60 Advances in Neonatal Care • Vol. 10, No. 2 • pp. 60-66

State of the ScienceHypoxic Ischemic Encephalopathy and Hypothermic Intervention for Neonates

Laura D. Selway, MSN, RN

SEARCH STRATEGY

A key word search was conducted using PubMedand the Cochrane Collection databases. Search termsincluded hypoxic ischemic encephalopathy, HIE,hypothermia, neonates, and total body and SHC.Specific search limits included infants only, Englishonly, and articles published within the last 7 years.Search results yielded 2 large, randomized, con-trolled trials with more than 200 patients in each trialthat explored hypothermia in neonates. Seven arti-cles explored neurodevelopmental outcomes, distri-bution of cerebral lesions, and determinants ofoutcomes. Smaller randomized controlled trialsexploring hypothermia for neonates were alsoincluded. Other articles explored the pathophysiol-ogy of HIE and side effects of hypothermia interven-tions in neonates.

PATHOPHYSIOLOGY OF PERINATALASPHYXIA AND THE DEVELOPMENT OF HIE

Acute hypoxic brain injury in a neonate can occurfor a variety of reasons. Any condition that leads todecreased oxygen supply (hypoxia) and decreasedblood supply to the brain (ischemia) can lead to this condition. Acute perinatal events such asplacental abruption, umbilical cord prolapsed,

Address correspondence to Laura D. Selway, MSN, RN, 539Constant Ridge Ct, Abingdon, MD 21009; NurseLaura3@aol.com.

Author Affiliation: School of Nursing, The Johns HopkinsUniversity, Baltimore, Maryland.Copyright © 2010 by the National Association of Neonatal Nurses.

Perinatal asphyxia and resulting hypoxicischemic encephalopathy (HIE) occur in 1 to 3per 1000 births in the United States.1-3 Higherrates occur in developing countries with limited diag-nostic and interventional resources.1 Worldwide,10% to 60% of infants who develop HIE will die andat least 25% of the survivors will have long-term neu-rodevelopmental sequelae.2 Hypoxic ischemicencephalopathy is the primary cause of 15% to 28%of cerebral palsy among children.3 Hypothermictherapy as either selective head cooling (SHC) ortotal body cooling as an intervention for asphyxiatedinfants offers promising results since its experimen-tal inception in the late 1990s. This article examinesthe pathophysiology of HIE, identifies infants at riskfor HIE as a result of perinatal asphyxia, reviewshypothermic intervention as a primary interventionfor compromised infants, and describes barriers to itsimplementation.

ABSTRACTPerinatal asphyxia and resulting hypoxic ischemic encephalopathy (HIE) occur in 1 to 3 per 1000 births in the UnitedStates. Induced hypothermia as an intervention for asphyxiated infants offers promising results in reducing neurodevel-opmental disabilities in surviving infants. Induced hypothermia and selective head cooling are effective interventionsfor asphyxiated infants that minimize continued neuronal damage and decrease neurodevelopmental disability at 18months of age. Identification of affected infants immediately after delivery and transfer to a facility that provides thistherapy is necessary to maximize the potential of this intervention. Standardization of hypothermia protocols withinneonatal intensive care units is essential for providing hypothermia as a treatment of HIE in infants. This article exploresthe pathophysiology of HIE, identifying infants at risk for HIE as a result of perinatal asphyxia, the use of hypothermicintervention for compromised infants, and barriers to the implementation of treatment.KEY WORDS: HIE, hypothermia, hypoxic ischemic encephalopathy, neonates, perinatal asphyxia, selective head cooling,total body cooling

LINDA IKUTA, RN, MN, CCNS, PHN • Section Editor

2.8HOURS

Continuing Education

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uterine rupture, tight nuchal cord, or an acute bloodloss are risk factors.3

In response to hypoxia, the neonate’s brain convertsto anaerobic metabolism in an effort to sustain func-tional ability. Anaerobic metabolism leads to rapiddepletion of adenosine triphosphate, accumulation oflactic acid, and failure of normal metabolic activity.4Intracellular pumps lose their efficiency resulting in anaccumulation of sodium, calcium, and water withinbrain cells. The resulting cascade of events includes anaccumulation of fatty acids, increasing oxygen-free rad-icals, cell apoptosis, and cell death.4 Following the acuteinjury and resuscitation, the neonate’s brain will expe-rience a second delayed insult if there is no interven-tion, despite restoration of oxygen to the brain.

Once cerebral perfusion and oxygenation arerestored, a second cascade of injury will occur at 6 to48 hours because the brain attempts to restore func-tion.4 Phosphorus metabolites and intracellular pHare restored; however, the brain has not recoveredfrom the initial injury and mitochondrial dysfunctioncontinues. The neonate’s body releases endogenousinflammatory cells and mediators following the initialinjury that contribute to ongoing brain injury in thesecond phase.4 The second stage of brain cell injuryis characterized by restoration of cellular metabolismwith continued suppression of electroencephalogramactivity.5 Cell apoptosis and death occur followinghypoxic injury, and the extent of cell death is propor-tional to the extent of the ischemic injury.

Perinatal asphyxia progresses to HIE based on thedegree of brain injury and resulting clinical presenta-tion. Clinical seizures are the hallmark of resultingencephalopathy following injury.1,4 Sarnat andSarnat’s criteria for clinical encephalopathy can beused to determine the degree of neuronal injurybased on the infant’s symptoms.6 The Sarnat andSarnats criteria include lethargy, stupor, or coma,with 1 or more of hypotonia, abnormal reflexes (ocu-lomotor or papillary abnormalities), an absent orweak suck, or evidence of seizures.6 An amplitude-integrated electroencephalogram (aEEG) can pro-vide further information about the degree of braininjury. Moderate to severe voltage changes seen onan aEEG are indicative of encephalopathy and fur-ther intervention is required to limit brain injury.1

Perinatal asphyxia and resulting HIE cannot beanticipated prior to delivery. Neuronal injury is aresult of precipitous events, rather than a diagnosis orknown complication of the pregnancy. Asphyxiatedand physiologically depressed infants show no clini-cal warning of delivery complications that can beanticipated during the pregnancy. During labor, vari-able and late decelerations of the fetal heart rate arethe main indicators of a stressed infant at risk forhypoxic injury.4 Primarily, term infants are at risk forneuronal injury because of change in blood flow andbrain metabolic activity after 34 weeks.

There is no known genetic predisposition fordeveloping HIE for some infants compared withother infants. There is also no evidence exploringindividual coping and adaptation processes amonginfants that can blunt neuronal injury followingasphyxia.

THERAPEUTIC HYPOTHERMIA

Mild hypothermia as a treatment for HIE was discov-ered in the 1950s when isolated reports that asphyx-iated infants were submersed in a cold tub of wateruntil spontaneous respirations began.7 In the 1980s,it was noted that hypothermic drowning victims sur-vived submersion for up to 40 minutes with no last-ing neurologic sequelae and experiments withhypothermia were conducted following cardiopul-monary resuscitation of adults.7 Studies have alsoexplored the use of hypothermia with stroke and car-diac patients.

Today, the effects of hypothermia on the neonatalbrain following acute brain injury are well knownand promising. A temperature reduction by 2�C to4�C decreases the rate of cell death and delays thecascade of metabolic changes that are normally asso-ciated with hypoxia.4 As a result, cerebral metabo-lism is reduced, adenosine triphosphate stores areconserved, anaerobic metabolism effects are blunted,and free radicals are not released. In addition,hypothermia can delay secondary brain injury andmitigate present injury in the neonatal hypoxicbrain.4

CoolCap TrialMild hypothermia for asphyxiated infants emergedin the late 1990s as a possible intervention for braininjury occurring between the initial phase and thesecond phase of neuronal damage associated withHIE. The first randomized controlled trial and cor-nerstone of hypothermic intervention in neonateswas the CoolCap trial.6 This trial recruited 234infants with evidence of asphyxia and resultingencephalopathy from 25 perinatal centers betweenJuly 1999 and January 2002 to participate in the trial.Strict inclusion criteria in the CoolCap trial hasallowed benchmarking with further criteria in laterHIE studies. Inclusion criteria of the CoolCap trialincluded the following6:

1. gestational age 36 weeks or more,2. Apgar score of 5 or less at 10 minutes following

birth,3. continued need for resuscitation (endotracheal

or mask ventilation) at 10 minutes followingbirth,

4. severe acidosis (pH � 7.00, base deficit � 16mmol/L from umbilical cord, or an arterial orvenous sample from infant within 1 hour follow-ing birth), and

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5. grade II or III encephalopathy based on theSarnat and Sarnat criteria.

The CoolCap trial cooled infants (n � 116) to 34�Cto 35�C rectally via a cooling cap within 6 hours ofdelivery and maintained a hypothermic state for 72hours. The control infants (n � 118) received conven-tional care and maintained temperatures of 36.5�C to37.2�C.

The results demonstrated that infants cooled priorto 6 hours following delivery had the most potentialto benefit from the therapy before the second phaseof neuronal damage occurred.6 The infants hadaEEGs performed prior to the initiation of therapy.Infants in the cooling group with the most severeaEEG changes received less benefit from coolingthan infants with less severe aEEG changes. Thestudy found that the initial encephalopathy gradingwas more predictive of future adverse outcomes thanthe Apgar scores or the presenting acidosis.6 Theauthors recommended aEEG recordings to identifyat-risk infants who could benefit from hypothermiabefore the small therapeutic window of 2 to 6 hoursfollowing delivery closed.

The CoolCap trial also concluded that largerinfants responded better to hypothermia than smallerinfants. The authors speculated that the size of thebrain could affect the temperature to which it wascooled in relation to outcomes, but more researchwas needed.1,6 Pyrexia (temperature � 38�C) wasclearly associated with worse outcomes, especially inthe control group, since heat production increasedcerebral metabolism and exacerbated neuronalinjury.1 Inadvertent warming occurred in both thecooling and control groups through seizures, inflamma-tory cytokine release, and the use of servo-controlledheaters.

COMPLICATIONS OF HYPOTHERMIAIN NEONATES

The safety of induced hypothermia and SHC hasbeen studied in relation to the risk—benefit ratio ofthe treatment in neonates. Hemodynamic changesassociated with hypothermia remain the major nega-tive outcome of the intervention. One study8 ana-lyzed the hemodynamic parameters of 7 cooledinfants by comparing cooling values with postre-warming values. The most significant side effect ofcooling was a decrease in heart rate, with a mean of129 beats per minute compared with a mean of 149beats per minute following rewarming. Cardiac out-put was reduced to 67% and stroke volume wasreduced to 77% while the infants were cooled, but allinfants returned to baseline following rewarming.8None of the infants experienced an alteration inblood pressure or left ventricular ejection time as aresult of hypothermia. The authors concluded thatdespite a decrease in heart rate, stroke volume, and

cardiac output, the infants were able to maintainperipheral perfusion with normal lactate levels dur-ing the hypothermia phase with all the parametersreturning to baseline with passive rewarming.8 Theauthors also cited heart arrhythmias, hypotensionwith rapid rewarming, and increased blood viscosityas potential side effects of hypothermia, but no infantin their study experienced these side effects.

A second study looked at 26 asphyxiated infantswith hypothermia as an intervention for half of theinfants.9 All of the cooled infants had some degree ofrenal impairment that resolved with rewarming. Allof the cooled infants demonstrated a fall in heart rate,less than 80 beats per minute in 2 infants, whichresolved with rewarming. One cooled infant had aprolonged QT interval that resolved followingrewarming. None of the cooled infants required anincrease in oxygen requirement compared with thecontrol infants. The authors found that coagu-lopathies within the cooling group were not signifi-cant when compared with the control group. Therewas no difference in the rates of thrombocytopenia,intraventricular hemorrhage, or abnormal coagula-tion tests in the cooled group when compared withthe control group.9 An additional study3 found noassociation with an increase in hemorrhagic lesions ininfants cooled to 33�C to 34�C when examining basalganglia and white matter lesions in asphyxiatedinfants.

Studies examining the side effects of hypothermiaacknowledge transient hemodynamic changes incooled infants who resolve with passive rewarming.3,8,9All studies recommend hypothermia for asphyxiatedinfants as the benefits of preventing continued neu-ronal damage outweighed the transient hemodynamicside effects. The original CoolCap trial data did notspecifically address side effects, but the same data wereused in other trials focusing on side effects and thesafety of hypothermia.

NEURODEVELOPMENTAL OUTCOMESFOLLOWING HYPOTHERMIA IN NEONATES

Using the original data obtained from the CoolCaptrial, investigators were able to follow up with theinfants who participated in the study to evaluate neu-rodevelopmental outcomes at 18 months of age.6 Ofthe original 234 infants who participated in theCoolCap trial, 218 infants were available for follow-up at 18 months. Investigators defined severe neurode-velopmental disability as a triad of symptoms, includ-ing gross motor function of 3 to 5 (nonambulant, sitswith support, or infants with no self-mobility),Bayley mental development index less than 70, andbilateral cortical visual impairment served as thethreshold indicators for severe neurodevelopmentaldisability.6 The authors found that 73 of the 110infants in the control group (66%) experienced death

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or severe disability by 18 months compared with 59of 108 infants in the cooled group (55%). It was alsonoted that for infants with the most severe changesin aEEG recordings prior to treatment, hypothermiahad offered minimal neuroprotective benefit andthat some infants incurred too much brain damagefrom the initial injury to benefit from any interven-tional treatment.6

Rutherford et al3 explored cerebral lesions foundin HIE infants who underwent cooling comparedwith normothermic infants. Cooling in this particu-lar study was divided into infants who had SHC andinfants who had whole body cooling (WBC).Cerebral lesions related to asphyxia and HIE aremost commonly found in the basal ganglia and thal-amus and are associated with the development ofcerebral palsy.3 Less commonly, lesions are found inthe white matter of the brain and are associated withlater cognitive impairments.3 Eighty-six infants wereenrolled in the study by Rutherford et al to determinewhether cooling altered the severity and pattern oflesions found in infants with HIE. Thirty-four cooledinfants (20 were whole body cooled and 14 wereselective head cooled) and 52 normothermic infantswere evaluated following recovery from an acutehypoxic injury. The study found that the prevalenceof intraventricular hemorrhage was the same for all3 groups but that the 2 cooling groups had a decreasein number and severity of basal ganglia and thalamiclesions.3 In the control group, 46 of the 52 infants(88%) had basal ganglia and thalamic lesions present.Seven of 14 infants (50%) in the SHC group and 15 of20 infants (75%) in the WBC group had basal gangliaand thalamic lesions present. Approximately 40% ofinfants with significant basal ganglia and thalamuslesions will have white matter infarction but in thisstudy there was no decrease in the incidence ofsevere white matter lesions in the cooled infants.3

Shankaran et al10 conducted a large hypothermiatrial with 208 enrolled infants with similar inclusioncriteria to that of the CoolCap trial. The researchersrecruited infants from 15 perinatal centers from July2000 to May 2003. Two hundred five infants receivedfollow-up neurodevelopmental assessments at 18 to22 months. Death or moderate or severe disabilityoccurred in 44% of the infants in the cooling group (n � 102) and in 62% of the infants in the controlgroup (n � 103). Table 1 illustrates the infants strati-fied based on disability from Shankaran’s results.

COOLING AND REWARMING

Since the CoolCap Trial, researchers have exploredvarious methods of cooling and the degree of coolingrequired to mitigate neuronal injury resulting fromHIE. The original CoolCap was a cooling deviceshaped as a hat that circulated water to maintain theinfant’s rectal temperature at 34�C to 35�C. Selective

head cooling seemed ideal because the infant’s brainproduces 70% of total body heat and systemic sideeffects of hypothermia would be minimal with onlythe infant’s head cooled.2 However, new researchindicates that WBC enables the infant to reach adeeper level of hypothermia, and deep internal brainstructures benefit from temperatures of 33�C.3,10Shankaran et al10 chose WBC for their randomizedcontrol trial since WBC provides even cooling to allbrain structures affected by hypoxic injury. Becausethe thalamus, internal capsule, and basal ganglia ofthe brain are most sensitive to hypoxic injury, WBCachieved homogenous hypothermia compared withSHC, which tends to cool the periphery of the brainrather than the central brain. The hemodynamic sideeffects of hypothermia do not differ between SHCand WBC.8 Stratified studies have divided cooledinfants into SHC and WBC and into differing degreesof cooling that complicate the results and delay trans-lation into practice.3,9 Cooling temperatures rangedfrom 33�C to 35� via rectal, skin, and esophagealmeasurements in the studies, with no standardizationevident.1,2,5,6,10

Once the infant has been in a hypothermic state for48 to 72 hours, the process of rewarming begins. Aswith the cooling of infants, the process of rewarminginfants varied among trials. In 1 study, active rewarm-ing occurred over 3 to 6 hours with the discontinua-tion of the cooling device and the addition of blanketsand a radiant warmer.8 Wyatt et al1 and Shankaran et al10 rewarmed infants slowly, no faster than 0.5�Cper hour until temperature was normothermic.

However, one point on temperature is clear.Temperatures greater than 38�C following acute neu-ronal injury increased cerebral metabolism andintensified injury. The CoolCap trial cautionedagainst inadvertent warming of infants in both thecontrol and cooled groups through seizure activityand the use of servo-controlled warmers.1

LIMITATIONS AND GAPS INTHE LITERATURE

The current literature on mild hypothermia is variablein translation and future application. The CoolCap

TABLE 1. Outcomes at 18 to 22 monthsof age10

Cooled Infants Controlled Infants (n � 102) (n � 103)

No. of deaths 24 38

Cerebral palsy, % 19 30

Blindness, % 7 14

Hearing aid use, % 4 6

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trial was the first multicenter, randomized controlledtrial to evaluate hypothermia as an effective interven-tion following perinatal asphyxia. Subsequent studieshave used the original inclusion criteria and incorpo-rated recommendations from the CoolCap trial sonow neonates must be enrolled within 6 hours ofdelivery to qualify for a hypothermia study and anaEEG is most often the diagnostic tool used to deter-mine baseline neuronal abnormality.

The neurodevelopmental outcomes of hypother-mia are promising but have not been validated byrepeated studies. The studies that examined neurode-velopmental outcomes all measure different outcomecriteria and continue to demonstrate high rates of dis-ability despite treatment. Despite discouraging ratesof disability, hypothermia still has benefits if initiatedpromptly and uniformly. Healthcare providersshould acknowledge that the severity of the initialhypoxic injury is most prognostic of the infant’s out-comes, regardless of intervention. Another limitationof neurodevelopmental outcomes is time. Becausehypothermia is relatively new, there are no data onhow these infants will progress as they age and howthey will perform in cognitive exercises.

In summary, what is known about hypothermia asan intervention for neonates with traumatic braininjury is that it is safe and affords minimal hemody-namic side effects. Hypothermia should be initiated assoon as possible because the therapeutic window closes6 hours after initial injury at delivery. Hypothermia hasdecreased the degree of neurodevelopmental disabilityfor some infants, but infants with more severe neuronalinjury may not respond to any intervention.

What is not known about hypothermia forneonates is the ideal cooling temperatures, method ofcooling, or duration of cooling because data have var-ied across studies. The duration of therapy in thestudies ranged from 48 to 72 hours and it was oftendiscontinued early for perceived hemodynamic insta-bility of a decreased heart rate related to hypother-mia. Unfortunately, rewarming practices of cooledinfants vary as much as the initial cooling practices.

Neurodevelopmental outcomes are prematurebecause of the short amount of time that the interven-tion has been available. It is apparent that more researchis required despite encouraging outcomes to date.

IMPLICATIONS FOR NURSING PRACTICE

Access to hypothermia for infants with acute asphyxiaat delivery varies across the United States. An anony-mous survey about hypothermia and HIE was sent tothe 809 medical directors of neonatal intensive careunits in the United States in October 2005. Only 28of the 441 respondents (6.4%) offered cooling as anintervention for HIE at their institution.11 Of therespondents who cooled infants, 64% offered totalbody cooling and 25% offered head cooling, the

remainder a combination of both interventions. Langet al11 reported that the majority of institutions thatoffered cooling were academic centers, with an aver-age patient census greater than 40. Approximatelyhalf (57%) of the centers offered Extra CorporealMembrane Oxygenation. Overwhelmingly, 69.1% ofthe responders felt that they “need more data” todetermine whether hypothermia was an effectiveintervention for infants with HIE.11 A major limitationof this survey was the convenience sample model, butit offers a glimpse into the access issue for infants bornin community hospitals with acute asphyxia and anarrow therapeutic window for successful interven-tion with hypothermia.

Nursing is central to the identification of infants atrisk for developing HIE as a result of acute asphyxiaat delivery. After the initial hypoxic injury, infantsmay appear to recover, but this leads to a false senseof safety because a second phase of neuronal injurywill inevitably follow. Ideally, infants at risk for HIEshould be transferred to a treatment center within 6hours to prevent further brain injury and to initiatehypothermia. Education about the clinical presenta-tion of asphyxia, presence of seizures, and criteria forhypothermia should be mandatory for all labor anddelivery, newborn nursery, and neonatal intensivecare unit nurses, regardless of whether hypothermiais practiced at that institution or not.

Although it is essential to initiate hypothermia forat-risk infants as soon as possible, it is equally imper-ative that it is initiated in a controlled manner and ina setting with hypothermia expertise. The transferringhospital should not begin hypothermic proceduresindependently prior to transfer. Efforts to avoid over-heating the infant should be made. If the patient can-not be transferred within 6 hours of delivery, coolingcan be initiated in transport, but only under the direc-tion of the accepting institution.12 Whole body cool-ing is easier to initiate than SHC in transport with icepacks and the use of ambient air temperature whilecontinuously monitoring rectal temperatures.

Care of the infant receiving either SHC or totalbody cooling requires a whole systems approach(Figure 1). In addition to managing the cooling appa-ratus, supportive care of the infant is essential.Promotion of oxygen and ventilation is important.Not all infants who qualify for hypothermic therapywill require mechanical ventilation. However, care-ful attention should be paid to avoid hypoxia, hyper-oxia, or hypercarbia.13,14

Cooling will frequently result in a mild decrease inresting heart rate. However, bradycardia (a heart rateless than 80 beats per minute) may indicate that theinfant needs to be warmed slightly. In addition, per-fusion should be maintained and hypotension shouldbe treated with volume expansion or vasopressordrugs as appropriate. Monitoring of intake and outputis essential because infants with asphyxia injury may

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also develop oliguria secondary to acute tubularnecrosis or “syndrome of inappropriate antidiuretichormone” release.14

Total parental nutrition will be required to main-tain appropriate blood glucose and provide for nutri-tion. Hypoglycemia and hyperglycemia should beavoided.14 In addition, electrolytes, including sodiumand potassium, should be monitored, along withcoagulopathy studies.

It is generally preferable that infants receivingcooling therapy be sedated as necessary. Excessactivity or agitation can result in elevation of bodytemperature. Infants with HIE are at risk for seizureactivity. Seizures should be identified and treated.13

Advanced practice nurses are pivotal in the appli-cation of research into practice. They can increasewhat is known about therapeutic hypothermia forneonates through formalized teaching arenas, publi-cation, and informal unit-based in-services with nurs-ing staff. Education should focus on identifying at-riskinfants who require intervention, describing the ben-efits of hypothermia, and gaps in the literature regard-

ing hypothermia in neonates. In turn, nurses can edu-cate families and caregivers about this intervention fortheir infant and support them emotionally as theirinfant’s prognosis evolves. Advanced practice nursesshould participate in further research to contribute tothe knowledge of hypothermia for neonates.Standardization of hypothermia practice is the goal asmore is discovered about this life-saving intervention.

References1. Wyatt JS, Gluckman PD, Liu PY, et al. Determinants of outcomes after head cool-

ing for neonatal encephalopathy. Pediatrics. 2007;119:912-921.2. Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns

with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007;(4):CD003311.

3. Rutherford MA, Azzopardi D, Whitelaw A, et al. Mild hypothermia and the distri-bution of cerebral lesions in neonates with hypoxic—ischemic encephalopathy.Pediatrics. 2005;116:1001-1006.

4. Perlman JM. Intervention strategies for neonatal hypoxic—ischemic cerebralinjury. Clin Ther. 2006;28:1353-1365.

5. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmentaloutcome of infants treated with head cooling and mild hypothermia after peri-natal asphyxia. Pediatrics. 2001;107:480-484.

6. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild sys-temic hypothermia after neonatal encephalopathy: multicentre randomised trial.Lancet. 2005;365:663-670.

FIGURE 1.

Infant with cooling cap in place. Used with permission from Dr Jan Paisely.

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7. Thoresen M, Whitelaw A. Therapeutic hypothermia for hypoxic—ischaemicencephalopathy in the newborn infant. Curr Opin Neurol. 2005;18:111-116.

8. Gebauer CM, Knuepfer M, Robel-Tillig E, Pulzer F, Vogtmann C. Hemodynamicsamong neonates with hypoxic—ischemic encephalopathy during whole-bodyhypothermia and passive rewarming. Pediatrics. 2006;117:843-850.

9. Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with headcooling and mild systemic hypothermia (35.0�C and 34.5�C) after perinatalasphyxia. Pediatrics. 2003;111:244-251.

10. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia forneonates with hypoxic—ischemic encephalopathy. N Engl J Med. 2005;353:1574-1584.

11. Lang TR, Hartman TKM, Hintz SR, Colby CE. Hypothermia for the treatment ofneonatal ischemic encephalopathy: is the genie out of the bottle? Am J Perinatol.2007;24:27-32.

12. Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemicencephalopathy. Arch Pediatr Adolesc Med. 2007;161:951-958.

13. Long M, Brandon DH. Induced hypothermia for neonates with hypoxic—ischemicencephalopathy. J Obstet Gynecol Neonatal Nurs. 2007;36:293-298.

14. Perlman JM. General supportive management of the term infant with neonatalencephalopathy following intrapartum hypoxia—ischemia. In: Perlman JM, PolinRA, eds. Neurology: Neonatology Questions and Controversies. Philadelphia, PA:Elsevier; 2008:79-87.

For more than 35 additional continuing education articlesrelated to neonatal, go to NursingCenter.com/CE.

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