REVIEW URRENT C OPINION
Therapeutic hypothermia for neonatal encephalopathy Seetha Shankaran
Purpose of review Hypothermia for neonatal encephalopathy is now the standard of care. The purpose of this review is to evaluate recent publications (during the past 18 months) that impact the practice of hypothermia as neuroprotection for neonatal hypoxic–ischemic encephalopathy. Recent findings The review will examine recent publications that influence clinical care, including committee opinion, meta-analysis, and reports of how this practice has evolved in the clinical arena. Biomarkers of acute injury and outcome will be examined. Research involving the future of hypothermia will be noted. Summary The rate of death or disability following hypothermia therapy has been reduced substantially; the challenge is to evaluate whether mortality or disability can be reduced further following combination therapy. Keywords encephalopathy, hypothermia, neonates, neuroprotection
INTRODUCTION The review of articles published within the past 18 months will focus on hypothermia as neuroprotection for neonatal encephalopathy. Metaanalyses of randomized trials, current committee opinion, cooling outside trial criteria, biomarkers of short-term outcome, and future of combination therapies will be examined.
RECENT CLINICAL ADVANCES Recent clinical advances will be reviewed based on data from meta-analyses, opinions published by governing bodies, and recent publications.
Meta-analyses The meta-analyses of studies evaluating hypothermia for newborns with hypoxic–ischemic encephalopathy (HIE) were updated in the 2013 Cochrane Review [1]. Eleven randomized controlled trials with 1505 term neonates were included in this review. Hypothermia at 33–348C for 72 h reduced death or major neurodevelopmental disability among survivors at 18 or 24 months of age [risk ratio 0.75, 95% confidence interval (CI) (0.68–0.83)] and mortality (risk ratio 0.75, 95% CI 0.64–0.88). The combined outcome of death or disability in survivors was reduced by both selective head cooling with mild www.co-pediatrics.com
systemic hypothermia (risk ratio 0.77, 95% CI 0.64–0.92) and whole body cooling (risk ratio 0.75, 95% CI 0.66–0.84), whereas mortality (as an independent outcome measure) was reduced only by whole body cooling (risk ratio 0.73, 95% CI 0.61–0.89), but not by selective head cooling (risk ratio 0.78, 95% CI 0.59–1.04). The major adverse events included sinus bradycardia and thrombocytopenia. Table 1 includes the following 18-month outcomes in infants treated with hypothermia after HIE: death or disability, death, severe disability, cerebral palsy, Psychomotor Developmental Index (PDI) below 70, and Mental Developmental Index (MDI) below 70. Table 1 also includes an analysis of the benefits of cooling for neonates with moderate encephalopathy versus those with severe encephalopathy. Therapeutic hypothermia is thus clearly effective for neonates above 36 weeks’ gestation,
Wayne State University School of Medicine, Neonatal-Perinatal Medicine, Children’s Hospital of Michigan and Hutzel Women’s Hospital, Detroit, Michigan, USA Correspondence to Seetha Shankaran, MD, Children’s Hospital of Michigan, 3901 Beaubien Blvd, Suite 4H46, Detroit, MI 48201, USA. Tel: +1 313 745 1436; fax: +1 313 745 5867; e-mail: sshankar@med. wayne.edu Curr Opin Pediatr 2015, 27:152–157 DOI:10.1097/MOP.0000000000000199 Volume 27 Number 2 April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Therapeutic hypothermia for neonatal encephalopathy Shankaran
Clinical opinion
KEY POINTS Hypothermia for neonatal HIE should be provided based on criteria from established protocols. Cooling for other causes of encephalopathy should be conducted in a research setting. Cooling should not be provided for neonates on extracorporeal membrane oxygenation. Possible biomarkers of injury should be evaluated against the gold standard of 18–24-month follow-up studies. Hypothermia for HIE in low-income countries needs to be examined with adequately powered randomized controlled trials.
The Clinical Report from the American Academy of Pediatrics Committee of Fetus and Newborn has stated the following: hospitals that provide therapeutic hypothermia should be able to provide comprehensive intensive care, targeted temperature monitoring, and continued follow-up of cooled neonates; eligibility criteria from published randomized controlled trials should be followed for patient selection; each hospital should establish written protocols for targeted temperature management, imaging studies and follow-up; hospitals should provide training for personnel at referral/outreach centers; and cooling should not be provided for a duration of more than 72 h, to a depth below 33.08C, for neonates less than 35 weeks and those with mild encephalopathy [2 ]. The American Academy of Pediatrics statement may lead to confusion regarding the 35-week gestational age neonate; currently there are insufficient data available on the benefit or risk for this specific gestational age, hence cooling &&
with evidence of peripartum asphyxia and moderate or severe encephalopathy when initiated within 6 h of birth.
Table 1. Meta analyses of trials by Gunn, CoolCap, NICHD, TOBY n.NEURO, Zhou, and ICE Outcome
Participants
Death or disability
RR (95% CI)
1344
0.75 (0.68–0.83)
Head cooling
443
0.77 (0.64–0.92)
Whole body cooling
901
0.75 (0.66–0.84)
Mortality Head cooling
1468
0.75 (0.64–0.88)
526
0.78 (0.59–1.04)
Whole body cooling
942
0.73 (0.61–0.89)
Disability among survivors
917
0.67 (0.55–0.80)
312
0.66 (0.47–0.94)
Head cooling Whole body cooling 18-month PDI 0.05). These data are consistent with that of the prior publications of the NICHD Neonatal research network and that of Thoresen, noting that the predictive ability of the aEEG is decreased in cooled neonates [26,27].
PROGNOSTIC TESTS IN TERM NEONATES WITH HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Neonatal imaging
&&
The recent data on prognostic tests include the clinical exam, and the neurophysiological, imaging, and serum markers.
&&
In a small study (n ¼ 15) in which MRI scans were performed on the same neonates at approximately day 4 and again in the second week of life, the findings on early scans were similar to those on later scans [28 ]. The relationship of MRI scans performed in the neonatal period among infants with HIE from three randomized trials had shown good correlation with death or disability at 18–24 months [29–31]; 18–24-month neurodevelopmental outcome is predictive of outcome in childhood [11,12,13 ]. &
Review of tests The role of prognostic indictors of outcome following HIE was assessed from studies published between 1980 and 2011; 29 studies out of 250 were
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&&
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155
Neonatology and perinatology
Recent reports of advanced imaging with nearinfrared spectroscopy and PET are informative; however, they need to be evaluated against the gold standard of follow-up (for at least 18–24 months) before they can be used as prognostic tools [32–34,35 ]. &
Serum biomarkers Cardiac troponin, a nonspecific marker of cardiac injury, was noted in a retrospective study to be decreased following hypothermia, compared to infants with a similar level of birth acidosis or requiring cardiac compression that were not cooled [36]. The authors suggest that cardiac troponin levels at 24 h of age of less than 0.22 ng/ml for infants not cooled (n ¼ 14) and less than 0.15 ng/ml for cooled infants (n ¼ 61) predict improved outcomes. Others have suggested that cardiac troponin 1 levels serve as a marker of neurodevelopmental outcome at 18 months of age [37 ]. The levels of serum cytokines and cortisol were examined in another study among 8 normothermia and 10 infants undergoing hypothermia for neonatal HIE at 6, 12, and 24 h of age [38]. Interleukin (IL)-6 levels at 6 h of age and IL-4 levels throughout the study period were lower in cooled infants, whereas vascular endothelial growth factor levels were higher among cooled infants at 6 and 12 h of age. IL-10 levels decreased in both groups between 6 and 12 h of age. Cortisol levels decreased in both groups over the study period. This is a very small study and no association with follow-up is reported; data from a randomized controlled pilot study have shown improved outcomes at 24 months associated with a decrease in IL-6, IL-8, and IL-10 from their peak values at 24 h to the nadir at 36 h [39].
that stem cell therapy for neonatal HIE should follow the same guidelines as those developed for stem cell therapy for adult stroke patients [42 ] with appropriate modifications. Two other approaches continue to be evaluated in the preclinical arena. In the newborn pig model of hypoxia–ischemia, hypothermia improves cerebral autoregulation following injury and hypothermia þ xenon further improves autoregulation [43]. Erythropoietin with hypothermia was evaluated in the primate model of hypoxia–ischemia. Cerebral palsy occurred among 43% of saline-treated, 44% hypothermia, and none of the hypothermia-Epo-treated animals. The animals receiving the combination therapy also had better motor and cognitive outcome, less brain injury on imaging, and less death or disability [44]. These studies of combination therapies offer promise and thus are being evaluated in clinical trials of neuroprotection for neonatal HIE. &&
&
IMPACT OF HYPOTHERMIA ON PHARMACOKINETICS OF MEDICATIONS IN HYPOXIC–ISCHEMIC ENCEPHALOPATHY Cooling may impair elimination of medications excreted through the kidney; hence increasing the interval used to dose gentamicin in cooled neonates was evaluated. In a recent study, 29 infants were dosed with gentamicin every 24 h, whereas 23 were dosed every 36 h. Only the 36-h dosing was consistent with adequate peak concentrations, as well as trough concentrations at less than 2 mg/l [40]. In another study, phenobarbital clearance was not influenced by hypothermia [41].
NEW THERAPIES FOR NEONATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY The use of stem cells for neonatal HIE is still in the experimental stages; a recent review has suggested 156
www.co-pediatrics.com
CONCLUSION The review outlines how hypothermia is practiced currently, within and outside trial eligibility criteria and conduct. Most of the clinical, neurophysiological, and imaging biomarkers evaluate short-term outcomes; it should be noted that 18–24 months is the earliest age that correlates with childhood outcome. The future of the combination therapies is to evaluate whether mortality or disability can be further reduced following hypothermia-plus therapy compared to hypothermia alone. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1:CD003311. 2. Papile LA, Baley JE, Benitz W, et al. Hypothermia and encephalopathy. && Pediatrics 2014; 113:1146–1150. Another important opinion from a governing body – the American Academy of Pediatrics – stressing the need for patient selection and therapy based on published data as well as a need for hospitals to have protocols and continuous education for staff and referral physicians. 3. Newell R, Clark RH, Ellsbury D, et al. Emerging use of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy. EJ Neonatol Res 2013; 3:38– 46.
Volume 27 Number 2 April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Therapeutic hypothermia for neonatal encephalopathy Shankaran 4. Soll RF. Cooling for newborns with hypoxic ischemic encephalopathy. Neonatology 2013; 104:260–262. 5. Smit E, Liu X, Jary S, et al. Cooling neonates who do not fulfil the standard & cooling criteria: short- and long-term outcomes. Acta Paediatr 2015; 104:138–145; doi: 10.1111/apa.12784. [Epub ahead of print] This is a study of cooling infants outside of evidence-based protocols. 6. Olsen SL, Dejonge M, Kline A, et al. Optimizing therapeutic hypothermia for neonatal encephalopathy. Pediatrics 2013; 131:e591–e603. 7. Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of && cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy. A randomized controlled trial. J Am Med Assoc 2014; 312:2629–2639. Patient enrollment into this randomized controlled trial was halted by the data and safety monitoring board for safety and futility concerns. The safety data note that longer or deeper cooling, or both, do not decrease NICU deaths; hence the need to follow only established cooling protocols. 8. Thoresen M, Tooley J, Liu X, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology 2013; 104:228–233. 9. Chaudhary R, Farrer K, Broster S, et al. Active versus passive cooling during neonatal transport. Pediatrics 2013; 132:841–846. 10. Kapadia VS, Chalak LF, DuPont TL, et al. Perinatal asphyxia with hyperoxemia within the first hour of life is associated with moderate to severe hypoxicischemic encephalopathy. J Pediatr 2013; 163:949–954. 11. Guillet R, Edwards AD, Thoresen M, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012; 71:205–209. 12. Shankaran S, Pappas A, McDonald SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012; 366:2085– 2092. 13. Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal && asphyxia on childhood outcomes. N Engl J Med 2014; 371:140–149. The TOBY trial data on childhood outcomes confirms hypothermia for neonatal HIE is neuroprotective; more cooled children survived with an IQ of greater than 85. 14. Laptook AR, McDonald SA, Shankaran S, et al. Elevated temperature and 6to 7-year outcome of neonatal encephalopathy. Ann Neurol 2013; 73:520– 528. 15. Natarajan G, Shankaran S, Laptook AR, et al. Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2013; 98:F473–F479. 16. Natarajan G, Shankaran S, Pappas A, et al. Functional status at 18 months of & age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy. Dev Med Child Neurol 2014; 56:1052–1058. The impact on the family needs to be assessed following HIE; independent functioning at 18 months is associated with a better outcome in childhood. 17. Vohr BR, Stephens BE, McDonald SA, et al. Cerebral palsy and growth failure at 6 to 7 years. Pediatrics 2013; 132:e905–e914. 18. Field D, Juszczak E, Linsell L, et al. Neonatal ECMO study of temperature (NEST): a randomized controlled trial. Pediatrics 2013; 132:e1247– e1256. 19. Pauliah SS, Shankaran S, Wade A, et al. Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis. PLoS One 2013; 8:e58834. 20. Thayyil S, Shankaran S, Wade A, et al. Whole-body cooling in neonatal encephalopathy using phase changing material. Arch Dis Child Fetal Neonatal Ed 2013; 98:F280–F281. 21. Lally PJ, Price DL, Pauliah SS, et al. Neonatal encephalopathic cerebral injury & in South India assessed by perinatal magnetic resonance biomarkers and early childhood neurodevelopmental outcome. PLoS One 2014; 9:e87874. The need to evaluate brain injury as a biomarker in low resource setting is described in this study. 22. Cotten CM, Goldstein RF, McDonald SA, et al. Apolipoprotein E genotype && and outcome in infants with hypoxic-ischemic encephalopathy. Pediatr Res 2014; 75:424–430. This is a study attempting to evaluate the genetic biomarkers of HIE. 23. van Laerhoven H, de Haan TR, Offringa M, et al. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics 2013; 131:88–98. 24. Horn AR, Swingler GH, Myer L, et al. Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 h. BMC Pediatr 2013; 13:52.
25. Azzopardi D; TOBY study group. Predictive value of the amplitude integrated EEG in infants with hypoxic ischaemic encephalopathy: data from a randomized trial of therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed 2014; 99:F80–F82. This study reports on aEEG from the TOBY trial participants; the lower predictive value of an abnormal aEEG among cooled compared to control infants is noted. 26. Shankaran S, Pappas A, McDonald SA, et al. Predictive value of an early amplitude integrated electroencephalogram and neurologic examination. Pediatrics 2011; 128:e112–e120. 27. Thoresen M, Hellstro¨m-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics 2010; 126:e131–e139. 28. Agut T, Leo´n M, Rebollo M, et al. Early identification of brain injury in infants with & hypoxic ischemic encephalopathy at high risk for severe impairments: accuracy of MRI performed in the first days of life. BMC Pediatr 2014; 14:177. This study found, in a small sample, that MRIs performed at 4 days may be predictive of those done at 2 weeks of age. 29. Rutherford M, Ramenghi LA, Edwards AD, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol 2010; 9:39–45. 30. Shankaran S, Barnes PD, Hintz SR, et al. Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2012; 97:F398–F404. 31. Cheong JL, Coleman L, Hunt RW, et al. Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med 2012; 166:634–640. 32. Shellhaas RA, Thelen BJ, Bapuraj JR, et al. Limited short-term prognostic utility of cerebral NIRS during neonatal therapeutic hypothermia. Neurology 2013; 81:249–255. 33. Massaro AN, Bouyssi-Kobar M, Chang T, et al. Brain perfusion in encephalopathic newborns after therapeutic hypothermia. Am J Neuroradiol 2013; 34:1649–1655. 34. Howlett JA, Northington FJ, Gilmore MM, et al. Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy. Pediatr Res 2013; 74:525–535. 35. Luo M, Li Q, Dong W, et al. Evaluation of mild hypothermia therapy for & neonatal hypoxic-ischaemic encephalopathy on brain energy metabolism using 18F-fluorodeoxyglucose positron emission computed tomography. Exp Ther Med 2014; 8:1219–1224. This study demonstrates that glucose metabolism is improved following hypothermia compared to noncooled control infants. 36. Liu X, Chakkarapani E, Stone J, Thoresen M. Effect of cardiac compressions and hypothermia treatment on cardiac troponin I in newborns with perinatal asphyxia. Resuscitation 2013; 84:1562–1567. 37. Montaldo P, Rosso R, Chello G, Gilberti P. Cardiac troponin 1 concentrations & as a marker of neurodevelopmental outcome at 18 months in newborns with perinatal asphyxia. J Perinatology 2014; 34:292–295. This study notes that cardiac troponin levels are associated with 18 months outcome. 38. Ro´ka A, Beko˝ G, Hala´sz J, et al. Changes in serum cytokine and cortisol levels in normothermic and hypothermic term neonates after perinatal asphyxia. Inflamm Res 2013; 62:81–87. 39. Jenkins DD, Rollins LG, Perkel JK, et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab 2012; 32:1888–1896. 40. Frymoyer A, Lee S, Bonifacio SL, et al. Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. J Perinatol 2013; 33:778–782. 41. Shellhaas RA, Ng CM, Dillon CH, et al. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. Pediatr Crit Care Med 2013; 14:194–202. 42. Gonzales-Portillo GS, Reyes S, Aguirre D, et al. Stem cell therapy for neonatal && hypoxic-ischemic encephalopathy. Front Neurol 2014; 5:147. This review of therapy with stem cells for neonatal HIE reviews preclinical and current trials in stem cell therapy. 43. Chakkarapani E, Dingley J, Aquilina K, et al. Effects of xenon and hypothermia on cerebrovascular pressure reactivity in newborn global hypoxic-ischemic pig model. J Cereb Blood Flow Metab 2013; 33:1752–1760. 44. Traudt CM, McPherson RJ, Bauer LA, et al. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci 2013; 35:491–503. &&
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157
Therapeutic hypothermia for neonatal encephalopathy Seetha Shankaran
Purpose of review Hypothermia for neonatal encephalopathy is now the standard of care. The purpose of this review is to evaluate recent publications (during the past 18 months) that impact the practice of hypothermia as neuroprotection for neonatal hypoxic–ischemic encephalopathy. Recent findings The review will examine recent publications that influence clinical care, including committee opinion, meta-analysis, and reports of how this practice has evolved in the clinical arena. Biomarkers of acute injury and outcome will be examined. Research involving the future of hypothermia will be noted. Summary The rate of death or disability following hypothermia therapy has been reduced substantially; the challenge is to evaluate whether mortality or disability can be reduced further following combination therapy. Keywords encephalopathy, hypothermia, neonates, neuroprotection
INTRODUCTION The review of articles published within the past 18 months will focus on hypothermia as neuroprotection for neonatal encephalopathy. Metaanalyses of randomized trials, current committee opinion, cooling outside trial criteria, biomarkers of short-term outcome, and future of combination therapies will be examined.
RECENT CLINICAL ADVANCES Recent clinical advances will be reviewed based on data from meta-analyses, opinions published by governing bodies, and recent publications.
Meta-analyses The meta-analyses of studies evaluating hypothermia for newborns with hypoxic–ischemic encephalopathy (HIE) were updated in the 2013 Cochrane Review [1]. Eleven randomized controlled trials with 1505 term neonates were included in this review. Hypothermia at 33–348C for 72 h reduced death or major neurodevelopmental disability among survivors at 18 or 24 months of age [risk ratio 0.75, 95% confidence interval (CI) (0.68–0.83)] and mortality (risk ratio 0.75, 95% CI 0.64–0.88). The combined outcome of death or disability in survivors was reduced by both selective head cooling with mild www.co-pediatrics.com
systemic hypothermia (risk ratio 0.77, 95% CI 0.64–0.92) and whole body cooling (risk ratio 0.75, 95% CI 0.66–0.84), whereas mortality (as an independent outcome measure) was reduced only by whole body cooling (risk ratio 0.73, 95% CI 0.61–0.89), but not by selective head cooling (risk ratio 0.78, 95% CI 0.59–1.04). The major adverse events included sinus bradycardia and thrombocytopenia. Table 1 includes the following 18-month outcomes in infants treated with hypothermia after HIE: death or disability, death, severe disability, cerebral palsy, Psychomotor Developmental Index (PDI) below 70, and Mental Developmental Index (MDI) below 70. Table 1 also includes an analysis of the benefits of cooling for neonates with moderate encephalopathy versus those with severe encephalopathy. Therapeutic hypothermia is thus clearly effective for neonates above 36 weeks’ gestation,
Wayne State University School of Medicine, Neonatal-Perinatal Medicine, Children’s Hospital of Michigan and Hutzel Women’s Hospital, Detroit, Michigan, USA Correspondence to Seetha Shankaran, MD, Children’s Hospital of Michigan, 3901 Beaubien Blvd, Suite 4H46, Detroit, MI 48201, USA. Tel: +1 313 745 1436; fax: +1 313 745 5867; e-mail: sshankar@med. wayne.edu Curr Opin Pediatr 2015, 27:152–157 DOI:10.1097/MOP.0000000000000199 Volume 27 Number 2 April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Therapeutic hypothermia for neonatal encephalopathy Shankaran
Clinical opinion
KEY POINTS Hypothermia for neonatal HIE should be provided based on criteria from established protocols. Cooling for other causes of encephalopathy should be conducted in a research setting. Cooling should not be provided for neonates on extracorporeal membrane oxygenation. Possible biomarkers of injury should be evaluated against the gold standard of 18–24-month follow-up studies. Hypothermia for HIE in low-income countries needs to be examined with adequately powered randomized controlled trials.
The Clinical Report from the American Academy of Pediatrics Committee of Fetus and Newborn has stated the following: hospitals that provide therapeutic hypothermia should be able to provide comprehensive intensive care, targeted temperature monitoring, and continued follow-up of cooled neonates; eligibility criteria from published randomized controlled trials should be followed for patient selection; each hospital should establish written protocols for targeted temperature management, imaging studies and follow-up; hospitals should provide training for personnel at referral/outreach centers; and cooling should not be provided for a duration of more than 72 h, to a depth below 33.08C, for neonates less than 35 weeks and those with mild encephalopathy [2 ]. The American Academy of Pediatrics statement may lead to confusion regarding the 35-week gestational age neonate; currently there are insufficient data available on the benefit or risk for this specific gestational age, hence cooling &&
with evidence of peripartum asphyxia and moderate or severe encephalopathy when initiated within 6 h of birth.
Table 1. Meta analyses of trials by Gunn, CoolCap, NICHD, TOBY n.NEURO, Zhou, and ICE Outcome
Participants
Death or disability
RR (95% CI)
1344
0.75 (0.68–0.83)
Head cooling
443
0.77 (0.64–0.92)
Whole body cooling
901
0.75 (0.66–0.84)
Mortality Head cooling
1468
0.75 (0.64–0.88)
526
0.78 (0.59–1.04)
Whole body cooling
942
0.73 (0.61–0.89)
Disability among survivors
917
0.67 (0.55–0.80)
312
0.66 (0.47–0.94)
Head cooling Whole body cooling 18-month PDI 0.05). These data are consistent with that of the prior publications of the NICHD Neonatal research network and that of Thoresen, noting that the predictive ability of the aEEG is decreased in cooled neonates [26,27].
PROGNOSTIC TESTS IN TERM NEONATES WITH HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Neonatal imaging
&&
The recent data on prognostic tests include the clinical exam, and the neurophysiological, imaging, and serum markers.
&&
In a small study (n ¼ 15) in which MRI scans were performed on the same neonates at approximately day 4 and again in the second week of life, the findings on early scans were similar to those on later scans [28 ]. The relationship of MRI scans performed in the neonatal period among infants with HIE from three randomized trials had shown good correlation with death or disability at 18–24 months [29–31]; 18–24-month neurodevelopmental outcome is predictive of outcome in childhood [11,12,13 ]. &
Review of tests The role of prognostic indictors of outcome following HIE was assessed from studies published between 1980 and 2011; 29 studies out of 250 were
1040-8703 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
&&
www.co-pediatrics.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
155
Neonatology and perinatology
Recent reports of advanced imaging with nearinfrared spectroscopy and PET are informative; however, they need to be evaluated against the gold standard of follow-up (for at least 18–24 months) before they can be used as prognostic tools [32–34,35 ]. &
Serum biomarkers Cardiac troponin, a nonspecific marker of cardiac injury, was noted in a retrospective study to be decreased following hypothermia, compared to infants with a similar level of birth acidosis or requiring cardiac compression that were not cooled [36]. The authors suggest that cardiac troponin levels at 24 h of age of less than 0.22 ng/ml for infants not cooled (n ¼ 14) and less than 0.15 ng/ml for cooled infants (n ¼ 61) predict improved outcomes. Others have suggested that cardiac troponin 1 levels serve as a marker of neurodevelopmental outcome at 18 months of age [37 ]. The levels of serum cytokines and cortisol were examined in another study among 8 normothermia and 10 infants undergoing hypothermia for neonatal HIE at 6, 12, and 24 h of age [38]. Interleukin (IL)-6 levels at 6 h of age and IL-4 levels throughout the study period were lower in cooled infants, whereas vascular endothelial growth factor levels were higher among cooled infants at 6 and 12 h of age. IL-10 levels decreased in both groups between 6 and 12 h of age. Cortisol levels decreased in both groups over the study period. This is a very small study and no association with follow-up is reported; data from a randomized controlled pilot study have shown improved outcomes at 24 months associated with a decrease in IL-6, IL-8, and IL-10 from their peak values at 24 h to the nadir at 36 h [39].
that stem cell therapy for neonatal HIE should follow the same guidelines as those developed for stem cell therapy for adult stroke patients [42 ] with appropriate modifications. Two other approaches continue to be evaluated in the preclinical arena. In the newborn pig model of hypoxia–ischemia, hypothermia improves cerebral autoregulation following injury and hypothermia þ xenon further improves autoregulation [43]. Erythropoietin with hypothermia was evaluated in the primate model of hypoxia–ischemia. Cerebral palsy occurred among 43% of saline-treated, 44% hypothermia, and none of the hypothermia-Epo-treated animals. The animals receiving the combination therapy also had better motor and cognitive outcome, less brain injury on imaging, and less death or disability [44]. These studies of combination therapies offer promise and thus are being evaluated in clinical trials of neuroprotection for neonatal HIE. &&
&
IMPACT OF HYPOTHERMIA ON PHARMACOKINETICS OF MEDICATIONS IN HYPOXIC–ISCHEMIC ENCEPHALOPATHY Cooling may impair elimination of medications excreted through the kidney; hence increasing the interval used to dose gentamicin in cooled neonates was evaluated. In a recent study, 29 infants were dosed with gentamicin every 24 h, whereas 23 were dosed every 36 h. Only the 36-h dosing was consistent with adequate peak concentrations, as well as trough concentrations at less than 2 mg/l [40]. In another study, phenobarbital clearance was not influenced by hypothermia [41].
NEW THERAPIES FOR NEONATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY The use of stem cells for neonatal HIE is still in the experimental stages; a recent review has suggested 156
www.co-pediatrics.com
CONCLUSION The review outlines how hypothermia is practiced currently, within and outside trial eligibility criteria and conduct. Most of the clinical, neurophysiological, and imaging biomarkers evaluate short-term outcomes; it should be noted that 18–24 months is the earliest age that correlates with childhood outcome. The future of the combination therapies is to evaluate whether mortality or disability can be further reduced following hypothermia-plus therapy compared to hypothermia alone. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1:CD003311. 2. Papile LA, Baley JE, Benitz W, et al. Hypothermia and encephalopathy. && Pediatrics 2014; 113:1146–1150. Another important opinion from a governing body – the American Academy of Pediatrics – stressing the need for patient selection and therapy based on published data as well as a need for hospitals to have protocols and continuous education for staff and referral physicians. 3. Newell R, Clark RH, Ellsbury D, et al. Emerging use of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy. EJ Neonatol Res 2013; 3:38– 46.
Volume 27 Number 2 April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Therapeutic hypothermia for neonatal encephalopathy Shankaran 4. Soll RF. Cooling for newborns with hypoxic ischemic encephalopathy. Neonatology 2013; 104:260–262. 5. Smit E, Liu X, Jary S, et al. Cooling neonates who do not fulfil the standard & cooling criteria: short- and long-term outcomes. Acta Paediatr 2015; 104:138–145; doi: 10.1111/apa.12784. [Epub ahead of print] This is a study of cooling infants outside of evidence-based protocols. 6. Olsen SL, Dejonge M, Kline A, et al. Optimizing therapeutic hypothermia for neonatal encephalopathy. Pediatrics 2013; 131:e591–e603. 7. Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of && cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy. A randomized controlled trial. J Am Med Assoc 2014; 312:2629–2639. Patient enrollment into this randomized controlled trial was halted by the data and safety monitoring board for safety and futility concerns. The safety data note that longer or deeper cooling, or both, do not decrease NICU deaths; hence the need to follow only established cooling protocols. 8. Thoresen M, Tooley J, Liu X, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology 2013; 104:228–233. 9. Chaudhary R, Farrer K, Broster S, et al. Active versus passive cooling during neonatal transport. Pediatrics 2013; 132:841–846. 10. Kapadia VS, Chalak LF, DuPont TL, et al. Perinatal asphyxia with hyperoxemia within the first hour of life is associated with moderate to severe hypoxicischemic encephalopathy. J Pediatr 2013; 163:949–954. 11. Guillet R, Edwards AD, Thoresen M, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res 2012; 71:205–209. 12. Shankaran S, Pappas A, McDonald SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012; 366:2085– 2092. 13. Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal && asphyxia on childhood outcomes. N Engl J Med 2014; 371:140–149. The TOBY trial data on childhood outcomes confirms hypothermia for neonatal HIE is neuroprotective; more cooled children survived with an IQ of greater than 85. 14. Laptook AR, McDonald SA, Shankaran S, et al. Elevated temperature and 6to 7-year outcome of neonatal encephalopathy. Ann Neurol 2013; 73:520– 528. 15. Natarajan G, Shankaran S, Laptook AR, et al. Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2013; 98:F473–F479. 16. Natarajan G, Shankaran S, Pappas A, et al. Functional status at 18 months of & age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy. Dev Med Child Neurol 2014; 56:1052–1058. The impact on the family needs to be assessed following HIE; independent functioning at 18 months is associated with a better outcome in childhood. 17. Vohr BR, Stephens BE, McDonald SA, et al. Cerebral palsy and growth failure at 6 to 7 years. Pediatrics 2013; 132:e905–e914. 18. Field D, Juszczak E, Linsell L, et al. Neonatal ECMO study of temperature (NEST): a randomized controlled trial. Pediatrics 2013; 132:e1247– e1256. 19. Pauliah SS, Shankaran S, Wade A, et al. Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis. PLoS One 2013; 8:e58834. 20. Thayyil S, Shankaran S, Wade A, et al. Whole-body cooling in neonatal encephalopathy using phase changing material. Arch Dis Child Fetal Neonatal Ed 2013; 98:F280–F281. 21. Lally PJ, Price DL, Pauliah SS, et al. Neonatal encephalopathic cerebral injury & in South India assessed by perinatal magnetic resonance biomarkers and early childhood neurodevelopmental outcome. PLoS One 2014; 9:e87874. The need to evaluate brain injury as a biomarker in low resource setting is described in this study. 22. Cotten CM, Goldstein RF, McDonald SA, et al. Apolipoprotein E genotype && and outcome in infants with hypoxic-ischemic encephalopathy. Pediatr Res 2014; 75:424–430. This is a study attempting to evaluate the genetic biomarkers of HIE. 23. van Laerhoven H, de Haan TR, Offringa M, et al. Prognostic tests in term neonates with hypoxic-ischemic encephalopathy: a systematic review. Pediatrics 2013; 131:88–98. 24. Horn AR, Swingler GH, Myer L, et al. Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 h. BMC Pediatr 2013; 13:52.
25. Azzopardi D; TOBY study group. Predictive value of the amplitude integrated EEG in infants with hypoxic ischaemic encephalopathy: data from a randomized trial of therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed 2014; 99:F80–F82. This study reports on aEEG from the TOBY trial participants; the lower predictive value of an abnormal aEEG among cooled compared to control infants is noted. 26. Shankaran S, Pappas A, McDonald SA, et al. Predictive value of an early amplitude integrated electroencephalogram and neurologic examination. Pediatrics 2011; 128:e112–e120. 27. Thoresen M, Hellstro¨m-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics 2010; 126:e131–e139. 28. Agut T, Leo´n M, Rebollo M, et al. Early identification of brain injury in infants with & hypoxic ischemic encephalopathy at high risk for severe impairments: accuracy of MRI performed in the first days of life. BMC Pediatr 2014; 14:177. This study found, in a small sample, that MRIs performed at 4 days may be predictive of those done at 2 weeks of age. 29. Rutherford M, Ramenghi LA, Edwards AD, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol 2010; 9:39–45. 30. Shankaran S, Barnes PD, Hintz SR, et al. Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2012; 97:F398–F404. 31. Cheong JL, Coleman L, Hunt RW, et al. Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med 2012; 166:634–640. 32. Shellhaas RA, Thelen BJ, Bapuraj JR, et al. Limited short-term prognostic utility of cerebral NIRS during neonatal therapeutic hypothermia. Neurology 2013; 81:249–255. 33. Massaro AN, Bouyssi-Kobar M, Chang T, et al. Brain perfusion in encephalopathic newborns after therapeutic hypothermia. Am J Neuroradiol 2013; 34:1649–1655. 34. Howlett JA, Northington FJ, Gilmore MM, et al. Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy. Pediatr Res 2013; 74:525–535. 35. Luo M, Li Q, Dong W, et al. Evaluation of mild hypothermia therapy for & neonatal hypoxic-ischaemic encephalopathy on brain energy metabolism using 18F-fluorodeoxyglucose positron emission computed tomography. Exp Ther Med 2014; 8:1219–1224. This study demonstrates that glucose metabolism is improved following hypothermia compared to noncooled control infants. 36. Liu X, Chakkarapani E, Stone J, Thoresen M. Effect of cardiac compressions and hypothermia treatment on cardiac troponin I in newborns with perinatal asphyxia. Resuscitation 2013; 84:1562–1567. 37. Montaldo P, Rosso R, Chello G, Gilberti P. Cardiac troponin 1 concentrations & as a marker of neurodevelopmental outcome at 18 months in newborns with perinatal asphyxia. J Perinatology 2014; 34:292–295. This study notes that cardiac troponin levels are associated with 18 months outcome. 38. Ro´ka A, Beko˝ G, Hala´sz J, et al. Changes in serum cytokine and cortisol levels in normothermic and hypothermic term neonates after perinatal asphyxia. Inflamm Res 2013; 62:81–87. 39. Jenkins DD, Rollins LG, Perkel JK, et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab 2012; 32:1888–1896. 40. Frymoyer A, Lee S, Bonifacio SL, et al. Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. J Perinatol 2013; 33:778–782. 41. Shellhaas RA, Ng CM, Dillon CH, et al. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. Pediatr Crit Care Med 2013; 14:194–202. 42. Gonzales-Portillo GS, Reyes S, Aguirre D, et al. Stem cell therapy for neonatal && hypoxic-ischemic encephalopathy. Front Neurol 2014; 5:147. This review of therapy with stem cells for neonatal HIE reviews preclinical and current trials in stem cell therapy. 43. Chakkarapani E, Dingley J, Aquilina K, et al. Effects of xenon and hypothermia on cerebrovascular pressure reactivity in newborn global hypoxic-ischemic pig model. J Cereb Blood Flow Metab 2013; 33:1752–1760. 44. Traudt CM, McPherson RJ, Bauer LA, et al. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci 2013; 35:491–503. &&
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