- Email: [email protected]
Neonatal Hypoxic-Ischemic Encephalopathy and Total-Body Cooling
Neonatal Hypoxic-Ischemic Encephalopathy and Total-Body Cooling Maya Munoz, DO,* and John F. Kerrigan, MD*,†
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ntil recently, therapy for neonatal hypoxic ischemic encephalopathy (HIE) was nonspecific and limited. Treatment, consisting of efforts to maintain physiological stability and treat seizures with anticonvulsants, was supportive in nature and did not intervene with the basic mechanisms of hypoxic-ischemic brain injury.1 Although relatively uncommon (1-2 cases per 1,000 births), HIE has the potential to be devastating with residual symptoms, including cerebral palsy, developmental retardation, and epilepsy. Recent treatment studies with either total-body or selective head cooling have shown promising outcomes. Several studies strongly suggest that hypothermic therapy reduces death and neurologic disability in neonates with HIE without clinically significant complications.2-7 Selective cooling of the head was approved by the United States Food and Drug Administration as a treatment for neonatal HIE in December 2006. Here, we present a case in which whole-body cooling of a term neonate with HIE appears to have contributed to a favorable outcome.
Case Presentation A female neonate was born at 39 weeks gestation to a gravida 1 now para 1 19-year-old white female. The pregnancy was uneventful, but labor was complicated by nonreassuring fetal heart tones by external monitor. Emergency delivery by cesarean section was performed with discovery of complete placental abruption. Immediately after delivery, the baby cried spontaneously but quickly became limp and pale. Resuscitation efforts included intubation in the delivery room, external chest compressions, and 3 doses of epinephrine administered via the endotracheal tube and 1 subsequent dose of epinephrine through an umbilical vein catheter. Copious amounts of blood were suctioned from the trachea during the resuscitation. Apgar scores were 3, 0, 0, and 3 at 1, 5, 10 and 15
*From the Children’s Health Center. †Division of Pediatric Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ. Address reprint requests to John F. Kerrigan, MD, Barrow Neurological Institute, 500 West Thomas Road, S-400 Phoenix, AZ 85013. E-mail: [email protected]
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minutes, respectively. The initial umbilical cord venous blood gas showed a pH level of 6.96 (normal range for venous cord blood 7.30-7.40), pCO2 of 97 mm Hg (32-44 mm Hg), and a base excess of ⫺11.7 mmol/L (⫺2 to ⫺6 mmol/L). The cord blood lactic acid level was 11 mEq/L (0.7-2.1 mEq/L). The initial neonatal arterial blood gas showed a pH level of 6.89 (normal range term neonate 7.35-7.45), PaCO2 of 50 mm Hg (35-45 mm Hg), PaO2 of 241 mm Hg (50-80 mm Hg), and HCO3 of 14.4 mEq/L (18-24 meg /L). The patient received 75 mL of packed red blood cells, after which the hematocrit was 44% (42%-65%). Subsequent blood gasses showed the pH improving to 7.15 and then 7.26 before transport to the referral newborn intensive care unit (NICU). Before transfer, intermittent clonic seizure activity was noted, and an intravenous dose of phenobarbital, 17 mg/kg, was given. The patient was 3.5 hours of age upon arrival at the referral NICU. The examination revealed an intubated, nondysmorphic newborn with a decreased level of consciousness. Weight, length, and head circumference were at the 90th percentile for her gestational age. Vital signs included a rectal temperature of 34.7°C, a heart rate of 120 to 130 beats/min, respiratory rate 50 breaths/min, and blood pressure ranged from 58 to 66 mm Hg systolic and 22 to 38 mm Hg diastolic. The general physical examination revealed absent bowel sounds but was otherwise unremarkable. There were no spontaneous movements. The pupils were constricted but equal. Her tone was increased, with flexed positioning of the limbs. Corneal responses were intact, but her gag reflex was absent, as were primitive neonatal reflexes. She was placed on a cooling mattress, with an esophageal temperature probe set to thermoregulate to 33.5°C. An intravenous infusion of fentanyl was initiated, and a maintenance dose of phenobarbital was continued. An electroencephalogram showed suppressed background with discontinuous features and small numbers of sharps over the left temporal region but no seizure activity (Fig 1). A head ultrasound was normal. Her serum creatinine and hepatic transaminases were abnormally elevated, which were attributed to hypoxicischemic injury. At age 24 hours, she remained intubated and became reactive to external stimuli. At 48 hours of age, she was
Neonatal HIE and total-body cooling
83
Figure 1 Ten seconds of an electroencephalographic sample obtained at several hours of age at the time of inducing total-body hypothermia. The electroencephalographic background is poorly sustained (discontinuous) with excessive numbers of sharp transients over the left temporal head region but without evidence of seizure activity (7 v/mm, LFF 1 Hz, HFF 15 Hz). (Color version of figure is available online.)
successfully extubated and was showing increasing spontaneous movement. After 72 hours of cooling, she was slowly warmed to normal body temperature over the course of 6 hours. Her subsequent clinical course was marked by steady improvement, with tolerated feedings, and increasingly normal sleep-wake patterns and spontaneous behavior. Magnetic resonance imaging showed a small intraparenchymal hemorrhage in the white matter in the right periatrial region, but diffusion-weighted sequences were normal (Fig 2). By the time of hospital discharge at 15 days of age, she was awake and visually interacting with her mother. She had good head control, a strong cry, moved all extremities, and had proven herself a successful bottle feeder. Her neurologic examination was normal. Follow-up is pending at this time.
Discussion Although not yet considered a standard of care, whole-body cooling and selective head cooling for the treatment of HIE in newborns is certainly promising. Studies examining the safety of mild hypothermia (32°-34°C) have consistently found no adverse effects of clinical significance.2,4-9 Studies examining the efficacy of mild hypothermia in the setting of hypoxic-ischemic injury in full-term newborns have used different techniques. The first pivotal study of this
nature applied selective cooling of the head with a proprietary cooling cap system (Cool–Cap; Olympic Medical Corporation, Seattle, WA).10 A total of 234 term newborns with moderate to severe HIE were randomized to selective head cooling (rectal temperature 34°-35°C for 72 hours) or conventional care. When analyzed on an intent-to-treat basis (16 subjects were lost to follow-up), there was no significant difference in the 2 treatment groups for the primary outcome measure (death or severe disability at 18 months of age in 55% of the study group and 66% of the control group, P ⫽ 0.1). However, a predetermined subgroup analysis of 172 newborns with less severe abnormalities on an amplitudeintegrated electroencephalogram did show significant differences in outcome, with death or severe disability in 48% and 66% of the cooling and control groups, respectively; P ⫽ .009).10 These results suggested that mild hypothermia may be more beneficial in newborns with less severe HIE. A US multicenter consortium (National Institute of Child Health and Human Development Neonatal Research Network) has conducted a randomized trial of total-body cooling for term newborns with severe and moderate HIE.4,6 Patients in the intervention group (n ⫽ 102 subjects) were cooled to a core (esophageal) temperature of 33.5°C within 6 hours of birth, underwent 72 hours of cooling, and then were slowly rewarmed over 6 hours, whereas the control group (n ⫽ 106 subjects) received conventional supportive care. The primary
M. Munoz and J.F. Kerrigan
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Figure 2 Magnetic resonance imaging at 5 days of age after whole-body cooling. (A) An axial T1 sequence (TR 500/TE 8) notable for a small area of hemorrhage (arrow) in the right periatrial region. (B) An axial diffusion-weighted sequence with no evidence of cerebral infarction.
outcome measure was death or major disability, with neurodevelopmental assessment of survivors at 18 to 22 months. A significant difference between the study groups was seen, with death or disability in 44% of the hypothermia cohort and in 62% of the control cohort (P ⫽ .01).6 With subgroup analysis, death or disability was less likely with total-body cooling in subjects with moderate encephalopathy (hypothermia 32%, control 48%; P ⫽ .09) but not for newborns with severe encephalopathy (hypothermia 72%, control 85%; P ⫽ .24).6 There was no significant difference in the likelihood of developmental or neurologic impairment in the survivors between the 2 study groups when assessed at 18 to 22 months (ie, the results of this study suggest that newborns with HIE are more likely to survive when treated with totalbody hypothermia but do not necessarily have better functional outcomes). More recently, a third pivotal study has been published by a British Consortium, the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY).9 The study design and treatment protocol were very similar to that used in the National Institute of Child Health trial noted previously, with randomization of term newborns with HIE to mild total-body hypothermia (n ⫽ 163) or conventional supportive care (n ⫽ 162). In the hypothermia cohort, patients underwent totalbody cooling to 33.5°C within 6 hours of birth, with 72 hours of treatment, followed by slow rewarming.9 The primary outcome measure (as with the earlier studies noted previously) was death or severe disability, which was determined at 18 months of age. A number of prespecified secondary outcome measures were also identified, including Bayley Scales of Infant Development II (BSID-II) and Gross Motor Function Classification System, in addition to others. The TOBY study did not show a significantly reduced rate of death or severe neurologic disability (45% of subjects in the hypothermia group, 53% in the control group; P ⫽ .17) but did show significantly improved functional outcomes for
the surviving infants in the cooled group. Infants in the hypothermia cohort had a significantly greater likelihood of survival without neurologic abnormality (44% treatment group, 28% control group; P ⫽ .003) and also did significantly better on the BSID-II Mental Developmental Index (P ⫽ .03), BSID-II Psychomotor Developmental Index (P ⫽ .03), and the Gross Motor Function Classification System (P ⫽ .01). In contrast to the National Institute of Child Health trial noted earlier, the TOBY study did not show an increase in survival for cooled patients but rather showed improved functional outcome in those who did survive relative to the untreated cohort. In common with the other studies involving therapeutic hypothermia in neonates, adverse events were not associated with cooling.9 Our patient met multiple inclusion criteria for enrollment in the pivotal studies, with her history of placental abruption, an Apgar score of 0 at 10 minutes, umbilical cord blood and arterial blood pH less than 7, and the need for mechanical ventilation for greater than 10 minutes. Our clinical treatment protocol for mild total-body hypothermia for neonatal HIE does not use an amplitude-integrated electroencephalogram but rather includes a standard electroencephalogram upon enrollment. Although the outcome for our recent patient appears to be particularly encouraging at the time of hospital discharge, long-term follow-up is required. The basic cellular and molecular mechanisms by which mild hypothermia exerts a neuroprotective effect is unknown.11 The current concept is that 2 phases of injury take place because of HIE.12-14 The first, primary energy failure, occurs because of decreased cerebral blood flow and tissue oxygenation, forcing a shift to nonoxidative metabolism with lactic acidosis. This results in an acute loss of transmembrane ionic balance from the depletion of adenosine triphosphate and other high-energy stores, impairing neuron function. Additionally, there is excessive release (and decreased reuptake) of glutamate, resulting in excitotoxic injury.13,15,16
Neonatal HIE and total-body cooling Together, these result in an increase in intracellular calcium, activating lipases, proteases, and endonucleases and increases nitric oxide and oxygen-free radicals.17 In many cases of neonatal HIE, the cause of this primary energy failure is difficult to identify. In some cases, a clear event, such as a placental abruption, initiates this process. A secondary cascade of downstream events follows.13,14 This represents the likely intervention point for therapeutic hypothermia.12,18 These changes are complex and incompletely understood but include mitochondrial dysfunction, the elaboration of inflammatory mediators, and the initiation of transcription pathways leading to apoptosis.14,19,20 Although a detailed discussion of the specific mechanisms relating to apoptosis associated with HIE is beyond the scope of this article, several interesting candidate pathways have been identified. Prominent among them is activation of the caspase family of cysteine proteases, which results from mitochondrial membrane failure and, in turn, leads to DNA fragmentation and programmed cell death.21,22 The brain-derived neurotrophic factor is protective against tissue injury in an animal model of HIE and may act by blocking caspase-3 activation.23 The time period between the 2 phases of tissue injury is a potential therapeutic window and appears to extend to 6 hours in most animal models.24 However, the neuroprotective mechanism of cooling may intervene in many pathways involved in both the primary and secondary phases of cerebral injury.12,25 Animal studies have also shown a linear relationship between the brain regional glucose utilization rate (regional metabolism) and the level of hypothermia.12 Although adverse reactions because of mild total-body hypothermia have not been noted in human studies,6,9,10,26 the concerns about adverse effects at lower temperatures are numerous, including bradycardia, changes in coagulation, increased need for vasopressor drugs, and increased susceptibility to infection. It will be important to follow these children to school age because certain disorders, such as mild cerebral palsy or learning disabilities, may not be apparent at these younger ages. However, the lack of multiyear follow-up in the existing randomized, controlled pivotal trials (as reviewed above) should not preclude offering this therapy to appropriate candidates.5 Recent articles have addressed the issue of regarding cooling therapies as “standard of care” despite a lack of robust evidence.2,7,8,18,25,27 We believe that cooling therapy (either selective head cooling or mild total-body hypothermia) should be used at level III NICUs28 for term newborns with moderate to severe HIE. However, it is clear that research relating to cooling therapy has much further to go. Still, devastating outcomes are seen in patients who have received cooling therapy, with death and disability rates of 44% to 55% in the hypothermia-treated cohorts in the 3 major pivotal studies available thus far.6,9,10 Long-term follow-up is ongoing, and it makes sense that neonates who receive cooling therapy should be closely followed and perhaps enrolled in database registries as a recent NICHD workshop suggested.19 A current registry can be found at http://www.vtoxford.org/ research/enceph/enceph.aspx. More studies on duration
85 and mechanism of therapy will be useful as well as research on cooling therapy in conjunction with other emerging treatments for HIE, such as topiramate.29 Finally, the availability of therapy is an important consideration. A recent pilot study from Cape Town, South Africa, showed an ability to induce and maintain hypothermia in neonates with a servo-controlled fan in combination with a servo-controlled radiant warmer. The cost of care was inexpensive and acknowledges the potential of more widespread cooling therapy.30
Conclusions Mild hypothermia treatment for neonatal HIE is a safe and potentially lifesaving, disability-reducing therapy for term newborns. Our patient experienced HIE because of placental abruption and tolerated 3 days of total-body cooling therapy, with early indications of a successful outcome. Long-term follow-up is necessary for our patient and for the randomized study cohorts.
References 1. Azzopardi D, Brocklehurst P, Edwards D, et al, for the TOBY Study Group: The TOBY study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial. BMC Pediatr 8:17-29, 2008 2. Perlman M, Shah P: Time to adopt cooling for neonatal hypoxic-ischemic encephalopathy: Response to a previous commentary. Pediatrics 121:616-618, 2008 3. Gunn AJ, Gluckman PD, Gunn TR: Selective head cooling in newborn infants after perinatal asphyxia: A safety study. Pediatrics 102:885-892, 1998 4. Shankaran S, Pappas A, Laptook AR, et al, for the NICHD Neonatal Research Network: Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics 122:e791-e798, 2008 5. Edwards AD, Azzopardi DV: Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 91:F127-F131, 2006 6. Shankaran S, Laptook AR, Ehrenkranz RA, et al, for the Neonatal Research Network: Whole-body hypothermia for neonates with hypoxicischemic encephalopathy. N Engl J Med 13:1574-1584, 2005 7. Shah PS, Ohlsson A, Perlman M: Hypothermia to treat neonatal hypoxic ischemic encephalopathy: Systematic review. Arch Pediatr Adolesc Med 161:951-958, 2007 8. Jacobs S, Hunt R, Tarnow-Mordi W, et al: Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 17: CD003311, 2007 9. Azzopardi DV, Strohm B, Edwards AD, et al, for the TOBY Study Group: Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 361:1349-1358, 2009 10. Gluckman PD, Wyatt JS, Azzopardi D, et al, on behalf of the CoolCap Study Group: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicenter randomized trial. Lancet 365:663-670, 2005 11. Polderman KH: Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 37:S186-S202, 2009 (suppl) 12. Shankaran S: Neonatal encephalopathy: Treatment with hypothermia. J Neurotrauma 26:437-443, 2009 13. Degos V, Loron G, Mantz J, et al: Neuroprotective strategies for the neonatal brain. Anesth Analg 106:1670-1680, 2008 14. Johnston MV, Hoon AH Jr: Cerebral palsy. Neuromol Med 8:435-450, 2006 15. Hagberg H, Thornberg E, Blennow M, et al: Excitatory amino acids in the cerebrospinal fluid of asphyxiated infants: Relationship to hypoxicischemic encephalopathy. Acta Paediatr 82:925-929, 1993
J.B. Bodensteiner
86 16. Pu Y, Li QF, Zeng CM, et al: Increased detectability of alpha brain glutamate/glutamine in neonatal hypoxic-ischemic encephalopathy. AJNR Am J Neuroradiol 21:203-212, 2000 17. Johnston MV, Trescher WH, Ishida A, et al: Neurobiology of hypoxicischemic injury in the developing brain. Pediatr Rev 49:735-741, 2001 18. Laptook A: Use of therapeutic hypothermia for term infants with hypoxicischemic encephalopathy. Pediatr Clin North Am 56:601-616, 2009 19. 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 148:170-175, 2006 20. Nakajima W, Ishida A, Lange MS, et al: Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci 20:7994-8004, 2000 21. Hagberg H, Mallard C, Rousset CI, et al: Apoptotic mechanisms in the immature brain: Involvement of mitochondria. J Child Neurol 24: 1141-1146, 2009 22. Kurokawa M, Kornbluth S: Caspases and kinases in a death grip. Cell 138:838-854, 2009 23. Han BH, D’Costa A, Back SA, et al: BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia. Neurobiol Dis 7:38-53, 2000
24. Laptook A, Corbett R: The effects of temperature on hypoxic-ischemic brain injury. Clin Perinatol 29:623-649, 2002 25. Schulzke SM, Rao S, Patole SK: A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy— Are we there yet? BMC Pediatr 7:30, 2007 26. Sarkar S, Barks JD, Bhagat I, et al: Effects of therapeutic hypothermia on multiorgan dysfunction in asphyxiated newborns: Whole-body cooling versus selective head cooling. J Perinatol 29:558-563, 2009 27. Higgins RD: Current commentary. Hypoxic ischemic encephalopathy and hypothermia: A critical look. Obstet Gynecol 106:1385-1387, 2005 28. Committee on Fetus and Newborn, American Academy of Pediatrics: Policy statement: Levels of neonatal care. Pediatrics 114:1341-1347, 2004 29. Liu Y, Barks JD, Xu G, et al: Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke 35:1460-1465, 2004 30. Horn A, Thompson C, Woods D, et al: Induced hypothermia for infants with hypoxic-ischemic encephalopathy using a servo-controlled fan: An exploratory pilot study. Pediatrics 123:e1090-e1098, 2009
EDITORIAL COMMENT
T
he case presented by Munoz and Kerrigan is interesting and I am sure gratifying to the physicians involved in the management of the child. The use of the “Cool Cap” or whole-body cooling is certainly gaining in popularity and is used in many neonatal intensive care units throughout the country. The theory seems to make sense; the practice, however, may not be so clearcut. It is not clear to me, for example, that the brain can actually be cooled sufficiently or in an appropriate timeframe to alter the metabolic changes occurring with hypoxic ischemic injury. Even more disturbing is the somewhat mixed results of the various articles studying the results of application of the technique as indicated in the case report. Does cooling just affect the death rate or the probability of disability or both or neither? Is cooling just the head sufficient or is it necessary to cool the entire infant? To what degree does the cooling have to be and for what duration? There are obviously many issues to be settled before the therapy can be recommended as the “standard of care.” This does not keep the physician who is anxious to do
something to help the infant from taking credit for the outcome when it is positive. I am reminded of the use of TPA in patients with cerebral vascular events in whom the good result is the norm even without the application of the therapy, but the physicians are certainly willing to take the credit for the positive outcome if they have had the opportunity to give the drug. Perhaps I am a bit skeptical, but I think it might not be justified to use the technology of cooling the head or the baby in the situation of moderate to severe hypoxicischemic injury unless the nursery doing so is collecting data to add to our understanding of the value of the treatment. This process has a long way to go before the claim can be made that the therapy is standard of care much less before it is even proven to be effective. John B. Bodensteiner, MD Barrow Neurological Institute Phoenix, AZ
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ntil recently, therapy for neonatal hypoxic ischemic encephalopathy (HIE) was nonspecific and limited. Treatment, consisting of efforts to maintain physiological stability and treat seizures with anticonvulsants, was supportive in nature and did not intervene with the basic mechanisms of hypoxic-ischemic brain injury.1 Although relatively uncommon (1-2 cases per 1,000 births), HIE has the potential to be devastating with residual symptoms, including cerebral palsy, developmental retardation, and epilepsy. Recent treatment studies with either total-body or selective head cooling have shown promising outcomes. Several studies strongly suggest that hypothermic therapy reduces death and neurologic disability in neonates with HIE without clinically significant complications.2-7 Selective cooling of the head was approved by the United States Food and Drug Administration as a treatment for neonatal HIE in December 2006. Here, we present a case in which whole-body cooling of a term neonate with HIE appears to have contributed to a favorable outcome.
Case Presentation A female neonate was born at 39 weeks gestation to a gravida 1 now para 1 19-year-old white female. The pregnancy was uneventful, but labor was complicated by nonreassuring fetal heart tones by external monitor. Emergency delivery by cesarean section was performed with discovery of complete placental abruption. Immediately after delivery, the baby cried spontaneously but quickly became limp and pale. Resuscitation efforts included intubation in the delivery room, external chest compressions, and 3 doses of epinephrine administered via the endotracheal tube and 1 subsequent dose of epinephrine through an umbilical vein catheter. Copious amounts of blood were suctioned from the trachea during the resuscitation. Apgar scores were 3, 0, 0, and 3 at 1, 5, 10 and 15
*From the Children’s Health Center. †Division of Pediatric Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ. Address reprint requests to John F. Kerrigan, MD, Barrow Neurological Institute, 500 West Thomas Road, S-400 Phoenix, AZ 85013. E-mail: [email protected]
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minutes, respectively. The initial umbilical cord venous blood gas showed a pH level of 6.96 (normal range for venous cord blood 7.30-7.40), pCO2 of 97 mm Hg (32-44 mm Hg), and a base excess of ⫺11.7 mmol/L (⫺2 to ⫺6 mmol/L). The cord blood lactic acid level was 11 mEq/L (0.7-2.1 mEq/L). The initial neonatal arterial blood gas showed a pH level of 6.89 (normal range term neonate 7.35-7.45), PaCO2 of 50 mm Hg (35-45 mm Hg), PaO2 of 241 mm Hg (50-80 mm Hg), and HCO3 of 14.4 mEq/L (18-24 meg /L). The patient received 75 mL of packed red blood cells, after which the hematocrit was 44% (42%-65%). Subsequent blood gasses showed the pH improving to 7.15 and then 7.26 before transport to the referral newborn intensive care unit (NICU). Before transfer, intermittent clonic seizure activity was noted, and an intravenous dose of phenobarbital, 17 mg/kg, was given. The patient was 3.5 hours of age upon arrival at the referral NICU. The examination revealed an intubated, nondysmorphic newborn with a decreased level of consciousness. Weight, length, and head circumference were at the 90th percentile for her gestational age. Vital signs included a rectal temperature of 34.7°C, a heart rate of 120 to 130 beats/min, respiratory rate 50 breaths/min, and blood pressure ranged from 58 to 66 mm Hg systolic and 22 to 38 mm Hg diastolic. The general physical examination revealed absent bowel sounds but was otherwise unremarkable. There were no spontaneous movements. The pupils were constricted but equal. Her tone was increased, with flexed positioning of the limbs. Corneal responses were intact, but her gag reflex was absent, as were primitive neonatal reflexes. She was placed on a cooling mattress, with an esophageal temperature probe set to thermoregulate to 33.5°C. An intravenous infusion of fentanyl was initiated, and a maintenance dose of phenobarbital was continued. An electroencephalogram showed suppressed background with discontinuous features and small numbers of sharps over the left temporal region but no seizure activity (Fig 1). A head ultrasound was normal. Her serum creatinine and hepatic transaminases were abnormally elevated, which were attributed to hypoxicischemic injury. At age 24 hours, she remained intubated and became reactive to external stimuli. At 48 hours of age, she was
Neonatal HIE and total-body cooling
83
Figure 1 Ten seconds of an electroencephalographic sample obtained at several hours of age at the time of inducing total-body hypothermia. The electroencephalographic background is poorly sustained (discontinuous) with excessive numbers of sharp transients over the left temporal head region but without evidence of seizure activity (7 v/mm, LFF 1 Hz, HFF 15 Hz). (Color version of figure is available online.)
successfully extubated and was showing increasing spontaneous movement. After 72 hours of cooling, she was slowly warmed to normal body temperature over the course of 6 hours. Her subsequent clinical course was marked by steady improvement, with tolerated feedings, and increasingly normal sleep-wake patterns and spontaneous behavior. Magnetic resonance imaging showed a small intraparenchymal hemorrhage in the white matter in the right periatrial region, but diffusion-weighted sequences were normal (Fig 2). By the time of hospital discharge at 15 days of age, she was awake and visually interacting with her mother. She had good head control, a strong cry, moved all extremities, and had proven herself a successful bottle feeder. Her neurologic examination was normal. Follow-up is pending at this time.
Discussion Although not yet considered a standard of care, whole-body cooling and selective head cooling for the treatment of HIE in newborns is certainly promising. Studies examining the safety of mild hypothermia (32°-34°C) have consistently found no adverse effects of clinical significance.2,4-9 Studies examining the efficacy of mild hypothermia in the setting of hypoxic-ischemic injury in full-term newborns have used different techniques. The first pivotal study of this
nature applied selective cooling of the head with a proprietary cooling cap system (Cool–Cap; Olympic Medical Corporation, Seattle, WA).10 A total of 234 term newborns with moderate to severe HIE were randomized to selective head cooling (rectal temperature 34°-35°C for 72 hours) or conventional care. When analyzed on an intent-to-treat basis (16 subjects were lost to follow-up), there was no significant difference in the 2 treatment groups for the primary outcome measure (death or severe disability at 18 months of age in 55% of the study group and 66% of the control group, P ⫽ 0.1). However, a predetermined subgroup analysis of 172 newborns with less severe abnormalities on an amplitudeintegrated electroencephalogram did show significant differences in outcome, with death or severe disability in 48% and 66% of the cooling and control groups, respectively; P ⫽ .009).10 These results suggested that mild hypothermia may be more beneficial in newborns with less severe HIE. A US multicenter consortium (National Institute of Child Health and Human Development Neonatal Research Network) has conducted a randomized trial of total-body cooling for term newborns with severe and moderate HIE.4,6 Patients in the intervention group (n ⫽ 102 subjects) were cooled to a core (esophageal) temperature of 33.5°C within 6 hours of birth, underwent 72 hours of cooling, and then were slowly rewarmed over 6 hours, whereas the control group (n ⫽ 106 subjects) received conventional supportive care. The primary
M. Munoz and J.F. Kerrigan
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Figure 2 Magnetic resonance imaging at 5 days of age after whole-body cooling. (A) An axial T1 sequence (TR 500/TE 8) notable for a small area of hemorrhage (arrow) in the right periatrial region. (B) An axial diffusion-weighted sequence with no evidence of cerebral infarction.
outcome measure was death or major disability, with neurodevelopmental assessment of survivors at 18 to 22 months. A significant difference between the study groups was seen, with death or disability in 44% of the hypothermia cohort and in 62% of the control cohort (P ⫽ .01).6 With subgroup analysis, death or disability was less likely with total-body cooling in subjects with moderate encephalopathy (hypothermia 32%, control 48%; P ⫽ .09) but not for newborns with severe encephalopathy (hypothermia 72%, control 85%; P ⫽ .24).6 There was no significant difference in the likelihood of developmental or neurologic impairment in the survivors between the 2 study groups when assessed at 18 to 22 months (ie, the results of this study suggest that newborns with HIE are more likely to survive when treated with totalbody hypothermia but do not necessarily have better functional outcomes). More recently, a third pivotal study has been published by a British Consortium, the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY).9 The study design and treatment protocol were very similar to that used in the National Institute of Child Health trial noted previously, with randomization of term newborns with HIE to mild total-body hypothermia (n ⫽ 163) or conventional supportive care (n ⫽ 162). In the hypothermia cohort, patients underwent totalbody cooling to 33.5°C within 6 hours of birth, with 72 hours of treatment, followed by slow rewarming.9 The primary outcome measure (as with the earlier studies noted previously) was death or severe disability, which was determined at 18 months of age. A number of prespecified secondary outcome measures were also identified, including Bayley Scales of Infant Development II (BSID-II) and Gross Motor Function Classification System, in addition to others. The TOBY study did not show a significantly reduced rate of death or severe neurologic disability (45% of subjects in the hypothermia group, 53% in the control group; P ⫽ .17) but did show significantly improved functional outcomes for
the surviving infants in the cooled group. Infants in the hypothermia cohort had a significantly greater likelihood of survival without neurologic abnormality (44% treatment group, 28% control group; P ⫽ .003) and also did significantly better on the BSID-II Mental Developmental Index (P ⫽ .03), BSID-II Psychomotor Developmental Index (P ⫽ .03), and the Gross Motor Function Classification System (P ⫽ .01). In contrast to the National Institute of Child Health trial noted earlier, the TOBY study did not show an increase in survival for cooled patients but rather showed improved functional outcome in those who did survive relative to the untreated cohort. In common with the other studies involving therapeutic hypothermia in neonates, adverse events were not associated with cooling.9 Our patient met multiple inclusion criteria for enrollment in the pivotal studies, with her history of placental abruption, an Apgar score of 0 at 10 minutes, umbilical cord blood and arterial blood pH less than 7, and the need for mechanical ventilation for greater than 10 minutes. Our clinical treatment protocol for mild total-body hypothermia for neonatal HIE does not use an amplitude-integrated electroencephalogram but rather includes a standard electroencephalogram upon enrollment. Although the outcome for our recent patient appears to be particularly encouraging at the time of hospital discharge, long-term follow-up is required. The basic cellular and molecular mechanisms by which mild hypothermia exerts a neuroprotective effect is unknown.11 The current concept is that 2 phases of injury take place because of HIE.12-14 The first, primary energy failure, occurs because of decreased cerebral blood flow and tissue oxygenation, forcing a shift to nonoxidative metabolism with lactic acidosis. This results in an acute loss of transmembrane ionic balance from the depletion of adenosine triphosphate and other high-energy stores, impairing neuron function. Additionally, there is excessive release (and decreased reuptake) of glutamate, resulting in excitotoxic injury.13,15,16
Neonatal HIE and total-body cooling Together, these result in an increase in intracellular calcium, activating lipases, proteases, and endonucleases and increases nitric oxide and oxygen-free radicals.17 In many cases of neonatal HIE, the cause of this primary energy failure is difficult to identify. In some cases, a clear event, such as a placental abruption, initiates this process. A secondary cascade of downstream events follows.13,14 This represents the likely intervention point for therapeutic hypothermia.12,18 These changes are complex and incompletely understood but include mitochondrial dysfunction, the elaboration of inflammatory mediators, and the initiation of transcription pathways leading to apoptosis.14,19,20 Although a detailed discussion of the specific mechanisms relating to apoptosis associated with HIE is beyond the scope of this article, several interesting candidate pathways have been identified. Prominent among them is activation of the caspase family of cysteine proteases, which results from mitochondrial membrane failure and, in turn, leads to DNA fragmentation and programmed cell death.21,22 The brain-derived neurotrophic factor is protective against tissue injury in an animal model of HIE and may act by blocking caspase-3 activation.23 The time period between the 2 phases of tissue injury is a potential therapeutic window and appears to extend to 6 hours in most animal models.24 However, the neuroprotective mechanism of cooling may intervene in many pathways involved in both the primary and secondary phases of cerebral injury.12,25 Animal studies have also shown a linear relationship between the brain regional glucose utilization rate (regional metabolism) and the level of hypothermia.12 Although adverse reactions because of mild total-body hypothermia have not been noted in human studies,6,9,10,26 the concerns about adverse effects at lower temperatures are numerous, including bradycardia, changes in coagulation, increased need for vasopressor drugs, and increased susceptibility to infection. It will be important to follow these children to school age because certain disorders, such as mild cerebral palsy or learning disabilities, may not be apparent at these younger ages. However, the lack of multiyear follow-up in the existing randomized, controlled pivotal trials (as reviewed above) should not preclude offering this therapy to appropriate candidates.5 Recent articles have addressed the issue of regarding cooling therapies as “standard of care” despite a lack of robust evidence.2,7,8,18,25,27 We believe that cooling therapy (either selective head cooling or mild total-body hypothermia) should be used at level III NICUs28 for term newborns with moderate to severe HIE. However, it is clear that research relating to cooling therapy has much further to go. Still, devastating outcomes are seen in patients who have received cooling therapy, with death and disability rates of 44% to 55% in the hypothermia-treated cohorts in the 3 major pivotal studies available thus far.6,9,10 Long-term follow-up is ongoing, and it makes sense that neonates who receive cooling therapy should be closely followed and perhaps enrolled in database registries as a recent NICHD workshop suggested.19 A current registry can be found at http://www.vtoxford.org/ research/enceph/enceph.aspx. More studies on duration
85 and mechanism of therapy will be useful as well as research on cooling therapy in conjunction with other emerging treatments for HIE, such as topiramate.29 Finally, the availability of therapy is an important consideration. A recent pilot study from Cape Town, South Africa, showed an ability to induce and maintain hypothermia in neonates with a servo-controlled fan in combination with a servo-controlled radiant warmer. The cost of care was inexpensive and acknowledges the potential of more widespread cooling therapy.30
Conclusions Mild hypothermia treatment for neonatal HIE is a safe and potentially lifesaving, disability-reducing therapy for term newborns. Our patient experienced HIE because of placental abruption and tolerated 3 days of total-body cooling therapy, with early indications of a successful outcome. Long-term follow-up is necessary for our patient and for the randomized study cohorts.
References 1. Azzopardi D, Brocklehurst P, Edwards D, et al, for the TOBY Study Group: The TOBY study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial. BMC Pediatr 8:17-29, 2008 2. Perlman M, Shah P: Time to adopt cooling for neonatal hypoxic-ischemic encephalopathy: Response to a previous commentary. Pediatrics 121:616-618, 2008 3. Gunn AJ, Gluckman PD, Gunn TR: Selective head cooling in newborn infants after perinatal asphyxia: A safety study. Pediatrics 102:885-892, 1998 4. Shankaran S, Pappas A, Laptook AR, et al, for the NICHD Neonatal Research Network: Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics 122:e791-e798, 2008 5. Edwards AD, Azzopardi DV: Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 91:F127-F131, 2006 6. Shankaran S, Laptook AR, Ehrenkranz RA, et al, for the Neonatal Research Network: Whole-body hypothermia for neonates with hypoxicischemic encephalopathy. N Engl J Med 13:1574-1584, 2005 7. Shah PS, Ohlsson A, Perlman M: Hypothermia to treat neonatal hypoxic ischemic encephalopathy: Systematic review. Arch Pediatr Adolesc Med 161:951-958, 2007 8. Jacobs S, Hunt R, Tarnow-Mordi W, et al: Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 17: CD003311, 2007 9. Azzopardi DV, Strohm B, Edwards AD, et al, for the TOBY Study Group: Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 361:1349-1358, 2009 10. Gluckman PD, Wyatt JS, Azzopardi D, et al, on behalf of the CoolCap Study Group: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicenter randomized trial. Lancet 365:663-670, 2005 11. Polderman KH: Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 37:S186-S202, 2009 (suppl) 12. Shankaran S: Neonatal encephalopathy: Treatment with hypothermia. J Neurotrauma 26:437-443, 2009 13. Degos V, Loron G, Mantz J, et al: Neuroprotective strategies for the neonatal brain. Anesth Analg 106:1670-1680, 2008 14. Johnston MV, Hoon AH Jr: Cerebral palsy. Neuromol Med 8:435-450, 2006 15. Hagberg H, Thornberg E, Blennow M, et al: Excitatory amino acids in the cerebrospinal fluid of asphyxiated infants: Relationship to hypoxicischemic encephalopathy. Acta Paediatr 82:925-929, 1993
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86 16. Pu Y, Li QF, Zeng CM, et al: Increased detectability of alpha brain glutamate/glutamine in neonatal hypoxic-ischemic encephalopathy. AJNR Am J Neuroradiol 21:203-212, 2000 17. Johnston MV, Trescher WH, Ishida A, et al: Neurobiology of hypoxicischemic injury in the developing brain. Pediatr Rev 49:735-741, 2001 18. Laptook A: Use of therapeutic hypothermia for term infants with hypoxicischemic encephalopathy. Pediatr Clin North Am 56:601-616, 2009 19. 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 148:170-175, 2006 20. Nakajima W, Ishida A, Lange MS, et al: Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci 20:7994-8004, 2000 21. Hagberg H, Mallard C, Rousset CI, et al: Apoptotic mechanisms in the immature brain: Involvement of mitochondria. J Child Neurol 24: 1141-1146, 2009 22. Kurokawa M, Kornbluth S: Caspases and kinases in a death grip. Cell 138:838-854, 2009 23. Han BH, D’Costa A, Back SA, et al: BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia. Neurobiol Dis 7:38-53, 2000
24. Laptook A, Corbett R: The effects of temperature on hypoxic-ischemic brain injury. Clin Perinatol 29:623-649, 2002 25. Schulzke SM, Rao S, Patole SK: A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy— Are we there yet? BMC Pediatr 7:30, 2007 26. Sarkar S, Barks JD, Bhagat I, et al: Effects of therapeutic hypothermia on multiorgan dysfunction in asphyxiated newborns: Whole-body cooling versus selective head cooling. J Perinatol 29:558-563, 2009 27. Higgins RD: Current commentary. Hypoxic ischemic encephalopathy and hypothermia: A critical look. Obstet Gynecol 106:1385-1387, 2005 28. Committee on Fetus and Newborn, American Academy of Pediatrics: Policy statement: Levels of neonatal care. Pediatrics 114:1341-1347, 2004 29. Liu Y, Barks JD, Xu G, et al: Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke 35:1460-1465, 2004 30. Horn A, Thompson C, Woods D, et al: Induced hypothermia for infants with hypoxic-ischemic encephalopathy using a servo-controlled fan: An exploratory pilot study. Pediatrics 123:e1090-e1098, 2009
EDITORIAL COMMENT
T
he case presented by Munoz and Kerrigan is interesting and I am sure gratifying to the physicians involved in the management of the child. The use of the “Cool Cap” or whole-body cooling is certainly gaining in popularity and is used in many neonatal intensive care units throughout the country. The theory seems to make sense; the practice, however, may not be so clearcut. It is not clear to me, for example, that the brain can actually be cooled sufficiently or in an appropriate timeframe to alter the metabolic changes occurring with hypoxic ischemic injury. Even more disturbing is the somewhat mixed results of the various articles studying the results of application of the technique as indicated in the case report. Does cooling just affect the death rate or the probability of disability or both or neither? Is cooling just the head sufficient or is it necessary to cool the entire infant? To what degree does the cooling have to be and for what duration? There are obviously many issues to be settled before the therapy can be recommended as the “standard of care.” This does not keep the physician who is anxious to do
something to help the infant from taking credit for the outcome when it is positive. I am reminded of the use of TPA in patients with cerebral vascular events in whom the good result is the norm even without the application of the therapy, but the physicians are certainly willing to take the credit for the positive outcome if they have had the opportunity to give the drug. Perhaps I am a bit skeptical, but I think it might not be justified to use the technology of cooling the head or the baby in the situation of moderate to severe hypoxicischemic injury unless the nursery doing so is collecting data to add to our understanding of the value of the treatment. This process has a long way to go before the claim can be made that the therapy is standard of care much less before it is even proven to be effective. John B. Bodensteiner, MD Barrow Neurological Institute Phoenix, AZ