Best Practice Guideline article
Therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy

https://doi.org/10.1016/j.earlhumdev.2010.05.013Get rights and content

Abstract

There is now a strong evidence base supporting therapeutic hypothermia for infants with moderate or severe neonatal hypoxic ischaemic encephalopathy. Experimental and clinical data indicate that induced hypothermia reduces cerebral hypoxic ischaemic injury and randomized clinical trials in newborns with hypoxic ischaemic encephalopathy confirm improved neurological outcomes and survival at 18 months of age with therapeutic hypothermia. Studies are on-going to confirm whether these benefits are maintained in later childhood. Efforts are now focused on optimal implementation of therapeutic hypothermia in clinical practice: training in the assessment of severity of encephalopathy; initiation and maintenance of hypothermia before admission to a cooling facility; care of the infant during cooling; and appropriate investigation and follow-up are crucial for optimizing neurological outcomes. The establishment of registries of infants with hypoxic ischaemic encephalopathy and audit are important for guiding clinical practice.

Section snippets

Clinical evidence supporting therapeutic hypothermia in newborns

Clinical studies of therapeutic hypothermia were based on the successful experimental studies and mostly utilized a similar therapeutic approach: a reduction in brain or body temperature by 3–4 °C for up to 72 h started within 6 h of birth. Studies used either selective head cooling (with mild whole body cooling) or whole body cooling methods using purposely designed cooling equipment or simply by placing cold bags around the body of the infant [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]

Mechanism of action of therapeutic hypothermia

The precise mechanism of neural rescue by moderate hypothermia is uncertain but may be related to the critical relationship between temperature and metabolic rate: for every 1 °C lowering of the core temperature cerebral metabolism is reduced by approximately 7%, with consequently a lower glucose and oxygen demand [28]. Both necrotic and apoptotic mechanisms are implicated in neuronal injury following neonatal hypoxia ischaemia and reperfusion [29]. Mitochondrial injury leads to energy failure,

Clinical application of therapeutic hypothermia

Current advice from national specialist bodies is that therapeutic hypothermia should only be provided according to the protocols used in the clinical trials [38], [39]. However, in view of the strength of the evidence supporting therapeutic hypothermia and the lack of serious adverse effects, it is not surprising that clinicians may wish to consider therapeutic hypothermia in other infants with clinical criteria that differ from those of the trial protocols, such as infants less than 36 weeks

Which infants should be considered for treatment with cooling?

The major clinical trials had similar eligibility criteria: infants were at least 36 weeks gestation, had profound depression at birth (Apgar score  5 at 10 min) or severe metabolic acidosis (pH < 7.0) and moderate or severe encephalopathy, although definitions differed slightly amongst trials. In two trials an abnormal amplitude integrated EEG was also required [20], [22]. Despite these differences the major randomized trials had remarkably similar outcomes and point estimates of treatment effect.

Therapeutic hypothermia in infants born outside treatment centres

In the majority of infants hypoxic ischaemic encephalopathy occurs unexpectedly following an uncomplicated pregnancy or following a complication occurring just before delivery. Therefore, many infants will be born in hospitals or in locations without resources for providing intensive care and therapeutic hypothermia. Experimental evidence suggests that the therapeutic response is diminished the later hypothermia is started so early assessment and initiation of therapeutic hypothermia is vital.

Therapeutic hypothermia in cooling centres

Early identification and assessment of newborns for evidence of hypoxic ischaemic encephalopathy and seizures are crucial. Passive cooling should be commenced in a controlled way as soon as possible after resuscitation is completed if the perinatal history is strongly suggestive for hypoxic ischaemic encephalopathy. Once the eligibility criteria are met active cooling preferably using certified cooling equipment can be commenced. In our experience the amplitude integrated EEG aids clinical

Assessment of prognosis following therapeutic hypothermia

A major challenge in the clinical care of infants with severe hypoxic ischaemic encephalopathy is the assessment of prognosis, which is vitally important for directing clinical management. It is often difficult to assess the therapeutic response to hypothermia during the first few days after birth, perhaps because routine use of sedation often in combination with large doses of anticonvulsants hinders clinical assessment. Although the clinical severity of encephalopathy correlates with

Conclusion

Therapeutic hypothermia for neonates with hypoxic ischaemic encephalopathy is rapidly being introduced into routine clinical practice. Clinical management should closely follow the published protocols but may need to be altered according to individual circumstances. The results of on-going studies may further refine the therapeutic approach. Continued surveillance of the use of therapeutic hypothermia in clinical practice is necessary to detect unusual complications and audit practice.

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      Current therapeutic approaches employed in the clinical settings are very limited and available treatments to newborn infants focus on supportive care, such as controlling hypoglycemia, treatment of convulsions and associated infections. The gold standard is hypothermia started within 6 h after birth, however it is used only in a small percentage of term (or near term) infants (McKenna et al., 2015; Roka and Azzopardi, 2010). This review aims to present evidence that pregnancy is a valuable period for preventing hypoxia-ischemia brain damage.

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