Despite the strong evidence of benefit from multiple large, well-controlled studies, many gaps in knowledge remain. Cooling was intended as a treatment for HIE, but neonatal encephalopathy may have diverse etiologies (not just hypoxia and ischemia), despite similar clinical presentation. Among infants with recognized HIE, the precise timing, nature, and severity of the hypoxic-ischemic insult is seldom certain. The infants' maturity, nutritional and hormonal status, inflammatory, and preexisting developmental abnormalities may alter the responses to acute insults. Further work is needed to determine the optimal application of hypothermia for different clinical conditions.
The high level of consistency among the large, randomized trials means that this could in part be addressed by individual patient meta-analysis using the patient populations studied in these large randomized trials. Such analyses could identify the response rates to variations in patient characteristics (age, race, ethnicity, sex, Apgar scores, medications used in mothers, and so forth) or treatment (timing of initiation of hypothermia, degree and duration of cooling, adjunct therapies etc). Additional questions that might be addressed include factors affecting responses to hypothermia, the role of infection, and the nature of insult (sentinel event, unprovoked signs of fetal distress, pre-labor events, and prenatal events) as predictive of outcomes. The panel recommended that an individual patient meta-analysis would be an opportunity to address these important clinical questions.
Other potential clinical issues related to hypothermia therapy include the impact of obstetric factors such as maternal history (prior losses, stillbirth, coagulopathy, infection, etc.), race/ethnicity, age, genetic background, folate deficiency, and vitamin D deficiency, which may affect encephalopathy as well as the response of the infant to interventions. The panel saw a need for multidisciplinary collaborations to address these questions.
Recent studies have suggested that hypothermia significantly reduces the predictive value of both clinical neurological examination and EEG recordings.31,32
The addition of amplitude integrated EEG at < 9 hours of age resulted in a non-significant increase in the predictive value of stage of HIE at random assignment at < 6 hours of age, 0.72 (95% CI, 0.64-0.80) to 0.75 (0.66-0.83).33
In contrast, the prognostic value of post-cooling MRI appears to be unaffected by hypothermia.,34,35,36
Thus, prospectively generated hypotheses regarding resuscitation variables, aEEG recordings, full EEG recording, seizure identification37
and treatment, concurrent care practices, and management of infants prior to active cooling could enrich the value of future trials. Similarly, utility of continuous monitoring of EEG activity during treatment, and of obtaining EEG and MRI studies prior to discharge and at specific times during follow-up for prognostic evaluation need to be evaluated. Interventional variables such as targeted temperature management,38
sedation practices and concurrent medications could be assessed to increase our knowledge of optimal management of infants with HIE. Investigation of the role of sedation and pain management in infants with brain injury is also desperately needed.
The appropriate management of patients eligible for therapeutic hypothermia at referring hospitals and during transport to treatment centers as well as management in level III and IV NICU's prior to the initiation of hypothermia is controversial and is in need of evidence based studies. If the healthcare team at a referring hospital decides to initiate hypothermic therapy prior to and during transport, care must be taken to avoid overcooling. Safety, in particular, must be documented if hypothermia is to be used on transport. Further, there is a need for developing devices that reproducibly target temperature appropriately. It is unclear whether medical management during cooling therapy affects outcomes. Co-therapies including fluid management, nutrition, electrolyte and glucose management, ventilator strategies, management of pH, PO2
, and PCO2
and concurrent medications, particularly anticonvulsant therapy whose hepatic clearance is reduced by cooling therapy, are all areas in need of further research.
Because overall timing, depth, and duration of hypothermia strategies used in all major trials of therapeutic hypothermia to date have been remarkably similar,1-6
the relative benefits of variation in the administration of hypothermia cannot be estimated from the current data. Thu temperature selection, duration of time of cooling, rewarming techniques and temperatur management were discussed as continued knowledge gaps in the area to optimize hypothermi therapy. Ideal temperature for cooling remains an unanswered question.40
The cost/benefit o incremental studies of any selective modification of parameters for hypothermia therapie requiring many years with large clinical trials was raised by the group as a controversy.
The spectrum of the potential window or windows for opportunities needs to b broadened beyond the 6-hour window following birth. Trial are underway to evaluate the safet and effectiveness of cooling commenced after 6 hours of age. 41,42
There are recent report indicating a significant portion of infants (13 and 18%) cooled beyond the 6 hour of age tested i the randomized trials43,44
and limited data supporting the potential benefit from such delayecoling.22
Because HIE is common in resource-limited countries, some have proposed that designing studies in such settings may be of benefit to all, including host countries.45
There are several reasons why the safety and efficacy data on therapeutic hypothermia from complete trials from high-income countries cannot be extrapolated to neonatal units in low and mi income countries.
In low resource countries, brain injury may occur at long intervals prior to birth due to multiple antenatal insults (such as maternal malnutrition and other co-morbidities), delayed hospital admissions often in obstructed labor, long delays in carrying out emergency caesarean sections and lack of effective networks for neonatal transport. It is possible that, at the time of birth or before hypothermia therapy can commence, the therapeutic window for hypothermia may have passed.
The incidence and profile of perinatal infections in this population is different. Cooling in the presence of infection might be deleterious as hypothermia may impair innate immune function, including neutrophil migration and function.46
Hypothermia during sepsis in adult patients has been associated with increased mortality, higher circulating levels of TNF-a and IL-6,47
prolongation of NF-KB activation48
and altered cytokine gene expression. Hypothermia for head injury in adults increases the risk of pneumonia.49
These factors may explain the higher morbidity and mortality associated with hypothermia in some clinical settings and emphasize the need for careful monitoring of infection and mortality in cooled infants. In addition, convincing experimental50-52
and epidemiological evidence suggests that the ‘dual hit’ of combined infection and ischemia results in more severe brain injury and increase in the risk of cerebral palsy.53
It is not known if therapeutic hypothermia would be neuroprotective in such situations. Cooling may be unsafe in the presence of meconium aspiration and pulmonary hypertension as facilities for advanced multi-organ support may not be available in low and mid income neonatal units.
Cooling equipment used in high-income countries is expensive, requires maintenance and has recurring costs. Cost and benefit should be considered for low resource settings. Many “low tech” cooling methods like ice or frozen gel packs are labor intensive,54,55
may result in marked temperature fluctuations and shivering 54, 56,57
with a potential loss of neuroprotective efficacy. It is therefore important that rigorous and carefully conducted randomized controlled trials of therapeutic hypothermia are performed where there are adequate facilities and health care infrastructure to determine whether hypothermia is safe and effective for infants with encephalopathy with different risk factors in low to mid resource settings.58
It should be emphasized that potential prevention of HIE as well as access to obstetric and neonatal care including resuscitation is needed prior to institution of therapy for encephalopathy.