Therapeutic Hypothermia Following Perinatal Asphyxia

Summary and Conclusions

SBU’s appraisal of the evidence

During birth, asphyxia occurs when the child suffers a combination of oxygen deficiency and reduced blood supply. In serious cases of asphyxia, the infant can develop symptoms of brain damage shortly following birth, ie, hypoxic ischemic encephalopathy (HIE). In moderate to severe asphyxia the lack of oxygen can cause serious damage to the brain and other organs, and some of the infants die. Children who survive are at higher risk for moderate or severe functional impairments, eg, cerebral palsy (CP) or impaired vision and hearing. Therapeutic hypothermia is a new method for treating HIE following birth asphyxia and is used to complement standard treatment.

• In full-term newborns affected by moderate or severe symptoms of brain injury (HIE) due to severe birth asphyxia, therapeutic hypothermia reduces the risk of death or severe functional impairment in the child (Evidence Grade 2)*. However, the scientific evidence is insufficient* to appraise the method’s effect beyond 18 months.
• The scientific evidence is insufficient* to draw firm conclusions on the adverse effects and complications related to therapeutic hypothermia. No serious adverse effects or complications have been identified in the studies reviewed for this report, but the studies were not specifically designed to investigate this.
• The scientific evidence is insufficient* to draw firm conclusions on the cost-effectiveness of the method. However, the fact that the extra costs for this method are relatively moderate and the outcomes are good would suggest that the method is cost-effective.
• The optimum way (best practice) to deliver treatment is not clear. Hence, it is important to monitor the experiences and outcomes of treatment, eg, via a central quality register. Also, continued research is essential to gain knowledge about best practices as well as the potential complications and adverse effects.

* Criteria for Evidence Grading SBU’s Conclusions
Evidence Grade 1 – Strong Scientific Evidence. The conclusion is corroborated by at least two independent studies with high quality, or a good systematic overview.
Evidence Grade 2 – Moderately Strong Scientific Evidence. The conclusion is corroborated by one study with high quality, and at least two studies with medium quality.
Evidence Grade 3 – Limited Scientific Evidence. The conclusion is corroborated by at least two studies with medium quality.
Insufficient Scientific Evidence – No conclusions can be drawn when there are not any studies that meet the criteria for quality.
Contradictory Scientific Evidence – No conclusions can be drawn when there are studies with the same quality whose findings contradict each other.

Target group and technology

The potential target group for therapeutic hypothermia includes full-term infants who have been affected by moderate or severe symptoms of HIE following serious asphyxia in conjunction with birth. In Sweden, 50 to 200 children per year could be potential candidates for therapeutic hypothermia.

Therapeutic hypothermia involves lowering the child’s body temperature to 33–35 degrees for 72 hours, which can be done by cooling the head only, or the whole body. Afterwards, the child’s body temperature is slowly raised to normal. Treatment requires specially trained staff and special cooling and monitoring devices. In Sweden, therapeutic hypothermia is not an established treatment method for HIE following birth asphyxia in newborns. The method is used, however, in approximately 10 hospitals across Sweden, mostly university hospitals.

Standard treatment for children with HIE is supportive and symptom relieving. Treatment includes neonatal intensive care since several organ systems can fail. During the past decade, clinical studies have shown that therapeutic hypothermia introduced within 6 hours of birth can have a protective effect on the brain.

Primary questions

• What effects does therapeutic hypothermia have on mortality and survival with moderate or severe functional disabilities in full-term infants affected by moderate or severe symptoms of hypoxic ischemic encephalopathy (HIE) following serious birth asphyxia?
• What are the potential complications and adverse effects of treatment?
• What does the treatment cost? Is it cost-effective?

Patient benefit

Three systematic reviews, appraised to be of high quality, show that therapeutic hypothermia of full-term infants with moderate or severe HIE following severe birth asphyxia reduces the risk of death or survival with severe functional disabilities. The children were followed until they were at least 12 months of age, but no older than 18 months. The results are statistically significant and clinically meaningful. The relative risk reduction was 22% to 24%, and the absolute risk reduction was 14 to 16 percentage points. This means that of 100 children with HIE who receive therapeutic hypothermia, on average 14 to 16 more children will survive without severe functional disabilities compared to if they hadn’t received therapeutic hypothermia. In separate analyses of the two endpoints, ie, death and survival with moderate/severe functional disabilities, the reviews show that therapeutic hypothermia reduces risk for both outcomes.

No serious adverse effects or complications related to therapeutic hypothermia have been identified in the studies reviewed in this report, but there are no well-executed studies that have been specifically designed to investigate this.

Ethical aspects

The quality of life for children receiving therapeutic hypothermia increases since fewer children die and fewer have severe functional disabilities. Likewise, the quality of life for parents and siblings also increases. This, however, must be weighed against the uncertainty regarding the optimum way to deliver the treatment and its long-term effects.

Therapeutic hypothermia must begin within 6 hours of birth. Access to therapeutic hypothermia varies in different parts of Sweden. Hence, there is a risk that therapeutic hypothermia cannot be offered within 6 hours to all children needing this care, which conflicts with the so-called equity principle in Sweden. Given the current diffusion of this method, hospitals need to have a high level of collaboration and a well functioning transportation system.

Starting therapeutic hypothermia requires an immediate decision. Hence, healthcare staff do not always have time to confer with the child’s parents before starting treatment. As quickly as possible, the parents should receive comprehensive, objective, and well-designed information about the method’s potential benefits and risks.

When the method is introduced in clinical practice there is a risk that the inclusion criteria used in the research studies, and which are currently recommended for clinical use, will not be strictly applied. This could result in treating children who are too severely damaged to benefit from therapeutic hypothermia, leading to survival with very severe functional disabilities that affect quality of life not only for the child, but also for the family. Less stringent application could also lead to unnecessarily treating children who do not have sufficiently severe injuries, and hence do not meet the criteria for therapeutic hypothermia. Against this background, it is important to follow the children who are treated and to coordinate this data in a quality register. Assuming that all children who require therapeutic hypothermia can receive it, that the parents’ informational needs are met, and that the children are carefully followed up, the method is appraised to be ethically defensible given its benefits regarding quality of life.

Economic aspects

The average extra cost per child receiving therapeutic hypothermia is roughly estimated at 5000 to 10 000 Swedish kronor (SEK), including the extra staff costs during the care episode. Additional costs would include any costs for transportation to and from the home hospital and the cost for followup examinations of the child’s motor and cognitive development. The only health economic study available, an American model study, shows that therapeutic hypothermia offers better effects at a lower cost than does the option of not using therapeutic hypothermia.

This summary is based on a report prepared by SBU in collaboration with Uwe Ewald, MD, Adjunct Professor, Uppsala University Hospital, Uppsala and Fredrik Serenius, MD, Adjunct Professor, Umeå University, Umeå. It has been reviewed by Mats Blennow, MD, Associate Professor, Astrid Lindgren Children’s Hospital, Stockholm and Vineta Fellman MD, Professor, Lund University Hospital, Lund. Project manager: Karin Rydin, SBU.

The complete report is available only in Swedish.

SBU Alert is a service provided by SBU in collaboration with the Medical Products Agency,the National Board of Health and Welfare, and the Swedish Association of Local Authorities and Regions

References

1. Shankaran S, Laptook AR. Hypothermia as a treatment for birth asphyxia. Clin Obstet Gynecol 2007;50(3):624-35.
2. Thoresen M, Bågenholm R, Løberg EM, Apricena F, Kjellmer I. Posthypoxic cooling of neonatal rats provides protection against brain injury. Arch Dis Child Fetal Neonatal Ed 1996;74(1):F3-9.
3. Sirimanne ES, Blumberg RM, Bossano D, Gunning M, Edwards AD, Gluckman PD et al. The effect of prolonged modification of cerebral temperature on outcome after hypoxic-ischemic brain injury in the infant rat. Pediatr Res 1996;39(4 Pt 1):591-7.
4. Yager J, Towfighi J, Vannucci RC. Influence of mild hypothermia on hypoxic-ischemic brain damage in the immature rat. Pediatr Res 1993;34(4):525-9.
5. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997;99(2):248-56.
6. Yager JY, Asselin J. Effect of mild hypothermia on cerebral energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat. Stroke 1996;27(5):919-25; discussion 926.
7. Laptook AR, Corbett RJ, Sterett R, Burns DK, Garcia D, Tollefsbol G. Modest hypothermia provides partial neuroprotection when used for immediate resuscitation after brain ischemia. Pediatr Res 1997;42(1):17-23.
8. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998;102(5):1098-106.
9. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res 1994;654(2):265-72.
10. Gunn AJ, Gluckman PD. Head cooling for neonatal encephalopathy: the state of the art. Clin Obstet Gynecol 2007;50(3):636-51.
11. Laptook A, Tyson J, Shankaran S, McDonald S, Ehrenkranz R, Fanaroff A et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics 2008;122(3):491-9.
12. Svensk barnläkarförening. Rekommendationer för hypotermibehandling av asfyktiska nyfödda barn från BLF:s Neonatalsektion, 2008. http://www.blf.net.
13. Levene MI, Sands C, Grindulis H, Moore JR. Comparison of two methods of predicting outcome in perinatal asphyxia. Lancet 1986;1(8472):67-9.
14. Gunn AJ, Gunn TR. Changes in risk factors for hypoxic-ischaemic seizures in term infants. Aust N Z J Obstet Gynaecol 1997;37(1):36-9.
15. 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):663-70.
16. 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):1574-84.
17. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol 2005;32(1):11-7.
18. Lin ZL, Yu HM, Lin J, Chen SQ, Liang ZQ, Zhang ZY. Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit. J Perinatol 2006;26(3):180-4.
19. Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics 2002;110(2 Pt 1):377-85.
20. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102(4 Pt 1):885-92.
21. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics 2001;107(3):480-4.
22. Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia. Pediatrics 2003;111(2):244-51.
23. Akisu M, Huseyinov A, Yalaz M, Cetin H, Kultursay N. Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia. Prostaglandins Leukot Essent Fatty Acids 2003;69(1):45-50.
24. Shankaran S, Pappas A, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics 2008;122(4):e791-8.
25. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol 2005;32(1):18-24.
26. Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy - are we there yet? BMC Pediatr 2007;7:30.
27. Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med 2007;161(10):951-8.
28. Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003311. DOI: 10.1002/14651858.CD003311.pub2.
29. Bhat MA. Re: Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 2006;91(6):F464; author reply F465.
30. Perinatal trials report PTO367 ICE: Infant Cooling Evaluation Trial.
31. Róka A, Melinda KT, Vasarhelyi B, Machay T, Azzopardi D, Szabo M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics 2008;121(4):e844-9.
32. O’Shea TM, Goldstein DJ. Follow-up data their use in evidence-based decision-making. Clin Perinatol 2003;30(2):217-50.
33. Hoehn T, Hansmann G, Buhrer C, Simbruner G, Gunn AJ, Yager J et al. Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. Resuscitation 2008;78(1):7-12.
34. Perlman JM. Intervention strategies for neonatal hypoxic-ischemic cerebral injury. Clin Ther 2006;28(9):1353-65.
35. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371(9628):1955-69.
36. Mishima K, Ikeda T, Yoshikawa T, Aoo N, Egashira N, Xia YX et al. Effects of hypothermia and hyperthermia on attentional and spatial learning deficits following neonatal hypoxia-ischemic insult in rats. Behav Brain Res 2004;151(1-2):209-17.
37. Yager JY, Armstrong EA, Jaharus C, Saucier DM, Wirrell EC. Preventing hyperthermia decreases brain damage following neonatal hypoxic-ischemic seizures. Brain Res 2004;1011(1):48-57.
38. Gray J, Geva A, Zheng Z, Zupancic JA. CoolSim: using industrial modeling techniques to examine the impact of selective head cooling in a model of perinatal regionalization. Pediatrics 2008;121(1):28-36.
39. TOBY: a study of treatment for Perinatal Asphyxia. http://www.clinicaltrials.gov/ct/show/NCT00147030?order=5.
40. Perlman JM. Hypothermia as a therapeutic intervention in term infants with neonatal encephalopathy: is it ready for prime time? Resuscitation 2008;78(1):1-2.
41. Higgins RD, Raju TN, Perlman J, Azzopardi DV, Blackmon LR, Clark RH et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr 2006;148(2):170-5.
42. Blackmon LR, Stark AR. Hypothermia: a neuroprotective therapy for neonatal hypoxic-ischemic encephalopathy. Pediatrics 2006;117(3):942-8.
43. Anderson ME, Longhofer TA, Phillips W, McRay DE. Passive cooling to initiate hypothermia for transported encephalopathic newborns. J Perinatol 2007;27(9):592-3.
44. Neo.nEuro.network - Induced systemic hypothermia in asphyxiated newborn infants: a randomized, controlled multicenter study. http://neonatal-research.at/php/portal.php.