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Current Controversies in Hypothermic Neuroprotection
Seminars in Fetal & Neonatal Medicine (2008) 13, 30e34 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/sinyCurrent controversies in hypothermicneuroprotectionJohn D.E. Barks*C. S. Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, MI 48109, USA KEYWORDS Summary In 2005, three randomised controlled trials (RCTs) showed that treating infants Hypoxiceischaemic with hypoxiceischaemic encephalopathy (HIE) with hypothermia decreased the combined out- encephalopathy; come of death or disability at 12e18 months, although treatment effects were modest. More Neonatal recently, the US Food and Drug Administration (FDA) approved a device for selective head cool- encephalopathy; ing. In addition, the protocol from another of the three trials, using equipment available in Newborn infant; many hospitals, has been in the public domain for over a year. Why has this not led to a con- Perinatal asphyxia; sensus that hypothermia is the standard of care for HIE? This is explored. Important questions Therapeutic for future research will focus on ways to improve on initial results with cooling, such as drug hypothermia plus hypothermia combination therapy and reﬁning duration and depth of cooling or duration of rewarming. Although the latter are important questions for future clinical trials, those who are convinced by the evidence to date should focus on safe implementation of cooling using protocols with established safety and efﬁcacy and should consider ways to increase access to cooling for eligible babies. ª 2007 Published by Elsevier Ltd.Introduction Why is everyone not convinced?More than 2 years have passed since the results of three Until recently, the most deﬁnite sign that the neonatalrandomised controlled trials (RCTs), which individually and community was not universally convinced of the efﬁcacycollectively demonstrated the efﬁcacy of hypothermia for of hypothermia was that an RCT (the ICE trial), with athe treatment of perinatal hypoxiceischaemic encephalop- non-hypothermic control group, continued to enroll pa-athy (HIE) in term or late preterm infants, were publish- tients in several countries. It would be logical to supposeed.1e4 Yet, to date, there is still no general consensus that that investigators who participated in the published orhypothermia is the standard of care for such infants. Why is completed trials are most likely to be convinced of thethis the case? This review aims to address some of the cur- safety and efﬁcacy of cooling, and that this convictionrent controversies surrounding hypothermia as a treatment would be demonstrated by their centres now offeringfor HIE. hypothermia to infants meeting their original trial criteria. This appears to be true for the National Institute of Child Health and Human Development (NICHD) and Neonatal * Tel.: þ1 734 763 4109; fax: þ1 734 763 7728. Research Network trial centres. Furthermore, many of the E-mail address: firstname.lastname@example.org centres in the Brain Cooling RCT also participated in the1744-165X/$ - see front matter ª 2007 Published by Elsevier Ltd.doi:10.1016/j.siny.2007.09.004
Current controversies in hypothermic neuroprotection 31subsequent FDA-approved continued access protocol and trial device, has never been ‘tested’ on a human infantare now transitioning to the commercial Cool Capâ device. prior to its commercial release. The Cool Capâ System One commonly expressed reservation about the early now features a graphical, touch-screen, user interfacecompleted trials is that none of them was powered to that walks the user through the entire cooling process. Al-address the death versus disability question, i.e. clinicians though the Cool Capâ system is quite expensive comparedmay still need to be convinced that cooling is not simply to the Blanketrol cooling mattress, economic modelling in-permitting more babies to survive with severe handicaps, dicates that, from a societal perspective, the Cool Capâwithout increasing the number of non-handicapped survi- system would be cost-effective under several different re-vors. It is likely that the results of the three pending RCTs gional implementation strategies in the state of Massachu-(see below) will provide enough patients to evaluate sepa- setts.8 Despite its cost-effectiveness at a regional/societalrately the effects of hypothermia on death and on disability level, individual hospitals might be deterred from coolingin survivors by using meta-analysis. A related concern is that by price concerns.outcome in later childhood, e.g. cognitive outcome at school The NICHD body cooling protocol is publicly available onage, is unknown; interestingly, other new therapies in the Internet as a written protocol at https://neonatal.neonatology, like surfactant or inhaled nitric oxide, have rti.org/studies_hypothermia.cfm. Unlike the FDA-approvednot been held to such a high standard before becoming head cooling system, the equipment used in the NICHD pro-accepted therapies. Both the NICHD trial and the Brain tocol, the Blanketrol IIâ Hypo/hyperthermia system (Cin-Cooling trial are planning school-age follow-up evaluations. cinnati Sub-Zero), was not designed or FDA-approved for For others, an important question is, ‘have enough neonates. Thus, its use for treatment of HIE in neonatespatients been studied to be reasonably certain that hypo- constitutes an ‘off-label’ use, and for some hospitals in par-thermia is really effective?’ In simple terms, the concern is ticularly litigious settings, this may be a deterrent to its usethat combining early ‘smaller’ trials of a new therapy in in the treatment of HIE. Yet, it might be argued that manya meta-analysis is similar to taking multiple ‘peeks’ at data medications commonly used in neonatology are used ‘off-and prematurely stopping a prospective trial e it increases label’ without hesitation. Although many neonatologiststhe chance of a type I error. One way of addressing this has may not be familiar with the Blanketrolâ, it is likely to berecently been proposed, using the ‘optimal information size’ found at least in limited numbers in the operating roomsconcept to calculate the number of infants needed in pooled and/or patient equipment departments of many Northtrials to conﬁrm that a treatment effect exists and that American hospitals and it is sold in other parts of the world,estimates of the treatment effect size are reasonable.5 Inves- including Europe and the Middle East. Thus, some neonataltigators in the Brain Cooling and NICHD trials would probably intensive care units (NICUs) would be able to implement thedispute their characterisation as ‘small’ given the time and NICHD cooling protocol after investing the time necessaryeffort involved in accruing over 200 patients each, but in to ﬁnd and connect the equipment and supplies within theirfact compared to some adult clinical trials in conditions of own institution, and adapting the NICHD protocol for theirgreater prevalence, they are relatively small trials. The re- own use (e.g. creating a graphic presentation of the proto-sults of three additional large RCTs that have closed enroll- col), as we have done at the University of Michigan Healthment (the Chinese selective head cooling trial, the TOBY System. Others would need to purchase at least two of thetrial and the ICE trial) should provide sufﬁcient numbers of pa- devices, one for the patient and one for back-up. It must betients to address the concern about optimal information size.5 emphasised that safe use of the Blanketrolâ device for hy- pothermia in neonates depends on strict adherence to the NICHD protocol, including use of a second, adult-sized mat-What are the practical barriers to tress suspended from a pole to damp out temperature ﬂuc-implementation? tuations that would otherwise occur with use of a system overpowered for neonates. The equipment setup and theAt the time of writing, there is no consensus that hypo- protocol are sufﬁciently complicated that body coolingthermia should be the standard of care for infants with should not be undertaken on the spur of the moment, butsuspected HIE. The advice from authoritative sources that only after advance planning.hypothermia should only be undertaken using established In Europe, the TOBY trial hypothermia protocol is in theprotocols with known safety and efﬁcacy is still sound.6,7 public domain on the Internet, but the hypothermia deviceFor those convinced by the published evidence, cost and/ used was not available for purchase at the time of writing,or limited equipment availability may be barriers to imple- and safety and efﬁcacy data have not yet been reported.mentation of cooling within an individual centre, while ge- Geographical barriers to cooling are relevant in someography may pose an additional barrier to implementation regions, because there is a consensus amongst all publishedof neonatal cooling at a regional level. However, lack of protocols that cooling needs to be initiated within 6 h ofavailability of detailed cooling protocols should no longer birth. This 6-h limit in clinical trials was based on animalbe an issue. data, which suggest that the effectiveness of cooling dimin- The Olympic Cool Capâ System for selective head cooling ishes as time increases from the hypoxiceischaemic insult tois the only FDA-approved device for treatment of perinatal initiation of cooling, with the closing of the ‘window’ atHIE with hypothermia. It is relatively expensive compared a time between 5.5 and 8 h after the insult.9 In many largerwith other cooling systems. Its availability is limited at the countries, babies may be born at great distances frompresent time due to the manufacturer’s phased roll-out, regional NICUs, so that they could not possibly reach awhich has been made necessary by the fact that the ‘cooling centre’ within 6 h of birth. If such infants are to ben-commercial device, a substantial update of the clinical eﬁt from therapeutic hypothermia, practical strategies will
32 J.D.E. Barksbe needed to evaluate and initiate cooling in the birth hos- not inﬂuence the effect of cooling on outcome. In a postpital, in collaboration with a regional referral NICU and prior hoc analysis, data from the NICHD body cooling trial were ex-to neonatal transport. Such strategies were implemented in amined to determine whether there were factors identiﬁ-the published trial of Eicher et al., which demonstrated able prior to 6 h of life that could be incorporated intooverall efﬁcacy1,10; cooling, prior to and/or during trans- either a scoring scheme or a decision tree scheme to deter-port, was also incorporated into the TOBY and ICE trial pro- mine which infants were likely to beneﬁt from cooling andtocols. Until the results of the latter two trials are which would not.13 Although both approaches yielded meanspublished, individual centres are left to consider whether of identifying infants in the NICHD study population thatthe results of the Eicher trial and the experimental evidence would not beneﬁt from cooling, very few infants (2e3%)are compelling enough to support implementation of a trans- had such scores, and neither scheme has yet been validatedport cooling protocol and, as we have done, they may prospectively in a new patient population. Thus, these scor-choose to adapt Eicher’s transport cooling protocol to ﬁt ing systems are not currently suitable as a tool for excludingtheir centre’s cooling strategy. Given the limited evidence, infants from hypothermic intervention. Similarly, the Brainsafety concerns should be paramount in developing proto- Cooling investigators have not advocated use of aEEG criteriacols for initiation of cooling at birth hospitals without NICUs to exclude infants from cooling. To date, the most that canand/or during neonatal transport. In particular, there must be said, based on common sense and consistent with clinicalbe a method of safely measuring core (oesophageal or rec- trial protocols, is that infants judged to be in extremis aretal) temperature; standard bedside digital thermometers not cooling candidates.may not register temperatures in the target range for the All currently published cooling protocols limit initiationestablished cooling protocols. of treatment to within 6 h of birth. There is no human data An often-overlooked barrier to cooling is denial of, or to support efﬁcacy of cooling initiated >6 h after birth. Thisfailure to recognise, an infant’s birth depression and/or may be an important question for future study. However,encephalopathy. Some practitioners delivering babies per- the question could become largely irrelevant if recognitionsist in paradoxically responding to a litigious environment of eligibility improves as evidence for, and acceptance of,by not drawing umbilical cord blood gases, in a misguided cooling increase, and if protocols for evaluation and initia-effort to ‘protect’ themselves. This omission eliminates tion of cooling at birth hospitals become more widelyvaluable information that could identify an infant requiring disseminated.further evaluation for cooling, or that might suggest a non-hypoxiceischaemic explanation for neonatal depression.Although not every infant 36 weeks’ gestation with a cord How might we improve upon our results withpH 7 is a candidate for cooling, all need evaluation for cooling?signs of encephalopathy. Sometimes, evaluation for enceph-alopathy and consideration for cooling may be overlooked in For those convinced by the current evidence, this is anthe ﬂurry of managing other critical complications associ- important question, which will be the focus for future re-ated with birth depression, such as hypotension, blood search. Several possible strategies include combinations ofloss, meconium aspiration syndrome and persistent pulmo- potentially neuroprotective drugs with hypothermia; earliernary hypertension. initiation of cooling; increased depth or duration of cooling; Even if the need to evaluate for encephalopathy is and prolonged rewarming. There is some experimentalrecognised, clinicians vary in their level of experience evidence supporting additive or synergistic effects of drugsand conﬁdence in performing the neonatal neurological with hypothermia, including some FDA-approved drugs (top-examination, and the signs of encephalopathy can be iramate, N-acetylcysteine).14,15 Many other FDA-approvedsubtle, may not always ﬁt neatly into published grading drugs, e.g. anticonvulsants and anti-inﬂammatories, stillschemes, can evolve over time, or may be mistaken for the need to be evaluated experimentally in combination withside-effects of sedatives or of severe systemic illness.11 Am- cooling, to provide a foundation for future human studies.plitude-integrated EEG (aEEG), which was originally used in Although experimental evidence indicates that cooling isthe Cool Cap trial to exclude infants anticipated to do well more effective when initiated earlier after the insult,9 thewithout intervention, might become a useful way of decid- therapeutic time window for the beneﬁt of cooling appearsing whether an infant with equivocal ﬁndings on examina- to decrease as the severity of the initial insult increases.16tion is ‘encephalopathic enough’ to beneﬁt from cooling. The two largest trials to date were unable to detect an ef- fect of time of initiation on outcome, perhaps because cooling of most infants was started relatively late in theWho should be cooled? Who should not be time window in both trials, between 4 and 5 h after birth.2,3cooled? In the Eicher trial, cooling was initiated with ice packs prior to or during transport, and enrollment time was thus earlierThe results of the Cool Cap trial indicated that the subgroup than in the two larger trials1; it is tempting to speculateof infants with the most severe aEEG tracings (severe that earlier time of initiation facilitated detection of efﬁ-suppression plus seizures) did not improve with cooling, cacy, despite a smaller sample size than either the Brainwhereas the majority of infants, who had less severe aEEG Cooling or the NICHD trial. Perhaps the results of the re-abnormalities, showed improved outcome with cooling.2 In maining RCTs or analysis of data from the VermonteOxfordcontrast, a post hoc analysis from the Cool Cap trial,12 consis- Neonatal Encephalopathy registry will shed additional lighttent with the results of the NICHD body cooling trial,3 showed on the importance of initiation time. There is no evidencethat clinical encephalopathy grade (Sarnat II versus III) did to indicate that longer durations of cooling or rewarming,
Current controversies in hypothermic neuroprotection 33or greater depth of cooling will result in better outcomes safety should be a priority, and data on cooled infants(nor that they are safe), so the use of these approaches should be collected systematically, e.g. via the Vermonteshould be limited to evaluation in RCTs. Oxford Network Neonatal Encephalopathy registry or the TOBY Register.Neurodevelopmental outcomeAs indicated earlier, it is not yet known whether the early Practice pointspromising results with hypothermia based on evaluation at12e24 months will translate into improved performance at Therapeutic hypothermia safely decreases theschool age. However, given the lack of any other therapies combined outcome of death or disability at 12efor HIE on the immediate horizon, this limitation is not likely 24 months, in infants with apparent HIE.to present a barrier to implementation for many neonatol- Published protocols and the necessary equipmentogists, nor is it likely to deter parents from accepting the are available.therapy. Use of therapeutic hypothermia for HIE is not yet Of more immediate concern, neonatologists and pediat- the standard of care.ric neurologists should remember that what we think we Only protocols with established safety and efﬁcacyknow about the prognostic implications of early neurolog- should be used.ical ﬁndings and early neuroimaging, such as magneticresonance imaging (MRI) is based almost entirely on datafrom the pre-cooling era. As a neonatologist, who hasparticipated in the cooling of over 50 infants, using bothselective head cooling and the NICHD body cooling pro-tocol, the author has noted that even infants that ulti- Research directionsmately do well at 18e24 months do not always showa dramatic improvement in neurological status after re- Does hypothermia reduce disability in survivors,warming, but rather many seem to show a gradual recovery independent of its effect on mortality?over several days. Does hypothermia change the prognostic implica- Regarding the prognostic implications of early MRI, e.g. tions of post-hypothermic neurological examina-at 7e10 days after birth, there is tantalising (but inconsis- tion or MR imaging?tent) preliminary data to suggest that cooling is associated Does earlier initiation of cooling, within the ﬁrstwith a change in the pattern and/or extent of injury,17,18 6 h of life, improve outcome?but this has so far not been evaluated in large numbers of Can drug plus hypothermia combinations safelypatients nor are there any reports so far of the correlation improve outcome?of early MRI ﬁndings in cooled infants with 18e24 months’ Could longer duration or lower target temperatureneurodevelopmental outcome. It is possible that MRI ﬁnd- safely improve outcome?ings at 7e10 days in infants with encephalopathy treatedwith cooling may represent reversible changes in evolution.The latter question is likely to be addressed by the NICHDtrial investigators in a secondary analysis. In the meantime,neonatologists and neurologists should exercise some cau- Referencestion in assuming that what they knew about prognostication 1. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypother-in the pre-cooling era will still be true in infants that have mia in neonatal encephalopathy: efﬁcacy outcomes. Pediatrrecently undergone therapeutic hypothermia, particularly Neurol 2005;32(1):11e7.regarding infants with moderate encephalopathy or inter- 2. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cool-mediate degrees of injury on MRI. ing with mild systemic hypothermia after neonatal encephalop- athy: multicentre randomised trial. Lancet 2005;365(9460): 663e70.Conclusion 3. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hy- pothermia for neonates with hypoxiceischemic encephalopa-Until the results of several, now-closed, RCTs are pub- thy. N Engl J Med 2005;353(15):1574e84.lished, the lack of consensus for therapeutic hypothermia 4. Edwards AD, Azzopardi DV. Therapeutic hypothermia followingas the standard of care for infants with apparent HIE is perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 2006;likely to continue. There is no evidence that one method of 91(2):F127e31.cooling is superior. Although devices and protocols to 5. Kirpalani H, Barks J, Thorlund K, Guyatt G. Cooling for neona-perform hypothermia according to already-published pro- tal hypoxiceischemic encephalopathy e is the answer in? Pedi-tocols are now available, it is unclear how rapidly this atrics 2007;120(5):1131e2. 6. Higgins RD, Raju TN, Perlman J, et al. Hypothermia and perina-technology will be disseminated while the results of the tal asphyxia: executive summary of the National Institute ofremaining trials are pending. It is reasonable for some Child Health and Human Development workshop. J Pediatrcentres, particularly those that participated in the pub- 2006;148(2):170e5.lished trials, to offer cooling according to the published 7. Blackmon LR, Stark AR. Hypothermia: a neuroprotective ther-protocols. It is also reasonable for centres that are not yet apy for neonatal hypoxiceischemic encephalopathy. Pediatricsconvinced to await further evidence. In this interim period, 2006;117(3):942e8.
34 J.D.E. Barks 8. Gray J, Geva A, Zheng Z, Zupancic J. CoolSim: using industrial 14. Liu Y, Barks JD, Xu G, Silverstein FS. Topiramate extends the modeling techniques to examine the impact of selective head therapeutic window for hypothermia-mediated neuroprotec- cooling in a model of perinatal regionalization. Pediatrics, in tion after stroke in neonatal rats. Stroke 2004;35(6):1460e5. press. 15. Jatana M, Singh I, Singh AK, Jenkins D. Combination of systemic 9. Gunn AJ, Gunn TR. The ‘pharmacology’ of neuronal rescue hypothermia and N-acetylcysteine attenuates hypoxiceische- with cerebral hypothermia. Early Hum Dev 1998;53(1):19e35. mic brain injury in neonatal rats. Pediatr Res 2006;59(5):10. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypother- 684e9. mia in neonatal encephalopathy: safety outcomes. Pediatr 16. Iwata O, Iwata S, Thornton JS, et al. ‘Therapeutic time win- Neurol 2005;32(1):18e24. dow’ duration decreases with increasing severity of cerebral11. Leviton A, Nelson KB. Problems with deﬁnitions and classiﬁcations hypoxiaeischaemia under normothermia and delayed hypo- of newborn encephalopathy. Pediatr Neurol 1992;8(2):85e90. thermia in newborn piglets. Brain Res 2007;1154:173e80.12. Wyatt JS, Gluckman PD, Liu PY, et al. Determinants of out- 17. Inder TE, Hunt RW, Morley CJ, et al. Randomized trial of systemic comes after head cooling for neonatal encephalopathy. Pediat- hypothermia selectively protects the cortex on MRI in term hypo- rics 2007;119(5):912e21. xiceischemic encephalopathy. J Pediatr 2004;145(6):835e7.13. Ambalavanan N, Carlo WA, Shankaran S, et al. Predicting out- 18. Rutherford MA, Azzopardi D, Whitelaw A, et al. Mild hypothermia comes of neonates diagnosed with hypoxemiceischemic en- and the distribution of cerebral lesions in neonates with hypo- cephalopathy. Pediatrics 2006;118(5):2084e93. xiceischemic encephalopathy. Pediatrics 2005;116(4):1001e6.