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

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

Robert R. Clancy, MD^{*, ¶, #}, Susan A. McGaurn, PharmD^{*, ¶, #}, James E. Goin, PhD^§§, Deborah G. Hirtz, MD, William I. Norwood, MD, PhD^{||, ¶¶}, J. William Gaynor, MD^{, **}, Marshall L. Jacobs, MD^{##, ***}, Gil Wernovsky, MD^{§, #}, William T. Mahle, MD^{§, #}, John D. Murphy, MD^{||, ¶¶}, Susan C. Nicolson, MD^, , James M. Steven, MD^, , and Thomas L. Spray, MD^{, **}

From the Divisions of ^* Neurology,  Cardiothoracic Surgery, ^§ Cardiology, and  Cardiac Anesthesiology of the Children's Hospital of Philadelphia, Pennsylvania; Departments of ^¶ Neurology, ^# Pediatrics, ^** Surgery, and  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  National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

	ABSTRACT

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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.

Approximately 30 000 infants with congenital heart disease (CHD) are born in the United States each year, with at least a third needing surgical intervention in early infancy.^1-3 Advances in cardiothoracic surgical and anesthetic techniques, including cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), have substantially decreased mortality, increasing the need to improve functional neurologic and cardiac outcomes in survivors.^3-5

Neurocardiac morbidity in infants with CHD undergoing surgery with DHCA is well described. Acute postoperative neurologic dysfunction, including seizures, occurs in up to 25% of infants.^4-6 Cardiocirculatory events including arrest and tissue hypoperfusion also occur. Neurocardiac consequences in survivors include cognitive, attentional, behavioral, and neuromuscular disabilities^7-14 and reduced exercise tolerance.^15,16 In this setting, new interventions to improve neurocardiac outcome are needed.

Numerous specific forms of CHD necessitate newborn heart surgery under DHCA, and associated perioperative mortality and morbidity rates vary substantially. In the context of a pharmacologic neurocardiac protection trial, it is important to stratify broad anatomic CHD groups with anticipated different risks of adverse events such as death or postoperative seizures. Hypoplastic left heart syndrome (HLHS) is a particularly severe form of CHD characterized as a diminutive left ventricle with atresia or severe hypoplasia of the aortic valve that necessitates staged reconstruction. Postoperative mortality is approximately 25% for Stage I repair,¹⁷ the goals of which are creating an unobstructed pathway for systemic blood flow by anastomosing the main pulmonary artery to the aorta, avoiding pulmonary venous hypertension by creating a nonrestrictive atrial septal defect, and controlling pulmonary blood flow with a modified Blalock-Taussig shunt. Many HLHS survivors have substantial long-term neurocardiac sequelae.^10,14,18 Infants with other forms of CHD (non-HLHS) necessitating life-saving surgery may experience lower mortality and morbidity risk by virtue of simpler operative plans, briefer DHCA times, or superior perioperative cardiovascular stability.

DHCA is an essential element of surgery in many life-threatening forms of CHD. Characteristically, core body temperature is reduced to 16°C to 18°C by CPB. Circulation is then totally arrested for 60 minutes or more. DHCA protects cellular processes by reducing metabolic demand and provides a motionless, bloodless surgical field for the intricate repair of the heart and great vessels. On surgery completion, the patient is rewarmed by CPB and circulation is restored, exposing the infant to potential ischemia-reperfusion injury. During ischemia, adenosine triphosphate (ATP) is rapidly catabolized to hypoxanthine (Fig 1). On reperfusion, oxygen, hypoxanthine, and xanthine oxidase (XO) generate oxygen free radicals, important mediators in cellular injury and tissue necrosis.^19-22 Enzymatic XO inhibition may reduce oxygen free radicals in ischemia-reperfusion. Allopurinol, a known XO inhibitor, has demonstrated neurologic and cardiac protection in some human and animal settings of ischemia-reperfusion injury.^23-31 The clinical trial reported here was conducted to test the hypothesis that allopurinol administration reduces postoperative death, seizures, coma, and cardiac events in infants undergoing heart surgery using DHCA. This patient population is an important model for pharmacologic protection trials in which a planned and quantifiable exposure to ischemia-reperfusion occurs and neurocardiac injuries may be anticipated.

View larger version (18K): [in this window] [in a new window]   Fig. 1.   Allopurinol inhibition of xanthine oxidase and oxygen free radicals in ischemia-reperfusion.

	METHODS

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Study Population

Infants admitted to the Children's Hospital of Philadelphia (CHOP) from July 1992 to September 1997 for evaluation of CHD were screened for enrollment into the trial. Infants were enrolled if they satisfied the following criteria: CHD necessitating surgery using DHCA, conceptional age <45 weeks, absence of coincident lethal genetic disorders or severe multiple congenital abnormalities, and informed consent provided by parent or guardian. (Conceptional age is determined by adding legal age [time from birth] to estimated gestational age.) Infants were excluded if they were neurologically unassessable (from neuromuscular blockade), demonstrated seizures or coma, or had laboratory findings consistent with known allopurinol hypersensitivity including elevated liver function tests (serum glutamic oxaloacetic transaminase [SGOT] >420 U/L or serum glutamic pyruvic transaminase [SGPT] >150 U/L) or neutropenia (total neutrophil count <1000/µL) or if enrollment would have occurred <16 hours before anticipated surgery. The study protocol was approved by the Committee for the Protection of Human Subjects at CHOP.

Conduct of Surgery and Anesthesia

Two cardiothoracic surgeons (W.I.N. and M.L.J.) performed the infant heart operations during the first half of the trial; 2 other surgeons (T.L.S. and J.W.G.) performed the remainder. Stage I palliation was performed for all infants with HLHS. Otherwise, there was no attempt to standardize the operations. A uniform method of cardiac anesthesia was maintained during the trial by study investigators (S.C.N. and J.M.S.) including  stat acid-base management. CPB cooling time was the period on bypass when core body temperature was lowered, ending with circulatory arrest. Duration of DHCA includes only the time of complete circulatory arrest. CPB rewarming time is the duration of bypass after DHCA, while the patient is rewarmed. Some patients underwent modified ultrafiltration after separation from CPB.

Study Design and Experimental Treatment

This was as a single-center, randomized, placebo-controlled, blinded trial (Fig 2). Enrolled infants were assigned to 1 of 2 strata by cardiac anatomy: HLHS or all other forms of CHD (non-HLHS). Within each stratum, block randomization was performed by a computer-generated sequence of allocation to allopurinol or matching placebo in a 1:1 ratio using a fixed block size of 8. All study investigators, caretakers, and parents were blinded to drug assignment, except the pharmacy staff involved in randomizing, preparing, and distributing the study drug.

View larger version (23K): [in this window] [in a new window]   Fig. 2.   Neurocardiac protection trial schematic.

The lyophilized sterile sodium salt of allopurinol (Burroughs Wellcome Company, Research Triangle Park, NC) was refrigerated at 15°C to 25°C and stored in the pharmacy. Each dose was reconstituted with sterile water for injection and diluted with 5% dextrose to a final concentration of 5 mg/mL. An equal volume of 5% dextrose solution was prepared for participants receiving placebo. Allopurinol and placebo doses appeared identical. Verification of drug identity was performed in the pharmacy by pH determinations (allopurinol is alkaline).

The following allopurinol dosage schedule was based on previous pharmacokinetic determinations of drug half-life, nadir levels, and uric acid reduction³²: Dose 1, 5 mg/kg intravenoulsy (IV) given at least 16 hours before anticipated surgery; Dose 2, 5 mg/kg IV given 8 hours before surgery; Dose 3, 10 mg/kg IV at 7 am on the morning of surgery; and Dose 4, 20 mg/kg intraoperatively, administered in the CPB pump circuitry. Nine postoperative doses (5 mg/kg/dose IV q 8 hr) were also administered. Because serum uric acid is significantly reduced after a single allopurinol dose,³² an adequate allopurinol exposure was defined as the administration of any 1 or more of the 4 intended doses on the day before or day of surgery. Serum uric acid levels were measured immediately before study drug initiation and repeated after drug administration on the morning of surgery to measure XO inhibition. Study investigators and data collectors remained blinded to these determinations.

Data Collection

Data recorded preoperatively included characteristics of gestation, labor and delivery, Apgar scores, demographics, socioeconomic status (Hollingshead index³³), microcephaly (head circumference less than or equal to the second percentile), and genetic or dysmorphic syndromes. CPB and DHCA times were included in intraoperative measurements. In the postoperative period, efficacy endpoints and adverse events were recorded, as described here.

Clinical Endpoints

The clinical endpoints were death, seizures, coma, and cardiac events evaluated during the postoperative intensive care unit (ICU) stay, not exceeding 6 weeks after surgery (Fig 2).

Death was defined as cessation of spontaneous cardiac or neurologic functions. Seizures were identified using established clinical criteria of tonic, clonic, or myoclonic activity of a limb, trunk, or cranial muscle that could not be aborted by holding the area. Coma was identified by examination by a child neurologist; comatose infants exhibited no spontaneous or responsive eye opening on repeated observations. Therapeutically paralyzed infants were not evaluable for this endpoint. Cardiac events were defined as periods of acute, severe cardiorespiratory deterioration necessitating immediate resuscitation such as chest compressions or massage, defibrillation, or acute boluses of inotropic agents.

Adverse Events

Infants were observed for allopurinol hypersensitivity reactions during study drug administration, including diffuse maculopapular skin rash, hepatic dysfunction (SGOT >420 U/L; SGPT >150 U/L), and neutropenia (total neutrophil count <1000/µL). Death was also considered an adverse event and was recorded throughout the hospitalization (Fig 2). Study drug was discontinued on identification of an adverse event.

Statistical Considerations

Randomized infants undergoing surgery for CHD using DHCA made up the intent-to-treat population for efficacy evaluation. The population evaluated for adverse events was those exposed to study drug. Infants remained in their assigned strata regardless of subsequent anatomic findings. Comparability between randomized groups, preoperatively and intraoperatively, was performed using t test for continuous variables and ² for categorical variables. The t test was used to compare treatment groups based on percentage changes in uric acid values before and after study drug administration. Clinical efficacy endpoint analysis was conducted using logistic regression, Fisher's exact test, Mantel-Haenszel ², and the Breslow-Day test for homogeneity of odds ratios over strata. Statistical Analysis Systems (SAS) (SAS Institute, Cary, NC) and LogXact (Cytel Software, Cambridge, MA) were used for data analysis.

The primary efficacy endpoint was a composite of death, seizures, or coma. The occurrence of any of these 3 events resulted in recording a primary efficacy endpoint event. The primary efficacy endpoint analysis model, as defined a priori, was the logistic model with the occurrence of a primary efficacy endpoint as the dependent variable and treatment, strata, and surgeon as independent variables. No interim efficacy analysis for early stopping was performed, but scheduled adverse event analyses were provided to an external Performance and Safety Monitoring Committee. A test for consistency of treatment effect over strata was planned and conducted using the logistic model.

Secondary analyses incorporated cardiac events into the primary efficacy endpoint model and evaluated treatment effects by individual and combinations of clinical events. Logrank methodology was used for tests for statistically significant differences between treatments using time-to-event as the endpoint. Fisher's exact test and Mantel-Haenszel ² was used for statistical testing for treatment effect on adverse events. A 2-sided P value of .05 was designated as significant for statistical testing, without adjustment for multiplicity. The study was powered to provide a >80% chance of detecting at least a 50% reduction in the primary efficacy endpoint using a 2-tailed type I error of 0.05.

Quality Assurance

A Manual of Operations was developed to guide the conduct of the study, specify the methods and procedures for data extraction and form completion, and define all efficacy endpoints. Quality assurance included scheduled auditing of data by the authors (R.R.C., S.A.M.). Endpoints were confirmed by independent medical record review. All ICU nurses were certified in neonatal seizure identification using instructional videotapes. Interobserver reliability of mental status examinations was demonstrated serially during the study. Pharmacy audits were performed quarterly on the storage, control, dispensing, labeling, and preparation of allopurinol study drug.

	RESULTS

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Study Population and Balance Between Treatment Groups

Between July 1992 and September 1997, 350 infants were enrolled into the study, with 348 randomized. Eight infants did not undergo surgery (2 HLHS, 6 non-HLHS), and 24 infants did not undergo DHCA (24 non-HLHS). Consequently, 318 randomized infants (131 (41%) HLHS, 187 (59%) non-HLHS) underwent surgery for CHD using DHCA and made up the intent-to-treat population for efficacy analysis. This represents 98% of the HLHS and 86% of the non-HLHS enrolled infants. All HLHS infants and 90% of non-HLHS infants received at least 3 of the 4 intended allopurinol doses. Of the non-HLHS infants, an additional 8% received 1 or 2 of the intended doses. Based on previous pharmacokinetic studies,³² adequate exposure was considered to be at least 1 of the 4 intended doses. Surgery was conducted in the first week of life in 91 (69%) of the HLHS and 111 (59%) of the non-HLHS infants, and 20 infants underwent surgery after 28 days. There was no statistical difference in type of cardiac defect distributions in non-HLHS infants between treatments (², P = .08; Table 1). There was no significant difference in demographics and preoperative characteristics between treatment groups in the HLHS infants (Table 2). In the non-HLHS infants, gestational age (39.0 vs 38.2 weeks) and birth weight (3.3 vs 3.0 kg) were significantly higher in the allopurinol group than controls, judged to be clinically unimportant. Allopurinol-treated infants demonstrated markedly reduced serum uric acid (Table 3), verifying XO inhibition. There were no significant differences in the intraoperative characteristics of CPB or DHCA times, use of modified ultrafiltration, or the need for additional CPB between treatment groups within strata (Table 4). DHCA time was longer in HLHS than non-HLHS infants (58.9 vs 50.1 minutes; P < .001).

Efficacy Endpoint Analyses

The primary efficacy endpoint analysis (death, seizures, and coma) did not reveal a treatment effect (P = .69), with odds ratio (OR) of .91 (95% confidence interval [CI], .56-1.48)). This was consistent over the 2 strata (P = .33). Adding cardiac events to the primary efficacy endpoint resulted in a lack of consistency of treatment effect over strata (P = .05) because of an allopurinol-related reduction in seizures and cardiac events in the HLHS infants, with no effect on these events in the non-HLHS infants. There was a lower event rate in the allopurinol treatment group (38% vs 60%; OR (95% CI) = .44 (.21, .91)) in the HLHS stratum but not in the non-HLHS stratum (30% vs 27%; OR = 1.17 (95% CI, .61-2.25); Table 5). No treatment-related reduction in death was observed. The numbers and percentages of infants experiencing clinical endpoints in the non-HLHS stratum varied markedly among the different types of cardiac defects (Table 6).

In HLHS survivors, 40 of 47 (85%) allopurinol-treated infants had no endpoint event, compared with 27 of 49 (55%) controls (Table 7; P = .002). In the allopurinol treatment group, 2 (4%) infants had no other endpoint than seizures, 2 (4%) had cardiac events only, 1 (2%) seizures and coma, and 2 (4%) seizures and cardiac events. In controls, 9 (18%) had seizures only, 10 (20%) had cardiac events only, 0 (0%) had seizures and coma, and 3 (6%) had seizures and cardiac events. There was a significant reduction in the allopurinol treated group in seizures only and cardiac events only (P = .05 and P = .03, respectively). In the non-HLHS stratum, 64 of 83 (77%) allopurinol-treated infants had no endpoint event, compared with 70 of 87 (80%) controls (Table 7; P = .71). In this stratum, there were no significant differences between treatment groups for individual or combinations of clinical endpoints.

Adverse Event Analysis

There was no difference between treatment groups for any adverse event including death, hepatic dysfunction, skin rash, and neutropenia (Table 8). Nine additional infants died, of whom 4 were assigned to allopurinol and 5 to placebo. This includes 3 from the intent-to-treat population who died after the 6-week ICU observation period.

	DISCUSSION

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The search for pharmacologic protection from ischemia-reperfusion injury in conditions such as birth asphyxia is hampered by their unexpected occurrence and the difficulties in predicting the magnitude of their damage in all but those with devastating insults. Infants with critical forms of CHD who need life-saving newborn heart surgery may undergo a deliberate, planned, and measurable period of ischemia followed by reperfusion, or DHCA. Although DHCA facilitates the successful technical conduct of surgery, it confers significant risks. This clinical situation provides a population of infants in whom pharmacologic ischemia-reperfusion protection trials can be conducted. Moreover, this population merits investigation in its own right. CHD threatens the well-being of thousands of infants each year, and any strategy to reduce its mortality and morbidity is highly desirable. The trial reported here represents a first attempt to study neurocardiac protection in infants with CHD who undergo surgery using DHCA.

Specific mechanisms by which tissue damage occurs after ischemia-reperfusion include the generation of toxic oxygen free radicals by XO. Allopurinol may be neuroprotective as a scavenger or inhibitor of free radical production. Allopurinol reduced cerebral cortical free radical production by 59% in hypoxic infant piglets and ameliorated neonatal rat brain damage by peri-injury administration.³⁴ Asphyxiated human neonates administered allopurinol experienced relative preservation of cerebral blood flow, cerebral electrical activity, and levels of malondialdehyde, a lipid peroxidation product.³⁵ During extracorporeal membrane oxygenation treatment for severe hypoxia in infants, allopurinol ameliorated purine metabolism disturbances.¹⁹ However, allopurinol failed to reduce periventricular leukomalacia in preterm infants.³⁶ Previous studies have also suggested that allopurinol provides cardiac protection after ischemia-reperfusion with improved myocardial function and reduced arrhythmias,^3037-39 but not all studies have shown these beneficial effects.⁴⁰

The purpose of this trial was to test the hypothesis that allopurinol administration would reduce a composite variable of death, seizures, or coma in the target population. The test of this treatment effect was negative (P = .69). However, secondary analyses that included cardiac events as an endpoint demonstrated clearly beneficial allopurinol treatment effects in the entire HLHS strata (P = .01) and in HLHS survivors (P = .002). No benefit was seen in non-HLHS infants.

Infants with HLHS clearly are a higher-risk population than the non-HLHS infants. HLHS mortality (35/131, 27%) was similar to that in contemporary literature reports^41,42 and significantly exceeded that of non-HLHS infants (17/186, 9%). The occurrence of any clinical endpoint (death, seizures, coma, or cardiac event) in HLHS (64/131, 49%) also exceeded that in the non-HLHS infants (53/186, 28%). Mean DHCA time in HLHS (58.9 ± 12.8 minutes) was longer than in non-HLHS infants (50.1 ± 15.8 minutes; Table 4). Both received adequate allopurinol exposure, and within HLHS efficacy results were not affected by the amount of drug administered. A possible explanation for the difference in treatment effect between strata is that HLHS infants have longer DHCA times. However, analysis revealed no association between overall treatment effect and DHCA time. Another explanation could be that there was a bias in assignment between placebo and allopurinol among various cardiac defects, but this was rejected because treatment was evenly balanced. Furthermore, non-HLHS infants with cardiac defects with postoperative physiology and occurrences of clinical endpoints similar to those of HLHS infants (eg, single ventricle, heterotaxy; Table 6) did not experience a treatment effect. Because treatment effect was not associated with the infants' intraoperative characteristics, it is possible that their preoperative oxygenation status influenced their response to allopurinol. Preoperative near infrared spectroscopy measurements of cerebral oxygen saturation (ScO₂) vary significantly among different types of CHD, and critically low values (ScO₂ <35%) occur in about 20% of HLHS.⁴³

Postoperative death was included as an efficacy endpoint because it is the most adverse neurocardiac event and precludes observation of other clinical endpoints. In this trial, death served as a censoring event for the occurrence of seizures and coma. Death was not affected by allopurinol treatment in either stratum. The predominant factors that influence immediate postoperative mortality are related to CHD anatomy, preoperative variables,^41,44 and the skill of the surgical and postoperative teams. The time from surgery to death provides insight into this complex risk-of-death issue. Death on the day of surgery occurred in 13 (37%) of the HLHS and 6 (35%) of the non-HLHS infants. Expired infants were subsequently unobservable for seizures, coma, or cardiac events. Consequently, the ability to observe coma and seizures is highly associated with death and time to death. Because of the competing risks of death for other clinical events, death was included in the primary endpoint definition. A differential bias could occur in counting the nondeath clinical events if allopurinol affected the time to death but not the event. Consequently, an increased observation time could result in increased morbid events in the allopurinol group. The time-to-death interval did not differ by treatment group in either stratum (P = .84 and P = .83, for HLHS and non-HLHS, respectively).

Many infants with complex CHD need multistaged reconstruction during the first years of life. In those patients, subsequent outcome may reflect the cumulative impact of multiple operations. For those reasons, immediate, postoperative, clinically relevant endpoints were chosen for this trial because of the need to demonstrate early benefits of pharmacologic protection. Coma and seizures are the major signs of acute neonatal encephalopathy. Clinical seizures occurred in 33 of 186 (18%) non-HLHS infants, including 15% of the infants with transposition of the great arteries (TGA) and ventricular septal defect and 8% of the infants with TGA and intact ventricular septum (Table 6), similar to Newburger et al's⁵ TGA population that underwent DHCA. In the present study, neuroprotection in HLHS was suggested by a reduction of seizures only from 18% in controls to 4% in allopurinol treated survivors (P = .05). In addition, the prevention of acute, severe cardiac events may also preserve neurocardiac integrity. In HLHS survivors, cardioprotection was suggested by a reduction of cardiac events only from 20% in controls to 4% in the allopurinol group (P = .03).

	CONCLUSION

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Infants undergoing cardiac surgery using DHCA are at high risk to develop ischemia-reperfusion neurocardiac injuries. Preoperative allopurinol administration to infants with HLHS should be considered because it was safe and appeared to provide significant neurocardiac protection immediately after surgery. Future trials may identify other subsets of infants with CHD who will benefit from pharmacologic protection.

	ACKNOWLEDGMENTS

This work was performed under contract with the National Institute of Neurologic Disorders and Stroke, National Institutes of Health, NS-N01-2315. Additional nursing support was used from the General Clinical Research Center, NIH MO1-RR00240. We are indebted to the following for their contributions:

NINDS Performance and Safety Monitoring Board: Walter Bell, Linda Cowan, John Freeman, Susan McCune, Solomon Moshe, Gordon Pledger, and Robert Vannucci.

Glaxo Wellcome for providing intravenous sodium allopurinol (lots 0Z2790, 2N2731, and 5 M2778).

The Center for Drug Evaluation and Research, Division of Cardio-Renal Drug Products of the Food and Drug Administration for approval of Investigational New Drug Application #34447 (R.R.C.).

CHOP Pharmacy: Kirkland Davis, Donna Sylvester, James Peterson, Michelle McErlane, Gerald Exil, David Jobes, Thomas McErlane, Brian Palmer, James Datillo, Heung Dong Kim, Barbara Sands, Carol Roberts, Monica Ashbridge, Maryanne Vivino, William DeCampli, Maryanne Dubois, Judi Galter, Mike Solominow, Linda Corcoran, Sharon Zirin, and Jane Fricko.

	FOOTNOTES

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

Reprint requests to (R.R.C.) Division of Neurology, Children's Hospital of Philadelphia, 324 South 34th St, Philadelphia, PA 19104. E-mail: clancy{at}email.chop.edu

	ABBREVIATIONS

CHD, congenital heart disease; CPB, cardiopulmonary bypass; DHCA, deep hypothermic circulatory arrest; HLHS, hypoplastic left heart syndrome; ATP, adenosine triphosphate; XO, xanthine oxidase; CHOP, Children's Hospital of Philadelphia; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; IV, intravenous(ly); ICU, intensive care unit; OR, odds ratio; CI, 95% confidence interval; ScO₂, cerebral oxygen saturation; TGA, transposition of the great arteries.

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