A Double-Blinded, Randomized, Placebo-Controlled Clinical Trial of Aminophylline to Prevent Acute Kidney Injury in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass*

Abstract

Objective Acute kidney injury (AKI) occurs commonly in children following congenital cardiac surgery with cardiopulmonary bypass (CPB) and has been associated with increased morbidity and mortality. Aminophylline, a methylxanthine nonselective adenosine receptor antagonist, has been effective in the management of AKI in certain populations. This study sought to determine if post-operative administration of aminophylline attenuates AKI in children undergoing congenital cardiac surgery with CPB. Design Single-center, double-blinded, placebo-controlled, randomized clinical trial (RCT). Setting Tertiary center, pediatric cardiovascular intensive care unit. Patients 144 children after congenital heart surgery with CPB. Interventions Seventy-two patients were randomized to receive aminophylline and 72 patients received placebo. Study drug was administered every six hours for 72 hours. Measurements and Main Results The primary outcome variable was development of any AKI, defined by the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes (KDIGO) criteria. Secondary outcomes included the development of severe AKI, time between CVICU admission and first successful extubation, percent fluid overload, total fluid balance, urine output, bioelectrical impedance, and serum neutrophil gelatinase-associated lipocalin (NGAL). The unadjusted rate and severity of AKI were not different between groups; 43/72 (60%) of the treatment group and 36/72 (50%) of the placebo group developed AKI (p=0.32). Stage 2/3 AKI occurred in 23/72 (32%) of the treatment group and 15/72 (21%) of the placebo group (p=0.18). Secondary outcome measures also demonstrated no significant difference between treatment and placebo groups. Aminophylline administration was safe; no deaths occurred in either group, and rates of adverse events were similar (14% in the treatment group versus 18% in the placebo group, p =0.30). Conclusions In this placebo-controlled RCT, we found no effect of aminophylline to prevent AKI in children recovering from cardiac surgery performed with CPB. Future study of pre-operative aminophylline administration to prevent AKI may be warranted.

Comparison of Intraoperative Aminophylline Versus Furosemide in Treatment of Oliguria During Pediatric Cardiac Surgery*

“…In this well designed and adequately powered study, the authors failed to demonstrate any positive effect of aminophylline to prevent CSA-AKI. Even though the domains of our study and Axelrod et al (50) study are very similar, there is yet one very important difference in the intervention. Axelrod et al (50) administered aminophylline postoperatively to all the randomized intervention group subjects regardless of their intraoperative or early postoperative urine outputs.…”

“…Even though the domains of our study and Axelrod et al (50) study are very similar, there is yet one very important difference in the intervention. Axelrod et al (50) administered aminophylline postoperatively to all the randomized intervention group subjects regardless of their intraoperative or early postoperative urine outputs. Therefore, their intervention may be considered late relative to the time of renal insult (CPB), causing the treatment to be less effective.…”

“…In a recently reported, double-blinded, randomized, placebo-controlled clinical trial, Axelrod et al (50) compared aminophylline to placebo to prevent CSA-AKI in children following congenital heart surgery with CPB. In this well designed and adequately powered study, the authors failed to demonstrate any positive effect of aminophylline to prevent CSA-AKI.…”

Leveraging Big Data and Electronic Health Records to Enhance Novel Approaches to Acute Kidney Injury Research and Care

“…The ability to predict AKI risk has profound implications since currently no treatments exist for AKI once it develops [16,17,18]. When patients at high AKI risk are identified, it becomes possible to modify care and implement preventative and harm avoidance strategies among these patients [19,20,21,22,23,24]. …”

Aminophylline for Acute Kidney Injury After Pediatric Cardiac Surgery

“…In this issue of Pediatric Critical Care Medicine, Axelrod et al (4) have taken that big needed step. They report a singlecenter double-blinded randomized clinical trial of aminophylline versus placebo to treat AKI in 144 children undergoing cardiac surgery (CS) with cardiopulmonary bypass (CPB).…”