buprenorphine and Sepsis

Sepsis research relies heavily on animal models. One of the most frequently used models, cecal ligation and puncture (CLP), involves surgery, and animal use committees may require the use of analgesics after CLP. However, some analgesics are immunomodulatory and may affect research outcomes. In addition, both septic inflammation and responses to opioids may vary with the sex of the subject. Therefore, we investigated the effects of buprenorphine in inbred mice of both sexes undergoing CLP. We hypothesized that buprenorphine would not significantly change the outcome or patterns of inflammation in C57BL/6 mice after CLP. Male and female C57BL/6 mice underwent CLP surgery and were randomized into 2 groups to receive either buprenorphine or saline. Three-week survival studies were performed (n = 20 per group). Survival did not differ between groups of female mice, but male mice that received buprenorphine had decreased survival compared with that of controls. Reducing the dose of buprenorphine in male mice ameliorated the difference in survival. To examine inflammation, mice (n = 10 per group) were euthanized at 12, 24, or 48 h after CLP. Cell counts and cytokines were measured in the blood and peritoneal lavage fluid. In female and male C57BL/6 mice, buprenorphine treatment resulted in few differences in inflammatory parameters, although peripheral neutrophil counts were decreased transiently in male mice. The findings suggest that the effects of buprenorphine on sepsis models in C57BL/6 mice may be sex-specific. Consequently the use of analgesics must be assessed on a study-by-study basis, and investigators should define analgesic regimens when publishing sepsis studies.

Topics: Analgesics, Opioid; Animal Welfare; Animals; Blood Chemical Analysis; Buprenorphine; Cecum; Cell Count; Coinfection; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Ligation; Male; Mice; Mice, Inbred C57BL; Peritoneal Lavage; Punctures; Sepsis

Topics: Analgesia; Animals; Biomarkers; Buprenorphine; Disease Models, Animal; Mice; Sepsis

Sepsis can be simulated in animals by perforating the cecum via a surgical procedure termed "cecal ligation and puncture" (CLP), which induces similar inflammatory responses as observed during the clinical course of human sepsis. In addition to anesthetic agents, many Institutional Animal Care and Use Committees often recommend the use of additional analgesic agents (such as opioid) to further augment the initial anesthetic effects. However, emerging evidence suggest that a commonly recommended opioid, buprenorphine, dramatically elevated circulating interleukin (IL)-6 levels, and reduced animal survival in male C57BL/6 mice, but not in female mice possibly due to the complex interference of estrous cycles, fueling an ongoing debate regarding the possible impact of analgesic administration on the sepsis-induced systemic inflammation. As per the recommendation of a local government agency, we performed a pilot study and confirmed that repetitive administration of buprenorphine indeed markedly elevated circulating levels of four sepsis surrogate markers (e.g., IL-6, KC, monocyte chemoattractant protein-1, and granulocyte-colony stimulating factor) in 20% to 60% of septic animals. This complication may adversely jeopardize our ability to use the CLP model to reliably simulate human sepsis, and to understand the complex mechanism underlying the pathogenesis of lethal sepsis. Thus, for experimental sepsis studies set to survey systemic inflammation and animal lethality at relatively later stages (e.g., at 24 h post CLP and beyond), we strongly recommend not to repetitively administer buprenorphine to eliminate its potential complication to animal sepsis models.

Topics: Animals; Biomarkers; Buprenorphine; Cytokines; Disease Models, Animal; Male; Mice; Mice, Inbred BALB C; Pilot Projects; Sepsis; Time Factors

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

Cecal ligation and perforation (CLP) is a common technique for studying sepsis in mice. Because of the invasiveness of the procedure and its effects on clinical condition, many animal care and use committees require the use of analgesics with CLP. However, some analgesics have immunomodulatory effects and thus can hinder the overall research outcomes of a project. Here we sought to determine the effects of buprenorphine hydrochloride (Bup HCl) compared with sustained-release buprenorphine (Bup SR) on clinical condition, plasma concentrations of monocyte chemoattractant protein (MCP) 1 and IL6, and overall mortality in a murine CLP model of sepsis. Male C57/BL6 mice underwent CLP surgery and received Bup HCl or Bup SR as a component of an IACUCapproved analgesic dosing regimen. Mice were observed twice daily for clinical condition scoring by the same blinded investigator for the duration of the study. MCP1 and IL6 levels and mortality did not differ significantly between the 2 groups. Scoring of clinical condition revealed a significant decrease in behaviors associated with perceived pain at 12 and 24 h postoperatively in mice in the Bup SR group compared with the Bup HCl group. Because of the lack of significant effect on MCP1 and IL6 levels and mortality and the superior analgesic effects of Bup SR, we recommend the use of Bup SR for analgesia during the murine CLP model of sepsis.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Chemokine CCL2; Delayed-Action Preparations; Disease Models, Animal; Humans; Interleukin-6; Kaplan-Meier Estimate; Ligation; Male; Mice; Mice, Inbred C57BL; Postoperative Period; Sepsis

The effect of opioids on the immunopathology of sepsis models in mice has been controversial. In previous work, we showed that mortality and various inflammatory parameters did not differ between female mice given saline or buprenorphine after cecal ligation and puncture. To investigate further, we hypothesized that buprenorphine would not affect outcomes of sepsis at any stage of estrous. Female mice were allocated into 4 groups (n = 20 per group) according to stage of estrous. Mice then underwent cecal ligation and puncture and received either buprenorphine or saline. In 3-wk survival studies, overall survival did not differ between buprenorphine- and saline-treated mice. When mice were stratified according to stage of estrous, survival did not vary among saline-treated groups but was lower in buprenorphine-treated mice in metestrus compared with proestrus. To investigate inflammation as a potential mechanism for survival, we measured cell counts and cytokine levels in the peripheral blood and peritoneal lavage fluid at 12 and 24 h after cecal ligation and puncture. At 24 h, buprenorphine-treated mice in proestrus had more circulating neutrophils and monocytes than did saline-treated mice in proestrus and more circulating WBC than did mice in any other stage with or without buprenorphine. Our current results suggest that the effects of buprenorphine on a 50% survival model of sepsis in BALB/c female mice are minimal overall but that the stage of estrous has various effects in this model. Investigators should consider the effects of buprenorphine and estrous cycle when using female mice in sepsis research.

Topics: Analgesics, Opioid; Animals; Ascitic Fluid; Behavior, Animal; Buprenorphine; Cecum; Cytokines; Disease Models, Animal; Estrous Cycle; Estrus; Female; Inflammation Mediators; Ligation; Metestrus; Mice; Mice, Inbred BALB C; Peritoneum; Proestrus; Punctures; Sepsis; Sex Factors; Time Factors

We report a 25-year-old Malay man with Subutex-related endocarditis, complicated by protein-losing enteropathy from severe tricuspid regurgitation and congestive heart failure. The intestinal protein loss was reversed with surgical valvular intervention. This case highlights the importance of recognising the rare association between protein-losing enteropathy and congestive heart failure in the setting of endocarditis.

Topics: Adult; Biopsy; Buprenorphine; Echocardiography, Doppler, Color; Echocardiography, Transesophageal; Endocarditis, Bacterial; Follow-Up Studies; Heart Failure; Heart Valve Prosthesis Implantation; Humans; Jejunum; Male; Mitral Valve Insufficiency; Narcotics; Postoperative Complications; Prosthesis Failure; Protein-Losing Enteropathies; Reoperation; Sepsis; Staphylococcal Infections; Substance Abuse, Intravenous; Surgical Wound Dehiscence; Tricuspid Valve Insufficiency