Commentary Hypothermia and Perinatal Asphyxia

COMMENTARY

HYPOTHERMIA AND PERINATAL ASPHYXIA: EXECUTIVE SUMMARY OF THE NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT WORKSHOP

ROSEMARY D. HIGGINS, MD, TONSE N.K. RAJU, MD, JEFFREY PERLMAN, MD, DENIS VICTOR AZZOPARDI, MD, LILLIAN R. BLACKMON, MD, REESE H. CLARK, MD, A. DAVID EDWARDS,FMED SCI,DONNA M. FERRIERO, MD, PETER D. GLUCKMAN, MBCHB, FRS, ALISTAIR J. GUNN, MBCHB, PHD, SUSAN E. JACOBS, MD, DOROTHEA JENKINS EICHER, MD, ALAN H. JOBE, MD, PHD, ABBOT R. LAPTOOK, MD, MICHAEL H. LEBLANC, MD, CHARLES PALMER , MBCHB, SEETHA SHANKARAN, MD, ROGER F. SOLL, MD, ANN R. STARK, MD, MARIANNE THORESEN, MD, JOHN WYATT, MD, THE NICHD HYPOTHERMIA WORKSHOP SPEAKERS AND DISCUSSANTS*

he National Institute of Child Health and Human Development (NICHD) held a workshop on hypothermia as a potential treatment modality for perinatal hypoxic-ischemic encephalopathy (HIE) in May 2005. A panel of experts summarized the Tcurrent evidence on the efficacy and safety of hypothermia and reviewed knowledge gaps. The panel concluded that mild, therapeutic hypothermia offered a potential for short-term benefits (up to 18 months of age) when used under strict experimental protocols in term infants. However, these findings have not been tested in preterm infants or severely growth-restricted infants with asphyxia. Many questions still remained about the optimal use of hypothermia for HIE in term infants, including the incidence of possible rare, short-, and long-term side effects. Moreover, the longer-term benefits in neurodevelopmental outcomes after hypothermia for HIE remain to be shown. Because of these and other reasons, the panel concluded that at the current time, therapeutic hypothermia for perinatal HIE should be considered an evolving therapy, the longer-term safety and efficacy of which are still to be established. The panel offered a framework for patient care emphasizing the need for standardized protocols for treatment and follow-up, including school-age outcome assessments. Research priorities were also recommended. The panel strongly urged that the ongoing hypothermia trials should be continued to enable assessment of its efficacy and safety. It recommended the formation of national and international HIE registries, so that scientific progress in this field can be assessed continuously to develop, refine, and optimize therapies for HIE. BACKGROUND There are no therapies other than supportive measures for perinatal HIE, a condition associated with high neonatal mortality rates and severe long-term neurologic morbidity. Although hypothermia was used for “asphyxia neonatorum” in 1955,1 only in the past decade have systematic studies been carried out to address the safety and efficacy of this therapy in HIE.2-16 Recently, 2 large trials have been completed providing the results of 18-month follow-up.17,18 Other trials are actively enrolling patients.19,20 Thus there seemed to be an urgent need to assess hypothermia as a potential neuroprotective strategy for perinatal HIE and to formulate a continuing research agenda. To address these, the NICHD organized a workshop in May 2005. The invited panel reviewed the available evidence, From Pregnancy and Perinatology Branch, Center for Developmental Biology and identified knowledge gaps, and suggested research priorities along with a framework for Perinatal Medicine, National Institute of translating evidence into patient care. This article provides a summary of the major points Child Health and Human Development, discussed at the workshop. National Institutes of Health, Bethesda, MD Submitted for publication: Oct 17, 2005; accepted Dec 5, 2005. AN OVERVIEW OF THE PATHOGENESIS OF HIE Reprint requests: Rosemary D. Higgins, M.D. Pregnancy and Perinatology Branch, The biochemical and molecular processes leading to brain injury after an hypoxic- Center for Developmental Biology and ischemic (HI) insult have been studied in fetal sheep, newborn mice, rat pups, piglets, and Perinatal Medicine, NICHD, NIH 6100 Ex- nonhuman primates,2-12,21,22 as has been reviewed elsewhere.23,24 Despite the wide range of ecutive Blvd, Room 4B03B MSC 7510 Be- thesda, MD 20892. E-mail: higginsr@ species and experimental paradigms used, a number of general conclusions can be drawn about mail.nih.gov this topic, as follows. *See Appendix for a complete list of speak- Brain injury after experimental HI insult is an evolving process. The nature and severity ers and discussants and their institutional affiliations, available at www.jpeds.com. J Pediatr 2006;148:170-5 aEEG Amplitude-integrated HIE Hypoxic-schemic encephalopathy 0022-3476/$ - see front matter electroencephalography NICHD National Institute of Child Health and Copyright © 2006 Elsevier Inc. All rights EEG Electroencephalography Human Development reserved. HI Hypoxic-ischemic TOBY Total Body Cooling Trial 10.1016/j.jpeds.2005.12.009

170 of the injury dictates the magnitude of the initial damage. After cooling should be initiated as early as feasible after the brain the initial reperfusion period, brain oxidative metabolism often injury, preferably within 2 hours, but not later than 6 hours; the recovers partially or completely, a phase referred to as the “latent rectal temperature should be reduced to between 32° to 34° C for phase.” However, in many cases, an ominous phase of secondary effective brain cooling with whole-body hypothermia; smaller deterioration follows, also known as the “delayed phase of in- reductions in rectal temperature (34°-35° C) may be needed for jury,” during which neurons and oligodendroglia continue to die head cooling; and cooling should be continued for about 48 to 72 for longer periods. The processes of cell injury and death during hours. Although optimal methods for rewarming were not tested the initial HI insult appear to be a predictable phenomenon: in newborn animals, adult animal studies indicated that slow deprivation of oxygen and nutrients leads to a shift to anaerobic rewarming was to be preferred.24,25 glycolysis, depletion of high-energy phosphate reserves, loss of cell membrane functions, accumulation of lactic acid, calcium, TRANSLATING THE RESULTS OF ANIMAL free radicals and neurotoxic, excitatory neurotransmitters such as STUDIES TO HUMAN TRIALS glutamate in the extracellular milieu, and deterioration of cell Many limitations had to be noted before extrapolating the function. If the insult is not interrupted, this cascade ultimately potentially beneficial effects seen in animal models of HIE and leads to acute or “primary” cell death. hypothermia to human HIE. In human beings, “perinatal en- However, the biochemical processes involved in evolving cephalopathy” is not a single disease entity, but a condition cell death that develops after reperfusion are more complex. A resulting from diverse causes manifesting signs of brain injury at series of interrelated mechanisms may be responsible for perpet- different phases of its evolution. Despite the etiologic diversity, uating the initial injury, some of which include the following: the clinical signs may be identical. The cause(s) of HIE is rarely cytosolic accumulations of calcium and exposure to free radicals, obvious, and the timing, nature, or severity of the HI injury is including formation of nitric oxide, and toxic effects caused by almost never known. The underlying status of the human brain, accumulating iron; injury from inflammatory mediators; and such as its maturity, nutritional and hormonal status, inflamma- mitochondrial dysfunction. These and other processes trigger tory, and preexisting developmental abnormalities may alter the apoptotic pathways contributing to continued neuronal and oli- responses to acute insults. godendroglial injury and death, which may evolve over hours, Moreover, one can only offer therapy for HIE in human days, or possibly weeks and months after an HI injury. infants at a known postnatal age—not after a known interval Although the sequence of evolution of the phases of en- from brain injury. However, in only about 25% of HIE cases ergy failure and cellular damage and dysfunction after HI injury can one discern signs of a sentinel event in the peripartum are strikingly consistent across animal species and among sub- period indicating the time of injury. There is considerable jects, the duration of these phases (especially that of the latent variability in the neuronal (and other brain cellular) responses and secondary deterioration) and the degree of continuing dam- to HI injury and to hypothermia among the experimental age can vary considerably. The factors that might affect the species, and in human infants. Thus one cannot determine length of the reperfusion and latent phases of injury are not well with precision how late after an ischemic injury one can known but likely include the following: the nature, magnitude, provide cooling and still expect neuroprotection. Further, in and the pattern or repetition of the initial HI insult; the matu- only a few experimental animal models of HIE and hypo- rational stage of the brain; the subject’s general health and thermia have there been attempts to characterize the fre- nutritional status; regional cerebral blood flow and metabolic quency of multisystem organ injury and other organ responses characteristics; and the species studied. These issues need to be to hypothermia. Because of this gap in knowledge, there is a considered when translating the results of animal experiments concern that hypothermia in infants with very severe HIE into clinical practice, since most experimental interventions have might increase their survival but with severe disability, as well been designed to halt or reduce brain injury after timed insults in as increase the risk for systemic complications. previously healthy animals during the reperfusion and latent phases. CLINICAL TRIALS

HYPOTHERMIA AND NEUROPROTECTION Pilot Trials Studies in fetal sheep showed that brain cooling to about In 1955 Westin et al1 showed that hypothermia was 32° and 34° C beginning 90 minutes or 5.5 hours after HI injury beneficial in perinatal asphyxia. However, systematic pilot stud- and continuing for 48 to 72 hours diminished the extent of ies were not done until Gunn et al,13 Azzopardi et al,14 and parasagittal neuronal damage(the effect of cooling was observed Thoresen and Whitelaw15 described simple approaches to cool- in other regions of brain as well).5,6,8,12 Studies in neonatal ing the head and the whole body for up to 72 hours without piglet, rat, and other models also led to the conclusion that mild serious, short-term adverse effects. The findings from these hypothermia was neuroprotective, even after experimental HI studies showed that although bradycardia occurred commonly, brain injury.2-4,7,9-11 Improved neurologic outcomes were con- other acute complications, such as severe hypotension, acute firmed by use of quantitative neuropathologic methods, imaging deterioration in pulmonary function, increased rates of infection, studies, and tests of learning and memory functions. or imbalances in blood viscosity, electrolytes, and clotting did not From the animal studies it could be concluded that brain occur with mild therapeutic hypothermia for 72 hours. Shanka-

Hypothermia And Perinatal Asphyxia: Executive Summary Of The NICHD Workshop 171 ran et al16 also confirmed the feasibility of providing whole-body according to physiological criteria and subsequently by a neuro- cooling for 72 hours without major short-term complications. In logic examination. Eligibility criteria included gestational age Ն a pilot study of whole-body cooling to a rectal temperature of 33° 36 weeks, a pH of 7.0 or less or a base deficit of 16 mmol/L or Ϯ 0.5° C for 48 hours in infants with severe HIE, Eicher et more in a sample of umbilical cord blood or any blood during the al26,27 reported a higher incidence of bradycardia and a greater first hour after birth. If, during this interval, pH was between use of inotropic agents during cooling in the hypothermia group 7.01 and 7.15, a base deficit was between 10 and 15.9 mmol/L, (n ϭ 33) compared with in the control subjects (n ϭ 32). The or a blood gas level was not available, additional criteria were hypothermia group also had longer prothrombin times and lower required. These included an acute perinatal event and either a platelet counts than the control subjects, but all of the values were 10-minute Apgar score of 5 or less or assisted ventilation initi- within normal range. ated at birth and continued for at least 10 minutes. Once these Thus the cumulative evidence from numerous animal criteria were met, all infants underwent a standard neurologic studies and the reassuring conclusions about the short-term examination performed by a certified examiner.18 Infants were safety and feasibility of providing therapeutic hypothermia in candidates when seizures or moderate or severe encephalopathy human infants led to the development of larger randomized was present. Infants randomized to whole-body hypothermia (n controlled trials. ϭ 102) were placed on cooling blankets such that the esophageal temperature was reduced to and maintained at 33.5° Ϯ 0.5° C for Large-Scale Clinical Trials 72 hours followed by rewarming by on-site research personnel using the Cincinnati Sub-Zero System, while the control infants In the first completed multicenter trial (CoolCap) con- (n ϭ 106) were given standard intensive care. ducted in 25 centers in New Zealand, Great Britain, and the At 18 months of age, the primary outcome status was United States, 234 infants with acute perinatal HIE were en- known for 205/208 (98%) infants; death or moderate/severe rolled.17 The stepwise biochemical/clinical, neurologic, and elec- disability occurred in 44% (45/102) of the hypothermia group troencephalography (EEG) criteria for entry were as follow: Ͼ36 and 62% (64/103) of the control group (risk ratio 0.72; 95 % CI, weeks gestation; an Apgar score Ͻ5 at 10 minutes after birth or 0.54–0.95, P ϭ .01), indicating 6 infants need to be treated on a continued need for resuscitation at 10 minutes after birth; or a average to result in 1 additional infant with a better outcome. pH Ͻ7.0 or base deficit Ͼ 16 mmol/L in the umbilical blood or The mortality rate was 24% in the hypothermia group and 37% venous blood sample within 60 minutes of birth; and a modified in the control group (risk ratio 0.68, 95% CI: 0.43-1.01, P ϭ Sarnat score and amplitude-integrated EEG (aEEG) criteria .08). The risk ratio for death or disability after moderate HIE consistent with a diagnosis of moderate to severe HIE. was 0.69 (95% CI, 0.44-1.07) and after severe HIE was 0.83 Infants in the experimental group (n ϭ 116) received (95% CI 0.64–1.13). For the hypothermia group versus the selective head cooling with mild systemic hypothermia induced control group, respectively, the risk of disabling cerebral palsy with a cooling cap device in which cold water was circulated. The was 19.2% and 30.0% RR 0.68 (0.38–1.22), blindness 7% versus rectal temperature was maintained between 34° to 35° C for 72 14% RR 0.50 (0.17–1.44) and hearing impairment requiring a hours, and the infants were rewarmed at a rate Ͻ0.5° C per hour. hearing aid was 4% and 6%, RR 0.54 (0.10–3.02). The fre- Conventional intensive care with normal body temperature was quency of adverse event rates during cooling was similar: 19% in provided for 118 infants in the control group. the hypothermia group and 15% in the control group. On intention to treat analysis, the incidence of death or severe disability was 55% in the cooled infants and 66% in the control subjects. Outcome information was known on 93% of Other Ongoing Trials the study population. A logistic regression analysis controlling In the Total Body Cooling Trial (TOBY) from En- for baseline aEEG severity, presence of seizures, and age at gland,19 infants with moderate-to-severe HIE are randomized to randomization indicated a possible treatment effect from hypo- receive whole-body cooling or standard intensive care. Thus far, thermia (odds ratio 0.57, 95% CI 0.32-1.01, P ϭ .05). In a 206 of the planned 239 (86%) infants (as of January 26, 2006) predetermined subgroup analysis of HIE severity (based on have been enrolled, and the study is continuing. The trial design prerandomization aEEG changes), the investigators found that features and the entry criteria for the TOBY trial are similar to although no evidence of benefit was seen in those with the most those of the CoolCap trial.17 Thus, upon completion, the find- severe changes in the prerandomization aEEG (n ϭ 46), a ings from the TOBY trial can be effectively compared with those significantly improved outcome (odds ratio 0.42; 95% CI, 0.22- of CoolCap to assess the relative benefits from whole-body 0.80, P ϭ .009) was observed in the less severe cases (n ϭ 172). versus selective head cooling in HIE. Such comparisons would On further post hoc analysis, when baseline clinical severity was be of great value, since these trials will constitute 2 of the largest added to the regression model, a significant protective effect cohorts of infants studied under an identical enrollment protocol. from hypothermia was observed for the entire cohort (odds ratio The ICE (Infant Cooling Evaluation) trial aims to 0.52, 95% CI 0.28-0.70, P ϭ .04).28 enroll infants from a wide geographic region, using simplified In the second large randomized controlled clinical trial, protocols.20 Hypothermia is achieved by turning off the am- Shankaran et al18 enrolled 208 infants from 16 Neonatal Re- bient heating systems and by applying “Hot-Cold” gel packs search Network centers and tested the effect of whole-body (at 10° C) around the infant’s head and over the chest, so that hypothermia in moderate to severe HIE. Infants were evaluated the rectal temperature is reduced to 33° to 34° C. After

172 Higgins et al The Journal of Pediatrics • February 2006 Table. Unresolved issues. Implementing hypothermia for HIE ● At the present time, hypothermia for HIE lacks long term safety and efficacy data. Institutions choosing to offer hypothermia should implement studied and reported protocols from existing or ongoing trials, and incorporate longer-term follow up plans. ● If hypothermia is offered to infants with HIE, the parents should be appraised about the knowledge gaps in this field and the uncertain nature of longer-term outcome. ● The ongoing TOBY, ICE, and other trials need be to be completed. ● National and international registries need to be organized for ongoing assessment of the global burden of HIE, its treatment and outcomes. ● International interest groups of scientists, practitioners, and others involved in public policy need to be formed for continued evaluation of accumulating evidence in this field. ● The role of therapeutic hypothermia in HIE for children born in countries with limited resources needs to be studied in the context of regional issues of feasibility, risks and potential benefits. Identification of infants for offering hypothermia ● The value of standardized clinical examinations, scoring systems (e.g., modified Sarnat score), and aEEG should be studied to assess eligibility for hypothermia. ● Although it has been tested in term infants and to a lesser extent in late preterm, (Ͼ35 weeks gestation) infants; the value of hypothermia in premature infants, and in those with severe intrauterine growth restriction has not been studied. The risk benefit ratio for these infants cannot be assessed at this time due to lack of data. ● The severity of HIE at which the risk versus benefit ratio favors hypothermia remains unknown. Whether developmental outcomes are affected by the type and timing of hypoxic-ischemic injury needs to be studied. ● The latest postnatal age at which initiation of therapeutic hypothermia might still be effective (“how late is not too late”) is unknown. ● The potential beneficial or deleterious effect of hypothermia during resuscitation and transfer needs to be studied. Cooling and rewarming ● Although it is postulated that deeper, longer, and earlier therapy with hypothermia is to be preferred, the optimal degree and duration of cooling is unknown. Whether the degree and duration of therapy should be based on the cause, severity, stage of brain injury, and the age at starting of hypothermia is unknown. ● The optimal mode of cooling (whole body or selective head) is unknown, especially with regard to their differential protective effects, if any, on various regions of the brain (generalized cortical versus deep brain nuclei), has not been established. The optimal/ safe pace of re-warming is unknown. ● The frequency of uncommon and rare systemic side effects, and the method of monitoring for these need to be studied. Long-term outcome ● The role of MRI or other anatomic or functional imaging modalities in prognosis and during follow-up remains to be studied. ● The duration of follow-up and the appropriate tests to assess outcome should be similar so that outcomes under differing protocols can be compared. ● Longer-term follow-up of infants who participated in the completed and ongoing and future hypothermai trials should be strongly supported.

demonstrating the feasibility of this approach in 17 infants, IMPLICATIONS FOR CLINICAL PRACTICE the investigators have enrolled 96 of the planned 276 infants from 15 participating centers in Australia, New Zealand, and The workshop participants suggested some salient Canada in this ongoing trial. points as a framework for consideration by practicing clinicians. MAJOR GAPS IN KNOWLEDGE ● Based on the available evidence and the known gaps in In spite of rapidly accumulating clinical and labora- knowledge, at the current time, therapeutic hypothermia tory data related to hypothermia as a neuroprotective strat- should be deemed as an evolving therapy, the long-term egy for HIE, the speakers and discussants at the workshop safety and efficacy of which need to be established. underscored numerous gaps in knowledge in this field. ● Perinatal HIE is not a single disease from a single cause, They noted that with only 2 completed studies providing with great diversity in the timing and magnitude of brain information on follow-up for only up to 18 months of age, injury. It is therefore unreasonable to expect any single the longer-term impact of hypothermia for HIE remains intervention will provide uniformly favorable outcome. unknown. This, they concluded, should lead to an overall ● The known heterogeneity in neuropathologic changes after measure of caution in applying the new therapy of hypo- perinatal HIE combined with potential regional heteroge- thermia indiscriminately for all cases of HIE. Some com- neity of treatment effects will lead to marked differential ponents of the panel’s discussion are outlined in the Table. effects on outcomes among survivors of HIE (eg, physical and briefly highlighted below. disability versus cognitive deficits). This underscores the

Hypothermia And Perinatal Asphyxia: Executive Summary Of The NICHD Workshop 173 need for longer-term follow-up of all infants with HIE Health; British Association of Perinatal Medicine; and the Canadian undergoing any treatment. Academy of Pediatrics for their support for the workshop. ● Therapeutic hypothermia, if offered, should be used only under published protocols as indicated in the CoolCap and REFERENCES NICHD trials, or as part of ongoing controlled trial(s) of 1. Westin B, Einhorning G. An experimental study of the human fetus induced hypothermia for HIE, with appropriate follow up with special reference to asphyxia neonatorum. Acta Paediatr 1955;44(Suppl mechanisms. This is vital in the current settings of evolving 103):79-81. research data, particularly until its safety and longer-term 2. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe efficacy have been demonstrated and can be systematically transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the replicated by additional ongoing studies. newborn piglet. Pediatr Res 1995;37:667-70. ● 3. Edwards AD, Yue X, Squier MV, et al. Specific inhibition of apoptosis The roles of standard EEG or aEEG in selecting subjects for after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Bio- treatment need to be further assessed and refined. Similarly, chem Biophys Res Commun 1995;217:1193-9. the value of continuous monitoring of EEG activity during 4. Laptook AR, Corbett RJ, Sterett R, Burns DK, Tollefsbol G, Garcia treatment, and of EEG and MRI before discharge and at D. Modest hypothermia provides partial neuroprotection for ischemic neo- specific times during follow-up for prognostic evaluation need natal brain. Pediatr Res 1994;35:436-42. 5. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. to be evaluated. Dramatic neuronal rescue with prolonged selective head cooling after isch- 19 20 ● The ongoing TOBY, ICE, and other hypothermia tri- emia in fetal lambs. J Clin Invest 1997;99:248-56. als need to be completed to enhance our understanding of 6. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. the role of hypothermia in perinatal asphyxia. Neuroprotection with prolonged head cooling before post ischemic seizures ● Scientists planning future trials may wish to consider protocol in fetal sheep. Pediatrics 1998;102:1098-106. 7. Bona E, Hagberg H, Loberg EM, Bagenholm R, Thoresen M. Pro- designs similar to the ones already implemented so that spe- tective effects of moderate hypothermia after neonatal hypoxia- ischemia: cific questions can be answered, and the results can be sys- short- and long-term outcome. Pediatr Res 1998;43:738-45. tematically compared with the existing experience. 8. Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral ● There is an urgent need for national and international regis- hypothermia is not neuroprotective when started after post ischemic seizures tries to enable ongoing collection of data on perinatal enceph- in fetal sheep. Pediatr Res 1999;46:274-80. 9. Laptook AR, Shalak L, Corbett RJ. Differences in brain temperature alopathy, its treatments, and long-term outcomes. and cerebral blood flow during selective head versus whole body cooling. ● The formation of international interest groups is highly Pediatrics 2001;108:1103-10. recommended along the models of pediatric oncology 10. Wagner BP, Nedelcu J, Martin E. Delayed postischemic hypothermia groups. Such groups might periodically evaluate the status improves long-term behavioral outcome after cerebral hypoxia-ischemia in of hypothermia and other treatment modalities for perina- neonatal rats. Pediatr Res 2002;51:354-60. 11. Tooley JR, Satas S, Porter H, Silver IA, Thoresen M. Head cooling tal HIE. with mild systemic hypothermia in anesthetized piglets is neuroprotective. ● Institutions offering hypothermia in non-research settings also Ann Neurol 2003;53:65-72. need to document clinical data in a systematic way and ensure 12. Roelfsema V, Bennet L, George S, Wu D, Guan J, Veerman M, Gunn long-term follow-up of treated infants using standardized AJ. Window of opportunity of cerebral hypothermia for post ischemic white matter injury in the near term fetal sheep. J Cereb Blood Flow Metab 2004; follow-up protocols developed by centers conducting hypo- 24:877-86. thermia trials and preferably submit information to registries. 13. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborns infants after perinatal asphyxia: a safety study. Pediatrics 1998; SUMMARY AND CONCLUSIONS 102:885-92. 14. Azzopardi A, Robertson NJ, Cowan FM, Rutherford MA, Rampling Based on the available data and large knowledge gaps, the M, Edwards AD. Pilot study of treatment with whole body hypothermia for expert panel suggested that although hypothermia appears to be neonatal encephalopathy. Pediatrics 2000;106:684-94. a potentially promising therapy for HIE, long-term efficacy and 15. Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infant with hypoxic-ischemic enceph- safety are yet to be established. Clinicians choosing to offer this alopathy. Pediatrics 2000;106:92-9. treatment should therefore understand all of the limitations of 16. Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, the available evidence, be prepared to keep up-to-date on evi- Fanaroff AA, et al. Whole-body hypothermia for neonatal encephalopathy: dence on this topic as it evolves, and counsel parents and family animal observations as a basis for a randomized, controlled pilot study in term about the limitations of the current evidence. infants. Pediatrics 2002;110:377-85. 17. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Addendum: Following the workshop, it was brought to Ferriero DM, et al. Selective head cooling with mild systemic hypothermia the attention of the participants that another whole-body after neonatal encephalopathy: multicenter randomized trial. Lancet cooling trial is ongoing and can be found at http://www. 2005;365:663-70. neonatal-research.at/php/detail.php?artnrϭ4367&ukatnr 18. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, ϭ11237&ukatnameϭDepartment&PHPSESSIDϭ55f Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic- ischemic encephalopathy. N Engl J Med 2004;353:1574-1584. 5686510032ad446fa93f0ea37379f. 19. TOBY Trial. http://www.npeu.ox.ac.uk/toby/ 20. Jacobs SE, Stewart M, Inder TE, Doyle L, Morley C. Feasibility We acknowledge the support of NIH Office of Rare Diseases; the Amer- of a pragmatic randomised controlled trial of whole body cooling for ican Academy of Pediatrics; Royal College of Pediatrics and Child term newborns with hypoxic-ischaemic encephalopathy. December 9–10,

174 Higgins et al The Journal of Pediatrics • February 2006 2002 Hot Topics in Neonatology Meetings Proceedings; Washing- 25. Nakamura T, Miyamoto O, Sumitani K, Negi T, Itano T, Nagao S. Do ton, D.C. rapid systemic changes of brain temperature have an influence on the brain? 21. Palmer C, Roberts RL, Young PL. Timing of neutrophil depletion Acta Neurochir (Wien) 2003;145:301-7. influences long term neuroprotection in neonatal rat hypoxic-ischemic brain 26. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kauf- injury. Pediatr Res 2004;55:549-56. man DA, et al. Moderate hypothermia in neonatal encephalopathy: efficacy 22. Yager JY. Animal models of hypoxic-ischemic brain damage in the outcomes. Pediatr Neurol 2005;32:11-7. newborn. Semin Pediatr Neurol 2004;11:31-46. 27. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kauf- 23. McLean, C, Ferriero, DM. Mechanisms of hypoxic-ischemic injury in man DA, et al. Moderate hypothermia in neonatal encephalopathy: safety the term infant. Semin Perinatol 2004;28:425-32. outcomes. Pediatr Neurol 2005;32:18-24. 24. Eshel G, Reisler G, Berkovitch N, Shapira S, Grauer E. Barr J. 28. Gunn AJ, Gluckman PD, Wyatt JS, Thoresen M, Edwards AD, on Comparison of fast versus slow rewarming following acute moderate hypo- behalf of the CoolCap Study Group. Selective head cooling after neonatal thermia in rats. Paediatr Anaesth 2002;12:235-42. encephalopathy. Lancet 2005;365:1619-20.

50 Years Ago in The Journal of Pediatrics

APSYCHOSOMATIC STUDY OF FIVE CHILDREN WITH DUODENAL ULCER Chapman AH, Loeb DG, Young JB. JPediatr 1956; 48: 248-61

The understanding of duodenal ulcer (DU) pathophysiology, and much of gastric peptic disease, has been revolu- tionized in the last 50 years. Chapman and colleagues published descriptions of 5 children with symptomatic DU and associated the findings with detailed descriptions of the patient’s under-privileged living conditions and maladaptive psychological states. They correctly differentiated these cases of DU from those seen in patients with severe physiological stress, such as those with burns and major trauma. They reference other authors who also suggested associations between DU and various psychological conditions. However, new evidence has demonstrated something that these physicians could not have guessed and had no way to investigate–these patients with DU most likely had an infectious disease. A myriad of basic science and clinical studies, since the first report by Warren and Marshall in 1983, have shown that 90-100% of DU cases in children are associated with, and are likely caused by, concurrent gastric infection with Helicobacter pylori. Although detailed knowledge of the pathophysiological cascade remains incomplete, it is evident that H. pylori can cause a chronic infection of the human gastric epithelium, incite an inflammatory response that produces a nodular, chronic gastritis, and elaborates toxins, which, in the presence of acid, are responsible of mucosal ulceration in the duodenum. H. pylori infection, which likely involves fecal-oral transmission, is known to be associated with poor sanitation, low socioeconomic conditions, infected family members, and residential institutions. The report by Chapman emphasizes many of these social problems; it also notes that parents with a history of DU live in the home. Studies of H. pylori-associated DU have shown a recurrence rate of at least 50% when H. pylori is not eradicated, but no recurrence when eradication is complete. The patients reported by Chapman, who were treated with antacids but not antibiotics, had chronic symptoms and long courses of recovery. Given the knowledge that ulcer disease is infectious, we now have the perspective to question the role of chronic pain in the development of psychopathology. Although this has been incompletely addressed for ulcer disease, it is well known that patients with inflammatory bowel disease who are burdened with chronic pain and difficult gastrointestinal symptoms have higher rates of depression and other psychosocial problems. Let this be a cautionary tale to continue questioning the causes of our patients’ ills, even when we think we know the answer. Jeffrey H. Teckman, MD Associate Professor of Pediatrics Chief, Pediatric Gastroenterology and Hepatology St. Louis University Cardinal Glennon Children’s Hospital St. Louis, MO 63104 YMPD2045 10.1016/j.jpeds.2006.01.030

Hypothermia And Perinatal Asphyxia: Executive Summary Of The NICHD Workshop 175 APPENDIX. of South Carolina, Charleston, South Carolina; Alan H. Workshop speakers, discussants, and moderators Jobe, MD, PhD, Cincinnati Children’s Hospital Medical Duane Alexander, MD, National Institute of Child Center, Cincinnati, Ohio; Abbot R. Laptook, MD, Health and Human Development (NICHD), Bethesda, Women & Infants Hospital, Providence, Rhode Island; Maryland; Denis Victor Azzoparki, MD, FRCP, Michael H. LeBlanc, MD, University Medical Center, Imperial College London, London, United Kingdom; Jackson, Mississippi; Charles Palmer, MB ChB, Milton Lillian R. Blackmon, MD, FAAP, University of Mary- S. Hershey Medical Center, Pennsylvania State University land Medical School, Baltimore, Maryland; Kenneth Carr, College of Medicine, Hershey, Pennsylvania; Jeffrey M. PhD, Meridian Medical Systems, Ayer, Massachusetts; Perlman, MB ChB, Weil Medical College at Cornell Reese H. Clark, MD, Pediatrix Medical Group, Inc., University, New York, New York; Tonse N. K. Raju, Sunrise, Florida; A. David Edwards, F Med Sci, Imperial MD, DCH, NICHD, Bethesda, Maryland; Seetha College of London, London, United Kingdom; Donna M. Shankaran, MD, Wayne State University School of Ferriero, MD, University of California, San Francisco, Medicine, Detroit, Michigan; Roger F. Soll, MD, California; Peter D. Gluckman, MBChB, FRS, Liggins Fletcher Allen Health Care, Burlington, Vermont; Institute, University of Auckland, Auckland, New Zea- Catherine Y. Spong, MD, NICHD, Bethesda, Maryland; land; Alistair J. Gunn, MBChB, PhD, University Ann R. Stark, MD, Baylor College of Medicine, Texas of Auckland, Auckland, New Zealand; James Hanson, Children’s Hospital, Houston, Texas; Marianne MD, NICHD, Bethesda, Maryland; Rosemary D. Hig- Thoresen, MD, University of Bristol, St. Michael’s gins, MD, NICHD, Bethesda, Maryland; Susan E. Hospital, Bristol, United Kingdom; John Wyatt, MD, Jacobs, MD, Royal Women’s Hospital, Victoria, Austra- University College of London, London, United lia; Dorothea Jenkins Eicher, MD, Medical University Kingdom.

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