Perioperative subcutaneous methylnaltrexone does not enhance gastrointestinal recovery after posterior short-segment spinal arthrodesis surgery: a randomized controlled trial.

BACKGROUND CONTEXT: Postoperative ileus is a major barrier to gastrointestinal recovery following surgery. Opioid analgesics likely play an important causative role, particularly in spinal or orthopedic surgeries not involving bowel manipulation. Methylnaltrexone, a peripherally-acting µ-opioid receptor antagonist, is a potential prophylactic treatment. PURPOSE: To assess the influence of perioperative subcutaneous methylnaltrexone administration on gastrointestinal recovery following short-segment lumbar arthrodesis surgeries. DESIGN: This is a randomized, double-blind, controlled trial. PATIENT SAMPLE: Eligible patients undergoing posterior short-segment lumbar arthrodesis surgeries at a single institution between February 2019 and April 2021 were enrolled in this study. OUTCOME MEASURES: The primary outcome measure was time-to-first bowel movement. Secondary outcome measures included time-to-discharge/discharge eligibility. Exploratory outcome measures included daily postoperative opioid consumption and pain scores. METHODS: In this study, eligible patients were enrolled to receive either methylnaltrexone or placebo perioperatively. Time-to-bowel movement, time-to-discharge/discharge eligibility, intra and postoperative analgesic administration, and pain scores were recorded and compared. RESULTS: Eighty two patients in total were enrolled; 41 to the methylnaltrexone and 41 to the placebo group. Both groups were similar in their baseline characteristics. There was no difference in median (range) time-to-bowel movement between the 2 groups [61.8 hours (35.7-93.6) versus 50.7 hours (17.8-110.8), p = .391]. There was also no difference in time-to-discharge/discharge eligibility [105.0 hours (81.0 - 201.3) versus 90.7 (77.5 - 184.5), p=.784]. Finally, there were no differences in either postoperative opioid consumption or numeric rating scores for back, leg, or abdominal pain on postoperative days 0 to 4 (p>.05). CONCLUSIONS: Methylnaltrexone did not accelerate gastrointestinal recovery and did not affect opioid consumption or pain scores following short-segment spinal surgery as compared to placebo. Additional studies will be needed to identify effective opioid receptor antagonist dosing regimens for patients undergoing either short- or long-segment spinal arthrodesis procedures.

Design and feasibility of a double-blind, randomized trial of peri-operative methylnaltrexone for postoperative ileus prevention after adult spinal arthrodesis.

BACKGROUND: Postoperative ileus (POI) is a common complication with no proven prophylactic measures in place. While perioperative opioid use has been implicated in POI development, current treatments fail to target this disease mechanism. Methylnaltrexone (MNTX) has been used to prevent the effects of opioids on the bowel and could reduce the incidence of POI when administered preoperatively. METHODS: In this phase IIb randomized controlled trial, we assessed the effect of perioperative MNTX on time-to-first-bowel movement following spinal arthrodesis surgeries. RESULTS: 82 patients were randomly selected in a 1:1 ratio to be included in either the treatment or placebo groups. Comparison of relevant factors of included patients to patients who refused to participate (n = 21) and to a prior retrospective series (n = 241) revealed no differences in age, male sex, liver disease, and number of surgical levels. Overall treatment fidelity (98% adherence) and retention (100% at one-month follow-up) were high. The predicted POI incidence (9.3-11.1%) was also equivalent to a prior retrospective series. However, the overall observed POI incidence (3.7%) was lower than expected, which could reflect a superimposed 'trial effect' related to standardized care in a research setting. CONCLUSIONS: Since exposure to significant opioid doses represents a barrier to enhanced recovery after surgery, the results of this innovative trial may provide further guidance for the peri-operative use of opioid-receptor blockers. Here, we show that MNTX can be effectively administered in the peri-operative period with appropriate follow-up achieved in a representative population of patients undergoing spinal surgery. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov - NCT03852524 and Institutional Review Board - 2018H0260.

Development of a postoperative ileus risk assessment scale: identification of intraoperative opioid exposure as a significant predictor after spinal surgery.

OBJECTIVE: Postoperative ileus (POI) is associated with abdominal pain, nausea, vomiting, and delayed mobilization that in turn lead to diminished patient satisfaction, increased hospital length of stay (LOS), and increased healthcare costs. In this study, the authors developed a risk assessment scale to predict the likelihood of developing POI following spinal surgery. METHODS: The authors undertook a retrospective review of a prospectively maintained registry of consecutive patients who underwent arthrodesis/fusion surgeries between May 2013 and December 2017. They extracted clinical information, including cumulative intraoperative and postoperative opioid doses using standardized converted morphine milligram equivalent (MME) values. Univariate and multivariate analyses were performed and several categorical and continuous variables were evaluated in a binary logistic regression model built with backward elimination to assess for independent predictors. A points-based prediction model was developed and validated to determine the risk of POI. RESULTS: A total of 334 patients who underwent spinal fusion surgeries were included. Fifty-six patients (16.8%) developed POI, more frequently in those who underwent long-segment surgeries compared to short-segment surgeries (33.3% vs 10.4%; p < 0.001). POI was associated with an increased LOS when compared with patients who did not develop POI (8.0 ± 4.5 days vs 4.4 ± 2.4 days; p < 0.01). The incidences of liver disease (16% vs 3.7%; p = 0.01) and substance abuse history (12.0% vs 3.2%; p = 0.04) were higher in POI patients than non-POI patients undergoing short-segment surgeries. While the incidences of preoperative opioid intake (p = 0.23) and cumulative 24-hour (87.7 MME vs 73.2 MME; p = 0.08) and 72-hour (225.6 MME vs 221.4 MME; p = 0.87) postoperative opioid administration were not different, remifentanil (3059.3 µg vs 1821.5 µg; p < 0.01) and overall intraoperative opioid (326.7 MME vs 201.7 MME; p < 0.01) dosing were increased in the POI group. The authors derived a multivariate model based on the 5 most significant factors predictive of POI (number of surgical levels, intraoperative MME, liver disease, age, and history of substance abuse) and calculated relative POI risks using a derived 32-point system. CONCLUSIONS: Intraoperative opioid administration, incorporated in a comprehensive risk assessment scale, represents an early and potentially modifiable predictor of POI. These data indicate that potential preventive strategies, implemented as part of enhanced recovery after surgery protocols, could be instituted in the preoperative phase of care to reduce POI incidence.

Sustained expression of lipocalin-2 during polymicrobial sepsis.

Sepsis is a major healthcare problem and a leading cause of death worldwide. There is no dependable diagnosis, and treatment for this condition remains mainly supportive. The etiology of sepsis is related to an overwhelming inflammatory response. In this regard, the antimicrobial protein lipocalin-2 (Lcn2) has been associated with several inflammatory conditions, but its contribution to polymicrobial sepsis is unclear. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and Lcn2 mRNA levels and protein expression were measured in liver and lung tissues. We observed that Lcn2 expression was robustly induced in liver and lung of C57BL/6 J (B6) mice, and remained elevated during the stage of innate immune dysfunction observed in sepsis. This response was different in A/J mice, suggesting a contribution of the genetic background, probably due to differences in IL-10 expression between these two mouse strains. Indeed, IL-10 was found to regulate Lcn2 expression in both primary and J774A.1 macrophages. Thus, Lcn2 expression is highly regulated during CLP-induced sepsis, suggesting that this antimicrobial protein could have a role as a potential biomarker for the diagnosis of sepsis.

Period of irreversible therapeutic intervention during sepsis correlates with phase of innate immune dysfunction.

Sepsis is a major health problem in the United States with high incidence and elevated patient care cost. Using an animal model of sepsis, cecum ligation, and puncture, we observed that mice became rapidly hypothermic reaching a threshold temperature of 28 °C within 5-10 h after initiation of the insult, resulting in a reliable predictor of mortality, which occurred within 30-72 h of the initial procedure. We also observed that the inflammatory gene expression in lung and liver developed early within 1-2 h of the insult, reaching maximum levels at 6 h, followed by a decline, approaching basal conditions within 20 h. This decrease in inflammatory gene expression at 20 h after cecal ligation and puncture was not due to resolution of the insult but rather was an immune dysfunction stage that was demonstrated by the inability of the animal to respond to a secondary external inflammatory stimulus. Removal of the injury source, ligated cecum, within 6 h of the initial insult resulted in increased survival, but not after 20 h of cecal ligation and puncture. We concluded that the therapeutic window for resolving sepsis is early after the initial insult and coincides with a stage of hyperinflammation that is followed by a condition of innate immune dysfunction in which reversion of the outcome is no longer possible.

Tumor necrosis factor expression is ameliorated after exposure to an acidic environment.

BACKGROUND: It has been well established that laparoscopic surgery presents several clinical benefits, including reduced pain and a shorter hospital stay. These effects have been associated with a decrease in the inflammatory response. Previous studies have demonstrated that reduced inflammation after laparoscopic surgery is the product of carbon dioxide insufflation, which decreases peritoneal pH. The objective of this study was to investigate the cellular and molecular mechanisms responsible for the reduced response after exposure to acidic environments. MATERIALS AND METHODS: A murine macrophage line (J744) was incubated in culture medium at pH 6.0 or pH 7.4 for 3 h at 37°C. Then, cells were stimulated with lipopolysaccharide (LPS) at pH 7.4, the expression of TNF-α (qRT-PCR or enzyme-linked immunosorbent assay (ELISA) and intracellular pH were measured. In addition, CD14 and Toll-like receptor 4 expression and NF-κB nuclear translocation were analyzed. RESULTS: A significant decrease in LPS-induced TNF-α expression levels was observed in cells pre-incubated at pH 6.0 in comparison with cells at neutral pH conditions. This decrease in TNF-α levels was not associated with a reduction in cell surface expression of CD14 and Toll-like receptor 4. Exposure to an extracellular acidic environment resulted in a reduction of IκB phosphorylation and NF-κB nuclear translocation, secondary to a significant drop in cytosolic pH. CONCLUSIONS: These observations provide a potential mechanism for the reduced expression of TNF-α after exposure to low extracellular pH, which may be related to acidification after CO(2) insufflation during laparoscopic surgery. In addition, extracellular acidic pH environments could emerge as an important regulator of macrophage function.

Acute acalculous cholecystitis-like phenotype in scavenger receptor A knock-out mice.

BACKGROUND: Sepsis is a major health problem in the United States that affects more than three-quarters of a million people every year. Previous studies have shown that scavenger receptor A (Sra), also known as macrophage scavenger receptor 1 (Msr1), is a modifier of interleukin 10 (IL-10) expression after injection of bacterial lipopolysaccharide (LPS). Therefore, we investigated the response to sepsis in Sra knock out mice. MATERIALS AND METHODS: C57BL/6J (B6) (n = 88) and Sra (-/-) mice (n = 88) were subjected to cecal ligation and puncture (CLP) using 18G or 16G needles, sham operation, or non-operated controls. At the end, mice were autopsied for the determination of abnormalities after the procedure. Cytokine gene expression was examined in lung and liver samples by quantitative RT-PCR (qRT-PCR), and circulating cholesterol levels were also measured. RESULTS: Sra (-/-) mice displayed an enlargement of the gallbladder after CLP that was not detected in sham or non-operated mice or in B6 mice (wild-type) after CLP. The enlarged gallbladder resembles a condition of acute acalculous cholecystitis observed in humans. Sra (-/-) mice presented high cholesterol levels in circulation as opposed to wild type B6 mice. Moreover, Sra (-/-) mice exhibited a reduction in IL-10 mRNA levels in lungs compared to wild-type B6 mice after CLP. CONCLUSIONS: The development of acute acalculous cholecystitis may be the combination of pre-existing conditions, such as hypercholesterolemia associated with a defect in Sra (Msr1) and a robust inflammation induced by sepsis.