In this cohort of newborns with congenital heart disease admitted to one of two university hospitals for surgery, nosocomial infection was present in almost 20 percent of the population. Overall, infection had no effect on white matter injury. Bloodstream infection was associated with a trend toward higher frequency of white matter injury in those infants with transposition of the great arteries, but not those with single ventricle anatomy. After adjusting for markers of illness severity, and when considering only the children without stroke, the effect was stronger and significant. Because the pneumonias, bloodstream, and surgical site infections that we identified were hospital acquired, nearly all were potentially preventable.
Newborns with congenital heart disease may be critically ill with unstable hemodynamics before, during and following surgical repair. Multiple risk factors for stroke or white matter injury have been identified in this population, including cyanosis, invasive catheterization, hypotension and cardiac arrest(1
). Each type of congenital heart disease may have variable exposure to specific risk factors such as intracardiac shunting. Given the complex interplay between infection, inflammation and adverse hemodynamics, perhaps it is not surprising that we were not able to uncover a strong association between infection and brain injury in this heterogeneous sample of newborns with congenital heart disease. Nevertheless, these results suggest that the association between bloodstream infection and white matter injury in children with congenital heart disease is not as clear as for preterm children(26
). The larger effect in children with transposition of the great arteries when compared with those with single ventricle anatomy may be related to differences in perioperative hemodynamic stability. The Norwood operation for palliation of single ventricle anatomy is associated with higher risk of mortality and hospital length of stay compared with the arterial switch procedure for correction of transposed great arteries (36
). For children with single ventricle anatomy, the presence of multiple potential risk factors for brain injury over a more prolonged admission may make an effect of infection more difficult to detect. The increased association after excluding those newborns with strokes highlights the fact that multiple potential risk factors, including infection, may have overlapping effects on the brain.
The reasons why children with congenital heart disease are susceptible to white matter injury, a pattern of injury more typically associated with premature birth is not known, but may be related to the fact that children with congenital heart disease appear to have delayed brain growth and maturation, making their brains resemble those of younger gestation children(16
). Brain immaturity is the substrate upon which other insults such as hypotension and hypoxemia provide the proximate injury mechanism. Furthermore, like their preterm counterparts, children with congenital heart disease often have prolonged hospitalizations, extending the period of risk for multiple potential factors including nosocomial infection and hemodynamic instability. White matter injury in preterm newborns appears to be related to damage to pre-oligodendroglial cells, which are important for myelination. These oligodendrocyte precursors are extremely vulnerable to glutamate-receptor mediated injury and cell death following exposure to free radicals, reactive oxygen and nitrogen species, as well as inflammatory cytokines (reviewed in(38
)). The causative “upstream mechanisms” – i.e., the events leading to production of these harmful factors -- are poorly understood, and may include ischemia, and/or infection/inflammation (reviewed in (39
)). There is increasing evidence from clinical studies in preterm newborns that nosocomial infection is an important risk factor for white matter injury (26
). It is not known whether the injury is a direct result of inflammation to the central nervous system or whether it is due to ischemia suffered as a result of impaired cerebral blood flow during periods of hypotension.
We acknowledge several limitations of this study. Although this is the largest reported cohort of newborns with congenital heart disease studied with pre- and post-operative imaging, the relatively small numbers of infants with infection requires our conclusions to be viewed with caution. Moreover, the cohort includes patients with multiple forms of congenital heart disease including transposition of the great arteries and single ventricle anatomy. In this critically ill population, there may be multiple causes for brain injury, and small cohort size may have limited the ability to find an association between our variables of interest. Finally, the optimal timing for detecting white matter injury in this cohort has not been determined; it is therefore possible that we missed white matter injury in some affected newborns who were imaged too early or too late to see changes related to infection, which would further restrict our ability to observe an effect.
The strong association of infection with white matter injury in premature newborns, combined with observations of delayed brain development in term newborns with congenital heart disease, provides clear rationale for the present study. However, heterogeneity inherent in the congenital heart disease population, along with multiple interacting risk factors may have obfuscated a relationship between infection and brain injury in this population. The fact remains that newborns with congenital heart disease suffer acquired brain injury at unacceptably high rates. In this study, we have provided a first measurement of the association of nosocomial infection with brain injury in infants with congenital heart disease. Interventions to reduce nosocomial infection may decrease brain injury, but a larger sample in more uniform populations will be necessary to definitively prove this concept. An alternative possibility is that previously identified risk factors for brain injury that directly impair brain oxygen delivery are relatively more potent, and thus more important, determinants of brain injury in newborns with congenital heart disease.
In order to improve developmental outcomes in this population, each of the risk factors for brain injury must be addressed individually. The infections that we identified in this study were hospital acquired, and therefore many may have been preventable. The suggestion that infection prevention has the potential to mitigate long-term neurologic impairment as a consequence of white matter injury underscores the importance of vigilant attention to infection control practices for pediatric patients undergoing cardiac surgery.