No increased SSI risk with dexamethasone

A single dose of dexamethasone during nonurgent, noncardiac surgery does not increase the risk of surgical-site infection (SSI), according to results of the PADDI* trial.

“[A] single 8-mg dose of dexamethasone was found to be noninferior to placebo with respect to the primary outcome of SSI within 30 days after surgery. This finding was consistent across all prespecified subgroups, including patients with or without diabetes mellitus,” said the investigators.

Participants in this international trial were 8,880 adults who were scheduled to undergo nonurgent, noncardiac surgery lasting ≥2 hours with a skin incision length >5 cm, and requiring ≥1 night hospitalization post-surgery. They were randomized to receive intravenous dexamethasone (8 mg) or placebo while under anaesthesia and before surgical incision. Patients requiring intraoperative dexamethasone or whose surgery was associated with a primary infection, and those with HbA_1c >9.0 percent were excluded.

The modified intention-to-treat (mITT) population comprised 8,725 patients (n=4,372 and 4,353 in the dexamethasone and placebo groups, respectively; mean age ~59 years, ~55 percent male), of whom 8,678 were included in the primary analysis. About 13 percent of the mITT population had diabetes (n=1,148), with a comparable number in each group, 97.2 percent of whom had type 2 diabetes.

Within 30 days following surgery, SSI** incidence was significantly reduced in the dexamethasone vs the placebo group (8.1 percent vs 9.1 percent; risk difference***, -0.9 percentage points, 95.6 percent confidence interval [CI], -2.1 to 0.3; risk ratio [RR], 0.89, 95.6 percent CI, 0.77–1.03; p_{noninferiority}<0.001). [N Engl J Med 2021;384:1731-1741]

This outcome was consistent in all prespecified subgroups, including diabetes status (risk difference, -2.9 and -0.7 percentage points for patients with and without diabetes, respectively) and when the infection subtypes were assessed separately.

Deep or organ-space infections within 90 days post-surgery in patients who had prosthetic material inserted occurred in a comparable proportion of dexamethasone and placebo recipients (1.9 percent vs 2.0 percent; RR, 0.94), as did other infections occurring within 30 days post-surgery (11.5 percent vs 12.5 percent; RR, 0.92).

Sepsis before discharge occurred in fewer dexamethasone than placebo recipients (0.9 percent vs 1.5 percent, RR, 0.58). At 6 months post-surgery, new-onset chronic postoperative pain was reported in 8.7 and 7.1 percent, respectively (RR, 1.23), while new-onset death or persistent disability were reported in 8.5 and 8.1 percent, respectively (RR, 1.05).

A smaller proportion of patients in the dexamethasone than placebo group experienced nausea and vomiting in the first 24 hours post-surgery (42.2 percent vs 53.9 percent; RR, 0.78).

Among patients without diabetes, hyperglycaemic events were recorded in 0.6 and 0.2 percent of dexamethasone and placebo recipients, respectively, and insulin administered in 0.5 and 0.1 percent, respectively.

Treatment nonadherence was low and comparable in the dexamethasone and placebo groups (6.3 and 6.6 percent, respectively), and was mainly due to post-surgical administration of supplemental non-trial glucocorticoids.

Dexamethasone: Safe to use?

“[Dexamethasone] has rapid and extensive effects on immune function [leading to] concern that [it] may increase the risk of postoperative infection, particularly in vulnerable populations such as patients with diabetes,” said the investigators.

“We have clearly shown that administering dexamethasone during surgery does not increase the risk of wound infection, in particular in patients with diabetes. Hence, it is safe to use this drug when clinically indicated,” said lead investigator Professor Tomás Corcoran, Director of Research, Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Western Australia.

The investigators pointed out that the findings in patients with diabetes were especially reassuring given the general reluctance to use dexamethasone in this group due to their higher risk for infection-related complications and hyperglycaemia.

“After a surgical procedure, there is always a concern that patients will suffer a major complication. There is an ongoing need to run large scale clinical studies such as PADDI, which produce reliable results to determine how to reduce major complications after surgery and to improve the safety of our patients,” said Corcoran.

The investigators acknowledged that the non-acquisition of data on perioperative SSI risk factors (eg, bowel and skin preparation, antibiotic prophylaxis) may have presented a limitation.