Now that therapeutic hypothermia has been proven effective and safe for infants with Hypoxic Ischemic Encephalopathy, one might ask what next? We still are not sure if it is of any value to cool infants after 6 hours of age, or if a different duration and different temperature might be preferable. Given the efficacy of hypothermia we will need trials to address those issues. We should also determine whether cooling infants who are slightly preterm is useful, as they are not currently eligible but might benefit.
Other additional therapies also should be examined, to my mind there are 4 that are of interest: allopurinol, erythropoietin, phenobarbitone, and xenon.
As for allopurinol a new publication describes the outcomes at long term of infants enrolled in 2 similar trials. Joepe Kaandorp and associates (Kaandorp JJ, van Bel F, Veen S, Derks JB, Groenendaal F, Rijken M, Roze E, Venema MMU, Rademaker CM, Bos AF et al: Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012, 97(3):F162-F166 http://fn.bmj.com/content/97/3/F162.abstract) collected long term follow up to 4 to 8 years of age from infants in the 2 trials in Holland, both trials were very small and were, generally speaking, negative. Other studies have suggested some biochemical benefit in terms of interrupting the oxidative stress associated with reperfusion. These 2 studies showed no clinical benefit, but were very underpowered. Combining the studies does suggest that perhaps there was some long term benefit; again, even combined the studies were underpowered, but there is a hint that maybe we should be studying allopurinol. There is one other RCT that I am aware of, that also primarily examined biochemical effects of allopurinol, it was also underpowered, but the authors (Gunes T, Ozturk MA, Koklu E, Kose K, Gunes I: Effect of Allopurinol Supplementation on Nitric Oxide Levels in Asphyxiated Newborns. Pediatric Neurology 2007, 36(1):17-24 http://www.sciencedirect.com/science/article/pii/S0887899406004875) showed a possible clinical and biochemical positive effect of allopurinol. Now in none of these studies were the infants treated with whole body cooling, but these studies do suggest that investigations of allopurinol given as soon as a potential cooling candidate is identified, might be beneficial.
How might this work? Well allopurinol is an inhibitor of xanthine oxidase which is involved in the production of superoxide during reperfusion, so a reduction in reperfusion-reoxygenation injury is the putative mechanism.
Allopurinol is readily available and cheap, with a good safety profile, also important issues in deciding where to go next.
How about erythropoietin? A recent article reviews the neuroprotective potential of this molecule. (Subirós N, del Barco DG, Coro-Antich RM: Erythropoietin: still on the neuroprotection road. Therapeutic Advances in Neurological Disorders 2012, 5(3):161-173. http://tan.sagepub.com/content/5/3/161.abstract) Other pre-clinical articles and reviews also suggest that erythropoietin may have a role in HIE in newborn babies. In addition another very underpowered study in newborn infants, (15 babies per group: Elmahdy H, El-Mashad A-R, El-Bahrawy H, El-Gohary T, El-Barbary A, Aly H: Human Recombinant Erythropoietin in Asphyxia Neonatorum: Pilot Trial. Pediatrics 2010, 125(5):e1135-1142 http://pediatrics.aappublications.org/content/125/5/e1135.abstract ) also suggested some positive effects, but again there was no use of therapeutic hypothermia in either group in that trial. A much larger (but still underpowered) Chinese study (n=167) was also positive (Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G et al: Erythropoietin Improved Neurologic Outcomes in Newborns With Hypoxic-Ischemic Encephalopathy. Pediatrics 2009, 124(2):e218-e226 http://pediatrics.aappublications.org/content/124/2/e218.abstract) with a reduction in adverse long term outcomes.
Erythropoietin has multiple potentially neuroprotective effects, including a reduction in apoptosis, protection from glutamate neurotoxicity, and promotion of angiogenesis and neurogenesis, among other effects. It is again, easily available, and in the doses required for newborn infants, cheap.
Phenobarbitone? Phenobarb is an anticonvulsant which decreases brain oxygen requirements, and has been shown to reduce adverse outcomes in asphyxiated infants in one small trial when given in high dose before the occurrence of seizures. (Hall RT, Hall FK, Daily DK: High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998, 132(2):345-348http://www.sciencedirect.com/science/article/pii/S0022347698704585 ). Interestingly in that trial, phenobarbitone wasn’t very good at preventing seizures! There was an improvement in outcomes at 3 years of age, with a few infants lost to follow-up, which in a trial of only 40 babies, even a few losses to follow up could be potentially important. Other trials of phenobarbitone have not reported follow up, and other barbiturates are not necessarily equivalent. Phenobarbitone is also cheap, readily available (most of the time, there have been some problems with availability over the last few years) and is often given anyway to infants with asphyxia. It may reduce the time it takes to make a baby hypothermic, probably because of a reduction in metabolic rate.
Finally xenon has been the focus of a great deal of activity. It is thought to act mostly as an anesthetic agent, but it is very expensive, so special equipment is required to scavenge and recycle the gas. Why xenon has been investigated rather than other neuroprotective agents is not entirely clear to me, it does appear promising in animal models (for example: Faulkner S, Bainbridge A, Kato T, Chandrasekaran M, Kapetanakis AB, Hristova M, Liu M, Evans S, De Vita E, Kelen D et al: Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia. Annals of Neurology 2011, 70(1):133-150 http://onlinelibrary.wiley.com/doi/10.1002/ana.22387/abstract). A recent study in rats even gave the agent to the mother before birth in a perinatal asphyxia model, and seemed to show some benefit. (Yang T, Zhuang L, Rei Fidalgo AM, Petrides E, Terrando N, Wu X, Sanders RD, Robertson NJ, Johnson MR, Maze M et al: Xenon and Sevoflurane Provide Analgesia during Labor and Fetal Brain Protection in a Perinatal Rat Model of Hypoxia-Ischemia. PLoS One 2012, 7(5):e37020 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0037020) In contrast to the other agents discussed, it will be long time before enough centers could have the equipment an expertise to use this agent. Also in contrast with the other agents, xenon has been investigated in combination with hypothermia, and seems to give additional benefit in the animal models.
I totally agree with you that we have to continue looking for therapies/combination of therapies for perinatal asphyxia since the outcome improvement that hypothermia alone offers is statistical significant but still 47% of the asphyxiated newborn are at risk for neurological morbidity and this is still a very bad outcome, obviously we are not there yet! (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03). I do not think that I am looking at a half glass empty.
It is surprising to find out than the pharmacological approaches to prevent neurological damage in the indication are so limited, with so many neuroprotectants under development. What is preventing the industry to jump in, even as a niche entry strategy to go to adult stroke or chronic indications such as alzheimer’s later on?