Should We Abandon Therapeutic Hypothermia for Neonatal Encephalopathy in Low and Middle-Income Countries?

December 16, 2021

MANUSCRIPT CITATION

Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P, Bassett P, Swamy R, Mendoza J, Moreno-Morales M, Lally PJ, Benakappa N, Bandiya P, Shivarudhrappa I, Somanna J, Kantharajanna UB, Rajvanshi A, Krishnappa S, Joby PK, Jayaraman K, Chandramohan R, Kamalarathnam CN, Sebastian M, Tamilselvam IA, Rajendran UD, Soundrarajan R, Kumar V, Sudarsanan H, Vadakepat P, Gopalan K, Sundaram M, Seeralar A, Vinayagam P, Sajjid M, Baburaj M, Murugan KD, Sathyanathan BP, Kumaran ES, Mondkar J, Manerkar S, Joshi AR, Dewang K, Bhisikar SM, Kalamdani P, Bichkar V, Patra S, Jiwnani K, Shahidullah M, Moni SC, Jahan I, Mannan MA, Dey SK, Nahar MN, Islam MN, Shabuj KH, Rodrigo R, Sumanasena S, Abayabandara-Herath T, Chathurangika GK, Wanigasinghe J, Sujatha R, Saraswathy S, Rahul A, Radha SJ, Sarojam MK, Krishnan V, Nair MK, Devadas S, Chandriah S, Venkateswaran H, Burgod C, Chandrasekaran M, Atreja G, Muraleedharan P, Herberg JA, Kling Chong WK, Sebire NJ, Pressler R, Ramji S, Shankaran S; HELIX consortium. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. Lancet Glob Health. 2021 Sep;9(9):e1273-e1285. doi: 10.1016/S2214-109X(21)00264-3. Epub 2021 Aug 3. PMID: 34358491.

REVIEWED BY

Nehad Nasef
Professor of Pediatrics,
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital, Mansoura, Egypt.

Islam Nour
Associate Professor of Pediatrics,
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital, Mansoura, Egypt.

Hesham Abdel-Hady
Professor of Pediatrics,
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital, Mansoura, Egypt.

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In neonates born in low-income and middle-income countries at or after 36 completed weeks’ gestation with moderate to severe HIE, (I) does therapeutic hypothermia that is initiated within 6 hours of birth and continued for 72 h (C) compared to normothermia, (O) reduce death or disability (T) at 18–22 months.

METHODS

  • Design: Randomized controlled, open label, multicenter trial, 7 neonatal intensive care units in India, Sri Lanka, and Bangladesh.
  • Allocation: Infants were randomly assigned (1:1) with a computer-generated web-based randomization system. The minimization method was used to minimize the imbalance in the number of infants assigned to each group across multiple prognostic factors (encephalopathy stage and study center), with a probability of 0·85 of being assigned to the treatment group.
  • Blinding: Parents and caregivers were not blinded; magnetic resonance (MR) biomarker analysis and neurodevelopmental outcome assessors were masked to the allocation.
  • Follow-up period: Until death or at 18-22 months of age.
  • Setting: Hospital setting.
  • Patients:
    • Inclusion criteria: Neonates delivered at or after 36 completed weeks’ gestation with moderate to severe HIE with a birth weight ≥1.8 kg who had been admitted to the neonatal unit within 6 h of birth. Eligibility criteria were: (1) evidence of perinatal depression as following: continued need for resuscitative efforts at 5 min of age; and/or 5 minute Apgar score of less than 6 (for babies born in a hospital); or an absence of crying by 5 min of age (for babies born at home); and (2) moderate/ severe encephalopathy within the first 6 hours of age according to modified Sarnat staging done by a certified examiner after admission to the neonatal unit.
    • Exclusion criteria: Absent heart rate at 10 min of age despite adequate resuscitation, or major life-threatening congenital malformations. Furthermore, infants of parents who were unable to attend follow-up assessments were considered ineligible.
  • Intervention:
    • Neonates in the hypothermia group underwent therapeutic hypothermia with the use of a servo controlled whole-body cooling device to a core temperature of 33.5 ° C for a period of 72 hours followed by gradual re-warming at a rate of 0.5° C per hour, whereas passive cooling before NICU admission was not permitted.
    • In the control group, normothermia was maintained with avoidance of iatrogenic hyperthermia.
    • In both groups, neonates received a standardized intensive supportive care (only one center had a facility for inhaled nitric oxide).
  • Outcomes:
    • Primary outcome: Combined endpoint of death or a moderate or severe disability at 18–22 months of age, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination.
    • Secondary outcomes: death before hospital discharge, a major intracranial hemorrhage on cranial ultrasonography, gastric bleeds, persistent hypotension, a pulmonary hemorrhage, persistent pulmonary hypertension, prolonged blood coagulation requiring blood products (abnormal increase in coagulation tests as per the local laboratory standards), culture-proven early-onset sepsis, necrotizing enterocolitis, cardiac arrhythmia, severe thrombocytopenia, persistent metabolic acidosis, pneumonia, renal failure, subcutaneous fat necrosis, an abnormal neurological examination at discharge, duration of the hospital stay, death from any cause at 18 months, severe disability among those who survived, and microcephaly, assessed at 18–22 months. Furthermore, exploratory MRI biomarker outcomes included brain injury scores on a conventional MRI; thalamic N-acetyl aspartate (NAA) concentrations; lactate: NAA, NAA: creatine, and NAA: choline peak area ratios; and whole brain white matter fractional anisotropy. Exploratory neurodevelopmental and growth outcomes included moderate disability; survival without disability; Bayley-III cognitive, motor, and language composite scores; persistent seizure disorder; disabling cerebral palsy; gross motor function classification system level; blindness; hearing impairment; severe microcephaly; wasting; and stunting.
  • Analysis and Sample Size:
    • The authors estimated the sample size to be competent to detect a 30% relative risk reduction in the primary outcome between the two groups from 50% in the control group to 35% in the hypothermia group. For this difference to be detected with a power of 80% and a 2-sided significance level 5%, 183 infants in each group had to be enrolled. In addition, with assumption of loss to follow-up of 10%, the size of the study population was estimated to be 204 infants per group. Authors did the primary analysis on an intention-to-treat basis.
  • Patient follow-up:
    • Of 2296 infants assessed for eligibility, 408 were recruited. 202 (49.5%) were allocated to hypothermia group and 206 infants (50.5%) to control group. The primary composite outcome of death or moderate or severe disability was analyzed for 195 and 199 infants, respectively.

MAIN RESULTS

  • The demographic data and clinical characteristics were matched in the 2 groups.
  • Cooling was initiated in the hypothermia group at a median age of 4·30 hours (IQR 1·09–6·00).
  • During the mean rectal temperature was 33·5°C (SD 0·10) in the hypothermic group and 36·7°C (0·06) in the control group.
  • At 24 hours, more infants in the hypothermic group had hyperglycemia and required more inotropic support than did infants in the control group.
  • The primary composite outcome of death or moderate or severe disability occurred in 98 of 195 neonates (50%) in the hypothermia group and 94 of 199 neonates (47%) in the control group (risk ratio 1·06; 95% CI 0·87–1·30; p=0·55).
  • Neonates in the hypothermia group had significantly higher rate of mortality (42% vs. 31%, P = 0.022) and longer duration of hospital stay [16·1 (12·9–23·2) vs. 13·9 (11·0–18·8) days, P = 0.0044] compared with the control group.
  • More infants in the hypothermia group experienced gastric bleeding, persistent hypotension, deranged coagulation, cardiac arrhythmias, severe thrombocytopenia, persistent metabolic acidosis, and death before discharge compared with the control group.
  • Conventional MRI were assessed for 271 infants (123 in the hypothermia group and 148 in the control group. The white matter injury pattern was reported as the as the predominant pattern of injury in both groups 100 (82%) in the hypothermic group and 112 (77%) in the control group had white matter injury (p=0·44).
  • No statistically significant difference between both arms regarding thalamic NAA concentrations, and metabolite peak area ratios and tract-based spatial statistics of white matter fractional anisotropy.

CONCLUSION

The authors conclude that therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, but significantly increased death alone. Therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in low-income and middle-income countries, even when tertiary neonatal intensive care facilities are available.

COMMENTARY

Therapeutic hypothermia (TH) is the standard of care in neonates with moderate and severe hypoxic ischemic encephalopathy (HIE) as it lowers the rates of mortality, cerebral palsy, hearing and visual impairment, and neurodevelopmental delay (1, 2) . The majority of evidence towards the effectiveness and safety of TH has been pooled out from data of well-designed randomized controlled trials which were conducted in high-income countries (3-7). The International Liaison Committee Resuscitation guidelines in 2015 recommendation of using TH in low-income and middle-income countries (LMICs) for neonatal HIE was based on weak evidence (8) . The authors of the HELIX trial questioned the value of TH for HIE in LMICs and found it neither effective nor safe, recommending against its use even if tertiary neonatal intensive care facilities are available (9) . Strengths of the HELIX trial include: it is the largest cooling trial in the world, the only phase III clinical trial in LMICs, and the rigorous research methodology. We question if neonatologists in LMICs should change their practice of providing TH to neonates with moderate or severe HIE considering the result of the HELIX trial?

To answer this question, we will discuss the effectiveness and the safety issues reported by the authors of the HELIX study. Regarding the effectiveness, the HELIX study found that death or disability occurred in 50% of infants in the TH group and 47% of infants in the control group (RR 1·06; 95% CI 0·87–1·30; p=0·55) concluding that TH is ineffective practice in LMICs. The authors did not necessitate the presence of severe metabolic acidosis in the cord or immediate postnatal arterial blood gases as a requirement for defining the evidence of perinatal asphyxia aiming to increase the generalizability of practice in LMICs. This may have resulted in inclusion of more out-born infants with sub-acute or partial prolonged hypoxia, due to deficient prenatal and perinatal care, in whom TH may not be as effective as in infants exposed to acute perinatal asphyxia. This observation was supported by the MRI finding of more white matter injury in infants of the HELIX study, which is suggestive of a sub-acute or partial prolonged hypoxia, compared to more hypothalamic injury and basal ganglia injury, which is suggestive of acute intra-partum asphyxia, in the TOBY and the NICHD trials. Additionally, more than 70% of the infants included in the HELIX trial were born outside the designed centers for the study, which may have impacted their initial stabilization and the timing of initiation of TH, and had early seizure at randomization indicating that TH was probably started after initiation of the secondary phase of injury.

Regarding safety, the HELIX study found that death before 18 months was significantly higher in the TH group compared to control group (number needed to harm = 9). The authors suggested that if mortality increases in selected well-resourced units with high technology devices, it is likely that practicing TH is more harmful in LMICs with low technology deceives and less-resourced settings. The authors attributed that the increased mortality in TH group may be related to hypothermia-induced suppression of hepatic metabolism in infants with an already compromised liver, leading to persistent metabolic acidosis and myocardial depression together with the higher incidence of gastric bleeding, coagulopathy, severe thrombocytopenia, cardiac arrhythmia, persistent metabolic acidosis, and persistent hypotension. We agree that TH should not be provided in LMICs with low technology deceives and less-resourced settings. However, more evidence is needed to evaluate the safety of TH in well-resourced units with high technology devices in LMICs, particularly in neonates with HIE who have no associated morbidity.

In conclusion, TH should not be considered as a standard of therapy in LMICs for infants with HIE who are admitted to centers with low-resourced settings and low-technology devices. A randomized controlled trial to assess the efficacy and safety of TH in infants with HIE due to acute perinatal asphyxia associated with severe metabolic acidosis at birth and sentinel events is urgently needed in LMICs. Until further evidence, it might be too early to abandon the practice of TH in selected tertiary centers with high technology devices of LMICs.

REFERENCES

  1. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013(1):CD003311.
  2. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2012;166(6):558-566.
  3. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365(9460):663-670.
  4. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584.
  5. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361(14):1349-1358.
  6. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165(8):692-700.
  7. Simbruner G, Mittal RA, Rohlmann F, Muche R. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010;126(4):e771-778.
  8. Perlman JM, Wyllie J, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (Reprint). Pediatrics. 2015;136 Suppl 2:S120-166.
  9. Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P, et al. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. Lancet Glob Health. 2021;9(9):e1273-e1285.

 

One Comment

  • Livert Mamani Flores 2 years ago

    Good morning, I do not agree that not performing therapeutic hypothermia should be included as a recommendation for all countries with medium or low resources, since there are many, and several have technology and have good results. Although they are not published, he has experience in performing therapeutic hypothermia.
    My personal opinion is that there is a lack of training and human resources to carry out this work.
    And I know that more in-depth and unbiased studies are needed to have a clearer vision.
    Thank you.
    Atte:
    Dr. Livert mamani Flores
    Neonatologist

  • css.php