Congenital heart disease (CHD), the most common significant birth defect, affects 8 per 1000 live births (estimated 30-40,000 children each year). Children with CHD often require surgical interventions. Support techniques integral to cardiac surgery include cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). These procedures may result in detrimental effects in these vulnerable pediatric patients. The early, enthusiastic use of DHCA, particularly in neonates, has been tempered by the finding of significant neurological morbidity associated with its prolonged exposure. Children who had undergone heart surgery with CPB and DHCA as neonates and infants were evaluated after they reached preschool and school age. These children were found to have distinctive patterns of neurological disturbance characterized by cognitive impairment, impaired executive function, expressive speech and language abnormalities, impaired visual-spatial and visual-motor skills, attention deficit/hyperactivity disorder, motor delays, and learning disabilities The neuropathological basis for these disturbances include (i) post-operative periventricular leukomalacia, seen in over 50% of post- operative MRI scans;(ii) post-operative seizures which arise in about 11%;and (iii) stroke, demonstrated in about 9% of post-operative MRIs. It is therefore extremely important to find the conditions which will decrease the neurologic sequelae of CPB and DHCA and protect the brain from injury. Further progress in the improvement of therapeutic and preventive strategies with respect to cerebral injury during cardiac bypass depends on increased understanding of how DHCA affects the critical cellular neuropathologic processes that lead to cell death. This research will continue to study the mechanisms responsible for DHCA-dependent neuronal injury and determine the efficacy of neuroprotection by two promising compounds, GCSF and topiramate, and of hypothermia during post-bypass recovery. In this series of experiments, we will characterize the brain injury patterns with commonly used clinical DHCA and CPB strategies, and extend the potential for neuroprotection by studying emerging neuroprotective stategies (hypothermia 32-34C) and clinically applicable agents (GCSF, topiramate), alone or in combination. We will discover how the timing, intensity, and duration of neuroprotective exposure affects vulnerable neonatal brain injury and the activation of cell injury and death processes. These findings will help define the contributions of selected mechanisms by which hypoxic- ischemic brain injury induced by DHCA, CPB and reperfusion is likely to occur, as well as evaluate clinically applicable neuroprotective strategies that have the potential to significantly improve neurologic outcomes for infants and children.

Public Health Relevance

Newborns who survive heart surgery face a variety of neurological deficits, including global cognitive dysfunction, visual-spatial disorders, impaired fine and gross motor control, impaired executive/planning function and attention deficit hyperactivity disorder. This research will determine the mechanisms brain injury by the surgical procedures, and critically evaluate mild hypothermia as well as two promising protective agents, Granulocyte Colony-Stimulating Factor (GCSF) and Topiramate both alone and together, for their efficacy in protecting the brain from injury resulting from the surgery.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058669-12
Application #
8280214
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Kaltman, Jonathan R
Project Start
1999-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
12
Fiscal Year
2012
Total Cost
$454,744
Indirect Cost
$148,487
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pastuszko, Peter; Schears, Gregory J; Greeley, William J et al. (2014) Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet. Neurochem Res 39:2085-92
Topjian, Alexis A; French, Benjamin; Sutton, Robert M et al. (2014) Early postresuscitation hypotension is associated with increased mortality following pediatric cardiac arrest. Crit Care Med 42:1518-23
Pastuszko, Peter; Schears, Gregory J; Pirzadeh, Afsaneh et al. (2012) Effect of granulocyte-colony stimulating factor on expression of selected proteins involved in regulation of apoptosis in the brain of newborn piglets after cardiopulmonary bypass and deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 143:1436-42
Wilson, David F; Vinogradov, Sergei A; Schears, Gregory J et al. (2012) Monitoring cardiopulmonary function and progression toward shock: oxygen micro-sensor for peripheral tissue. Adv Exp Med Biol 737:221-7
Pirzadeh, Afsaneh; Schears, Gregory; Pastuszko, Peter et al. (2011) Effect of deep hypothermic circulatory arrest followed by low-flow cardiopulmonary bypass on brain metabolism in newborn piglets: comparison of pH-stat and *-stat management. Pediatr Crit Care Med 12:e79-86
Wilson, David F; Finikova, Olga S; Lebedev, Artem Y et al. (2011) Measuring oxygen in living tissue: intravascular, interstitial, and "tissue" oxygen measurements. Adv Exp Med Biol 701:53-9
Pirzadeh, A; Mammen, A; Kubin, J et al. (2011) Early regional response of apoptotic activity in newborn piglet brain following hypoxia and ischemia. Neurochem Res 36:83-92
Mammen, A; Kubin, J; Greeley, W J et al. (2011) Effect of hypoxia on expression of selected proteins involved in regulation of apoptotic activity in striatum of newborn piglets. Neurochem Res 36:746-53
Pastuszko, Peter; Pirzadeh, Afsaneh; Reade, Erin et al. (2009) The effect of hypothermia on neuronal viability following cardiopulmonary bypass and circulatory arrest in newborn piglets. Eur J Cardiothorac Surg 35:577-81;discussion 581
Wilson, David F (2008) Quantifying the role of oxygen pressure in tissue function. Am J Physiol Heart Circ Physiol 294:H11-3

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