Initiation of therapeutic hypothermia comprise of induction, maintenance and rewarming phases. Experimental studies indicate that
the earlier the cooling is commenced the better the outcome . The natural reduction in core temperature after asphyxia and avoiding active warming has reduced the induction phase in most situations. A systematic neurological assessment as in Table 1 with aEEG assessment is needed to decide if the infant qualifies for
therapeutic hypothermia. In the clinical trials, a minimum of 20 minutes of aEEG was recorded within the first 6 hours to decide eligibility. aEEG should be monitored for a longer duration preferably 6 hours before concluding the ineligibility for therapeutic hypothermia. If the infant does not qualify for hypothermia, slow rewarming can be commenced at a rate of 0.2°-0.4°C/h. There can be overshooting of the target temperature during induction of cooling in some cases. However, with the servo-controlled devices, overshoot does not occur
The target core temperature of 33.5°C and 34.5°C is maintained for 72 hours with whole body cooling and selective head cooling respectively. The goal during the maintenance phase is to avoid large fluctuations in the core temperature, monitor and maintain physiology within the normal range. Though there is no data delineating the independent effect of the fluctuations of core temperature on the neurological outcome, it is possible that large temperature fluctuations can lead to unfavourable cardiovascular and cerebral hemodynamic fluctuations.
In animal studies, fast re-warming may transiently affect the cerebral blood flow- metabolism balance and affect the neuronal cytoskeleton
[28, 29]. During re-warming, seizures, hypotension , hypoglycaemia or hypokalemia can occur. Seizures usually respond to anticonvulsants; slowing down the pace of rewarming or halting the rewarming briefly is recommended
. During rewarming, the dilation of skin blood vessels and decreased effective blood volume can lead to hypotension if the intravascular compartment is not adequately filled. Though the clinical trials have re-warmed at a rate of 0.5°C/h, we suggest a slower rate of 0.2°C/h in the first two hours and 0.4°C/h thereafter to reach the normothermic target of 36.5°C
. We also recommend monitoring core temperature for a further 24 hours after attaining normothermia to avoid hyperthermia after rewarming, as hyperthermia (> 36.5°C) can affect the neurodevelopment outcome
Intensive Care During Hypothermia
Most of the asphyxiated infants present with mixed metabolic and respiratory acidosis. Most severely asphyxiated infants need respiratory support. We aim to maintain normocapnia, as fluctuations in pCO2 may worsen the cerebral blood flow perturbations in the asphyxiated infants. However, their own and compensatory respiratory drive often causes hypocapnia, despite mechanically ventilated. Though there is evidence for hypocapnia causing adverse neurodevelopmental outcome in preterm ventilated infants
[32, 33], this has not been documented in the term infants and spontaneously breathing hypocapnic postasphyxic term infants can have good short term neurologic outcome
. Hypocapnia < 2.6 KPa (OR 2.34, 95% CI 1.02 to 5.37) and hyperoaxemia >26.6KPa (OR 3.85, 95% CI 1.67 to 8.88) individually increased the risk of adverse outcome in normothermic asphyxiated term newborn infants, and the combination of both hypocapnia and hyperoxaemia
further increased the risk of adverse outcome (OR 4.56, 95% CI 1.4 to 14.9) . The decreased metabolism associated with hypothermia will reduce the CO2
production  The incidence of Persistent Pulmonary Hypertension (PPHN) in the clinical trials is similar in the normothermic and hypothermic groups
[16, 18, 19]. In asphyxiated infants with PPHN, we provide hypothermia
along with the standard therapy for PPHN (i.e, high Fraction of inspired oxygen and inhaled nitric oxide). There is no difference in the occurrence of PPHN between selective head cooling or whole body cooling
The partial pressure of CO2 is reduced by 4% per degree centigrade reduction in core temperature
. There is higher cerebral blood flow with higher PCO2
 and reduced threshold for seizures with hypocapnic alkalosis
. Hence, in ventilated infants cooled to 33.5°C, we shift the normal PCO2 range of 36-44mmHg at 37°C to 41-51mm Hg. We use the same normothermic range for pO2 and pH as the influence of temperature on these variables is less
Hypothermia decreases cardiac output and heart rate (sinus bradycardia). No large effect on stroke volume, blood pressure and cardiac performance has been reported during hypothermia
[40, 41]. Hypothermia does not cause arrhythmia; in fact low temperature
stabilizes cardiac conduction and is a recommended treatment for junctional ectopic tachycardia
. Hypotension needs prompt correction as it may affect cerebral blood flow in the face of deranged cerebral autoregulation.
Central nervous system
Electrical and clinical Seizures should be actively monitored using aEEG and treated, as seizures worsen neurodevelopmental outcome independent of the severity of hypoxic-ischemic brain injury
. Though hypothermia has been reported to reduce the duration of seizures in experimental studies,
[9, 44] there has been no substantial difference in the clinical trials [16, 18, 19].
The incidence of proven sepsis in the normothermic and hypothermic groups in the 3 trials vary between 2 and 12%. Infection is not an exclusion criterion for cooling as this diagnosis is rarely known at birth. There is no evidence that infection in asphyxiated newborns was worsened by
Glucose and Electrolytes
Glycemic control and electrolytes particularly magnesium should be maintained within the normal ranges. Hypo or hyperglycemia may affect neuroprotection. Magnesium can increase the threshold for shivering. There is experimental evidence for the neuroprotective effect of magnesium
. Postnatal magnesium sulphate infusion in asphyxiated newborn infants maintaining Mg ≥ 1.2mmol/L improved the short term outcome
. In adults, Mg > 1mmol/L have been shown to reduce shivering during HT. We suggest to keep plasma Mg~ 1mmol/L. However supranormal levels (> 2.5 mmol/L) can lead to unacceptable hypotension and respiratory depression
Asphyxiated neonates often have abnormal clotting. Ideally one would like to
correct this first and then cool, however the therapeutic time window for
cooling will be lost. Although it is a fact that hypothermia prolongs bleeding
time, there was no difference between normothermic and hypothermic infants in the trials regarding the complication related to abnormal coagulation. Nonetheless, clinical increased bleeding tendency should be treated as soon as possible, before any clotting results are available to avoid treatment delay.
Hypothermia in Low Resourced Settings
In low resourced settings, there are many ethical issues to be considered. It is argued that evidence for hypothermia comes from countries who can afford decent health care and extrapolating the evidence may not be appropriate. The patient population is very likely to differ with either more of severely asphyxiated infants or their early demise, can leave a population of moderately asphyxiated infants. Most of these infants are naturally hypothermic which may offer natural neuroprotection. Some argue that infants in low resource settings should be maintained normothermic and hypothermia is still experimental, which is ethically debatable. Though cooling can be achieved with many low cost techniques, there should be adequate counseling of parents of the long term outcome, where the burden of looking after infants with disabilities is unaffordable and one often visits the question of acting in the best interest of the infant and the risk benefit balance. The ongoing trials in the low resource settings must take this into account during the informed consenting process. There was a trend of increased poor outcome in the cooled group in the two pilot studies undertaken in Uganda
 and India.
Future of Neuroprotection in Asphyxiated Infants
NNT of 9 is a fantastic result for the three first ever large trials in newborns
with perinatal asphyxia. It is likely that the effectiveness of hypothermia could be improved by improved protocols and intensive care. Many research groups study HT combined with other drugs. Inhaling the inert gas Xenon while hypothermic doubles the neuroprotection in both small
 and large animal model
. Anticonvulsants [51, 52] and erythropoietin  have yielded neuroprotection in animal and human studies. However, there is a lack of data on combination of these with optimum duration of HT. Entering data locally as well as internationally like the Vermont Oxford Network is important to document outcome in the clinical setting. This part of the journey may be less exciting than the previous one but equally important. The outcome after specialist treatment improves with experience and patient volume in the treating institutions
. To develop and validate a new treatment and improve protocols rigorous documentation and follow up is needed. While it is advisable to centralise the management of medically very sick infants in cooling centres, it is equally important to educate all hospitals with obstetric and newborn care, the entry criteria for cooling therapy, diagnostic evaluation and the initiation of early cooling before transport team arrives.
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