To view this article in PDF form, click here.

Hypothermia: A cool intervention for hypoxic-ischemic encephalopathy

The window of time for diagnosis of hypoxic-ischemic insult is short. Quick recognition and fast referral ensure the best possible outcome for affected infants.

Stephanie L. Jorgensen, PA-C

Stephanie Jorgensen is a graduate of Weill Cornell Medical College PA program and works in urgent care at Burlington Memorial Hospital in Burlington, Wisconsin. She has indicated no relationships to disclose relating to the content of this article.

Hypoxic-ischemic encephalopathy (HIE) is a serious condition that causes significant neonatal morbidity and mortality. The incidence of HIE is estimated at 2.8 cases per 1,000 live births.^1-3 Ten percent to 15% of affected infants die during the neonatal period, and 25% to 30% of the survivors will have permanent neurologic damage, typically manifesting as mental retardation, cerebral palsy, and/or epilepsy.^4,5 The timing of the injury remains controversial. HIE was believed to be caused by an intrapartum event such as cord prolapse, breech extraction, forceps delivery, abruptio placentae, or maternal pyrexia.^6,7 However, intrapartum factors have been found to account for only 4% of cases of neonatal encephalopathy, whereas 69% of cases had evidence of antepartum risk factors,^6,8 including maternal thyroid disease, severe preeclampsia, presumed viral infection, moderate-to-severe vaginal bleeding during pregnancy, and maternal hypertension.^9,10 Primary and secondary intrauterine growth restriction were also found to have a strong association with HIE.⁹

HIE is an evolving process. After the initial hypoxic-ischemic insult, the brain undergoes a reperfusion period during which cerebral blood flow is restored.^3,11 The restitution of blood flow allows for a transient recovery period, the latent phase, that lasts 2 to 8 hours.^3,5,11 Oxidative cerebral metabolism is partially to completely restored during this phase.^3,5,11 However, a rapid decline in brain cell function, or secondary energy failure, caused by the lack of oxygen and nutrients during the insult typically follows the latent phase.^3,5,11,12 This final phase includes delayed seizure activity, cell edema, accumulation of cytotoxins, and, ultimately, brain cell demise.³ The severity of the initial insult becomes a chief predictor of the infant’s neurologic outcome.

MECHANISMS OF NEURONAL DEATH

Pathogenic mechanisms of action that follow a hypoxic-ischemic event include oxidative stress, excitotoxicity, and programmed cell death. How these processes relate to the developing brain explains the neuronal cell death that occurs.

Oxidative stress Byproducts of normal metabolism produce low concentrations of reactive oxygen species such as nitric oxide. In a healthy adult brain, enzymatic and nonenzymatic antioxidants help to neutralize the potentially toxic effects of these destructive species.¹³ The immature brain has high concentrations of unsaturated fatty acids and redox-active iron that potentiate the generation of free radicals, which are highly reactive and destructive to tissues; a high rate of oxygen consumption; and low concentrations of antioxidants.^10,13,14 These characteristics suggest that the neonatal brain is vulnerable to oxidative damage because it lacks sufficient antioxidant reserves.

Excitotoxicity Cell death mediated by excessive activation of excitatory neurotransmitter receptors is one of the primary processes involved in hypoxic-ischemic brain injury.^15,16 Normally, glutamate is released from the synapse and briefly enters the extracellular space. Signal transduction pathways are achieved via activation of glutamate receptors and are quickly removed by the energy-dependent neuronal and glial reuptake pumps before toxicity occurs.¹⁵ However, hypoxic ischemia results when neuronal release of glutamate increases and glutamate reuptake pump activity decreases.^16-18 Prolonged stimulation of glutamate receptors triggers a neurotoxic cascade of events. Excessive extracellular glutamate combined with membrane depolarization opens channels and floods cells with calcium.¹⁶ Once through the channels, calcium activates the enzyme nitric oxide synthase and free radicals form. Nitric oxide alone can cause cell demise, but when combined with a superoxide ion, it has an even more devastating effect on brain cell membranes.¹⁶ This process becomes a self-propagating cascade of neuronal damage that persists for days to weeks, depending on the degree and location of the initial insult.

Programmed cell death (PCD) Apoptosis has a well-established, essential role in normal human growth and development.^19-22 Some laboratory data suggest up to 50% of the developing neuronal cells undergo PCD.^22,23 Although a part of normal fetal development, immature neuronal cells may be more prone to PCD.^23,24

WHY IS HYPOTHERMIA EFFECTIVE?

Hypothermia is defined as a body temperature significantly below 37°C (see Table 1). When initiated within the latent period, posthypoxic hypothermia can have neuroprotective properties, thus improving neonatal survival and outcome.^25-28 Reducing the temperature of a chemical reaction is a well-established method of prolonging the end-product; however, when applied to the human body, this process is much more intricate. Erecinska and colleagues reported that for each degree Celsius reduction in body temperature, cerebral metabolism is reduced by 5% to 7%.²⁹ Specifically, hypothermia reduces the release of excitatory amino acids and nitric oxide³⁰ that otherwise could result in a neuronal death spiral. Edwards and colleagues suggested that apoptosis is reduced by postinsult hypothermia.³¹ Posthypoxic hypothermia was proven to reduce seizure activity in neonates.³²

Mild hypothermia (33°C) was used to treat out-of-hospital cardiac arrest in adults in two randomized clinical trials.^33,34 The results showed increased survival and improved neurologic outcome in patients who received 12 to 24 hours of hypothermia.^33,34 However, results were not as favorable when hypothermia was used to treat patients with stroke and traumatic head injuries.^35-37

THE CLINICAL TRIALS

Several clinical trials show promising results for the future of hypothermia treatment. The four published studies reviewed here examined selective head cooling and whole body hypothermia in neonates with HIE.

Pilot trial The first randomized, multicenter pilot trial utilized moderate hypothermia.³⁸ Criteria for inclusion were age (35 weeks or younger); birth weight (2,000 g or less); abnormal clinical signs (such as metabolic base deficit); low Apgar scores; and indicators of neurologic dysfunction such as posturing, seizures, and autonomic dysfunction. The infants were randomly assigned to the control group (n = 33), in whom rectal temperatures were maintained at 37°C, or hypothermic group (n = 32). Hypothermia was initiated within 6 hours of birth and achieved with ice packs and/or cooling blankets. The infants were cooled to a rectal temperature of 33 ± 0.5°C for 48 hours.

The original 65 enrolled infants were re-evaluated at age 12 months. Ten (31%) of the cooled infants had died and 14 (42%) of the normothermic infants had died. Thirteen of the infants were withdrawn (3%) or lost to follow-up (17%). Of those with a known outcome (n = 28), death or severe motor disabilities was observed in 52% of the cooled infants compared with 84% of the normothermic group.³⁸

CoolCap study In this large multicenter trial, 234 full-term infants, defined as at 36 weeks’ gestation or later, were enrolled based on diagnostic criteria similar to the pilot study.³⁹ A diagnosis of HIE was established according to clinical stages based on accepted guidelines⁴⁰ (see “Clinical stages of perinatal hypoxic-ischemic brain injury”). Amplitude-integrated electroencephalography (aEEG) recordings were obtained at various times after 1 hour postpartum. The infants were then randomly assigned to either a control group (n = 118), in whom rectal temperatures were maintained at 37°C, or a selective head-cooling group (n = 116).³⁹ Infants in the head-cooling group wore custom-fitted cooling caps for 72 hours, rectal temperatures were maintained at 34°C to 35°C (see Figure 1). At 72 hours, the infants were slowly rewarmed until their body temperatures returned to within normal limits.³⁹

Sixteen infants, 8 from each group, were lost to follow-up. Of the remaining 218 (93%) infants, 73 (66%) in the control group and 59 (55%) in the head cooling group died or had severe disability at age 18 months. Initial results in a mixed population of infants with moderate to severe HIE were statistically insignificant. However, the investigators hypothesized a priori that head cooling would not affect the outcome of infants with the most severe aEEG readings (n = 46; 21%) and these infants were excluded. After excluding this group, the percentage of infants that died or had severe disability in the cooled group was reduced to 48%. The authors concluded that selective head cooling was not protective in a mixed population but may benefit and improve survival in neonates with moderate aEEG changes.³⁹

Whole body hypothermia In a second multicenter randomized trial, cooling blankets were used on 239 full-term infants;⁴¹ inclusion criteria were the same as for the earlier trials. After a thorough neurologic examination, infants were eligible when a diagnosis of moderate to severe encephalopathy could be made or seizure activity occurred. Consent was not obtained or it was refused for 31 eligible infants. The remaining infants were randomly assigned to either the control group (n = 106) or the cooling group (n = 102). Hypothermia was achieved in the cooling group within the first 6 hours of life using cooling blankets for 72 hours; esophageal temperature was maintained at 33.5°C. At 72 hours, the infants were slowly rewarmed.

Infants were reassessed at age 18 to 22 months. Three infants from the control group were lost to follow-up. Of the remaining 205 infants, death or moderate-to-severe disability occurred in 45 (44%) in the cooling group compared to 64 (62%) in the control group. Death occurred in 24 (24%) cooled infants and 38 (37%) in the normothermia group. In this study, whole-body hypothermia improved the survival rate and outcome in neonates with moderate to severe HIE.⁴¹

Single-center trial Using similar inclusion criteria, Chinese researchers enrolled 62 full-term infants in a single-center study.⁴² The infants were randomized to the hypothermia group (n = 32) or the control group (n = 30). Hypothermia was achieved within 6 hours via a cooling cap set at 34ûC to 35°C for a 72-hour period. CT was obtained on all infants at postnatal days 5 to 7. Enrolled infants were then given a Neonatal Behavioral Assessment Scale (NBAS) score at postnatal days 7 to 10.

Four infants, two from each group, died shortly after enrollment and were withdrawn. Of the 58 infants that completed the study, results favored the hypothermia group based on CT scans and NBAS scores. Four of the 30 (13%) cooled infants showed moderate to severe hypoxic-ischemic changes on CT, compared to 18 (64%) in the control group. In addition, NBAS scores were significantly improved in the hypothermia group. Analyzed data suggest selective head cooling in neonates with HIE has definitive neuroprotective effects.⁴²

Ongoing clinical trials Several clinical trials with similar designs and inclusion criteria are underway worldwide. In England, 18-month follow-up in the Total Body Cooling Trial is scheduled to be complete in the fall of this year.⁴³ Two international studies that were actively recruiting infants at press time are the Infant Cooling Evaluation (ICE) Trial (Melbourne University, Australia) and the neo.nEuro.network (Medical University Innsbruck, Germany).^44,45 Simultaneous with the ongoing trials, the Cool-Cap device received FDA approval for the treatment of neonatal HIE in the United States and is currently being used in some high-risk neonatal centers.^46,47

SAFETY AND OUTCOMES

Hypothermia, even mild cases, is associated with a wide range of systemic side effects. The most common adverse effects are bradycardia, hypertension, and hypotension.¹² Lowering the core body temperature to less than 34°C significantly increases the risk for cardiac arrhythmias, platelet dysfunction, coagulopathies, and sepsis.¹² Despite these well-described risks, little data exist on the safety of therapeutic hypothermia in neonates with HIE. The studies discussed in this article showed no significant sequelae from hypothermia other than bradycardia and hypertension, which resolved upon conclusion of therapy.^38,39,41,42

In a small, randomized trial to determine the safety of head cooling in neonates with HIE, none of the infants developed adverse effects secondary to head cooling.⁴⁸ The investigators concluded that mild hypothermia in full-term newborns was a safe and efficacious method to reduce cerebral temperature.⁴⁸

A randomized, controlled pilot trial examined the safety outcomes of neonates treated with 48 hours of moderate hypothermia (33°C).⁴⁹ Adverse effects such as bradycardia, mild cardiac compromise with longer duration of pressor use, increased prothrombin times, and lower platelet counts requiring blood products were more commonly seen in the cooled infants compared to the normothermic group. Surprisingly, seizure activity was also more common in the treated group.⁴⁹

A more recent study assessed the hemodynamic parameters of seven infants with HIE during whole-body hypothermia (a rectal temperature of 33ûC to 34ûC) followed by a rewarming period.⁵⁰ Hypothermia was initiated 2 hours after birth via a cooling mattress for 72 hours; rewarming to a normal rectal temperature was achieved in 3 to 7 hours. A decreased heart rate was noted during hypothermia; however, bradycardia (less than 80 beats per minute) did not occur. Heart rates returned to normal during rewarming. In addition, the researchers noted that a decrease in stroke volume (72%) and cardiac output (67%) significantly increased during passive rewarming.⁵⁰

DISCUSSION

HIE continues to be an important cause of neonatal brain injury. Currently, no universal treatment modalities exist; however, hypothermia shows promise as a treatment. Present strategies include selective head cooling and total body hypothermia.

The studies reviewed in this article show strong evidence that hypothermia improves the outcome of infants with moderate to severe HIE. In the larger trials, data appear to favor whole-body hypothermia over head cooling.^39,41 Although the trials had similar study designs and inclusion criteria, the protocol used during the cooling period varied. The CoolCap study used custom-fitted cooling caps to cool infants to a rectal temperature of 34°C to 35°C. During the 72-hour cooling period, infants were placed under a radiant overhead heater. In comparison, the whole-body hypothermia study used two cooling blankets—one underneath and one on top—to cool infants to an esophageal temperature of 33.5°C; no heat sources were utilized during the cooling period. Cooling in the whole-body group was achieved up to 30 minutes faster than in the head-cooling group (90 minutes vs 2 hours). A randomized trial comparing the two cooling methods is needed to determine which is more effective.

Hypothermia, when initiated within 6 hours (latent period) of perinatal asphyxia, has neuroprotective properties that significantly improve the outcome of infants with HIE. However, several additional considerations should be noted. Presently, long-term efficacy and safety data are not available. Current follow-up data are limited to approximately age 2 years. Furthermore, the short-term effects of therapeutic hypothermia are well-documented in infants and adults, but the long-term sequelae are unknown. Despite these unanswered questions, medically induced hypothermia has been shown thus far to significantly improve neonatal morbidity and mortality.

Because of the shortened window in which hypothermia can be initiated, early recognition is crucial. PAs who work with newborns should be aware of the clinical signs of a hypoxic event. In addition, they should know of a high-risk perinatal center in their area, should a referral be warranted. The need for adequate time to inform and counsel the family of the newborn should not be overlooked. This, too, is an essential factor in neonatal outcome. Although only a small subset of PAs work directly in neonatology, PAs who work in pediatrics, obstetrics/gynecology, and family practice should become familiar with HIE and its treatment. JAAPA

REFERENCES

	1.	Spong CY. Therapy for hypoxic ischemic encephalopathy: a cool idea. Obstet Gynecol. 2005;106(6):1226-1227.
	2.	Levene ML, Kornberg J, Williams TH. The incidence and severity of post-asphyxial encephalopathy in full-term infants. Early Hum Dev. 1985;11(1):21-26.
	3.	Gunn AJ. Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr. 2000;12(2):111-115.
	4.	Fenichel GM. Hypoxic-ischemic encephalopathy in the newborn. Arch Neurol. 1983;40(5):261-266.
	5.	Wyatt JS, Robertson NJ. Time for a cool head—neuroprotection becomes a reality. Early Hum Dev. 2005;81(1):5-11.
	6.	Badawi N, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998;317(7172):1554-1558.
	7.	Higgins RD. Hypoxic ischemic encephalopathy and hypothermia: a critical look. Obstet Gynecol. 2005;106(6):1385-1387.
	8.	The Report of ACOG’s Task Force on Neonatal Encephalopathy and Cerebral Palsy has been Published. American College of Obstetricians and Gynecologists Web site. http://www.acog.org/from_home/Misc/neonatalEncephalopathy.cfm. Accessed May 1, 2008.
	9.	Badawi N, Kurinczuk J, Keogh JM, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998;317(7172):1549-1553.
	10.	Ferriero DM. Neonatal brain injury. N Engl J Med. 2004;351(19):1985-1995.
	11.	Higgins RD, Raju TN, Perlman J, et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr. 2006;148(2):170-175.
	12.	Saugstad OD. Some like it cool: hypothermia for newborn infants with hypoxic ischemic encephalopathy. J Perinatol. 2006;26(3):144-146.
	13.	McQuillen PS, Ferriero DM. Selective vulnerability in the developing central nervous system. Pediatr Neurol. 2004;30(4):227-235.
	14.	Siddappa AJ, Rao RB, Wobken JD, et al. Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci Res. 2002;68(6):761-775.
	15.	Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci. 1990;13:171-182.
	16.	Johnston MV, Trescher WH, Ishida A, Nakajima W. Neurobiology of hypoxic-ischemic injury in the developing brain. Pediatr Res. 2001;49(6):735-741.
	17.	Delivoria-Papadopoulos M, Mishra OP. Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention. J Pediatr. 1998;132(3, pt 2):S30-S34.
	18.	Pu Y, Li QF, Zeng CM, et al. Increased detectability of alpha brain glutamate/glutamine in neonatal hypoxic-ischemic encephalopathy. AJNR Am J Neuroradiol. 2000;21(1):203-212.
	19.	Saunders JW Jr. Death in embryonic systems. Science. 1966;154(3749):604-612.
	20.	Glucksmann A. Cell deaths in normal vertebrate ontogeny. Biol Rev. 1951;26:59-86.
	21.	Hurle JM. Cell death in developing systems. Methods Achiev Exp Pathol. 1988;13:55-86.
	22.	Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453-501.
	23.	Edwards AD, Yue X, Cox P, et al. Apoptosis in the brains of infants suffering intrauterine cerebral injury. Pediatr Res. 1997;42(5):684-689.
	24.	Blaschke AJ, Staley K, Chun J. Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex. Development. 1996;122(4):1165-1174.
	25.	Gunn AJ, Gunn TR, Gunning MI, et al. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics. 1998;102(5):1098-1106.
	26.	Yager JY, Asselin J. Effect of mild hypothermia on cerebral energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat. Stroke. 1996;27(5):919-926.
	27.	Bona E, Hagberg H, Loberg EM, et al. Protective effects of moderate hypothermia after neonatal hypoxic-ischemia: short- and long-term outcome. Pediatr Res. 1998;43(6):738-745.
	28.	Agnew D, Koehler RC, Guerguerian AM, et al. Hypothermia for 24 hours after asphyxic cardiac arrest in piglets provides striatal neuroprotection that is sustained 10 days after rewarming. Pediatr Res. 2003;54(2):253-262.
	29.	Erecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab. 2003;23(5):513-530.
	30.	Thoresen M, Satas S, Puka-Sundvall M, et al. Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport. 1997;8(15):3359-3362.
	31.	Edwards AD, Yue X, Squier MV, et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun. 1995;217(3):1193-1199.
	32.	Thoresen M, Tooley J, Satas S, et al. Cooling ameliorates seizures in encephalopathic newborn infants. Pediatr Res. 2003;53:23A.
	33.	Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563.
	34.	Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556.
	35.	Olsen TS, Weber UJ, Kammersgaard LP. Therapeutic hypothermia for acute stroke. Lancet Neurol. 2003;2(7):410-416.
	36.	Ginsberg MD, Busto R. Combating hypothermia in acute stroke: a significant clinical concern. Stroke. 1998;29(2):529-534.
	37.	Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344(8):556-563.
	38.	Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005;32(1):11-17.
	39.	Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial. Lancet. 2005;365(9460):663-670.
	40.	Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696-705.
	41.	Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584.
	42.	Lin ZL, Yu HM, Lin J, et al. Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit. J Perinatol. 2006;26(3):180-184.
	43.	Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy. National Perinatal Epidemiology Unit Web site. http://www.npeu.ox.ac.uk/Toby/. Accessed May 1, 2008.
	44.	Perinatal trials report. http://www.ctc.usyd.edu.au/6registry/PTO367.htm. Accessed May 1, 2008.
	45.	Induced systemic hypothermia in asphyxiated new-born infants: a randomized, controlled, multicenter study. Neonatal Research Web site. http://neonatal-research.at/php/detail.php?artnr=4367&ukatnr=11237&ukatname=department. Accessed May 1, 2008.
	46.	Olympic Medical. Summary of safety and effectiveness data. Food and Drug Administration Web site. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4162b1_03_SSED.pdf. Published May 11, 2005. Accessed May 5, 2008.
	47.	International trial shows cooling cap prevents brain injury in newborns. University of Michigan Health System Web site. http://www.med.umich.edu/opm/newspage/2004/coolingcap.htm. Published May 11, 2004. Accessed May 1, 2008.
	48.	Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics. 1998;102(4, pt 1):885-892.
	49.	Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005;32(1):18-24.
	50.	Gebauer CM, Knuepfer M, Robel-Tillig E, et al. Hemodynamics among neonates with hypoxic-ischemic encephalopathy during whole-body hypothermia and passive rewarming. Pediatrics. 2006;117(3):843-850.