Effects of Perioperative Administration of Dexamethasone on Postoperative Complications and Mortality After Non-cardiac Major Surgery

NCT ID: NCT03218553

Last Updated: 2020-06-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1222 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-13
• Study Completion Date: 2019-04-16

Brief Summary

Postoperative complications are major healthcare problems and are associated with a reduced short-term and long-term survival after surgery. Major surgery is associated with a predictable and usually transient Systemic Inflammatory Response (SIRS), depending on the magnitude of the surgical trauma. An excessive SIRS syndrome participates to the development of postoperative organ dysfunction, infection and mortality. Corticosteroids may decrease the postsurgical SIRS in cardiac surgery: in a large multicenter randomized trial, a single intravenous administration of high-dose dexamethasone did not reduce the incidence of a composite endpoint of adverse events but was associated with a reduced incidence of postoperative pulmonary complications and infections and with a reduction in hospital stay. However, a similar study, recently published in the Lancet was negative. Evidences from one meta-analysis, including 11 studies of moderate quality (439 patients in total), suggest that intraoperative administration of corticosteroids during major abdominal surgery decreases postoperative complications, including infectious complications, without significant risk of anastomotic leakage. At present, no large randomized controlled trial has been performed in patients undergoing major non-cardiac surgery. In acute medicine, several lines of evidence have shown that low to moderate doses of corticosteroids decrease the excessive inflammatory response, without inducing immuno suppression. However, despite the widespread use of corticosteroids to reduce postoperative nausea and vomiting and to improve analgesia, concerns continue to be raised about their safety, especially regarding an increased risk of postoperative infection.

We hypothesize that the perioperative administration of glucocorticoids would reduce postoperative morbidity after major non-cardiac surgery through dampening of the inflammatory response. Given the number of surgical patients for whom the question applies, the study is of significant clinical importance

Detailed Description

Background :

Postoperative complications are major healthcare problems and are associated with a reduced short-term and long-term survival after surgery. Corticosteroids may decrease the postsurgical SIRS in cardiac surgery, but this treatment is not recommended yet. The aim of the current study is to assess the efficiency and the safety of dexamethasone to prevent on postoperative complications.

Methods :

The PACMAN trial is a multicenter, randomized, controlled, double-blind, two-arms study. 1222 patients undergoing major surgery (duration >90 minutes and one or more risk factor of postoperative complication) are randomized to dexamethasone (0.2mg/kg at the end of the surgery and at day1) or to placebo. The primary outcome is a composite outcome of major postoperative complication during 14 days after the surgery.

Analyzes will be conducted, first, on data from the intention-to-treat (ITT) population, second, in the modified intention-to-treat (mITT) population as well as in the per-protocol population. All statistical analyzes will take into account stratified randomization (cancer and type of surgery) and will be adjusted on the center as random effect as.

Discussion :

The PACMAN trial is the first randomized controlled trial powered to investigate whether perioperative administration of dexamethasone in high risk patients improve outcomes.

Conditions

Major Non-cardiac Surgery

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Dexamethasone

Standard cares plus postoperative administrations of glucocorticoid

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Dexamethasone : first dose : 0,2mg.kg-1 at the end of the surgical procedure, second dose (0,2 mg.kg-1) 24 hours after the surgery

placebo

Standard cares plus postoperative administrations of placebo

Group Type: PLACEBO_COMPARATOR

Placebos

Intervention Type: DRUG

placebo : first infusion at the end of the surgical procedure, second 24 hours after the surgery

Interventions

Dexamethasone

Dexamethasone : first dose : 0,2mg.kg-1 at the end of the surgical procedure, second dose (0,2 mg.kg-1) 24 hours after the surgery

Intervention Type: DRUG

Placebos

placebo : first infusion at the end of the surgical procedure, second 24 hours after the surgery

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Major surgery (> 90 minutes and realized under general anesthesia) of the abdomen, pelvis, thorax, face/neck, vascular surgery in a patient older than 65 years Or Major surgery (> 90 minutes and realized under general anesthesia) of the abdomen, pelvis, thorax, face/neck, vascular surgery in a patient older than 50 years and presenting one of the following criteria

• Presence of a defined risk factor for cardiac or respiratory disease (exercise tolerance equivalent to 6 metabolic equivalents or less)
• Medical history of stroke
• Moderate to severe renal impairment (clearance of creatinine ≤ 30 mll/L)
• Active smoking
• Averaged observed blood losses over 500 ml
• Emergency surgery

Exclusion Criteria

• Pregnant women, Minors, Adults under guardianship or trusteeship
• Treatment with systemic corticosteroids at a dose > 5 mg.day-1 of equivalent prednisolone in the previous 3 months
• Patients with chronic renal failure (clearance of creatinine < 10 ml/min)
• Patients for which death is deemed imminent and inevitable or patients with an underlying disease process with a life expectancy of less than 1 month
• Patient with preoperative shock (defined by the need for vasoactive drugs before surgery)
• Acute Pulmonary edema in the last 7 days
• Active bacterial or viral infection
• Allergy to the intravenous formulation of dexamethasone
• Uncontrolled psychotic disorder (acute or chronical)

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Nantes University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

CHU Angers

Angers, , France

CHU La Cavale Blanche

Brest, , France

Hôpital Estaing, CHU de Clermont Ferrand

Clermont-Ferrand, , France

Hôpital Beaujon

Clichy, , France

CHD Vendée

La Roche-sur-Yon, , France

Centre Hospitalier Du Mans

Le Mans, , France

Hôpital Claude Huriez

Lille, , France

Hopital Edouard Herriot

Lyon, , France

Institut Paoli Calmettes

Marseille, , France

Hôpital Timone

Marseille, , France

Hôpital Nord

Marseille, , France

Hôpital Saint-Eloi

Montpellier, , France

Clinique Jules Verne

Nantes, , France

Le Confluent

Nantes, , France

Hotel Dieu Nantes

Nantes, , France

Hôpital Laennec

Nantes, , France

C.R.L.C.C. Nantes Atlantique

Nantes, , France

Hôpital Saint Antoine

Paris, , France

Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand Widal

Paris, , France

CHU Lyon Sud

Pierre-Bénite, , France

CHU de Poitiers

Poitiers, , France

Ch Quimper

Quimper, , France

Hôpital Pontchaillou

Rennes, , France

CHU de Rouen

Rouen, , France

CHU Saint Etienne

Saint-Etienne, , France

Nouvel Hôpital Civil

Strasbourg, , France

CHU de Toulouse

Toulouse, , France

CH Valenciennes

Valenciennes, , France

Institut Gustave Roussy

Villejuif, , France

Countries

France

References

Asehnoune K, Le Moal C, Lebuffe G, Le Penndu M, Josse NC, Boisson M, Lescot T, Faucher M, Jaber S, Godet T, Leone M, Motamed C, David JS, Cinotti R, El Amine Y, Liutkus D, Garot M, Marc A, Le Corre A, Thomasseau A, Jobert A, Flet L, Feuillet F, Pere M, Futier E, Roquilly A; PACMAN study group. Effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery: multicentre, double blind, randomised controlled trial. BMJ. 2021 Jun 2;373:n1162. doi: 10.1136/bmj.n1162.

Reference Type: DERIVED

PMID: 34078591 (View on PubMed)

Asehnoune K, Futier E, Feuillet F, Roquilly A; PACMAN group. PACMAN trial protocol, Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac major surgery: a randomised, multicentre, double-blind, superiority study. BMJ Open. 2019 Mar 23;9(3):e021262. doi: 10.1136/bmjopen-2017-021262.

Reference Type: DERIVED

PMID: 30904834 (View on PubMed)

Other Identifiers

RC17_0029

Identifier Type: -

Identifier Source: org_study_id