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

Nantes University Hospital (NUH)

Status and phase

Completed

Phase 3

Conditions

Major Non-cardiac Surgery

Treatments

Drug: Placebos

Drug: Dexamethasone

Study type

Interventional

Funder types

Other

Identifiers

NCT03218553

RC17_0029

Details and patient eligibility

About

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

Full 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.

Enrollment

1,222 patients

Sex

All

Ages

50 to 90 years old

Volunteers

No Healthy Volunteers

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)