Advances in Neonatology

At NewYork-Presbyterian Komansky Children’s Hospital, neonatologists take a holistic approach to the application of therapeutic hypothermia as a neuroprotective strategy in high risk newborns. “Since 2007 we have been cooling the newborn brain to prevent brain injury and improve outcomes,” said Jeffrey Perlman, MD, Chief of Newborn Medicine and Professor of Pediatrics at Weill Cornell Medicine. “Over this period we have conducted a multitude of studies to identify the relevant entry criteria and the optimal timing to employ this modality, so that we can enhance neuroprotection, recovery and improve the quality of life of the most fragile infants, well beyond their time in the NICU.”

Once considered a novel modality in neonatology, therapeutic hypothermia gained widespread acceptance in 2010, when the Neonatal Task Force of the International Liaison Committee on Resuscitation (ILCOR) recommended that “newly born infants born at term or near-term with evolving moderate to severe hypoxic-ischemic encephalopathy should be offered therapeutic hypothermia.” Dr. Perlman, the former co-chair of the Neonatal Task Force and lead author on the paper, advised that “cooling should be initiated and conducted in neonatal intensive care facilities using protocols consistent with those used in the randomized clinical trials, i.e., commence within 6 hours, continue for 72 hours, and rewarm over at least 4 hours.” Additionally, infants should be carefully monitored for known adverse effects of cooling such as thrombocytopenia and hypotension, and all treated infants should be followed longitudinally.

Over the past decade, Dr. Perlman and a multidisciplinary team consisting of Neonatology, Neurology, Nursing, Neuroradiology and Psychology offered therapeutic hypothermia to over 165 infants at high risk, defined as having had an acute perinatal insult comprised of cardiorespiratory depression at birth, severe fetal acidemia (cord arterial pH < 7.00) and early evidence of moderate to severe encephalopathy. After every 20 patients, the team analyzed the treatment strategy and identified specific biomarkers that were associated with subsequent neurodevelopmental outcomes. These included profound early postnatal metabolic acidosis (associated with poor long-term outcome), early recovery of sleep-wake cycling i.e. within 72 hours (associated with favorable outcome), identifying the inherent vulnerability of the hippocampus to hypoxia-ischemia (associated with long term short memory loss), and noted the critical importance of timing of a hypoxic ischemia insult to outcome (see below).

“Looking back over these past ten years, our collective experience has demonstrated that hypothermia has had a favorable impact in many infants who present with neonatal encephalopathy and treated within six hours, particularly in those presenting with severe encephalopathy, which during the pre-hypothermia era was associated with universal adverse outcomes, i.e., mortality and severe neurodevelopmental deficits,” said Dr. Perlman. “Our approach is one in which we try to assess the big picture to understand the entire constellation of findings around the time of birth in order to determine if the patient will derive benefit from cooling. Once we have these findings, we examine the patient to determine the stage of encephalopathy and if cooling is appropriate.”

Expanding Therapeutic Hypothermia to Infants with Mild Neonatal Encephalopathy

“For several years, we used therapeutic hypothermia only in neonates presenting with moderate or severe encephalopathy,” says Dr. Perlman. “In 2013, with research suggesting that neonates with mild encephalopathy may also be at risk for adverse neurodevelopmental outcomes, and our own observations that some babies who presented with mild encephalopathy progressed to moderate disease within 24 hours, we began cooling babies that presented with mild encephalopathy. The goal was to prevent progression to moderate or perhaps even severe encephalopathy, states that lead to neurological damage.”

In 2018, Dr. Perlman and his team conducted a retrospective cohort review of term infants presenting with mild and moderate neonatal encephalopathy who underwent selective head cooling at the Neonatal Intensive Care Unit at NewYork-Presbyterian Komansky Children’s Hospital between 2011-2017 to describe the characteristics, short-term clinical outcomes, and long-term neurodevelopmental deficits among the two study groups. Eligible candidates for therapeutic hypothermia had to have a combination of at least three findings, including a sentinel event, need for resuscitation at birth, cord arterial pH < 7.00, and base deficit > -12. Mild encephalopathy was based on some of the following symptoms: hyperalertness, subtle mouthing or eye movements, weak suck, central hypotonia, and hyperreflexia. Eleven infants with mild encephalopathy and 37 with moderate encephalopathy were evaluated. ¹

“Developmental findings at 18 months for the mild encephalopathy group compared to the moderate encephalopathy group found that no infant with mild encephalopathy developed cerebral palsy (CP), whereas four of the infants with moderate encephalopathy developed CP,” explains Dr. Perlman. “This study suggests that infants with mild encephalopathy may also derive benefit from therapeutic hypothermia.”

“Although the benefits versus risks of therapeutic hypothermia in patients with mild encephalopathy require further study, at Weill Cornell Medicine if a newborn presents with mild, moderate or severe encephalopathy we cool,” says Dr. Perlman. “While many colleagues agonize about whether to cool infants with mild encephalopathy, I’ve been cooling mild cases since 2013, because I know within 6-12 hours that baby could progress to a state of a moderate encephalopathy. So far, the outcomes in these babies have been terrific.”

Challenges in the Use of Therapeutic Hypothermia for Infants with Subacute Injury

“In spite of our use of a fairly set protocol for therapeutic hypothermia, the application for this modality can be very complicated,” says Dr. Perlman. “For instance, although the evidence shows a clear benefit in cooling a baby within 6 hours of an acute insult, it is often difficult to estimate the actual time of onset of injury and whether the injury is acute or subacute.”

“The timing of an acute insult is obvious when there is evidence of an acute perinatal event such as placental abruption or uterine rupture,” he explains. “However, in cases in which there is subacute insult, such as abnormal fetal heart rate patterns of uncertain duration, feto-maternal hemorrhage, the exact time of onset of the severe hypoxic ischemic event is often unclear, and hence the benefit of therapeutic hypothermia becomes even less apparent.”

In 2015, Dr. Perlman and his team examined the characteristics of infants with subacute injury and found that all had exhibited severe magnetic resonance imaging changes and abnormal outcomes after therapeutic hypothermia. The research demonstrated a greater benefit of therapeutic hypothermia for infants who presented with acute versus subacute hypoxia-ischemia injury, the latter likely occurred before delivery and beyond the six-hour window for therapeutic hypothermia. ²

“The further away from the onset of the hypoxic ischemia, invariably the more likely these babies are going to have an abnormal outcomes irrespective of whether you cool them or not,” says Dr. Perlman. “Even though we cooled these groups at the same time, which was within 6 hours, the outcome was dismal for babies with a subacute insult.”

“I do not recommend cooling neonates with clinical evidence suggestive of a subacute or more longstanding insult, because the outcomes even after applying therapeutic hypothermia are uniformly dismal,” says Dr. Perlman. “However, for these neonates, we always give parents the option of cooling or not. In these cases, most parents elect to cool in the hope that these babies will have the best opportunity for a good outcome.”

Reflecting on his extensive therapeutic hypothermia experience, Dr. Perlman concludes, “Cooling a newborn infant is an intense process that requires close attention to details and a holistic view of the baby, including the circumstances before and during birth, in order to determine the optimal supportive interventions and the best approach to the cooling process. Long after these infants leave the NICU, they require long-term follow up to identify cognitive deficits that may only become apparent at school age.”