Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy (HIE)

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European Review for Medical and Pharmacological Sciences 2017; 21 (4 Suppl): 50-53 Hypothermia in neonatal hypoxic-ischemic encephalopathy (HIE)

G. LIU, Z.-G. LI, J.-S. GAO

Department of Neonatology, Xunzhou Children’s Hospital, Xuzhou, Jiangsu, China

Abstract. – Neonatal hypoxic-ischemic en- Moreover, a recent report noticed the reduction cephalopathy (HIE) significantly affects neuro- of free radicals, as well as glutamate levels fol- development in infants and is also considered lowing hypothermia therapy, which has provided as an important cause of neonatal deaths world- another dimension of thought for mechanistic wide. Medical research is being focused world- 3 wide for the development of therapeutic ave- justification for the hypothermia therapy . This nues but it is still managed by supportive care. act of reduction in free radicals and glutamate The latest studies in the above field have shown levels, in turn, helped in further protection of the efficacy of prolonged cooling of neonate’s mitochondrial function and showed a decline in head or whole body at the age of 18 months (ap- inflammatory responses. Another study noticed prox.) in providing relief from the pathological a significant decline in the caspase activity along state of HIE. Moreover, hypothermia is the first with an increment of Bcl2 expression during hy- reported therapeutic modality that proved ben- 4,5 eficial for HIE young patients. Further, it acts by pothermia therapy . Thus, inhibition of caspase decreasing the cerebral metabolism to mitigate and stimulation of Bcl2 emerged as one of the neurological outcomes of the pathological state. mechanistic effects of the hypothermia thera- The present review article would discuss all-im- py. Figure 1 shows the underlying processes in portant aspects of hyperthermia therapy in the pathophysiology and possible target points for improvement of young patients affected by HIE. treatment. The present review article would cover Key Words: all the important aspects of hypothermia. Hyperthermia, HIE, Neonates. Proposed Mechanisms Behind Hypothermia Therapy The exact mechanism responsible for neural Introduction rescue by application of moderate hypothermia is not certain. It might be related to the critical Hypothermia is associated with decline in ce- relationship between temperature and metabolic rebral metabolism and is the prime therapeutic rate. Both necrotic and apoptotic mechanisms intervention that can improvise neurological out- were implicated in neuronal injury following comes. The temperature has the ability to affect neonatal hypoxia-ischemia and reperfusion. The physiological metabolic rate of the physiological deprivation of oxygen and glucose caused by the system. This idea forms the basis of moderate reduction of cerebral blood flow leads to a se- hypothermia therapy for the application as a vere decrease in high-energy phosphate reserves neural rescue; however, it is still a dilemma1. To including adenosine triphosphate. The inability further understand in numbers, it was estimated to maintain the polarity of the membrane, in that for every 10 degrees fall in the core tem- neurons, as well as glial cells, results in energy perature, cerebral metabolism declined to the failure of sodium-potassium-adenosine pump. tune of 7%, along with decline in glucose and So, this inability of sodium-potassium-adenosine oxygen demand2. Moreover, necrotic as well as pump finally causes excessive glutamate release apoptotic mechanisms were involved in neuro- within the synaptic cleft, leading to a significant nal injury following neonatal hypoxia-ischemia influx of sodium as well as calcium to the cells. and reperfusion. On the whole, apoptosis was The elevation in calcium levels stimulates several considered responsible for the progressive neuro- enzymes including phospholipase, proteases, and nal injury following neonatal hypoxia-ischemia. endonucleases or nitric oxide synthase. The com-

50 Corresponding Author: Zhenguang Li, MD; e-mail: [email protected] Hypothermia in neonatal hypoxic-ischemic encephalopathy (HIE)

Figure 1. Various processes in pathophysiology and possible target points. bined consequences of cellular energy failure, therapeutic module during cerebral injury follow- lactate acidosis, glutamate release, calcium accu- ing hypoxic ischemia. Also, hypothermia result- mulation and oxidative damage disrupt essential ed in the elevation of normal survival, thereby components of the cells that in turn cause death. reduced rates of severe disability, cerebral palsy and improvised the developmental index. On the Clinical Evidence Supporting Therapeutic other hand, there are reports showing heterogene- Hypothermia in Newborns ity amongst the trials in severely encephalopathic As discussed before, it is the prime therapeutic infants undergoing hypothermia therapy. The on- module for the hypoxic-ischemic encephalopathy ly crucial complication observed to be associated patients and was initially thought to be the meth- with hypothermia therapy was the subcutaneous od of reanimation by immersion in cold water6,7. fat necrosis11. However, further researches, as However, upon the development of experimental well as experiences, are still required for rein- model of HIE and advancements in technological surance about the safety aspects of therapeutic knowledge, later studies confirmed brief peri- hypothermia, especially in the cases of infants ods of post-insult, to be the main mechanisms with systemic impediments like pulmonary hy- working behind hypothermia8,9. The above mech- pertension or myocardial ischemia12. anisms are documented as prime mechanisms responsible for observed neuro-protection in lit- Some Uncertainties of Hypothermia erature. Further, hypothermia therapy helps in Despite observed remarkable results, there significant healing during the trauma events like are some uncertainties in hypothermia therapy13. stroke, cardiac arrest or brain injury, as observed Firstly, no study has reported therapeutic hypo- in earlier experimental human studies9,10. So, the thermia outcomes beyond 18 months of age in above observations of the earlier studies con- young infants. Secondly, despite the therapeutic firmed the moderate hypothermia as an important efficacy of hypothermia therapy, 40% of infants

51 G. Liu, Z.-G. Li, J.-S. Gao in the trials developed disabilities or showed Conclusions mortality14. This might be the result of selection bias. Thirdly, there are limited or no studies on The present review article highlighted both the application of therapeutic hypothermia in positive and negative aspects of hypothermia resource poor countries, where the incidence therapy during neonatal hypoxic-ischemic en- of hypoxic ischemic encephalopathy has greatly cephalopathy. The hypothermia therapy is an elevated. Further, a report from Uganda observed emerging therapeutic approach against hypox- an increased mortality in the treatment group, ic-ischemic encephalopathy, but some negative which might be due to the chance allocation of aspects have to be taken care of in the future. infants with severe encephalopathy in the treatment group15. Therefore, field trials are essential extrapolation of hypothermia to variable environ- Conflict of Interest ments in the near future. The Authors declare that they have no conflict of interests.

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