A total of 355 infants have been treated with ECMO at our hospital between 1985 and 1996, 271 of whom have been enrolled in an ongoing prospective study; of the 271 infants enrolled, 223 (82%) survived, and most function within the normal range of development. Nevertheless, handicapping sequelae, including spastic forms of CP, hearing loss, and cognitive deficiencies at school age, have been noted in a significant minority of ECMO-treated survivors. The need for RCCA cannulation during venoarterial ECMO may increase the risk of a cerebrovascular injury, and lateralized CBF abnormalities have been noted on CDI and pulsed Doppler ultrasound studies during and after venoarterial bypass; however, post-ECMO CT scans, HUS, MR images, or clinical evaluations have not indicated selective or greater injury to the right, compared with the left, cerebral hemisphere in our survivors, nor was there a significant predilection for right, rather than left, cerebral hemispheric EEG abnormalities during or following venoarterial bypass. Although we routinely repair the RCCA following venoarterial ECMO, the long-term consequences of a permanently ligated artery have not as yet been demonstrated. We have noted the ominous predictive value of two or more recordings that disclose ES and BS EEG abnormalities before or during venoarterial ECMO and found that the need for vigorous CPR before or during RCCA cannulation significantly increased the risk of these two markedly abnormal bioelectric patterns. Because 85% of infants with severe respiratory failure have moderate to marked EEG abnormalities (including 23% who have BS or ES patterns) before ECMO, we believe that fetal and neonatal complications related to the occurrence and treatment of severe cardiorespiratory failure are responsible in large part for the neurologic sequelae in ECMO survivors. The risk for CP was significantly increased in survivors of neonatal venoarterial ECMO treated at our hospital who required CPR or who independently had a systolic BP below 39 mm Hg before or during ECMO. We also noted that the risk for hearing loss was increased significantly in surviving neonates who had a PaCO2 below 14 mm Hg before ECMO. The possibility that undetected confounding variables were, in part, responsible for the neurologic, audiologic, and cognitive sequelae in ECMO survivors could not be excluded entirely by our data analyses. Although the pathogenesis of severe brain damage has not been defined fully in neonates treated with ECMO, focal, multifocal, or diffuse cerebral ischemia is the most likely final common pathway; thrombosis, infarction, or hemorrhage may follow and contribute to the brain injury. The cause of isolated SNHL is unknown in most affected ECMO survivors, but in some very likely is associated with the complications and treatment of severe cardiorespiratory failure, including profound hypocarbia prior to ECMO. The results of our studies to date are consistent with the following conclusions: (1) hypotension before or during ECMO and the need for CPR before ECMO contribute to the pathogenesis of CP, probably through the mechanism of cerebral ischemia; (2) profound hypocarbia before ECMO and delayed ECMO treatment are associated with a significantly increased risk of hearing loss; (3) hypoxemia without hypotension does not result in CP; (4) the type and severity of neurologic and cognitive sequelae in ECMO survivors depends, in part, on the primary cause of the neonatal cardiorespiratory failure; (5) early neurodevelopment, except for severe deficits, may not predict school-age performance; and (6) abnormally low or borderline WPPSI-R IQ scores and academic deficiencies at early school age, without evidence of a congenital abnormality of brain or CP or SNHL, remain unexplained. The criteria for initiating ECMO in the neonate with severe cardiorespiratory failure include decreasing oxygenation despite mechanical hyperventilation with 100% oxygen. (ABSTRACT TRUNCATED)