We demonstrated a 10% prevalence of stroke in neonates and infants with CHD undergoing cardiac operations using CPB, half of which occurred preoperatively. This large, prospective cohort study evaluating stroke in infants with CHD, in which brain MRI was used for case ascertainment, shows that infarcts in these infants are almost always clinically covert, with a wide spectrum of size, chronicity, and anatomic distributions. In keeping with the clinically silent nature of these lesions acutely, we found that the most reliable assessment of stroke in this population is by prospective systematic imaging with MRI examination. Both arterial-occlusive and watershed infarcts were found, suggesting a multifactorial mechanism of stroke in patients with CHD that may include thromboembolism and hypoperfusion. The varying ages of the infarcts indicate multiple time points from birth, and possibly prenatally, when these children are vulnerable to brain injury.
Variables associated with stroke in our cohort included lower birth weight, preoperative intubation, lower hematocrit level after hemodilution on bypass, and elevated SBP upon CICU admission. Gestational age, PGE1
use, cardiac anatomy, and DHCA duration were not significantly different between patients with and without stroke. The number of patients with stroke was too small to differentiate between risk factors for focal arterial occlusive and watershed lesions. The association of low birth weight would suggest that fetal blood flow patterns and placental sufficiency might be involved in the pathogenesis of stroke in infants with CHD [14
]. Preoperative mechanical ventilation might be a marker of increased cardiopulmonary instability in the preoperative period and has been identified as a risk factor for both death and CICU morbidity [15
]. Hypotension and hypoxemia have previously been shown to be associated with PVL [8
]; however, these risk factors were not significantly associated with stroke in our population. A possible explanation may be that cerebral blood flow patterns are different in children with PVL compared with those who with perioperative stroke. Variations in other factors that affect cerebral oxygen delivery, such as pH and Paco2
, were not identified as risk factors for stroke.
In the Boston Circulatory Arrest Study (BCAS), limited to patients with transposition of the great arteries, brain MRI imaging at age 1 year revealed definite abnormalities in 15% and possible abnormalities in an additional 8% [16
]. Stroke was not specifically reported. The only significant risk factor for MRI abnormalities was preoperative acidosis. Similarly, our data show no significant association of DHCA use or duration or total CPB time with stroke. The sole intraoperative variable associated with stroke was a lower hematocrit after hemodilution on CPB. Hemodilutional anemia during CPB has been shown to be associated with histologic evidence of cerebral ischemic damage in animal models and lower Psychomotor Developmental Index scores in children at 1 year [17
Other studies evaluating brain MRI abnormalities have also demonstrated varying ages of lesions relative to birth and procedures, with preoperative and postoperative periods presenting a continuum of risk in infants with CHD. Dent and colleagues [19
] reported focal or diffuse ischemic lesions in 23% and 53% of patients in the preoperative and postoperative periods, respectively, after the Norwood procedure. In their study, a greater base deficit was associated with preoperative ischemia, whereas prolonged low regional cerebral oxygen saturation (< 45% for > 90 minutes) was associated with postoperative changes. In another study limited to patients with transposition, McQuillen and colleagues [20
] found low Apgar scores at 5 minutes and need for balloon atrial septostomy to be associated with preoperative stroke. Risk factors for postoperative injury included lowest flow and largest base deficit during CPB and decreased mean blood pressure on postoperative day 1.
The current study has several limitations. The absence of preoperative MRIs precludes definitive identification of the timing of occurrence of stroke and limits the interpretation of cause and effect among potential risk factors. In addition, only 1 patient underwent a detailed neurologic examination in the immediate postoperative period, potentially limiting the clinical identification of strokes identified on the MRI studies.
This study was also not designed to systematically evaluate all patients for other risk factors for stroke such as thrombophilia or anatomic anomalies in the cervical or cranial circulation.
Finally, our results may have been affected by selection bias, because not all patients from the ongoing studies had postoperative MRIs. Patients who were discharged before undergoing a MRI would overestimate the prevalence of stroke, whereas patients with instability precluding a MRI might underestimate the prevalence.
In conclusion, we found a 10% prevalence of stroke on postoperative MRI imaging in neonates and infants undergoing operations for CHD that used CBP with or without DHCA. Almost all strokes were clinically silent. Focal arterial occlusive and watershed infarcts were present, suggesting thromboembolism and hypoperfusion were both mechanisms of injury. Risk factors for stroke included lower birth weight, preoperative mechanical ventilation, and lower hematocrit during CPB. Importantly, other operative variables, such as duration of CPB and the use of DHCA, were not significantly associated with an increased risk of stroke. In contrast to our study evaluating risk factors for PVL in the same cohort, postoperative hypoxemia and hypotension were not associated with an increased risk of stroke, suggesting that the mechanisms underlying the two forms of cerebral injury are different.
Ongoing neurodevelopmental studies will investigate the effect of stroke on short-term and long-term functional outcomes. More complete evaluation of stroke risk factors, including thrombophilia and vascular anomalies as well as serial neuroimaging, may provide additional insight concerning mechanisms and potential treatment strategies.