemic vascular resistance without a significant preferential effect in the circulations measured. However, moderately greater doses of vasopressin had a very heterogeneous vasoconstrictor action; although there was no significant vasoconstriction in the carotid and iliac circulations, mesenteric and renal blood flows decreased markedly. Furthermore, at pressor doses vasopressin improved cerebral perfusion.. The vasoconstrictor action of exogenous low-dose vasopressin in endotoxic shock does not impair blood flow to any of the vascular beds examined. However, moderately higher doses of vasopressin may induce ischemia in the mesenteric and renal circulations. The data indicate that the safe dose range for exogenous vasopressin in septic shock is narrow and support the current practice of fixed low-dose administration, generally 0.04 units/min and in no case exceeding 0.1 units/min.

Topics: Animals; Blood Pressure; Cardiac Output; Carotid Arteries; Cerebrovascular Circulation; Female; Heart Rate; Iliac Artery; Mesenteric Arteries; Phenylephrine; Pulmonary Artery; Renal Artery; Shock, Septic; Swine; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Shock, Septic; Vasopressins

Topics: Arginine Vasopressin; Blood Circulation; Blood Pressure; Humans; Lypressin; Pulmonary Circulation; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Vasopressin is a potent vasopressor in septic shock, but it may impair splanchnic perfusion. We compared the effects of vasopressin alone and in combination with dobutamine on systemic and splanchnic circulation and metabolism in porcine endotoxin shock.. Twelve pigs were randomized to receive either vasopressin (VASO, n = 6) or vasopressin in combination with dobutamine (DOBU, n = 6) during endotoxin shock (E. coli endotoxin infusion). Endotoxin infusion rate was increased to induce hypotension after which vasoactive drugs were started. We aimed to keep systemic mean arterial pressure (MAP) >70 mmHg by vasopressin; the goal of dobutamine infusion was to prevent decrease in cardiac output often associated with vasopressin infusion. Regional blood flows, oxygen delivery and consumption, arterial and regional lactate concentrations were measured.. Mean arterial pressure >70 mmHg was achieved in both the VASO and DOBU groups. After the primary decrease of cardiac output by vasopressin, systemic blood flow remained stable in vasopressin-treated animals. However, vasopressin as a monotherapy decreased portal venous blood flow. This was prevented by dobutamine. Vasopressin also induced splanchnic lactate release and arterial hyperlactatemia, which were not observed when dobutamine was combined with vasopressin.. Dobutamine prevents adverse hemodynamic and metabolic effects of vasopressin in septic shock.

Topics: Adrenergic beta-Agonists; Animals; Blood Gas Analysis; Cardiac Output; Dobutamine; Female; Fluid Therapy; Hemodynamics; Hemostatics; Hypotension; Lactic Acid; Microdialysis; Pyruvic Acid; Regional Blood Flow; Shock, Septic; Splanchnic Circulation; Swine; Vasopressins

During sepsis, limited data on the survival effects of vasopressors are available to guide therapy. Therefore, we compared the effects of three vasopressors on survival in a canine septic shock model. Seventy-eight awake dogs infected with differing doses of intraperitoneal Escherichia coli to produce increasing mortality were randomized to receive epinephrine (0.2, 0.8, or 2.0 microg.kg(-1).min(-1)), norepinephrine (0.2, 1.0, or 2.0 microg.kg(-1).min(-1)), vasopressin (0.01 or 0.04 U/min), or placebo in addition to antibiotics and fluids. Serial hemodynamic and biochemical variables were measured. Increasing doses of bacteria caused progressively greater decreases in survival (P <0.06), mean arterial pressure (MAP) (P <0.05), cardiac index (CI) (P <0.02), and ejection fraction (EF) (P=0.02). The effects of epinephrine on survival were significantly different from those of norepinephrine and vasopressin (P=0.03). Epinephrine had a harmful effect on survival that was significantly related to drug dose (P=0.02) but not bacterial dose. Norepinephrine and vasopressin had beneficial effects on survival that were similar at all drug and bacteria doses. Compared with concurrent infected controls, epinephrine caused greater decreases in CI, EF, and pH, and greater increases in systemic vascular resistance and serum creatinine than norepinephrine and vasopressin. These epinephrine-induced changes were significantly related to the dose of epinephrine administered. In this study, the effects of vasopressors were independent of severity of infection but dependent on the type and dose of vasopressor used. Epinephrine adversely affected organ function, systemic perfusion, and survival compared with norepinephrine and vasopressin. In the ranges studied, norepinephrine and vasopressin have more favorable risk-benefit profiles than epinephrine during sepsis.

Topics: Animals; Anti-Bacterial Agents; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Epinephrine; Escherichia coli Infections; Infusions, Intravenous; Norepinephrine; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

To investigate the early blood pressure effects of vasopressin compared with titrated catecholamines as initial drug therapy in patients with septic shock.. Retrospective cohort, single-center study.. Intensive care units at the Mayo Clinic, Rochester, Minnesota.. Fifty, 49, and 51 intensive care patients treated initially with vasopressin, norepinephrine, and dopamine, respectively.. Patients received either intravenous infusion of fixed-dose vasopressin 0.04 U/minute or titrated infusions of norepinephrine or dopamine for low systemic arterial pressures.. Patients treated with vasopressin, norepinephrine, and dopamine were similar in all measured characteristics except for their score on the Acute Physiology and Chronic Health Evaluation (APACHE) III (dopamine > vasopressin, p=0.049), renal comorbidities (dopamine > vasopressin, p=0.03) and baseline mean arterial pressure (MAP) (norepinephrine < vasopressin, p=0.005 or dopamine < vasopressin, p=0.05). In all patients, MAP 1 hour before and 1 hour afte intervention, heart rate, and systolic blood pressure were obtained. No treatment differences were identified in achieving postvasopressin MAP after adjusting for APACHE III score, renal dysfunction, and baseline MAP. In patients receiving vasopressin, 28-day mortality was 52%, similar to those receiving norepinephrine (65%, p=0.28) and dopamine (60%, p=0.53).. Initial, fixed-dose vasopressin infusions increased MAP to 70 mm Hg or greater at 1 hour in intensive care patients with septic shock, similar to titrated norepinephrine or dopamine. Fixed-dose vasopressin appears appropriate as an alternative agent for hemodynamic support in patients with septic shock.

Topics: Aged; APACHE; Blood Pressure; Cardiac Output; Dopamine; Female; Humans; Infusions, Intravenous; Length of Stay; Male; Middle Aged; Norepinephrine; Retrospective Studies; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Fluid Therapy; Humans; Hypotension; Lypressin; Rats; Shock, Septic; Terlipressin; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Infusions, Intravenous; Norepinephrine; Shock, Septic; Vasopressins

After induction of cecal perforation, 20 anesthetized sheep were randomized to be treated, when arterial blood pressure fell below 75 mm Hg, with vasopressin (fixed dose of 0.02 U/minute), norepinephrine (0.5-5 microg/kg/minute titrated to maintain mean arterial pressure between 75 and 85 mm Hg), vasopressin + norepinephrine (vasopressin at fixed dose 0.01 U/minute plus norepinephrine titrated as for norepinephrine only group), or no vasopressor (Ringer's lactate [control]). Mean arterial pressure was well maintained in all treatment groups. Superior mesenteric arterial blood flow was significantly lower in the vasopressin + norepinephrine group than in the vasopressin group. Vasopressin alone or combined with norepinephrine limited the increase in blood lactate concentration and ileal PCO2-gap compared with control and norepinephrine groups. Urine output was higher in the vasopressin group than in control and norepinephrine groups. Survival time was longer in the vasopressin (30 +/- 6 hours) and vasopressin + norepinephrine (30 +/- 3 hours) groups than in the norepinephrine group (20 +/- 1 hours, p < 0.05) and in all treatment groups than in the control group (17 +/- 2 hours, p < 0.05). Tissue injury was less severe in the vasopressin and vasopressin + norepinephrine groups than in the others. In this clinically relevant model of septic shock due to peritonitis, vasopressin administration (alone or with norepinephrine) can prolong survival.

Topics: Animals; Blood Pressure; Carbon Dioxide; Cecum; Ileum; Intestinal Perforation; Isotonic Solutions; Lactates; Mesenteric Arteries; Norepinephrine; Proportional Hazards Models; Random Allocation; Ringer's Lactate; Sheep; Shock, Septic; Splanchnic Circulation; Statistics, Nonparametric; Survival Rate; Vasoconstrictor Agents; Vasopressins

To assess the frequency of vasopressin deficiency in septic shock.. Prospective cohort study.. Intensive care unit at Raymond Poincaré University Hospital.. A cohort of 44 patients who met the usual criteria for septic shock for < 7 days. A second cohort of 18 septic shock patients were enrolled within the first 8 hrs of disease onset.. None.. General demographics, severity scores, vital signs, standard biochemical data, and circulating vasopressin levels were systematically obtained at baseline in the two cohorts. Vasopressin deficiency was defined by a normal plasma vasopressin level in the presence of a systolic blood pressure of <100 mm Hg or in the presence of hypernatremia. Baroreflex sensitivity was systematically evaluated in patients of the first cohort when vasopressin deficiency was noted. In the second cohort of patients, plasma levels of vasopressin were obtained at baseline, 6, 24, 48, and 96 hrs after shock onset. In the first population, plasma vasopressin levels were inversely correlated to the delay from shock onset. Fourteen patients had relative vasopressin deficiency: 12 patients had systolic blood pressure <100 mm Hg, with impaired baroreflex sensitivity in four, and three patients had hypernatremia. In the second population, only two patients had relative vasopressin deficiency. The plasma levels of vasopressin significantly decreased over time (p < 10-3).. Plasma vasopressin levels are almost always increased at the initial phase of septic shock and decrease afterward. Relative vasopressin deficiency is seen in approximately one-third of late septic shock patients.

Topics: Analysis of Variance; Baroreflex; Blood Pressure; Female; France; Humans; Inappropriate ADH Syndrome; Male; Middle Aged; Osmolar Concentration; Prospective Studies; Shock, Septic; Sodium; Statistics, Nonparametric; Time Factors; Vasopressins; Water-Electrolyte Balance

Vasopressin (AVP) response has been reported to be inappropriately low in adult established septic shock. We studied admission AVP levels in children with meningococcal septic shock (MSS).. All children with meningococcal infection admitted to our PICU between May 2001 and August 2002 were classified as MSS (persistent hypotension despite fluid therapy, with perfusion abnormalities and the need for vasoactive drug infusion for at least 24 h or until death), or meningococal infection without shock (fever and purpura, with or without meningitis). Blood samples were collected at admission and AVP levels were subsequently determined using Nichols Institute Diagnostics vasopressin assay. Eighteen of 19 children with MSS (7 deaths) and 15 without shock (no death) were included.. In children with MSS median admission AVP level was 41.6 pg/ml (1.4-498.9) and in those without 3.3 pg/ml (1.6-63.8). In children with MSS the AVP level was not correlated with duration of shock and fluid expansion prior to AVP sampling, or with age-adjusted blood pressure and natremia at the time of blood sampling. AVP levels were higher in nonsurvivors, but not significantly so. Only one nonsurvivor had an admission AVP level below 30 pg/ml.. In our children with established MSS who died the admission AVP level Delta were not inappropriately low. Further studies including serial AVP level assessments are needed before concluding that AVP administration is of little interest in children with MSS.

Topics: Child, Preschool; Hospitalization; Humans; Infant; Infant, Newborn; Meningococcal Infections; Predictive Value of Tests; Prospective Studies; Shock, Septic; Vasopressins

Topics: Bacillus cereus; Blood Pressure Determination; Female; Humans; Hypotension; Infant; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Septic shock is still the major cause of death in surgical intensive care unit. Fluid support, inotropic agents, and broad spectrum antibiotics are still the mainstay of traditional therapy. Here, we present a case of septic shock arising from gangrenous ischemic bowel, complicated by chronic pulmonary hypertension, which was refractory to catecholamine vasoprerssors. We successfully stabilized the hemodynamics and reduce the pulmonary hypertension with low-dose vasopressin infusion.

Topics: Aged; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Shock, Septic; Vasoconstrictor Agents; Vasopressins

We compared the effects of vasopressin and norepinephrine on systemic and splanchnic circulation and metabolism in endotoxin shock in pigs. Twenty-one pigs were randomized to endotoxin shock (Escherichia coli endotoxin infusion) (n = 6), endotoxin and vasopressin (VASO; n = 6), endotoxin and norepinephrine (NE; n = 6), and controls (n = 3). Endotoxin infusion was increased to induce hypotension, after which vasopressin or norepinephrine was started to keep systemic mean arterial blood pressure >70 mm Hg. Regional blood flows and arterial and regional lactate concentrations were measured. Tonometers with microdialysis capillaries were inserted into the stomach, jejunum, and colon. Systemic mean arterial blood pressure >70 mm Hg was achieved in the VASO and NE groups. Vasopressin decreased cardiac output, superior mesenteric artery, and portal vein blood flow, whereas hepatic arterial blood flow increased. Arterial lactate concentration increased from 2.0 mM (1.6-2.1 mM) to 4.7 mM (4.7-4.9 mM) (P = 0.007). Systemic and mesenteric oxygen delivery and consumption decreased and oxygen extraction increased in the VASO group. Vasopressin increased mucosal-arterial PCO(2) gradients in all three locations, whereas luminal lactate release occurred only in the jejunum. Animals in the NE group remained stable. Vasopressin reversed hypotension but decreased systemic and gut blood flow. This was associated with hyperlactatemia, signs of visceral dysoxia, and jejunal luminal lactate release.. Although vasopressin induces vasoconstriction in visceral region, its effects on splanchnic circulation and metabolism during septic-endotoxin shock are still poorly characterized. We evaluated the metabolic and hemodynamic effects of vasopressin and norepinephrine within the splanchnic area in porcine endotoxin shock.

Topics: Animals; Blood Gas Analysis; Blood Volume; Endotoxins; Female; Fluid Therapy; Hemodynamics; Lactic Acid; Liver Circulation; Microdialysis; Norepinephrine; Oxygen Consumption; Regional Blood Flow; Shock, Septic; Splanchnic Circulation; Swine; Vasopressins

To describe a case of severe skin necrosis resulting from peripheral intravenous administration of low-dose vasopressin in a patient with catecholamine-resistant septic shock.. Case report.. Medical intensive care unit at the University of Chicago, Chicago, IL.. A 46-yr-old female with ventilator-dependent, proliferative-phase acute respiratory distress syndrome complicated by Pseudomonas aeruginosa bacteremia and sepsis.. A patient recovering from acute respiratory distress syndrome developed septic shock from Pseudomonas aeruginosa bacteremia while in the medical intensive care unit. Vasopressin (0.04 units/min) was administered through a peripheral venous catheter for hypotension unresponsive to exogenous catecholamines. The patient subsequently developed severe ischemic necrosis of the skin and soft tissue surrounding the catheter site. The vasopressin was stopped, and the skin lesion progressed to bullae formation with extensive superficial erosion.. Peripheral administration of low-dose vasopressin for septic shock should be discouraged because of the risk of ischemic skin complications.

Topics: Dose-Response Relationship, Drug; Extravasation of Diagnostic and Therapeutic Materials; Female; Humans; Illinois; Infusions, Intravenous; Middle Aged; Necrosis; Pseudomonas Infections; Shock, Septic; Skin; Treatment Failure; Vasoconstrictor Agents; Vasopressins

Vasodilatory shock is a syndrome with high mortality. It is becoming evident that depletion of antidiuretic hormone (ADH) after cardiac surgery or during sepsis plays an important role in the pathogenesis of this condition. Established vasodilatory shock responds well to exogenous ADH infusion. It is possible that preventing ADH depletion at an earlier stage may abrogate the onset of vasodilatory shock, or at least reduce its severity. This paper examines the evidence supporting this concept, and the potential areas of concern in considering this particular type of hormone replacement therapy.

Topics: Animals; Cardiopulmonary Bypass; Drug Administration Schedule; Heart-Lung Machine; Humans; Hypotension; Infusions, Intravenous; Models, Animal; Pulsatile Flow; Randomized Controlled Trials as Topic; Retrospective Studies; Safety; Shock, Septic; Shock, Surgical; Vasodilation; Vasopressins

Topics: Adult; Hemodynamics; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Shock, Septic; Treatment Outcome; Vasopressins

To assess the mechanisms underlying the inappropriately low plasma vasopressin levels reported in septic shock.. Prospective case series.. A 26-bed general medical intensive care unit at a university hospital.. Septic shock patients.. In three consecutive patients with septic shock, plasma vasopressin levels, circulating vasopressinase activity, baroreflex sensitivity, and neurohypophyseal vasopressin content were assessed. Plasma vasopressin concentration was unexpectedly within normal range in two patients (1.6 pg/mL and 1.8 pg/mL) and increased in one (16 pg/mL). In all cases, vasopressinase activity was undetectable, baroreflex sensitivity was decreased, and the high signal intensity of the posterior lobe of the pituitary gland on T1-weighted magnetic resonance images was absent. Magnetic resonance imaging and plasma vasopressin levels normalized after recovery from shock in the patient who survived.. These data suggest that in septic shock, inappropriately low plasma levels of vasopressin are at least partly related to a depletion of vasopressin stores in the neurohypophysis.

Topics: Aged; Baroreflex; Cystinyl Aminopeptidase; Fourier Analysis; Gas Gangrene; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Gland, Posterior; Pneumonia; Prospective Studies; Shock, Septic; Soft Tissue Infections; Statistics, Nonparametric; Vasopressins

Topics: Humans; Magnetic Resonance Imaging; Pituitary Gland, Posterior; Shock, Septic; Vasopressins

Topics: Hemodynamics; Humans; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Septic shock is characterized by arteriolar vasodilation and hypotension. We have tested the hypothesis that nitric oxide arising from inducible nitric oxide synthase in the central nervous system is responsible for the deficiency in vasopressin release and consequent hypotension during experimental septic shock.. Septic shock was induced in male Wistar rats by intravenous injection of 1.5 mg/kg lipopolysaccharide. After lipopolysaccharide administration, we found a significant decrease in mean arterial pressure with a concomitant increase in heart rate, a significant decrease in diuresis, and a transitory decrease in body temperature. An increase in plasma vasopressin concentrations occurred in these animals and was present for 2 hrs after lipopolysaccharide administration, returning close to basal concentrations thereafter and remaining unchanged for the next 24 hrs. When lipopolysaccharide was combined with central administration of aminoguanidine, an inducible nitric oxide synthase inhibitor, we observed a sustained increase in plasma vasopressin concentration and in the maintenance of blood pressure at 4 and 6 hrs after lipopolysaccharide treatment compared with rats treated with lipopolysaccharide alone.. These data indicate that central nitric oxide arising from the inducible nitric oxide synthase pathway plays an important inhibitory role in vasopressin release during experimental septic shock and may be responsible for the hypotension occurring in this vasodilatory shock.

Topics: Animals; Central Nervous System; Enzyme Inhibitors; Guanidines; Hemodynamics; Hypotension; Lipopolysaccharides; Male; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Shock, Septic; Vasopressins

Topics: Animals; Enzyme Inhibitors; Guanidines; Humans; Nitric Oxide; Nitric Oxide Synthase; Rats; Shock, Septic; Vasoconstrictor Agents; Vasopressins

We retrospectively investigated the effects of continuous arginine vasopressin (AVP) infusion on systemic hemodynamics, acid/base status, and laboratory variables in patients (mean age [mean +/- SD]= 66.3 +/- 10.1 yr) with catecholamine-resistant septic (n = 35) or postcardiotomy shock (n = 25). Hemodynamic and acid/base data were obtained before; 30 min after; and 1, 4, 12, 24, 48, and 72 h after the start of AVP infusion. Laboratory examinations were recorded before and 24, 48, and 72 h after the start of AVP infusion. For statistical analysis, a mixed-effects model was used. The overall intensive care unit mortality was 66.7%. AVP administration caused a significant increase in mean arterial pressure (+29%) and systemic vascular resistance (+56%), accompanied by a significant decrease in heart rate (-24%) and mean pulmonary arterial pressure (-11%) without any change in stroke volume index. Norepinephrine requirements could be reduced by 72% within 72 h. During AVP infusion, a significant increase in liver enzymes and total bilirubin concentration and a significant decrease in platelet count occurred. Arginine vasopressin was effective in reversing systemic hypotension. However, adverse effects on gastrointestinal perfusion and coagulation cannot be excluded.. In this retrospective analysis, the influence of a continuous infusion of an endogenous hormone (arginine vasopressin) on systemic hemodynamics and laboratory variables was assessed in patients with vasodilatory shock unresponsive to conventional therapy. Arginine vasopressin was effective in reversing systemic hypotension. However, adverse effects on gastrointestinal perfusion and coagulation cannot be excluded.

Topics: Acid-Base Equilibrium; Aged; Cardiac Surgical Procedures; Catecholamines; Critical Care; Drug Resistance; Female; Hemodynamics; Humans; Male; Models, Biological; Norepinephrine; Postoperative Complications; Retrospective Studies; Shock; Shock, Septic; Stroke Volume; Survivors; Vasoconstrictor Agents; Vasopressins

To review all cases of septic shock treated with vasopressin to determine the effects on hemodynamic and renal function and to document any adverse effects.. A 14-bed mixed medical-surgical ICU of St. Paul's Hospital, a 450-bed tertiary referral hospital affiliated with the University of British Columbia.. All ICU patients who received vasopressin for treatment of severe septic shock between August 5, 1997, and March 21, 1999.. We identified 50 patients: age 60 (+/-14); APACHE II score 27 (+/-7). Baseline data (T0) was compared to data at T4, T24 and T48 (4, 24 and 48 h) on infusion. Mean arterial pressure (MAP) increased by 18% from T0 to T4 and remained stable at T24 (p=0.006) and T48 (p=0.008). Systolic pulmonary artery pressure (PAP) was unchanged at 45+/-13 mmHg. Mean cardiac index (CI) decreased by 11% at T4 (p=0.03). Urine output increased 79% at T4 (p=0.005) and further increases were not significant at T24 and T48. Mean pressor dosage decreased by 33% at T4 (p=0.001), by 53% at T24 (p=0.002) and by 48% at T48 (p=0.01). Hospital mortality was 85%. There were six cardiac arrests; all but one occurred at a vasopressin dose of 0.05 U/min or more.. In this group of patients with severe septic shock, vasopressin infusion increased MAP and urine output and decreased catecholamine requirements. Doses higher than 0.04 U/min were not associated with increased effectiveness and may have been associated with higher adverse effects.

Topics: Analysis of Variance; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Retrospective Studies; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

We studied the effects of vasopressin on contraction in normal and endotoxin-treated human gastroepiploic arterial rings in vitro. In this tissue, vasopressin (50-500 pg/mL) produced concentration-dependent, endothelium-independent contractions. Vasopressin also potentiated the contraction elicited by 1.0 micromol/L norepinephrine (NE) in both the presence and absence of endothelium. Endotoxin (10 microg/mL) attenuated the 1.0 micromol/L NE-induced contractions, and this attenuation was reversed by 300 micromol/L N(G)-nitro-L-arginine-methyl ester (L-NAME) and by 300 micromol/L N(G)-nitro-L-arginine (L-NoArg). After 12 h endotoxin treatment, the vasopressin-induced contraction was attenuated, and the enhancing effect of vasopressin was diminished. However, both before and after endotoxin, the enhancement produced by vasopressin was larger than the vasopressin-contraction itself. An antagonist of the vasopressin V1 receptor, 1.0 micromol/L beta-mercapto-[beta,beta-cyclopentamethylenpropionyl1,O-MeTyr2+ ++,Arg8]-vasopressin, and an antagonist of V1 + V2 receptor receptor, 1.0 micromol/L des-Gly9-[beta-mercapto-beta,beta-cyclopentamethylenepropionyl1 ,O-Et-Tyr2,Val,Arg8]-vasopressin, each diminished the vasopressin-induced enhancement of the NE contraction.. The results of our study suggest that, in addition to its direct vasoconstrictor effect, vasopressin strongly enhances the responses to norepinephrine through V1-receptor stimulation and that vasopressin could find a role in the management of endotoxin-induced vasodilation.

Topics: Adult; Aged; Arteries; Drug Synergism; Endothelium, Vascular; Endotoxins; Humans; In Vitro Techniques; Middle Aged; Muscle Contraction; Omentum; Shock, Septic; Stomach; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Shock, Septic; Vasodilation; Vasopressins

Topics: Animals; Shock, Septic; Vasodilation; Vasopressins

Administration of a low dose of endotoxin (from Escherichia coli, 3 mg kg(-1), i.v.), which does not affect vascular permeability or blood pressure over 1 h, leads to the release of endogenous vasopressin and damage to the mucosal microvasculature. Thus, endogenous vasopressin could be involved in septic shock. In the present study, we investigated the role of endogenous vasopressin in gastrointestinal mucosal injury induced by acute endotoxin shock, which was generated in rats by administering a high dose of E. coli endotoxin (50 mg kg(-1), i.v.). Tissues were removed 15 min after endotoxin. The vasopressin V1 receptor antagonist, d[CH2]5Tyr[Me]arginine-vasopressin (0.2-1 microg kg(-1), i.v.), was injected 10 min before endotoxin. Monastral blue (30 mg kg(-1), i.v.), which stains damaged vasculature, was injected 10 min before autopsy. Endotoxin reduced systemic arterial blood pressure (from 115+/-5 to 42+/-4 mmHg), generated macroscopic and microvascular injury, and elevated plasma vasopressin levels (from 3.4+/-0.2 to 178+/-16 pg ml(-1)). The vasopressin V1 receptor antagonist reduced this macroscopic injury, and in the vasopressin-deficient Brattleboro rat a similar reduction of gastrointestinal mucosal damage was found. Substantial decreases in endotoxin-induced microvascular damage were observed in each tissue, e.g., the gastric Monastral blue staining was reduced by 47+/-3% and 96+/-3% (P < 0.01) after vasopressin V1 receptor antagonist treatment and in Brattleboro rats, respectively. Vasopressin, acting through its V1 receptors, thus appears to be involved in acute endotoxin shock-provoked gastrointestinal injury.

Topics: Animals; Endotoxins; Female; Gastric Mucosa; Intestinal Mucosa; Rats; Rats, Brattleboro; Rats, Wistar; Shock, Septic; Species Specificity; Vasopressins

Arginine vasopressin V1 receptor antagonist (AVPRA) was administered to investigate the influence of vasopressin blockade on hemodynamics and metabolism during endotoxin shock.. Anesthetized rats were divided into four groups: control (0.9% saline solution, n = 5), drug control (AVPRA, n = 5), endotoxin (endotoxin, 5 mg/kg, n = 10), and pretreatment (AVPRA and endotoxin, n = 10). Hemodynamics and oxygen transport were evaluated for 2 hours. Terminal arterial and portal venous concentrations of endotoxin, pyruvate, lactate, and ketone bodies were determined.. The endotoxin group maintained blood pressure levels similar to those of control animals. AVPRA pretreatment decreased vascular resistance and resulted in lower blood pressure than endotoxin alone. Endotoxin decreased oxygen consumption and the oxygen extraction ratio and increased arterial lactate concentration and the lactate/pyruvate ratio. Endotoxin also decreased arterial ketone body concentration and markedly decreased ketone body availability in the mesenteric circulation. AVPRA pretreatment improved oxygen consumption, oxygen extraction ratio, and ketone body availability; arterial lactate concentration, lactate/pyruvate ratio, and arterial ketone body concentration were not affected. Pretreatment with AVPRA also decreased arterial and portal venous concentrations of endotoxin.. Vasopressin receptor blockade during endotoxemia resulted in lower blood pressure than endotoxin alone. Vasopressin receptor blockade also maintained oxygen extraction ratio and ketone body availability in the mesenteric circulation. Vasopressin may play a key role in the response to endotoxemia.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Endotoxins; Hemodynamics; Hormone Antagonists; Ketone Bodies; Male; Mononuclear Phagocyte System; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Shock, Septic; Vasopressins

The hypotension of septic shock is due to systemic vasodilation. On the basis of a clinical observation, we investigated the possibility that a deficiency in vasopressin contributes to the vasodilation of septic shock.. In 19 patients with vasodilatory septic shock (systolic arterial pressure [SAP] of 92 +/- 2 mm Hg [mean +/- SE], cardiac output [CO] of 6.8 +/- 0.7 L/min) who were receiving catecholamines, plasma vasopressin averaged 3.1 +/- 1.0 pg/mL. In 12 patients with cardiogenic shock (SAP, 99 +/- 7 mm Hg; CO, 3.5 +/- 0.9 L/min) who were also receiving catecholamines, it averaged 22.7 +/- 2.2 pg/mL (P < .001). A constant infusion of exogenous vasopressin to 2 patients with septic shock resulted in the expected plasma concentration, indicating that catabolism of vasopressin is not increased in this condition. Although vasopressin is a weak pressor in normal subjects, its administration at 0.04 U/min to 10 patients with septic shock who were receiving catecholamines increased arterial pressure (systolic/diastolic) from 92/52 to 146/66 mm Hg (P < .001/P < .05) due to peripheral vasoconstriction (systemic vascular resistance increased from 644 to 1187 dyne.s/cm5; P < .001). Furthermore, in 6 patients with septic shock who were receiving vasopressin as the sole pressor, vasopressin withdrawal resulted in hypotension (SAP, 83 +/- 3 mm Hg), and vasopressin administration at 0.01 U/min, which resulted in a plasma concentration (approximately 30 pg/mL) expected for the level of hypotension, increased SAP from 83 to 115 mm Hg (P < .01).. Vasopressin plasma levels are inappropriately low in vasodilatory shock, most likely because of impaired baroreflex-mediated secretion. The deficiency in vasopressin contributes to the hypotension of vasodilatory septic shock.

Topics: Adult; Blood Pressure; Cardiac Output; Dopamine; Epinephrine; Heart Rate; Hemodynamics; Humans; Norepinephrine; Shock, Cardiogenic; Shock, Septic; Sodium; Vascular Resistance; Vasodilation; Vasopressins

The cardiovascular effects of intracerebroventricular (i.c.v.) administration of choline were studied in endotoxin-treated rats. Intravenous (i.v.) endotoxin (20 mg/kg) caused a moderate hypotension and tachycardia within 10 min of treatment. Choline (50, 100, and 150 microg; i.c.v.) increased blood pressure and decreased heart rate in this condition in a dose-dependent manner. Mecamylamine (50 microg; i.c.v.) pretreatment prevented the pressor and bradycardic responses to choline, whereas atropine (10 microg; i.c.v.) failed to alter both responses. Atropine pretreatment, alone, inhibited endotoxin-induced hypotension. The pressor responses to choline in endotoxin-treated rats were attenuated by pretreatment with hemicholinium-3 (20 microg; i.c.v.), a high-affinity neuronal choline-uptake inhibitor. Plasma vasopressin levels of endotoxin-treated rats were severalfold higher than those of control animals, and choline (50-150 microg; i.c.v.) produced further increases in plasma vasopressin in this condition. Mecamylamine abolished vasopressin response to endotoxin as well as to choline. The vasopressin receptor antagonist, (beta-mercapto-beta,beta-cyclopentamethylene-propionyl(1)-O-Me-Tyr2,Arg8 )-vasopressin (10 microg/kg; i.v.) administered 5 min after choline decreased blood pressure from the increased level to the precholine levels but did not alter bradycardia. These results indicate that, in rats treated with endotoxin, choline increases blood pressure and decreases heart rate by a presynaptic mechanism leading to the activation of central nicotinic cholinergic pathways. An increase in plasma vasopressin levels seems to be involved in the pressor, but not in the bradycardic response, to choline.

Topics: Animals; Blood Pressure; Choline; Cholinergic Agents; Dose-Response Relationship, Drug; Endotoxins; Heart Rate; Hormone Antagonists; Hypotension; Injections, Intravenous; Injections, Intraventricular; Male; Muscarinic Antagonists; Nicotinic Antagonists; Rats; Rats, Wistar; Shock, Septic; Tachycardia; Vasopressins

Hypotension during endotoxic shock is related to reduced vascular responsiveness to vasoconstrictors. Neuropeptide Y (NPY) is known to potentiate the pressor response to some agonists, and NPY infusion has been shown to improve hemodynamics and survival in endotoxemic rats. We therefore studied the effect of NPY infusion on the suppressed pressor effect of norepinephrine (NE), angiotensin II (AII), vasopressin (VP), and endothelin (ET) in conscious endotoxemic rats. Chronically cannulated conscious rats were infused with a non-hypotensive dose of endotoxin (LPS, 10 micrograms/10 microliters/min) throughout the experiment. Infusion of NPY, 40 pmol/10 microliters/min was started 15 minutes before the LPS infusion, and continued for 65 minutes. Five minutes after the termination of NPY infusion, increasing agonist doses were administered i.v. to construct dose-response curves. Each experiment included one control group where saline replaced LPS, and one control group where saline replaced NPY. LPS infusion caused suppression of the pressor responses to all four agonists, as expressed by ED50 and by decreased pressor response to the individual agonist doses. In addition, LPS infusion altered the bradycardic response to AII and ET. NPY infusion prior to the administration of NE, AII and VP resulted in partial reversal of the LPS-induced suppressed responsiveness to these agonists. NPY infusion had no effect on the response to ET in either control or endotoxemic rats. Partial reversal of the suppressed responsiveness to the three agonists by NPY infusion may contribute to the observed NPY-induced improvement of blood pressure and survival rate during endotoxic shock.

Topics: Animals; Endothelins; Endotoxins; Hemodynamics; Hypotension; Lipopolysaccharides; Male; Neuropeptide Y; Norepinephrine; Pressoreceptors; Rats; Rats, Wistar; Shock, Septic; Vasopressins

Hepatocytes from chronically endotoxemic rats, or appropriate saline controls, were maintained in primary culture for 3 or 20 h. The ability of a variety of hormones to stimulate glycogen phosphorylase a was examined. At 3 h in culture, hepatocytes from endotoxemic rats had lower basal activities and exhibited impaired response to vasopressin, angiotensin II, and, to a lesser extent, norepinephrine and glucagon. The norepinephrine response was predominantly of the alpha-type in the saline rats but mixed alpha- and beta-type in the endotoxic cells. After 20 h in culture, vasopressin and angiotensin II responses were still impaired, while norepinephrine and glucagon responses were similar to those seen in the saline cells. The response to norepinephrine was predominantly of the beta-type in the endotoxic cells but still of the alpha-type in the saline cells. The results show that multiple mechanisms are involved in endotoxin-mediated inhibition of glycogen phosphorylase a activity and that alterations in intracellular calcium homeostasis play more of a significant role than adenosine 3',5'-cyclic monophosphate-mediated processes in diminished responsiveness of the liver seen in endotoxemia.

Topics: Angiotensin II; Animals; Cells, Cultured; Chlorides; Endotoxins; Escherichia coli; Glucagon; Inositol Phosphates; Kinetics; Lithium; Lithium Chloride; Liver; Male; Norepinephrine; Phosphorylase a; Prazosin; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Shock, Septic; Vasopressins

Topics: Hemodynamics; Hemorrhage; Humans; Male; Middle Aged; Postoperative Complications; Shock, Septic; Vasopressins

Topics: Acetylcholine; Animals; Aorta, Thoracic; Endothelium, Vascular; In Vitro Techniques; Indomethacin; Inositol Phosphates; Interleukin-1; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Phorbol 12,13-Dibutyrate; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Recombinant Proteins; Reference Values; Second Messenger Systems; Shock, Septic; Tumor Necrosis Factor-alpha; Vasoconstriction; Vasopressins

Our studies addressing various aspects of lipid metabolism linked to the activation of alpha 1-adrenergic and vasopressin receptors suggest the following conclusions: 1) Adjustments in lipid metabolic flux seem to compensate for catabolic processes known to be triggered by endotoxin; 2) the diminished DG signal generation for vasopressin1 receptor-linked transduction mechanisms is likely to underlie some concomitant functional impairments and 3) defective acylation of AA may contribute to cellular metabolic perturbations by affecting the turnover of PI, a phospholipid involved in signal transmission, and leading to increased availability of AA for eicosanoid synthesis.

Topics: Animals; Arachidonic Acids; Cell Membrane; Liver; Membrane Lipids; Rats; Receptors, Adrenergic, alpha; Receptors, Angiotensin; Receptors, Vasopressin; Reference Values; Second Messenger Systems; Shock, Septic; Type C Phospholipases; Vasopressins

In septic patients the clinical course of the disease is characterized by high DIT and rT3 serum concentrations as well as a low T3-syndrome. While rT3 is elevated in almost all critically ill patients, the increase in DIT is indicative of severe infection. Prolactin levels are regularly elevated in sepsis although to variable degrees. Catecholamines and vasopressin should be regarded as acute responders. The pattern of cortisol secretion is uncertain. In most situations the secretion appears to be elevated; the circadian rhythm is disturbed.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Aged, 80 and over; Diiodothyronines; Hormones; Humans; Hydrocortisone; Middle Aged; Postoperative Complications; Prolactin; Sepsis; Shock, Septic; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Vasopressins

Vasopressin is the primary physiological factor regulating renal water reabsorption in mammals. Inhibitors of vasopressin-stimulated water reabsorption have previously been used as water diuretic agents in both experimental animals and man. The present studies describe and characterize the pharmacological effects of the potent vasopressin antagonist desGly d(CH2)5D-Tyr(Et)VAVP (SK&F 101926) and related analogs on renal water and solute excretion in conscious rats. Administration of SK&F 101926 was associated with dose-dependent increases in renal water excretion in conscious hydropenic rats. A selective vasopressin pressor (V1) antagonist (SK&F 100273) was inactive as a diuretic agent in these tests. SK&F 101926 antagonized, in a competitive fashion, exogenous vasopressin-stimulated antidiuresis in conscious water-loaded rats. Only modest increases in renal excretion of Na+, K+, and urea were observed when SK&F 101926 was administered. No changes in endogenous creatinine excretion were associated with the administration of SK&F 101926, suggesting that this drug does not affect glomerular filtration rate. The rank order of bioequivalency of alternative routes of administration of SK&F 101926 was intraperitoneal = intravenous = intramuscular = subcutaneous greater than intranasal much greater than rectal, ocular, and oral. SK&F 101926 (20 micrograms/kg/day) was effective in blocking the development of hyponatremia in a rat model of the syndrome of inappropriate antidiuretic hormone (SIADH). SK&F 100273 (100 micrograms/kg) hastened the onset of endotoxin-associated shock in rats. We conclude that SK&F 101926 is a potent water diuretic (aquaretic) agent in rats. The mechanism of action is most probably antagonism of vasopressin at renal epithelial (V2) receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine Vasopressin; Dehydration; Diuresis; Dose-Response Relationship, Drug; Inappropriate ADH Syndrome; Male; Osmolar Concentration; Rats; Shock, Septic; Vasopressins

The role of the sympathetic nervous system, angiotensin II (ANG II), and arginine vasopressin (AVP) in maintaining blood pressure (BP) during endotoxic shock was investigated in 117 conscious male Wistar rats. After intravenous injection of 2 mg Escherichia coli endotoxin, mean BP fell within 5 min by approximately 50 mmHg and rose again to approach base-line levels within 90 min. At that time, plasma renin activity, plasma norepinephrine (NE), and vasopressin levels of the endotoxin-treated animals were, respectively, 12-, 10-, and 54-fold (P less than 0.001) higher than those of the controls. The BP effect of either prazosin (0.125 mg iv), captopril (2.5 mg iv), or d(CH2)5Tyr(Me)AVP (5 micrograms iv), a specific antagonist of the vascular effect of AVP, was evaluated over a 30-min observation period starting 90 min after administration of endotoxin or its vehicle. Captopril reduced mean BP from 116 +/- 1.8 to a low of 109 +/- 2.1 (SE) mmHg (P less than 0.05, n = 8) only in rats pretreated with endotoxin, whereas the vasopressin antagonist had no depressor effect even during endotoxemia. The BP drop induced by prazosin in rats exposed to endotoxin (-21 +/- 3.3 mmHg, n = 6) did not significantly differ from that observed in control rats (-14 +/- 3.4 mmHg, n = 6). A dose-response curve to NE, ANG II, and lysine vasopressin was also performed. In endotoxin-treated rats the mean BP response to all agonists was markedly suppressed (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Arginine Vasopressin; Blood Pressure; Captopril; Endotoxins; Epinephrine; Male; Norepinephrine; Pentobarbital; Prazosin; Rats; Rats, Inbred Strains; Renin; Shock, Septic; Sympathetic Nervous System; Vasopressins

To eliminate the influence of anesthesia while investigating the role of vasoactive hormones during shock, we have developed an unanesthetized rat model that provides information on key cardiovascular parameters pertinent to shock. Enfluane anesthesia was used while the animals were being catheterized. After recovery from anesthesia, endotoxin (40 mg/kg) was given, and after 4 hr of measurements, animals (11) were killed. Cardiac index (CI) fell significantly 5 min after endotoxin and remained depressed for 4 hr. Mean blood pressure (MBP) decreased from 121 +/- 5.7 mmHg to 79 +/- 5.6 at 5 and 15 min, and increased to 113 +/- 3.0 at 180 min. Central venous pressure (CVP) was decreased from 30 min to the end of the study. Heart rate (HR) increased from 357 +/- 13 to a high of 448 +/- 14 at 5 min and remained at well over 400 for the 4-hr monitoring period. Total peripheral vascular resistance (TPVR) was twice that of the control at 30 min and remained elevated. Stroke volume decreased to 37% of that of the control at 15 and 30 min and remained at 50% of that of the control until sacrifice. Plasma concentrations of vasopressin measured by radioimmunoassay increased from 14 pg/ml (+/- 2.2, SEM) to 144 (+/- 56) and 144 (+/- 66) at 15 and 240 min after endotoxin. Pathological examination at the end of the study revealed extensive hemorrhage in all areas of the small intestine. We conclude that in the conscious endotoxic rat decreases in CI, MBP, and CVP are accompanied by compensatory increases in HR and TPVR; plasma vasopressin concentrations are greatly elevated; and severe small intestinal hemorrhage occurs. The control animals (12) were stable throughout the entire study period, establishing the conscious, instrumented, unrestrained rat presented here as an attractive model for the study of shock without the bias of anesthesia.

Topics: Animals; Blood Pressure; Cardiac Output; Endotoxins; Male; Rats; Rats, Inbred Strains; Shock, Septic; Vascular Resistance; Vasoconstriction; Vasopressins

Topics: Animals; Catecholamines; Coenzymes; Dogs; Hemodynamics; Shock, Septic; Ubiquinone; Vascular Resistance; Vasopressins

Circulatory shock mechanisms that may result in the acute renal failure (ARF) syndrome are summarized. Both circulatory and neurohumoral mechanisms leading to the shock state and ARF are emphasized. Release of vasoactive hormones, with a review of vasodilators and vasoconstrictors, is discussed in terms of release mechanisms, onset of release, magnitude and duration of plasma elevation, and the basal plasma level of each. Hemodynamic diagnoses in shock in both the classical low cardiac output and the early sepsis high cardiac output syndromes are commented upon with emphasis on the importance of early diagnosis and adequate measurements of the circulatory state for optimum therapy. The septic hyperdynamic syndrome is reviewed with particular regard to changes in the renal circulation and function. Mechanisms of lactic acidemia in the hyperdynamic syndrome in the presence of adequate nutrient tissue flow are discussed. Elevations of vasoactive hormones and their relationship to the early shock state are mentioned. Their elevations in late shock are reviewed with critical comments given as to the possible interactions and importance of the vasodilator and vasoconstrictor actions on organ function and survival. Blood pressure alone is not a good indicator of progress in the management of septic shock.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Pressure; Endorphins; Epoprostenol; Hemodynamics; Histamine; Hormones; Humans; Shock, Septic; Thromboxanes; Vasoconstriction; Vasodilation; Vasopressins

This study was conducted as an initial step to elucidate the role of vasopressin in the events leading to irreversible shock. The influence of vasopressin on the maintenance of cardiovascular and respiratory function during early endotoxin shock was evaluated. Conscious, unrestrained male Sprague-Dawley rats (SD) and male homozygous Brattleboro rats (B) lacking vasopressin were anesthetized with 2% enflurane and cannulas were placed in the carotid artery and jugular vein. After recovery from anesthesia, endotoxin (20 mg/kg) was administered. Endotoxin in the B caused an immediate drop in blood pressure to below 40 mm Hg with no recovery. This resulted in death for all ten animals within 3 1/2 hours; eight of ten had expired within 90 min. In contrast, the blood pressure response of the SD dropped to 70 mm Hg but recovered to values near control until sacrificed 240 min after endotoxin. Corticosteroid treatment (300 mg/kg) administered 30 min before endotoxin in the B prevented the severe decrease in blood pressure with values falling to and remaining near 70 mm Hg for the 240-min observation period. All treated animals survived this period. Heart rates in the SD increased sharply after endotoxin and continued to rise, whereas both treated and untreated B increased slowly. Respiration rates for the untreated B were severely depressed until death after endotoxin, whereas the SD and treated B remained at or above control. The results implicate vasopressin in the maintenance of cardiovascular function during the early phase of shock induced by endotoxin, and demonstrate the ability of corticosteroid to substantially improve cardiovascular integrity in the absence of vasopressin.

Topics: Adrenal Cortex Hormones; Animals; Blood Pressure; Cardiovascular System; Heart Rate; Male; Pulse; Rats; Rats, Brattleboro; Rats, Inbred Strains; Respiration; Shock, Septic; Vasopressins

Plasma vasopressin concentrations, measured by radioimmunoassay, were remarkably elevated during endotoxin and E. coli shock. The concentrations were often above 500 pg/ml in dogs and above 300 pg/ml in baboons; they reached 1200 pg/ml in two dogs and 1800 pg/ml in another. Plasma concentration in a quiet, hydrated subject is 4 pg/ml; osmoregulation is maximally effective at 20 pg/ml. Elevation of plasma vasopressin occurred by 15 minutes after beginning infusion of endotoxin or E. coli and reached concentrations of 200-350 pg/ml with a decrease in cardiac output but before hypotension, which suggests decreased thoracic blood volume and decompression of left atrial stretch receptors. Even higher vasopressin levels were associated with a reduction of arterial blood pressure. The typical pattern was an early peak elevation followed by a sustained plateau of plasma vasopressin concentration in dogs and baboons with endotoxin and/or E. coli-induced circulatory shock.

Topics: Animals; Blood Pressure; Cardiac Output; Dogs; Endotoxins; Escherichia coli; Escherichia coli Infections; Lethal Dose 50; Papio; Shock, Septic; Vasopressins; Water-Electrolyte Balance

Plasma vasopressin concentration was measured by radioimmunoassay in lightly anesthetized baboons and dogs before and during experimental Escherichia coli septic shock. Since vasopressin is a potent vasoconstrictor, and activator of clotting factors and a myocardial depressant, we postulated that, if found in substantial amounts in the plasma, vasopressin may contribute to the physiopathology of the septic shock syndrome. Quite high plasma vasopressin concentrations were found in both baboons and dogs. In the baboons, increased plasma vasopressin concentrations occurred, while mean arterial blood pressure was still within normal limits and remained elevated for as long as 12 hours during septic shock. Plasma vasopressin concentrations of this magnitude have been previously reported only with direct hypothalamic stimulation or after hypotensive shock secondary to hemorrhage.

Topics: Animals; Dogs; Escherichia coli Infections; Papio; Radioimmunoassay; Sepsis; Shock, Septic; Vasopressins

Topics: Aldosterone; Animals; Bucladesine; Dogs; Hormones; Kidney; Renin; Shock, Septic; Ubiquinone; Vasopressins

Topics: Aldosterone; Animals; Blood Pressure; Cardiac Output; Dexamethasone; Dogs; Epinephrine; Hormones; Hydrocortisone; Hydrogen-Ion Concentration; Insulin; Kidney; Methylprednisolone; Norepinephrine; Osmolar Concentration; Potassium; Regional Blood Flow; Shock, Septic; Sodium; Vasopressins

Topics: Adrenocorticotropic Hormone; Aldosterone; Animals; Dogs; Kidney; Renin; Shock, Septic; Steroids; Vasopressins

Topics: Aldosterone; Animals; Dogs; Dopamine; Hydrocortisone; Insulin; Kidney; Renin; Shock, Septic; Vasopressins

Topics: Aldosterone; Animals; Catecholamines; Dogs; Endocrine Glands; Kidney; Renin; Shock, Septic; Vasopressins

1. Long-lasting haemorrhagic hypotension (4.5 hr at 35 mmHg) leading to irreversible haemorrhagic shock, has been studied in normal dogs, in dogs treated with a bradykinin potentiating nonapeptide (BPP(9a)), which blocks the conversion of angiotensin I to angiotensin II, and in dogs with experimental chronic diabetes insipidus (DI dogs). BPP(9a) was given by I.V. injection before the start of bleeding (BPP pre-treated group), 45 min after blood pressure had reached 35 mmHg (BPP early treated group) or 2 hr after blood pressure had reached 35 mmHg (BPP late-treated group). After retransfusion of blood all dogs were allowed to recover and observed for a further period of 3 days.2. Untreated control dogs developed haemorrhagic shock with tachycardia, low cardiac output, low total peripheral conductance and low stroke volume. All died within 24 hr of retransfusion, with pathological lesions typical of irreversible haemorrhagic shock.3. BPP pre-treated dogs developed haemorrhagic shock with bradycardia (during early shock), high cardiac output, high peripheral vascular conductance and high stroke volume when compared with the untreated controls. All pre-treated animals survived the 3 day observation period. They were then killed and on post-mortem showed no signs of irreversible haemorrhagic shock.4. BPP early-treated animals behaved like controls before BPP, but like pre-treated animals after the drug. Only one out of eight died within the 3 day observation period.5. BPP late-treated dogs behaved like controls before BPP. They responded to the drug with a rise in cardiac output, peripheral vascular conductance and stroke volume, and with a fall in heart rate. These responses were, however, short-lived. Four out of these eight animals died within the 3 day observation period, with lesions of irreversible haemorrhagic shock.6. DI dogs developed haemorrhagic shock with tachycardia (like controls), but with high cardiac output and peripheral vascular conductance (like BPP pre-treated dogs). The stroke volume of DI dogs was intermediate between those of controls and pre-treated groups. All six dogs survived the 3 day observation period.7. BPP(9a) had no measurable effect on the course of endotoxic shock.8. It is suggested that the normally severe vasoconstriction of the mesenteric vascular bed, which is thought to be responsible for irreversible haemorrhagic shock, is absent or attenuated in the absence of vasopressin or angiotensin. The consequences of this on th

Topics: Angiotensin II; Animals; Blood Pressure; Blood Volume; Cardiac Output; Diabetes Insipidus; Dogs; Heart Rate; Intestines; Kidney; Liver; Male; Oligopeptides; Peptides; Shock, Hemorrhagic; Shock, Septic; Stomach; Vasopressins

Topics: Anesthesia, Intravenous; Animals; Aorta; Blood Cell Count; Blood Platelets; Blood Pressure; Carbon Dioxide; Cardiac Output; Cell Aggregation; Dextrans; Dogs; Endotoxins; Escherichia coli; Heart Atria; Hydrogen-Ion Concentration; Hypertension, Pulmonary; Leukocytes; Oxygen; Phenobarbital; Pulmonary Circulation; Shock, Septic; Time Factors; Urethane; Vasopressins; Venous Pressure

Topics: Adrenocorticotropic Hormone; Animals; Bicarbonates; Dextrans; Dogs; Drug Synergism; Female; Heparin; Isoproterenol; Male; Norepinephrine; Phenoxybenzamine; Plasma Substitutes; Shock, Septic; Sodium; Stanozolol; Tromethamine; Vasopressins

Topics: Aged; Female; Humans; Hydrocortisone; Hypernatremia; Male; Methylprednisolone; Middle Aged; Pituitary Gland; Sepsis; Shock, Septic; Spironolactone; Vasopressins

Topics: Angiotensins; Arginine Vasopressin; Endotoxins; Felypressin; Intestinal Diseases; Ischemia; Norepinephrine; Pharmacology; Rats; Research; Shock, Septic; Shock, Traumatic; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Biomedical Research; Blood Circulation; Blood Pressure; Carotid Arteries; Dogs; Endotoxins; Escherichia coli Infections; Felypressin; Femoral Artery; Hemodynamics; Inulin; Kidney; Kidney Function Tests; Lipopolysaccharides; Pharmacology; Research; Shock, Hemorrhagic; Shock, Septic; Vasopressins; Water-Electrolyte Balance

Hemodynamic studies have demonstrated that the fall of blood pressure in shock caused by endotoxin in dogs does not result primarily from dilatation or "vasomotor collapse." Indeed, vasoconstriction is increased and may be excessive. Progression of shock has recently been blamed on such excessive vasoconstriction. For this reason the use of sympathomimetic drugs as vasopressor agents has been challenged and sympatholytic or adrenolytic agents have been recommended. In the present study, vasopressor and vasodilator drugs were used for the treatment of shock in dogs caused by endotoxin. Vasodilator drugs, when used after the onset of shock, hastened a fatal outcome but vasopressor agents were not detrimental when used in moderate doses. The effectiveness of the vasopressor agent is not necessarily due to a primary vasoconstrictor action on arteries and arterioles, as previously assumed.

Topics: Animals; Antitoxins; Arginine Vasopressin; Arterioles; Blood Pressure; Dogs; Hemodynamics; Shock; Shock, Septic; Toxins, Biological; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins