PEDIATRICS Vol. 106 No. 4 October 2000, pp. 684-694

Pilot Study of Treatment With Whole Body Hypothermia for Neonatal Encephalopathy

Received May 24, 1994; accepted Jan 10, 2000.

Denis Azzopardi^*, Nicola J. Robertson^*, Frances M. Cowan^*, Mary A. Rutherford^*, Michael Rampling^*, , and A. David Edwards^*

From the ^* Department of Paediatrics and the  Biomedical Sciences Division, Imperial College School of Medicine, London, United Kingdom.

Background.  There is extensive experimental evidence to support the investigation of treatment with mild hypothermia after birth asphyxia. However, clinical studies have been delayed by the difficulty in predicting long-term outcome very soon after birth and by concern about adverse effects of hypothermia.

Objectives.  The objectives of this study were to determine whether it is feasible to select infants with a bad neurological prognosis and to begin hypothermic therapy within 6 hours of birth, and to observe the effect of this therapy on relevant physiologic variables.

Methods.  Sixteen newborn infants with clinical features of birth asphyxia (median cord blood pH: 6.74; range: 6.58-7.08) were assessed by amplitude integrated electroencephalography (aEEG), and mild whole body hypothermia was instituted within 6 hours of birth in the 10 infants with an aEEG prognostic of a bad outcome. Rectal temperature was maintained at 33.2 ± (standard deviation) .6°C for 48 hours. Rectal and tympanic membrane temperature, blood pressure, heart rate, blood gases, blood lactate, full blood count, blood electrolytes, high and low shear rate viscosity, and coagulation studies were monitored during and after cooling. A preliminary assessment of neurological outcome was made by repeated magnetic resonance imaging (MRI) and neurological examination.

Results.  All infants selected to receive hypothermia developed convulsions and a severe encephalopathy. During 48 hours of hypothermia infants had prolonged metabolic acidosis (median pH: 7.30; base excess: 6.3 mmol · L¹, a high blood lactate (median lactate: 5.3 mmol · L¹) and low blood potassium levels (median value: 3.9 mmol · L¹). Hypothermia was associated with lower heart rate and higher mean blood pressure. However, these changes did not seem to be clinically relevant and no significant complication of hypothermia was encountered. Blood viscosity and coagulation studies were similar during and after cooling. Unusual MRI findings were noted in 3 infants: transverse sinus thrombosis with subsequent small cerebellar infarct; probable thrombosis in the straight sinus; and hemorrhagic cerebral infarction. Six of the 10 cooled infants had minor abnormalities only or normal follow-up neurological examination; 3 infants died and 1 had major abnormalities. None of the 6 infants with a normal aEEG developed severe neonatal encephalopathy or neurological sequel.

Conclusions.  After birth asphyxia infants can be objectively selected by aEEG and hypothermia started within 6 hours of birth in infants at high risk of developing severe neonatal encephalopathy. Prolonged mild hypothermia to 33°C to 34°C is associated with minor physiologic abnormalities. Further studies of both the safety and efficacy of mild hypothermia, including further neuroimaging studies, are warranted.  Key words:  hypothermia, neonatal encephalopathy, birth asphyxia, amplitude integrated electroencephalography.

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]

				A. Horn, C. Thompson, D. Woods, A. Nel, A. Bekker, N. Rhoda, and C. Pieper Induced Hypothermia for Infants With Hypoxic- Ischemic Encephalopathy Using a Servo-Controlled Fan: An Exploratory Pilot Study Pediatrics, June 1, 2009; 123(6): e1090 - e1098. [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]

				R. W. Neumar, J. P. Nolan, C. Adrie, M. Aibiki, R. A. Berg, B. W. Bottiger, C. Callaway, R. S.B. Clark, R. G. Geocadin, E. C. Jauch, et al. Post-Cardiac Arrest Syndrome: Epidemiology, Pathophysiology, Treatment, and Prognostication A Consensus Statement From the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council Circulation, December 2, 2008; 118(23): 2452 - 2483. [Full Text] [PDF]

				S. Shankaran, A. Pappas, A. R. Laptook, S. A. McDonald, R. A. Ehrenkranz, J. E. Tyson, M. Walsh, R. N. Goldberg, R. D. Higgins, A. Das, et al. Outcomes of Safety and Effectiveness in a Multicenter Randomized, Controlled Trial of Whole-Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy Pediatrics, October 1, 2008; 122(4): e791 - e798. [Abstract] [Full Text] [PDF]

				D. K. Shah, M. T. Mackay, S. Lavery, S. Watson, A. S. Harvey, J. Zempel, A. Mathur, and T. E. Inder Accuracy of Bedside Electroencephalographic Monitoring in Comparison With Simultaneous Continuous Conventional Electroencephalography for Seizure Detection in Term Infants Pediatrics, June 1, 2008; 121(6): 1146 - 1154. [Abstract] [Full Text] [PDF]

				A. Okereafor, J. Allsop, S. J. Counsell, J. Fitzpatrick, D. Azzopardi, M. A. Rutherford, and F. M. Cowan Patterns of Brain Injury in Neonates Exposed to Perinatal Sentinel Events Pediatrics, May 1, 2008; 121(5): 906 - 914. [Abstract] [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]

				L. Bennet, V. Roelfsema, S. George, J. M. Dean, B. S. Emerald, and A. J. Gunn The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep J. Physiol., January 15, 2007; 578(2): 491 - 506. [Abstract] [Full Text] [PDF]

				D. K. Shah, S. Lavery, L. W. Doyle, C. Wong, P. McDougall, and T. E. Inder Use of 2-Channel Bedside Electroencephalogram Monitoring in Term-Born Encephalopathic Infants Related to Cerebral Injury Defined by Magnetic Resonance Imaging Pediatrics, July 1, 2006; 118(1): 47 - 55. [Abstract] [Full Text] [PDF]

				M. Thoresen, A. Whitelaw, D. Azzopardi, S. Renowden, A. D. Edwards, and M. A. Rutherford Does Oxygen Concentration Used for Resuscitation Influence Outcome of Asphyxiated Newly Born Infants Treated With Hypothermia?: In Reply Pediatrics, June 1, 2006; 117(6): 2328 - 2328. [Full Text] [PDF]

				Intracardiac temperature monitoring in infants after cardiac surgery. J. Thorac. Cardiovasc. Surg., March 1, 2006; 131(3): 614 - 620.

				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]

				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]

				L G M van Rooij, M C Toet, D Osredkar, A C van Huffelen, F Groenendaal, and L S de Vries Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia Arch. Dis. Child. Fetal Neonatal Ed., May 1, 2005; 90(3): F245 - f251. [Abstract] [Full Text] [PDF]

				M. C. Morris, V. M. Nadkarni, F. R. Ward, and R. M. Nelson Exception From Informed Consent for Pediatric Resuscitation Research: Community Consultation for a Trial of Brain Cooling After In-Hospital Cardiac Arrest Pediatrics, September 1, 2004; 114(3): 776 - 781. [Abstract] [Full Text] [PDF]

				J.P. Nolan, P.T. Morley, T.L. Vanden Hoek, R.W. Hickey, W.G.J. Kloeck, J. Billi, B.W. Bottiger, P.T. Morley, J.P. Nolan, K. Okada, et al. Therapeutic Hypothermia After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation Circulation, July 8, 2003; 108(1): 118 - 121. [Full Text] [PDF]

				S Ichiba, H M Killer, R K Firmin, S Kotecha, A D Edwards, and D Field Pilot investigation of hypothermia in neonates receiving extracorporeal membrane oxygenation Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2003; 88(2): F128 - F133. [Abstract] [Full Text] [PDF]

				M. R. Battin, J. Penrice, T. R. Gunn, and A. J. Gunn Treatment of Term Infants With Head Cooling and Mild Systemic Hypothermia (35.0{degrees}C and 34.5{degrees}C) After Perinatal Asphyxia Pediatrics, February 1, 2003; 111(2): 244 - 251. [Abstract] [Full Text] [PDF]

				R. Berger, Y. Garnier, and A. Jensen Perinatal Brain Damage: Underlying Mechanisms and Neuroprotective Strategies Reproductive Sciences, November 1, 2002; 9(6): 319 - 328. [Abstract] [PDF]

				S. Shankaran, A. Laptook, L. L. Wright, R. A. Ehrenkranz, E. F. Donovan, A. A. Fanaroff, A. R. Stark, J. E. Tyson, K. Poole, W. A. Carlo, et al. Whole-Body Hypothermia for Neonatal Encephalopathy: Animal Observations as a Basis for a Randomized, Controlled Pilot Study in Term Infants Pediatrics, August 1, 2002; 110(2): 377 - 385. [Abstract] [Full Text] [PDF]

				A. J. Gunn and L. Bennet Cerebral Hypothermia in the Management of Hypoxic-Ischemic Encephalopathy NeoReviews, June 1, 2002; 3(6): e116 - 122. [Full Text]

				M. C. Toet, W. van der Meij, L. S. de Vries, C. S. P. M. Uiterwaal, and K. C. van Huffelen Comparison Between Simultaneously Recorded Amplitude Integrated Electroencephalogram (Cerebral Function Monitor) and Standard Electroencephalogram in Neonates Pediatrics, May 1, 2002; 109(5): 772 - 779. [Abstract] [Full Text] [PDF]

				A. R. Laptook, L. Shalak, and R. J. T. Corbett Differences in Brain Temperature and Cerebral Blood Flow During Selective Head Versus Whole-Body Cooling Pediatrics, November 1, 2001; 108(5): 1103 - 1110. [Abstract] [Full Text] [PDF]

				S. Niermeyer, W. Carlo, D. Boyle, J. Goldsmith, B. Nightengale, J. Perlman, A. Solimano, M. Speer, and T. Wiswell What Is on the Horizon for Neonatal Resuscitation? NeoReviews, February 1, 2001; 2(2): e51 - 57. [Full Text]

eLetters: