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

Clancy, Robert R.; McGaurn, Susan A.; Goin, James E.; Hirtz, Deborah; Norwood, William I.; Gaynor, J. William; Jacobs, Marshall L.; Wernovsky, Gil; Mahle, William T.; Murphy, John D.; Nicolson, Susan C.; Steven, James M.; Spray, Thomas L.

doi:10.1542/peds.108.1.61

Cited by 123 publications

(73 citation statements)

References 43 publications

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“…With the exception of hypothermia (60,61) and allopurinol (62), the clinical application of these therapies in the treatment of the brain injury in the human newborn has been limited. Accordingly, there is a need for further therapeutic modalities for perinatal brain injury, which, alone or in combination with other therapies, are neuroprotective but have a low risk of adverse side effects in the asphyxiated newborn.…”

Section: Discussionmentioning

confidence: 99%

L-Carnitine Reduces Brain Injury after Hypoxia-Ischemia in Newborn Rats

et al. 2003

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Perinatal hypoxia-ischemia remains a significant cause of neonatal mortality and neurodevelopmental disability. Numerous lines of evidence indicate that cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine (3-hydroxy-4-N-trimethylammonium-butyrate) has an essential role in fatty acid transport in the mitochondrion and in modulating potentially toxic acyl-CoA levels in the mitochondrial matrix. There are no naturally occurring esterases available to reduce the accumulation of acyl-CoA but this process can be overcome by exogenous carnitine. We used a newborn rat model of perinatal hypoxia-ischemia to test the hypothesis that treatment with Lcarnitine would reduce the neuropathologic injury resulting from hypoxia-ischemia in the developing brain. We found that treatment with L-carnitine during hypoxia-ischemia reduces neurologic injury in the immature rat after both a 7-and 28-d recovery period. We saw no neuroprotective effect when L-carnitine was administered after hypoxia-ischemia. Treatment with D-carnitine resulted in an increase in mortality during hypoxia-ischemia. Carnitine is easy to administer, has low toxicity, and is routinely used in neonates as well as children with epilepsy, cardiomyopathy, and inborn errors of metabolism. L-Carnitine merits further investigation as a treatment modality for the asphyxiated newborn or as prophylaxis for the at-risk fetus or newborn. Hypoxic-ischemic injury in the developing brain is characterized by a cascade of cellular events that evolve for hours or days, a distinct clinical syndrome manifest as encephalopathy, a combination of ischemia superimposed on hypoxia, and specific regional brain vulnerability to injury (1-3). Cerebral ischemia in the adult (4) and hypoxia-ischemia in the newborn (5) disrupt mitochondrial function leading to a collapse in cell energy metabolism.The amino acid derivative carnitine (3-hydroxy-4-Ntrimethylammonium-butyrate) is required for the maintenance of normal mitochondrial function. Carnitine has three major functions: facilitating transport of acyl moieties between organs and across the mitochondrial inner membrane and the buffering of potentially toxic intracellular acyl-CoA moieties (6, 7). High levels of acyl-CoA esters impair numerous mitochondrial processes (Fig. 1) (8 -10). There are no endogenous esterases available to reduce the accumulation of acyl-CoA esters. This process can be overcome by the addition of exogenous carnitine. Carnitine may function therefore in acute metabolic crises to trap toxic acyl-CoA moieties that impair fatty acid oxidation, urea cycle function metabolism, and gluconeogenesis (6,7,11).Carnitine has been tested as a neuroprotective therapy in adult animal models of cerebral ischemia (12-14). However, there are no data directly addressing the effect of L-carnitine treatment on cerebral ischemic injury in the newborn. LCarnitine is potentially an attractive therapeutic modality for perinatal asphyxia given the extensive pediatric clinical experience with the use of th...

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Section: Discussionmentioning

confidence: 99%

L-Carnitine Reduces Brain Injury after Hypoxia-Ischemia in Newborn Rats

et al. 2003

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“…128,129 Notably, a study that assessed brain maturation by magnetic resonance imaging (MRI) in a cohort of full-term neonates with CHD after birth revealed an average brain maturation of only 35 weeks' gestation. 69 Newborns with complex CHD who require a palliative or reparative surgical procedure as a neonate or infant have a prevalence of microcephaly that varies from 8% to 33%, depending on the specific lesion, 68,70,125,130,131 and half will have abnormal neurobehavioral findings (hypotonia, hypertonia, jitteriness, motor asymmetries, and absent suck) before any cardiothoracic surgical intervention. 70 Low brain maturity scores have been shown to be associated with a higher risk of acquired brain injury in newborns with CHD.…”

Section: Significant Abnormalities On Neuroimaging or Microcephalymentioning

confidence: 99%

Neurodevelopmental Outcomes in Children With Congenital Heart Disease: Evaluation and Management

Marino¹,

Lipkin²,

Newburger³

et al. 2012

Circulation

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1,336

1,156

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Background— The goal of this statement was to review the available literature on surveillance, screening, evaluation, and management strategies and put forward a scientific statement that would comprehensively review the literature and create recommendations to optimize neurodevelopmental outcome in the pediatric congenital heart disease (CHD) population. Methods and Results— A writing group appointed by the American Heart Association and American Academy of Pediatrics reviewed the available literature addressing developmental disorder and disability and developmental delay in the CHD population, with specific attention given to surveillance, screening, evaluation, and management strategies. MEDLINE and Google Scholar database searches from 1966 to 2011 were performed for English-language articles cross-referencing CHD with pertinent search terms. The reference lists of identified articles were also searched. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. A management algorithm was devised that stratified children with CHD on the basis of established risk factors. For those deemed to be at high risk for developmental disorder or disabilities or for developmental delay, formal, periodic developmental and medical evaluations are recommended. A CHD algorithm for surveillance, screening, evaluation, reevaluation, and management of developmental disorder or disability has been constructed to serve as a supplement to the 2006 American Academy of Pediatrics statement on developmental surveillance and screening. The proposed algorithm is designed to be carried out within the context of the medical home. This scientific statement is meant for medical providers within the medical home who care for patients with CHD. Conclusions— Children with CHD are at increased risk of developmental disorder or disabilities or developmental delay. Periodic developmental surveillance, screening, evaluation, and reevaluation throughout childhood may enhance identification of significant deficits, allowing for appropriate therapies and education to enhance later academic, behavioral, psychosocial, and adaptive functioning.

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“…Both are triggered by cardiac surgery with CPB (7,26,27) and suspected to contribute to the postoperative neurologic dysfunctions (6,28). We expected ␦P to increase when oxidative stress (e.g.…”

Section: Discussionmentioning

confidence: 99%

Electroencephalographic Changes after Pediatric Cardiac Surgery with Cardiopulmonary Bypass: Is Slow Wave Activity Unfavorable?

et al. 2005

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Pediatric cardiac surgery with cardiopulmonary bypass (CPB) is frequently associated with neurologic deficits. We describe the postoperative EEG changes, assess their possible causes, and evaluate their relevance to neurologic outcome. Thirty-one children and five neonates with congenital heart disease were included. EEG recording started after intubation and continued until 22-96 h after CPB. In addition to conventional analysis, spectral analysis was performed for occipital and frontal electrodes, and differences between pre-and postoperative delta power (delta-␦P) were calculated. Maximum values of occipital delta-␦P that occurred within 48 h after CPB were correlated with clinical variables and with perioperative markers of oxidative stress and inflammation. Occipital delta-␦P correlated with frontal delta-␦P, and maximum delta-␦P correlated with conventional rating. Distinct rise of ␦P was detected in 18 of 21 children without any acute or long-term neurologic deficits but only in five of 10 children with temporary or permanent neurologic deficits. Furthermore, maximally registered delta-␦P was inversely associated with duration of CPB and postoperative ventilation. Maximal delta-␦P was also inversely associated with the loss of plasma ascorbate (as an index of oxidative stress) and plasma levels of IL-6 and IL-8. Slow wave activity frequently occurs within 48 h after CPB. However, our data do not support the notion that EEG slowing is associated with adverse neurologic outcome. This is supported by the fact that EEG slowing was associated with less oxido-inflammatory stress. Abbreviations AC, aortic cross-clamping CPB, cardiopulmonary bypass FFT, fast Fourier transformation max delta-␦P, maximum difference between pre-and postoperative delta power MDA, malondialdehyde MDA-TNL, malondialdehyde corrected for total neutral lipids ␦P, delta power delta-␦P, difference between pre-and postoperative delta power Cardiac surgery with cardiopulmonary bypass (CPB) in children and neonates is frequently associated with acute neurologic symptoms and long-term neurologic deficits (1-4). Neuropsychological deficits persist in a substantial number of patients. During the intraoperative period, a global decrease in perfusion and oxygen delivery and focal ischemia related to embolic insults or diffuse microvascular changes are the principal mechanisms of brain damage (5). Systemic inflammation and reactive oxygen species generated by CPB might contribute to postoperative neurologic dysfunction (6,7). Impaired cerebral vasoregulation and ischemia/reperfusion injury continues in the early postoperative period (8,9). Postoperative cardiopulmonary dysfunction may additionally threaten cerebral perfusion pressure and oxygen delivery. However, there is an increased energy demand to restore neuronal membrane function and ionic gradients that are compromised by CPB.Events that affect the brain are usually followed by neuronal dysfunction, which can often be detected by EEG changes.

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

Cited by 123 publications

References 43 publications

L-Carnitine Reduces Brain Injury after Hypoxia-Ischemia in Newborn Rats

L-Carnitine Reduces Brain Injury after Hypoxia-Ischemia in Newborn Rats

Neurodevelopmental Outcomes in Children With Congenital Heart Disease: Evaluation and Management

Electroencephalographic Changes after Pediatric Cardiac Surgery with Cardiopulmonary Bypass: Is Slow Wave Activity Unfavorable?

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