Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial

Abstract

In 2005, the Lancet Neonatal Survival Series1Lawn JE Cousens S Zupan J for the Lancet Neonatal Survival Steering Team4 million neonatal deaths: When? Where? Why?.Lancet. 2005; 365: 891-900Summary Full Text Full Text PDF PubMed Scopus (2562) Google Scholar highlighted the fact that 4 million babies die in the neonatal period; 99% of these deaths arise in low-income and middle-income countries. Globally, 23% of neonatal deaths are directly related to birth asphyxia;1Lawn JE Cousens S Zupan J for the Lancet Neonatal Survival Steering Team4 million neonatal deaths: When? Where? Why?.Lancet. 2005; 365: 891-900Summary Full Text Full Text PDF PubMed Scopus (2562) Google Scholar additionally, birth asphyxia leads to a substantial burden of long-term neurological disability and impairment.In the developed world, trials in term babies have suggested that therapeutic hypothermia (whole-body cooling2Shankaran S Laptook AR Ehrenkranz RA et al.for the National Institute of Child Health and Human Development (NICHD) Neonatal Research NetworkWhole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.N Engl J Med. 2005; 353: 1574-1584Crossref PubMed Scopus (2084) Google Scholar for 72 h to a core temperature of 33·5°C or selective head cooling and mild body cooling3Gluckman PD Wyatt JS Azzopardi D et al.Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.Lancet. 2005; 365: 663-670Summary Full Text Full Text PDF PubMed Scopus (1793) Google Scholar) is effective and safe as a treatment for neonatal encephalopathy caused by birth asphyxia. Three systematic reviews4Jacobs S Hunt R Tarnow-Mordi W Inder T Davis P Cooling for newborns with hypoxic ischaemic encephalopathy.Cochrane Database Syst Rev. 2007; 4 (CD003311.)Google Scholar, 5Shah P Ohlsson A Perlman M Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review.Arch Pediatr Adolesc Med. 2007; 161: 951-958Crossref PubMed Scopus (149) Google Scholar, 6Schulzke S Rao S Patole S A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy—are we there yet?.BMC Pediatr. 2007; 5: 30Crossref Scopus (103) Google Scholar concluded that therapeutic hypothermia can significantly reduce death and medium-term disability after neonatal encephalopathy and that it is safe in an intensive-care setting.It is essential, however, that the risks and benefits of therapeutic hypothermia are systematically assessed in low-resource settings. Differences specific to such settings include: (i) impaired maternal nutrition, inadequate maternal pelvis size, poor obstetric care, and a high incidence of obstructed labour; (ii) lack of skilled personnel and basic equipment for optimum neonatal resuscitation; (iii) lack of ventilatory support in neonatal units; (iv) high rate of HIV and puerperal sepsis and possible neutrophil compromise due to hypothermia; (v) high incidence of “natural” cooling; (vi) different facilities for disabled children; and (vii) the unrealistic cost of the cooling equipment used in affluent countries. Attempts at developing low-tech cooling methods have not been successful so far.7Horn A Woods D Thompson C Eis I Kroon M Selective cerebral hypothermia for post-hypoxic neuroprotection in neonates using a solid ice cap.S Afr Med J. 2006; 96: 976-981PubMed Google ScholarWe aimed to: (i) determine the feasibility of whole-body cooling to 33–34°C for 72 h by use of simple methods in a low-resource setting; and (ii) inform a larger randomised controlled trial in this setting. We also studied the temperature profile over the first 80 h in term infants with neonatal encephalopathy undergoing standard care to assess to what degree infants cool “naturally”.Outcome measures were: (i) rectal temperature during the 72 h of cooling or standard care; (ii) neurological assessment on days 1–4 and on day 17; (iii) clinical seizures; and (iv) death before discharge from hospital. There were no power calculations in this pilot phase since this was a convenience sample to inform power calculations for the main trial, and there were no interim analyses or stopping rules. The local ethics committee (Makerere University Medical School) approved the study.The study was done at Mulago Hospital, Kampala, Uganda, between July 27, 2007, and Oct 31, 2007. After written informed parental consent (requested in both English and Luganda), infants were randomly assigned standard care plus therapeutic hypothermia or standard care alone within 3 h of birth. Randomisation was done with sealed envelopes in consecutive eligible infants up to a total of four study infants at a time. The allocation sequence was generated by the UK-based study team and assignment was done by the Uganda-based team. For this pilot phase a simple 1:1 randomisation with no stratification or restrictions was used. Analysis was by intention to treat.Inclusion criteria were: gestational age at birth 37 weeks or more, requirement for resuscitation, and/or Apgar score less than 6 at 5 min plus an abnormal neurological assessment (>5 on Thompson score8Thompson CM Puterman AS Linley LL et al.The value of a scoring system for hypoxic-ischaemic encephalopathy in predicting neurodevelopmental outcome.Acta Pediatr. 1997; 86: 757-761Crossref PubMed Scopus (271) Google Scholar) from 30 min to 3 h after birth. Exclusions included apnoea or cyanosis, absent cardiac output for more than 10 min after birth, and birthweight less than 2 kg.Infants in the therapeutic hypothermia group underwent whole-body cooling with a mattress made of three commercially available water bottles (cost about US$10) laid sideways in the cot and filled with cool water from the tap in the neonatal unit; cooling with this simple method had been previously validated in animals.9Iwata S, Iwata O, Olson L, et al. Therapeutic hypothermia can be induced and maintained using either commercial water bottles or a “phase changing material” mattress in a newborn piglet model. Arch Dis Child Fetal Neonatal Ed (in press).Google Scholar Infants wore only a nappy (diaper) and were otherwise naked or wrapped in cotton sheets or blankets. The tap water and ambient temperature of the neonatal unit had been measured previously; both were constant at 25–26°C with minimum diurnal or seasonal variation. The core (rectal) temperature was maintained within target range (33–34°C) by adding or removing sheets, blankets, or water bottles. The rectal, axillary, and ambient temperatures were recorded continuously with multichannel data loggers (Grant instruments, UK).Encephalopathy severity was graded with the Thompson score on days 1, 2, 3, and 4. The more widely used Sarnat stage was assessed on day 3 (ie, when worsening neurological signs indicative of progression of neonatal encephalopathy usually peak). Clinical seizures were diagnosed by nursing and medical staff as paroxysmal alterations in motor or autonomic function and included clonic, tonic, and subtle seizure manifestations. A full neurological examination with a structured, scorable assessment was done at follow-up on day 17 (total maximum score 34, optimum 30·5–34·0 based on British norms);10Dubowitz L Mercuri E Dubowitz V An optimality score for the neurologic examination of the term newborn.J Pediatr. 1998; 133: 406-416Summary Full Text Full Text PDF PubMed Scopus (141) Google Scholar these assessments were done without knowledge of the random allocation group. The infants were brought back to Mulago hospital for clinic review if they had already been discharged from hospital. Further follow-up at 12–18 months is planned as part of this pilot feasibility study.During the 3-month study period, there were 4957 deliveries, of which 419 were stillborn. 110 term infants with neonatal encephalopathy were admitted to the neonatal unit and screened. The encephalopathy was too severe for inclusion in 55 infants and too mild in six. Six infants were too old, informed consent was not possible in two owing to the postanaesthetic conscious state of the mother and no other available relative, three infants were not enrolled owing to staff shortages, and the remaining two infants were less than 2 kg in birthweight. 36 infants were thus eligible for study inclusion. 21 were assigned therapeutic hypothermia and 15 standard care. Baseline characteristics are shown in the table.TableBaseline characteristics and outcomes of babies with neonatal encephalopathy assigned therapeutic hypothermia or standard careTherapeutic hypothermia (n=21)Standard care (n=15)Baseline characteristicsMaternal age (years)22·9 (4·9)21·5 (4·0)Primigravida (n)1110HIV positive mother32Mode of delivery (n)In-labour caesarean section43Vaginal delivery (cephalic)1512Vaginal delivery (breech)20Gestational age at birth (weeks)38 (1·45)38 (1·38)Birthweight (g)3300 (550)3200 (268)Apgar score at 5 min4·75·2Age at randomisation (min)115 (35)99·4 (29)Rectal temp at randomisation (°C)33·66 (1·04)34·43(1·12)Thompson score at randomisation9 (2·28)9 (1·78)OutcomesMean rectal temp over 72 h (°C)33·62 (0·69)36·29(0·64)Seizures day 2 (n)62Seizures day 3 (n)62Abnormal neurological exam day 17 (n)8*n=12.4†n=5.Length of hospital stay (days)8·0 (2·3)7·3 (1·3)Deaths (n)Total71Sarnat stage I0/50/4Sarnat stage II1/100/10Sarnat stage III6/61/1Data are mean (SD) unless otherwise stated.* n=12.† n=5. Open table in a new tab The rectal temperature was hypothermic in both the therapeutic hypothermia and standard care groups at randomisation. It took a mean of 15·6 h (SD 14·6) for the rectal temperature to reach normothermia (defined as ≥36·5°C) in the standard care group by standard methods (swaddling and gloves filled with warm water). Despite the “natural” cooling in the standard care group, the mean rectal temperature over 72 h was lower in the therapeutic hypothermia group than in the standard care group (mean difference −2·66°C, 95% CI −3·12 to −2·20; p<0·0001; table, figure).Eight infants died before discharge from hospital: seven in the therapeutic hypothermia group and one in the standard care group (table). The median age of death was 75 h (range 34–144). Infection could have contributed to two of the deaths, although the cause is difficult to validate because no blood cultures or blood indices suggestive of infection were available.Although Thompson scores were similar between groups at randomisation and on day 1, there were more seizures in the therapeutic hypothermia group than in the standard care group on days 2 and 3 (table). There were more infants with Sarnat stage III in the therapeutic hypothermia group than in the standard care group; nevertheless the proportion of deaths according to Sarnat stage was similar across groups (table). Indeed, evidence from Nepal has shown that, in settings where long-term ventilation and stabilisation are not available, the mortality rate for infants with Sarnat stage III neonatal encephalopathy is 100%.11Ellis M Manandhar N Manandhar D Costello A Risk factors for neonatal encephalopathy in Kathmandu, Nepal, a developing country: unmatched case control study.BMJ. 2000; 320: 1229-1236Crossref PubMed Scopus (108) Google ScholarOur data suggest that therapeutic hypothermia with whole-body cooling, screening, informed consent, and randomisation are feasible and inexpensive in a special-care baby unit in a low-resource setting. Rigorous randomised trials to determine the safety and efficacy of therapeutic hypothermia in this context are urgently needed so that any benefits of this novel therapy can reach areas of the world that might need it most.Such trials will need to consider several points. First, the natural cooling in babies receiving standard care alone is consistent with historical data12Burnard ED Cross KW Rectal temperature in the newborn after birth asphyxia.BMJ. 1958; 2: 1197-1199Crossref PubMed Scopus (77) Google Scholar and implies that any power calculation would need to take into consideration a “dilution of the hypothermic effect” in the cooled group by the standard care group, since natural cooling could be an endogenous neuroprotective response. Second, any future randomised controlled trial might need to consider a-priori stratification on the basis of severity of neonatal encephalopathy at randomisation. Third, more precise methods to differentiate infection-related from encephalopathy-related deaths are required. Finally, any future randomised trial would need strict stopping rules about mortality rates agreed by a data-safety-monitoring board.On the basis of these results we now plan to initiate such a trial including Mulago Hospital and other centres in developing countries.This project was initiated as part of the Uganda Women's Health Initiative (UWHI) involving the University College London Institute for Women's Health, Mulago Hospital, Makerere University, and Hospice Africa, Uganda. We are grateful to Graham Evans (Project Manager UWHI) for his support and guidance. The UWHI and this project were supported by generous donations from Lee and Roger Myers and Ann-Margaret and John Walton. These funding sources had no involvement in study design, collection, analysis, and interpretation of data in the writing of report or the decision to submit the letter for publication. We declare that we have no conflict of interest. In 2005, the Lancet Neonatal Survival Series1Lawn JE Cousens S Zupan J for the Lancet Neonatal Survival Steering Team4 million neonatal deaths: When? Where? Why?.Lancet. 2005; 365: 891-900Summary Full Text Full Text PDF PubMed Scopus (2562) Google Scholar highlighted the fact that 4 million babies die in the neonatal period; 99% of these deaths arise in low-income and middle-income countries. Globally, 23% of neonatal deaths are directly related to birth asphyxia;1Lawn JE Cousens S Zupan J for the Lancet Neonatal Survival Steering Team4 million neonatal deaths: When? Where? Why?.Lancet. 2005; 365: 891-900Summary Full Text Full Text PDF PubMed Scopus (2562) Google Scholar additionally, birth asphyxia leads to a substantial burden of long-term neurological disability and impairment. In the developed world, trials in term babies have suggested that therapeutic hypothermia (whole-body cooling2Shankaran S Laptook AR Ehrenkranz RA et al.for the National Institute of Child Health and Human Development (NICHD) Neonatal Research NetworkWhole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.N Engl J Med. 2005; 353: 1574-1584Crossref PubMed Scopus (2084) Google Scholar for 72 h to a core temperature of 33·5°C or selective head cooling and mild body cooling3Gluckman PD Wyatt JS Azzopardi D et al.Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.Lancet. 2005; 365: 663-670Summary Full Text Full Text PDF PubMed Scopus (1793) Google Scholar) is effective and safe as a treatment for neonatal encephalopathy caused by birth asphyxia. Three systematic reviews4Jacobs S Hunt R Tarnow-Mordi W Inder T Davis P Cooling for newborns with hypoxic ischaemic encephalopathy.Cochrane Database Syst Rev. 2007; 4 (CD003311.)Google Scholar, 5Shah P Ohlsson A Perlman M Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review.Arch Pediatr Adolesc Med. 2007; 161: 951-958Crossref PubMed Scopus (149) Google Scholar, 6Schulzke S Rao S Patole S A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy—are we there yet?.BMC Pediatr. 2007; 5: 30Crossref Scopus (103) Google Scholar concluded that therapeutic hypothermia can significantly reduce death and medium-term disability after neonatal encephalopathy and that it is safe in an intensive-care setting. It is essential, however, that the risks and benefits of therapeutic hypothermia are systematically assessed in low-resource settings. Differences specific to such settings include: (i) impaired maternal nutrition, inadequate maternal pelvis size, poor obstetric care, and a high incidence of obstructed labour; (ii) lack of skilled personnel and basic equipment for optimum neonatal resuscitation; (iii) lack of ventilatory support in neonatal units; (iv) high rate of HIV and puerperal sepsis and possible neutrophil compromise due to hypothermia; (v) high incidence of “natural” cooling; (vi) different facilities for disabled children; and (vii) the unrealistic cost of the cooling equipment used in affluent countries. Attempts at developing low-tech cooling methods have not been successful so far.7Horn A Woods D Thompson C Eis I Kroon M Selective cerebral hypothermia for post-hypoxic neuroprotection in neonates using a solid ice cap.S Afr Med J. 2006; 96: 976-981PubMed Google Scholar We aimed to: (i) determine the feasibility of whole-body cooling to 33–34°C for 72 h by use of simple methods in a low-resource setting; and (ii) inform a larger randomised controlled trial in this setting. We also studied the temperature profile over the first 80 h in term infants with neonatal encephalopathy undergoing standard care to assess to what degree infants cool “naturally”. Outcome measures were: (i) rectal temperature during the 72 h of cooling or standard care; (ii) neurological assessment on days 1–4 and on day 17; (iii) clinical seizures; and (iv) death before discharge from hospital. There were no power calculations in this pilot phase since this was a convenience sample to inform power calculations for the main trial, and there were no interim analyses or stopping rules. The local ethics committee (Makerere University Medical School) approved the study. The study was done at Mulago Hospital, Kampala, Uganda, between July 27, 2007, and Oct 31, 2007. After written informed parental consent (requested in both English and Luganda), infants were randomly assigned standard care plus therapeutic hypothermia or standard care alone within 3 h of birth. Randomisation was done with sealed envelopes in consecutive eligible infants up to a total of four study infants at a time. The allocation sequence was generated by the UK-based study team and assignment was done by the Uganda-based team. For this pilot phase a simple 1:1 randomisation with no stratification or restrictions was used. Analysis was by intention to treat. Inclusion criteria were: gestational age at birth 37 weeks or more, requirement for resuscitation, and/or Apgar score less than 6 at 5 min plus an abnormal neurological assessment (>5 on Thompson score8Thompson CM Puterman AS Linley LL et al.The value of a scoring system for hypoxic-ischaemic encephalopathy in predicting neurodevelopmental outcome.Acta Pediatr. 1997; 86: 757-761Crossref PubMed Scopus (271) Google Scholar) from 30 min to 3 h after birth. Exclusions included apnoea or cyanosis, absent cardiac output for more than 10 min after birth, and birthweight less than 2 kg. Infants in the therapeutic hypothermia group underwent whole-body cooling with a mattress made of three commercially available water bottles (cost about US$10) laid sideways in the cot and filled with cool water from the tap in the neonatal unit; cooling with this simple method had been previously validated in animals.9Iwata S, Iwata O, Olson L, et al. Therapeutic hypothermia can be induced and maintained using either commercial water bottles or a “phase changing material” mattress in a newborn piglet model. Arch Dis Child Fetal Neonatal Ed (in press).Google Scholar Infants wore only a nappy (diaper) and were otherwise naked or wrapped in cotton sheets or blankets. The tap water and ambient temperature of the neonatal unit had been measured previously; both were constant at 25–26°C with minimum diurnal or seasonal variation. The core (rectal) temperature was maintained within target range (33–34°C) by adding or removing sheets, blankets, or water bottles. The rectal, axillary, and ambient temperatures were recorded continuously with multichannel data loggers (Grant instruments, UK). Encephalopathy severity was graded with the Thompson score on days 1, 2, 3, and 4. The more widely used Sarnat stage was assessed on day 3 (ie, when worsening neurological signs indicative of progression of neonatal encephalopathy usually peak). Clinical seizures were diagnosed by nursing and medical staff as paroxysmal alterations in motor or autonomic function and included clonic, tonic, and subtle seizure manifestations. A full neurological examination with a structured, scorable assessment was done at follow-up on day 17 (total maximum score 34, optimum 30·5–34·0 based on British norms);10Dubowitz L Mercuri E Dubowitz V An optimality score for the neurologic examination of the term newborn.J Pediatr. 1998; 133: 406-416Summary Full Text Full Text PDF PubMed Scopus (141) Google Scholar these assessments were done without knowledge of the random allocation group. The infants were brought back to Mulago hospital for clinic review if they had already been discharged from hospital. Further follow-up at 12–18 months is planned as part of this pilot feasibility study. During the 3-month study period, there were 4957 deliveries, of which 419 were stillborn. 110 term infants with neonatal encephalopathy were admitted to the neonatal unit and screened. The encephalopathy was too severe for inclusion in 55 infants and too mild in six. Six infants were too old, informed consent was not possible in two owing to the postanaesthetic conscious state of the mother and no other available relative, three infants were not enrolled owing to staff shortages, and the remaining two infants were less than 2 kg in birthweight. 36 infants were thus eligible for study inclusion. 21 were assigned therapeutic hypothermia and 15 standard care. Baseline characteristics are shown in the table. Data are mean (SD) unless otherwise stated. The rectal temperature was hypothermic in both the therapeutic hypothermia and standard care groups at randomisation. It took a mean of 15·6 h (SD 14·6) for the rectal temperature to reach normothermia (defined as ≥36·5°C) in the standard care group by standard methods (swaddling and gloves filled with warm water). Despite the “natural” cooling in the standard care group, the mean rectal temperature over 72 h was lower in the therapeutic hypothermia group than in the standard care group (mean difference −2·66°C, 95% CI −3·12 to −2·20; p<0·0001; table, figure). Eight infants died before discharge from hospital: seven in the therapeutic hypothermia group and one in the standard care group (table). The median age of death was 75 h (range 34–144). Infection could have contributed to two of the deaths, although the cause is difficult to validate because no blood cultures or blood indices suggestive of infection were available. Although Thompson scores were similar between groups at randomisation and on day 1, there were more seizures in the therapeutic hypothermia group than in the standard care group on days 2 and 3 (table). There were more infants with Sarnat stage III in the therapeutic hypothermia group than in the standard care group; nevertheless the proportion of deaths according to Sarnat stage was similar across groups (table). Indeed, evidence from Nepal has shown that, in settings where long-term ventilation and stabilisation are not available, the mortality rate for infants with Sarnat stage III neonatal encephalopathy is 100%.11Ellis M Manandhar N Manandhar D Costello A Risk factors for neonatal encephalopathy in Kathmandu, Nepal, a developing country: unmatched case control study.BMJ. 2000; 320: 1229-1236Crossref PubMed Scopus (108) Google Scholar Our data suggest that therapeutic hypothermia with whole-body cooling, screening, informed consent, and randomisation are feasible and inexpensive in a special-care baby unit in a low-resource setting. Rigorous randomised trials to determine the safety and efficacy of therapeutic hypothermia in this context are urgently needed so that any benefits of this novel therapy can reach areas of the world that might need it most. Such trials will need to consider several points. First, the natural cooling in babies receiving standard care alone is consistent with historical data12Burnard ED Cross KW Rectal temperature in the newborn after birth asphyxia.BMJ. 1958; 2: 1197-1199Crossref PubMed Scopus (77) Google Scholar and implies that any power calculation would need to take into consideration a “dilution of the hypothermic effect” in the cooled group by the standard care group, since natural cooling could be an endogenous neuroprotective response. Second, any future randomised controlled trial might need to consider a-priori stratification on the basis of severity of neonatal encephalopathy at randomisation. Third, more precise methods to differentiate infection-related from encephalopathy-related deaths are required. Finally, any future randomised trial would need strict stopping rules about mortality rates agreed by a data-safety-monitoring board. On the basis of these results we now plan to initiate such a trial including Mulago Hospital and other centres in developing countries. This project was initiated as part of the Uganda Women's Health Initiative (UWHI) involving the University College London Institute for Women's Health, Mulago Hospital, Makerere University, and Hospice Africa, Uganda. We are grateful to Graham Evans (Project Manager UWHI) for his support and guidance. The UWHI and this project were supported by generous donations from Lee and Roger Myers and Ann-Margaret and John Walton. These funding sources had no involvement in study design, collection, analysis, and interpretation of data in the writing of report or the decision to submit the letter for publication. We declare that we have no conflict of interest.