Clinical trial NCT03218553: Effects of Perioperative Administration of Dexamethasone on Postoperative Complications and Mortality After Non-cardiac Major Surgery
Official title: Effects of Perioperative Administration of Dexamethasone on Postoperative Complications and Mortality After Non-cardiac Major Surgery : a Randomized, Multicentre, Double Blind, Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Major Non-cardiac Surgery
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2017-07-14
Enrollment: 1222
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: 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
timeFrame: 14 days
Secondary outcomes:
measure: All cause mortality
timeFrame: 28 days
measure: Hospital free days
timeFrame: 28 days
measure: Rate of patients with post operative sepsis
timeFrame: 28 days
measure: Postoperative intubation rate for respiratory failure
timeFrame: 28 days
measure: Rate of patients with postoperative respiratory failure requiring non-invasive ventilation
timeFrame: 28 days
measure: Surgical complications
timeFrame: 28 days
measure: Duration of hospitalization
timeFrame: 28 days
measure: Rate of unplanned hospitalization in intensive care unit
timeFrame: 28 days
measure: Rate of patients developing postoperative organ failures
timeFrame: 28 days
measure: Blood level of marker of inflammation (C Reactive protein)
timeFrame: 28 days
measure: Delayed healing defined as non hermetic scar
timeFrame: 28 days
measure: ICU length of stay
timeFrame: 28 days
measure: Rate of patients with Gastric ulcer
timeFrame: 28 days
measure: Rate of patients with Digestive bleeding
timeFrame: 28 days
measure: Rate of patients with Anastomotic leakage
timeFrame: 28 days
measure: Dose of insulin
timeFrame: 3 days
measure: Rate of patients with Hypokaliemia (< 4 mmol/l)
timeFrame: 28 days
measure: Rate of patients with Dysnatremia (<139 mmol/l or > 145 mmol/l)
timeFrame: 28 days
measure: Rate of patients with Hypocalcemia (<2.2 mmol/l)
timeFrame: 28 days
measure: Rate of patients with Cardiac events (Atrial fibrillation / cardiac flutter, Acute coronary syndrome or Cardiac failure)
timeFrame: 28 days
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers
city: Brest
country: France
facility: CHU La Cavale Blanche
city: Clermont Ferrand
country: France
facility: Hôpital Estaing, CHU de Clermont Ferrand
city: Clichy
country: France
facility: Hôpital Beaujon
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: Le Mans
country: France
facility: Centre Hospitalier Du Mans
city: Lille
country: France
facility: Hôpital Claude Huriez
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Marseille
country: France
facility: Hôpital Timone
city: Marseille
country: France
facility: Hôpital Nord
city: Montpellier
country: France
facility: Hôpital Saint-Eloi
city: Nantes
country: France
facility: Clinique Jules Verne
city: Nantes
country: France
facility: Le Confluent
city: Nantes
country: France
facility: Hotel Dieu Nantes
city: Nantes
country: France
facility: Hôpital Laennec
city: Nantes
country: France
facility: C.R.L.C.C. Nantes Atlantique
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand Widal
city: Pierre-Bénite
country: France
facility: CHU Lyon Sud
city: Poitiers
country: France
facility: CHU de Poitiers
city: Quimper
country: France
facility: Ch Quimper
city: Rennes
country: France
facility: Hôpital Pontchaillou
city: Rouen
country: France
facility: CHU de Rouen
city: Saint-Étienne
country: France
facility: CHU Saint Etienne
city: Strasbourg
country: France
facility: Nouvel Hôpital Civil
city: Toulouse
country: France
facility: CHU de Toulouse
city: Valenciennes
country: France
facility: CH Valenciennes
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
References:
citation: 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.
citation: 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.