Repetitive apnea is commonly associated with the perinatal period. Apneic episodes longer than 15 s and accompanied by hypoxia or bradycardia have been reported to occur in all infants with gestational ages less than 34 weeks. Apneic episodes requiring ventilatory support or pharmacologic intervention occur in at feast 50% of surviving infants weighing less than 1500 g at birth. The cumulative effect of brief but repetitive apnea may have clinical significance for later neurological function. The physiological mechanisms of apneic spells, however, are still poorly understood, due in part to the lack of reliable measurements of oxygenation of the brain. In these studies, the oxygen dependent quenching of phosphorescence, a noninvasive optical method for measuring oxygen developed in our laboratory, will be used to measure the oxygen in the microvasculature of the brain tissue. This method will allow continuous evaluation of the status of tissue oxygenation during apnea and post-apneic recovery. Thus, it will be possible, for the first time, to comprehensively analyze the changes in oxygen pressure that occur in the brain during apnea and recovery. Our experimental model will be newborn piglets. The different levels of inspired oxygen used during apnea models and post-apnetic recovery will represent clinically relevant conditions. The oxygen measurements will be coupled with measurements of the status of brain metabolism and the extent of brain injury. The mechanism(s) of cellular dysfunction and/or injury induced by the apnea will be examined at both the cellular and molecular levels. Changes in extracellular levels of dopamine and hydroxyl radicals, measured by in vivo microdialysis, will be used as markers of tissue hypoxia and a cellular dysfunction. The role of dopamine and hydroxyl radicals in brain injury will be also determined. The amplified antisense RNA (aRNA) technique will be used to screen multiple genes that may be altered in expression level during apnea and recovery. The genes which were chosen are directly or indirectly associated with dopamine. The morphological, immunohistochemical, temporal patterns and the severity of damage will be determined using standard histologic staining with Fluoro-Jade, and antibodies against APP/APLP and GFAP. These studies will result in a better understanding of the mechanisms causing the brain injury in response to repetitive apnea and provide an approach to evaluating the efficacy of procedural alterations designed to minimize this injury.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041484-03
Application #
6790603
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Higgins, Rosemary
Project Start
2002-07-17
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$320,963
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Mendoza-Paredes, Alberto; Liu, Huiping; Schears, Gregory et al. (2008) Resuscitation with 100%, compared with 21%, oxygen following brief, repeated periods of apnea can protect vulnerable neonatal brain regions from apoptotic injury. Resuscitation 76:261-70
Markowitz, Scott D; Mendoza-Paredes, Alberto; Liu, Huiping et al. (2007) Response of brain oxygenation and metabolism to deep hypothermic circulatory arrest in newborn piglets: comparison of pH-stat and alpha-stat strategies. Ann Thorac Surg 84:170-6
Pastuszko, Peter; Liu, Huiping; Mendoza-Paredes, Alberto et al. (2007) Brain oxygen and metabolism is dependent on the rate of low-flow cardiopulmonary bypass following circulatory arrest in newborn piglets. Eur J Cardiothorac Surg 31:899-905
Schultz, Steven; Antoni, Diego; Shears, Gregory et al. (2006) Brain oxygen and metabolism during circulatory arrest with intermittent brief periods of low-flow cardiopulmonary bypass in newborn piglets. J Thorac Cardiovasc Surg 132:839-44
Schears, Gregory; Zaitseva, Tatiana; Schultz, Steven et al. (2006) Brain oxygenation and metabolism during selective cerebral perfusion in neonates. Eur J Cardiothorac Surg 29:168-74
Zaitseva, Tatiana; Schultz, Steven; Schears, Gregory et al. (2006) Regulation of brain cell death and survival after cardiopulmonary bypass. Ann Thorac Surg 82:2247-53
Wilson, David F; Vinogradov, Sergei A; Grosul, Pavel et al. (2006) Imaging oxygen pressure in the rodent retina by phosphorescence lifetime. Adv Exp Med Biol 578:119-24
Schears, Gregory; Creed, Jennifer; Antoni, Diego et al. (2006) Brain injury following repetitive apnea in newborn piglets. Adv Exp Med Biol 578:323-9
Schears, Gregory; Antoni, Diego; Schultz, Steven et al. (2005) Brain oxygenation and metabolism during repetitive apnea with resuscitation of 21% and 100% oxygen in newborn piglets. Neurochem Res 30:1453-61

Showing the most recent 10 out of 15 publications