Effect of colchicine on perioperative atrial fibrillation and myocardial injury after non-cardiac surgery in patients undergoing major thoracic surgery (COP-AF): an international randomised trial.

BACKGROUND: Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications. METHODS: COP-AF was a randomised trial conducted at 45 sites in 11 countries. Patients aged 55 years or older and undergoing major non-cardiac thoracic surgery were randomly assigned (1:1) to receive oral colchicine 0·5 mg twice daily or matching placebo, starting within 4 h before surgery and continuing for 10 days. Randomisation was done with use of a computerised, web-based system, and was stratified by centre. Health-care providers, patients, data collectors, and adjudicators were masked to treatment assignment. The coprimary outcomes were clinically important perioperative atrial fibrillation and MINS during 14 days of follow-up. The main safety outcomes were a composite of sepsis or infection, and non-infectious diarrhoea. The intention-to-treat principle was used for all analyses. This trial is registered with ClinicalTrials.gov, NCT03310125. FINDINGS: Between Feb 14, 2018, and June 27, 2023, we enrolled 3209 patients (mean age 68 years [SD 7], 1656 [51·6%] male). Clinically important atrial fibrillation occurred in 103 (6·4%) of 1608 patients assigned to colchicine, and 120 (7·5%) of 1601 patients assigned to placebo (hazard ratio [HR] 0·85, 95% CI 0·65 to 1·10; absolute risk reduction [ARR] 1·1%, 95% CI -0·7 to 2·8; p=0·22). MINS occurred in 295 (18·3%) patients assigned to colchicine and 325 (20·3%) patients assigned to placebo (HR 0·89, 0·76 to 1·05; ARR 2·0%, -0·8 to 4·7; p=0·16). The composite outcome of sepsis or infection occurred in 103 (6·4%) patients in the colchicine group and 83 (5·2%) patients in the placebo group (HR 1·24, 0·93-1·66). Non-infectious diarrhoea was more common in the colchicine group (134 [8·3%] events) than the placebo group (38 [2·4%]; HR 3·64, 2·54-5·22). INTERPRETATION: In patients undergoing major non-cardiac thoracic surgery, administration of colchicine did not significantly reduce the incidence of clinically important atrial fibrillation or MINS but increased the risk of mostly benign non-infectious diarrhoea. FUNDING: Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, Population Health Research Institute, Hamilton Health Sciences, Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong.

Lost in Translation: Failure of Preclinical Studies to Accurately Predict the Effect of Regional Analgesia on Cancer Recurrence.

The major goal of translational research is to evaluate the efficacy and effectiveness of treatments and interventions that have emerged from exhaustive preclinical evidence. In 2007, a major clinical trial was started to investigate the impact of paravertebral analgesia on breast cancer recurrence. The trial was based on preclinical evidence demonstrating that spinal anesthesia suppressed metastatic dissemination by inhibiting surgical stress, boosting the immunological response, avoiding volatile anesthetics, and reducing opioid use. However, that trial and three more recent randomized trials with a total of 4,770 patients demonstrate that regional analgesia does not improve survival outcomes after breast, lung, and abdominal cancers. An obvious question is why there was an almost complete disconnect between the copious preclinical investigations suggesting benefit and robust clinical trials showing no benefit? The answer is complex but may result from preclinical research being mechanistically driven and based on reductionist models. Both basic scientists and clinical investigators underestimated the limitations of various preclinical models, leading to the apparently incorrect hypothesis that regional anesthesia reduces cancer recurrence. This article reviews factors that contributed to the discordance between the laboratory science, suggesting that regional analgesia might reduce cancer recurrence and clinical trials showing that it does not-and what can be learned from the disconnect.

Rationale and design of the colchicine for the prevention of perioperative atrial fibrillation in patients undergoing major noncardiac thoracic surgery (COP-AF) trial.

BACKGROUND: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. METHODS AND RESULTS: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (eg, severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The 2 independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the 2 co-primary outcomes. The COP-AF main results are expected in 2023. CONCLUSIONS: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery.

Antiemetic prophylaxis with droperidol in morphine-based intravenous patient-controlled analgesia: a propensity score matched cohort study.

BACKGROUND: There are limited real-world data regarding the use of droperidol for antiemetic prophylaxis in intravenous patient-controlled analgesia (IV-PCA). This study aimed to evaluate the antiemetic benefits and sedation effects of droperidol in morphine-based IV-PCA. METHODS: Patients who underwent major surgery and used morphine-based IV-PCA at a medical center from January 2020 to November 2022 were retrospectively analyzed. The primary outcome was the rate of any postoperative nausea and/or vomiting (PONV) within 72 h after surgery. Propensity score matching was used to match patients with and without the addition of droperidol to IV-PCA infusate in a 1:1 ratio. Multivariable conditional logistic regression models were used to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: After matching, 1,104 subjects were included for analysis. The addition of droperidol to IV-PCA reduced the risk of PONV (aOR: 0.49, 95% CI: 0.35-0.67, p < 0.0001). The antiemetic effect of droperidol was significant within 36 h after surgery and attenuated thereafter. Droperidol was significantly associated with a lower risk of antiemetic uses (aOR: 0.58, 95% CI: 0.41-0.80, p = 0.0011). The rate of unintentional sedation was comparable between the patients with (9.1%) and without (7.8%; p = 0.4481) the addition of droperidol. Postoperative opioid consumption and numeric rating scale acute pain scores were similar between groups. CONCLUSIONS: The addition of droperidol to IV-PCA reduced the risk of PONV without increasing opiate consumption or influencing the level of sedation. However, additional prophylactic therapies are needed to prevent late-onset PONV.

Developing expert international consensus statements for opioid-sparing analgesia using the Delphi method.

INTRODUCTION: The management of postoperative pain in anaesthesia is evolving with a deeper understanding of associating multiple modalities and analgesic medications. However, the motivations and barriers regarding the adoption of opioid-sparing analgesia are not well known. METHODS: We designed a modified Delphi survey to explore the perspectives and opinions of expert panellists with regard to opioid-sparing multimodal analgesia. 29 anaesthetists underwent an evolving three-round questionnaire to determine the level of agreement on certain aspects of multimodal analgesia, with the last round deciding if each statement was a priority. RESULTS: The results were aggregated and a consensus, defined as achievement of over 75% on the Likert scale, was reached for five out of eight statements. The panellists agreed there was a strong body of evidence supporting opioid-sparing multimodal analgesia. However, there existed multiple barriers to widespread adoption, foremost the lack of training and education, as well as the reluctance to change existing practices. Practical issues such as cost effectiveness, increased workload, or the lack of supply of anaesthetic agents were not perceived to be as critical in preventing adoption. CONCLUSION: Thus, a focus on developing specific guidelines for multimodal analgesia and addressing gaps in education may improve the adoption of opioid-sparing analgesia.

Risk of Intraoperative Hyperthermia and Outcomes in Adults Undergoing Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is commonly used to treat peritoneal surface malignancies. We aimed to identify risk factors of intraoperative patient hyperthermia and the postoperative outcome of adults undergoing HIPEC PATIENTS AND METHODS: A retrospective, IRB approved, single center cohort study was conducted. Adults treated with cytoreductive surgery and HIPEC between 2006 and 2021 were included. The primary outcome was bladder hyperthermia during perfusion, stratified by severity and duration. Secondary outcomes were postoperative complications and recurrence-free (RFS) and overall (OS) survival. Multivariable logistic regression models were fit to estimate the effects of important covariates. RESULTS: Out of 214 patients, 114 had mild hyperthermia (≥ 38 °C) at any time, and in 73 of these it lasted for ≥ 30 min. Independent prognostic factors of mild hyperthermia ≥ 30 min were age (OR = 0.958, 95% CI 0.933-0.984), body mas index (BMI; OR = 0.959 95% CI 0.917-1.002), gender (OR = 0.199, 95% CI 0.092-0.431), and type of chemotherapy [cisplatin versus mitomycin (OR = 0.186, 95% CI 0.070-0.491; oxaliplatin versus mitomycin (OR = 0.430, 95% CI 0.163-1.139)]. Prognostic factors of moderate-to-severe hyperthermia (≥ 39 °C) at any time were perfusion duration (OR = 1.094, 95% CI 1.018-1.177) and blood transfusion (OR = 5.689, 95% CI 1.784-18.137). Intraoperative hyperthermia was not associated with increased postoperative complications but was associated with better RFS and OS. CONCLUSIONS: Our study demonstrates age, gender, BMI, and chemotherapy type to be associated with hyperthermia ≥ 38 °C for ≥ 30 min, whereas longer perfusion time and blood transfusion were associated with hyperthermia ≥ 39 °C. Mild hyperthermia at the end of perfusion is associated with better RFS and OS.

Immunological Insights into Opioid-Free Anaesthesia in Oncological Surgery: A Scoping Review.

PURPOSE OF REVIEW: The influence of opioids on outcomes after cancer surgery when used, or avoided, intraoperatively remains unclear. There is a need to conduct a scoping review to explore the wider context and provide direction for future research. The review will examine the current state of evidence in humans, with a focus on immunological biomarkers and clinically relevant cancer outcomes in trials comparing opioid-free to opioid-based general anaesthesia. RECENT FINDINGS: There is limited research on this subject area, which is mainly focused on breast cancer. The most frequently evaluated immunological parameter is the neutrophil-to-lymphocyte ratio. Cancer outcomes are mainly focused on recurrence. The central knowledge gap is understanding how the cellular effects of opioids translate into longer-term patient outcomes. The major challenge for future research is accounting for the immunomodulatory effects of a wide range of confounding factors, which have yet to be clarified.

Perioperative considerations in patients with chemotherapy-induced cognitive impairment: a narrative review.

Patients with cancer may suffer from a decline in their cognitive function after various cancer therapies, including surgery, radiation, and chemotherapy, and in some cases, this decline in cognitive function persists even years after completion of treatment. Chemobrain or chemotherapy-induced cognitive impairment, a well-established clinical syndrome, has become an increasing concern as the number of successfully treated cancer patients has increased significantly. Chemotherapy-induced cognitive impairment can originate from direct neurotoxicity, neuroinflammation, and oxidative stress, resulting in alterations in grey matter volume, white matter integrity, and brain connectivity. Surgery has been associated with exacerbating the inflammatory response associated with chemotherapy and predisposes patients to develop postoperative cognitive dysfunction. As the proportion of patients living longer after these therapies increases, the magnitude of impact and growing concern of post-treatment cognitive dysfunction in these patients has also come to the fore. We review the clinical presentation, potential mechanisms, predisposing factors, diagnostic methods, neuropsychological testing, and imaging findings of chemotherapy-induced cognitive impairment and its intersection with postoperative cognitive dysfunction.

Intraoperative lidocaine infusion in patients undergoing pancreatectomy for pancreatic cancer: a mechanistic, multicentre randomised clinical trial.

BACKGROUND: Intravenous lidocaine has been postulated to improve long-term survival after surgery for pancreatic cancer through anti-inflammatory effects, anti-tumour effects, or both. We investigated whether intraoperative lidocaine improves survival after pancreatectomy for pancreatic cancer and whether lidocaine modified the formation of neutrophil extracellular traps (NETs), high levels of which are associated with poor prognosis. METHODS: Patients undergoing pancreatectomy were randomly assigned to i.v. lidocaine (continuous intraoperative infusion of 2 mg kg-1 h-1, after 1.5 mg kg-1 bolus at induction of anaesthesia) or saline placebo. The co-primary outcomes were survival/disease-free survival 3 yr after surgery. Secondary outcomes (masked to treatment allocation) included intraoperative opioid (sufentanil) dose, postoperative complications, and circulating and tumour-associated NETs (immunofluorescence assay, enzyme-linked immune assay, or both). RESULTS: A total of 563 participants (34.6% female; median age, 64 yr) completed 3 yr of clinical follow-up. Overall, 283 participants were randomised to lidocaine infusion, and 280 participants were randomised to placebo. Infusion of lidocaine did not alter overall (hazard ratio [HR]=0.98; 95% confidence interval [CI], 0.81-1.17; P=0.79) or disease-free survival (HR=0.91; 95% CI, 0.71-1.17; P=0.44). Mean intraoperative sufentanil dose was reduced by lidocaine infusion (47.6 µg [4.6]) compared with placebo (68.4 µg [4.8]; P<0.001), but postoperative complications and length of hospital stay were similar between groups. Circulating NETs were lower after lidocaine infusion up to 3 days after surgery, but tumour-associated NETs were not altered by intraoperative treatment. CONCLUSION: In patients undergoing pancreatectomy for pancreatic cancer, intraoperative infusion of lidocaine did not improve overall or disease-free survival. Reduced formation of circulating NETs was absent in pancreatic tumour tissue. CLINICAL TRIAL REGISTRATION: NCT03245346; updated in Chi-CTR-2000035469.

Augmented reality in anesthesia, pain medicine and critical care: a narrative review.

Augmented reality (AR) is the integration of computer-generated information with the user's environment in real time. AR is used in many industries, including healthcare, where it has gained significant popularity. Recent strides in hardware and software engineering have reduced the cost of AR, while significantly improving the experience for users and developers. One of the first applications of AR technology in perioperative medicine has been in the identification of anatomical structures for regional blocks and peripheral or central vascular access. AR has also been implemented in pediatric care to reduce periprocedural anxiety. In this narrative review, we summarize the current role of AR in anesthesiology, pain medicine, and critical care.

Long-Term Survival Impact of High-Grade Complications after Liver Resection for Hepatocellular Carcinoma: A Retrospective Single-Centre Cohort Study.

Background and Objectives: Although complications after liver resection for hepatic cancer are common, the long-term impact of these complications on oncological outcomes remains unclear. This study aimed to investigate the potential effect of high-grade postoperative complications on long-term mortality and cancer recurrence after surgical resection of hepatocellular carcinoma. Materials and Methods: In a retrospective cohort study, patients undergoing curative liver resection for primary hepatocellular carcinoma between 2005 and 2016 were evaluated. The Clavien-Dindo (CD) grading system was used to classify patients into two groups of either high-grade complications (grade III or IV) or none or low-grade complications (grade 0 to II) within 30 days after surgery. The primary endpoint was all-cause mortality. Secondary endpoints were cancer-specific mortality and cancer recurrence. Weighted Cox proportional hazards regression models were used to calculate the adjusted hazard ratio (aHR) with a 95% confidence interval (CI) for the outcomes of interest. Results: A total of 1419 patients with a median follow-up time of 46.6 months were analysed. Among them, 93 (6.6%) developed high-grade complications after surgery. The most common complications were bile leakage (n = 30) in CD grade III and respiratory failure (n = 13) in CD grade IV. High-grade complications were significantly associated with all-cause mortality (aHR: 1.78, 95% CI: 1.55-2.06) and cancer-specific mortality (aHR: 1.34, 95% CI: 1.13-1.60), but not cancer recurrence (aHR: 0.92, 95% CI: 0.84-1.02). Independent influential factors for complications were sex, diabetes mellitus, clinically significant portal hypertension, oesophageal varices, multifocal cancer, intraoperative blood loss, and anaesthesia duration. Conclusions: Patients who had high-grade postoperative complications had a greater risk of long-term mortality after liver resection for hepatocellular carcinoma. Prevention of postoperative complications may serve as an effective strategy for improving long-term survival.

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer.

Morphine, a mu-opioid receptor (MOR) agonist, has been extensively used to treat advanced cancer pain. In particular, in patients with cancer metastasis, both morphine and anticancer drugs are given simultaneously. However, evidence showed that morphine might be a risk factor in promoting the tumor's malignant potential. In this study, we report that treatment with morphine could activate MOR and lead to the promotion of proliferation, migration, and invasion in HCT116 and DLD1 colorectal cancer (CRC) cells with time-concentration dependence. Moreover, morphine can also contribute to cetuximab's drug resistance, a targeted drug widely used to treat advanced CRC by inducing the activation of epidermal growth factor receptor (EGFR). The cell phenotype includes proliferation, migration, invasion, and drug resistance, which may be reversed by MOR knockdown or adding nalmefene, the MOR receptor antagonist. Receptor tyrosine kinase array analysis revealed that morphine selectively induced the transactivation of EGFR. EGFR transactivation resulted in the activation of ERK1/2 and AKT. In conclusion, morphine induces the transactivation of EGFR via MOR. It activates the downstream signal pathway AKT-MTOR and RAS-MAPK, increases proliferation, migration, and invasion, and promotes resistance to EGFR inhibitors in a CRC cell line. Furthermore, we verified that EGFR inhibition by cetuximab strongly reversed the protumoral effects of morphine in vitro and in vivo. Collectively, we provide evidence that morphine-EGFR signaling might be a promising therapeutic target for CRC patients, especially for cetuximab-resistant CRC patients.

Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu-opioid receptor.

The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and metastasis in lung cancer cell lines. The effect of MNTX on other cell lines such as head and neck squamous cell carcinoma (HNSCC) has not been investigated. We measured the expression and activity of the receptor in different HNSCC cell lines. Then, we evaluated the impact of modulating the expression MOR and the effect of MNTX on the proliferation, clonogenic activity, invasion, and migration of two HNSCC (FaDu and MDA686Tu) cell lines expressing MOR and one cell line (UMSCC47) not expressing the receptor. We also evaluated the impact of MNTX on tumor growth and metastasis formation in vivo. Activation of the receptor with [d-Ala2,N-Me-Phe4, Gly5-ol] (DAMGO) caused a significant reduction in cyclic adenosine monophosphate levels in FaDu cells. Knockdown of MOR inhibited in vitro aggressive cell behaviors on FaDu and MDA686Tu cells and correlated with a reduction in markers of epithelial-mesenchymal transition. In vitro studies showed that MNTX strongly inhibited the proliferation, clonogenic activity, invasion, and migration of FaDu and MDA686Tu cells but has no effect on UMSCC47 cells. In vivo experiments demonstrated that MNTX suppresses tumor growth in HNSCC cell tumor-bearing mice. Our studies indicate that MOR could be considered as a therapeutic target to treat HNSCC.

The Impact of Thoracic Epidural Analgesia Versus Four Quadrant Transversus Abdominis Plane Block on Quality of Recovery After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Surgery: A Single-Center, Noninferiority, Randomized, Controlled Trial.

BACKGROUND: Recovery after CRS-HIPEC influenced by several factors, including pain and opioid consumption. We hypothesized that 4Q-TAP blocks provide not inferior quality of recovery compared with TEA after CRS-HIPEC. We conducted a randomized, controlled trial to determine whether 4-quadrant transversus abdominis plane (4Q-TAP) block analgesia was noninferior to thoracic epidural (TEA) among patients who underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS HIPEC). METHODS: Patients 18 years or older who underwent a CRS-HIPEC surgery were randomly assigned to have either TEA or 4Q-TAP blocks. The primary outcome of this study was the change in quality of recovery 2 days after surgery. Secondary outcomes included quality of recovery on Days 1, 3, 5, 7, 10, and 30 postoperatively, opioid consumption, pain intensity, length of stay, and postoperative complications. Analyses were performed on a per-protocol basis. RESULTS: Sixty-eight patients were included in the analysis. The difference between 4Q-TAP and TEA in the mean QoR-15 change from surgery at postoperative Days 1, 2, and 3 was 0.80 (P = 0.004), -4.5 (P = 0.134), and 3.4 (P = 0.003), respectively. All differences through postoperative day 30 were significantly within the noninferiority boundary of -10 except at postoperative Day 2 (P = 0.134). Length of stay, opioid-related adverse events, and frequency and grade of complications were not significantly different between TEA and 4Q-TAP patients. CONCLUSIONS: Despite the significantly higher use of opioids after CRS-HIPEC in patients with 4Q-TAP blocks, their short-term quality of recovery was not inferior to those treated with TEA. Patients undergoing CRS-HIPEC can be effectively managed with 4Q-TAP blocks.

Incidence of acute kidney injury after open gynecologic surgery in an enhanced recovery after surgery pathway.

OBJECTIVE: To determine the incidence of postoperative AKI after open gynecologic surgery within ERAS, compare AKI in pre-ERAS and ERAS cohorts, and identify factors associated with AKI. METHODS: We compared postoperative AKI in patients who underwent open gynecologic surgery at one institution before and after ERAS implementation. AKI was defined as acute risk, injury, or failure by RIFLE criteria. Pre-ERAS and ERAS cohorts were matched using propensity score analysis in a 1:1 fashion using the nearest neighbor technique. Chi-squared, Fisher's Exact, and Wilcoxon rank-sum tests were used. RESULTS: Among 1334 ERAS and 191 pre-ERAS patients, postoperative AKI incidence was higher in the ERAS cohort (13.1% vs 5.8%, p = .004). In 166 matched pairs, ERAS patients had higher incidence (16.9% vs 5.4%, p < .001) and odds (OR 3.54, 95% CI 1.61-7.76) of AKI. Within ERAS, AKI was associated with older age (median age 65 vs 57, p < .001), Charlson Comorbidity Index score ≥ 3 (71.4% vs 57.9%, p < .001), and higher intraoperative estimated blood loss (400 vs 225 mL, p < .001), fluid administration (net fluid balance +1535 vs 1261 mL, p < .001), and hypotension lasting >5 min (41.7% vs 30.7%, p < .001). ERAS patients with AKI had longer hospital stays (median 4 vs 3 days, p < .001) and more readmissions (19% vs. 10%, p < .001) and grade 3+ complications (26% vs. 7%, p < .001). CONCLUSIONS: The incidence and odds of postoperative AKI was higher after gynecologic surgery within ERAS, and patients with AKI were more likely to have complications. Potential strategies to prevent postoperative AKI include perioperative fluid and blood pressure optimization.

Effect of preoperative intravenous vs oral acetaminophen on postoperative opioid consumption in an enhanced recovery after surgery (ERAS) program in patients undergoing open gynecologic oncology surgery.

OBJECTIVE: Both intravenous (IV) and oral acetaminophen provide effective opioid-sparing analgesia after surgery when used as part of a multimodal preemptive pain management strategy. The purpose of this study was to compare postoperative opioid consumption in patients undergoing open gynecologic oncology surgery who received preoperative IV vs oral acetaminophen within an enhanced recovery after surgery (ERAS) program. METHODS: Retrospective data were collected on consecutive patients undergoing open gynecologic oncology surgery from May 1, 2016 to February 28, 2018 in patients receiving either 1 g IV or oral acetaminophen preoperatively. Patients were given a preoperative multimodal analgesia regimen including acetaminophen, celecoxib, pregabalin and tramadol. The primary outcomes were morphine equivalent daily doses (MEDD) on postoperative days (POD) 0 and 1. Secondary outcomes included highest patient-reported pain score in the post-anesthesia care unit (PACU) and intraoperative MEDD. Regression models adjusted by matched pairs were fit to estimate the average treatment effect of IV vs oral acetaminophen on MEDD. RESULTS: Of 353 patients, 178 (50.4%) received IV acetaminophen and 175 (49.6%) received oral acetaminophen. When balancing across the matched samples, there was no difference in postoperative MEDD for POD 0 between the IV and oral acetaminophen groups (Beta = -1.11; 95% CI: -4.83 to 2.60; p = 0.56). On POD 1, there was no difference between the IV and oral groups (Beta = 2.24; 95% CI: -2.76 to 7.25; p = 0.38). CONCLUSIONS: There was no difference in postoperative opioid consumption between patients receiving preoperative IV or oral acetaminophen within an ERAS program for patients undergoing open gynecologic oncology surgery.

Anaesthetic depth and complications after major surgery: an international, randomised controlled trial.

BACKGROUND: An association between increasing anaesthetic depth and decreased postoperative survival has been shown in observational studies; however, evidence from randomised controlled trials is lacking. Our aim was to compare all-cause 1-year mortality in older patients having major surgery and randomly assigned to light or deep general anaesthesia. METHODS: In an international trial, we recruited patients from 73 centres in seven countries who were aged 60 years and older, with significant comorbidity, having surgery with expected duration of more than 2 h, and an anticipated hospital stay of at least 2 days. We randomly assigned patients who had increased risk of complications after major surgery to receive light general anaesthesia (bispectral index [BIS] target 50) or deep general anaesthesia (BIS target 35). Anaesthetists also nominated an appropriate range for mean arterial pressure for each patient during surgery. Patients were randomly assigned in permuted blocks by region immediately before surgery, with the patient and assessors masked to group allocation. The primary outcome was 1-year all-cause mortality. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000632897, and is closed to accrual. FINDINGS: Patients were enrolled between Dec 19, 2012, and Dec 12, 2017. Of the 18 026 patients screened as eligible, 6644 were enrolled, randomly assigned to treatment or control, and formed the intention-to-treat population (3316 in the BIS 50 group and 3328 in the BIS 35 group). The median BIS was 47·2 (IQR 43·7 to 50·5) in the BIS 50 group and 38·8 (36·3 to 42·4) in the BIS 35 group. Mean arterial pressure was 3·5 mm Hg (4%) higher (median 84·5 [IQR 78·0 to 91·3] and 81·0 [75·4 to 87·6], respectively) and volatile anaesthetic use was 0·26 minimum alveolar concentration (30%) lower (0·62 [0·52 to 0·73] and 0·88 [0·74 to 1·04], respectively) in the BIS 50 than the BIS 35 group. 1-year mortality was 6·5% (212 patients) in the BIS 50 group and 7·2% (238 patients) in the BIS 35 group (hazard ratio 0·88, 95% CI 0·73 to 1·07, absolute risk reduction 0·8%, 95% CI -0·5 to 2·0). Grade 3 adverse events occurred in 954 (29%) patients in the BIS 50 group and 909 (27%) patients in the BIS 35 group; and grade 4 adverse events in 265 (8%) and 259 (8%) patients, respectively. The most commonly reported adverse events were infections, vascular disorders, cardiac disorders, and neoplasms. INTERPRETATION: Among patients at increased risk of complications after major surgery, light general anaesthesia was not associated with lower 1-year mortality than deep general anaesthesia. Our trial defines a broad range of anaesthetic depth over which anaesthesia may be safely delivered when titrating volatile anaesthetic concentrations using a processed electroencephalographic monitor. FUNDING: Health Research Council of New Zealand; National Health and Medical Research Council, Australia; Research Grant Council of Hong Kong; National Institute for Health and Research, UK; and National Institutes of Health, USA.

Effect of reversal of deep neuromuscular block with sugammadex or moderate block by neostigmine on shoulder pain in elderly patients undergoing robotic prostatectomy.

BACKGROUND: For some laparoscopic procedures, deep neuromuscular block has been shown to facilitate lower insufflation pressures and lower patient pain scores, and enhance postoperative recovery. We investigated the impact of deep neuromuscular block and its reversal on postoperative shoulder pain and outcomes after robotic prostate surgery. METHODS: Elderly men undergoing robotic prostatectomy were randomised to deep neuromuscular block (target post-tetanic twitch of 1-2 at the facial nerve) with sugammadex reversal or moderate neuromuscular block (target 1-2 train-of-four ratio) with neostigmine reversal. The primary endpoint was postoperative shoulder pain. The secondary endpoints included intraoperative insufflation pressure, surgical rating score, incidence of residual neuromuscular block, and postoperative recovery. RESULTS: A total of 50 subjects for each treatment arm were included in the analysis. The degree of neuromuscular block had no effect on the incidence of shoulder pain (deep block group 12% vs moderate block group 10%; P=1.0) or average insufflation pressure (median [inter-quartile range]) (13.3 [12.5-13.6] mm Hg vs 13.3 [11.7-14] mm Hg, P=0.86). After surgery, the deep block group had a higher normalised train-of-four ratio (0.98 [0.79-1.11] vs 0.85 [0.74-1.00]; P=0.008). The presence of postoperative shoulder pain was associated with higher BMI (31.8 [28-33.9] kg m-2vs 28 [24.8-31.1] kg m-2; P=0.036) and longer insufflation time (186 [156-257] min vs 154 [126-198] min; P=0.028). CONCLUSIONS: The use of deep neuromuscular block during surgery does not decrease postoperative shoulder pain or enhance recovery after robotic prostatectomy. CLINICAL TRIAL REGISTRATION: NCT03210376.

Increased mu-opioid receptor expression is associated with reduced disease-free and overall survival in laryngeal squamous cell carcinoma.

BACKGROUND: Expression of the mu-opioid receptor (MOR) is associated with poor long-term outcomes in various types of cancer. The association between MOR expression and clinical outcomes in laryngeal squamous cell carcinoma (LSCC) is not clear. METHODS: This retrospective study included patients who underwent laryngectomy for LSCC. The expression pattern of the MOR protein and OPRM1 gene in tumours and corresponding adjacent non-carcinoma specimens was measured. Propensity score matching was used to minimise bias. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were intraoperative sufentanil consumption, grade of surgical complications according to the Clavien-Dindo classification, and hospital length of stay. RESULTS: A total of 207 LSCC patients were enrolled. After propensity score matching, there was a significant difference in DFS between groups at 1, 3, and 5 yr (60.2% vs 81.2%, P=0.019; 39.4% vs 50.2%, P=0.026; 37.5% vs 42.5%, P=0.023, respectively) in patients with high MOR expression. The OS rates at 1, 3, and 5 yr were significantly lower in the high MOR expression group (81.2% vs 93.2%, P=0.027; 57.7% vs 78.3%, P<0.001; 42.5% vs 60.3%, P<0.001, respectively). The multivariate analysis indicated that high MOR expression was associated with worse DFS and OS (hazard ratio: 1.52, 95% confidence interval: 1.07, 2.25, P=0.034; hazard ratio: 1.42, 95% confidence interval: 1.17, 2.34, P=0.032). CONCLUSION: High MOR expression may be associated with poor prognosis in patients with LSCC, suggesting that MOR could be used as a valuable molecular biomarker to predict prognosis of LSCC patients.

Association between intraoperative intravenous lidocaine infusion and survival in patients undergoing pancreatectomy for pancreatic cancer: a retrospective study.

BACKGROUND: Intravenous lidocaine has been shown to reduce opioid consumption and is associated with favourable outcomes after surgery. In this study, we explored whether intraoperative lidocaine reduces intraoperative opioid use and length of stay (LOS) and improves long-term survival after pancreatic cancer surgery. METHODS: This retrospective study included 2239 patients who underwent pancreatectomy from January 2014 to December 2017. The patients were divided into non-lidocaine and lidocaine (bolus injection of 1.5 mg kg-1 at the induction of anaesthesia followed by a continuous infusion of 2 mg kg-1 h-1 intraoperatively) groups. The overall use of postoperative rescue analgesia and LOS were recorded. Propensity score matching was used to minimise bias, and disease-free survival and overall survival were compared between the two groups. RESULTS: After propensity score matching, patient characteristics were not significantly different between groups. Intraoperative sufentanil consumption and use of postoperative rescue analgesia in the lidocaine group were significantly lower than those in the non-lidocaine group. The LOS was similar between groups. There was no significant difference in disease-free survival between groups (hazard ratio [HR]=0.913; 95% confidence interval [CI], 0.821-1.612; P=0.316). The overall survival rates at 1 and 3 yr were significantly higher in the lidocaine group than in the non-lidocaine group (68.0% vs 62.6%, P<0.001; 34.1% vs 27.2%, P=0.011). The multivariable analysis indicated that intraoperative lidocaine infusion was associated with a prolonged overall survival (HR=0.616; 95% CI, 0.290-0.783; P=0.013). CONCLUSION: Intraoperative intravenous lidocaine infusion was associated with improved overall survival in patients undergoing pancreatectomy.