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

Effects of Perioperative Administration of Dexamethasone on Postoperative Complications and Mortality After Non-cardiac Major Surgery : a Randomized, Multicentre, Double Blind, Study

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

Study Overview

• Status: Completed
• Conditions: Major Non-cardiac Surgery
• Intervention / Treatment: Drug: Dexamethasone; Drug: Placebos

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.

• Study Type: Interventional
• Enrollment (Actual): 1222
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France, 49933
    • CHU Angers
  • Brest, France, 29609
    • CHU La Cavale Blanche
  • Clermont Ferrand, France, 63000
    • Hôpital Estaing, CHU de Clermont Ferrand
  • Clichy, France, 92110
    • Hôpital Beaujon
  • La Roche-sur-Yon, France, 85000
    • CHD Vendee
  • Le Mans, France, 72037
    • Centre Hospitalier du Mans
  • Lille, France, 59037
    • Hopital Claude Huriez
  • Lyon, France, 69003
    • Hopital Edouard Herriot
  • Marseille, France, 13009
    • Institut Paoli Calmettes
  • Marseille, France, 13385
    • Hôpital Timone
  • Marseille, France, 13975
    • Hôpital Nord
  • Montpellier, France, 34295
    • Hopital Saint-Eloi
  • Nantes, France, 44000
    • Clinique Jules Verne
  • Nantes, France, 44000
    • Le Confluent
  • Nantes, France, 44093
    • Hotel Dieu Nantes
  • Nantes, France, 44093
    • Hopital Laennec
  • Nantes, France, 44805
    • C.R.L.C.C. Nantes Atlantique
  • Paris, France, 75000
    • Hôpital Saint Antoine
  • Paris, France, 75475
    • Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand Widal
  • Pierre-Bénite, France, 69310
    • CHU Lyon Sud
  • Poitiers, France, 86021
    • Chu de Poitiers
  • Quimper, France, 29107
    • CH Quimper
  • Rennes, France, 35033
    • Hôpital Pontchaillou
  • Rouen, France, 76031
    • CHU de ROUEN
  • Saint-Étienne, France, 42055
    • Chu Saint Etienne
  • Strasbourg, France, 67098
    • Nouvel Hôpital Civil
  • Toulouse, France, 31059
    • CHU de Toulouse
  • Valenciennes, France, 59300
    • Ch Valenciennes
  • Villejuif, France, 94805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dexamethasone; Standard cares plus postoperative administrations of glucocorticoid	Drug: 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
PLACEBO_COMPARATOR: placebo; Standard cares plus postoperative administrations of placebo	Drug: Placebos; placebo : first infusion at the end of the surgical procedure, second 24 hours after the surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Composite outcome at least one item among the following:-Postoperative sepsis, severe sepsis, septic shock-Postoperative pulmonary complication: pneumonia, need for invasive and/or noninvasive ventilation for respiratory failure-All-cause mortality	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause mortality		28 days
ICU length of stay		28 days
Hospital free days		28 days
Rate of patients with post operative sepsis		28 days
Postoperative intubation rate for respiratory failure	Postoperative respiratory failure requiring invasive ventilation	28 days
Rate of patients with postoperative respiratory failure requiring non-invasive ventilation		28 days
Surgical complications	The Clavien-Dindo classification	28 days
Duration of hospitalization		28 days
Rate of unplanned hospitalization in intensive care unit		28 days
Rate of patients developing postoperative organ failures		28 days
Blood level of marker of inflammation (C Reactive protein)		28 days
Delayed healing defined as non hermetic scar		28 days
Rate of patients with Gastric ulcer		28 days
Rate of patients with Digestive bleeding		28 days
Rate of patients with Anastomotic leakage		28 days
Dose of insulin		3 days
Rate of patients with Hypokaliemia (< 4 mmol/l)		28 days
Rate of patients with Dysnatremia (<139 mmol/l or > 145 mmol/l)		28 days
Rate of patients with Hypocalcemia (<2.2 mmol/l)		28 days
Rate of patients with Cardiac events (Atrial fibrillation / cardiac flutter, Acute coronary syndrome or Cardiac failure)		28 days

Collaborators and Investigators

• Sponsor: Nantes University Hospital

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 13, 2017
• Primary Completion (ACTUAL): April 16, 2019
• Study Completion (ACTUAL): April 16, 2019

Study Registration Dates

• First Submitted: July 10, 2017
• First Submitted That Met QC Criteria: July 12, 2017
• First Posted (ACTUAL): July 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 1, 2020
• Last Update Submitted That Met QC Criteria: May 28, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: RC17_0029

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No