This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Web of Science (60) Citing Articles via Google Scholar Google Scholar Articles by Shankaran, S. Articles by McDonald, S. Search for Related Content PubMed PubMed Citation Articles by Shankaran, S. Articles by McDonald, S. Related Collections Premature & Newborn Social Bookmarking                         What's this?

PEDIATRICS Vol. 110 No. 2 August 2002, pp. 377-385

Whole-Body Hypothermia for Neonatal Encephalopathy: Animal Observations as a Basis for a Randomized, Controlled Pilot Study in Term Infants

Seetha Shankaran, MD^*, Abbot Laptook, MD, Linda L. Wright, MD, Richard A. Ehrenkranz, MD^||, Edward F. Donovan, MD^¶, Avroy A. Fanaroff, MB, BCh^#, Ann R. Stark, MD^**, Jon E. Tyson, MD, Kenneth Poole, PhD, Waldemar A. Carlo, MD^||||, James A. Lemons, MD^¶¶, William Oh, MD^##, Barbara J. Stoll, MD^***, Lu-Ann Papile, MD, Charles R. Bauer, MD, David K. Stevenson, MD^||||||, Sheldon B. Korones, MD^¶¶¶ and Scott McDonald

^* Wayne State University, Detroit, Michigan
University of Texas Southwestern Medical Center, Dallas, Texas
National Institute of Child Health and Human Development, Bethesda, Maryland
^|| Yale University, New Haven, Connecticut
^¶ University of Cincinnati, Cincinnati, Ohio
^# Case Western Reserve University, Cleveland, Ohio
^** Brigham and Women’s Hospital, Boston, Massachusetts
University of Texas-Houston Medical School, Houston, Texas
Research Triangle Institute, Research Triangle Park, North Carolina
^|||| University of Alabama, Birmingham, Alabama
^¶¶ University of Indiana, Indianapolis, Indiana
^## Women and Infants’ Hospital, Providence, Rhode Island
^*** Emory University, Atlanta, Georgia
University of New Mexico, Albuquerque, New Mexico
University of Miami, Miami, Florida
^|||||| Stanford University, Stanford, California
^¶¶¶ University of Tennessee at Memphis, Memphis, Tennessee

Objective. Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth.

Methods. In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5°C for 72 hours followed by slow rewarming.

Results. In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 ± 0.2°C (mean ± standard deviation) around the set point of 33.5°C were reduced to 0.7 ± 0.2°C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 ± 0.3°C). In the human investigation, the infants were randomized at 4.1 ± 1.3 hours (mean ± standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5°C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 ± 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups.

Conclusions. Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at <6 hours of age to a constant esophageal temperature using servo control and provides no evidence that hypothermia involved greater hazard than benefit.

Key Words: enceph-alopathy • hypothermia • asphyxia • term infants

Abbreviations: HIE, hypoxic-ischemic encephalopathy • bpm, beats per minute • MRI, magnetic resonance imaging • SD, standard deviation • aEEG, amplitude-integrated EEG

---

Received for publication Oct 17, 2001; Accepted Mar 13, 2002.

CiteULike    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D Azzopardi, B Strohm, A D Edwards, H Halliday, E Juszczak, M Levene, M Thoresen, A Whitelaw, P Brocklehurst, and on behalf of the Steering Group and TOBY Cooling R Treatment of asphyxiated newborns with moderate hypothermia in routine clinical practice: how cooling is managed in the UK outside a clinical trial Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2009; 94(4): F260 - F264. [Abstract] [Full Text] [PDF]

				S Iwata, O Iwata, L Olson, A Kapetanakis, T Kato, S Evans, Y Araki, T Kakuma, T Matsuishi, F Setterwall, et al. Therapeutic hypothermia can be induced and maintained using either commercial water bottles or a "phase changing material" mattress in a newborn piglet model Arch. Dis. Child., May 1, 2009; 94(5): 387 - 391. [Abstract] [Full Text] [PDF]

				A. A. Topjian, R. A. Berg, and V. M. Nadkarni Pediatric Cardiopulmonary Resuscitation: Advances in Science, Techniques, and Outcomes Pediatrics, November 1, 2008; 122(5): 1086 - 1098. [Abstract] [Full Text] [PDF]

				M. Perlman and P. Shah Time to Adopt Cooling for Neonatal Hypoxic-Ischemic Encephalopathy: Response to a Previous Commentary Pediatrics, March 1, 2008; 121(3): 616 - 618. [Full Text] [PDF]

				P. S. Shah, A. Ohlsson, and M. Perlman Hypothermia to Treat Neonatal Hypoxic Ischemic Encephalopathy: Systematic Review Arch Pediatr Adolesc Med, October 1, 2007; 161(10): 951 - 958. [Abstract] [Full Text] [PDF]

				American Heart Association, American Academy of Pe 2005 American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) of Pediatric and Neonatal Patients: Neonatal Resuscitation Guidelines Pediatrics, May 1, 2006; 117(5): e1029 - e1038. [Full Text] [PDF]

				The International Liaison Committee on Resuscitati The International Liaison Committee on Resuscitation (ILCOR) Consensus on Science With Treatment Recommendations for Pediatric and Neonatal Patients: Neonatal Resuscitation Pediatrics, May 1, 2006; 117(5): e978 - e988. [Full Text] [PDF]

				C. M. Gebauer, M. Knuepfer, E. Robel-Tillig, F. Pulzer, and C. Vogtmann Hemodynamics Among Neonates With Hypoxic-Ischemic Encephalopathy During Whole-Body Hypothermia and Passive Rewarming Pediatrics, March 1, 2006; 117(3): 843 - 850. [Abstract] [Full Text] [PDF]

				L. R. Blackmon, A. R. Stark, and and the Committee on Fetus and Newborn, American A Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Encephalopathy Pediatrics, March 1, 2006; 117(3): 942 - 948. [Full Text] [PDF]

				A D Edwards and D V Azzopardi Therapeutic hypothermia following perinatal asphyxia. Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2006; 91(2): F127 - F131. [Abstract] [Full Text] [PDF]

				Part 13: Neonatal Resuscitation Guidelines Circulation, December 13, 2005; 112(24_suppl): IV-188 - IV-195. [Full Text] [PDF]

				Part 7: Neonatal Resuscitation Circulation, November 29, 2005; 112(22_suppl): III-91 - III-99. [Full Text] [PDF]

				S. Shankaran, A. R. Laptook, R. A. Ehrenkranz, J. E. Tyson, S. A. McDonald, E. F. Donovan, A. A. Fanaroff, W. K. Poole, L. L. Wright, R. D. Higgins, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N. Engl. J. Med., October 13, 2005; 353(15): 1574 - 1584. [Abstract] [Full Text] [PDF]

				L. A. Papile Systemic hypothermia--a "cool" therapy for neonatal hypoxic-ischemic encephalopathy. N. Engl. J. Med., October 13, 2005; 353(15): 1619 - 1620. [Full Text] [PDF]

				M. A. Rutherford, D. Azzopardi, A. Whitelaw, F. Cowan, S. Renowden, A. D. Edwards, and M. Thoresen Mild Hypothermia and the Distribution of Cerebral Lesions in Neonates With Hypoxic-Ischemic Encephalopathy Pediatrics, October 1, 2005; 116(4): 1001 - 1006. [Abstract] [Full Text] [PDF]

				D Fugelseth, S Satas, P A Steen, and M Thoresen Cardiac output, pulmonary artery pressure, and patent ductus arteriosus during therapeutic cooling after global hypoxia-ischaemia Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2003; 88(3): F223 - F228. [Abstract] [Full Text] [PDF]