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PEDIATRICS Vol. 111 No. 2 February 2003, pp. 358-363

Vascular Endothelial Growth Factor in the Cerebrospinal Fluid of Infants Who Died of Sudden Infant Death Syndrome: Evidence for Antecedent Hypoxia

Objectives. Recurrent hypoxemia has been proposed as an important pathophysiological mechanism underlying sudden infant death syndrome (SIDS). However, conflicting results emerged when xanthines were used as markers for hypoxia. The vascular endothelial growth factor (VEGF) gene is highly sensitive to changes in tissue partial oxygen tension, and changes in genomic and protein expression occur even after changes in oxygenation within the physiologic range.

Methods. For determining whether hypoxia precedes SIDS, VEGF levels were measured using an enzyme-linked immunosorbent assay in the cerebrospinal fluid (CSF) of 51 SIDS infants and in 33 additional control infants who died of an identifiable cause. In addition, 6 rats that had a chronically implanted catheter in the lateral ventricle were exposed to a short hypoxic challenge, and VEGF concentrations were measured in CSF at various time points for 24 hours. Another set of 6 rats were killed with a pentobarbital overdose, and VEGF CSF levels were obtained at different time points after death.

Results. Mean VEGF concentrations in CSF were 308.2 ± 299.1 pg/dL in the SIDS group and 85.1 ± 82.9 pg/dL in those who died of known causes. Mean postmortem delay averaged 22 hours for both groups. In rat experiments, hypoxic exposures induced time-dependent increases in VEGF, peaking at 12 hours and returning to baseline at 24 hours. Postmortem duration in the animals was associated with gradual increases in VEGF that reached significance only at 36 hours.

Conclusions. We conclude that VEGF CSF concentrations are significantly higher in infants who die of SIDS. We postulate that hypoxia is a frequent event that precedes the sudden and unexpected death of these infants.

Kimberly L. Jones, MD*, Henry F. Krous, MD{ddagger}, Julie Nadeau, RN{ddagger}, Brian Blackbourne, MD§, H. Ronald Zielke, PhD|| and David Gozal, MD*

* Kosair Children’s Hospital Research Institute, Departments of Pediatrics, Pharmacology, and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
{ddagger} Departments of Pathology and Pediatrics, University of California at San Diego, School of Medicine, San Diego, California
§ Office of the Medical Examiner, County of San Diego, San Diego, California
|| Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
Section of Pediatric Pulmonology, Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana

Key Words: hypoxia • sudden infant death syndrome • vascular endothelial growth factor

Abbreviations: SIDS, sudden infant death syndrome • VEGF, vascular endothelial growth factor • CSF, cerebrospinal fluid • SD, standard deviation


Received for publication Feb 26, 2002; Accepted Aug 20, 2002.


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