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Altered Circulating Leukocytes and Their Chemokines in a Clinical Trial of Therapeutic Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy*

Jenkins, Dorothea D. MD1; Lee, Timothy MD2; Chiuzan, Cody MS3; Perkel, Jessica K. BS1; Rollins, Laura Grace BS4; Wagner, Carol L. MD1; Katikaneni, Lakshmi P. MD1; Bass, W. Thomas MD5; Kaufman, David A. MD6; Horgan, Michael J. MD7; Laungani, Sheela MD8; Givelichian, Laurence M. MD9; Sankaran, Koravangatta MD9; Yager, Jerome Y. MD10; Martin, Renee PhD3

Pediatric Critical Care Medicine: October 2013 - Volume 14 - Issue 8 - p 786–795
doi: 10.1097/PCC.0b013e3182975cc9
Neonatal Intensive Care

Objectives: To determine systemic hypothermia’s effect on circulating immune cells and their corresponding chemokines after hypoxic ischemic encephalopathy in neonates.

Design: In our randomized, controlled, multicenter trial of systemic hypothermia in neonatal hypoxic ischemic encephalopathy, we measured total and leukocyte subset and serum chemokine levels over time in both hypothermia and normothermia groups, as primary outcomes for safety.

Setting: Neonatal ICUs participating in a Neurological Disorders and Stroke sponsored clinical trial of therapeutic hypothermia.

Patients: Sixty-five neonates with moderate to severe hypoxic ischemic encephalopathy within 6 hours after birth.

Interventions: Patients were randomized to normothermia of 37°C or systemic hypothermia of 33°C for 48 hours.

Measurements and Main Results: Complete and differential leukocyte counts and serum chemokines were measured every 12 hours for 72 hours. The hypothermia group had significantly lower median circulating total WBC and leukocyte subclasses than the normothermia group before rewarming, with a nadir at 36 hours. Only the absolute neutrophil count rebounded after rewarming in the hypothermia group. Chemokines, monocyte chemotactic protein-1 and interleukin-8, which mediate leukocyte chemotaxis as well as bone marrow suppression, were negatively correlated with their target leukocytes in the hypothermia group, suggesting active chemokine and leukocyte modulation by hypothermia. Relative leukopenia at 60–72 hours correlated with an adverse outcome in the hypothermia group.

Conclusions: Our data are consistent with chemokine-associated systemic immunosuppression with hypothermia treatment. In hypothermic neonates, persistence of lower leukocyte counts after rewarming is observed in infants with more severe CNS injury.

1Department of Pediatrics, Medical University of South Carolina, Charleston, SC.

2Department of Pediatric Emergency Medicine, Akron Children’s Hospital, Akron, OH.

3Department of Medicine, Division of Biostatistics and Epidemiology, Medical University of South Carolina, Charleston, SC.

4Department of Clinical Psychology, University of Massachusetts, Boston, MA.

5Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA.

6Department of Pediatrics, University of Virginia, Charlottesville, VA.

7Department of Pediatrics, Albany Medical Center, Albany, NY.

8Department of Pediatrics, Brooklyn Hospital Center, Brooklyn, NY.

9Department of Pediatrics, University of Saskatchewan, Saskatoon, SK, Canada.

10Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

* See also p. 823.

Category of study: Clinical trial.

The principal investigator, Dr. Jenkins, wrote the first draft of the manuscript.

Supported by R01 NS38602 from National Institutes of Neurologic Disorders and Stroke. The study sponsor had no input into the collection, analysis, and interpretation of data and the writing or submission of the manuscript for publication.

Dr. Givelichian’s work on this project was supported by the Saskatchewan Health Research foundation. No form of payment was received for this manuscript. Dr. Jenkins received grant support from NINDS, is employed by the Medical University of SC and University Medical Associates, provided expert testimony for various legal firms, received grant support from the National Institutes of Health (NIH), other: NIH scientific review groups, and received support for article research from NIH. Drs. Rollins, Wagner, Katikaneni, Bass, Kaufman, Horgan, Laungani, and Sankaran received funding from NIH. Dr. Givelichian received funding from funding from NIH and the Saskatchewan Health Research Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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©2013The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies