Modified Cleveland Clinic Insulin Infusion Protocol Versus Physician-Directed Intravenous Insulin Adjustment After Cardiac Surgery: A Randomized Controlled Trial (NUSULIN Trial)

Background: Postoperative hyperglycemia is associated with adverse outcomes after cardiac surgery. Physician-directed intravenous insulin adjustment may lead to treatment delays and variability in glycemic management. Evidence supporting protocol-guided insulin adjustment in Southeast Asian populations remains limited. We compared glycemic control and safety between a modified Cleveland Clinic insulin infusion protocol and physician-directed insulin adjustment after cardiac surgery.

Methods: In this prospective randomized superiority trial, 50 adults who (1) aged 20–90 years (2) with diabetes and (3) undergoing open cardiac surgery between July 2023 and August 2025 were randomized 1:1 to a modified Cleveland Clinic insulin infusion protocol or physician-directed insulin adjustment using computer-generated block randomization with concealed allocation. Patients were followed during insulin infusion for up to 72 hours after ICU admission. The primary outcome was percentage of time within the target blood glucose range (80–150 mg/dL). Secondary outcomes included time to target, glycemic variability, hypoglycemia (<70 mg/dL), and severe hypokalemia (<3.0 mmol/L). Analyses followed the intention-to-treat principle. The trial was prospectively registered with a planned sample size of 56 patients but was terminated early after enrollment of 50 patients because of apparent differences in glycemic control.

Results: Twenty-five patients were analyzed in each group with well-balanced baseline characteristics, including age (mean 65.7 vs 65.3 years; p=0.85), HbA1c (median 6.6% vs 7.1%; p= 0.23), coronary artery bypass grafting (68% vs 72%; p=0.92), cardiopulmonary bypass time (179.4 vs 170.7 minutes; p=0.39), and aortic cross-clamp time (140.8 vs 127.2 minutes; p=0.09). The protocol group reached target glucose faster (2.0 vs 5.0 hours; P<0.001), had greater time in range (83.3% vs 58.4%; P<0.001), and had a lower J-index (24.1 vs 31.2; P=0.002). Hypoglycemia occurred in 0.9% versus 0.2% of blood glucose measurements (P>0.99), and severe hypokalemia occurred in 0.19% versus 0% (P>0.99), respectively.

Conclusions: The modified Cleveland Clinic insulin infusion protocol improved postoperative glycemic control during the postoperative critical period. Hypoglycemia and severe hypokalemia were infrequent in both groups; however, the study was not adequately powered to establish comparative safety. Larger multicenter trials are needed to confirm safety and determine whether improved glycemic control translates into better clinical outcomes.

Trial Registration: TCTR20230719001 (Thailand Clinical Trial Registry). Registration Date: 15 July 2023