naloxone and Shock--Septic

Topics: Analgesics, Opioid; Animals; Corticotropin-Releasing Hormone; Cytokines; Forecasting; Gene Expression Regulation; Hormones; Humans; Inflammation; Leukocytes; Lymphocytes; Naloxone; Narcotic Antagonists; Neuroimmunomodulation; Neuropeptides; Neurosecretory Systems; Opioid Peptides; Pro-Opiomelanocortin; Rats; Receptors, Corticotropin-Releasing Hormone; Receptors, Opioid; Shock, Septic

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Child, Preschool; Diagnosis, Differential; Female; Humans; Inflammation Mediators; Interleukins; Lipid A; Naloxone; Narcotic Antagonists; Nitric Oxide; Receptors, Immunologic; Shock, Septic; Tumor Necrosis Factor-alpha

Topics: Animals; Antibodies, Monoclonal; Escherichia coli; Glucocorticoids; Humans; Immunization, Passive; Immunoglobulins, Intravenous; Lipopolysaccharides; Naloxone; Pentoxifylline; Shock, Septic; Tumor Necrosis Factor-alpha

In summary, an increased understanding of the pathogenesis and pathophysiology of septic shock has led to the development and evaluation of potential adjunctive therapies. Although several agents show promise in certain experimental settings, definitive recommendations regarding the use of these agents are not yet possible. Although several therapies have shown benefit when the subject receives treatment prior to the onset of sepsis, most have had varying degrees of success following the development of septicemia.

Topics: Animals; Cyclooxygenase Inhibitors; Endotoxins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Naloxone; Pentoxifylline; Shock, Septic

Bacteremia from gram-negative rods is a great cause of concern for hospital physicians today. Shock-complicating gram-negative sepsis has a mortality rate of 60% and above, despite early diagnosis and treatment. Intensive research efforts have shown new pathophysiological mechanisms and mediators involved in septic shock, with changes in recommended treatment protocols. In this report, the authors review the use of corticosteroids, fibronectin, naloxone hydrochloride, and immunotherapy, with emphasis on theoretical considerations and relevant clinical experience. Although these treatment methods may have been promising initially, data from large double-blind human trials are either lacking or unencouraging. While continued research and modern therapeutic approaches should improve future survival rates from septic shock, use of the therapies reviewed should be considered experimental at this time.

Topics: Adrenal Cortex Hormones; Combined Modality Therapy; Drug Therapy, Combination; Fibronectins; Humans; Immunotherapy; Naloxone; Shock, Septic

Septic shock is a common clinical problem in the intensive care setting. The high mortality rate associated with septic shock, regardless of age, reflects the inadequacy of available therapeutic approaches. The purpose of this article is to review the current pharmacologic approaches to the treatment of septic shock with an emphasis on the pathophysiologic correlations of these treatments.

Topics: Adrenergic Agonists; Amrinone; Glucagon; Humans; Naloxone; Shock, Septic

Topics: Animals; Endorphins; Naloxone; Shock, Septic

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Drug Evaluation; Drug Evaluation, Preclinical; Endorphins; Humans; Naloxone; Shock, Hemorrhagic; Shock, Septic

Topics: Aminoglycosides; Anti-Bacterial Agents; Humans; Naloxone; Shock, Septic; Steroids

Endogenous opioid peptides are released in response to stressful situations, such as circulatory shock, both as hormones and as central and peripheral neurotransmitters. Naloxone, an opiate antagonist, improves cardiovascular function in a variety of animal models of shock caused by endotoxemia, hemorrhage, anaphylaxis, or spinal trauma. Administration of thyrotropin-releasing hormone (TRH) in supraphysiologic doses also has pressor effects in these shock models. Given acutely after injury, TRH improves recovery in models of spinal trauma; however, the experimental effects of TRH do not involve action at the opiate receptor. Clinical evaluation of the use of naloxone in patients with shock has been largely limited to treatment of sepsis. The paucity of prospective, randomized trials makes these clinical data difficult to evaluate, but in septic patients the use of naloxone does not seem to improve survival. The use of naloxone in shock of other etiologies has not been clinically investigated, and may hold greater promise. Acute-phase treatment of spinal trauma victims with TRH is currently undergoing clinical trials.

Topics: Adult; Animals; Blood Pressure; Endorphins; Humans; Hypotension; Ischemia; Naloxone; Shock, Hemorrhagic; Shock, Septic; Shock, Traumatic; Thyrotropin-Releasing Hormone

The recent evolution of our understanding of endogenous OPs has led to important new insights into the pathophysiology of many disease states. Opiate antagonism may provide the critical care physician with yet another lifesaving weapon. Opiate antagonists are not approved for human use in the various conditions discussed in this article; their use is strictly experimental and should be restricted to controlled trials. We look forward to continued research and clinical trials involving these agents.

Topics: Animals; Body Temperature Regulation; Cardiovascular System; Clonidine; Endorphins; Halothane; Humans; Hypotension; Naloxone; Narcotic Antagonists; Rats; Receptors, Opioid; Respiration; Shock, Hemorrhagic; Shock, Septic; Shock, Surgical; Spinal Cord; Thyrotropin-Releasing Hormone

Topics: Anesthetics; Animals; Arousal; Cerebrovascular Circulation; Cerebrovascular Disorders; Child, Preschool; Female; Gerbillinae; Humans; Male; Middle Aged; Naloxone; Poisoning; Rats; Respiration; Respiratory Insufficiency; Shock, Septic; Spinal Cord Injuries

In summary, naloxone has proved to be effective and safe during its years of use for narcotic antagonism. Its usefulness in non-narcotic coma and shock remains controversial, although some encouraging but inconclusive evidence exists. The final answer lies on the horizon of medicine; it awaits further delineation of the role of endogenous opioids in health and disease and clear statistical verification of naloxone's efficacy in such disease states.

Topics: Animals; Arousal; Coma; Humans; Naloxone; Shock; Shock, Cardiogenic; Shock, Hemorrhagic; Shock, Septic

Topics: Animals; Binding Sites; Cardiovascular System; Cerebrovascular Disorders; Endorphins; Humans; Hypertension; Naloxone; Narcotic Antagonists; Pressoreceptors; Shock; Shock, Septic; Spinal Cord Injuries; Thyrotropin-Releasing Hormone; Wounds and Injuries

Topics: Animals; Brain; Brain Ischemia; Cardiovascular Physiological Phenomena; Cardiovascular System; Endorphins; Enkephalins; Humans; Hypertension; Hypotension; Morphine; Naloxone; Pressoreceptors; Receptors, Opioid; Reflex; Shock; Shock, Hemorrhagic; Shock, Septic; Spinal Cord Injuries; Thyrotropin-Releasing Hormone

Naloxone has been used as a pharmacological tool to investigate the role of endorphins and opiate receptors in the cardiovascular pathophysiology of shock. It would appear that endorphins act on opiate receptors to contribute to the abnormalities found and that naloxone improves survival as well as cardiovascular function in shock. Preliminary studies in humans and the subhuman primate create cautious optimism regarding the clinical application of this information. Naloxone has served us well as a key to unlock the involvement of endorphins and opiate receptors in shock. However, further advances in our understanding may depend on the development and use of opiate receptor agonists and antagonists specific for the different opiate receptors described, each subserving different functions. Naloxone's disadvantage of increasing pain awareness may limit its clinical usefulness but might be overcome by using drugs that reverse the behavioral and neuroendocrine changes produced by beta-endorphin without altering pain relief. Thyrotropin-releasing hormone (TRH) is just such a "physiological" opiate antagonist which has been shown to increase MAP in experimental endotoxic and hemorrhagic shock [32].

Topics: Adrenal Cortex Hormones; Animals; Blood Pressure; Disease Models, Animal; Dogs; Endorphins; Hemodynamics; Horses; Humans; Macaca fascicularis; Naloxone; Narcotic Antagonists; Rats; Receptors, Opioid; Shock, Septic; Swine

A complete understanding of naloxone's role in shock has not been well established; however, it has been accepted that naloxone applied specifically to the central nervous system can improve the course of the cardiovascular response. The currently available data would suggest that these central effects are mediated via nuclei that 1) are found in both the rostral and caudal regions of the brainstem, 2) contain opiate receptors, 3) interact with the fastigial nuclei of the cerebellum, and 4) possibly receive input from peripheral thermoreceptors. Recordings of neural activity from specific nuclei during shock as well as microinjections and iontophoresis of naloxone onto specific sites is needed to improve the current understanding of this apparently complex process.

Topics: Animals; Blood Pressure; Brain Chemistry; Brain Stem; Cerebellum; Dogs; Haplorhini; Naloxone; Narcotic Antagonists; Parasympathetic Nervous System; Rabbits; Rats; Receptors, Opioid; Shock, Septic

Topics: Animals; Blood Pressure; Hemodynamics; Humans; Hypotension; Naloxone; Pressoreceptors; Rats; Shock, Hemorrhagic; Shock, Septic

The specific opiate-antagonist naloxone rapidly reverses hypotension caused by endotoxin, hypovolemia, and spinal transection. In endotoxin shock in rats, naloxone's effects were stereospecific and were observed with intravenous (iv) doses as low as 0.1 mg/kg. In endotoxin shock in dogs, naloxone treatment significantly improved both cardiovascular parameters and survival. Naloxone, given iv, similarly improved blood pressure and survival in rat and canine models of hypovolemic shock. Moreover, intracerebroventricular (ivt) naloxone at a dose of 10 micrograms restored blood pressure after hypovolemia; this effect was blocked by hypophysectomy. In addition naloxone, given ivt, stereospecifically restored blood prssure after spinal shock. From these findings it is suggested that (1) pituitary endorphins are pathophysiologic factors in shock; (2) endorphins' cardiodepressant effects are mediated by opiate receptors within the central nervous system; and (3) use of opiate antagonists may be of therapeutic benefit in the treatment of shock in humans.

Topics: Animals; Blood Pressure; Cardiac Output; Cardiovascular System; Dogs; Dose-Response Relationship, Drug; Endorphins; Heart Rate; Humans; Hypotension; Naloxone; Rats; Receptors, Opioid; Shock, Septic; Vascular Resistance

To determine whether naloxone infusion is efficacious in severe hyperdynamic septic shock, we conducted a prospective study of 22 patients randomly assigned to a naloxone or placebo group. Patients were treated 12 +/- 2 h (SEM) after the onset of shock, with a mean arterial pressure (MAP) of 63 +/- 3 mm Hg. All patients had clinical evidence of an infectious process and required dopamine 20 +/- 2 micrograms/kg.min. Five (46%) of 11 patients in the naloxone group and one (9%) of the other 11 patients in the placebo group responded clinically. The MAP among the five responders increased from 62 +/- 5 to 89 +/- 4 mm Hg within 20 min of naloxone treatment (p less than .01). This favorable hemodynamic response was sustained throughout the patients' clinical course. In contrast, the MAP did not change significantly in the nonresponders who received naloxone, nor did it change in the placebo group. More patients in the naloxone group than in the placebo group received steroids concurrently. Survival rate was 100% in those who responded to naloxone clinically. However, overall survival rate in each group was essentially the same. No adverse effects were observed, except for mild agitation in some of the patients receiving naloxone. We conclude that naloxone infusion is clinically efficacious in improving the hemodynamic profile of a subgroup of patients with severe early hyperdynamic septic shock, but does not appear to improve the overall survival rate.

Topics: Aged; Bacterial Infections; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Naloxone; Pneumonia; Prospective Studies; Randomized Controlled Trials as Topic; Shock, Septic; Steroids

Fourteen patients suffering sixteen episodes of septic shock requiring inotrope and/or vasopressor support were randomised to receive a 30 micrograms/kg naloxone intravenous bolus followed by a 30 micrograms/kg/h infusion or an equivalent volume placebo bolus and infusion for 8-16 h in a double-blind study. pH and pulmonary wedge pressure were kept constant, and inotrope and/or vasopressor were titrated to maintain a preselected mean blood pressure. Inotrope/vasopressor requirements in the naloxone-treated group were significantly lower than those in the control group at 8 h (eight patients in each group, p less than 0.005) and at 16 h (five patients in each group, p less than 0.02). Late but significant improvements in stroke volume (p less than 0.02) and heart rate (p less than 0.05) were also noted in the eight naloxone-treated patients.

Topics: Adult; Aged; Analysis of Variance; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Female; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Male; Naloxone; Pulmonary Wedge Pressure; Random Allocation; Shock, Septic; Stroke Volume; Time Factors; Vascular Resistance

Treatment of septic shock with naloxone was evaluated in a prospective, randomised, double-blind, placebo-controlled study in which ten episodes of shock were treated with naloxone (0.4 to 1.2 mg intravenously) and 13 with the vehicle for injection. Treatment groups were similar in terms of demographic characteristics, type of primary infection, prevalence of septicaemia, type of underlying disease, duration in shock, and vasopressor therapy. Mean systolic blood pressure rose by 13.3% in the naloxone group and 11.3% in the placebo group. Two-way analysis of variance for repeated measures of blood pressure, obtained over 30 min periods before and after treatment, revealed no significant difference (p greater than 0.10) between treatment groups. Survival rates in the two groups at 48 h and 7 days after the start of treatment were similar. Naloxone, 0.4 to 1.2 mg intravenously, was no better than placebo in ameliorating hypotension in septic shock.

Topics: Aged; Blood Pressure; Double-Blind Method; Drug Evaluation; Female; Humans; Injections, Intravenous; Male; Middle Aged; Naloxone; Pharmaceutical Vehicles; Placebos; Random Allocation; Shock, Septic

Topics: Aged; Clinical Trials as Topic; Critical Care; Humans; Male; Naloxone; Shock, Septic

Naloxone and methylprednisolone sodium succinate (MPSS) may act in synergy to improve hemodynamics in patients with septic shock by enhancement of sympathomedullary discharge. This randomized double-blind study describes the effect of various dosing regimens of naloxone and MPSS upon hemodynamics and plasma catecholamines in patients with septic shock (n = 57). Consecutive bolus doses of naloxone were given 30 minutes apart (10 micrograms/kg;-100 micrograms/kg) and a single dose of MPSS (30 mg/kg); bolus doses of 5% dextrose in water solution plus single dose of MPSS as above; bolus dose of naloxone (30 micrograms/kg) followed by continuous infusion (30 micrograms/kg/hr for 1 hour) with single dose of MPSS as above; a bolus and continuous infusion of naloxone as above without MPSS; MPSS alone and standard therapy alone. In patients treated with bolus doses of naloxone in combination with MPSS, plasma levels of epinephrine and norepinephrine were increased approximately five-to tenfold. In patients treated with bolus plus continuous infusion of naloxone given with or without MPSS, only plasma epinephrine levels were increased. Systolic blood pressure and left ventricular stroke work index were improved within 15 minutes in groups which received naloxone and corticosteroids regardless of dose. In those groups, there were no changes in heart rate or filling pressure. Systemic vascular resistance improved significantly only in the group which received low dose bolus and continuous infusion of naloxone and MPSS. Naloxone and MPSS quickly improved cardiac function in patients with septic shock by enhanced sympathomedullary discharge and may be useful as an adjunct in the therapy of this disorder.

Topics: Bacteria; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Epinephrine; Heart Rate; Hemodynamics; Humans; Methylprednisolone; Methylprednisolone Hemisuccinate; Naloxone; Norepinephrine; Shock, Septic; Stroke Volume; Vascular Resistance

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Clinical Trials as Topic; Critical Care; Cross Infection; Disseminated Intravascular Coagulation; Hemodynamics; Heparin; Humans; Immunization, Passive; Infections; Naloxone; Sepsis; Shock, Septic

Topics: Female; Humans; Infant, Newborn; Naloxone; Narcotic Antagonists; Shock, Septic

Naloxone hydrochloride is an agent capable of antagonizing respiratory depression and analgesic actions which are inherent to the opioid by competitively acting at opioid receptors. It greatly contributed to basic research on antagonistic action of opioid receptors due to its high affinity to opioid receptors, in particular, micro-receptor. Naloxone has been recommended as an analeptic agent at a guideline level for patients with revealed or suspicious opioid addiction. Further, it has also been used as a preventive and treatment agent for spinal cord ischemia. Moreover, even though it has been confirmed in 1980's that naloxone has vasopressor effect in septic shock, further clinical trials are required for its wide clinical application.

Topics: Central Nervous System Stimulants; Humans; Naloxone; Receptors, Opioid; Shock, Septic

1. Taking into consideration the effect of septic shock on releasing various mediators, the present study was undertaken in an attempt to elucidate the effect of endotoxin on naloxone-induced withdrawal contractions in the guinea-pig isolated ileum. 2. To induce withdrawal contractions, preparations removed either from saline- or endotoxin (2.5 mg/kg in 0.4 mL, i.p.)-treated animals were incubated for 5 min with morphine (40 micromol/L) and naloxone (50 micromol/L) was then applied. 3. In tissues removed from endotoxin-treated animals, a significant reduction in withdrawal contractions was observed. In control preparations, indomethacin (1 micromol/L for 15 min) significantly reduced naloxone-induced contractions, whereas N(G)-nitro-L-arginine methyl ester (L-NAME; 10 micromol/L for 15 min) had no effect. However, indomethacin pretreatment of tissues removed from endotoxin-treated animals did not modify the withdrawal contractions, whereas L-NAME pretreatment enhanced the amplitude of the withdrawal-induced contractions. 4. These results suggest that attenuation of the withdrawal contractions in guinea-pig isolated ileum induced by endotoxin-pretreatment may be due, in part, to the activation of an L-arginine-nitric oxide pathway.

Topics: Animals; Endotoxins; Female; Guinea Pigs; Ileum; In Vitro Techniques; Indomethacin; Male; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; NG-Nitroarginine Methyl Ester; Shock, Septic; Substance Withdrawal Syndrome

Topics: Hemodynamics; Humans; Lower Body Negative Pressure; Male; Naloxone; Narcotic Antagonists; Shock, Hemorrhagic; Shock, Septic

Pregabalin [S-(+)-3-isobutylgaba] is a novel compound under development for its analgesic, anxiolytic, and anticonvulsant properties, and its interaction with the alpha(2)delta-subunit of voltage-dependent Ca(2+) channels. In this study, we investigate the antinociceptive activity of pregabalin in a rat model of delayed visceral hyperalgesia induced by i.p. lipopolysaccharide (LPS) administration. LPS (Escherichia coli, serotype O111:B4) leads to a delayed lowering threshold (9-12 h) of abdominal contractions in response to rectal distension (RD) in awake rats surgically prepared for electromyography of abdominal muscles. This allodynic effect of LPS was blocked by morphine (0.3 mg/kg s.c.), and the action of morphine was antagonized by naloxone (2.5 mg/kg s.c.). A single i.p. (10, 30 mg/kg) and oral (1, 3, 10 and 30 mg/kg) treatment of pregabalin dose dependently suppressed LPS-induced rectal hypersensitivity. When administered 2 h before RD (but preceded 12 h by LPS injection), the oral dose of 10 mg/kg was effective both in the allodynic response induced by LPS and in the intensity of the nociceptive response related to RD. Pretreatment by either naloxone or bicuculline (a GABA(A) antagonist, 0.5 mg/kg i.p.) did not affect the antiallodynic effect of pregabalin. We conclude that pregabalin is a therapeutic candidate in the treatment of gut hypersensitivity not acting through GABA(A) and opiate receptors.

Topics: Analgesics, Non-Narcotic; Animals; Calcium Channels; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Hyperalgesia; Lipopolysaccharides; Male; Morphine; Naloxone; Pregabalin; Rats; Rats, Wistar; Rectum; Shock, Septic

Endogenous opioids are known to mediate some of the cardiovascular sequelae of sepsis. Inhibition of adrenergic action has been implicated as a physiological path by which endogenous opioids cause deleterious changes in cardiovascular function during endotoxin shock, but where and to what extent this accounts for changes in regional vascular resistance remains unclear. In this study, we addressed this question by examining the role of alpha-adrenergic actions in cardiovascular performance and the regional perfusion changes caused by naloxone during endotoxin shock. Rats had catheters inserted into the tail artery, left cardiac ventricle, and jugular vein. Twenty-four hours later, rats received saline or endotoxin (2 mg/kg) challenge intravenously over 30 min, followed at 40 min by intravenous naloxone (or saline) treatment (4 mg/kg + 2 mg/kg x h) in the presence or absence of phentolamine (100 micrograms/kg + 600 micrograms/kg x h) or yohimbine (40 micrograms/kg + 4 micrograms/kg x h). Radiolabeled microspheres were used to determine cardiac outputs and blood flows at 0, 30, 60, and 120 min after beginning endotoxin infusion. Naloxone attenuated the endotoxin-induced decline in mean arterial pressure (MAP) and cardiac output (CO), but had no effect on increased systemic vascular resistance (SVR). Phentolamine blocked naloxone's ability to increase MAP and CO, but permitted an increase in SVR by naloxone. In the presence of yohimbine, naloxone still increased MAP, but not CO nor SVR. Regional vascular responses varied, with naloxone demonstrating a vasoconstrictive effect despite alpha-adrenergic receptor blockade in some beds, and no effect in others. The response of individual organs in the hepatosplanchnic circulation was heterogenous as well. These data suggest that some effects of endogenous opioids during endotoxin shock are mediated via inhibition of alpha-adrenergic effects, but that some cardiovascular effects of endogenous opioids are independent of adrenergic control during endotoxin shock.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Flow Velocity; Blood Pressure; Cardiac Output; Endotoxins; Hemodynamics; Hypotension; Male; Naloxone; Narcotic Antagonists; Phentolamine; Rats; Rats, Sprague-Dawley; Shock, Septic; Vascular Resistance; Vasoconstriction; Yohimbine

To clarify the relationship between changes in haemodynamics, liberation of tumour necrosis factor and generation of plasma kallikrein, and to see if treatment with a combination of drugs was successful in preventing activation of tumour necrosis factor and plasma kallikrein in experimental endotoxic shock.. Controlled study.. 22 juvenile pigs.. 15 animals received 0.01 mg/kg endotoxin infusion, the rest being given the same volume of saline. 10 received no treatment, and 5 were given a combination of methylprednisolone, naloxone, ketanserin, promethazine, C1 esterase inhibitor, antithrombin III and aprotinin.. Assessment of the liberation of tumour necrosis factor, generation of plasma kallikrein, and haemodynamic and cellular effects of endotoxaemia.. There was a linear statistical relationship between decreases in cardiac output and increases in packed cell volume, and between increases in packed cell volume and plasma kallikrein activity. The combination treatment totally blocked all the effects of the infusion of endotoxin.. Endotoxin affects several mediators, but combination treatment can prevent some of these effects.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Escherichia coli Infections; Hemodynamics; Kallikreins; Ketanserin; Methylprednisolone; Naloxone; Promethazine; Protease Inhibitors; Shock, Septic; Swine; Tumor Necrosis Factor-alpha

Endotoxic shock is presented with a complex pathophysiology and is associated with high mortality. Recently, it has been reported that endogenous opioids play an important role in endotoxic shock. Pressor effect of naloxone in shock may be mediated through antagonism of endogenous opioid inhibition of the sympatho-adrenal catecholaminergic system. In endotoxemic animal, circulating catecholamine levels were not elevated by naloxone. It is possible that naloxone acts upon opiate receptors to enhance catecholamine actions at the receptor level or post-receptor level. We investigated endotoxic shock using a rat model. The animals anesthetized with phenobarbital were infused with E. coli LPS for 30 minutes. They were divided into 5 groups. After an endotoxin i.v. infusion of 15 mg/kg (LD 60), a significant fall in mean arterial pressure (MAP), heart rate and pH occurred in all groups. Treatment with naloxone or buprenorphine or naloxone + epinephrine resulted in significant improvement in MAP, pH and base excess. Treatment with morphine resulted in a decrease in MAP and an increase in heart rate. The pressor response to epinephrine 10, 30, 60 microgram/kg i.v. caused an increase of 62%, 48% and 17% of control values respectively in endotoxic treated rats. The duration of the pressor response to epinephrine was significantly increased by naloxone, although no significant effects on survival were seen at 4 hours after the start of treatment. These findings suggest that the buprenorphine may prove to be an alternative to naloxone, the co-administration of naloxone and epinephrine may be of benefit in the management of septic shock.

Topics: Animals; Blood Pressure; Buprenorphine; Epinephrine; Heart Rate; Male; Morphine; Naloxone; Rats; Rats, Sprague-Dawley; Shock, Septic

Naloxone, an opioid antagonist, has been shown to improve cardiovascular status during endotoxin shock, including splanchnic perfusion. Enhancement of adrenergic action has been implicated as a physiological path by which naloxone effects changes in cardiac function during endotoxin shock, but the mechanism for changes in various splanchnic vascular beds has not been examined. In this study, we examined the role of beta-adrenergic actions in cardiovascular performance and the splanchnic perfusion changes caused by naloxone during endotoxin shock. Rats were instrumented with catheters in the tail artery, left cardiac ventricle, and jugular vein. Twenty-four hours later, rats received saline or endotoxin (2 mg/kg) challenge intravenously over 30 min, followed at 40 min by i.v. naloxone (or saline) treatment (4 mg/kg + 2 mg/kg.hr) in the presence or absence of propranolol (1 mg/kg + 1 mg/kg.hr). Radiolabelled microspheres were used to determine cardiac outputs and blood flows at 0, 30, 60, and 120 min after beginning endotoxin infusion. Blood pressure was not affected by endotoxin challenge, but cardiac output and most organ blood flows fell over time. beta-Adrenergic blockade did not alter this response. Naloxone improved cardiac output and blood flow to the stomach, small intestine, colon, and spleen but not to other splanchnic organs. Naloxone also increased renal and coronary blood flows. The improvements in cardiac output with naloxone were ablated in the presence of propranolol, as were the increases in gastric, colonic, splenic, coronary, and renal blood flows. However, the beneficial effect of naloxone on small bowel blood flow was not diminished by blockage of beta receptors. These results suggest that the effects of opioid antagonism are mediated, in part, by enhancing endogenous beta-adrenergic actions in vivo. Improvements in the splanchnic circulation are selectively altered by naloxone during endotoxin shock, some independent of beta-adrenergic actions. Understanding this phenomenon can lead to the appropriate use of opioid antagonism, should it prove clinically useful in the treatment of septic shock.

Topics: Animals; Hemodynamics; Male; Naloxone; Perfusion; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Shock, Septic; Splanchnic Circulation

Septic shock is frequently associated with acute renal failure. Management of these patients becomes complicated if either the renal or systemic hemodynamic derangement cannot be corrected. Although previously large doses of furosemide and naloxone infusion have been used separately in managing these patients, the combination of both agents has not been employed. We therefore report our limited experience with this combined treatment in 5 patients with septic shock, of which 4 had acute renal failure.

Topics: Acute Kidney Injury; Adult; Aged; Dopamine; Female; Furosemide; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Naloxone; Retrospective Studies; Shock, Septic

In the present study, we observed the effects of indomethacin, ibuprofen, naloxone and morphine on plasma CGRP concentration 3 h after endotoxin shock in conscious rats. The results showed that indomethacin, ibuprofen and naloxone significantly inhibited the elevation of plasma CGRP concentration as well as reduced the lesion in the intestine during endotoxin shock. However, morphine had no significant effect. The data are consistent with our hypothesis that prostaglandin, as one of the inflammatory mediators which increase in shock may be an important endogenous factor for triggering the CGRP release during endotoxin shock.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcitonin Gene-Related Peptide; Ibuprofen; Indomethacin; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Shock, Septic

Little is known of the endorphins' role in sepsis-induced respiratory distress and naloxone's effect as a treatment of it. Thirteen piglets were infused with live Escherichia coli at a rate of 2 to 10 x 10(8) colony-forming units per hour for six hours or until death and were divided into two groups: the septic control group (n = 8), and the naloxone-treated group (n = 5), which received 8 mg/kg/h of naloxone by continuous infusion. The results showed a significant reduction of QS/QT, VD/VT, and arterial carbon dioxide pressure at one hour and a significant increase of arterial carbon dioxide pressure and minute ventilation at 1, 3, and 4 hours in the naloxone-treated group, compared with the untreated septic group. None of the piglets in the naloxone-treated group developed ventilatory depression, while 75% of those in the untreated septic group did. Among the latter ficial effects of naloxone are likely related to its action on the central and peripheral respiratory regulatory mechanisms. A transient protection of the cardiac output and relatively decreased extravascular lung water with naloxone treatment may also, in part, improve the ventilation-perfusion maldistribution and secondarily reduce QS/QT and VD/VT.

Topics: Animals; Bacteremia; Escherichia coli Infections; Naloxone; Respiratory Dead Space; Shock, Septic; Swine; Ventilation-Perfusion Ratio

Current research suggests that the secretion of beta-endorphin from the pituitary gland may be associated with the refractory hypotension seen in patients with septic shock. Extensive animal research and a few clinical studies have demonstrated that naloxone, a narcotic antagonist, can increase MAP, cardiac output, and cardiac contractility and improve survival in victims of endotoxic shock. The ability of naloxone to improve MAP, however, appears to decrease with prolonged persistent hypotension (greater than eight hours). Studies also suggest that a synergistic effect exists between naloxone and the steroid methylprednisolone in improving the hemodynamics of these patients. In the future, naloxone may prove to be essential in the management of patients in the early stages of septic shock, but more complete clinical trials are warranted. It is imperative that nurses be involved in this type of clinical research.

Topics: beta-Endorphin; Education, Nursing, Continuing; Female; Humans; Infant, Newborn; Naloxone; Shock, Septic

Treatment of septic shock is a persistent dilemma. The clinical use of agents such as naloxone has resulted in variable success. Because the dosage and timing of these agents are considered critical factors in their efficacy, we investigated both dosage and timing of naloxone. Thirteen consecutive patients with documented septic shock and resistance to a one-liter fluid challenge underwent invasive hemodynamic monitoring and the administration of naloxone by initial bolus of 0.03 mg/kg followed by infusion at a rate of 0.2 mg/kg.h over one hour. During the one-hour observation period, iv fluid administration, concomitant pressor agents, and respirator values were constant. After infusion, adjustments in fluid administration, respirator status, and pressor agents were made as required by the clinical situation. A significant increase in mean arterial pressure (MAP) over baseline (60 +/- 3 mm Hg) was noted at 5 min (77 +/- 6 mm Hg, p less than .005) and at 30 min (73 +/- 6 mm Hg, p less than .025). Similarly, a significant increase in systolic arterial pressure was noted over prenaloxone levels (89 +/- 3 mm Hg) at 5 min (114 +/- 6 mm Hg, p less than .001), 30 min (107 +/- 8 mm Hg, p less than .05), and at one hour (106 +/- 8 mm Hg, p less than .05). There was a moderate nonsignificant increase in cardiac index, pulmonary capillary wedge pressure, and systemic vascular resistance. No side-effects to naloxone were noted in our group. No effect on survival could be demonstrated. We found no overall effect on mortality. However, by its increase of MAP, naloxone may serve as a temporizing agent during the treatment of critically ill patients with septic shock.

Topics: Adult; Blood Pressure; Cardiac Output; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Naloxone; Pulmonary Wedge Pressure; Shock, Septic; Time Factors; Vascular Resistance

The use of naloxone to reverse the hypotension caused by endotoxins and endogenous opiates is currently under investigation. This report provides a description of the pathophysiology of endotoxic shock and the therapeutic use of naloxone in order to provide the critical care nurse with the scientific rationale, research-based clinical trials, and the clinical implications for its use.

Topics: Critical Care; Education, Nursing, Continuing; Humans; Male; Middle Aged; Naloxone; Shock, Septic

Two groups of awake dogs were given an iv bolus of endotoxin (3.0 mg/kg from Salmonella typhimurium); one group (n = 9) was pretreated with either naloxone (2.0 mg/kg iv bolus with 1.7 mg/kg.h; n = 6) or naltrexone (2.0 mg/kg iv bolus with repeat bolus of 1.0 mg/kg at 1, 3 and 5 h; n = 3) and the second group (n = 10) received no opiate antagonist. All of nine dogs that were pretreated with an antagonist survived for 24 h, compared to only five of ten dogs that were not pretreated. Survival correlated with improved BP (mean of 91 vs. 61 mm Hg) and cardiac output (3.9 vs. 2.45 L/min) measured during the first 3 h after the infliction of shock. However, both antagonist-treated and nonantagonist-treated survivors had BP and cardiac output which were statistically lower than their baseline values or saline-treated controls at comparable times. Nonsurvivors had significantly higher levels of norepinephrine (peak level: 1149 ng/ml) and epinephrine (peak level: 31.29 ng/ml) than survivors. Opiate antagonists thus appeared to increase survival in a subgroup of dogs that might not otherwise have survived if they had not been so treated; this survival was associated with improved hemodynamics, but not with increased adrenergic activity.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Pressure; Cardiac Output; Dogs; Endotoxins; Epinephrine; Male; Naloxone; Naltrexone; Norepinephrine; Receptors, Opioid; Salmonella typhimurium; Shock, Septic

Experimental and clinical evidence show that endogenous opiates (endorphins) contribute to the pathophysiology of circulatory shock. The authors evaluated the effectiveness and safety of continuous infusion of naloxone in five septic patients with prolonged hypotension unresponsive to volume replacement and dopamine infusion. Naloxone (2 mg bolus) was intravenously administered and continued at 0.25 mg/hr for 24 to 48 hours. All five patients had significant increase in mean arterial pressure of between 20 and 30 mmHg (P less than 0.0012). Cardiac index, systemic vascular resistance, and pulmonary arterial pressure were not significantly altered; however, there was a significant difference in pulmonary capillary wedge pressure (P less than 0.034) and urinary output (P less than 0.0273). Subjects did not experience side effects with naloxone. We conclude that continuous infusion of naloxone can reverse endorphin-mediated hypotension in septic shock patients.

Topics: Aged; Dopamine; Drug Therapy, Combination; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Naloxone; Shock, Septic

Topics: Blood Pressure; Humans; Naloxone; Pharmaceutical Vehicles; Shock, Septic

A relationship between increased peripheral resistance (TPRI) and decreased cardiac index (CI) and mortality from sepsis has been suggested. The relationship between endogenous opiates and this response was evaluated.. Chronically instrumented sheep were given E. coli endotoxin (LPS, 1.5 mcg/kg x 30 minutes). In one study, survivors (n = 9) and nonsurvivors (n = 11) of LPS were compared along with survivors (n = 8) of half the dose of LPS. In a second study, two groups of animals received naloxone: one (n = 11) had a bolus of 2 mg/kg followed by a 2 mg/kg/hr continuous infusion started 30 minutes before LPS while the other had the bolus and infusion started 1 hour after LPS was begun.. Both vasoconstrictive and vasodilative phases were seen. Vasoconstriction was associated with elevated beta endorphin levels, a pattern sustained until death in the nonsurvivors. Both pre- and posttreatment with naloxone lessened the maximum increase in total peripheral resistance index compared with untreated sheep.. The vasoconstrictive aspects of the response to LPS correlated with elevated beta endorphin levels and with mortality. This vascular response is attenuated with naloxone blockade.

Topics: Animals; beta-Endorphin; Escherichia coli; Female; Hemodynamics; Lipopolysaccharides; Naloxone; Pulmonary Circulation; Sheep; Shock, Septic; Vasoconstriction; Vasodilation

This study evaluated the effects of naloxone hydrochloride in the treatment of Escherichia coli-induced shock in baboons. The baboons were studied for 12 hours and monitored for survival times. All baboons were intravenously infused for two hours with E coli and treated as follows: group 1, E coli (control); group 2, E coli plus naloxone hydrochloride, 0.5 mg/kg bolus plus 0.5 mg/kg/h for 9.5 hours; and group 3, E coli plus naloxone hydrochloride, 2.0 mg/kg bolus plus 2.0 mg/kg/h for 3.8 hours. Naloxone was administered after arterial pressure had reached the nadir (more than two hours following initiation of E coli infusion). Mean arterial pressure was supported by the lower dose of naloxone; however, sustained leukopenia and neutropenia were not reversed by its infusion. Naloxone prevented the increase in plasma beta-endorphin level and blunted the increase in plasma cortisol level. Despite these effects, naloxone did not prevent multiple-organ disease and did not decrease mortality.

Topics: Animals; beta-Endorphin; Blood Pressure; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli Infections; Female; Heart Rate; Hydrocortisone; Injections, Intravenous; Male; Monitoring, Physiologic; Naloxone; Papio; Sepsis; Shock, Septic; Time Factors

The cardiovascular and metabolic responses to treatment with naloxone or buprenorphine (a partial opiate agonist) were investigated in a porcine model of septicaemia. Animals anaesthetised with alpha-chloralose were infused with live E. coli over two hours. They were then divided into three groups and received either naloxone (2 mg kg-1 + 1.5 mg kg-1 hr-1) or buprenorphine (0.3 mg kg-1) or an equivalent volume of normal saline. Treatment was started one hour after commencing the infusion, by which time a significant fall in cardiac index (CI), stroke index (SI), mean arterial pressure (MAP), and pH had occurred in all groups, together with a significant rise in mixed venous blood lactate and packed cell volume. Treatment with both naloxone and buprenorphine resulted in significant improvements in CI, pH, and base excess and in a fall in mixed venous lactate and packed cell volume. Although no significant effect on survival was seen at three hours after the start of treatment, buprenorphine may prove to be a suitable alternative to naloxone in the management of septic shock.

Topics: Animals; Blood Pressure; Buprenorphine; Cardiac Output; Disease Models, Animal; Erythrocyte Indices; Escherichia coli Infections; Female; Lactates; Naloxone; Shock, Septic; Swine

Naloxone's pressor effects in shock may be mediated through antagonism of endogenous opioid inhibition of sympathoadrenal catecholaminergic systems. Since circulating catecholamine levels are not further elevated by naloxone in endotoxemic animals, it is possible that naloxone acts upon opiate receptors to enhance catecholamine actions at the receptor or postreceptor level. To investigate this hypothesis, we sought to determine whether naloxone treatment would augment the pressor actions of exogenous catecholamines (epinephrine) in normal and endotoxemic rats. Naloxone (3 mg/kg intravenous [i.v.] bolus followed by 3 mg/ml/hr infusion) significantly augmented the pressor response to 10, 20, and 50 micrograms/kg of i.v. epinephrine by 69%, 48% and 14%, respectively, in endotoxin (5 mg/kg, LD20, i.v.) -treated rats but not in normal rats. Likewise, the duration of the pressor response to epinephrine was significantly increased by naloxone. These findings suggest that the coadministration of naloxone and epinephrine may be of benefit in the treatment of shock.

Topics: Animals; Blood Pressure; Drug Synergism; Epinephrine; Escherichia coli; Heart Rate; Male; Naloxone; Rats; Rats, Inbred Strains; Shock, Septic

This study examined the effects of naloxone on glucose and insulin dyshomeostasis during endotoxicosis in ad libitum fed and overnight-fasted rats. Plasma glucose levels were measured in vivo to assess the effects of naloxone on glucose regulation during endotoxicosis. Naloxone's effects on endotoxin-induced portal and systemic hyperinsulinemia were evaluated in vivo. In addition, the ability of naloxone to alter the insulin hypersecretory state of the endotoxic pancreas was evaluated using the in vitro perfused rat pancreas preparation. Naloxone did not alter endotoxin-induced glucose dyshomeostasis in fasted rats, but potentiated hypoglycemia in fed, endotoxic rats. Naloxone potentiated endotoxin-induced hyperinsulinemia and insulin hypersecretion from the endotoxic pancreas in fed, but not fasted, rats. Thus the results indicated that naloxone had no apparent beneficial effects on glucose and insulin dyshomeostasis during endotoxicosis in either fed or fasted rats, and potentiated glucose and insulin dyshomeostasis in fed, endotoxic rats. Since naloxone is a specific opiate antagonist, these results suggested that endogenous opiate systems do not play a significant deleterious role in the glucose and insulin dyshomeostasis of endotoxic shock. In addition, this study identified prior feeding history of rats (ad libitum feeding vs. overnight fasting) as an important variable relative to the study of naloxone's effects on glucose and insulin regulation during endotoxicosis.

Topics: Animals; Blood Glucose; Fasting; In Vitro Techniques; Insulin; Insulin Secretion; Male; Naloxone; Pancreas; Perfusion; Rats; Rats, Inbred Strains; Shock, Septic

Antagonism of endogenous opioids has been shown to improve survival time, increase blood pressure, and attenuate acidosis during endotoxin shock. However, some of the most severe problems associated with this condition arise from the circulatory disturbances that occur. We investigated the circulatory effects of naloxone during endotoxin shock as they relate to hemodynamic parameters in conscious, unrestrained rats. Blood flow and hemodynamic variables were measured in male, Sprague-Dawley rats (300-400 g) 24 h after surgical preparation. Rats were challenged with either 10 mg/kg Escherichia coli endotoxin (100% lethal dose) or intravenous saline. Measurements were made at 0, 10, 30, and 60 min postchallenge. Naloxone (2 mg/kg) or saline was given as a treatment (intravenous bolus) at 25 min postchallenge. Cardiac output and blood distribution (%CO) and flow were measured with radiolabeled microspheres. Cardiac output was depressed and total peripheral resistance was elevated 10 min into endotoxin shock. Naloxone treatment improved blood pressure significantly during endotoxin shock, as would be expected with the observed increase in total peripheral vascular resistance and no significant change in cardiac output. Improved perfusion of skeletal muscle is a likely explanation for lower serum lactate levels that have been reported to occur in this model after naloxone administration. Our data also indicate that naloxone may improve cardiac efficiency and does not interfere with maintenance of global cerebral blood flow. Collectively, these effects would contribute to the observed improved survival time after naloxone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adrenal Glands; Animals; Blood Circulation; Blood Pressure; Cardiac Output; Cerebrovascular Circulation; Coronary Circulation; Heart Rate; Liver Circulation; Male; Naloxone; Rats; Rats, Inbred Strains; Regional Blood Flow; Renal Circulation; Shock, Septic; Stroke Volume; Testis; Vascular Resistance

Plasma levels of catecholamines and neuropeptides (met-enkephalin, ME; neurotensin, NT; neuropeptide Y, NPY; peptide YY, PYY; vasoactive intestinal polypeptide, VIP; cholecystokinin, CCK; bombesin, BMB) were examined in the femoral artery (FA), adrenal vein (AD), and portal vein (PV), in eight cats under halothane anesthesia at baseline (S1), at the end of a 2-hr ligation period of the major splanchnic arteries (celiac trunk, superior and inferior mesenteric arteries) (S2), immediately (S3) and 30 min (S4) after splanchnic reperfusion, and after the administration of naloxone (1 mg/kg, i.v.) (S5). During S2, there was a significant increase in portal vein VIP levels, while the other variables (hemodynamics, hormone levels) remained unchanged. During early shock (S3), significant (10- to 30-fold) increases in adrenal secretion of all catecholamines, ME, NT, NPY, and PYY occurred, while VIP and PYY were significantly released into the PV, and two- to tenfold increases in femoral artery catecholamine and ME levels were observed. Later shock (S4) led to a further fivefold increase, compared to S3, in adrenal release of norepinephrine (NE), dopamine (DA), and ME. Following naloxone administration (S5), the adrenal medullary release of NE, epinephrine (EPI), DA, NT, and NPY was significantly (twofold) increased; however, the animals' hemodynamic situation did not improve.

Topics: Adrenal Glands; Animals; Bombesin; Catecholamines; Cats; Cholecystokinin; Enkephalin, Methionine; Hemodynamics; Intestinal Mucosa; Ischemia; Ligation; Mesenteric Arteries; Naloxone; Neuropeptide Y; Neuropeptides; Neurotensin; Peptide YY; Peptides; Shock, Septic; Vasoactive Intestinal Peptide

The alterations in plasma levels of immunoreactive metenkephalin (ir-metenkephalin) and catecholamines in adrenal vein and arterial blood in response to endotoxin, as well as the effects of subsequent naloxone administration, have been investigated in a canine model. Animals were anaesthetised with alpha chloralose and allowed to breathe spontaneously. The left lumbar adrenal vein was cannulated and an intermittent choke allowed retrograde sampling of the adrenal effluent. Severe shock was produced by the administration of a large bolus of E. coli endotoxin (5 mg/kg) followed by a continuous infusion (2 mg/kg per hour). One hour after induction of shock the circulating volume was expanded using a colloidal gelatin solution. Thirty minutes later one group of five animals received a bolus of naloxone (2 mg/kg) followed by a continuous infusion of (1.5 mg/kg per hour), while a control group of five animals was given an equivalent volume of isotonic saline. The production of endotoxin shock was associated with marked increases in adrenal vein and systemic levels of adrenaline and noradrenaline. Naloxone administration transiently limited the fall in adrenal vein levels of adrenaline and noradrenaline (P less than 0.05) following volume replacement and was associated with a sustained increase in systemic adrenaline levels (P less than 0.05). Changes in mean arterial pressure confirmed a significant haemodynamic response to naloxone (P less than 0.05). Alterations in ir-metenkephalin levels in the adrenal vein closely followed the changes in catecholamines, whereas arterial levels rose progressively and were unaffected by naloxone. We conclude that in canine endotoxin shock the opiate antagonist naloxone can transiently increase catecholamine levels in the adrenal effluent and produce a more sustained rise in systemic adrenaline levels. Moreover, the adrenal medulla is not the only source of circulating ir-metenkephalin.

Topics: Adrenal Glands; Animals; Arteries; Disease Models, Animal; Dogs; Endotoxins; Enkephalin, Methionine; Epinephrine; Naloxone; Norepinephrine; Radioimmunoassay; Reference Values; Shock, Septic; Veins

Topics: Animals; Blood Pressure; Cinanserin; Cinnamates; Female; Injections, Intraventricular; Male; Naloxone; Phentolamine; Rabbits; Shock, Hemorrhagic; Shock, Septic

The opiate antagonist naloxone (NAL) improves cardiovascular performance in canine hemorrhagic and endotoxic shock. If the release of neural and adrenal catecholamines is attenuated, NAL does not produce the expected improvement in cardiovascular function in canine hemorrhagic shock. This study tests the hypothesis that an endorphin-catecholamine interaction at the heart is responsible for a part of the cardiovascular depression of endotoxic shock. Two groups of five dogs were instrumented to measure mean arterial pressure (MAP), the first derivative of left ventricular pressure over time (LV dP/dt max), cardiac output, and heart rate (HR); they were then subjected to bilateral adrenalectomy and given chlorisondamine to produce ganglionic blockade. At t = 0 min the dogs were given Escherichia coli endotoxin at 1 mg/kg (LD80). Group I animals received NAL at 2 mg/kg + 2 mg/kg.hr iv from t = 30 to t = 60. At t = 45 these animals were treated with epinephrine (EPI) at 20 micrograms/kg.hr iv until t = 60. Group II animals got EPI from t = 30 to t = 60 and NAL from t = 45 to t = 60 at the same doses as Group I. In Group I, NAL alone had no effect on MAP, LV dP/dt max, or HR. EPI significantly increased (P less than 0.002) cardiovascular parameters with MAP increasing from 52 +/- 7 to 159 +/- 14 mm Hg. In Group II, EPI produced a significant increase in all parameters, and the addition of NAL produced a further significant increase; MAP increased from 37 +/- 3 to 126 +/- 16 mm Hg with EPI and then to 175 +/- 11 mm Hg with NAL. These data support the above hypothesis and indicate that circulating catecholamines need to be present to allow naloxone to reverse the cardiovascular depression in endotoxic shock.

Topics: Animals; Blood Pressure; Dogs; Epinephrine; Female; Heart; Heart Rate; Male; Naloxone; Norepinephrine; Shock, Septic

Topics: Animals; Endorphins; Humans; Naloxone; Shock; Shock, Septic

The effects of an opiate antagonist naloxone and a cyclooxygenase inhibitor ibuprofen on organ blood flow during endotoxic shock were evaluated in a fluid-resuscitated porcine endotoxic shock model. Radiolabeled microspheres were used to measure regional blood flow. Escherichia coli endotoxin (0.1 mg/kg), infused intravenously over 40 min, reduced mean arterial blood pressure to 50 mmHg and systemic vascular resistance to 57% of control without affecting cardiac output. Endotoxin reduced blood flow to cerebrum (to 49% of control), kidney (to 25% of control), spleen, and skeletal muscle, while blood flow to left ventricle, stomach, and small and large intestines were unaffected. Sixty minutes after endotoxin administration, animals were randomized to one of three groups. Group I animals were controls and received no drug, group II animals received ibuprofen (12.5 mg/kg iv), and group III animals received naloxone (2 mg/kg iv) 60 min after endotoxin. Ibuprofen increased mean arterial blood pressure to 80 mmHg and increased blood flow to both cerebrum (to 92% of control) and kidney (to 47% of control). Plasma levels of thromboxane B2 and 6-ketoprostaglandin F1 alpha were increased 8- and 16-fold, respectively, after endotoxin, and both were decreased by ibuprofen. Naloxone increased mean arterial blood pressure to 62 mmHg but had no effect on regional blood flow or plasma cyclooxygenase metabolite levels. These data suggest that cyclooxygenase metabolites may contribute to decreased mean arterial blood pressure and reduced organ blood flow during endotoxic shock in the pig.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Hemodynamics; Ibuprofen; Microspheres; Naloxone; Regional Blood Flow; Shock, Septic; Swine; Thromboxane B2

Hyperinsulinism has been associated with infection and endotoxin shock in rodents, dogs, and humans. In dogs with Escherichia coli-induced endotoxin shock, this hyperinsulinism was in response to glucose administration. To determine the role of endogenous opiates in endotoxin-induced glucose-stimulated hyperinsulinism, plasma beta-endorphin, Met-enkephalin, Leu-enkephalin, insulin, and glucose concentrations were measured for 6 h in fasted, anesthetized dogs given LD70 of E. coli endotoxin; endotoxin and glucose; endotoxin, glucose, and naloxone (an opiate antagonist); glucose and naloxone; or glucose alone. Plasma endogenous opiate immunoreactivity was elevated in dogs that received endotoxin, regardless of the presence of glucose or naloxone. The elevation of plasma Met-enkephalin and beta-endorphin preceded the onset of hyperinsulinism, but the elevation of plasma Leu-enkephalin did not. Plasma insulin was elevated 100-fold by 360 min in dogs given endotoxin and glucose. The magnitude of this hyperinsulinism was markedly reduced by naloxone, supporting the hypothesis that endogenous opiates are involved in the development of the glucose-stimulated hyperinsulinism associated with endotoxin shock. Interestingly, naloxone, given in conjunction with glucose, appeared to have a stimulatory effect on insulin secretion.

Topics: Animals; beta-Endorphin; Blood Glucose; Dogs; Endorphins; Endotoxins; Enkephalin, Leucine; Enkephalin, Methionine; Escherichia coli; Glucose; Hyperinsulinism; Insulin; Kinetics; Male; Naloxone; Shock, Septic

The effect of naloxone (4.4-5.9 mg i.v.) was evaluated in 10 patients with circulatory shock (sepsis, n = 7; intoxication, n = 1; cardiogenic shock, n = 2) not responding to full conventional therapy. In addition, we measured plasma ACTH and immunoreactive beta-endorphin before and 60 min after administration of naloxone and compared the results with hormone concentrations in 10 intensive care patients without shock. Only in two patient with septic shock a transient increase (duration 15 min and 60 min, respectively) of systolic blood pressure was observed, while naloxone was ineffective in the remaining eight patients. No adverse effects of naloxone were found. Plasma ACTH and immunoreactive beta-endorphin concentrations in patients with shock were not different from those in controls (ACTH, 79 +/- 28 vs 120 +/- 60 pg/ml; immunoreactive beta-endorphin, 952 +/- 262 vs 1,070 +/- 378 pg/ml). Our findings suggest that naloxone in a single dose of 4.4-5.9 mg i.v. does not improve the management of circulatory shock unresponsive to conventional treatment. beta-endorphin seems to play no major role in the hypotension of shock.

Topics: Adrenocorticotropic Hormone; Adult; Aged; beta-Endorphin; Endorphins; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Naloxone; Shock; Shock, Cardiogenic; Shock, Septic

Little is known of the endorphins' role in sepsis-induced respiratory distress and naloxone's effect as a treatment of it. Thirteen piglets were infused with live Escherichia coli at a rate of 2 to 10 X 10(8) colony-forming units per hour for six hours or until death and were divided into two groups: the septic control group (n = 8), and the naloxone-treated group (n = 5), which received 8 mg/kg/h of naloxone by continuous infusion. Hemodynamic parameters, the intrapulmonary shunt fraction (QS/QT), physiologic dead space (VD/VT), minute ventilation, and blood gas levels were measured. Lung lymph flow was obtained by cannulating the right lymphatic duct. The extravascular lung water weight was also measured. The results showed a significant reduction of QS/QT, VD/VT, and arterial carbon dioxide pressure at one hour and a significant increase of arterial carbon dioxide pressure and minute ventilation at 1, 3, and 4 hours in the naloxone-treated group, compared with the untreated septic group. None of the piglets in the naloxone-treated group developed ventilatory depression, while 75% of those in the untreated septic group did. Among the latter piglets, three died of apnea within one hour. These beneficial effects of naloxone are likely related to its action on the central and peripheral respiratory regulatory mechanisms. A transient protection of the cardiac output and relatively decreased extravascular lung water with naloxone treatment may also, in part, improve the ventilation-perfusion maldistribution and secondarily reduce QS/QT and VD/VT. We conclude that endorphins play a role in septic ventilatory depression and that naloxone is effective in ameliorating it.

Topics: Animals; Carbon Dioxide; Escherichia coli Infections; Female; Hemodynamics; Leukocyte Count; Lung; Male; Naloxone; Oxygen; Respiration; Respiratory Insufficiency; Shock, Septic; Swine; Ventilation-Perfusion Ratio

Topics: Animals; Drug Therapy, Combination; Endotoxins; Escherichia coli; Hemodynamics; Kallikreins; Ketanserin; Methylprednisolone; Naloxone; Oxygen; Promethazine; Protease Inhibitors; Shock, Septic; Swine

Topics: Animals; Drug Therapy, Combination; Endotoxins; Escherichia coli; Hemodynamics; Ketanserin; Lipopolysaccharides; Methylprednisolone; Naloxone; Oxygen; Promethazine; Protease Inhibitors; Pulmonary Circulation; Shock, Septic; Swine

Topics: Adrenal Cortex Hormones; Blood Transfusion; Humans; Immunization, Passive; Indomethacin; Naloxone; Sepsis; Shock, Septic

We used naloxone to investigate the role of central nervous system opiate receptors in the cardiovascular depression of canine hemorrhagic and endotoxic shock. Shock was induced by bleeding dogs into a reservoir to achieve and maintain a mean arterial pressure (MAP) of 45 mmHg for 30 min; at 30 min the reservoir was clamped and the animals were treated with intracerebroventricular (ICV) perfusion of naloxone 0.1 mg/kg (n = 5) or artificial CSF (n = 5) for 30 min. Endotoxemic shock was induced by the iv injection of E. coli endotoxin 1 mg/kg; 15 min later the animals were given naloxone 0.1 mg/kg (n = 5) or artificial CSF (n = 5) ICV for 30 min. ICV naloxone significantly increased MAP, cardiac output (CO), and left ventricular performance (LV dP/dt max) compared to artificial CSF in canine endotoxic shock but not hemorrhagic shock. Naloxone 0.1 mg/kg (n = 5) given into the cisterna magna failed to significantly improve MAP, CO, or LV dP/dt max in dogs subjected to reservoir hemorrhagic shock for 60 min compared to artificial CSF (n = 5). These results are compatible with opiate-receptor-mediated central cardiovascular depression in endotoxic shock and peripheral cardiovascular depression in hemorrhagic shock. Accordingly, the sites of action of naloxone are mainly central in endotoxic shock and peripheral in hemorrhagic shock.

Topics: Animals; Brain; Cardiovascular System; Cisterna Magna; Dogs; Female; Injections, Intraventricular; Male; Naloxone; Shock, Hemorrhagic; Shock, Septic

Naloxone, a commonly used narcotic antagonist, may be beneficial in reversing the hemodynamic alterations seen in septic shock. In normal subjects, naloxone pharmacokinetics are characterized by rapid distribution and elimination. We investigated the pharmacokinetics of high-dose naloxone in four patients with septic shock and multiorgan failure. The pharmacokinetics of naloxone in these patients can be described by a two-compartment model with a rapid alpha distribution similar to that observed in normal humans. However, in these critically ill patients there was virtually no drug elimination as levels were followed for 5 h post-termination of a 6-h infusion of 2.4 mg/kg X h. This dramatic accumulation of naloxone may explain why responses have been reported by others to small doses of naloxone in septic shock patients. No significant side-effects were seen in our patients with plasma naloxone levels as high as 3.78 micrograms/ml. Caution is warranted when one administers naloxone to patients whose ability to eliminate this drug is minimal.

Topics: Double-Blind Method; Female; Humans; Infusions, Intravenous; Kinetics; Male; Middle Aged; Naloxone; Shock, Septic; Time Factors

Maintenance of cerebral blood flow (CBF) is vital during cardiovascular shock. Since opioids have been implicated in the pathophysiology of endotoxin shock and have been shown to alter cerebral perfusion patterns, we determined whether opioids were responsible for any of the changes in regional CBF observed during endotoxin shock and whether the use of naloxone might impair or aid in the maintenance of CBF. When blood flow (BF) is studied with microspheres in rats, the left ventricle of the heart is often cannulated via the right carotid artery. Questions have arisen concerning the potential adverse effects of this method on CBF in the hemisphere ipsilateral to the ligated artery. We measured right and left regional CBF by use of this route of cannulation. Twenty-four hours after cannulations were performed, flow measurements were made using radiolabeled microspheres in conscious unrestrained male Sprague-Dawley rats (300-400 g) before and 10, 30 and 60 min after challenging with 10 mg/kg Escherichia coli endotoxin (etx) or saline. Naloxone (2 mg/kg) or saline was given as a treatment 25 min post-etx. We found no significant differences between right and left cortical, midbrain, or cerebellar BF at any time in any treatment group. After etx, the whole brain received a large share of the depressed cardiac output. Thus global CBF was not significantly reduced below its pre-etx value, an effect unaltered by naloxone. Regionally, BF was reduced to cerebellum and midbrain by 30 min post-etx. Naloxone prevented this depression. No region was affected to a greater or lesser degree than others.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cardiac Output; Cerebellum; Cerebral Cortex; Cerebrovascular Circulation; Hemodynamics; Hypothalamus; Medulla Oblongata; Mesencephalon; Microspheres; Naloxone; Pons; Rats; Regional Blood Flow; Shock, Septic; Thalamus

Naloxone treatment of endotoxin shock has been shown to alter many cardiovascular parameters. However, since opioids can affect ventilatory function we thought it important to assess the effects of naloxone on some respiratory variables during endotoxin shock. Male Sprague-Dawley rats (300-400 g) were surgically prepared with carotid artery and jugular vein cannulas 24 hours before experiments were begun. Conscious, unrestrained rats were challenged with 10 mg/kg E. coli endotoxin or saline. Measurements of blood gases, pH, respiratory rate, serum lactate, and medullary/pontine blood flow (radio labelled microsphere method) were made 0, 10, 30, and 60 minutes postchallenge. Rats were treated with either 2 mg/kg naloxone or saline at 25 minutes postchallenge. Arterial PO2 rose and PCO2 fell in a stepwise fashion in saline-treated endotoxic rats. These changes were unrelated to medullary/pontine perfusion or to arterial pH (up to 30 minutes postchallenge). In naloxone-treated endotoxic rats the increased ventilatory drive at 60 minutes was attenuated, apparently as a result of prevention of acidosis at this time. These data further support uncoupling of ventilatory drive and arterial pH reported earlier and also indicate that naloxone's ability to prevent acidosis in these animals is not mediated through respiratory compensation.

Topics: Acid-Base Equilibrium; Acidosis; Animals; Endorphins; Gases; Hemodynamics; Male; Naloxone; Rats; Rats, Inbred Strains; Respiration; Shock, Septic

We examined the importance of timing with endorphin involvement in shock by giving the opiate receptor antagonist naloxone as a pretreatment in canine endotoxic shock. Dogs anesthetized with pentobarbital (30 mg/kg iv) were given Escherichia coli endotoxin at LD80 doses iv. Naloxone (2 mg/kg plus 2 mg/kg/hr iv, N = 10) started 15 min before endotoxin attenuated the fall in mean arterial pressure, cardiac index, and the first derivative of left ventricular pressure due to endotoxin in comparison with control animals given 0.9% NaCl (N = 10). Naloxone attenuated the endotoxin-induced decrease in superior mesenteric arterial blood flow and the increases in portal venous pressure and pulmonary arterial pressures. Moreover, naloxone pretreatment prevented the characteristic bloody diarrhea and reduced mortality. Our findings implicate endorphins acting on opiate receptors as important mediators of endotoxin-induced cardiovascular failure and bloody diarrhea in canine endotoxemia. These are early manifestations and dictate expeditious use of naloxone in endotoxic shock.

Topics: Animals; Blood Pressure; Diarrhea; Dogs; Endotoxins; Female; Hemodynamics; Male; Naloxone; Shock, Septic

Chemical antagonists were used to assess the role of beta-endorphin and arginine-vasopressin (AVP) in canine endotoxin shock. Fifteen awake dogs were given Escherichia coli endotoxin IV. Within 5 min, CO decreased to 28%, LV dP/dt to 46%, and MAP to 52% baseline. Fifteen minutes after endotoxin, five dogs each received naloxone, AVP antagonist, or no treatment. Control (untreated) animals exhibited persistent cardiovascular depression, with CO 49%, LV dP/dt 69%, and MAP 91% of baseline after 45 min. Naloxone improved CO to 69%, LV dP/dt to 94%, and MAP to 91% by 30 min after treatment. AVP blockade improved CO to 105%, LV dP/dt to 107%, and MAP to 95% of baseline by 30 min after treatment, and caused significant tachycardia. Plasma cortisol and AVP increased markedly in all groups after endotoxin administration. AVP antagonist treatment increased mean survival from 1.4 to 4 days. These data suggest that abnormally elevated AVP contributes to cardiovascular depression in canine endotoxin shock and that AVP blockade is therapeutic in the animal model studied.

Topics: Animals; Arginine Vasopressin; beta-Endorphin; Blood Pressure; Cardiac Output; Cardiovascular Diseases; Dogs; Endorphins; Endotoxins; Escherichia coli; Female; Heart Rate; Hydrocortisone; Kinetics; Male; Naloxone; Shock, Septic

To investigate the possible involvement of the adrenal cortex and medulla in the cardiovascular effects of naloxone and thyrotropin-releasing hormone (TRH) in endotoxic shock, plasma epinephrine, norepinephrine, dopamine, and corticosterone were measured along with hemodynamic variables during naloxone and TRH treatment of normal and endotoxemic rats. In the absence of endotoxemia, naloxone (3 mg/kg, iv) did not significantly alter mean arterial pressure or plasma catecholamine or corticosterone levels. In contrast, following TRH administration (4 mg/kg, iv), an increase in mean arterial pressure was associated with significant increases in plasma epinephrine, norepinephrine, and corticosterone. TRH also produced a transient increase in plasma glucose levels. Endotoxic shock was associated with marked increases in plasma catecholamine levels, with epinephrine levels showing the greatest change, and significant though less pronounced increases in corticosterone. Both naloxone and TRH significantly elevated mean arterial pressures of endotoxemic rats, although neither of these compounds significantly altered the plasma catecholamine and corticosterone responses to endotoxin. Naloxone and TRH also failed to alter endotoxin-induced changes in plasma glucose levels. These results indicate that the cardiovascular effects of naloxone and TRH in endotoxic shock do not simply arise from an enhancement of adrenal catecholamine or corticosterone secretion.

Topics: Animals; Blood Glucose; Blood Pressure; Catecholamines; Corticosterone; Endotoxins; Escherichia coli; Male; Naloxone; Rats; Rats, Inbred Strains; Shock, Septic; Thyrotropin-Releasing Hormone; Time Factors

Adult respiratory distress syndrome (ARDS) is a common and serious complication of septic shock. Pulmonary trapping of platelets (PPT) and leukocytes, and release of vasoactive and toxic substances such as prostaglandins, lysozymes and oxygen-radicals have been implicated as mediators of the lung injury. beta-Endorphin is regarded as one of the substances released during shock, and has been shown to cause cell damage similar to that seen with endotoxin, and also PPT. We recently reported that combined treatment with methylprednisolone, ibuprofen and naloxone significantly increased lasting survival in an LD100 canine endotoxin shock model. In the present study the effects of these drugs in various combinations were evaluated as regards blood pressure, hematocrit, peripheral platelet and leukocyte counts, intestinal damage and PPT in the same model. The effects of combined treatment were significantly decreased PPT, rise in blood pressure and abolition of bloody diarrhea. We concluded that ibuprofen and naloxone have additive action and that methylprednisolone has no effect on PPT.

Topics: Animals; Blood Platelets; Blood Pressure; Diarrhea; Dogs; Endotoxins; Escherichia coli; Female; Hematocrit; Ibuprofen; Leukocyte Count; Male; Methylprednisolone; Naloxone; Platelet Count; Respiratory Distress Syndrome; Shock, Septic

To explain the high neonatal mortality from peritonitis-induced septic shock despite current resuscitation practices, the efficacy of dopamine, naloxone, and prostacyclin was evaluated in an experimental neonatal model. Hemodynamics were monitored and survival was measured in anesthetized neonatal swine, which were subjected to fatal fecal-Escherichia coli peritonitis-induced septic shock. All the animals received fluid resuscitation, antibiotics, and bicarbonate to correct acidosis. Pharmacologic resuscitation began when cardiac output dropped below baseline in the experimental groups. Although significant differences were observed between groups in cardiac output, mean arterial and mean pulmonary arterial pressures, left ventricular stroke work, stroke volume, and pulmonary vascular resistance indices (P less than 0.02), and each animal exhibited favorable hemodynamic responses during the first several hours of dopamine and naloxone infusion, these drugs failed to prolong survival. Also, 5 of the 9 naloxone-treated pigs (56%), died with histologically proven intestinal ischemia (P less than 0.02). Thus, dopamine, naloxone, and prostacyclin (at doses commonly recommended for the treatment of septic shock) fail to positively influence the fatal course of this condition, and the use of naloxone in this model is associated with profound intestinal ischemia.

Topics: Analysis of Variance; Animals; Animals, Newborn; Dopamine; Drug Evaluation; Epoprostenol; Escherichia coli Infections; Feces; Hemodynamics; Intestinal Perforation; Naloxone; Peritonitis; Resuscitation; Shock, Septic; Swine; Time Factors

Topics: Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Naloxone; Shock, Septic

The effect of naloxone on a number of experimental shock models, using the anaesthetized rat, was studied with special emphasis on mean arterial blood pressure (MABP) and chance of survival. Only a slight increase in MABP was noted in haemorrhagic shock models whereas survival was not affected. Naloxone was without effect in endotoxin shock (i.p. administration of endotoxin). In endotoxin shock (i.v. administration) naloxone increased MABP especially at a high dose of endotoxin. Although survival time was prolonged, the chance of permanent survival was not improved. Naloxone had practically no effect in anaphylactic shock and intestinal ischaemia shock. It is concluded that if naloxone has any effect it is relatively slight. However, this does not exclude the possibility that naloxone might still be considered as an adjunct to other forms of shock treatment at least in certain types of shock.

Topics: Anaphylaxis; Animals; Blood Pressure; Female; Intestines; Ischemia; Male; Naloxone; Rats; Rats, Inbred Strains; Shock; Shock, Hemorrhagic; Shock, Septic; Time Factors

Naloxone has been shown to reverse the hemodynamic sequelae of experimental septic shock in adult animal models. Its effectiveness in the newborn has not been studied. To further investigate the efficacy of naloxone, we instrumented 18 piglets for continuous measurement of mean arterial pressure, mean pulmonary arterial pressure, central venous pressure, heart rate, left ventricular pressure, contractility, cardiac output, and O2. Oxygen consumption, systemic vascular resistance, and pulmonary vascular resistance were calculated. Following a stabilization period, group B beta-hemolytic Streptococci were infused over 30 min. Following the infusion, naloxone (1 mg/kg) was given followed by a continuous infusion of 1 mg/kg/h in nine treatment animals. Nine control animals were given an equal volume of saline. Both groups developed significant increases in mean pulmonary arterial pressure followed by a return to baseline. Oxygen consumption, cardiac output, contractility and mean arterial pressure decreased in both groups. Treatment with naloxone was associated with a cessation in the fall in the mean arterial pressure and the contractility. The difference in mean arterial pressure and contractility between groups was significant. The naloxone group had significantly improved 5-h survival. We speculate that naloxone may reverse some of the hemodynamic sequelae and improve survival in newborns with septic shock.

Topics: Animals; Animals, Newborn; Blood Pressure; Cardiac Output; Hemodynamics; Myocardial Contraction; Naloxone; Oxygen Consumption; Shock, Septic; Swine; Vascular Resistance

Administration of endotoxin (20 mg/kg i.p.) produced a moderate degree of gastric mucosal damage in rats. The lesions remained confined to the glandular mucosa and consisted of small punctiform lesions, erosions and petechial hemorrhage. The characteristic feature of these lesions was a typical submucosal ecchymosis in the glandular stomach observed in about 30% of the animals. Pretreatment with ranitidine, pirenzepine, proglumide, sucralfate and naloxone produced varying degrees of protection. The ulcerogenic effect of endotoxin shock is apparently mediated through the release of endorphins.

Topics: Animals; Anti-Ulcer Agents; Endotoxins; Female; Gastric Mucosa; Male; Naloxone; Rats; Rats, Inbred Strains; Shock, Septic; Stomach Ulcer

Topics: Humans; Naloxone; Shock, Septic

Administration of endotoxin, a lipopolysaccharide extracted from cell walls of gram negative bacteria, elicited alterations in various metabolic parameters and in the electrocardiogram of rats. Cardiac glycogen and serum glucose were decreased, while serum pyruvate and acid phosphatase levels were increased. There was initial tachycardia followed by significant bradycardia and elevation of the ST segment in the animals with shock. Erythrocyte count, haemoglobin and haematocrit were not changed after shock. Treatment with naloxone caused significant decreases in the metabolic and electrocardiographic changes induced by endotoxin.

Topics: Acid Phosphatase; Alanine Transaminase; Animals; Blood Cell Count; Blood Coagulation; Blood Glucose; Electrocardiography; Female; Glycogen; Hemoglobins; Male; Myocardium; Naloxone; Rats; Rats, Inbred Strains; Shock, Septic

Topics: Humans; Naloxone; Pharmaceutical Vehicles; Shock, Septic

Topics: Humans; Naloxone; Shock, Septic

A 0.01 and 0.1-mg/kg dose of iv naloxone was administered to seven patients in septic shock, in order to evaluate naloxone's hemodynamic effect and possible relation to changes in plasma beta-endorphin and catecholamine levels. Naloxone failed to modify cardiac index, blood pressure, heart rate, and systemic vascular resistance. Plasma beta-endorphin, norepinephrine, and epinephrine were elevated but did not change after naloxone administration. These results suggest that beta-endorphin release is a consequence but not a cause of shock, and that the beneficial hemodynamic effects of naloxone in animal studies could be related to species differences or nociceptive stimulations.

Topics: Adult; Aged; Bacterial Infections; beta-Endorphin; Endorphins; Epinephrine; Female; Hemodynamics; Humans; Male; Middle Aged; Naloxone; Norepinephrine; Shock, Septic

Plasma beta-endorphin-like immunoreactivity (beta-ELIR) levels were measured during hyper and hypodynamic phases of septic shock in patients (n = 36) due to a variety of microorganisms. Plasma beta-ELIR levels were elevated in all groups, but were most marked in patients with hyperdynamic circulation due to gram-positive and gram-negative organisms, followed by hypodynamic circulation due to gram-negative organisms and were least elevated in hypodynamic shock due to gram-positive organisms. There was strong correlation between plasma beta-ELIR levels and cardiac index in patients with a hyperdynamic circulation (gram-negative organisms, rs = 0.79, p less than 0.01; gram-positive, rs = 0.85, p less than 0.01) but little to no correlation in patients with hypodynamic circulation (gram-negative, rs = 0.32, p = NS; gram-positive organisms rs = 0.04, p = NS). These results imply that plasma beta-ELIR levels may be involved in the early phases of septic shock and may contribute to a hyperdynamic circulation, whereas plasma beta-ELIR levels may be normal or may not be related to hypodynamic circulation as seen in later phases of shock.

Topics: Bacteria; beta-Endorphin; Endorphins; Female; Hemodynamics; Humans; Male; Middle Aged; Naloxone; Shock, Septic

The effect of high dose corticosteroids on survival has been studied in a limited number of canine septic shock models which are reviewed in this presentation. Following injection of live bacteria neither methylprednisolone, nor gentamicin but a combination improved survival. Methylprednisolone increased survival following a slow but not a bolus infusion of endotoxin. In a recent study the effects of short term treatment with methylprednisolone, naloxone and ibuprofen were studied in endotoxin shock. All control animals died within 36 hours. Five of 9 dogs receiving the combination methylprednisolone, naloxone and ibuprofen were permanent survivors. The combined treatment with methylprednisolone and ibuprofen also increased survival. Dogs treated with methylprednisolone alone did not differ significantly from controls. It is concluded that methylprednisolone alone has no significant effect on survival in septic shock, but seems to be an important therapeutic factor to achieve increased survival.

Topics: Animals; Dogs; Drug Therapy, Combination; Endotoxins; Humans; Ibuprofen; Methylprednisolone; Naloxone; Shock, Septic

A model of endotoxin-induced shock was developed in anesthetized spontaneously hypertensive rats. E. coli lipopolysaccharide (13 mg/kg i.v.) reduced systolic and diastolic blood pressure by at least 51 mm Hg in 80-90% of rats. Naloxone (1.25-10.0 mg/kg i.v.) partially restored blood pressure of hypotensive rats for 6-15 minutes after injection. Win 44441-3 (0.25-2.0 mg/kg i.v.) raised blood pressure for 3-12 minutes after injection. Ten minute pretreatment with naloxone (10 mg/kg i.v.) or Win 44441-3 (0.5 mg/kg i.v.) did not appreciably reduce the hypotensive effect of E. coli lipopolysaccharide. This model is a rapid and convenient bioassay for evaluating the effects of opioid antagonists in endotoxin shock. In this model naloxone and Win 44441-3 exhibited beneficial effects but a prolonged duration of action of the Win compound over naloxone was not observed.

Topics: Animals; Azocines; Disease Models, Animal; Escherichia coli; Lipopolysaccharides; Male; Naloxone; Rats; Rats, Inbred SHR; Shock, Septic

Topics: Animals; Escherichia coli Infections; Humans; Infant, Newborn; Naloxone; Shock, Septic; Swine

We evaluated the effectiveness and safety of iv naloxone in 12 septic patients who remained hypotensive despite volume replacement, appropriate antibiotics, and vasopressor therapy. Only four patients responded positively to naloxone, by increases in mean arterial pressure of between 10 to 15 mm Hg that lasted for 15 to 60 min. These patients could not be distinguished from the others on the basis of underlying illness, laboratory or physical findings, length of preceding hypotension, or glucocorticoid therapy. Four patients had adverse reactions: one developed pulmonary edema, one patient had a grand-mal seizure, and two patients became severely hypotensive. We conclude that in patients with well-established septic shock, naloxone does not reliably improve mean arterial pressure or other physiologic variables, and may cause severe adverse reactions.

Topics: Aged; Analysis of Variance; Blood Pressure; Critical Care; Drug Evaluation; Female; Hemodynamics; Humans; Hypotension; Injections, Intravenous; Male; Middle Aged; Naloxone; Shock, Septic

Topics: Blood Pressure; Body Temperature; Heart Rate; Hematocrit; Humans; Infant; Methylprednisolone; Naloxone; Oxygen; Shock, Septic

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Drug Synergism; Drug Therapy, Combination; Glucocorticoids; Gram-Negative Bacteria; Humans; Immunization, Passive; Naloxone; Rabbits; Rats; Shock, Septic

Topics: Animals; Humans; Naloxone; Shock, Septic

In 1978 Holaday and Faden reported that naloxone prevented and reversed endotoxin-induced hypotension in rats. Since then, the potential of endogenous opioid peptides in the treatment of shock has come under scrutiny. This brief review puts the work of the last 8 years in perspective.

Topics: Animals; Autonomic Nervous System; Hemodynamics; Humans; Naloxone; Narcotic Antagonists; Shock; Shock, Septic

Circulatory shock and pain were associated as frequent consequences of surgery and trauma prior to the development of anesthetics. The recent discovery of the endogenous opioid systems affords the opportunity to link the occurrence of pain and circulatory shock at a functional level. The involvement of opioid systems in endogenously and exogenously induced analgesia is well established. In this review, evidence is presented indicating that endogenously activated opioid systems contribute to the pathophysiology of circulatory shock following such diverse causes as endotoxemia, hemorrhage, and spinal cord trauma. The opiate antagonist naloxone (Narcan), acting to oppose endogenous opiates, rapidly reverses the hemodynamic, metabolic, and biochemical sequelae of shock in experimental animal models. Additionally, naloxone has been shown to prevent paralysis following acute cervical spinal cord injury. As with all drugs, several physiologic and pathophysiologic circumstances limit the usefulness of naloxone in reversing shock and improving tissue perfusion. They include acidosis, hypothermia, interactions with administered steroids, and the potential for antagonizing opioid-induced analgesia, which may exacerbate pain in the traumatized patient. Two approaches have yielded potential ways to circumvent these limitations: first, the development of specific opioid-receptor antagonists, which reverse shock without affecting opioid analgesia, and second, the pharmacologic use of thyrotropin releasing hormone (TRH), which acts through its own effector system, independent of endogenous opioid receptors, to produce autonomic effects that reverse shock in experimental animals without affecting analgesia.

Topics: Animals; Humans; Naloxone; Narcotic Antagonists; Rodentia; Shock; Shock, Hemorrhagic; Shock, Septic; Spinal Cord Injuries; Thyrotropin-Releasing Hormone; Wounds and Injuries

Previous studies established that naloxone reverses hypotension in endotoxin, hemorrhagic, and spinal shock. We studied endotoxin shock in hypophysectomized (Hx) rats, which have little circulating beta-endorphin. Hx or intact rats received surgically implanted jugular catheters for drug injection and aortic catheters for arterial blood pressure (MAP) recording. On the second day after implantation, rats were pretreated with either naloxone or saline. Two minutes later each rat received endotoxin. Following endotoxin, all rats showed a brief biphasic hypertensive-hypotensive response followed by stabilization of MAP near baseline. Within 20 min, all Hx rats, regardless of pretreatment, and the saline-treated intact rats, showed progressive hypotension (P less than 0.005). Only the naloxone-pretreated intact rats maintained a stable MAP. Plasma endorphin measured at 20 min was undetectable in Hx rats in contrast to intact rats (P less than 0.001); plasma corticosterone levels were likewise suppressed in the Hx rats (P less than 0.01). Thus (1) naloxone protected only the rats with an intact pituitary-adrenal-sympathetic system, and (2) pituitary endorphin is not required to generate endotoxin shock in hypophysectomized rats.

Topics: Animals; beta-Endorphin; Blood Pressure; Corticosterone; Endorphins; Hypophysectomy; Hypotension; Male; Naloxone; Pituitary Gland; Rats; Rats, Inbred Strains; Shock, Septic

Sepsis remains the most common associated factor in acute respiratory failure (ARF). Endogenous opiates are known to have both respiratory and cardiovascular depressant effects. Because there is a high level of circulating endogenous opiates in sepsis, the possible role of opioids in the ARF syndrome seen in sepsis was studied. Sixteen piglets were infused with an LD100 dose (7.5 X 10(10) organisms/kg) of live Escherichia coli (Type 09-41). The pigs were hemodynamically monitored. Serial blood samples were taken for arterial blood gases and lactate. Serial lung biopsies were taken for determining wet/dry lung weight ratios and for histology. Group I (n = 8): septic shock controls without naloxone; group II (n = 8): naloxone treated, given as 2 mg/kg/hr intravenous boluses, starting within 1 min of E. coli infusion. All animals died of septic shock. Survivors at 150 min in group II had a higher blood pressure than group I (67.7 +/- 5.33 SEM vs 39.0 +/- 9.39) and cardiac output was also greater (1.07 +/- 0.23 vs 0.25 +/- 0.25). By 210 min, group I had no survivors (0/8) while 3/8 in group II survived. Pulmonary vascular resistance in group II at 90 and 120 min (870.8 +/- 274.1 and 942.5 +/- 12.9, respectively) was lower than in group I (2868.3 +/- 843.6 and 4156 +/- 1067). The PO2 was markedly better in group II and at 90 min; controls had a PO2 70.7 +/- 13.0, while group II had a PO2 111.4 +/- 8.4 (P less than 0.05). PCO2 levels showed a progressive rise in group I from 39.25 +/- 1.4 to 49.4 +/- 8.57.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Drug Evaluation, Preclinical; Endorphins; Escherichia coli Infections; Hemodynamics; Lung; Naloxone; Organ Size; Respiratory Insufficiency; Shock, Septic; Swine; Time Factors

This study was designed to investigate the concept that endogenous opioids are involved in the pathogenesis of septic shock. Infusion of live Escherichia coli (1.0-1.6 X 10(10) organisms/kg) in splenectomized dogs induced profound hypotension (p less than 0.001), peripheral vasodilatation (p less than 0.001), and metabolic acidosis (p less than 0.05) with maintenance of cardiac index as compared to control splenectomized dogs. Treatment with naloxone (3 mg/kg bolus and 2 mg/kg/hr infusion for 2.5 hours), a specific opiate antagonist, during septic shock attenuated the hypotension (p less than 0.002) and systemic acidosis (p less than 0.02) without altering cardiac index or total peripheral resistance. These experimental results indicate that naloxone may be of therapeutic value in the management of the early vasodilatory stage of septicemia.

Topics: Animals; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Escherichia coli Infections; Female; Heart Rate; Hemodynamics; Male; Naloxone; Sepsis; Shock, Septic; Splenectomy; Vascular Resistance

Dogs and baboons were infused intravenously (IV) with Escherichia coli and treated with the opiate antagonist, naloxone hydrochloride, and the antibiotic, gentamicin sulfate, to determine the therapeutic efficacy of naloxone. Naloxone hydrochloride (2 mg/kg) was injected IV when one fourth of the E coli had been infused and then infused at 2 mg/kg/hr (six hours for dogs and 12 hours for baboons). Four of five naloxone-treated dogs survived permanently (greater than seven days), while all dogs that were given only E coli died. Arterial BP, blood glucose levels, PCO2, and PO2 were supported at higher levels and lesions of the gastrointestinal tract were prevented in naloxone-treated dogs. A steady decline in blood glucose levels after an initial hyperglycemia was observed in naloxone-treated baboons, indications of peripheral vasoconstriction were noted, and all baboons died within 42 hours.

Topics: Animals; Blood Pressure; Body Temperature; Dogs; Drug Therapy, Combination; Epinephrine; Escherichia coli Infections; Gentamicins; Naloxone; Norepinephrine; Papio; Shock, Septic

Increased pancreatic insulin secretion may be one of the factors associated with the insulinlike activity (ILA) of endotoxemia. While there is little doubt that the prominent hypoglycemia of endotoxicosis is often preceded by systemic hyperinsulinemia, the cause of this increased secretion and its cause-and-effect relationship to the glucose deficit is less obvious. Recently, a "misinformed B-cell" hypothesis was proposed in which it was suggested that increased glucose flux across the pancreatic B-cell early in endotoxemia might lead to a misinterpretation of the existing glycemic state, resulting in increased insulin release. This possibility was based in part on the observation that increased 6-3H-glucose-derived rates of glucose disappearance (Rd) in endotoxic Yucatan minipigs preceded the onset of systemic hyperinsulinemia. Examination herein of the chronological order of events in this group of pigs and three other groups treated with lidocaine, naloxone, or captopril reveals an increase in pancreatic insulin secretory rate most often before increases in systemic Rd. Each of the three therapies were administered as a primed continuous intravenous infusion, 1 hour after the initiation of a continuous intravenous infusion of Difco 055:B5 E. coli lipopolysaccharide at an LD67 dose of 15 micrograms/kg/hr. In those pigs receiving no therapy, lidocaine, or naloxone, significant increases in pancreatic insulin secretion recurred at 40, 40, and 60 min following the onset of endotoxemia respectively. This was followed in 20 min by the first significant increase in relative glucose disappearance rates (%Rd). Captopril-treated pigs experienced a significant increase in %Rd at 60 min, which was followed in 20 min by a significant increase in pancreatic insulin secretion. In all groups, a significant hyperinsulinemia occurred transiently at 80 min postendotoxin, followed in 20 min by the onset of significant hypoglycemia. These observations suggest that increases in %Rd and transient increases in insulin secretion may be simultaneous events at best, and that along with significant increases in absolute levels of hepatic insulin extraction (observed in all groups at 60 or 80 min postendotoxin) may indicate some local effect of insulin release on hepatic glucose.

Topics: Animals; Blood Glucose; Captopril; Endotoxins; Insulin; Islets of Langerhans; Kinetics; Lidocaine; Liver; Liver Circulation; Naloxone; Shock, Septic; Splanchnic Circulation; Swine; Swine, Miniature

Two cases are reported describing the use of intravenous naloxone in surgical patients with prolonged hypotension unresponsive to conventional intensive care, including dopamine, intravenous fluids, diuretics, and steroids.The findings were in agreement with those of previous reports suggesting that endorphins may contribute to the hypotension of sepsis and that naloxone's antagonistic effect on endorphin may have therapeutic value in the treatment of septic shock.

Topics: Aged; Endorphins; Female; Humans; Male; Middle Aged; Naloxone; Shock, Septic

Topics: Female; Humans; Infant, Newborn; Infusions, Parenteral; Male; Naloxone; Shock, Septic

The specific opiate receptor antagonist, naloxone, can produce haemodynamic improvement and increased survival in experimental shock. The efficacy of naloxone therapy in a canine model of endotoxin shock has been evaluated both with and without intravascular volume replacement. Animals were anaesthetized with alpha-chloralose and allowed to breathe spontaneously. A large bolus dose of endotoxin was followed by a continuous infusion and treatment was instituted one hour after the endotoxin bolus. In the absence of volume replacement, naloxone caused only limited and transient increases in mean arterial pressure (MAP) and left ventricular (LV) dp/dt max, with little effect on cardiac index (CI). Total peripheral resistance index (TPRI) tended to rise in both control and naloxone-treated dogs. In volume-replaced animals, naloxone produced substantial and sustained increases in the MAP and LV dp/dt max with an associated rise in the CI. TPRI rose initially in this series and then fell progressively. Further analysis of the improvements in the CI showed an increase in stroke index with a tendency for heart rate to fall. These findings suggest a myocardial action of naloxone in endotoxin shock, which is augmented by volume replacement. An initial, transient vasoconstrictor effect cannot, however, be excluded. Further work is required to determine the mechanism of the effects described.

Topics: Animals; Blood Cell Count; Blood Pressure; Capillaries; Cardiac Output; Disease Models, Animal; Dogs; Hemodynamics; Naloxone; Plasma Substitutes; Pulmonary Circulation; Shock, Septic; Time Factors; Vascular Resistance

The effects of methylprednisolone, naloxone, and ibuprofen--alone and in various combinations--on survival, blood pressure, hematocrit, and peripheral platelet and white blood cell counts were studied in a canine Escherichia coli endotoxin LD100 shock model. Treatment was started 10 minutes after shock induction. The dogs were kept on a respirator and given intravenous fluids for 4 hours, then disconnected from the respirator and allowed to recover. Dogs surviving 7 days were considered permanent survivors. All control animals died within 36 hours. Five of nine dogs receiving a combined treatment of methylprednisolone, naloxone, and ibuprofen were permanent survivors and showed no macroscopic abnormalities when autopsied. The combined treatment with methylprednisolone and ibuprofen also increased survival. Mortality was delayed in animals treated with methylprednisolone and naloxone. Dogs receiving ibuprofen, a cyclooxygenase inhibitor, had a rapid reversal of hypotension. Hematocrit and platelet counts were similar in all groups. The combined treatment caused an increase in the recovery rate of white blood cells.

Topics: Animals; Blood Cell Count; Blood Pressure; Dogs; Drug Therapy, Combination; Endotoxins; Female; Ibuprofen; Male; Methylprednisolone; Naloxone; Shock, Septic; Time Factors

Topics: Humans; Naloxone; Shock, Cardiogenic; Shock, Septic

Topics: Chromatography, High Pressure Liquid; Humans; Naloxone; Shock, Septic

Septic shock in obstetric patients can be prevented by recognition of patients at risk and aggressive intervention in the warm-hypotensive phase. These patients must be monitored closely. Rarely will an obstetrical floor be capable of providing adequate monitoring of these patients; therefore, the patient should be transferred to an intensive care unit. Individualize therapy, but do not procrastinate in the surgical removal of the nidus of infection.

Topics: Animals; Anti-Bacterial Agents; Aspirin; Disseminated Intravascular Coagulation; Dopamine; Emergencies; Endotoxins; Female; Humans; Intensive Care Units; Kidney; Liver; Lung; Naloxone; Pregnancy; Pregnancy Complications, Infectious; Prostaglandins; Shock, Septic

Naloxone clorhidrate was administered intravenously to 15 patients with endotoxic shock and refractary hypotension, following meningococcal sepsis. Doses used were between 0.01-0.2 mg/kg. Three patients (two of them with moderate shock) showed an increase in sistolic arterial pressure, which was maintained and above 20 mm/Hg. Among the rest of them (except one with severe shock) naloxone action was non-existent in nine cases, or with short action and without answer to next doses in other three. Eleven patients died. A blood pressure increase was maintained only in two of the four survivors. Usefulness of naloxone in this kind of patients is not clear. Presence in endotoxin shock of a variety of refractory factors besides beta endorphins, greatly limits therapeutic efficiency of this drug.

Topics: Adolescent; Child; Child, Preschool; Endorphins; Humans; Hypotension; Infant; Meningococcal Infections; Naloxone; Shock, Septic

Many vasoactive mediators have been implicated in causing or maintaining the hypotension of endotoxic shock. What has yet to be firmly established is the relative importance of each of these mediators in a given shock model. In a canine endotoxic shock model (LD100), we studied the effects of opiate and prostaglandin inhibition 60 min after endotoxin administration. After thiopental anesthesia, the animals were instrumented to measure various cardiovascular parameters. Endotoxic shock was induced by injecting E. coli endotoxin (0111:B4) (1 mg/kg i.v.). Drug intervention occurred 60 min after endotoxin administration. Naloxone (2 mg/kg i.v.) improved mean arterial pressure (MAP) transiently. A more significant increase of MAP (85% of preshock levels) was attained after ibuprofen (12.5 mg/kg i.v.) administration secondary to an increase in total peripheral resistance (TPR). All groups had 0% 24-hour survival. These data suggest that the endogenous opioids, presumably inhibited by naloxone, seem to contribute little to this lethal canine endotoxic shock model. By contrast, the prostanoids which are inhibited by ibuprofen appear to be more hemodynamically significant in this model.

Topics: Animals; Blood Pressure; Disease Models, Animal; Dogs; Endorphins; Hemodynamics; Ibuprofen; Male; Naloxone; Prostaglandins; Shock, Septic; Vascular Resistance

Antibiotic therapy should be directed toward any recognized or suspected pathogens. Multiple broad-spectrum antibiotics are most often successful. Ancillary measures ensure adequate oxygenation, maintenance of adequate urinary output, and support of the cardiovascular system. A team approach using an intensive care facility should result in an optimum outcome in the management of elderly septic patients.

Topics: Adrenal Cortex Hormones; Aged; Anti-Bacterial Agents; Cardiac Catheterization; Cardiotonic Agents; Female; Fluid Therapy; Humans; Male; Naloxone; Shock, Septic

The effects of naloxone on the cardiovascular, hematologic and metabolic derangements associated with endotoxic and hemorrhagic shock were studied in unanesthetized horses. In the first of 3 experiments blood glucose and lactate levels, hematocrit, white, red and differential white cell counts, rectal temperature and clinical signs were obtained before and after endotoxin (10 micrograms/Kg) administration in 5 horses. In the second experiment, two groups of 3 horses received either intravenous naloxone (0.04 mg/Kg) or saline, 7 minutes prior to endotoxin. In a third experiment two groups of 4 horses received either saline or naloxone (0.20 mg/Kg) immediately following acute hemorrhage. In the second and third experiments, pulse, mean arterial and right ventricular pressures, and heart rate were also observed. Endotoxin and acute hemorrhage produced hypothermia, leukopenia, lymphopenia, neutropenia, elevations in hematocrit, blood glucose and blood lactate, and clinical signs of shock. Naloxone (0.040 mg/Kg IV) significantly lowered endotoxin-induced increases in right ventricular pressure and heart rate, and at a higher dose (0.20 mg/Kg) antagonized the decrease in pulse and heart rate, and tachycardia observed after acute hemorrhage. These results suggest endogenous opioids are involved in the pathogenesis of shock. Naloxone appeared to attenuate some of the cardiovascular responses associated with shock and thus may be of therapeutic value in shock management.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endotoxins; Female; Heart Rate; Hemodynamics; Horses; Male; Naloxone; Pulse; Shock, Hemorrhagic; Shock, Septic

To improve understanding of the role of endorphins in septic shock, we examined the effects of anesthesia, splenectomy, live Escherichia coli infusion, and treatment with naloxone, respectively, on plasma beta-endorphin immunoreactivity (beta-EI) and plasma cortisol in dogs. Baseline levels of plasma beta-EI and cortisol were established in awake dogs. Pentobarbital anesthesia alone did not affect plasma beta-EI, but splenectomy was followed by a significant (P less than 0.001) rise in both plasma beta-EI and cortisol. Infusion of saline over a 3-hour period following splenectomy induced no further increase in plasma beta-EI, but infusion of live E. coli in splenectomized dogs caused a further rise in plasma beta-EI (P less than 0.02). Following induction of septic shock in a separate group of splenectomized animals, treatment with naloxone (3 mg/kg bolus and 2 mg/kg/hr infusion) did not alter the rise in plasma beta-EI. These results confirm release of beta-endorphin during septic shock and further implicate the hypothalamic-pituitary-adrenal axis in its pathophysiology. Based on the finding that naloxone did not affect the dynamics of plasma beta-EI, mechanisms are postulated to explain the therapeutic value of this drug in septic shock.

Topics: Anesthesia; Animals; beta-Endorphin; Dogs; Endorphins; Escherichia coli; Hydrocortisone; Naloxone; Postoperative Complications; Radioimmunoassay; Sepsis; Shock, Septic; Splenectomy

Topics: Animals; Cats; Endorphins; Humans; Naloxone; Rats; Receptors, Opioid; Shock; Shock, Hemorrhagic; Shock, Septic; Spinal Cord Injuries; Thyrotropin-Releasing Hormone

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; beta-Lipotropin; Catecholamines; Dogs; Endorphins; Female; Hemodynamics; Male; Naloxone; Shock, Hemorrhagic; Shock, Septic

Naloxone, 0.3 mg/kg of a 10 mg/ml solution, was administered as a single bolus to patients in septic shock if their systolic blood pressure (BP) was less than 100 mm Hg or MAP less than 70 mm Hg with evidence of renal or cerebral hypoperfusion. Patients with chronic or acute (less than 12 h) administration of narcotics were excluded. Ten patients received naloxone; 5 patients had significant increases in blood pressure; 5 had no response. Maximal response in BP occurred by 15 min, and lasted 45-165 min. Responders could not be separated by nonresponders by analysis of baseline, hemodynamics, or prior steroid therapy; nonresponders were hemodynamically compromised greater than 24 h; responders less than or equal to 8. Two patients in each group were chronically on high-dose steroids and responded to a 2nd smaller dose of naloxone when effects of initial bolus had ended. Naloxone, 0.3 mg/kg, can reverse endorphin-mediated hypotension in acute septic shock in patients who have received chronic steroid therapy.

Topics: Adult; Blood Pressure; Cardiac Output; Female; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Naloxone; Receptors, Opioid; Shock, Septic; Time Factors

Cardiovascular effects of the high affinity, irreversible opiate antagonist, naloxazone, were investigated in conscious rats subjected to endotoxic shock. Unlike other less selective opiate antagonists such as naloxone, naloxazone failed to block or reverse the hemodynamic effects of endotoxemia. However, naloxazone pretreatment prevented the usual therapeutic effects of naloxone in endotoxic shock. Results indicate that high affinity (mu 1-site) opiate binding is not involved in the pathophysiological actions of endogenous opiates in shock, and suggest that interactions among opioid receptor subtypes may occur in vivo.

Topics: Animals; Blood Pressure; Injections, Intravenous; Male; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Shock, Septic

Topics: Animals; beta-Endorphin; Catecholamines; Dogs; Endorphins; Hemodynamics; Naloxone; Shock, Septic

The effects of naloxone on endotoxic hypotension in adrenalectomized and selectively adrenal demedullated rats were evaluated. In sham-operated rats, naloxone administered intracerebroventricularly (ICV) and intravenously (IV) produced an elevation of arterial pressure in this conscious rat model of endotoxemia. By contrast, both adrenalectomy and selective adrenal demedullation (wherein cortical function remained) not only enhanced the sensitivity to endotoxin-induced hypotension at least 10- to 15-fold, but also completely prevented the pressor response to ICV or IV naloxone. These results indicate that 1) adrenal enkephalins are probably not the endogenous opiates responsible for shock hypotension since their removal enhances shock susceptibility; 2) pituitary-derived endorphins in the circulation also appear to be uninvolved since naloxone fails to reverse shock hypotension despite reported elevations of circulating beta-endorphin in adrenalectomized rats; 3) since evidence indicates that naloxone acts centrally in intact endotoxemic rats and fails to do so following adrenal demedullation, we suggest that endotoxic shock results in an endogenous opiate inhibition of central autonomic sites regulating sympatho-medullary outflow. Naloxone, by reversing these actions, may result in the increased release of pressor substances from the adrenal medulla.

Topics: Adrenal Medulla; Adrenalectomy; Animals; Autonomic Nervous System; Blood Pressure; Endorphins; Male; Models, Biological; Naloxone; Rats; Receptors, Opioid; Shock, Septic; Time Factors

Using antagonists with selectivity for the delta (ICI 154,129) and mu (beta-funaltrexamine) binding sites, evidence was obtained to indicate that delta receptors within the brain mediate the endogenous opioid component of endotoxic hypotension. The therapeutic actions of intravenous ICI 154,129 were dose related, with effective doses between 15-60 mg/kg. Evidence for a functional interaction between mu and delta binding sites was obtained: prior occupancy of the mu binding site by beta-funaltrexamine prevented the usual therapeutic response to the delta antagonist ICI 154,129 in endotoxemic rats. These data indicate that mu and delta binding sites may be a part of the same macromolecular complex which interact through allosteric coupling.

Topics: Animals; Blood Pressure; Enkephalin, Leucine; Heart Rate; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pulse; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Shock, Septic

The value of naloxone (1 mg/kg of body weight/hr for 4 hrs), a beta-endorphin antagonist, was assessed in the management of endotoxin-induced shock in ponies. Three groups of 5 ponies each were used: controls, ponies given Escherichia coli endotoxin put untreated, and ponies given endotoxin and then treated with naloxone. Endotoxin-induced changes in hemodynamics, blood chemical values, regional blood flow, plasma enzymes, and energy supplies were measured at selected times during the first 6 hours after endotoxin was given. There was no evidence that beta-endorphins released during shock were responsible for the hemodynamic changes, blood flow changes, plasma enzyme changes, or energy deficits, because naloxone, at this dosage level, did not prevent these endotoxin-induced changes.

Topics: Animals; Blood Chemical Analysis; Endotoxins; Escherichia coli; Female; Hemodynamics; Horse Diseases; Horses; Hydrogen-Ion Concentration; Male; Naloxone; Shock, Septic

The effects of naloxone on sympathetic nerve activity during E coli endotoxin hypotension were studied in alpha-chloralose anesthetized cats. Blood pressure and left preganglionic splanchnic nerve (PSN) activity were measured. Naloxone (2 mg/kg) was injected intravenously 30 min after endotoxin. In control group, 30 min after endotoxin, both mean blood pressure (MBP) and PSN activity decreased by 68 +/- 7% and 47 +/- 10%, respectively, and were followed by a gradual decline, so that after 60 min MBP and PSN activity were 54 +/- 8% and 48 +/- 7% of the pre-endotoxin level. The reduced blood pressure recovered to 81 +/- 4% of the pre-endotoxin level 5 min after naloxone. However, the naloxone-induced recovery of blood pressure was transient and there was a decline to the pre-naloxone level within 30 min after the injection. At the end of the experiment (60 min after endotoxin), the level of MBP was significantly higher than in the control group. Similarly, there was a modest recovery in PSN activity (61 +/- 7% of the pre-endotoxin level 5 min after naloxone) that was maintained for 20 min only to decline again. Three of five cats treated with an intermittent bolus injection (2 mg/kg, 30 min and 6 h after endotoxin) of naloxone survived, compared to only one of five nontreated cats. These observations suggest that at least part of the beneficial cardiovascular actions of naloxone in endotoxin shock involves activation of the efferent sympathetic system. To improve longterm survival it may be necessary to continuously administer naloxone.

Topics: Animals; Blood Pressure; Cats; Endotoxins; Escherichia coli; Hypotension; Naloxone; Shock, Septic; Splanchnic Nerves; Stimulation, Chemical

The opiate antagonist, naloxone, has been shown to obviate hypotension and to improve survival of animals with shock induced by endotoxin, hypovolemia, and spinal transection. This study was done to evaluate the effects of naloxone on pulmonary platelet trapping (PPT) and on platelet aggregability in dogs with endotoxin shock. Dogs with 51Cr labelled platelets were treated with naloxone before and after induction of endotoxin shock. PPT was assessed by measuring 51Cr activity in lung and blood using a gamma scintillation counter. ADP induced platelet aggregability was measured in an aggregometer. PPT seen in endotoxin shocked controls was obviated by naloxone treatment; this effect was more pronounced in pretreated dogs. Naloxone treated animals did not show the increased platelet aggregability normally seen in endotoxin shocked dogs. These results suggest the applicability of naloxone therapy for adult respiratory distress associated with shock.

Topics: Animals; Blood Platelets; Blood Pressure; Dogs; Endotoxins; Escherichia coli; Female; Lung; Male; Naloxone; Platelet Aggregation; Respiratory Distress Syndrome; Shock, Septic

Topics: Adrenal Cortex Hormones; Catecholamines; Fluid Therapy; Hemodynamics; Humans; Naloxone; Positive-Pressure Respiration; Shock, Septic

Topics: Aged; Humans; Hypotension; Male; Naloxone; Shock, Septic

Topics: Animals; Blood Glucose; Dogs; Hemodynamics; Naloxone; Shock, Septic

Topics: Adult; Female; Humans; Naloxone; Shock, Septic

Topics: Critical Care; Cross Infection; Hemodynamics; Humans; Infections; Internal Medicine; Multiple Organ Failure; Naloxone; Prognosis; Sepsis; Shock, Septic

Topics: Humans; Hypotension; Naloxone; Shock, Septic

The effects of naloxone (2 mg/kg body weight) on hemodynamics, oxygen transport, and some metabolic variables were studied in mongrel dogs under general anesthesia and controlled ventilation. All 19 dogs received Escherichia coli endotoxin (1.5 mg/kg) and subsequently were randomized into three groups. The first group (N = 7) served as a control group in which at 90 min after endotoxin (t 90), NaCl (0.65%, 4 ml/kg) was infused during 30 min. In the second group (N = 7) naloxone (2 mg/kg) dissolved in the same amount of fluid was administered at t 90 in 30 min. In the third group (N = 5) naloxone (2 mg/kg) was injected as a bolus in 5 ml NaCl (0.65%) at t 90, which was followed by NaCl (0.65%, 4 ml/kg) infused in 30 min. Differences in the three groups after intervention were tested statistically. After naloxone, blood pressure, cardiac output, and left ventricular stroke work increased significantly. Although oxygen availability increased, oxygen consumption and serum lactate did not change when compared with the control group. As to all other measured and calculated variables, no systematic differences were found in the three groups. In six dogs, plasma beta-endorphins were measured and were shown to rise substantially after induction of endotoxin shock. As to the hemodynamic changes, our observations confirm data from the literature. Naloxone apparently improves hemodynamics in endotoxin shock, but at least in this study fails to influence oxygen consumption and serum lactate levels.

Topics: Animals; Biological Transport; Blood Pressure; Cardiac Output; Dogs; Endorphins; Female; Hemodynamics; Lactates; Male; Muscle Contraction; Naloxone; Oxygen; Oxygen Consumption; Shock, Septic

The administration of small dosages of endotoxin to sheep results in cardiopulmonary changes characterized by an elevation in pulmonary lymph flow, vascular resistance, and hemoconcentration, and a reduction in cardiac output. These changes are not as great when the narcotic antagonist, naloxone (2 mg/kg/h for 5 h), is infused prior to and during the endotoxin response. The present study evaluates the ovine response to endotoxin when naloxone is administered 1 h after the endotoxin infusion. Sheep were prepared by implanting cardiopulmonary and lung lymphatic catheters. One week following the last surgical procedure, the sheep, in the awake state, were given 0.75 micrograms/kg of endotoxin and the variables were measured. Three days later, a second dose of endotoxin was administered and variables were again measured. An infusion of naloxone was given with one of the dosages of lipopolysaccharide. Two dosages of the narcotic antagonist were used. One group received 2 mg/kg bolus + 2 mg/kg/h for 5 h; another group was given twice this amount. Both dosages were started 1 h after endotoxin. The response to endotoxin was essentially the same whether or not the sheep were treated with naloxone. If naloxone pretreatment is effective and posttreatment is not, then it is possible that an opiatelike substance might be released by endotoxin which in turn results in the ultimate release of the lesion-producing substance.

Topics: Animals; Blood Proteins; Cardiac Output; Cardiovascular System; Female; Lung; Lymph; Naloxone; Narcotic Antagonists; Sheep; Shock, Septic; Vascular Resistance

Topics: Female; Humans; Infusions, Parenteral; Middle Aged; Naloxone; Shock, Septic; Streptococcal Infections

The pathophysiological role of endorphins in septic shock was studied in a porcine model. Septic shock was induced by the intravenous infusion of live Escherichia coli. Naloxone hydrochloride, an opiate receptor blocker, given during profound septic shock, increased blood concentrations of glucagon and cyclic adenosine monophosphate (cAMP), while BP and cardiac output increased transiently. Heart rate and hepatic glycogen value decreased, but insulin and cortisol levels remained unchanged. In contrast, exogenous morphine injection produced further reduction of BP, increased pulmonary wedge pressure, and increased substance P, while growth hormone level and cardiac output remained unchanged. Neither hormonal nor hemodynamic changes were noted in saline controls. Thus, the endogenous opiates appear partly responsible for the hemodynamic derangements during septic shock, and naloxone is able to reverse such depression, even though the effects are transient and relatively minor when naloxone is given late in the course of septic shock. Endogenous opiates also affect the hormonal homeostasis in shock, and there are indications that this may be mediated by the adenylate cyclase-cAMP system.

Topics: Animals; Blood Glucose; Blood Pressure; Endorphins; Female; Hemodynamics; Hormones; Male; Morphine; Naloxone; Pulmonary Wedge Pressure; Receptors, Opioid; Shock, Septic; Swine

Topics: Animals; Body Temperature; Dogs; Endotoxins; Escherichia coli; Female; Hypotension; Male; Naloxone; Receptors, Opioid; Shock, Septic; Temperature

Topics: Animals; Blood Pressure; Cardiac Output; Drug Synergism; Endorphins; Escherichia coli; Lactates; Methylprednisolone; Naloxone; Pulmonary Wedge Pressure; Pyruvates; Shock, Septic; Swine

Topics: Animals; Blood Pressure; Female; Humans; Hypotension; Middle Aged; Naloxone; Rats; Shock, Septic; Stimulation, Chemical

Topics: Child; Child, Preschool; Hemodynamics; Humans; Meningococcal Infections; Naloxone; Shock, Septic

Naloxone was given intravenously to thirteen patients with prolonged hypotension. Eight patients with sepsis who were not receiving corticosteroids had a 45% increase in systolic blood-pressure within minutes of receiving 0.4--1.2 mg of naloxone. The increase in blood-pressure lasted for at least 45 min. In two patients a second dose, given after recurrence of hypotension, resulted in another increase in blood-pressure. Four patients with hypoadrenocorticotropism had no pressor response to naloxone. These observations suggest that endorphins may contribute to the hypotension of sepsis and that naloxone may have therapeutic value in the treatment of septic shock.

Topics: Adrenal Insufficiency; Adult; Aged; Blood Pressure; Cardiac Output; Endorphins; Female; Humans; Hypotension; Male; Middle Aged; Naloxone; Shock, Septic

Topics: Blood Pressure; Endorphins; Humans; Naloxone; Shock, Septic

Topics: Humans; Myocardium; Naloxone; Receptors, Opioid; Shock, Septic

Experiments were done upon anesthetized and unanesthetized dogs given endotoxin only, endotoxin plus naloxone or naloxone only. Dogs given endotoxin and treated with naloxone showed marked hemodynamic and metabolic improvements compared with the dogs given endotoxin only. Beneficial effects of naloxone treatment following the administration of endotoxin are attentuated hypotension, hemoconcentration and acidosis and prevention of hypoglycemia. Results of mortality studies in unanesthetized dogs given endotoxin suggest that naloxone treatment increases the survival time.

Topics: Animals; Blood Glucose; Carbon Dioxide; Dogs; Endotoxins; Escherichia coli; Female; Hematocrit; Hemodynamics; Hydrogen-Ion Concentration; Male; Naloxone; Oxygen; Shock, Septic

In conscious rats subjected to endotoxic shock, thyrotropin releasing hormone (TRH) is shown to produce a rapid increase in cardiovascular variables and respiratory rates at intravenous doses between 0.20 and 6.34 mg/kg. Moreover, these doses of TRH significantly improve survival following endotoxemia. The absence of an effect of TRH upon analgesic latencies, combined with its demonstrated efficacy in reversing shock, suggest that it may have therapeutic advantage over the opiate antagonist naloxone.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Male; Naloxone; Rats; Rats, Inbred Strains; Shock, Septic; Thyrotropin-Releasing Hormone

The current study investigates the possibility that the cerebellum may be involved in the regulation of mean arterial pressure (MAP) during endotoxin shock in the anesthetized dog. The effect of intravenously injected Escherichia coli endotoxin on MAP in the cerebellectomized dog was compared to that observed in the intact animal. Even though removal of the cerebellum did not significantly affect MAP in a control group, the cerebellectomized animal (unlike the intact animal) was unable to recover from the initial hypotension typically seen immediately following an intravenous endotoxin injection. Previous investigators have demonstrated that stimulation of fastigial nuclei in the cerebellum increases MAP via beta-adrenergic activation of the renin-angiotensin system. Captopril (SQ 14,225, an angiotensin I-converting enzyme inhibitor) was used to determine whether this system could be responsible for the maintenance of MAP during endotoxin shock. When continuously infused into the intact dog given endotoxin, captopril suppressed MAP to a level similar to that of the cerebellectomized group. A similar response pattern to endotoxin was also observed in animals with a spinal transection at C2.

Topics: Animals; Blood Pressure; Captopril; Cerebellum; Decerebrate State; Dogs; Endotoxins; Escherichia coli; Female; Male; Naloxone; Shock, Septic

Topics: Animals; Cats; Dogs; Endorphins; Naloxone; Rats; Shock, Hemorrhagic; Shock, Septic

Topics: Adult; Aged; Female; Humans; Hypotension; Male; Middle Aged; Myocardial Infarction; Naloxone; Shock, Septic

Topics: Child; Humans; Injections, Intravenous; Injections, Subcutaneous; Naloxone; Shock, Septic

Endogenous opiates (endorphins) like exogenous opiates can, even in small doses, profoundly depress blood pressure and heart rate. Since endorphins are released in response to stressors, it appeared possible that endorphins might be released during shock and serve to further reduce blood pressure. We used the specific opiate-antagonist naloxone to block there anticipated effects of endorphins in a conscious rat endotoxin-shock model. Naloxone treatment resulted in a rapid increase in mean arterial pressure (MAP) in animals made hypotensive by endotoxin administration. Naloxone was effective in reversing this hypotension at a dose as small as 0.1 mg/kg. This therapeutic effect of naloxone was stereospecific: (-)-naloxone reversed the hypotension, although its stereoisomer (+)-naloxone did not. A single 10 mg/kg i.v. bolus injection of naloxone significantly improved MAP for a period of 30 min, and MAP remained elevated as compared to saline controls for approximately 2 hr. Bolus injections of naloxone followed by continuous i.v. infusion produced similar changes in MAP. Despite the rapid effect of naloxone in restoring MAP toward base-line levels, 24 hr survival was not significantly improved by this narcotic antagonist. This suggests that factors other than hypotension are critical determinants of survival in this rat model. Collectively, these findings support the hypothesis that endorphins are hypotensive factors in endotoxin shock and suggest that the therapeutic effects of naloxone are specific and are mediated by the opiate receptor.

Topics: Animals; Blood Pressure; Endorphins; Heart Rate; Infusions, Parenteral; Male; Naloxone; Pulse; Rats; Respiration; Shock, Septic; Stereoisomerism; Time Factors

Topics: Animals; Blood Pressure; Dogs; Hypotension; Injections, Intraventricular; Naloxone; Shock, Septic

Topics: Animals; Bacterial Toxins; Blood Pressure; Endotoxins; Escherichia coli; Heart Rate; Naloxone; Rats; Shock, Septic