Neonatal Encephalopathy: Treatment With Hypothermia Seetha Shankaran. DOI: /neo.11-2-e85

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1 Neonatal Encephalopathy: Treatment With Hypothermia Seetha Shankaran NeoReviews 2010;11;e85-e92 DOI: /neo.11-2-e85 The online version of this article, along with updated information and services, is located on the World Wide Web at: NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since NeoReviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 2010 by the American Academy of Pediatrics. All rights reserved. Online ISSN:

2 Article neurology Neonatal Encephalopathy: Treatment With Hypothermia Seetha Shankaran, MD* Author Disclosure Dr Shankaran has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of a commercial product/device. Objectives After completing this article, readers should be able to: 1. Review the criteria for diagnosing hypoxic-ischemic insult. 2. Delineate the pathophysiology of brain injury from hypoxic-ischemic insult. 3. Review diagnostic findings of encephalopathy in infants. 4. Describe the mechanisms of protection of hypothermia. Abstract This article evaluates the pathophysiology of brain injury from hypoxia-ischemia in preclinical models and the role of hypothermia as neuroprotection following this injury. The diagnosis of encephalopathy due to hypoxia and ischemia in term and near-term infants following acute perinatal asphyxia is clarified. The neuroprotective effect of hypothermia when initiated before 6 hours of age for 72 hours to a depth of 33.0 C to 34.0 C in reducing death and disability is reviewed. Therapeutic hypothermia is safe and effective when applied according to published clinical trial protocols, although gaps in knowledge still remain. Abbreviations aeeg: amplitude-integrated electroencephalography ATP: adenosine triphosphate CI: confidence interval HIE: hypoxic-ischemic encephalopathy NICHD: National Institute of Child Health and Human Development OR: odds ratio Neonatal Encephalopathy Neonatal encephalopathy due to hypoxia-ischemia occurs in 1 to 6 per 1,000 live term births in developed countries. Approximately 15% to 20% of affected newborns die in the postnatal period, and an additional 25% sustain childhood disabilities. Abnormal findings on the neurologic examination in first few days after birth is the single most useful predictor in childhood that a brain insult has occurred in the perinatal period. Neonates who have mild encephalopathy do not have an increased risk of motor or cognitive deficits. Those who have severe encephalopathy have an increased risk of death and an increased risk of cerebral palsy and intellectual disability among survivors. Neonates who have moderate encephalopathy have significant motor deficits, memory impairment, and visual motor or visual perceptive dysfunction; increased hyperactivity; and delayed school readiness. (1)(2) The essential criteria suggested as prerequisites for a diagnosis of a hypoxic-ischemic insult resulting in moderate or severe encephalopathy in term newborns include: metabolic acidosis, with a cord ph less than 7 or a base deficit of at least 12 mmol/l; early onset of encephalopathy; multisystem organ dysfunction; and exclusion of other causes such as trauma, coagulation disorders, metabolic disorders, and genetic causes. (3) Pathophysiology of Neonatal Hypoxic-Ischemic Brain Injury The pathophysiology of brain injury due to hypoxia-ischemia has been well studied. Hypoxia-ischemia is associated with two phases of pathologic events that culminate in brain injury (Table 1). These phases of primary and secondary energy failure are based on characteristics of the cerebral energy state used to describe the temporal sequence in newborn animals. (4) Primary energy failure is characterized by reductions in *Professor of Pediatrics, Wayne State University School of Medicine; Director, Division of Neonatal-Perinatal Medicine, Children s Hospital of Michigan and Hutzel Women s Hospital, Detroit, Mich. NeoReviews Vol.11 No.2 February 2010 e85

3 Table 1. Mechanisms of Damage in Fetal/Neonatal Model of Hypoxia-Ischemia Primary Energy Failure Increased release and decreased uptake of excitatory amino acids Loss of ionic homeostasis across membranes Decreased adenosine triphosphate production Generation of reactive oxygen species Activation of lipases and proteases Secondary Energy Failure Activation of microglia: inflammatory response Activation of caspase proteins: trigger apoptosis Reduction in growth factors, protein synthesis Further accumulation of excitotoxic neurotransmitters cerebral blood flow and oxygen/substrates. (4)(5) Concentrations of high-energy phosphorylated compounds such as adenosine triphosphate (ATP) and phosphocreatine are reduced and tissue acidosis is prominent. This phase is an essential prerequisite for all deleterious events that follow. Primary energy failure is associated with acute intracellular derangements such as loss of membrane ionic homeostasis, release/blocked reuptake of excitatory neurotransmitters, defective osmoregulation, and inhibition of protein synthesis. (6) Excessive stimulation of neurotransmitter receptors and loss of ionic homeostasis mediate an increase in intracellular calcium and osmotic dysregulation. Elevation in intracellular calcium concentrations triggers a number of destructive pathways by activating lipases, proteases, and endonucleases. (7) Resolution of hypoxia-ischemia within a specific time interval reverses the decrease in highenergy phosphorylated metabolites and intracellular ph and promotes recycling of neurotransmitters. The duration of time required for reversal of hypoxia-ischemia and promotion of recovery is affected by maturation, preconditioning events, substrate availability, body temperature, and simultaneous disease processes. Although the cerebral energy state may recover following primary energy failure, a second interval of energy failure may occur at a time remote from the initiating event. Secondary energy failure differs from primary energy failure in that declines in phosphocreatine and ATP are not accompanied by brain acidosis. (4) The presence and severity of secondary energy failure depends on the extent of primary energy failure. The pathogenesis of secondary energy failure is not as well understood as primary energy failure but likely involves multiple pathophysiologic processes, including accumulation of excitatory neurotransmitters, oxidative injury, apoptosis, inflammation, and altered growth factors and protein synthesis. (8)(9)(10)(11)(12) The interval between primary and secondary energy failure represents a latent phase that corresponds to a therapeutic window. Initiation of therapies during the latent phase in perinatal animals has been successful in reducing brain damage and substantiates the presence of a therapeutic window. The duration of the therapeutic window is approximately 6 hours in near-term fetal sheep, based on the neuroprotection associated with brain cooling initiated at varying intervals following brain ischemia. (13)(14)(15) Current Therapies for Neonatal Hypoxic- Ischemic Encephalopathy The management of hypoxic-ischemic encephalopathy (HIE) has been limited to supportive intensive care. Such measures include correction of hemodynamic and pulmonary disturbances (hypotension, metabolic acidosis, and hypoventilation), correction of metabolic disturbances (glucose, calcium, magnesium, and electrolytes), treatment of seizures, and monitoring for other organ system dysfunction. This management approach does not target any component of the pathophysiologic sequence leading to hypoxic-ischemic brain injury and is directed at avoiding injury from secondary events associated with hypoxia-ischemia. Diagnosis of Encephalopathy in Term Infants A detailed history should be obtained regarding the pregnancy and intrapartum period as the first step in diagnosing encephalopathy. Any event likely to compromise blood or oxygen supply to the fetus should be examined. These events include a history of placental abruption, uterine rupture, amniotic fluid embolism, tight nuchal cord, cord prolapse/avulsion, maternal hemorrhage, trauma or cardiorespiratory arrest, severe and sustained fetal bradycardia, and prolonged labor. Most infants who have encephalopathy do not have an obvious cause. There is currently no clear diagnostic test for encephalopathy due to hypoxia-ischemia. A history of maternal elevation of temperature is crucial because moderate temperature elevation in the mother increases the risk of. A history of fetal tachycardia and maternal tachycardia also may raise suspicions of chorioamnionitis. Laboratory evaluations that should be performed include placenta pathology to eval- e86 NeoReviews Vol.11 No.2 February 2010

4 uate for the presence of placental infection. Elevated biomarkers (elevated cytokines) may improve the ability to predict outcome. All neonates should undergo a detailed neurologic examination to evaluate the presence of mild, moderate, or severe encephalopathy. (16) Cerebral Function Monitoring in the Neonatal Period Currently, a bedside tool for cerebral function monitoring in term and near-term infants is amplitude-integrated electroencephalography (aeeg). The aeeg records a single-channel EEG from biparietal or central electrodes, and the signal is filtered, rectified, smoothed, and amplitude-integrated. The aeeg interpretation is based primarily on background pattern recognition or amplitude, and the aeeg correlates well with conventional EEG. Recent reports indicate that the aeeg performed during the first few days after birth predicts neurodevelopmental outcome in term infants who have HIE. (17) Coupled with an early neurologic examination, the aeeg correlates well with persistent encephalopathy. The aeeg should not be used for the detection and treatment of neonatal seizures because it has not been proven to detect subclinical seizures reliably. (18) Hypothermia as Neuroprotection Neuroprotection with brain-specific therapies has been well studied in the preclinical arena over the past 20 years, with the aim of blocking or dampening the cascade of events triggered by hypoxia and ischemia. Brain hypothermia is a promising therapy for neuroprotection against encephalopathy presumably due to hypoxic ischemia. Preclinical Studies Established evidence in fetal and neonatal animal models and across species shows that cooling by a depth of 4.0 C to 6.0 C compared with controls has been neuroprotective while being well tolerated. (13)(14)(19)(20)(21) (22)(23)(24)(25)(26)(27)(28)(29)(30)(31) The duration of cooling in these studies varied from 3 to 72 hours, and each study compared a specific depth of cooling to controls. The depth of cooling achieved in each of these studies was a rectal temperature of 28.0 C to 33.0 C. (19)(21)(23)(27) Scalp temperatures achieved in preclinical neuroprotection studies were documented as 21.3 C to 23.9 C. (29) Extradural brain temperatures in studies by Gunn are reported as low as 30.0 C. (14)(15) Studies measuring brain temperatures have evaluated effects of cooling to 30.0 C to 32.2 C, (28) 31.1 C, (30) and 32.0 C. (22) None of these studies comparing a specific depth of hypothermia to controls reported any adverse effects, except one report of a piglet shivering during the cooling. (30) The mechanism of protection has been documented by many modalities, including a decrease in brain energy utilization measured by magnetic resonance spectroscopy, (32) reduction of infarct size, (33) decrease in neuronal cell loss, (14) retention of sensory motor function, (19) preservation of hippocampal structures, (21)(22) and recovery of electroencephalographic activity (14) (Table 2). Neuroprotection with hypothermia is temperature-specific, with progressively increased protection associated with increasing depth of temperature. Covey and Oorschot (34) noted that hypothermia of 5.0 C below normal administered postinsult for 6 hours offered better neuroprotection for striatal neurons than a depth of 2.0 C below normal. Iwata and colleagues (35) have demonstrated that cooling at two different regimens (rectal temperatures of 35.0 C and 33.0 C compared with normothermia of 38.5 C to 39.0 C) for 48 hours resulted in a progressive increase in neuronal viability in gray matter at 33.0 C compared with 35.0 C. Laptook and colleagues (32) noted a linear relationship between brain energy utilization rate and brain temperature over the range of temperatures between 27.6 C and 41 C, with a 1 C reduction in brain temperature leading to 5.3% reduction in brain energy utilization rate. Taylor and coworkers (33) evaluated infarct size with cooling to 33.0 C and 30.0 C compared with normothermia and found smaller infarct size at both depths compared with normothermia. Williams and associates (36) have evaluated cerebral energy metabolism during hypoxia-ischemia and demonstrated that when compared with controls, nuclear magnetic resonance metabolites were preserved at 31.0 C and 34.0 C. None of these studies comparing different depths of temperature Table 2. Mechanism of Action of Hypothermia Reduces cerebral metabolism, prevents edema Decreases energy utilization Reduces/suppresses cytotoxic amino acid accumulation and nitric oxide Inhibits platelet-activating factor, inflammatory cascade Suppresses free radical activity Attenuates secondary energy failure Inhibits apoptosis (cell death) Reduces extent of brain injury NeoReviews Vol.11 No.2 February 2010 e87

5 to controls in the same models documented adverse effects of hypothermia. In addition, adjusting brain temperatures from 28.0 C and 41.0 C did not alter any systemic variable in the piglet model except for heart rate, which directly correlated with brain temperature. (32) Clinical Studies To date, two randomized, controlled trials and one large pilot study have been published evaluating hypothermia as neuroprotection for term and near-term infants who have HIE. The multicenter Cool Cap Study involved 243 infants who had moderate or severe encephalopathy and abnormal aeeg amplitudes and were either cooled to a temperature of 34.0 C to 35.0 C for 72 hours or treated with temperature maintenance in the normothermia range with conventional care. (37) The primary outcome of the study was death or disability at 18 months. Cooling was provided by selective head cooling and mild systemic cooling. Death or severe disability occurred in 66% of infants randomized to conventional care and 55% randomized to the cooled group (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.34 to 1.09, P 0.10). The effect of head cooling for infants who had the most severe aeeg changes was not protective, but the effect of head cooling for infants who had less severe aeeg changes (n 172) was protective (OR 0.42, 95% CI 0.22 to 0.80, P 0.009). The large randomized, controlled pilot study performed at seven centers of 65 infants involved moderate systemic whole body hypothermia to 33.0 C for 48 hours compared with normothermia maintained at 37.0 C. (38) The safety report of this pilot study documented that infants in the hypothermia group had more significant bradycardia, longer dependence on pressor medications, higher prothrombin times, more seizures, and need for more plasma and platelet transfusions. At 12 months of age, death or severe motor scores were documented in 52% of the hypothermia group compared with 84% of the normothermia group (P 0.02). In a subgroup analysis, outborn infants were more likely to die than inborn infants (OR 10.7, 95% CI 1.3 to 90.0). The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial of whole-body hypothermia for infants who had moderate and severe encephalopathy (in three of six categories in Table 3) randomized 102 infants to hypothermia to 33.5 C for 72 hours and 106 control infants to conventional care. (39) The primary outcome was death or moderate/severe disability at 18 months of age. The infants in the hypothermia group had significantly lower heart rates than the infants in the control group throughout the 72-hour intervention period. There was no significant difference in systolic or diastolic blood pressure between groups. The frequency of adverse events during study intervention was low: one infant in each group had arrhythmia, two infants in the hypothermia group had acidosis, three infants in the hypothermia group and two control group infants had bleeding, and four cooled infants had altered skin integrity. The primary outcome was noted in 44% of infants in the hypothermia group compared with 62% of infants in the control group, with a risk ratio of 0.72 (0.54 to 0.95). There was a trend for cooling to benefit infants in both moderate and severe encephalopathy groups. The Cool Cap and the NICHD Whole Body Hypothermia Trial used different entry criteria, distinguished primarily by the use of the aeeg in the Cool Cap trial. The mode of cooling used in each trial was different, Table 3. Neurologic Examination Category Moderate Encephalopathy Severe Encephalopathy 1. Level of consciousness Lethargic Stupor/coma 2. Spontaneous activity Decreased activity No activity 3. Posture Distal flexion, full extension Decerebrate 4. Tone Hypotonic (focal, general) Flaccid 5. Primitive reflexes: - Suck Weak Absent - Moro Incomplete Absent 6. Autonomic system: - Heart Rate Bradycardia Variable heart rate - Respiration Periodic breathing Apnea - Pupils Constricted Skew deviation, dilated or nonreactive to light Adapted from Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal stress. A clinical and electroencephalographic study. Arch Neurol. 1976;33: e88 NeoReviews Vol.11 No.2 February 2010

6 and it is not known if one cooling regimen is superior to the other. The primary outcomes were not defined in a similar manner in the two trials. Although not powered to evaluate moderate or severe encephalopathy separately, decreases in death and moderate/severe disability were seen in the whole body cooling trial in both the moderate and severe encephalopathy groups. The primary outcome of each trial was the combined end point of death or disability; hypothermia therapy did not salvage infants who had severe disabilities and would have died in the absence of the intervention. The rate of disabling cerebral palsy was reduced from 31% in the control group to 18% in the Cool Cap Study and from 30% in the control to 19% in the whole-body cooling trial of the NICHD Network. Elevated Temperatures in Infants Who Have HIE The NICHD trial of whole-body hypothermia demonstrated the occurrence of elevated core body temperature in the control group infants when temperatures were measured consistently in the 76 hours of study intervention and rewarming phase. (39) Of the 102 infants randomized to the usual care group, 28 had a median esophageal temperature of at least 38.0 C. Higher core temperatures were associated with significant increases in risk of death or impairment in the control group. (40) In a secondary analysis of the Cool Cap trial, investigators also noted an association between elevated temperatures in the control group and increased risk of death or disability. (41) Hyperthermia after brain injury adds to the risk of more severe neurologic damage, and studies in adults consistently support the association between higher core temperatures and worse outcome. (42) In the animal model, seizures associated with a hypoxicischemic insult result in neuronal cell death, specifically within the hippocampus. (43) The damage to the hippocampus occurs in the setting of spontaneously occurring hyperthermia of 1.5 C above normothermia; rat pups in whom hyperthermia was prevented during seizures displayed significant reductions in brain damage compared with controls. In another study, neonatal rats subjected to hypoxic-ischemic injury had selective and long-lasting learning and memory impairments during behavioral tasks, and hypothermia to 27.0 C significantly reduced the attentional deficit in behavioral tasks, whereas hyperthermia aggravated the behavioral deficit and the brain injury. (44) Four secondary analyses have been published from the NICHD randomized, controlled trial. In one study examining the relationship of elevated temperature after HIE, 22% of esophageal core temperatures measured among the control group infants were higher than 37.5 C. (40) The odds of death or disability were increased 3.6- to 4-fold for each centigrade increase in the highest quartile of temperature in the control group. Another study evaluating predictors of outcome revealed that the classification and regression tree model, rather than the scoring system developed from identified variables and odds ratios, was superior to the early neurologic examination in predicting death/disability in this study. (45) A secondary study involving spot urine samples collected in 58 study participants revealed that a high urinary lactate-to-creatinine ratio was associated with death/disability. (46) Lastly, detailed analysis of the randomized, controlled trial data revealed the safety of hypothermia during the study intervention period, the entire hospital course, and follow-up to 18 to 22 months. (47) Meta-analyses of Trials Three independent systematic reviews have concluded that therapeutic hypothermia significantly reduces both death and disability after perinatal encephalopathy and is safe and that outcomes are homogeneous both within and between trials. (Table 4). (48)(49)(50) Gaps in Knowledge All of the current published trials have evaluated hypothermia as a neuroprotective strategy with the primary outcome of death or disability at 18 months of age. To Table 4. Meta-Analysis of Hypothermia for Term Infants Who Have Encephalopathy Outcome Relative Risk (95% Confidence Interval) Death or Moderate/Severe Disability Shah 2007 (48) 0.76 (0.65 to 0.88) Schulzke 2007 (49) 0.78 (0.66 to 0.92) Jacobs 2007 (50) 0.76 (0.65 to 0.89) Mortality Schulzke 2007 (49) 0.75 (0.59 to 0.96) Jacobs 2007 (50) 0.74 (0.58 to 0.94) Moderate/Severe Disability Schulzke 2007 (49) 0.72 (0.53 to 0.98) Jacobs 2007 (50) 0.68 (0.51 to 0.92) NeoReviews Vol.11 No.2 February 2010 e89

7 Table 5. Stage of Hypoxic-Ischemic Encephalopathy (HIE) and Response to Therapeutic Hypothermia Moderate HIE Whole body cooled NICHD trial (Shankaran et al, 2005) (39) Cool Cap trial (Wyatt et al, 2007) (41) Severe HIE Whole body cooled NICHD trial (Shankaran et al, 2005) (39) Cool Cap trial (Wyatt et al, 2007) (41) Death or Disability: Cooled assess efficacy in childhood, assessments of school-age outcome are being evaluated in the Cool Cap and NICHD Network Trial. The role of cranial imaging in predicting outcome among infants undergoing hypothermia is being evaluated from magnetic resonance imaging studies obtained in the NICHD trial. The role of initiating hypothermia beyond 6 hours of age in term infants is being examined because evidence suggests that effects of brain injury following hypoxia-ischemia in the preclinical model continues beyond the 6-hour therapeutic window. Hypothermia as neuroprotection for the 34 to 36-weeks gestation neonate who has encephalopathy also is being investigated. The impact of hypothermia initiated during transport at less than 6 hours of age has not been demonstrated. The results of current whole-body cooling trials are pending. The optimum depth and duration of cooling for demonstrating greater neuroprotection is unknown. The role of pharmacologic agents used in conjunction with hypothermia as neuroprotection for hypoxic-ischemic brain injury is being investigated in preclinical studies. Of note, disability is high with severe HIE in spite of therapeutic hypothermia (Table 5). American Board of Pediatrics Neonatal-Perinatal Medicine Content Specifications Know the clinical features, diagnosis, and management of perinatal hypoxic ischemic encephalopathy. Know the management of perinatal asphyxia, including neural protective strategies. 32% 48% 45% 57% 72% 85% 70% 91% Death or Disability: Control References 1. Roberston CMT, Finer NN, Grace MGA. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr. 1989;114: Shankaran S, Woldt E, Koepke T, Bedard MP, Nandyal R. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev. 1991;25: American College of Obstetricians and Gynecologist and American Academy of Pediatrics. Neonatal Encephalopathy and Cerebral Palsy. Defining the Pathogenesis and Pathophysiology. Washington, DC: Lorek A, Takei Y, Cady EB, et al. Delayed ( secondary ) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1994;36: Laptook AR, Corbett RJ, Arencibia- Mireles O, Ruley J. Glucose-associated alterations in ischemic brain metabolism of neonatal piglets. Stroke. 1992;23: Johnston MV, Trescher WH, Ishida A, Nakajima W. Neurobiology of hypoxic-ischemic injury in the developing brain. Pediatr Res. 2001;49: Siesjo BK, Bengtsson F. Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J Cereb Blood Flow Metab. 1989;9: Fellman V, Raivio KO. Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res. 1997;41: Liu XH, Kwon D, Schielke GP, Yang GY, Silverstein FS, Barks JD. Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. J Cereb Blood Flow Metab. 1999;19: Mehmet H, Yue X, Squier MV, et al. Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxiaischaemia is related to the degree of high energy phosphate depletion during the insult. Neurosci Lett. 1994;181: Tan WK, Williams CE, During MJ, et al. Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep. Pediatr Res. 1996;39: Gluckman PD, Guan J, Williams C, et al. Asphyxial brain injury the role of the IGF system. Mol Cell Endocrinol. 1998;140: Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997;99: Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics. 1998;102: Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res. 1999;46: Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33: e90 NeoReviews Vol.11 No.2 February 2010

8 17. Spitzmiller RE, Phillips T, Meinzen-Derr J, Hoath SB. Amplitude-integrated EEG is useful in predicting neurodevelopment outcome in full term infants with hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol. 2007;22:9: Freeman JM. The use of amplitude-integrated electroencephalography: beware of its unintended consequences. Pediatrics. 2007;119: Bona E, Hagberg H, Løberg EM, Bågenholm R, Thoresen M. Protective effect of moderate hypothermia after neonatal hypoxiaischemia: short and long term outcome. Pediatr Res. 1998;43: Busto R, Dietrich WD, Globus MYT, Valdes I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab. 1987;7: Carroll M, Beek O. Protection against hippocampal CA cell loss by post-ischemic hypothermia is dependent of delay of initiation and duration. Metab Brain Dis. 1992;7: Colbourne F, Corbett D. Delayed and prolonged postischemic hypothermia is neuroprotective in the gerbil. Brain Res. 1994;656: O Brien FE, Iwata O, Thornton JS, et al. Delayed whole body cooling to 33 to 35C and the development of impaired energy generation consequential to transient cerebral hypoxia-ischemia in the newborn piglet. Pediatrics. 2006;117: Sirimanne ES, Blumberg RM, Bossano D, et al. The effect of prolonged modification of cerebral temperature on outcome after hypoxia-ischemic brain injury in the infant rat. Pediatr Res. 1996; 39: Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia following severe transient hypoxia-ischemic ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res. 1995;5: Thoresen M, Bågenholm R, Løberg EM, Apricena F, Kjellmer I. Posthypoxic cooling of neonatal rats provides protection against brain injury. Arch Dis Child. 1996;74:F3 F9 27. Thoresen M, Simmonds M, Satas S, Tooley J, Silver IA. Effective selective head cooling during posthypoxic hypothermia in newborn piglets. Pediatr Res. 2001;49: Tooley J, Satas S, Eagle R, Silver IA, Thoresen M. Significant selective head cooling can be maintained long-term after global hypoxia ischemia in newborn piglets. Pediatrics. 2002;109: Tooley J, Satas S, Porter H, Silver IA, Thoresen M. Head cooling with mild systemic hypothermia in anesthetized piglets in neuroprotection. Ann Neurol. 2003;53: Tooley JR, Eagle RC, Satas S, Thoresen M. Significant head cooling can be achieved while maintaining normothermia in the newborn piglet. Arch Dis Child Fetal Neonatal Ed. 2005;90: F262 F Yager JY, Asselin J. Effects of mild hypothermia on cerebral energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat. Stroke. 1996;27: Laptook AR, Corbett RJ, Sterett R, Garcia D, Tollefsbol G. Quantitative relationship between brain temperature and energy utilization rate measured in vivo using P and H magnetic resonance spectroscopy. Pediatr Res. 1995;38: Taylor DL, Mehmet H, Cady EB, Edwards AD. Improved neuroprotection with hypothermia delayed by 6 hours following cerebral hypoxia-ischemia in the 14-day-old rat. Pediatr Res. 2002; 51: Covey MV, Oorschot DE. Effect of hypothermic posttreatment on hypoxic-ischemic striatal injury, and normal striatal development, in neonatal rats: a stereological study. Pediatr Res. 2007;62: Iwata O, Thornton JS, Sellwood MW, et al. Depth of delayed cooling alters neuroprotection pattern after hypoxia-ischemia. Ann Neurol. 2005;58: Williams G, Dardzinski BJ, Buckalew AR, Smith MB. Modest hypothermia preserves cerebral energy metabolism during hypoxiaischemia and correlates with brain damage: a P nuclear magnet resonance study in unanesthetized neonatal rats. Pediatr Res. 1997; 42: Gluckman PD, Wyatt J, Azzopardi DV, et al, on the behalf of the Cool Cap Study Group. Selective head cooling with mild systemic hypothermia after : multicenter randomized trial. Lancet. 2005;365: Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in : efficacy outcomes. J Pediatr Neurol. 2005;32: Shankaran S, Laptook AR, Ehrenkranz RA, et al, and the NICHD and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353: Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: a risk factor for adverse outcome. Pediatrics. 2008;122: Wyatt JS, Gluckman PD, Liu PY, et al, for the Cool Cap Study Group. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics. 2007;119: Bramlett HM, Dietrich WD. Progressive damage after brain and spinal cord injury; pathomechanisms and treatment strategies. Prog Brain Res. 2007;161: Yager JY, Armstrong EA, Jaharus C, Saucier DM, Wirrell EC. Preventing hypothermia decreases brain damage following neonatal hypoxic-ischemic seizures. Brain Res. 2004;1011: Mishima K, Ikeda T, Yoshikawa T, et al. Effects of hypothermia and hyperthermia on attention and spatial learning deficits following neonatal hypoxia-ischemic insult in rats. Behav Brain Res. 2004;151: Ambalavanan N, Carlo WA, Shankaran S, et al; National Institute of Child Health and Human Development Neonatal Research Network. Predicting outcomes of neonates diagnosed with hypoxemicischemic encephalopathy. Pediatrics. 2006;118: Oh W, Perritt R, Shankaran S, et al. Association between urinary lactate to creatinine ratio and neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy. J Pediatr. 2008;153: Shankaran S, Pappas A, Laptook AR, et al for the NICHD Neonatal Research Network. 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9 NeoReviews Quiz 9. A term newborn is delivered by emergent cesarean section for fetal distress from spontaneous placental abruption. The infant s Apgar scores are 1, 2, and 4 at 1, 5, and 10 minutes after birth, respectively. The umbilical cord blood gas shows a ph of 6.84 and a base deficit of 18 meq/l. There is no evidence of trauma, coagulopathy, metabolic disorder, or genetic abnormality. Neonatal hypoxic-ischemic encephalopathy is suspected. The mother inquires about the possibility of a brain insult in her infant. Of the following, the single most useful predictor of brain insult in this infant is the evidence of: A. Abnormal neurologic examination findings. B. Cerebral edema on cranial ultrasonography. C. Elevated creatine phosphokinase. D. Hemodynamic and pulmonary imbalance. E. Multisystem organ dysfunction. 10. The pathologic events resulting from hypoxia-ischemia that culminate in neonatal brain injury occur in two phases, characterized as primary energy failure and secondary energy failure. Of the following, the pathologic event most characteristic of secondary energy failure is: A. Activation of lipases and proteases. B. Decreased production of adenosine triphosphate and phosphocreatine. C. Generation of reactive oxygen species. D. Loss of ionic homeostasis across neural membranes. E. Release of apoptosis-triggering caspase proteins. 11. Brain hypothermia is a promising treatment for neuroprotection in neonatal hypoxic-ischemic encephalopathy. This neuroprotection is temperature-specific, with progressively increased protection associated with increasing depth of cooling, although adverse effects of cooling occur at temperatures below 32.0 C. Conversely, hyperthermia following a hypoxic-ischemic insult may aggravate brain injury. Of the following, spontaneous hyperthermia following a hypoxic-ischemic insult can result in neuronal cell death most specifically involving the: A. Cerebellar vermis. B. Cerebral cortex. C. Hippocampus. D. Periventricular white matter. E. Thalamocaudate region. e92 NeoReviews Vol.11 No.2 February 2010

10 Neonatal Encephalopathy: Treatment With Hypothermia Seetha Shankaran NeoReviews 2010;11;e85-e92 DOI: /neo.11-2-e85 Updated Information & Services Permissions & Licensing Reprints including high-resolution figures, can be found at: s;11/2/e85 Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: