Puneet Kumar

Role of Induced Hypothermia in Management of Perinatal Asphyxia: Current status

Hypoxic-ischemic encephalopathy (HIE) is a common cause of neonatal deaths and neurodevelopmental abnormalities in survivors. In fact, it contributes to 23% of the four million neonatal deaths every year globally (1). In the absence of any specific therapy, currently the management of HIE consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants. Development of better therapeutic strategies for HIE has always been a hot topic of research in neonatology. Although several novel pharmacological agents have been found to be effective in animal models (2-4), the results could not be replicated in human studies (5, 6). Early evidence in favour of induced hypothermia, however, is stronger. Today, research on induced hypothermia is focused on fine-tuning the therapeutic strategies (selection of patients, whole-body or selective head cooling, timing of hypothermia, degree of hypothermia, timing and speed of rewarming, etc.). The present article summarizes the current status of induced hypothermia in the management of HIE.


Mechanisms of action
Experimental studies have shown that a severe perinatal hypoxic-ischemic insult results in an evolving process of adverse biochemical events that include increased levels of neurotransmitters, excessive production of free radicals, increased intracellular calcium, and stimulation of inflammatory mediators and messengers that initiate apoptotic cell death. Alterations in cerebral energy metabolism can also be observed during and following such an insult. Cerebral metabolism is impaired and cerebral high-energy phosphate levels fall precipitously. Following termination of the insult, cerebral energy metabolism initially recovers, but then deteriorates 6–24 hours later. Although the secondary phase of impaired cerebral energy metabolism resolves after about 72 hours, a persistent disturbance may be detected for several months (7, 8).

Studies in adult and newborn animals have shown that a reduction of body temperature of 3–4°C after cerebral insults is associated with improved histological and behavioral outcome (9-11). Several mechanisms may help explain these benefits: the increases in extracellular glutamate and free radical and nitric oxide synthesis are suppressed (12, 13), cerebral energy phosphates are preserved and cerebral alkalosis and lactate reduced (14, 15). Mild hypothermia may also suppress the activation of microglia (16, 17). These changes may preserve cerebral energy metabolism, reduce cytotoxic cerebral edema and intracranial pressure and inhibit apoptosis (18). Thus, in contrast to pharmacological agents, which tend to target only one step in the process that leads to brain injury, hypothermia inhibits many steps in the biochemical cascade that produces severe brain injury after hypoxia-ischemia.

Hoeger et al (19) have suggested that hypothermia is not able to prevent morphological changes in the brain, but able to preserve brain functions very well. That indicates that with hypothermia, the neurological deficits are well-compensated functionally in affected newborn animal models.

Selective or whole body cooling
Selective head cooling seems to be an attractive option, as the therapy is directed towards the target organ, thus reducing the potential adverse effects on other organs. Early experimental studies (20) reported beneficial results. One of the large key human trials on selective head cooling was published in Lancet in 2005 (21). Popularly known as the “cool-cap” study, this was a multicentre controlled trial with 234 term infants with moderate or severe HIE plus abnormal amplitude integrated encephalography (aEEG), randomized to either head cooling for 72 hours within 6 hours of birth or conventional care. The primary outcome was death or severe disability at 18 months. Although the study did not demonstrate overall significant difference in these outcomes, in a subset of babies with less severe aEEG changes, selective head cooling did provide significant benefit.

However, it is uncertain whether head cooling alone effectively lowers deep brain temperature. In anaesthetized piglets, which have a much smaller head than the human newborn infant, it was possible to cool the basal ganglia 5°C more than rectal temperature (22). In adults, a steep temperature gradient has been observed between the surface of the head and deep brain structures and the deep brain temperature remains very close to core temperature even when extreme cold is applied to the surface of the head (23). The possibility of temperature gradients within the brain and the importance of damage to deep structures in causing severe neurodevelopmental impairment (24) and the lack of precise, non-invasive methods for measuring regional brain temperature pose major difficulties with selective head cooling. In fact, even in the landmark “cool cap” study (21), the authors used “mild” systemic hypothermia (Rectal temp 34-35ºC) in the brain-cooled group of babies.

Timing of hypothermia
Since cerebral damage starts soon after hypoxic-ischemic insult, it is plausible that therapy should start early to prevent/minimize damage. Current consensus is that the maximum benefit occurs when treatment is started within six hours of the insult (9, 25), although limited neuroprotection has been observed when hypothermia is started as late as 12 hours. Therefore, hypothermic treatment following perinatal asphyxia is to be started as soon as practically possible. The benefit may be minimal if treatment is delayed beyond six hours after birth.

Duration of Hypothermia
Duration of hypothermia varies with timing of initiation of hypothermia, degree of hypothermia and severity of hypoxic-ischemic insult. Most experimental studies have employed moderate hypothermia for at least 12-24 hours for favourable outcome. However, up to 72 hours of hypothermia may be required if the interval before inducing hypothermia is prolonged or milder degree of hypothermia is used (20). In fact, it has been seen in some studies that a rebound rise in epileptiform activity in fetal lambs (20) and in intracranial pressure in adults with stroke (26) can occur when hypothermia is discontinued before 72 hours.


Efficacy
Experimental studies on animal models have shown that a reduction of body temperature of 3–4°C after cerebral insults is associated with improved histological and behavioral outcome (9-11). Preliminary studies in adults of whole body hypothermia following head injury (27), cardiac arrest (28-30) and stroke (26) also suggested benefit. In neonates, hypothermia was first reported as therapy for resuscitation, before modern resuscitation techniques were introduced (31-33). It was soon realized that induced hypothermia can be beneficial in minimizing secondary brain injury in neonates who have suffered perinatal asphyxia. Pilot studies of head cooling combined with mild whole body hypothermia and of moderate whole body cooling to 33.5°C in infants with encephalopathy reported favourable results. More recently, results of large multicentre controlled trials have been published (21, 34-36).

Debillon et al (34) conducted a small pilot study on 25 infants (median postmenstrual age 38 weeks, 19 Sarnat II and six Sarnat III). Out of 25 babies, 18 survived, including 13 (72%) with normal cerebral signal by MRI.

Eicher et al (35) conducted a multicentre, randomized controlled trial where 32 babies in intervention group were cooled to 33ºC within 6 hours of birth or hypoxic event (for 48 hours). The outcome (death and severe disability) was favourable. The entry criteria selected a severely affected group of neonates, with 77% Sarnat stage III. Ten hypothermia (10/32, 31%) and 14 normothermia (14/33, 42%) patients expired. Controlling for treatment group, outborn infants were significantly more likely to die than hypoxic-ischemic infants born in participating tertiary care centers (odds ratio 10.7, 95% confidence interval 1.3-90). Severely abnormal motor scores (Psychomotor Development Index < 70) were recorded in 64% of normothermia patients and in 24% of hypothermia patients. The combined outcome of death or severe motor scores yielded fewer bad outcomes in the hypothermia group (52%) than the normothermia group (84%) (P = 0.019). Although these results need to be validated in a large clinical trial, this pilot trial provided important data for clinical trial design of hypothermia treatment in neonatal hypoxic-ischemic injury.

Shankaran et al (36) conducted a large multicentre trial of whole body hypothermia for HIE. A total of 208 infants (≥ 36 weeks gestation, age <6 hours, cord pH ≤ 7.0 in first hour of life or a history of perinatal event requiring resuscitation at birth) were randomized into the trial. The babies in the hypothermia group were cooled within 45 minutes to a target of 33.5ºC for 72 hours. The primary outcome of the study was death or severe disability at 18 months of age. The risk of death and moderate/ severe disability was 45% in the hypothermia, whereas it was 62% in the normothermia group. Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

TOBY study (37) is an ongoing a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling". At least 236 babies are being recruited. Outcomes will be assessed at 18 months of age using neurological and neurodevelopmental testing methods. Moreover, long-term follow-up to at least 6 years of age may also be done, as a secondary study, for detailed assessment of intellectual function.

Recently a systematic review of good-quality randomized trials on hypothermia in HIE has been published (38). It concluded that the combined outcome of death or neurodevelopmental disability in childhood was reduced in infants receiving hypothermia compared with control infants (4 studies including 497 infants; relative risk, 0.76, 95% confidence interval, 0.65-0.88; number needed to treat, 6; 95% confidence interval, 4-14), as were death and moderate to severe neurodevelopmental disability when analyzed separately.

The recent Cochrane review (39) also concluded that there is evidence from the eight randomized controlled trials (n = 638) that therapeutic hypothermia is beneficial to term newborns with hypoxic ischemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. However, it cautioned that results from ongoing trials (n= 829) may alter the conclusions. Further trials to determine the appropriate method of providing therapeutic hypothermia, including comparison of whole body with selective head cooling with mild systemic hypothermia, are also required.

Most studies till date have focused on term babies, as hypothermia is a well known adverse risk factor in preterm babies. However, very recently there is evidence from an experimental study that selective head cooling may be beneficial even in preterms (40).

Safety
The risk of adverse effects of hypothermia is a critical issue, given the poor outcome conventionally associated with hypothermia (41). Impaired cardiac function, disordered coagulation and increased sepsis have been reported with profound hypothermia. Thrombocytopenia, hypokalemia and increased sepsis have been noted in studies of hypothermia to 33°C in adults, but these were not associated with an adverse outcome (26). The metabolic rate is reduced during hypothermia and this results in bradycardia and prolonged PR and QT intervals. However, significant arrhythmia has only been reported in adults with head injury when the rectal temperature is less than 32°C (42), whereas most studies on HIE in newborn have used moderate hypothermia (33-34ºC).

No clinically significant adverse effects due to cooling were observed in the recent pilot studies of whole body (34-36, 43-45) and selective head cooling (21, 46) following encephalopathy. As expected, the heart rate reduced to below 100 bpm with cooling but this was not accompanied by arrhythmia, and the blood pressure and perfusion were maintained. Very recently, Compagnoni et al (47) reported safety of even deep hypothermia (30-33ºC) in moderate-severe hypoxic-ischemic encephalopathy in newborn term infants.

Challenges
Role of induced hypothermia in management of these patients is still evolving. Large, multicentre, controlled trials with long term follow up are needed to validate results of published studies. Many questions still need more accurate answers. Which patients respond best to this treatment? What is the best method of cooling? What should be the timing and speed of rewarming? Does it improve long-term outcome? However, as Laing (48) said, perhaps the most challenging of all is the ethical requirement of informed parental consent for randomized studies: if obtaining fully informed consent takes a few hours, causing the window of opportunity to be lost, is it ethical to embark on this new form of treatment without parental consent?

Early identification of infants at risk of perinatal asphyxial encephalopathy is also difficult. Perinatal asphyxial encephalopathy is reported to occur in between one and two infants per thousand deliveries in developed countries, and much more frequently in countries without adequate obstetric facilities. Early identification by clinical features of infants at risk of developing encephalopathy is difficult. Fetal heart rate patterns are not very helpful (49, 50) and neither the Apgar scores recorded immediately after birth (51, 52) nor umbilical cord blood gas analysis (53, 54) are good predictors of the likelihood or severity of post asphyxial encephalopathy. Most experts, however, agree that a continuing need for resuscitation and acidaemia with a cord blood pH < 7.0, are useful features of perinatal asphyxia.

The extremely high cost of the equipment and the need to rigorously monitor and control the temperatures limits the use of this modality for most settings in developing countries (55). Procedural difficulties requiring repeated revisions in the cooling techniques have earlier been reported (56). Also, the quantum of benefit of this intervention is modest and a direct cost-benefit analysis is not available.

Another big challenge is that such studies cannot be blinded or placebo-controlled. There is always a possibility of bias in studies because of this. Parents of infants randomized to hypothermia group may have some faith in the protective effect of this “new” treatment and thus may be more reluctant in giving consent to withdrawal of active intensive neonatal care (48).

Puneet Kumar
Kumar Child Clinic, Dwarka, New Delhi

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