naloxone and Sepsis

During the past few years, many promising new agents for the treatment of sepsis have been studied to varying degrees in vitro as well as in vivo in animals and humans. Although there is a relative plethora of animal data, full-scale clinical trials of size sufficient to yield clear answers are rare. Many of the agents appear to hold promise based on preliminary data in animals or from small human studies, and some are undergoing multicenter clinical investigation. At present, however, none of the agents discussed clearly has shown survival benefit when administered to patients with sepsis. Certainly, none can be recommended as standard therapy, and others such as glucocorticoids should be avoided. Nevertheless, the pharmacotherapy of sepsis remains an area of intense research, and ongoing clinical trials as well as continuing basic research into the pathophysiologic mechanisms of sepsis yet may yield a well-studied drug that offers survival benefit to patients with sepsis.

Topics: Acetylcysteine; Antioxidants; Bradykinin; Cyclooxygenase Inhibitors; Humans; Naloxone; Pentoxifylline; Platelet Activating Factor; Sepsis

Concentrations of beta-endorphin were quantified in peripheral blood plasma of sheep by a radioimmunoassay that cross-reacted with beta-lipotrophin. Plasma concentrations of beta-endorphin increased abruptly after physical confinement, bacteraemia, and electroacupuncture treatment for induction of analgesia. In these experimental situations in which plasma concentrations of beta-endorphin increased, plasma concentrations of LH often decreased. To test the hypothesis that increases in blood-borne beta-endorphin actually caused the decrease in LH release, naloxone was administered to antagonize the opioid receptors at which blood-borne beta-endorphin might act. In no case did administration of naloxone disrupt the temporal correlation between experimentally induced increases in plasma beta-endorphin and decreases in plasma LH. It was concluded that the increases in blood-borne beta-endorphin did not cause the decrease in LH release. Other research investigated whether beta-endorphin might be delivered via blood from pituitary to hypothalamus in locally enriched concentrations. Even when pituitary release of beta-endorphin was acutely stimulated, it was not possible to demonstrate retrograde delivery of beta-endorphin to the hypothalamus without dilution in the systemic circulation. In conclusion, it is unlikely that blood-borne beta-endorphin inhibits the release of LH, and beta-endorphin should not be classified as a hormone until blood concentrations of the peptide can be shown to exert some effect at a location distant from its site of secretion.

Topics: Acupuncture Therapy; Animals; beta-Endorphin; Endorphins; Female; Hormones; Hypothalamus; Luteinizing Hormone; Naloxone; Pituitary Gland; Sepsis; Sheep; Stress, Physiological

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Endotoxins; Humans; Naloxone; Sepsis

Gram-negative bacteremia is an increasingly important nosocomial infectious problem. Endotoxin, endorphins, leukocyte agglutination and deficient opsonization all appear to be major factors in the pathogenesis of Gram-negative septic shock. Outcome has previously correlated best to underlying disease state. With appropriate double antibiotic therapy and hemodynamic support, however, mortality has decreased even for neutropenic patients. Corticosteroids, naloxone, granulocyte transfusions and immunotherapy are experimental adjunctive modes of therapy that offer hope for even better survival in the future.

Topics: Adrenal Cortex Hormones; Blood Transfusion; Gram-Negative Bacteria; Humans; Immunotherapy; Naloxone; Sepsis

In all respects, the child with fulminant meningococcemia presents a formidable challenge to those who care for him/her. Only with prompt recognition of the disease and immediate institution of intensive treatment can the likelihood of survival be improved and morbidity minimized.

Topics: Anti-Bacterial Agents; Cardiovascular Agents; Child; Child, Preschool; Chloramphenicol; Humans; Infant; Meningococcal Infections; Naloxone; Penicillin G; Plasmapheresis; Prognosis; Sepsis; Steroids

Topics: Adolescent; Adult; Amenorrhea; Arthritis, Infectious; Bone Diseases; Chemical and Drug Induced Liver Injury; Coma; Endocarditis, Bacterial; Extremities; Female; Fetal Growth Retardation; Hepatitis, Viral, Human; Heroin Dependence; Humans; Infant, Newborn; Ischemia; Male; Naloxone; Neurologic Manifestations; Pregnancy; Pregnancy Complications; Respiratory Tract Diseases; Sepsis; Skin Manifestations; Tetanus

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: Algorithms; Analgesics, Opioid; Anti-Bacterial Agents; Buprenorphine; Drug Combinations; Endocarditis; Female; Humans; Inpatients; Morphine; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain, Postoperative; Sepsis; Young Adult

We investigated the effects of the opiate antagonist naloxone on the release of beta-endorphin and cortisol in rats subjected to sepsis. Sepsis was induced in weanling male Wistar albino rats (3-4 weeks old, 75-90 g) by cecal ligation and double perforation (CLP). Forty animals were randomly allocated to four groups. Group 1 was given naloxone hydrochloride 0.5 mg/kg subcutaneously after CLP and this treatment was repeated at 2-h intervals until the rats were killed. Group 2 rats underwent a sham operation. Group 3 (control group) rats had CLP. Group 4 consisted of nonoperated animals used to establish normal reference values. Eighteen hours after CLP or sham operation, the rats were killed by cervical dislocation and a blood sample was drawn via cardiac puncture to determine the beta-endorphin and cortisol levels. The beta-endorphin levels were significantly higher in the control group than in the sham-operated, naloxone-treated (NT), and nonoperated rats (P < 0.05). However, there were no significant differences in plasma beta-endorphin levels between sham-operated, NT and nonoperated rats (P > 0.05). Plasma cortisol levels were significantly higher in the control group compared with the other three groups and this difference was more significant in sham-operated and nonoperated rats (P < 0.01). However, no difference existed between sham-operated, NT, and nonoperated rats (P > 0.05). This study demonstrates that the endogenous opioid system may play a role in the activation of the pituitary-adrenal axis following sepsis, and shows that the increase in beta-endorphin and cortisol could be blocked by naloxone.

Topics: Animals; beta-Endorphin; Disease Models, Animal; Hydrocortisone; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Sepsis

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

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

Acute bacteremia in sheep caused a surge of plasma beta-endorphin/beta-lipotropin (beta-EP/beta-LPH) associated with shivering behavior, tachycardia, hyperthermia, hemoconcentration, and decreased respiration rate. The surge of plasma beta-EP/beta-LPH was immediately followed by increases (P less than 0.05) in plasma prolactin and growth hormone (GH) concentrations and a depression (P less than 0.05) of plasma luteinizing hormone. These changes in pituitary hormone release were consistent with opioid-induced changes described in the literature. To examine possible opioid mediation, naloxone (2.5 mg X kg-1 X h-1) was continuously infused intravenously from 3 h before to 3 h after induction of an E. coli bacteremia. With the exception of plasma GH, naloxone failed to alter any of the hormonal or clinical parameters associated with bacteremia. For plasma GH, naloxone delayed (P less than 0.01) the increase but did not attenuate its magnitude, suggesting that an opioid mechanism may influence the timing of the pituitary GH release resulting from bacteremia. In general, opioid mechanisms sensitive to the present dosage of naloxone do not appear to mediate bacteremia-induced changes in hormonal or clinical parameters.

Topics: Animals; beta-Endorphin; beta-Lipotropin; Endorphins; Escherichia coli Infections; Female; Growth Hormone; Heart Rate; Hematocrit; Luteinizing Hormone; Naloxone; Pituitary Hormones; Prolactin; Radioimmunoassay; Receptors, Opioid; Respiration; Sepsis; Sheep; Shivering; 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

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