In the PADDI trial, does a single 8 mg intravenous dose of dexamethasone given immediately after induction improve postoperative nausea and vomiting while remaining non‑inferior for surgical‑site infection in patients undergoing non‑urgent non‑cardiac surgery, including those with diabetes?

PADDI Trial: Dexamethasone 8 mg for PONV and Surgical-Site Infection

A single 8 mg intravenous dose of dexamethasone given after induction of anesthesia is safe and effective for reducing postoperative nausea and vomiting in non-urgent non-cardiac surgery, and remains non-inferior for surgical-site infection risk, including in patients with diabetes.

Evidence from the PADDI Trial

The landmark PADDI trial 1 definitively established that 8 mg IV dexamethasone is non-inferior to placebo for surgical-site infection in 8,725 patients undergoing non-urgent, noncardiac surgery. The surgical-site infection rate was actually numerically lower with dexamethasone (8.1%) versus placebo (9.1%), with a risk difference of -0.9 percentage points (95.6% CI, -2.1 to 0.3). This non-inferiority held true even in the 13.2% of patients who had diabetes mellitus 1.

For postoperative nausea and vomiting outcomes, dexamethasone demonstrated clear superiority: PONV occurred in 42.2% of dexamethasone patients versus 53.9% of placebo patients in the first 24 hours (risk ratio 0.78; 95% CI 0.75-0.82) 1. While a prespecified substudy 2 found that dexamethasone did not significantly reduce "clinically significant PONV" as measured by a patient-reported questionnaire (7.1% vs 9%, P=0.18), it did reduce severe PONV on day 2 (3.9% vs 6.7%, NNT=37) and was associated with lower nausea scores, less frequent antiemetic use, and fewer vomiting events 2.

Special Consideration: Patients with Diabetes

The concern about hyperglycemia in diabetic patients should not preclude dexamethasone use. A preplanned PADDI substudy 3 of 1,130 patients with diabetes mellitus showed that while dexamethasone increased maximum perioperative blood glucose (12.5 mM vs 10.3 mM, difference 1.86 mM), this modest elevation did not translate into increased surgical-site infection risk (11.1% vs 14.4%, RR 0.74). Additional insulin requirements and hypoglycemic episodes were similar between groups 3.

Reconciling Guideline Recommendations

There is a notable divergence between general anesthesia guidelines and diabetes-specific guidelines:

• General anesthesia guidelines 4 recommend 8 mg dexamethasone for PONV prophylaxis and pain reduction in adults
• Diabetes-specific guidelines 5 recommend only 4 mg dexamethasone combined with another antiemetic in diabetic patients, citing hyperglycemia risk

The PADDI trial evidence supersedes these older diabetes guidelines. The 2018 diabetes guidelines predated the PADDI trial results and were based on theoretical concerns rather than robust clinical trial data. The PADDI trial's diabetes substudy 3 provides the highest-quality, most recent evidence showing that 8 mg dexamethasone is safe in diabetic patients.

Clinical Algorithm

For all patients undergoing non-urgent non-cardiac surgery (including those with diabetes):

1. Administer 8 mg IV dexamethasone after induction of anesthesia and before surgical incision 1

2. In diabetic patients specifically:

   • Expect a modest blood glucose increase of approximately 1.9 mM (34 mg/dL) 3
   • Monitor blood glucose every 1-2 hours perioperatively 5
   • Target glucose 5-10 mmol/L (90-180 mg/dL) 5
   • Have insulin therapy available if needed, but additional insulin is typically not required 3

3. Combine with multimodal PONV prophylaxis as indicated by patient risk factors (consider adding 5-HT3 antagonist or droperidol for high-risk patients) 5

Important Caveats

• The PADDI trial excluded urgent/emergent surgery and cardiac surgery 1
• Hyperglycemic events in non-diabetic patients were rare but slightly increased (0.6% vs 0.2%) 1
• The trial required surgery duration ≥2 hours, skin incision >5 cm, and overnight hospital stay 1
• Recent data from periprosthetic joint infection surgery 6 and cesarean delivery 7 further support dexamethasone safety, showing no increased infection risk and potential benefit

The evidence strongly supports using 8 mg dexamethasone in all patients, including those with diabetes, prioritizing the proven benefits for PONV reduction and the demonstrated safety profile for surgical-site infection risk.