key: cord-0707881-401irqth
authors: Asehnoune, Karim; Le Moal, Charlene; Lebuffe, Gilles; Le Penndu, Marguerite; Josse, Nolwen Chatel; Boisson, Matthieu; Lescot, Thomas; Faucher, Marion; Jaber, Samir; Godet, Thomas; Leone, Marc; Motamed, Cyrus; David, Jean Stephane; Cinotti, Raphael; El Amine, Younes; Liutkus, Darius; Garot, Matthias; Marc, Antoine; Le Corre, Anne; Thomasseau, Alexandre; Jobert, Alexandra; Flet, Laurent; Feuillet, Fanny; Pere, Morgane; Futier, Emmanuel; Roquilly, Antoine; Oudot, Mathieu; Rimmelé, Thomas; Molliex, Serge; Huet, Olivier; Minville, Vincent; Dureuil, Bertrand; Capron, Florian; Plaud, Benoit; Lasocki, Sigismond; Le Maguet, Pascale; Beloeil, Hélène
title: Effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery: multicentre, double blind, randomised controlled trial
date: 2021-06-02
journal: BMJ
DOI: 10.1136/bmj.n1162
sha: 327a8770d7b42e81436bbae7a2f62a210b27601e
doc_id: 707881
cord_uid: 401irqth

OBJECTIVE: To assess the effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery. DESIGN: Phase III, randomised, double blind, placebo controlled trial. SETTING: 34 centres in France, December 2017 to March 2019. PARTICIPANTS: 1222 adults (>50 years) requiring major non-cardiac surgery with an expected duration of more than 90 minutes. The anticipated time frame for recruitment was 24 months. INTERVENTIONS: Participants were randomised to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Randomisation was stratified on the two prespecified criteria of cancer and thoracic procedure. MAIN OUTCOMES MEASURES: The primary outcome was a composite of postoperative complications or all cause mortality within 14 days after surgery, assessed in the modified intention-to-treat population (at least one treatment administered). RESULTS: Of the 1222 participants who underwent randomisation, 1184 (96.9%) were included in the modified intention-to-treat population. 14 days after surgery, 101 of 595 participants (17.0%) in the dexamethasone group and 117 of 589 (19.9%) in the placebo group had complications or died (adjusted odds ratio 0.81, 95% confidence interval 0.60 to 1.08; P=0.15). In the stratum of participants who underwent non-thoracic surgery (n=1038), the primary outcome occurred in 69 of 520 participants (13.3%) in the dexamethasone group and 93 of 518 (18%) in the placebo group (adjusted odds ratio 0.70, 0.50 to 0.99). Adverse events were reported in 288 of 613 participants (47.0%) in the dexamethasone group and 296 of 609 (48.6%) in the placebo group (P=0.46). CONCLUSIONS: Dexamethasone was not found to significantly reduce the incidence of complications and death in patients 14 days after major non-cardiac surgery. The 95% confidence interval for the main result was, however, wide and suggests the possibility of important clinical effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03218553.

Center-specific estimates of the odds ratio of the primary outcome. The size of the square representing the odds ratio reflects the relative numbers in each subgroup and horizontal bars represent 95% confidence intervals. 

The PACMAN Trial

Blinding was ensured thanks to identical-appearing investigational medicinal products (IMPs). A pretrial evaluation of the identity of appearance of the two compared treatments was conducted by a committee of experts.

Dexamethasone phosphate 20 mg/5 mL vials (Mylan, Saint-Priest, France) and matching placebo (sodium chloride 0.9%/5 mL vials, Chaix et du Marais, Paris, France) were supplied in similar plain glass vials. Both were 5 mL sterile, clear, colorless solution for IV injection.

First, dexamethasone and placebo vials labels were removed on separate days. An ampule breaker was fitted on each vial, and then it was labeled with the allocated medication kit number (see images below: a labelled dexamethasone or placebo vial and a specimen of label).

Second, active drug on the one hand and matching placebo on the other hand were packed in 4-vial kits, then labelled with the matching allocated kit number. So the IMPs were identical in appearance, packaging, and labeling. Both vials and kits labelling complied with the regulatory requirements. All this process was performed by Nantes University Hospital' Pharmacy Department (Nantes, France). 

Primary outcome: Composite outcome (all-cause mortality and major postoperative complications) within 14 days after surgery, at least one item among the following:

• Postoperative sepsis, severe sepsis, septic shock • Postoperative pulmonary complication (postoperative pneumonia, need for invasive ventilation and/or noninvasive ventilation for respiratory failure)

• All-cause mortality

All definitions are assessed according to previously defined criteria:

SIRS: if at least 2 of the following 4 criteria are present:

1. Core temperature >38°C or <36°C. (Core temperature is rectal or tympanic). If oral, inguinal or axillary temperatures are used, add 0.5°C to the measured value. The most deranged value recorded must be used.

2. Heart rate >90 beats/minute. If patient had an atrial arrhythmia, record the ventricular rate. If patients have a known medical condition or are receiving treatment that would prevent tachycardia (for example, heart block or beta blockers), they must meet two of the remaining three SIRS criteria. The most deranged value recorded must be used.

3. Respiratory rate > 20 breaths per minute or a PaCO2 <4.3 kPa (32 mmHg) or mechanical ventilation for an acute process. The most deranged respiratory rate or PaCO2 recorded must be used. 

Criteria for defining nosocomial pneumonia

Participants in the National Veterans Affairs. Surgical Quality Improvement Program. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery