pituitrin and Sepsis

Sepsis is a potentially life-threatening systemic inflammatory syndrome characterized by dysregulated host immunological responses to infection. Uncontrolled immune cell activation and exponential elevation in circulating cytokines can lead to sepsis, septic shock, multiple organ dysfunction syndrome, and death. Sepsis is associated with high re-hospitalization and recovery may be incomplete, with long term sequelae including post-sepsis syndrome. Consequently, sepsis continues to be a leading cause of morbidity and mortality across the world. In our recent review of human chorionic gonadotropin (hCG), we noted that its major properties including promotion of fertility, parturition, and lactation were described over a century ago. By contrast, the anti-inflammatory properties of this hormone have been recognized only more recently. Vasopressin, a hormone best known for its anti-diuretic effect, also has anti-inflammatory actions. Surprisingly, vasopressin's close cousin, oxytocin, has broader and more potent anti-inflammatory effects than vasopressin and a larger number of pre-clinical studies supporting its potential role in limiting sepsis-associated organ damage. This review explores possible links between oxytocin and related octapeptide hormones and sepsis-related modulation of pro-inflammatory and anti-inflammatory activities.

Topics: Anti-Inflammatory Agents; Female; Humans; Oxytocin; Peptide Hormones; Sepsis; 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

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

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

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

Sepsis affects patients of all ages with multiple comorbidities and underlying diagnoses, and is the result of infection by many potential pathogens infecting various organs or sites. Many molecules have been clinically tested in recent years for their potential immunomodulatory effects, but have been shown to have no beneficial effects on outcomes in heterogeneous populations of patients with sepsis. There are, therefore, no specific antisepsis therapies and mortality and morbidity rates remain high despite improved overall management of these patients. This review covers promising agents currently used in clinical trials.. There are several candidates currently undergoing early and later phase of clinical testing, including thrombomodulin, alkaline phosphatase, interferon-beta, and selepressin. Other approaches including immunoglobulins, extracorporeal therapies, and pharmaconutrients will also be discussed.. Despite multiple trials of potential therapies for sepsis, no strategies have yet been persistently shown to have beneficial effects on outcomes. The main reason for the disappointing results is that patient populations in these studies have been too heterogeneous. Selecting patients on the basis of general symptoms is not enough. Rather patients should be selected according to the likely action of the drug in question. To achieve this, improved biomarkers of sepsis and of the immune response are needed and the activities of the individual agents need to be carefully characterized. New candidates are being developed and the results of ongoing and recent clinical trials of immunomodulatory therapies are eagerly awaited as new therapies for sepsis are urgently needed.

Topics: Alkaline Phosphatase; Extracorporeal Circulation; Humans; Immunoglobulins; Interferon-beta; Nutrition Therapy; Sepsis; Thrombomodulin; Vasopressins

Hypotensive state is frequently observed in several critical conditions. If an adequate mean arterial pressure is not promptly restored, insufficient tissue perfusion and organ dysfunction may develop. Fluids and catecholamines are the cornerstone of critical hypotensive states management. Catecholamines side effects such as increased myocardial oxygen consumption and development of arrhythmias are well known. Thus, in recent years, interest in catecholamine-sparing agents such as vasopressin, terlipressin and methylene blue has increased; however, few randomized trials, mostly with small sample sizes, have been performed. We therefore conducted a meta-analysis of randomized trials to investigate the effect of non-catecholaminergic vasopressors on mortality.. PubMed, BioMed Central and Embase were searched (update December 31st, 2014) by two independent investigators. Inclusion criteria were: random allocation to treatment, at least one group receiving a non-catecholaminergic vasopressor, patients with or at risk for vasodilatory shock. Exclusion criteria were: crossover studies, pediatric population, non-human studies, studies published as abstract only, lack of data on mortality. Studied drugs were vasopressin, terlipressin and methylene blue. Primary endpoint was mortality at the longest follow-up available.. A total of 1,608 patients from 20 studies were included in our analysis. The studied settings were sepsis (10/20 studies [50%]), cardiac surgery (7/20 [35%]), vasodilatory shock due to any cause (2/20 [19%]), and acute traumatic injury (1/20 [5%]). Overall, pooled estimates showed that treatment with non-catecholaminergic agents improves survival (278/810 [34.3%] versus 309/798 [38.7%], risk ratio = 0.88, 95% confidence interval = 0.79 to 0.98, p = 0.02). None of the drugs was associated with significant reduction in mortality when analyzed independently. Results were not confirmed when analyzing studies with a low risk of bias.. Catecholamine-sparing agents in patients with or at risk for vasodilatory shock may improve survival. Further researches on this topic are needed to confirm the finding.

Topics: Databases, Factual; Humans; Lypressin; Methylene Blue; Randomized Controlled Trials as Topic; Sepsis; Shock; Terlipressin; 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

Sepsis, severe sepsis, and septic shock cause significant morbidity and mortality worldwide. Rapid diagnosis and therapeutic interventions are desirable to improve the overall mortality in patients with sepsis. However, gold standard laboratory diagnostic methods for sepsis, pose a significant challenge to rapid diagnosis of sepsis by physicians and laboratories. This article discusses the usefulness and potential of biomarkers and molecular test methods for a more rapid clinical and laboratory diagnosis of sepsis. Because new technologies are quickly emerging, physicians and laboratories must appreciate the key factors and characteristics that affect the clinical usefulness and diagnostic accuracy of these test methodologies.

Topics: Acute-Phase Proteins; Bacteremia; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Carrier Proteins; Clinical Laboratory Techniques; Humans; Interleukin-6; Interleukin-8; Laboratories; Membrane Glycoproteins; Nucleic Acid Amplification Techniques; Protein Precursors; Sepsis; Serum Amyloid P-Component; 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

Severe sepsis is a common occurrence in critically ill patients and a major cause of morbidity and mortality in this population. Management relies on the early identification and treatment of the underlying causative infection, adequate and rapid hemodynamic resuscitation, support of associated organ failure and modulation of the immune response with drotrecogin alfa (activated) when it is not contraindicated, and corticosteroids in severe septic shock. We will review current approaches to each of these categories.

Topics: Acute Kidney Injury; Adrenal Cortex Hormones; Adult; Anti-Bacterial Agents; Critical Illness; Fluid Therapy; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Immunologic Factors; Protein C; Recombinant Proteins; Resuscitation; Sepsis; Vasopressins

Topics: Beryllium; Environmental Exposure; Health Education; Humans; Lung Diseases; Norepinephrine; Occupational Diseases; Occupational Exposure; Ozone; Pulmonary Disease, Chronic Obstructive; Respiration, Artificial; Risk Assessment; Sepsis; Sleep Apnea, Obstructive; 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

Topics: Cardiac Surgical Procedures; Child; Heart Arrest; Humans; Sepsis; 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

Exogenous arginine vasopressin (VP) has been increasingly used in the hemodynamic management of critically ill patients with septic shock, but its use in septic burn patients has not been systematically examined.. To review our experience with the use of VP in septic burn patients.. Retrospective review of all patients who received VP at a tertiary care adult regional burn centre. Only patients who strictly met the American College of Chest Physicians/Society of Critical Care Medicine Consensus Criteria for sepsis at the time of VP initiation were analysed.. There were 30 septic burn patients treated on 43 distinct occasions with VP. This group had a mean (+/-S.D.) age of 49+/-19 years, a mean % TBSA burn of 41+/-15% and a 37% incidence of inhalation injury. A significant increase in mean arterial pressure (MAP), a significant decrease in heart rate (HR), and a trend towards increased urine output (UO) occurred following initiation of VP. When VP was added to an existing infusion of norepinephrine (NE), there was a significant NE sparing effect. VP was implicated in the death of one patient who developed diffuse upper gastrointestinal necrosis while on VP. Other complications in patients treated with VP included peripheral ischemia (2), skin graft failure (1) and donor site conversion (1). In all complications, VP had been administered in combination with prolonged NE infusions (mean of 10 microg/min over a mean of 177 h).. VP is a useful adjunctive pressor that spares NE requirements in septic burn patients, but its use is not without risks, particularly when VP is combined with sustained moderate to high infusions of NE.

Topics: Adult; Blood Pressure; Burns; Graft Survival; Heart Rate; Hemostatics; Hospital Mortality; Humans; Middle Aged; Retrospective Studies; Sepsis; Skin Transplantation; Vasoconstrictor Agents; Vasopressins

The metabolic support of critically ill patients is a relatively new topic of active research and discussion, and surprisingly little is known about the effects of critical illness on metabolic physiology and activity. The metabolic changes seen in critical illness are highly complex, and how and when to treat them are only just beginning to be determined. Studies have demonstrated that the acute phase and the later phase of critical illness behave differently from a metabolic point of view for many organs, and while many of the alterations in metabolism seen during early critical illness may be appropriate and beneficial responses to cellular stress, whether this is true for all the metabolic alterations in all forms of critical illness is unclear. Currently we face more questions than answers, and further study is needed to elucidate the various components of the metabolic response to acute and chronic critical illness and to develop better techniques to assess and monitor these changes so that we can determine which therapeutic approaches should be used in what combinations and in which patients.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Amino Acids; Blood Glucose; Critical Care; Critical Illness; Human Growth Hormone; Humans; Mitochondria; Multiple Organ Failure; Nutritional Support; Sepsis; Vasopressins

Systemic changes in blood pressure and cardiac output induced by pressors and inotropes do not always correlate to improvements in regional perfusion. Since the gut is often referred to as the 'motor' of the systemic inflammatory response syndrome, the impact of vasoactive agents on splanchnic perfusion has theoretical importance. This review will highlight recent studies examining secondary effects of vasoactive agents on intestinal perfusion, metabolism, and barrier function.. Norepinephrine has minimal impact on mesenteric blood flow although the combination of norepinephrine and dobutamine increases splanchnic blood flow in sepsis. Dopamine also increases mesenteric blood flow although this may be associated with negative hepatic energy balance at high does. Vasopressin and epinephrine both have negative effects on splanchnic blood flow. Newer inodilators levosimendan and olprinone preferentially improve mesenteric perfusion in animal models.. Secondary effects of norepinephrine and dopamine on splanchnic perfusion are minor compared with their systemic effects. While vasopressin usage is increasing in the intensive care unit, caution should be used because of its adverse effects on gut perfusion. Experimental agents for the treatment of heart failure have beneficial gut-specific effects although the clinical significance of this is currently limited by their availability.

Topics: Adrenergic beta-Agonists; Animals; Dobutamine; Drug Interactions; Humans; Intestinal Mucosa; Intestines; Norepinephrine; Sepsis; Splanchnic Circulation; 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

Topics: Adrenal Cortex Hormones; Anemia; Anti-Bacterial Agents; Blood Coagulation Factors; Humans; Hyperglycemia; Hypoglycemic Agents; Immune Tolerance; Insulin; Protein C; Renal Replacement Therapy; Respiration, Artificial; Sepsis; Vasopressins

Severely septic patients continue to experience excessive morbidity and mortality despite recent advances in critical care. Although significant resources have been invested in new treatments, almost all have failed to improve outcomes. An improved understanding of sepsis pathophysiology, including the complex interactions between inflammatory, coagulation, and fibrinolytic systems, has accelerated the development of novel treatments. Recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated) (DAA), is currently the only US Food and Drug Administration (FDA)-approved medicine for the treatment of severe sepsis, and only in patients with a high risk of death. This review will discuss the treatment of severe sepsis, focusing on recent discoveries and unresolved questions about DAA's optimal use. Increasing pharmacological experience has generated enthusiasm for investigating medicines already approved for other indications as treatments for severe sepsis. Replacement doses of hydrocortisone and vasopressin may reduce mortality and improve hypotension, respectively, in a subgroup of patients with catecholamine-refractory septic shock. In addition to discussing these new indications, this review will detail the provocative preliminary data from four promising treatments, including two novel modalities: antagonizing high mobility group box protein and inhibiting tissue factor (TF). Observational data from the uncontrolled administration of heparin or statins in septic patients will also be reviewed.

Topics: Adrenal Cortex Hormones; Anti-Infective Agents; Anti-Inflammatory Agents; Anticoagulants; Antidiuretic Agents; Drug Administration Schedule; Drug Therapy; Hemorrhage; Heparin; HMGB1 Protein; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Patient Selection; Protein C; Recombinant Proteins; Sepsis; Severity of Illness Index; Thromboplastin; Treatment Outcome; Vasopressins

Vasopressin and terlipressin are increasingly used as alternative non-adrenergic vasopressors for hemodynamic support of septic patients with arterial hypotension. Despite excellent vasopressive effects, vasopressin analogues may potentially impair macro-hemodynamics, oxygen transport and microvascular blood flow. Due to those unwanted side-effects, vasopressin and terlipressin may potentially compromise organ function and possibly foster the development of multiple organ failure. This review article discusses the results of clinical and experimental studies to judge the effects of vasopressin and terlipressin on microcirculation, oxygen supply, metabolism and organ function in patients with sepsis or systemic inflammatory response syndrome (SIRS). Although vasopressin analogues are emerging as promising alternatives to treat catecholamine-refractory hypotension, there is no evidence that vasopressin receptor agonists improve outcome. To date, vasopressin and terlipressin can, therefore, not be recommended for routine clinical use.

Topics: Animals; Humans; Lypressin; Microcirculation; Oxygen Consumption; Sepsis; Systemic Inflammatory Response Syndrome; 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

Endocrinopathy during sepsis can manifest as hyperglycemia and insulin resistance or as insufficient production of either adrenal corticosteroids or vasopressin. The results of a recent large clinical trial have demonstrated that tight glycemic control with insulin can confer survival benefit to selected intensive care unit patients. Relative impairment of adrenocortical reserve has been suggested to be an important contributor to the pathogenesis of shock in sepsis. Replacement doses of glucocorticoids and mineralocorticoids have been associated with improved survival in the subset of patients with blunted results on adrenocorticotropin hormone stimulation tests. Posterior pituitary production of vasopressin is diminished in septic shock while sensitivity to its vasopressor effects is enhanced. Clinical trials are underway to determine whether administration of vasopressin can improve outcomes in patients with septic shock. Whether the euthyroid sick syndrome represents an adaptive or a maladaptive response to severe illness remains unclear.

Topics: Animals; Clinical Trials as Topic; Endocrine System; Humans; Renal Insufficiency; Sepsis; Vasopressins

The main clinical characteristics of sepsis and septic shock are derangements of cardiocirculatory and respiratory function. Additionally, profound alterations in metabolic pathways occur leading to hypermetabolism, enhanced energy expenditure, and insulin resistance. The clinical hallmarks are hyperglycemia, hyperlactatemia, and enhanced protein catabolism. These metabolic alterations are even more pronounced during sepsis as a result of cytokine release and subsequent induction of inflammatory pathways. Increased oxygen demands from mitochondrial oxygen utilization and oxygen consumption related to oxygen radical formation may contribute to hypermetabolism. In addition, mitochondrial dysfunction with impaired cellular respiration may be present. Mainstay therapeutic interventions for hemodynamic stabilization are adequate volume resuscitation and vasoactive agents, which, however, have additional impact on metabolic activity. Therefore, beyond hemodynamic effects, specific drug-related metabolic alterations need to be considered for optimal treatment during sepsis. This review gives an overview of the typical metabolic alterations during sepsis and septic shock and highlights the impact of vasoactive therapy on metabolism.

Topics: Adrenergic Agonists; Catecholamines; Critical Illness; Energy Metabolism; Epoprostenol; Glucose; Humans; Lactates; Mitochondria; Sepsis; 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

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

Sepsis-induced acute kidney injury (AKI) is a common condition with high morbidity and mortality. Neutrophil-derived heparin-binding protein (HBP) induces vascular leakage and is a promising biomarker of sepsis-induced organ dysfunction. It remains unknown if HBP is prognostic of AKI in septic shock and if HBP could play a role in the pathophysiology of sepsis-induced AKI.. To determine the association of plasma HBP levels with development of AKI, investigate the role of HBP in the pathophysiology of sepsis-induced AKI, and test the effect of blocking HBP using heparin derivatives.. In 296 septic shock patients from the randomized multicenter Vasopressin and Septic Shock Trial (VASST) plasma HBP levels were associated with development of AKI and need for renal replacement therapy (RRT). Human renal tubular cells were exposed to recombinant HBP to evaluate inflammation and heparin derivatives were used to abrogate these effects. Finally, mice were exposed to HBP with and without heparin derivatives and the kidneys examined for signs of inflammation.. Plasma HBP levels were significantly higher in patients with AKI and those requiring RRT. HBP levels identified patients with moderate AKI with an area under curve (AUC) of 0.85. HBP increased IL-6 production in renal tubular epithelial cells. Different heparin derivatives abrogated the HBP-induced increased inflammatory response in vitro and in vivo.. Elevated plasma HBP is associated with development of sepsis-induced AKI and HBP is involved in its pathophysiology. Our studies suggest that heparin(s) could be tested for efficacy and safety of prevention of sepsis-induced AKI.

Topics: Acute Kidney Injury; Adult; Aged; Antimicrobial Cationic Peptides; Biomarkers; Blood Proteins; Carrier Proteins; Cell Line; Female; Heparin; Humans; Male; Middle Aged; Sepsis; Vasopressins

Inflammatory response during sepsis is incompletely understood due to small sample sizes and variable timing of measurements following the onset of symptoms. The vasopressin in septic shock trial (VASST) compared the addition of vasopressin to norepinephrine alone in patients with septic shock. During this study plasma was collected and 39 cytokines measured in a 363 patients at both baseline (before treatment) and 24 hours. Clinical features relating to both underlying health and the acute organ dysfunction induced by the severe infection were collected during the first 28 days of admission.. Cluster analysis of cytokines identifies subgroups of patients at differing risk of death and organ failure.. Circulating cytokines and other signaling molecules were measured using a Luminex multi-bead analyte detection system. Hierarchical clustering was performed on plasma values to create patient subgroups. Enrichment analysis identified clinical outcomes significantly different according to these chemically defined patient subgroups. Logistic regression was performed to assess the importance of cytokines for predicting patient subgroups.. Plasma levels at baseline produced three subgroups of patients, while 24 hour levels produced two subgroups. Using baseline cytokine data, one subgroup of 47 patients showed a high level of enrichment for severe septic shock, coagulopathy, renal failure, and risk of death. Using data at 24 hours, a larger subgroup of 81 patients that largely encompassed the 47 baseline subgroup patients had a similar enrichment profile. Measurement of two cytokines, IL2 and CSF2 and their product were sufficient to classify patients into these subgroups that defined clinical risks.. A distinct pattern of cytokine levels measured early in the course of sepsis predicts disease outcome. Subpopulations of patients have differing clinical outcomes that can be predicted accurately from small numbers of cytokines. Design of clinical trials and interventions may benefit from consideration of cytokine levels.

Topics: Aged; Disease-Free Survival; Double-Blind Method; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hemostatics; Humans; Interleukin-2; Male; Middle Aged; Norepinephrine; Predictive Value of Tests; Risk Factors; Sepsis; Survival Rate; Time Factors; Vasoconstrictor Agents; Vasopressins

To identify predictors of hospital mortality among patients with severe sepsis who were treated with drotrecogin alfa (activated).. Prospective observational cohort study.. A 1400-bed academic medical center.. One hundred two patients treated with drotrecogin alfa (activated) for severe sepsis.. To identify potential risk factors for hospital mortality, the main outcome evaluated, all patients who received drotrecogin alfa (activated) were segregated according to hospital survival. The following characteristics were recorded: age, sex, weight, surgical or nonsurgical, Acute Physiology and Chronic Health Evaluation (APACHE) II score, number of acquired organ-system derangements, mechanical ventilation, use of vasopressors or dobutamine, patient location 24 hours before receiving drotrecogin alfa (activated), source of infection, microbiologically positive culture, and other process-of-care variables. Of the 102 patients, 43 (42.2%) died during their hospitalization. Potential predictors of hospital mortality identified by univariate analysis included greater APACHE II scores, administration of vasopressin or dobutamine, number of acquired organ-system derangements, time to treatment with drotrecogin alfa (activated), intravenous fluid administered before receiving vasopressors or drotrecogin alfa (activated), number of red blood cell transfusions, and administration of inappropriate initial antimicrobial treatment. Multivariate analysis revealed that vasopressin administration (odds ratio [OR] 3.72, 95% confidence interval [CI] 1.95-7.10), number of acquired organ-system derangements (OR 2.30, 95% CI 1.59-3.31), and administration of inappropriate initial antimicrobial treatment (OR 15.5, 95% CI 6.78-35.6) were independently associated with hospital mortality.. Number of acquired organ-system derangements, vasopressin administration, and treatment with an inappropriate initial antimicrobial regimen are independently associated with an increased risk of hospital mortality among patients treated with drotrecogin alfa (activated) for severe sepsis. These findings suggest that other specific medical interventions may increase survival in this patient population.

Topics: Gastrointestinal Diseases; Hospital Mortality; Humans; Inpatients; Intensive Care Units; Lung Diseases; Middle Aged; Prospective Studies; Protein C; Recombinant Proteins; Risk Factors; Sepsis; Severity of Illness Index; Skin Diseases, Bacterial; Soft Tissue Infections; 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

Sepsis impairs gastrointestinal microcirculation and it is hypothesized that this might increase patient's mortality. Sub-therapeutic vasopressin improves gastric microcirculation under physiologic conditions whereas a therapeutic dosing regimen seems to be rather detrimental. However, the effects of sub-therapeutic vasopressin on gastrointestinal microcirculation in sepsis are largely unknown. Therefore, we conducted this trial to investigate the effect of sub-therapeutic as well as therapeutic vasopressin on gastrointestinal microcirculation in sepsis.. 40 male Wistar rats were randomized into 4 groups. Colon ascendens stent peritonitis (CASP)-surgery was performed to establish mild or moderate sepsis. 24 hours after surgery, animals received either vasopressin with increasing dosages every 30 min (6.75, 13.5 (sub-therapeutic), 27 mU · kg-1 · h-1 (therapeutic)) or vehicle. Microcirculatory oxygenation (μHBO2) of the colon was recorded for 90 min using tissue reflectance spectrophotometry. Intestinal microcirculatory perfusion (total vessel density (TVD; mm/mm2) and perfused vessel density (PVD; mm/mm2)) were measured using incident dark field-Imaging at baseline and after 60 min.. In mild as well as in moderate septic animals with vehicle-infusion intestinal μHbO2, TVD and PVD remained constant. In contrast, in moderate sepsis, sub-therapeutic vasopressin with 13.5 mU · kg-1 · h-1 elevated intestinal μHBO2 (+ 6.1 ± 5.3%; p < 0.05 vs. baseline) and TVD (+ 5.2 ± 3.0 mm/mm2; p < 0.05 vs. baseline). μHBO2, TVD and PVD were significantly increased compared to moderate sepsis alone. However, therapeutic vasopressin did not change intestinal microcirculation. In mild septic animals sub-therapeutic as well as therapeutic vasopressin had no relevant effect on gastrointestinal microcirculation. Systemic blood pressure remained constant in all groups.. Sub-therapeutic vasopressin improves gastrointestinal microcirculatory oxygenation in moderate sepsis without altering systemic blood pressure. This protective effect seems to be mediated by an enhanced microcirculatory perfusion and thereby increased oxygen supply. In contrast, therapeutic vasopressin did not show this beneficial effect.

Topics: Animals; Blood Pressure; Gastrointestinal Tract; Heart Rate; Male; Microcirculation; Oxygen; Perfusion; Placebos; Rats, Wistar; Sepsis; Vasopressins

Sepsis promotes an inflammatory state in the central nervous system (CNS) that may cause autonomic, cognitive, and endocrine changes. Microglia, a resident immune cell of the CNS, is activated in several brain regions during sepsis, suggesting its participation in the central alterations observed in this disease. In this study, we aimed to investigate the role of microglial activation in the neuroendocrine system functions during systemic inflammation. Wistar rats received an intracerebroventricular injection of the microglial activation inhibitor minocycline (100 μg/animal), shortly before sepsis induction by cecal ligation and puncture. At 6 and 24 h after surgery, hormonal parameters, central and peripheral inflammation, and markers of apoptosis and synaptic function in the hypothalamus were analyzed. The administration of minocycline decreased the production of inflammatory mediators and the expression of cell death markers, especially in the late phase of sepsis (24 h). With respect to the endocrine parameters, microglial inhibition caused a decrease in oxytocin and an increase in corticosterone and vasopressin plasma levels in the early phase of sepsis (6 h), while in the late phase, we observed decreased oxytocin and increased ACTH and corticosterone levels compared to septic animals that did not receive minocycline. Prolactin levels were not affected by minocycline administration. The results indicate that microglial activation differentially modulates the secretion of several hormones and that this process is associated with inflammatory mediators produced both centrally and peripherally.

Topics: Animals; Brain; Corticosterone; Disease Models, Animal; Male; Microglia; Minocycline; Neurons; Neurosecretory Systems; Oxytocin; Rats; Rats, Wistar; Sepsis; Vasopressins

BACKGROUND The aim of this study was to assess the impact of norepinephrine (NE), norepinephrine plus vasopressin (NE+VAS) and dopamine in patients with sepsis and heart failure. MATERIAL AND METHODS Data were extracted from the Medical Information Mart for Intensive Care III database, v1.4. Adults aged >18 years in an Intensive Care Unit (ICU) who had heart failure and took vasopressors were included. The patients were divided into 3 groups: NE, NE+VAS, and dopamine. Differences in survival, treatment time, and organ function among the 3 groups were compared. Propensity score matching (PSM) was used to screen for possible prognostic differences, and regression analysis was used to further analyze and predict prognoses. RESULTS A total of 1864 patients were included. There were significant differences among the 3 groups in 7-, 28-, and 90-day mortality after PSM. The 5-year survival rates among the 3 groups also were significantly different (P<0.001). After Cox regression analysis, NE+VAS was an independent risk factor affecting 5-year survival (P<0.001). After multiple linear regression, dopamine was the factor related to ICU and hospital lengths of stay. CONCLUSIONS Compared with NE or dopamine alone, NE+VAS can reduce survival in patients with sepsis and heart failure who need vasopressors. Compared with the other 2 treatment options, dopamine can shorten ICU and hospital stays for these patients.

Topics: Acute Disease; Aged; Cardiotonic Agents; Cohort Studies; Critical Illness; Dopamine; Female; Heart Failure; Humans; Length of Stay; Male; Norepinephrine; Retrospective Studies; Sepsis; Survival Rate; Vasoconstrictor Agents; Vasopressins

To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury.. Interventional Study.. Research Institute.. Adult Merino ewes.. Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis.. Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%).. In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

Topics: Acute Kidney Injury; Animals; Arterial Pressure; Disease Models, Animal; Female; Hemodynamics; Kidney; Kidney Function Tests; Norepinephrine; Sepsis; Sheep; Vasoconstrictor Agents; Vasopressins

Topics: Anesthesia; Diverticulum, Colon; Humans; Hypotension; Intestinal Perforation; Male; Middle Aged; Norepinephrine; Postoperative Complications; Receptors, Adrenergic; Sepsis; Sympathomimetics; Vasoconstrictor Agents; Vasopressins

Randomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design.. We assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term.. The ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p < 0.001). The HTE patterns were inconsistent across the secondary risk measures. The sensitivity analyses of HTE effects for vasopressin, hydrocortisone and levosimendan were consistent with the main analyses and attenuated for simvastatin.. We assessed HTE in three recent ICU RCTs, using multivariable baseline risk of death models. There was considerable within-trial variation in the baseline risk of death. We observed potential HTE for simvastatin in ARDS, but no evidence of HTE for vasopressin, hydrocortisone or levosimendan in the two sepsis trials. Our findings could be explained either by true lack of HTE (no benefit of vasopressin, hydrocortisone or levosimendan vs comparator for any patient subgroups) or by lack of power to detect HTE. Our results require validation using similar trial databases.

Topics: Adult; Aged; Anti-Inflammatory Agents; APACHE; Cardiotonic Agents; Critical Illness; Female; Guideline Adherence; Hospital Mortality; Humans; Hydrocortisone; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intensive Care Units; Male; Middle Aged; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome; Sepsis; Simendan; Simvastatin; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

During the early phase of sepsis, hypotension is accompanied by increase of plasma vasopressin hormone (AVP) levels, which decline during the late phase. This hypotension is due in part to increase of nitric oxide (NO) synthesis by nitric oxide synthase (NOS) enzyme. Neuronal isoform of this enzyme (nNOS) is present in vasopressinergics neurons of hypothalamus, but its role in vasopressin secretion during sepsis is unknown.. We evaluated the role of nNOS in NO production and vasopressin secretion during sepsis. Wistar rats received 7-nitroindazole (50 mg/kg, i.p.), an inhibitor of nNOS activity, or vehicle and were submitted to septic stimulus by cecal ligation and puncture (CLP). At the time points 0, 4, 6, 18 and 24 h after sepsis induction the animals were decapitated and neurohypophysis and hypothalamus were removed for analysis of vasopressin content and NOS activity, respectively. Hematocrit, serum sodium, osmolality, proteins and plasmatic AVP were quantified.. Mortality was not affected by 7-nitroindazole (7-NI). Sodium and plasma proteins levels decreased after CLP and the treatment anticipated the protein loss, and delayed serum sodium decrease. Septic animals treated with 7-NI showed decrease of osmolality 4 h after CLP. Nitric oxide synthase activity in hypothalamus increased at 4 and 24 h after CLP and was reduced with 7-NI. Neurohypophysis content of AVP diminished after CLP and 7-NI did not alter this parameter. Plasma AVP levels increased at 6 h and decreased 18 and 24 h after CLP. Treatment with 7-NI did not alter plasma vasopressin levels.. We concluded that nNOS does not have a substantial role in vasopressin secretion during experimental sepsis.

Topics: Animals; Arginine Vasopressin; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Radioimmunoassay; Rats; Rats, Wistar; Sepsis; Vasopressins

Microvascular oxygen saturation (μHBO2) plays an essential role in the development and outcome of sepsis. Hypercapnia (HC) improves the microvascular oxygenation of the mucosa in both healthy and septic animals. Vasopressin V1A receptor blockade prevents this positive effect under otherwise physiological conditions. The aim of this study was to investigate the effects and mechanisms of the vasopressin system during hypercapnia under septic conditions.. 80 rats were randomized into 8 groups (N=10). Colon ascendens stent peritonitis (CASP) or sham surgery was performed on 40 animals each to establish a moderate polymicrobial sepsis or sham control, respectively. 24h after sepsis induction the animals were subjected to 120min of volume-controlled and pressure-limited ventilation with either normocapnic (pCO2 35-45mmHg) or moderate hypercapnic (pCO2 of 65-75mmHg) ventilation targets. Animals received either vasopressin V1A receptor blockade (SR 49059, 1mgkg(-1) i.v.) or vehicle solution (dimethyl sulfoxide, 1%). Blood pressure, heart rate, pO2 and pCO2 were measured and microcirculatory oxygenation (μHBO2) and microcirculatory flow (μflow) were recorded using tissue reflectance spectrophotometry. Oxygen supply (μDO2) and consumption (μVO2) were calculated from intermittent blood gas analysis.. In septic animals, μHBO2 declined during normocapnia (-11±10.3) but remained unchanged during hypercapnia. μHBO2 declined with vasopressin V1A receptor blockade both during normocapnia (-7.4±10.6) and hypercapnia (-9.2±9.8). Microcirculatory oxygen consumption was significantly reduced by hypercapnia in septic animals (-2.4·10(5) [AU]±2.4·10(5) [AU]). In sham animals, μHBO2 and μVO2 did not change.. Vasopressin V1A receptors mediate the beneficial effects of hypercapnia on microcirculatory oxygenation during sepsis. The effects of vasopressin on μHBO2 might be related to decreased oxygen consumption during hypercapnia.

Topics: Animals; Biomarkers; Disease Models, Animal; Hemoglobins; Hormone Antagonists; Hypercapnia; Intestinal Mucosa; Male; Microcirculation; Oxygen; Oxygen Consumption; Rats, Wistar; Receptors, Vasopressin; Regional Blood Flow; Sepsis; Signal Transduction; Splanchnic Circulation; Time Factors; Vasopressins

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

Sepsis is a life-threatening condition caused by the systemic inflammatory response to a bacterial infection. Although much is known about the cellular and molecular changes that characterize the peripheral inflammatory response to sepsis, almost nothing is known of the neuronal changes that cause associated perturbations in the central control of homeostasis. Osmoregulation is one of the key homeostatic systems perturbed during sepsis. In healthy subjects, systemic hypertonicity normally excites osmoreceptor neurons in the organum vasculosum laminae terminalis (OVLT), which then activates downstream neurons that induce a parallel increase in water intake and arginine vasopressin (AVP) secretion to promote fluid expansion and maintain blood pressure. However, recent studies have shown that the early phase of sepsis is associated with increased AVP levels and suppressed thirst. Here we examined the electrophysiological properties of OVLT neurons and magnocellular neurosecretory cells (MNCs) in acute in vitro preparations obtained from rats subjected to sham surgery or cecal ligation and puncture (CLP). We found that the intrinsic excitability of OVLT neurons was not affected significantly 18-24 h after CLP. However, OVLT neurons in CLP rats were hyperpolarized significantly compared with shams. Moreover, a reduced proportion of these cells displayed spontaneous electrical activity and osmoresponsiveness in septic animals. In contrast, the osmoresponsiveness of MNCs was only attenuated by CLP, and a larger proportion of these neurons displayed spontaneous electrical activity in septic animals. These results suggest that acute sepsis disrupts centrally mediated osmoregulatory reflexes through differential effects on the properties of neurons in the OVLT and supraoptic nucleus.. Sepsis is a life-threatening condition caused by the systemic inflammatory response to bacterial infection. Although the early phase of sepsis features impaired thirst and enhanced vasopressin release, the basis for these defects is unknown. Here, we show that cecal ligation and puncture (CLP) in rats impairs the osmoresponsiveness of neurons in the organum vasculosum lamina terminalis (OVLT; which drives thirst) and attenuates that of neurosecretory neurons in the supraoptic nucleus (SON; which secrete oxytocin and vasopressin). Notably, we found that OVLT neurons are hyperpolarized and electrically silenced. In contrast, CLP increased the proportion of SON neurons displaying spontaneous electrical activity. Therefore, CLP affects the properties of osmoregulatory neurons in a manner that can affect systemic osmoregulation.

Topics: Action Potentials; Animals; Disease Models, Animal; Drinking Behavior; Male; Neurons; Organum Vasculosum; Osmoregulation; Patch-Clamp Techniques; Rats; Rats, Long-Evans; Sepsis; Thirst; Vasopressins; Water-Electrolyte Balance

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

To determine if the selective vasopressin type 1a receptor agonist selepressin (FE 202158) is as effective as the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist vasopressor hormone arginine vasopressin when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis.. Prospective, randomized, controlled laboratory experiment.. University animal research facility.. Forty-five chronically instrumented sheep.. Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure fell by more than 10 mm Hg from baseline level, an additional continuous IV infusion of arginine vasopressin or selepressin was titrated to raise and maintain mean arterial pressure within no less than 10 mm Hg from baseline level. Effects of combination treatment of selepressin with the selective vasopressin V2 receptor agonist desmopressin were similarly investigated.. In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index decreased by ~50%, and ~7 L of fluid were retained over 24 hours; this fluid accumulation was partially reduced by arginine vasopressin and almost completely blocked by selepressin; and combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to arginine vasopressin treatment.. Resuscitation with the selective vasopressin type 1a receptor agonist selepressin blocked vascular leak more effectively than the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist arginine vasopressin because of its lack of agonist activity at the vasopressin V2 receptor.

Topics: Animals; Arginine Vasopressin; Drug Therapy, Combination; Hemodynamics; Pneumonia, Bacterial; Pseudomonas aeruginosa; Random Allocation; Receptors, Vasopressin; Respiratory Mechanics; Sepsis; Sheep; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Arginine Vasopressin; Receptors, Vasopressin; Sepsis; Vasoconstrictor Agents; Vasopressins

Vasopressin administration has been tested in cardiac arrest. However it has not been tested when cardiac arrest occurs in certain circumstances, as in sepsis, where it may have a major role. The aim of the study was to investigate survival after cardiac arrest in a septic porcine model compared with healthy animals and to explore the effectiveness of adding vasopressin vs epinephrine alone administration.. Thirty five healthy piglets of both genders were studied. The piglets were randomly assigned into three groups: group A (n = 8), group B (n = 14), group C (n = 13). Animals of groups B and C were given endotoxin to mimic a septic state before arrest. We applied the same resuscitation protocol to all pigs but we replaced the first dose of epinephrine with vasopressin in pigs of group C. Following surgical preparation and 30 min resting period, baseline measurements were recorded. In order to assess tissue oxygenation, we implemented Near Infrared Spectroscopy (NIRS) with the vascular occlusion technique (VOT) in thirteen lipopolysaccharide (LPS)-treated animals, occluding abdominal aorta and inferior vena cava. Afterwards, LPS (100 μg/kg) was infused in a 30 min period to animals of groups B and C and normal saline to group A. New NIRS measurements were obtained again. Subsequently, we provoked ventricular fibrillation (VF). After 3 min of untreated VF, open chest cardiopulmonary resuscitation (CPR) was performed manually. Primary end point was the restoration of spontaneous circulation (ROSC).. The chance of ROSC for the groups A, B and C was 75%, 35.7%, and 30.7% respectively. A significant difference in ROSC was established between septic (group B + C) and non septic piglets (group A) (P = 0.046). Vasopressin administration had no effect in outcome. LPS administration decreased oxygen consumption rate, as assessed by NIRS, in peripheral tissues (22.6 ± 7.2. vs 18.5 ± 7.2, P = 0.07).. Septic piglets have fewer chances to survive after cardiac arrest. No difference in outcome was observed when the first dose of epinephrine was replaced with vasopressin to treat cardiac arrest in the LPS-treated animals.

Topics: Animals; Epinephrine; Female; Heart Arrest; Lipopolysaccharides; Male; Resuscitation; Sepsis; Spectroscopy, Near-Infrared; Swine; Vasopressins

We investigated whether the vasopressin (AVP) secretion deficiency observed during cecal ligation and puncture (CLP)-induced sepsis may be caused by apoptosis in hypothalamic magnocellular neurons. Plasma cytokines (TNF-α, IL-1β and IL-6) and nitrate levels were increased during sepsis and plasma AVP levels were higher in the early phase returning to basal levels in the late phase. Concomitantly, expression of the apoptosis effector, cleaved caspase 3, was increased in magnocellular neurons, inferring that this increase in hypothalamic neurons may be caused by cytokines and elevated nitrate levels. This in turn could compromise AVP secretion in the late phase of sepsis.

Topics: Animals; Apoptosis; Blotting, Western; Caspase 3; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hypothalamus; Immunohistochemistry; Male; Neurons; Nitrates; Radioimmunoassay; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; 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

Low-dose arginine vasopressin (AVP) has been proposed as an adjunctive vasopressor for the treatment of advanced vasodilatory shock. However, its effects on renal, hepatic, and intestinal dysfunction during sepsis remain controversial.. Fecal peritonitis was induced in 20 anesthetized, invasively monitored, mechanically ventilated female pigs. Following the time point of septic shock (defined as mean artery pressure (MAP) ≤65 mmHg), animals were randomly assigned to the following groups (n = 10): 1) a norepinephrine group with MAP between 65 and 75 mmHg; and 2) an AVP group with a constant infusion rate of 0.5 mU.kg(-1).min(-1).. MAP, pulmonary capillary wedge pressure, hematocrit, TNF-α, IL-6, and IL-10 were similar in the two groups during the 28-h observation period. Infusion of AVP was associated with lower total norepinephrine and fluid requirements. There was a statistically significant improvement in renal function as assessed by increased urine output and renal blood flow, and decreased serum creatinine, in the AVP group when compared with the norepinephrine group (P < 0.05). Histological analyses of the intestine, liver, and kidney showed similar light microscopical appearance of the two groups. Apoptotic cells in the liver were significantly fewer in the AVP group when compared with the norepinephrine group (P < 0.05).. An adjunctive AVP to norepinephrine infusion exhibits a favorable impact on renal function without deleterious effects on the liver and intestine in a porcine model of experimental sepsis when compared with norepinephrine infusion alone.

Topics: Animals; Cytokines; Intestinal Mucosa; Intestines; Kidney; Liver; Sepsis; Swine; Vasopressins

Topics: Humans; Sepsis; Vasoconstrictor Agents; Vasopressins

The effects of moderate-dose vasopressin on gastric mucosal perfusion and its relation to global and hepatosplanchnic hemodynamic and oxygen transport variables were investigated in patients with severe sepsis.. Vasopressin was administered at a dose of 0.04 IU · kg⁻¹ · h⁻¹ over 4 h in 12 patients with severe sepsis who were receiving norepinephrine. During the study period, the norepinephrine infusion rate was reduced to keep mean arterial blood pressure constant. Hepatosplanchnic blood flow, oxygen delivery, and oxygen consumption (via hepatic venous catheterization using the Fick principle and continuous indocyanine green infusion technique), global hemodynamics (transpulmonary thermodilution method), and the difference between the gastric mucosal and arterial carbon dioxide tension (Pco₂-gap) were measured at baseline and 4 h after the start of the vasopressin infusion.. The administration of 0.04 IU · kg⁻¹ · h⁻¹ vasopressin over 4 h was associated with minimal changes in global hemodynamics. Heart rate decreased slightly from 99 [81-115] (median [interquartile range]) to 96 [74-109] beats/min (P = 0.016) and cardiac index from 3.7 [2.8-4.7] to 3.5 [2.7-3.6] L · min⁻¹ · m⁻² (P = 0.003). Global oxygen delivery index decreased significantly from 461 [375-637] to 419 [352-551] ml · min⁻¹ · m⁻² (P = 0.002), whereas hepatosplanchnic blood flow and oxygen uptake remained unchanged. Gastric mucosal Pco₂-gap increased significantly from 13.3 [8.0-16.7] to 17.1 [10.3-28.7] mmHg (P = 0.002), suggesting that blood flow may have been redistributed away from the gut mucosa.. Vasopressin at a dosage of 0.04 IU · kg⁻¹ · h⁻¹ may impair gastric mucosal perfusion with minimal global hemodynamic effects.

Topics: Adult; Aged; Aged, 80 and over; Blood Flow Velocity; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Humans; Male; Middle Aged; Oxygen Consumption; Pilot Projects; Sepsis; Vasopressins

The aim was to analyze the effect of leukotriene synthesis inhibitor administered intraperitoneally in vasopressin release during sepsis. Male Wistar rats received injections of MK-886 (1.0, 2.0 or 4.0 mg/kg) or vehicle (DMSO 5%) 1 h before cecal ligation and puncture. There was some variation on the survival rate depending on the dose used but the drug did not modify the hematocrit, osmolality, serum sodium and nitrate, plasma protein, and neutrophil recruitment, in any dose. Nevertheless, vasopressin (AVP) release decreased in a dose-response manner in the early phase of sepsis. These results support the suggestion that leukotrienes (LTs) are involved in AVP release during sepsis.

Topics: Animals; Cecum; Cell Movement; Disease Models, Animal; Enzyme Inhibitors; Hematocrit; Indoles; Leukotrienes; Ligation; Lipoxygenase Inhibitors; Male; Neutrophils; Nitrates; Osmolar Concentration; Peritoneal Cavity; Proteins; Punctures; Radioimmunoassay; Rats; Rats, Wistar; Sepsis; Sodium; Vasopressins

Acute renal failure (ARF) is frequently associated with polyuria and urine concentration defects and it is a severe complication of sepsis because it increases the mortality rate. Inhibition of NF-kappaB activation has been suggested to provide a useful strategy for the treatment of septic shock. However, the impact on sepsis-induced ARF is still unclear. Therefore, we examined the effect of pyrrolidine dithiocarbamate (PDTC) and of small interfering RNA (siRNA) silencing NF-kappaB p50/p105 on sepsis-induced downregulation of vasopressin V(2) receptors and aquaporin (AQP)-2 channels using a cecal ligation and puncture (CLP) mouse model. CLP caused a time-dependent downregulation of renal vasopressin V(2) receptor and of AQP2 expression without alterations in plasma vasopressin levels. Renal activation of NF-kappaB in response to CLP was attenuated by PDTC pretreatment, which also attenuated the downregulation of V(2) receptor and AQP2 expression. Furthermore, a strong nuclear staining for the NF-kappaB p50 subunit throughout the whole kidney in response to CLP was observed. siRNA against NF-kappaB p50 attenuated the CLP-induced nuclear translocation of the p50 subunit and the CLP-induced downregulation of V(2) receptor and AQP2 expression. Additionally, PDTC and siRNA pretreatment inhibited the CLP-induced increase in renal TNF-alpha and IL-1beta concentration and NOS-2 mRNA abundance. Moreover, PDTC and siRNA pretreatment ameliorated CLP-induced hypotension and ARF. Our findings suggest that NF-kappaB activation is of importance for the downregulation of AQP2 channel and vasopressin V(2) receptor expression during sepsis. In addition, our data indicate that NF-kappaB inhibition ameliorates sepsis-induced ARF.

Topics: Acute Kidney Injury; Animals; Antioxidants; Aquaporin 2; Cecum; Disease Models, Animal; Down-Regulation; Interleukin-1beta; Ligation; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Pyrrolidines; Receptors, Vasopressin; Sepsis; Thiocarbamates; Tumor Necrosis Factor-alpha; Vasopressins

The extent of neuroendocrine dysfunction (NED) has not been well defined in critically ill children and likely varies significantly from that in adults. We sought to define the prevalence of neuroendocrine dysfunction in a group of children in a multidisciplinary pediatric intensive care unit and determine the relationship of neuroendocrine dysfunction with severity of illness and presence of sepsis.. Prospective observational study in a pediatric intensive care unit at a referral childrens hospital. Blood samples were evaluated within 12 hrs of admission for serum cortisol, thyroid stimulating hormone, total triiodothyronine (T3), reverse triiodothyroine (rT3), free thyroxine, and arginine vasopressin. Pediatric risk of mortality, pediatric logistic organ dysfunction scores, and length of stay were calculated.. Seventy-three children were enrolled over a 13-month period. Median patient age was 72 months (range, 3-228 months). Overall prevalence of absolute adrenal insufficiency ranged from 7% to 58% based on cortisol cutoff chosen. Presence of absolute adrenal insufficiency, low T3 syndrome (LT3S), or vasopressin insufficiency did not differ between septic or nonseptic patients. NED did not correlate with pediatric logistic organ dysfunction, Pediatric Risk of Mortality Score III, length of stay, or mortality. Prevalence of multiple NED was 62% (28 of 45 children), where 62% had 2 neurohormonal deficiencies and 24% had 3 neurohormonal deficiencies.. NED is common in both septic and nonseptic critically ill children in a single pediatric intensive care unit. Larger scale studies are necessary to determine whether presence of NED, or specific combinations of neurohormonal dysfunction, is important in predicting outcomes or benefit of early hormonal replacement therapies in critically ill children.

Topics: Adolescent; Age Factors; APACHE; Cause of Death; Chi-Square Distribution; Child; Child, Preschool; Critical Illness; Endocrine System Diseases; Female; Hospital Mortality; Humans; Hydrocortisone; Infant; Intensive Care Units, Pediatric; Male; Multiple Organ Failure; Neurosecretory Systems; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Sepsis; Sex Factors; Statistics, Nonparametric; Survival Analysis; Thyrotropin; Vasopressins

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

The early use of vasopressors in sepsis has been associated with a decrease in immune activation independent of hemodynamic effects, although the mechanism behind this remains unclear. We hypothesize that low dose vasopressin will reduce the pulmonary inflammation associated with sepsis. Our aims were to (1) determine whether vasopressin reduces lipopolysaccharide (LPS)-induced pulmonary inflammation and (2) determine which vasopressin receptor is responsible for pulmonary immune modulation. Mice were treated with intraperitoneal LPS to induce both systemic and pulmonary inflammation. Vasopressin or saline was infused via peritoneal pump and interleukin 6 (IL-6) in lung and serum was measured at 6h. NF-kappaB activation as was determined in the lung through immunoblotting total and phospho-IkappaB. Hemodynamic data was also obtained at the 6h mark. In a separate series of experiments mice received both LPS and vasopressin infusion following pretreatment with vasopressin receptor antagonists to V1R, V2R and OTR. Low dose LPS dramatically raises both serum IL-6 and pulmonary levels of IL-6 and phospho-IkappaB despite no significant changes in mean arterial pressure at 6h. Compared to saline, vasopressin infusion significantly decreases both the pulmonary IL-6 levels and phospho-IkappaB in LPS treated mice without raising arterial pressure. Pretreatment with V2R antagonist results in complete attenuation of vasopressin's immunosuppressive effects, with restoration of pulmonary IL-6 and phospho-IkappaB levels to those seen with LPS alone.. Vasopressin exerts a local anti-inflammatory effect on the lung through the V2R in a model of sepsis.

Topics: Animals; Cell Culture Techniques; Disease Models, Animal; Epithelial Cells; Humans; Interleukin-6; Lipopolysaccharides; Mice; NF-kappa B; Pneumonia; Pulmonary Alveoli; Receptors, Vasopressin; Sepsis; Signal Transduction; 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

Clinical and experimental studies with LPS injection have shown an increase in vasopressin (AVP) secretion in the early phase of severe sepsis, which is subsequently reduced despite persistent hypotension. The aim of this study was to evaluate the role of inducible nitric oxide synthase (iNOS)-derived NO in hypothalamic activation and in AVP release during severe sepsis induced by cecal ligation and puncture (CLP). Male Wistar rats received i.p. injections of aminoguanidine, an iNOS inhibitor, or saline 30 min before CLP or sham surgeries (controls). CLP led to increased plasma nitrate levels, protein leakage and hypotension and caused mortality of 80% by 24 h. Expression of c-fos in paraventricular (PVN), supraoptic (SON) and organum vasculosum of lamina terminalis (OVLT) nuclei, as well as plasma AVP concentration were increased at 6 h but reduced to basal levels 24 h after CLP. Aminoguanidine pre-treatment prevented the increase in plasma nitrate levels and hypotension in the first 6 h. It also reduced AVP secretion and hypothalamic c-fos expression. After 24 h, the pre-treatment reduced plasma nitrate levels, protein leakage and caused a partial recovery of c-fos expression in SON and OVLT but did not affect AVP release. Furthermore, mortality was reduced to 43%. We conclude that during the early phase of severe sepsis hypotension caused by the iNOS-derived NO is partially responsible for the hypothalamic activation and AVP release. In the late phase, however, the iNOS-derived NO prevents brain activation blunting AVP secretion contributing to hypotension, irreversible shock and animal death.

Topics: Animals; Bacterial Infections; Blood Pressure; Drinking; Enzyme Inhibitors; Gene Expression Regulation; Guanidines; Hypothalamus; Immunohistochemistry; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Osmolar Concentration; Proto-Oncogene Proteins c-fos; Radioimmunoassay; Rats; Rats, Wistar; Sepsis; Time Factors; Vasopressins

Tachyphylaxis against catecholamines often complicates hemodynamic support in patients with septic shock. Recent experimental and clinical research suggests that the hemodynamic response to exogenous arginine vasopressin (AVP) infusion may also be blunted. The purpose of the present study was therefore to clarify whether the efficacy of a continuous AVP infusion (0.04 U x min(-1)) decreases over time in ovine endotoxemia. An additional objective was to determine whether the anticipated hyporesponsiveness can be counteracted by corticosteroids. Fourteen adult ewes (37 +/- 1 kg) were instrumented for chronic hemodynamic monitoring. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation. After 16 h of endotoxemia, the sheep were randomized to receive either AVP (0.04 U x min(-1)) or the vehicle (normal saline; n = 7 each). After 6 h of AVP or placebo infusion, respectively, methylprednisolone (30 mg x kg(-1)) was injected. Arginine vasopressin infusion increased mean arterial pressure and systemic vascular resistance index at the expense of a reduced cardiac index (P < 0.05 each). Supraphysiologic AVP plasma levels in the treatment group (298 +/- 15 pg x mL(-1)) were associated with increased surrogate parameters of liver, mesenterial, and myocardial dysfunction. After 6 h of continuous AVP infusion, the vasopressor effect was significantly reduced. Interestingly, a bolus infusion of methylprednisolone (30 mg x kg(-1)) reestablished mean arterial pressure by increasing both cardiac index and systemic vascular resistance index. The present study demonstrates that in endotoxemia, (a) the vasopressor effect of AVP infusion may be reduced, (b) corticosteroids may potentially be useful to increase the efficacy of AVP infusion, and (c) even moderate AVP doses may potentially impair myocardial and hepatic function.

Topics: Adrenal Cortex Hormones; Animals; Arginine Vasopressin; Blood Pressure; Endotoxemia; Endotoxins; Female; Methylprednisolone; Oxygen; Pressure; Sepsis; Sheep; Shock; Time Factors; Vasopressins

To measure arginine vasopressin (AVP) serum concentrations in critically ill patients.. Prospective study.. Twelve-bed general and surgical intensive care unit in a tertiary, university teaching hospital.. Two-hundred-thirty-nine mixed critically ill patients and 70 healthy volunteers.. None.. Demographic data, hemodynamic variables, vasopressor drug requirements, blood gases, AVP serum concentrations within 24 hrs after admission, multiple organ dysfunction score, and outcome were recorded. Twenty-four hours after admission, study patients had significantly higher AVP concentrations (11.9 +/- 20.6 pg/mL) than healthy controls (0.92 +/- 0.38 pg/mL; p < .001). Males had lower AVP concentrations than females (9.7 +/- 19.5 vs. 15.1 +/- 20.6 pg/mL; p = .014). Patients with hemodynamic dysfunction had higher AVP concentrations than patients without hemodynamic dysfunction (14.1 +/- 27.1 vs. 8.7 +/- 10.8 pg/mL; p = .042). Patients after cardiac surgery (n = 96) had significantly higher AVP concentrations when compared to patients admitted for other diagnoses (n = 143; p < .001). AVP concentrations were inversely correlated with length of stay in the intensive care unit (correlation coefficient, -0.222; p = .002). There was no correlation between serum AVP concentrations and the incidence of shock or specific hemodynamic parameters. Four (1.7%) of the 239 study patients met criteria for an absolute AVP deficiency (AVP, <0.83 pg/mL), and 32 (13.4%) met criteria for a relative AVP deficiency (AVP, <10 pg/mL, and mean arterial pressure, <70 mm Hg). In shock patients, relative AVP deficiency occurred in 22.2% (septic shock), 15.4% (postcardiotomy shock), and 10% (shock due to a severe systemic inflammatory response syndrome) (p = .316).. AVP serum concentrations 24 hrs after intensive care unit admission were significantly increased in this mixed critically ill patient population. The lack of a correlation between AVP serum concentrations and hemodynamic parameters suggests complex dysfunction of the vasopressinergic system in critical illness. Relative and absolute AVP deficiency may be infrequent entities during acute surgical critical illness, mostly remaining without significant effects on cardiovascular function.

Topics: Case-Control Studies; Critical Illness; Female; Hospital Mortality; Humans; Intensive Care Units; Male; Middle Aged; Sepsis; Shock; 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

The effect of low-dose vasopressin (AVP) on vital regional circulations may be clinically relevant but has not been fully described. We sought to determine the effect of low-dose AVP on systemic haemodynamics, coronary, mesenteric and renal circulations in the conscious normal and septic mammal. We studied seven Merino sheep using a prospective randomized cross-over double-blind placebo-controlled animal design. We inserted flow probes around aorta, coronary, mesenteric and renal arteries and, three weeks later, we infused low-dose AVP (0.02 IU/min) or placebo in the normal and septic state induced by intravenous E. coli. In normal sheep, AVP (0.02 IU/min) induced a 17% decrease in mesenteric blood flow (393.0+/-134.9 vs 472.1+/-163.8 ml/min, P<0.05) and a 14% decrease in mesenteric conductance (P<0.05). In septic sheep, AVP decreased heart rate and cardiac output by 28% and 22%, respectively (P<0.05). It also decreased mesenteric blood flow and mesenteric conductance by 23% (flow: 468.5+/-159.7 vs 611.3+/-136.3 ml/min, P<0.05; conductance: 6.3+/-2.7 vs 8.2+/-2.7 ml/min/mmHg; P<0.05). Renal blood flow was unchanged but urine output and creatinine clearance increased (P<0.05). We conclude that low-dose AVP infusion has similar effects in the normal and septic mammalian circulation: bradycardia, decreased cardiac output, decreased mesenteric blood flow and conductance and increased urine output and creatinine clearance. This information is important to clinicians considering its administration in humans.

Topics: Animals; Catheterization, Peripheral; Creatinine; Escherichia coli Infections; Hemodynamics; Infusions, Intravenous; Ovariectomy; Regional Blood Flow; Renal Circulation; Sepsis; Sheep; Splanchnic Circulation; Urodynamics; Vasoconstrictor Agents; Vasopressins

Blindness caused by ischemic optic neuropathy in the hospital setting occurs perioperatively and in critically ill patients, but its etiology remains ill defined. We describe four critically ill patients who developed blindness within 1 mo of one another. Three cases occurred outside of the operative arena. Potential risk factors for the development of ischemic optic neuropathy, such as use of vasopressors, venous congestion, and hypotension, are described.

Topics: Accidents, Traffic; Blindness; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Diverticulitis; Female; Flail Chest; Hemothorax; Humans; Intensive Care Units; Lung Injury; Male; Middle Aged; Myasthenia Gravis; Myocardial Infarction; Optic Nerve Injuries; Optic Neuropathy, Ischemic; Pancreatitis; Pelvic Bones; Prone Position; Risk Factors; Sepsis; Spinal Fractures; 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

Topics: Acute Kidney Injury; Fluid Therapy; Humans; Respiratory Distress Syndrome; Sepsis; Vasoconstrictor Agents; Vasopressins

The European Society of Intensive Care Medicine Annual Congress offers the opportunity for basic scientists and clinicians to share recent findings. Apart from the large number of free communications, several sessions of the congress were dedicated to state-of-the-art tutorials given by established speakers. The areas of interest of the attendees were widely distributed as usual, a reflection of the large array of so-called 'critical illnesses'. The results of clinical trials and experimental findings using recently developed drugs were presented, essentially in the fields of inflammation, sepsis, and acute lung injury. The benefits of several new compounds observed experimentally need to be confirmed clinically. The European Society of Intensive Care Medicine Congress is well established as a unique opportunity to implement and to promote a collaboration between European basic scientists and clinicians.

Topics: Anti-Bacterial Agents; Critical Care; Critical Illness; Ethics, Clinical; Ethics, Medical; Europe; Humans; Inflammation; International Cooperation; Nitric Oxide; Respiratory Distress Syndrome; Sepsis; Signal Transduction; Vasopressins

To evaluate mechanisms of vasodilation in sepsis by comparing responses of resistance arterioles to vasopressin in rat cremaster muscle of septic and control rats.. Prospective, experimental study.. Experimental animal laboratory.. Twenty male rats, anesthetized with ketamine and acepromazine.. Topical superfusion of vasoactive compounds on skeletal muscle resistance arterioles.. The effect of sepsis on responses to local application of vasopressin was investigated using in vivo videomicroscopy. Vasopressin was superfused topically on the cremaster muscle resistance arterioles (15 to 25 microns) of rats made septic by cecal ligation and puncture, and the responses were compared with the responses of controls that underwent sham ligation. Responses to topically suffused vasopressin were also assessed in septic and control rats, before and after superfusion of the muscle with the nitric oxide synthase inhibitor NG-methyl-L-arginine (NMA). Sepsis produced a decrease in the vasoconstrictive effects of vasopressin; the maximal response was lower, and the concentration-response curve was shifted to the right in septic rats (p < .05). Contractions at vasopressin concentrations of 0.01, 1, and 10 nM were 39%, 36%, and 40%, respectively, of sham controls. Superfusion of the muscle with NMA partially restored arteriolar responsiveness in the septic rats, significantly increasing the arteriolar constriction of the septic rats in response to vasopressin. This effect was reversed with superfusion of excess L-arginine (1 mM).. This study illustrates the reduced responsiveness of the resistance arterioles of septic rats in response to vasopressin in vivo, and the partial restoration of responsiveness by concurrent application of NMA. In previous studies using this model, we have shown similar results using norepinephrine and endothelin-1, as well as angiotensin II. These findings, and the findings of this study, suggest a generalized abnormality in responsiveness of resistance arterioles to endogenous vasoconstrictors in sepsis. Partial reversal of this abnormality with NMA supports an important role for nitric oxide in mediating abnormal vasopressor responsiveness in sepsis.

Topics: Animals; Arterioles; Enzyme Inhibitors; Ligation; Male; Muscle, Smooth, Vascular; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Rats, Sprague-Dawley; Sepsis; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

Inhibitors of nitric oxide (NO) synthesis have been used in the treatment of septic and endotoxic shock. However, several studies question the beneficial effect of inhibiting NO production in sepsis and endotoxemia. We have investigated the effect of inhibition of NO synthesis after endotoxemia in the isolated perfused rat heart. In hearts from endotoxin-treated animals, coronary flow was elevated 64% and oxygen consumption was elevated 20% compared with control hearts. NADH fluorescence imaging was used as an indicator of regional hypoperfusion. A homogeneous low-surface NADH fluorescence, indicative of adequate tissue perfusion, was observed in both control and endotoxin-treated hearts. The increase in coronary flow and oxygen consumption could only partially be prevented by pretreatment of the animals with dexamethasone. Addition of N omega-nitro-L-arginine (NNLA), an inhibitor of NO synthesis, to the perfusion medium eliminated differences in coronary flow and oxygen consumption between normal and endotoxin-treated hearts. However, NADH surface fluorescence images of endotoxin-treated hearts after NNLA revealed areas of high fluorescence, indicating local ischemia, whereas the control hearts remained without signs of ischemia. The ischemic areas were present at various perfusion pressures and disappeared after the infusion of L-arginine, the natural precursor of NO, or the exogenous NO donor sodium nitroprusside. Methylene blue (MB), an inhibitor of soluble guanylate cyclase, the effector enzyme of NO, also eliminated differences in coronary flow and produced similar areas of local myocardial ischemia in endotoxin-treated hearts but not in control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Coronary Circulation; Dexamethasone; Endotoxins; Male; Methylene Blue; Myocardial Ischemia; NAD; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxygen Consumption; Rats; Rats, Wistar; Sepsis; Vasopressins

Continuous pump-driven veno-venous hemofiltration (CVVH) has become an established method for treatment of acute renal failure (ARF). Since severe disturbances of (micro-) circulation are intimately involved in the bad outcome of these patients, the profile of endocrinological regulators of circulation was prospectively and serially measured in patients undergoing pump-driven CVVH (n = 15). 15 patients with similar APACHE II score, but without ARF and without CVVH were also studied. Endothelin-1 (ET-1), atrial natriuretic peptide (ANP), vasopressin, renin, and catecholamine (epinephrine, norepinephrine) plasma levels were measured before start of CVVH (= "baseline") (in the non-CVVH patients: admission to intensive care unit) and during the next 5 days. Various hemodynamic parameters were additionally monitored. MAP, HR, PAP, CI, and right ventricular hemodynamics (RVEF, RVEDV, RVESV) remained almost unchanged in the CVVH patients and were without differences to the non-CVVH group within the entire investigation period. PCWP and RAP were higher in the CVVH patients already at baseline (RAP, 17.8 +/- 4.0 mmHg; PCWP, 22.1 +/- 4.5 mmHg) (p < .02) and remained elevated in the further course of the investigation. Renin plasma level was higher already at baseline in the CVVH patients (907 +/- 184 pg/ml) (p < .05) and further increased during CVVH (to 1453 +/- 186 pg/mL). Vasopressin increased only in the CVVH group (from 3.80 +/- .66 to 11.85 +/- 1.05 pg/mL) (p < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Blood Circulation; Blood Pressure; Creatinine; Dopamine; Endothelins; Epinephrine; Female; Hemodynamics; Hemofiltration; Humans; Lactates; Lactic Acid; Male; Middle Aged; Norepinephrine; Renin; Sepsis; Time Factors; Vascular Resistance; Vasopressins; Wounds and Injuries

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 (VP)-stimulated 32P-inositol lipid metabolism was studied in hepatocytes obtained from rats rendered septic by cecal ligation and puncture. Basal 32P-phosphatidylinositol (PI) labeling, as well as its hormone-stimulated turnover, were greatly reduced in septic rats compared with sham-operated rats. The earliest VP-induced degradation of 32P-polyphosphoinositides (poly-PI) was greatly attenuated in septic rats. Moreover, while 32P-poly-PI labeling reached its lowest value by 60 sec of VP stimulation in cells from sham-operated rats, maximal changes in 32P-phosphatidylinositol 4,5-bisphosphate (32PIP2) occurred within 30 sec in septic rats. In contrast, the recovery of 32PIP2 labeling was more active in cells from septic rats, overcoming the impairment in its resynthesis triggered by surgical trauma in cells from sham-operated rats. The lower uptake of 32P into phosphatidic acid (PA) at the different time points analyzed was a sensitive indicator of the lower production of diacylglycerols from the VP-induced degradation of inositol phospholipids in septic rats. These observations support the idea that sepsis is associated with perturbations in the earliest events of the hepatocyte signal transmission pathway, namely, at the level of a receptor coupled to inositol lipid metabolism. Such perturbations are likely to be involved in the previously reported defective cell physiologic response to external hormone stimulation.

Topics: Animals; Blood Glucose; Kinetics; Lactates; Lactic Acid; Liver; Male; Phosphatidic Acids; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Rats; Rats, Inbred Strains; Sepsis; Vasopressins

Topics: Blood Transfusion; Brain Diseases; Critical Care; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostatic Techniques; Humans; Lypressin; Sepsis; Somatostatin; Terlipressin; Vasopressins

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: Animals; Body Composition; Body Water; Dogs; Humans; Mathematics; Parenteral Nutrition; Potassium; Potassium Deficiency; Radioisotope Dilution Technique; Regression Analysis; Sepsis; Sodium; Sodium Isotopes; Starvation; Surgical Procedures, Operative; Tritium; Uremia; Vasopressins

Topics: Catheterization; Esophageal and Gastric Varices; Gangrene; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Humans; Intestinal Diseases; Male; Mesenteric Arteries; Mesenteric Vascular Occlusion; Middle Aged; Portal Vein; Sepsis; Thrombophlebitis; Thrombosis; Vasopressins

Topics: Adult; Blood Glucose; Blood Urea Nitrogen; Blood Volume; Burns; Diabetes Complications; Diuresis; Female; Glycosuria; Humans; Hypernatremia; Infusions, Parenteral; Male; Middle Aged; Nitrogen; Osmolar Concentration; Sepsis; Vasopressins; Water-Electrolyte Balance

Topics: Animals; Blood Volume; Desoxycorticosterone; Dextrans; Disease Models, Animal; Diuresis; Dogs; Female; Glomerular Filtration Rate; Kidney; Plasma Substitutes; Sepsis; Vasopressins

Topics: Cephalothin; Chloramphenicol; Humans; Hypokalemia; Male; Meningoencephalitis; Middle Aged; Oxacillin; Penicillin G; Penicillin Resistance; Polyuria; Potassium; Sepsis; Staphylococcal Infections; Vancomycin; Vasopressins

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

Topics: Adrenocorticotropic Hormone; Arginine Vasopressin; Bacteremia; Corticosterone; Escherichia coli Infections; Hypophysectomy; Hypothalamo-Hypophyseal System; In Vitro Techniques; Negotiating; Physiology; Pituitary Gland; Rats; Research; Sepsis; Vasopressins

Topics: Arginine Vasopressin; Female; Humans; Pre-Eclampsia; Pregnancy; Sepsis; Toxemia; Vasopressins