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Article Reviewed:

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

Clancy RR, MCGaurn SA, Goin JE, et al.

Pediatrics 2001;108 61-70. [abstract][full-text for subscribers/AAP members]

Reviewed by Amr Shahin, MBBCh, University of Tennessee, Memphis, TN

Review posted July 13, 2002

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I. What is being studied?:

The study objective:

The hypothesis tested by this study is that allopurinol, a scavenger and inhibitor of oxygen free radical production reduces death, seizures, coma, and cardiac events in infants who undergo heart surgery using deep hypothermic circulatory arrest (DHCA).

The study design:

Single center, randomized, placebo controlled, blinded trial. Enrolled infants were assigned to one of two strata based on cardiac lesion. The first stratum is comprised of infants with hypoplastic left heart syndrome (HLHS). The second stratum is comprised of infants with other cardiac lesions (non-HLHS) requiring DHCA. The surgery performed on all HLHS infants was stage 1 palliation, whereas there was no standard operation for the non-HLHS sub-group.

The patients included:

Infants who underwent surgery for congenital heart disease with DHCA between 1992 and 1997 at Children's Hospital Of Philadelphia. All infants' postconceptual age was less than 45 weeks (weeks of age plus weeks of gestation) and without lethal genetic disorders or severe multiple congenital anomalies. The intention-to-treat population was made up of 318 patients that met these criteria. Of these, 131 infants (41%) were in the HLHS subgroup, and 187 (59%) were in the non-HLHS subgroup. The non-HLHS subgroup included infants with anomalies such as single ventricle, transposition of the great arteries, Tetralogy of Fallot, VSD and others.

The patients excluded:

• Patients neurologically not assessable prior to surgery (presence of neuromuscular blockade, coma, or seizures).
• Patients with liver chemistry values consistent with known Allopurinol hypersensitivity, and those with neutropenia.
• Patients that would have had to be enrolled less than 16 hours before surgery. Sixteen hours was the predetermined time for administration of the Allopurinol regimen based on pharmacokinetic determination of drug half-life, nadir levels, and uric acid reduction effect.

The interventions compared:

Allopurinol or placebo was given to all infants according to a schedule started before the operation. The dosage schedule was based on known pharmacokinetic determinants of the drug. The first dose was given at least 16 hours before anticipated surgery. The second 8 hours before surgery; the third at 7 am on the morning of surgery, and the fourth dose was given intraoperatively, administered into the CPB pump circuitry. Nine postoperative q 8 hr doses were also administered. 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.

The authors stated that based on previous pharmacokinetic studies adequate exposure was considered to be at least 1 of the 4 intended doses on the day before or day of surgery. Two observations must be made here. The first is that there was no mention of compliance in either group with the 9 postoperative doses. The second is that it was not clear from the study nor from the reference quoted the duration of by-product reducing effect after administration of allopurinol. More specifically, is one dose equal to 13 doses when it comes to allopurinol effect?

The outcomes evaluated:

The primary efficacy endpoint was a composite of death, seizures or coma. The occurrence of any of these three events resulted in recording a primary efficacy endpoint event. Secondary analysis incorporated cardiac events into the primary efficacy endpoint model. Treatment effects were evaluated by individual endpoint events and combinations of endpoint events. Cardiac events were defined as periods of acute, severe cardiorespiratory deterioration necessitating immediate resuscitation such as chest compressions or cardiac massage, defibrillation, or acute boluses of inotropic agents.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Within each stratum or subgroup, the assignment of patients to either allopurinol or placebo was randomized. 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.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes, no patients were lost to followup in the post-operative period (not exceeding 6 weeks after surgery).

Were patients analyzed in the groups to which they were randomized?

Yes. There was no crossover between groups; analysis was by intention-to-treat.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes, all were, except for the pharmacy staff. Investigators and data collectors were also masked to treatment assignment.

4. Was the group homogeneous at the start of the trial?

The groups were similar for demographic characteristics, but the treated patients in the non-HLHS strata were significantly more mature (approximately 1 week higher gestational age) and heavier at birth (~3.3 vs. 3.0 kg).

5. Aside from the experimental intervention, was the group treated consistently?

The groups were similar with respect to type of anesthesia, CPB time, and type of anesthesia, the DHCA time, and the performance of modified ultrafiltration and intensive care practices. The investigators state that they included "surgeon, treatment group, and stratum" as independent variables in their logistic regression analysis, with the occurrence of a clinical endpoint event as the dependent variable. This implies that the odds ratios given for treatment effect are controlled for any effect that differences in surgeons would make.

III. What were the results?

1. How large was the treatment effect?

There was no treatment effect when the primary definition of endpoints (death, coma, seizures) was applied. However, with the expansion of the definition of efficacy endpoint to include occurrence of cardiac events as well, this led to the observation of a treatment effect. This treatment effect however was noted only in the HLHS stratum, with fewer occurrences of "death, seizures, coma or cardiac events" in the treatment arm of this stratum compared to the placebo arm 38% vs. 60%. The OR (95%CI) = 0.40 (0.20, 0.82). A more useful number to report is the RR, not the OR - the RR is 0.63 with 95% CI's of 0.43, 091] the RRR (95% CI) = 37% (9%, 56%). The number needed to treat to prevent one endpoint event is NNT (95%CI) = 5 (3, 19). No treatment-related reduction in death was observed.

Further analysis of treatment effect in the survivor groups of both strata revealed significantly (p=0.002) fewer occurrences of efficacy endpoints in HLHS stratum treatment arm. In HLHS survivors, 40 of 47 (85%) allopurinol-treated infants had no endpoint event, compared with 27 of 49 (55%) controls. The RR (95% CI) in the treated vs. control groups was 0.35 (0.16, 0.75). Although they prospectively studied the primary and secondary endpoints in the two strata, there is no mention of evaluating subgroups of survivors. There is a risk of over-interpretation in such multiple subgroup post-hoc analysis.

2. How precise was the estimate of the treatment effect?

95% confidence intervals for the relative risk of death, seizures, coma or cardiac events in the HLHS patients suggests the relative risk could be as great as 0.91 or as little as 0.43. The 95% confidence intervals for relative risk in the survivor treated arm vs. controls could be as high as 0.75 and as low as 0.16.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

The results suggest that allopurinol is of no benefit to non-HLHS patients, and may be of benefit to those with HLHS. A study from the same hospital looked at the use of allopurinol for potential prevention or amelioration of ischemia reperfusion injury in infants undergoing ECMO and was published in Pediatric Research in 1997 (1). That study demonstrated that allopurinol given before cannulation for and during ECMO significantly inhibits purine degradation and uric acid production, and may reduce the production of oxygen free radicals during reoxygenation and reperfusion of hypoxic neonates recovered on bypass. That study looked at purine metabolism and did not look at outcomes. The numbers enrolled were small (n=25).

The present study certainly presents us with an interesting research question, but the "jury's still out."

2. Were all clinically important outcomes considered?

Yes, all clinically important outcomes are considered in this complex patient population. A longer observation period could result in the occurrence of more endpoint events in either group.

3. Are the likely treatment benefits worth the potential harms and costs?

Until further research concludes a definitive role for free radical scavengers in this patient population, this question will continue to be one answered on an individual basis.

References

1. Marro PJ, Baumgart S, Delivoria-Papadopoulos M, et al. Purine metabolism and inhibition of xanthine oxidase in severely hypoxic neonates going onto extracorporeal membrane oxygenation. Pediatr Res. 1997;41(4 Pt 1):513-20. [abstract]
2. McGaurn SP, Davis LE, Krawczeniuk MM, et al. The pharmacokinetics of injectable allopurinol in newborns with the hypoplastic left heart syndrome. Pediatrics. 1994;94(6 Pt 1):820-3. [abstract]

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