Methemoglobin formation in children with congenital heart disease treated with inhaled nitric oxide after cardiac surgery

Background

Inhaled nitric oxide is used as a therapy of pulmonary hypertension in children after cardiac surgery. Hemoglobin binds to nitric oxide with great affinity and forms methemoglobin by oxidation in the erythrocyte. Once produced, methemoglobin is unable to transport and unload oxygen in the tissues. The amount of available hemoglobin in the body for oxygen transport is thereby reduced. Anemia, acidosis, respiratory compromise, and cardiac disease may render patients more susceptible than expected for a given methemoglobin level. The goal of the present study was to investigate the effect of inhaled nitric oxide on methemoglobin formation in critical ill children. We therefore measured methemoglobin levels in children with congenital heart disease after cardiac surgery who where treated with inhaled nitric oxide in a range of 5 to 40 ppm.

Methods

We enrolled 38 children with congenital heart disease after cardiac surgery into a retrospective chart review study. We extracted demographic data and physiological measurements at the following time points: (1) T0 = before starting inhaled nitric oxide therapy, (2) T1 = 24 hours after begin of inhaled nitric oxide therapy, (3) T2 = half-time therapy, (4) T3 = end of therapy, (5) T4 = 24 hours after finishing inhaled nitric oxide therapy.

Results

Median duration of inhaled nitric oxide therapy was 5.5 days (quarter percentiles 3/9, range 2–29), nitric oxide concentration at T1 and T2 was 16 ppm (10/20, 5–40) and 12.5 ppm (7.7/20, 2–40) respectively. Median cumulative dose of inhaled nitric oxide was 1699 ppm (809/3122, 193–7018). Methemoglobin levels increased moderately but significantly during therapy (T0 vs T1, P < 0.05 and T0 vs T2, P < 0.001). Comparing methemoglobin levels during therapy showed a significant difference between: T1 vs T3 (P < 0.05), T1 vs T4 (P < 0.001) T2 vs T3 and T4 (P < 0.001). The highest measured methemoglobin level was 3.9%. Methemoglobin levels correlated positively with the applied inhaled nitric oxide doses at T1 (r² = 0.4086; P < 0.01) and at T2 (r² = 0.5477; P < 0.01). At T1 methemoglobin level was negatively correlated with T1 blood pH value. The overall mortality rate was 13.2% (five of 38 study patients died).

Conclusion

This study extends the findings of previous reports that methemoglobin levels did not cause toxic adverse effects in children with congenital heart disease after cardiac surgery treated with inhaled nitric oxide. We recommend the use of the minimal effective dose of inhaled nitric oxide and continuous monitoring of methemoglobin levels especially in cases of anemia or sepsis.