Randomised, double-blind, parallel group, placebo-controlled study to evaluate the analgesic efficacy and safety of VVZ-149 injections for postoperative pain following laparoscopic colorectal surgery.

INTRODUCTION: In spite of advances in understanding and technology, postoperative pain remains poorly treated for a significant number of patients. In colorectal surgery, the need for developing novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids worsen ileus, nausea and constipation. We describe a prospective, double-blind, parallel group, placebo-controlled randomised controlled trial testing the hypothesis that a novel analgesic drug, VVZ -149, is safe and effective in improving pain compared with providing opioid analgesia alone among adults undergoing laparoscopic colorectal surgery. METHODS AND ANALYSIS: Based on sample size calculations for primary outcome, we plan to enrol 120 participants. Adult patients without significant medical comorbidities or ongoing opioid use and who are undergoing laparoscopic colorectal surgery will be enrolled. Participants are randomly assigned to receive either VVZ-149 with intravenous (IV) hydromorphone patient-controlled analgesia (PCA) or the control intervention (IV PCA alone) in the postoperative period. The primary outcome is the Sum of Pain Intensity Difference over 8 hours (SPID-8 postdose). Participants receive VVZ-149 for 8 hours postoperatively to the primary study end point, after which they continue to be assessed for up to 24 hours. We measure opioid consumption, record pain intensity and pain relief, and evaluate the number of rescue doses and requests for opioid. To assess safety, we record sedation, nausea and vomiting, respiratory depression, laboratory tests and ECG readings after study drug administration. We evaluate for possible confounders of analgesic response, such as anxiety, depression and catastrophising behaviours. The study will also collect blood sample data and evaluate for pharmacokinetic and pharmacodynamic relationships. ETHICS AND DISSEMINATION: Ethical approval of the study protocol has been obtained from Institutional Review Boards at the participating institutions. Trial results will be disseminated through scientific conference presentations and by publication in scientific journals. TRIAL REGISTRATION NUMBER: NCT02489526; pre-results.

Incidence of serotonin syndrome in patients treated with fentanyl on serotonergic agents.

BACKGROUND: There has been a recent surge in the literature highlighting the association of fentanyl as precipitating serotonin syndrome in patients on a serotonergic agent. OBJECTIVE: The purpose of our study was to understand the incidence of serotonin syndrome in patients who receive fentanyl while on serotonergic agents. STUDY DESIGN: This retrospective analysis was conducted from 2012 to 2013 after approval from the Institutional Review Board. We searched for all patients that had received a serotonergic agent and were admitted to the hospital during the study period. Next, we split these patients into 2 groups by placing all patients who had received fentanyl and a serotonergic agent into one group. We then searched for any of the Hunter Serotonin Toxicity Criteria in the records of patients that had received both fentanyl and a serotonergic agent. Further, we searched for all patients with serotonin syndrome mentioned in their records. SETTING: This study was conducted at a 900 bed tertiary care academic center. RESULTS: Over the 2 year study period, 112,045 patients were on a serotonergic agent, and 4,538 of these patients were treated with both fentanyl and a serotonergic agent. A search for Hunter's Criteria through the records of the patients receiving both fentanyl and a serotonergic agent revealed 23 patients had been documented with some of these symptoms. On detailed chart review, only 4 [95% CI 1 - 10] of these patients truly met Hunter's Criteria for serotonin syndrome. We then searched all admissions for a diagnosis code of serotonin syndrome during the study period. Five additional cases of serotonin syndrome were found, but none of these patients were treated with fentanyl. LIMITATIONS: Some of the limitations of our study include that it represents a single institution, although it is a large academic center. An inherent limitation may be the under diagnosis of serotonin syndrome. CONCLUSION: The incidence of serotonin syndrome in patients who receive both fentanyl and a serotonergic agent is low.

Neurotoxicity of adjuvants used in perineural anesthesia and analgesia in comparison with ropivacaine.

BACKGROUND AND OBJECTIVES: Clonidine, buprenorphine, dexamethasone, and midazolam (C, B, D, M) have been used to prolong perineural local anesthesia in the absence of data on the influence of these adjuvants on local anesthetic-induced neurotoxicity. Therefore, the impact of these adjuvants on ropivacaine (R)-induced death of isolated sensory neurons was assessed. METHODS: The trypan blue exclusion assay was used to assess death of sensory neurons isolated from adult male Sprague-Dawley rats. Drugs were applied, alone or in combination, for 2 or 24 hrs at 37°C. RESULTS: Neuronal viability was halved by 24-hr exposure to R (2.5 mg/mL), far exceeding the neurotoxicity of C, B, D, or M (at 2-100 times estimated clinical concentrations). Plain M at twice the estimated clinical concentration produced a small but significant increase in neurotoxicity at 24 hrs. After 2-hr exposure, high concentrations of B, C, and M increased the neurotoxicity of R; the combination of R + M killed more than 90% of neurons. Estimated clinical concentrations of C + B (plus 66 µg/mL D) had no influence on (i) R-induced neurotoxicity, (ii) the increased neurotoxicity associated with the combination of R + M, or (iii) the neurotoxicity associated with estimated clinical concentrations of M. There was increased neurotoxicity with 133 µg/mL D combined with R + C + B. CONCLUSIONS: Results with R reaffirm the need to identify ways to mitigate local anesthetic-induced neurotoxicity. While having no protective effect on R-induced neurotoxicity in vitro, future research with adjuvants should address if the C + B + D combination can enable reducing R concentrations needed to achieve equianalgesia (and/or provide equal or superior duration, in preclinical in vivo models).

The economic effect of screening orthopedic surgery patients preoperatively for methicillin-resistant Staphylococcus aureus.

BACKGROUND AND OBJECTIVE: Patients undergoing orthopedic surgery are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, which can result in increased morbidity, hospital lengths of stay, and medical costs. We sought to estimate the economic value of routine preoperative MRSA screening and decolonization of orthopedic surgery patients. METHODS: A stochastic decision-analytic computer simulation model was used to evaluate the economic value of implementing this strategy (compared with no preoperative screening or decolonization) among orthopedic surgery patients from both the third-party payer and hospital perspectives. Sensitivity analyses explored the effects of varying MRSA colonization prevalence, the cost of screening and decolonization, and the probability of decolonization success. RESULTS: Preoperative MRSA screening and decolonization was strongly cost-effective (incremental cost-effectiveness ratio less than $6,000 per quality-adjusted life year) from the third-party payer perspective even when MRSA prevalence was as low as 1%, decolonization success was as low as 25%, and decolonization costs were as high as $300 per patient. In most scenarios this strategy was economically dominant (ie, less costly and more effective than no screening). From the hospital perspective, preoperative MRSA screening and decolonization was the economically dominant strategy for all scenarios explored. CONCLUSIONS: Routine preoperative screening and decolonization of orthopedic surgery patients may under many circumstances save hospitals and third-party payers money while providing health benefits.

Screening cardiac surgery patients for MRSA: an economic computer model.

OBJECTIVE: To estimate the economic value of preoperative methicillin-resistant Staphylococcus aureus (MRSA) screening and decolonization for cardiac surgery patients. STUDY DESIGN: Monte Carlo decision-analytic computer simulation model. METHODS: We developed a computer simulation model representing the decision of whether to perform preoperative MRSA screening and decolonizing those patients with a positive MRSA culture. Sensitivity analyses varied key input parameters including MRSA colonization prevalence, decolonization success rates, the number of surveillance sites, and screening/decolonization costs. Separate analyses estimated the incremental cost-effectiveness ratio (ICER) of the screening and decolonization strategy from the third-party payer and hospital perspectives. RESULTS: Even when MRSA colonization prevalence and decolonization success rate were as low as 1% and 25%, respectively, the ICER of implementing routine surveillance was well under $15,000 per quality-adjusted life-year from both the third-party payer and hospital perspectives. The surveillance strategy was economically dominant (less costly and more effective than no testing) for most scenarios explored. CONCLUSIONS: Our results suggest that routine preoperative MRSA screening of cardiac surgery patients could provide substantial economic value to third-party payers and hospitals over a wide range of MRSA colonization prevalence levels, decolonization success rates, and surveillance costs. Healthcare administrators, infection control specialists, and surgeons can compare their local conditions with our study's benchmarks to make decisions about whether to implement preoperative MRSA testing. Third-party payers may want to consider covering such a strategy.

Should vascular surgery patients be screened preoperatively for methicillin-resistant Staphylococcus aureus?

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) can cause severe infection in patients who are undergoing vascular surgical operations. Testing all vascular surgery patients preoperatively for MRSA and attempting to decolonize those who have positive results may be a strategy to prevent MRSA infection. The economic value of such a strategy has not yet been determined. METHODS: We developed a decision-analytic computer simulation model to determine the economic value of using such a strategy before all vascular surgical procedures from the societal and third-party payer perspectives at different MRSA prevalence and decolonization success rates. RESULTS: The model showed preoperative MRSA testing to be cost-effective (incremental cost-effectiveness ratio, <$50,000 per quality-adjusted life year) when the MRSA prevalence is > or = 0.01 and the decolonization success rate is > or = 0.25. In fact, this strategy was dominant (ie, less costly and more effective) at the following thresholds: MRSA prevalence > or = 0.01 and decolonization success rate > or = 0.5, and MRSA prevalence > or = 0.025 and decolonization success rate > or = 0.25. CONCLUSION: Testing and decolonizing patients for MRSA before vascular surgery may be a cost-effective strategy over a wide range of MRSA prevalence and decolonization success rates.