Perioperative ADministration of Dexamethasone and blood glucose concentrations in patients undergoing elective non-cardiac surgery – the randomised controlled PADDAG trial

BACKGROUND The hyperglycaemic effect of dexamethasone in diabetic and nondiabetic patients in the peri-operative period is unknown. OBJECTIVE To assess the effect of a single dose of intra-operative dexamethasone on peri-operative blood glucose. DESIGN Multicentre, stratified, randomised trial. SETTING University hospitals in Australia and Hong Kong. PATIENTS A total of 302 adults scheduled for elective, noncardiac and nonobstetric surgical procedures under general anaesthesia, stratified by diabetes mellitus status, were randomised to receive placebo, 4 or 8 mg dexamethasone administered intravenously after induction of anaesthesia. MAIN OUTCOME MEASURES Maximum blood glucose within 24 h of surgery, and the interaction between glycated haemoglobin (HbA1c) and dexamethasone were the primary and secondary outcomes. RESULTS The median [IQR] baseline blood glucose in the nondiabetes stratum in the placebo (n=81), 4 mg (n=81) and 8 mg dexamethasone (n=77) trial arms were respectively 5.3 [4.6 to 5.8], 5.0 [4.7 to 5.4] and 5.0 [4.2 to 5.9] mmol l−1. In the diabetes stratum these values were 6.6 [6.0 to 8.3]; (n=22), 6.1 [5.5 to 10.4]; (n=22) and 6.7 [5.6 to 8.3]; (n=19) mmol l−1. The median [IQR] maximum peri-operative blood glucose values in the nondiabetes stratum were 6.0 [5.3 to 6.8], 6.3 [5.5 to 7.3] and 6.3 [5.8 to 7.4] mmol l−1 in the control, dexamethasone 4 mg and dexamethasone 8 mg arms, respectively. In the diabetes stratum these values were 10.3 [8.1 to 12.4], 12.6 [10.3 to 18.3] and 13.6 [11.2 to 20.1] mmol l−1. There was a significant interaction between pre-operative HbA1c value and 8 mg dexamethasone: every 1% increment in HbA1c produced a 4.0 mmol l−1 elevation in maximal peri-operative glucose concentration. CONCLUSION Dexamethasone 4 mg or 8 mg did not induce greater hyperglycaemia compared with placebo for nondiabetic and well controlled diabetic patients. Maximal peri-operative blood glucose concentrations in patients with diabetes were related to baseline HbA1c values in a concentration-dependent fashion after 8 mg of dexamethasone

Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX)

Background: In a post hoc analysis of the ENIGMA-II trial, we sought to determine whether intraoperative dexamethasone was associated with adverse safety outcomes.Methods: Inverse probability weighting with estimated propensity scores was used to determine the association of dexamethasone administration with postoperative infection, quality of recovery, and adverse safety outcomes for 5499 of the 7112 non-cardiac surgery subjects enrolled in ENIGMA-II.Results: Dexamethasone was administered to 2178 (40%) of the 5499 subjects included in this analysis and was not associated with wound infection [189 (8.7%) vs 275 (8.3%); propensity score-adjusted relative risk (RR) 1.10; 95% confidence interval (CI) 0.89-1.34; P=0.38], severe postoperative nausea and vomiting on day 1 [242 (7.3%) vs 189 (8.7%); propensity score-adjusted RR 1.06; 95% CI 0.86-1.30; P=0.59], quality of recovery score [median 14, interquartile range (IQR) 12-15, vs median 14, IQR 12-16, P=0.10), length of stay in the postanaesthesia care unit [propensity score-adjusted median (IQR) 2.0 (1.3, 2.9) vs 1.9 (1.3, 3.1), P=0.60], or the primary outcome of the main trial. Dexamethasone administration was associated with a decrease in fever on days 1-3 [182 (8.4%) vs 488 (14.7%); RR 0.61; 95% CI 0.5-0.74; PConclusion: Dexamethasone administration to high-risk non-cardiac surgical patients did not increase the risk of postoperative wound infection or other adverse events up to day 30, and appears to be safe in patients either with or without diabetes mellitus. </p

Dexamethasone and surgical-site infection

BACKGROUND The glucocorticoid dexamethasone prevents nausea and vomiting after surgery, but there is concern that it may increase the risk of surgical-site infection. METHODS In this pragmatic, international, noninferiority trial, we randomly assigned 8880 adult patients who were undergoing nonurgent, noncardiac surgery of at least 2 hours’ duration, with a skin incision length longer than 5 cm and a postoperative overnight hospital stay, to receive 8 mg of intravenous dexamethasone or matching placebo while under anesthesia. Randomization was stratified according to diabetes status and trial center. The primary outcome was surgical-site infection within 30 days after surgery. The prespecified noninferiority margin was 2.0 percentage points. RESULTS A total of 8725 participants were included in the modified intention-to-treat population (4372 in the dexamethasone group and 4353 in the placebo group), of whom 13.2% (576 in the dexamethasone group and 572 in the placebo group) had diabetes mellitus. Of the 8678 patients included in the primary analysis, surgical-site infection occurred in 8.1% (354 of 4350 patients) assigned to dexamethasone and in 9.1% (394 of 4328) assigned to placebo (risk difference adjusted for diabetes status, −0.9 percentage points; 95.6% confidence interval [CI], −2.1 to 0.3; P<0.001 for noninferiority). The results for superficial, deep, and organ-space surgical-site infections and in patients with diabetes were similar to those of the primary analysis. Postoperative nausea and vomiting in the first 24 hours after surgery occurred in 42.2% of patients in the dexamethasone group and in 53.9% in the placebo group (risk ratio, 0.78; 95% CI, 0.75 to 0.82). Hyperglycemic events in patients without diabetes occurred in 22 of 3787 (0.6%) in the dexamethasone group and in 6 of 3776 (0.2%) in the placebo group. CONCLUSIONS Dexamethasone was noninferior to placebo with respect to the incidence of surgical-site infection within 30 days after nonurgent, noncardiac surgery. (Funded by the Australian National Health and Medical Research Council and others; PADDI Australian New Zealand Clinical Trials Registry number, ACTRN12614001226695. opens in new tab.

Systematic review and consensus definitions for the Standardised Endpoints in Perioperative Medicine initiative: patient-centred outcomes

BACKGROUND: Patient-centred outcomes are increasingly used in perioperative clinical trials. The Standardised Endpoints in Perioperative Medicine (StEP) initiative aims to define which measures should be used in future research to facilitate comparison between studies and to enable robust evidence synthesis. METHODS: A systematic review was conducted to create a longlist of patient satisfaction, health-related quality of life, functional status, patient well-being, and life-impact measures for consideration. A three-stage Delphi consensus process involving 89 international experts was then conducted in order to refine this list into a set of recommendations. RESULTS: The literature review yielded six patient-satisfaction measures, seven generic health-related quality-of-life measures, eight patient well-being measures, five functional-status measures, and five life-impact measures for consideration. The Delphi response rates were 92%, 87%, and 100% for Rounds 1, 2, and 3, respectively. Three additional measures were added during the Delphi process as a result of contributions from the StEP group members. Firm recommendations have been made about one health-related quality-of-life measure (EuroQol 5 Dimension, five-level version with visual analogue scale), one functional-status measure (WHO Disability Assessment Schedule version 2.0, 12-question version), and one life-impact measure (days alive and out of hospital at 30 days after surgery). Recommendations with caveats have been made about the Bauer patient-satisfaction measure and two life-impact measures (days alive and out of hospital at 1 yr after surgery, and discharge destination). CONCLUSIONS: Several patient-centred outcome measures have been recommended for use in future perioperative studies. We suggest that every clinical study should consider using at least one patient-centred outcome within a suite of endpoints

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality.Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.Maura Marcucci, Thomas W. Painter, David Conen, Kate Leslie, Vladimir V. Lomivorotov, Daniel Sessler ... et al

Tranexamic Acid in Patients Undergoing Noncardiac Surgery

BACKGROUND Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established.P.J. Devereaux, M. Marcucci, T.W. Painter, D. Conen, V. Lomivorotov, D.I. Sessler, M.T.V. Chan, F.K. Borges, M.J. Martínez, Zapata, C.Y. Wang, D. Xavier, S.N. Ofori, M.K. Wang, S. Efremov, G. Landoni, Y.V. Kleinlugtenbelt, W. Szczeklik, D. Schmartz, A.X. Garg, T.G. Short, M. Wittmann, C.S. Meyhoff, M. Amir, D. Torres, A. Patel, E. Duceppe, K. Ruetzler, J.L. Parlow, V. Tandon, E. Fleischmann, C.A. Polanczyk, A. Lamy, S.V. Astrakov, M. Rao, W.K.K. Wu, K. Bhatt, M. de Nadal, V.V. Likhvantsev, P. Paniagua, H.J. Aguado, R.P. Whitlock, M.H. McGillion, M. Prystajecky, J. Vincent, J. Eikelboom, I. Copland, K. Balasubramanian, A. Turan, S.I. Bangdiwala, D. Stillo, P.L. Gross, T. Cafaro, P. Alfonsi, P.S. Roshanov, E.P. Belley, Côté, J. Spence, T. Richards, T. VanHelder, W. McIntyre, G. Guyatt, S. Yusuf, and K. Leslie, for the POISE-, Investigator

Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery : An International Randomized Controlled Trial

Background: Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. Objective: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. Design: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723) Setting: 110 hospitals in 22 countries. Patients: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. Intervention: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80mm Hg or greater; before and for 2 days after surgery, renin– angiotensin–aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60mm Hg or greater; all antihypertensive medications were continued before and after surgery. Measurements: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. Results: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P =0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. Limitation: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. Conclusion: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications.Maura Marcucci, Thomas W. Painter, David Conen, Vladimir Lomivorotov, Daniel I. Sessler, Matthew T.V. Chan, Flavia K. Borges, Kate Leslie, Emmanuelle Duceppe, María Jose Martínez-Zapata, Chew Yin Wang, Denis Xavier, Sandra N. Ofori, Michael Ke Wang, Sergey Efremov, Giovanni Landoni, Ydo V. Kleinlugtenbelt, Wojciech Szczeklik, Denis Schmartz, Amit X. Garg, Timothy G. Short, Maria Wittmann, Christian S. Meyhoff, Mohammed Amir, David Torres, Ameen Patel, Kurt Ruetzler, Joel L. Parlow, Vikas Tandon, Edith Fleischmann, Carisi A. Polanczyk, Andre Lamy, Raja Jayaram, Sergey V. Astrakov, William Ka Kei Wu, Chao Chia Cheong, Sabry Ayad, Mikhail Kirov, Miriam de Nadal, Valery V. Likhvantsev, Pilar Paniagua, Hector J. Aguado, Kamal Maheshwari, Richard P. Whitlock, Michael H. McGillion, Jessica Vincent, Ingrid Copland, Kumar Balasubramanian, Bruce M. Biccard, Sadeesh Srinathan, Samandar Ismoilov, Shirley Pettit, David Stillo, Andrea Kurz, Emilie P. Belley-Côte, Jessica Spence, William F. McIntyre, Shrikant I. Bangdiwala, Gordon Guyatt, Salim Yusuf, and P.J. Devereaux, on behalf of the POISE-3 Trial Investigators and Study Group

Targeted genotyping identifies susceptibility locus in brain-derived neurotrophic factor gene for chronic postsurgical pain.

BACKGROUND: The purpose of this study was to evaluate the association between single-nucleotide polymorphisms and chronic postsurgical pain. METHODS: Using GoldenGate genotyping assays, we genotyped 638 polymorphisms within 54 pain-related genes in 1,152 surgical patients who were enrolled in our Persistent Pain after Surgery Study. Patients were contacted by phone to determine whether they had chronic postsurgical pain at 12 months. Polymorphisms identified were validated in a matched cohort of 103 patients with chronic postsurgical pain and 103 patients who were pain free. The functions of targeted polymorphisms were tested in an experimental plantar incisional nociception model using knock-in mice. RESULTS: At 12 months after surgery, 246 (21.4%) patients reported chronic postsurgical pain. Forty-two polymorphisms were found to be associated with chronic postsurgical pain, 19 decreased the risk of pain, and 23 increased the risk of pain. Patients carrying allele A of rs6265 polymorphism in brain-derived neurotrophic factor (BDNF) had a lower risk of chronic postsurgical pain in the discovery and validation cohorts, with an adjusted odds ratio (95% CI) of 0.62 (0.43 to 0.90) and 0.57 (0.39 to 0.85), respectively. Age less than 65 yr, male sex, and prior history of pain syndrome were associated with an increased risk of pain. Genetic polymorphisms had higher population attributable risk (7.36 to 11.7%) compared with clinical risk factors (2.90 to 5.93%). Importantly, rs6265 is a substitution of valine by methionine at amino acid residue 66 (Val66Met) and was associated with less mechanical allodynia in BDNF mice compared with BDNF group after plantar incision. CONCLUSIONS: This study demonstrated that genetic variation of BDNF is associated with an increased risk of chronic postsurgical pain