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PEDIATRICS Vol. 108 No. 1 July 2001, pp. 61-70

Allopurinol Neurocardiac Protection Trial in Infants Undergoing Heart Surgery Using Deep Hypothermic Circulatory Arrest

Received August 25, 2000; accepted October 30, 2000..

Robert R. Clancy*, , #, Susan A. McGaurn*, , #, James E. Goin§§, Deborah G. HirtzDagger Dagger Dagger , William I. Norwood||, ¶¶, J. William GaynorDagger , **, Marshall L. Jacobs##, ***, Gil Wernovsky§, #, William T. Mahle§, #, John D. Murphy||, ¶¶, Susan C. Nicolsonparallel , Dagger Dagger , James M. Stevenparallel , Dagger Dagger , and Thomas L. SprayDagger , **

From the Divisions of * Neurology, Dagger  Cardiothoracic Surgery, § Cardiology, and parallel  Cardiac Anesthesiology of the Children's Hospital of Philadelphia, Pennsylvania; Departments of  Neurology, # Pediatrics, ** Surgery, and Dagger Dagger  Anesthesiology and Critical Care Medicine of the School of Medicine, University of Pennsylvania, Philadelphia; §§ The DataMedix Corporation, Media, Pennsylvania; || The Nemours Cardiac Center, Alfred I. duPont Hospital for Children, Wilmington, Delaware; the ¶¶ Departments of Surgery and Pediatrics of the Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; ## St Christopher's Hospital for Children, Philadelphia, Pennsylvania; *** Department of Cardiothoracic Surgery, MCP.Hahneman School of Medicine, Philadelphia, Pennsylvania; and the Dagger Dagger Dagger  National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

Objective.  This pharmacologic protection trial was conducted to test the hypothesis that allopurinol, a scavenger and inhibitor of oxygen free radical production, could reduce death, seizures, coma, and cardiac events in infants who underwent heart surgery using deep hypothermic circulatory arrest (DHCA).

Design.  This was a single center, randomized, placebo-controlled, blinded trial of allopurinol in infant heart surgery using DHCA. Enrolled infants were stratified as having hypoplastic left heart syndrome (HLHS) and all other forms of congenital heart disease (non-HLHS). Drug was administered before, during, and after surgery. Adverse events and the clinical efficacy endpoints death, seizures, coma, and cardiac events were monitored until infants were discharged from the intensive care unit or 6 weeks, whichever came first.

Results.  Between July 1992 and September 1997, 350 infants were enrolled and 348 subsequently randomized. A total of 318 infants (131 HLHS and 187 non-HLHS) underwent heart surgery using DHCA. There was a nonsignificant treatment effect for the primary efficacy endpoint analysis (death, seizures, and coma), which was consistent over the 2 strata. The addition of cardiac events to the primary endpoint resulted in a lack of consistency of treatment effect over strata, with the allopurinol treatment group experiencing fewer events (38% vs 60%) in the entire HLHS stratum, compared with the non-HLHS stratum (30% vs 27%). In HLHS surgical survivors, 40 of 47 (85%) allopurinol-treated infants did not experience any endpoint event, compared with 27 of 49 (55%) controls. There were fewer seizures-only and cardiac-only events in the allopurinol versus placebo groups. Allopurinol did not reduce efficacy endpoint events in non-HLHS infants. Treated and control infants did not differ in adverse events.

Conclusions.  Allopurinol provided significant neurocardiac protection in higher-risk HLHS infants who underwent cardiac surgery using DHCA. No benefits were demonstrated in lower risk, non-HLHS infants, and no significant adverse events were associated with allopurinol treatment.congenital heart defects, hypoplastic left heart syndrome, induced hypothermia, ischemia-reperfusion injury, neuroprotective agents, allopurinol, xanthine oxidase, free radicals, seizures, coma. .




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