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

Major Non-cardiac Surgery Clinical Trial

— PACMAN  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03218553
• Other study ID #: RC17_0029
• Status: Completed
• Phase: Phase 3
• Start date: December 13, 2017
• Est. completion date: April 16, 2019

Study information

• Verified date: May 2020
• Source: Nantes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1222
• Est. completion date: April 16, 2019
• Est. primary completion date: April 16, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 90 Years

Eligibility

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)

Related Conditions & MeSH terms

• Major Non-cardiac Surgery
• Postoperative Complications

Intervention

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

Locations

Country	Name	City	State
France	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	Hôpital Nord	Marseille
France	Hôpital Timone	Marseille
France	Institut Paoli Calmettes	Marseille
France	Hôpital Saint-Eloi	Montpellier
France	C.R.L.C.C. Nantes Atlantique	Nantes
France	Clinique Jules Verne	Nantes
France	Hôpital Laennec	Nantes
France	Hotel Dieu Nantes	Nantes
France	Le Confluent	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-Étienne
France	Nouvel Hôpital Civil	Strasbourg
France	CHU de Toulouse	Toulouse
France	CH Valenciennes	Valenciennes
France	Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Nantes University Hospital

Country where clinical trial is conducted

France, 

Outcome

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