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Therapeutic Hypothermia for Neonatal Encephalopathy

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Outline

The origins of Therapeutic Hypothermia

The Cooling trials

Pathophysiology of Therapeutic Hypothermia

Lingering questions about cooling

Summary

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Content prepared by

�Dr. Benjamin Courchia MD

&

Dr. Daphna Yasova Barbeau MD

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The origins of therapeutic hypothermia

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“Sarah Parks . . . gave still-birth to a baby boy . . . A young doctor assisting the Parks’ regular physician begged for an opportunity to experiment with an idea he had to rouse the lifeless infant. A tub of ice was ordered and the young doctor plunged the baby into it. Out came the screaming little Parks and he was named Gordon after the doctor who prodded him to life.”

—Sir John Floyer, 1697

Wyatt, J. S. & Thoresen, M. Hypothermia Treatment and the Newborn. Pediatrics 100, 1028–1029 (1997).

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Miller, J. A. Factors in Neonatal Resistance to Anoxia. I. Temperature and Survival of Newborn Guinea Pigs Under Anoxia. Science 110, 113–114 (1949).

B iutt would not be until the early 1950s that the first animal studies would be conducted on hypothermia for neonatal encephalopathy.
How did they even have the presence of mind to study hypothermia in neonates? Well the author of the first paper Dr. James A Miller who conducted most of his career in Louisana, quotes the Van't Hoff principle.
Jacobus Henry Van't Hoff was a dutch chemist who outlined the following principle: the rates of chemical reactions increase 2 times or more for each 10^oC rise in temperature.
Based on this principle James Miller conducted an experiment on guinea pigs where he concludes: "[...] it appears that the effects of reduction of colonic temperatures on one-day-old guinea pigs subjected to anoxic anoxia is to prolong life at about the same rate as might be expected from Vant Hoff's rule [...]”

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J. A. Miller., Miller, F. S. & Westin, B. Hypothermia in the Treatment of Asphyxia Neonatorum. Neonatology 6, 148–163 (1964).

13 patients died

52 alive and well

And so, in the early 1960s came the first clinical reports of hypothermia for the management of neonatal hypoxia.
Interestingly, hypothermia was thought of as a resuscitative measure, and in turn something that had to be initiated very quickly after birth.
In the first case series of ten asphyxiated infants (longest 79 mins 😱) only one baby died within 48 hours due to respiratory distress (recall this is 1960). But, the report is impressive in that the nine remaining infants who underwent cooling survived, and were “neurodevelopmentally intact.”
Additional cases series with more infants were subsequently published with similarly encouraging results.

For clarification, they selected babies that had :

low 1min Apgar scores (<5)
who appeared apneic at birth.

The mechanism to induce hypothermia was not controlled. Babies were cooled quite variably between 20-34^oC and were taken out of cooling baths once spontaneous breathing began (so I cannot imagine for more than a few minutes). Sometimes babies were cooled multiple times. And, importantly rewarming was passive and not active.

Some of the case series reported survival rates ˜80% others reported 90% survival after cooling, all with "good" developmental outcomes. The measure of development was reported as EEG, EKG and multidisciplinary evaluations up to 24 mo of age.The recommendation from Miller and other investigators was that resuscitation protocols be adjusted to include hypothermia in asphyxiated infants. But nothing changed for the next 20 years.

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Papers recommending normothermia in preterm infants are published…. and hypothermia for full term infants with HIE gets sidelined for ˜20 years

As we have grown accustomed to see on the podcast, the field gets (yet again) distracted by other studies that steered the community away from the potential benefits of hypothermia.
In 1958, Dr. William Silverman published in Pediatrics, a paper called The Influence of the Thermal Environment upon the Survival of Newly Born Premature Infants. In that paper, Silverman outlines what he calls the "normothermic hypothesis" which states that the survival of premature infants in the first five days of life would be favorably influenced by environments which raised the body temperature of these subjects.
Another paper, a few years later in 1964, another paper published in Pediatrics called Effect of Maintenance of "Normal"Skin Temperature on the Survival of Infants of Low Birth Weight strengthened the normothermic hypothesis and sucked the life out of the work of hypothermia.
One of the most fascinating aspect of this story is the halo effect this data on preemies had on asphyxiated full terms.... incredible.

[5] Silverman, W. A., Fertig, J. W. & Berger, A. P. THE INFLUENCE OF THE THERMAL ENVIRONMENT UPON THE SURVIVAL OF NEWLY BORN PREMATURE INFANTS. Pediatrics 22, 876–886 (1958).

[6] Buetow, K. C. & Klein, S. W. EFFECT OF MAINTENANCE OF “NORMAL” SKIN TEMPERATURE ON SURVIVAL OF INFANTS OF LOW BIRTH WEIGHT. Pediatrics 34, 163–170 (1964).

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Robertson, C. M. T., Finer, N. N. & Grace, M. G. A. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatrics 114, 753–760 (1989).

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Coimbra, C. & Wieloch, T. Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol 87, 325–331 (1994).

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Thoresen, M. & Wyatt, J. Keeping a cool head, post‐hypoxic hypothermia–an old idea revisited. Acta Paediatr 86, 1029–1033 (1997).

This new wave of research almost 30 years after the first description of the benefits of hypothermia on hypoxic injury is punctuated by the continued use of hypothermia in adult medicine. Cooling for trauma in adult medicine reminded the neonatology community of the potential benefits of this therapy. This sudden epiphany was nicely written up in 1997 by Thoresen and Wyatt in a review paper called Keeping a cool head, post-hypoxic hypothermia-an old idea revisited published in ACTA PEDIATRICA. In that paper they review animal, adult and neonatal evidence taunting the use of hypothermia, the urgent needs to understand its mechanism of action and conclude:

"In our view, mild hypothermia is currently the most promising option for a clinically feasible neural rescue therapy in encephalopathic newborn infants following acute perinatal asphyxia. However there is probably insufficient evidence at present to commence clinical trials of hypothermia treatment in newborn infants. Several important questions remain unresolved. What degree and duration of hypothermia provide an optimal protective effect? How long may treatment be delayed following resuscitation for a protective effect to be detected? Does the protective effect of hypothermia differ in subjects exposed to mild vs severe hypoxia-ischaemia? What are the most appropriate early selection criteria that can be applied in a routine clinical setting? How can possible adverse consequences on other organ systems be ameliorated? Further studies are urgently required to address these issues before clinical trials can be designed. Haphazard application of hypothermia as a clinical intervention is clearly undesirable and collaboration between research groups is essential to agree on protocols for future clinical trials." [10]

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Gunn, A. J., Gunn, T. R., Gunning, M. I., Williams, C. E. & Gluckman, P. D. Neuroprotection With Prolonged Head Cooling Started Before Postischemic Seizures in Fetal Sheep. Pediatrics 102, 1098–1106 (1998).

Hypothermia group

Normothermia group

A year later, Alistair Gunn from New Zealand pulished what would be one of the most influential animal studies in the context of neonatal HIE. In this paper called Neuroprotection With Prolonged Head Cooling Started Before Postischemic Seizures in Fetal Sheep and published in Pediatrics, Gunn and colleagues outlined a few important principles of hypothermia for HIE.
In that study they aimed to figure out how long we had to initiate cooling before the neuroprotective effects of hypothermia were lost.
This research was based on the premise that clinician may need a few hours to recognize the presence of encephalopathy and aimed to identify a therapeutic window for the initiation of cooling.
In this study sheeps were cooled starting at 6hours of life for a duration of 72hours. Temperature was aimed to reach 30-33^oC and the outcomes showed that animals cooled had much better outcomes (on brain pathology) than controls. [11] We are thus starting to see the inception of the cooling protocols we are using today....

In 2002 the NICHD neonatal research network published in Pediatrics a paper called: Whole-Body Hypothermia for Neonatal Encephalopathy: Animal Observations as a Basis for a Randomized, Controlled Pilot Study in Term Infants. [12] In this animal study they tested what would be the backbone of the famous trial they would publish a few years later in the New England Journal of Medicine.

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The NICHD NRN Cooling Trial

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Shankaran, S. et al. Whole-Body Hypothermia for Neonatal Encephalopathy: Animal Observations as a Basis for a Randomized, Controlled Pilot Study in Term Infants. Pediatrics 110, 377–385 (2005).

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Shankaran, S. et al. Whole-Body Hypothermia for Neonatal Encephalopathy: Animal Observations as a Basis for a Randomized, Controlled Pilot Study in Term Infants. Pediatrics 110, 377–385 (2005).

The aim of the trial was to evaluate whether whole-body cooling initiated before 6 hours of age and continued for 72 hours in term infants with encephalopathy would reduce death or disability at 18 to 22 months of age as compared with infants given usual care.

Babies were >36wks and the eligibility criteria for the trial were basically the cooling criteria we use today for mod-severe encephalopathy:

a pH of 7.0 or less or a base deficit of 16 mmol on 1st gas.
If, during this interval, a pH was between 7.01 and 7.15, a base deficit was between 10 and 15.9 mmol per liter, or a blood gas was not available, additional criteria were required. These included:

an acute perinatal event (e.g., late or variable decelerations, cord prolapse, cord rupture, uterine rupture, maternal trauma, hemorrhage, or cardiorespiratory arrest)
and either a 10-minute Apgar score of 5 or less
or assisted ventilation initiated at birth and continued for at least 10 minutes.

Once these criteria were met, all infants underwent a standardized neurologic examination performed by a certified examiner. Infants were candidates for the study when encephalopathy or seizures were present. Encephalopathy was defined as the presence of one or more signs in at least three of the following six categories (Table 1)

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Shankaran, S. et al. Whole-Body Hypothermia for Neonatal Encephalopathy: Animal Observations as a Basis for a Randomized, Controlled Pilot Study in Term Infants. Pediatrics 110, 377–385 (2005).

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The Cool Cap Trial

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Gluckman, P. D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomised trial. Lancet 365, 663--670 (2005).

Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predeﬁned subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation—ie, severe loss of background amplitude, and seizures—and those with less severe changes.

Inclusion criteria:

an Apgar score of 5 or less at 10 min after birth
a continued need for resuscitation, including endotracheal or mask ventilation at 10 min after birth
or severe acidosis

Eligible infants were then assessed for evidence of moderate or severe encephalopathy via SARNAT staging
aEEG recordings were used to improve the speciﬁcity of case selection to control for severity of injury and to allow subgroup analysis to test the hypothesis that hypothermia is not protective in infants with the most severe abnormalities on aEEG before randomisation.

Babies underwent HEAD cooling onlu

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Gluckman, P. D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomised trial. Lancet 365, 663--670 (2005).

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Gluckman, P. D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomised trial. Lancet 365, 663--670 (2005).

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Gluckman, P. D. et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomised trial. Lancet 365, 663--670 (2005).

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The TOBY Trial

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Azzopardi, D. V. et al. Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy. New Engl J Medicine 361, 1349–1358 (2009).

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Azzopardi, D. V. et al. Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy. New Engl J Medicine 361, 1349–1358 (2009).

In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P = 0.17).

Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P = 0.003).

Among survivors:

cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P = 0.03)
improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P = 0.03 for each) and the Gross Motor Function Classification System (P = 0.01).
Improvements in other neurologic outcomes in the cooled group were not significant.

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Meta Analysis

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Shah, P. S. Hypothermia: a systematic review and meta-analysis of clinical trials. Seminars Fetal Neonatal Medicine 15, 238–246 (2010).

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Shah, P. S. Hypothermia: a systematic review and meta-analysis of clinical trials. Seminars Fetal Neonatal Medicine 15, 238–246 (2010).

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How does Therapeutic Hypothermia work?

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Volpe’s Neurology of the Newborn

Encephalopathy: subnormal level of consciousness or seizures and often accompanied by difficulty with initiating or maintaining respiration ande depression of tone and reflexes. but the differential for encephalopathy is wide: metabolic, infectious, thromboembolic, intracranial hemorrhage, genetic syndromes and hypoxia ischemia.

Now in severe, acute hypoxia, the underlying pathologic events of HIE are a result of impaired cerebral blood flow and oxygen delivery to the brain with resulting primary and secondary energy failure.
One of the hallmarks of HIE, is the reperfusion injury that accompanies our resuscitation of infants, after the acute ischemic phase which differentiates it from something like ischemic stroke. In addition, the patterns of neuronal cell injury occur in two phases.

The first phase, or Primary Energy Failure: occurs within minutes, as a result of the initial reduction of cerebral blood flow. The impairment of cerebral blood flow leads to decreases in oxygen and glucose, which leads to significantly less energy or adenosine triphosphate (ATP) production and increased lactate production. The low ATP levels causes failure of multiple cellular mechanisms via cessation of sodium/potassium (Na/K) pumps and mechanisms to maintain low intracellular calcium. When the Na/K pumps fail, there is an excessive influx of sodium ions which precipitates massive depolarization of neurons which leads to the release of glutamate, an excitatory neurotransmitter. The glutamate binds to glutamate receptors allowing additional influx of intracellular calcium and sodium. Increased intracellular calcium has significant detrimental effects leading to cerebral edema, ischemia, microvascular damage, and most of the effects of the primary energy failure lead to necrotic cell death through impaired cellular integrity, disruption of the cytoskeleton and cell membrane. In addition, the original influx of sodium also elicits an osmotic accumulation of cellular water, or cytotoxic edema and the creation of reactive oxidation species, excitatory amino acids and Nitric oxide. In the first phase, reperfusion is established, but the cells are still relatively hypoperfused.

Secondary Energy Failure The secondary energy failure phase begins approximately 6 hours after insult and persists for up to 48 hours after the initial injury. This second phase is marked by hyperperfusion of the ischemic tissue. ->>> See next slide

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Volpe’s Neurology of the Newborn

The exact mechanisms of secondary energy failure appear to be related to oxidative stress from the hyperperfusion leading to mitochondrial dysfunction via the overproduction of free radicals which leads to the delayed apoptotic cell death. Oxidative stress is particularly harmful to the neonatal brain because there are low concentrations of antioxidants and a high consumption of oxygen when transitioning from fetal to neonatal life. Neonates also have high concentrations of unsaturated fatty acids that break down to form more oxygen free radicals. In addition, neonates have higher concentrations of free, or unbound iron which also reacts with peroxides and form free radicals. Ischemia itself also causes increased intraneuronal free iron. The intracellular Ca influx also propogates the production of neuronal NO, which in excessive concentrations is neurotoxic by the creation of caspases that cause DNA strand breaks. The decreased ability of the neonatal brain to eliminate free radicals and the increased susceptibility to the free radials leads to apoptotic damage of neuronal tissue. Excitotoxicity from the first phase also continues allowing for additional influx of sodium and calcium into the neural cells. Glutamate is used by a variety of neuronal pathways including hearing, vision, somatosensory function, learning and memory, which can account for the disruptive effect of HIE on subsequent development. The cytotoxic edema also continues following ongoing influx of sodium ions. Inflammation is also thought to be important in the development of the HIE-related brain injury via proinflammatory cytokines but the exact mechanism remains unknown.In addition, it’s during the secondary phase that epigenetic modifications occur that predict programmed cell death.It’s really the severity of this second phase that predicts poor neurodevelopmental outcomes, which is exactly where Therapeutic hypothermia comes in.

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Volpe’s Neurology of the Newborn

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Lingering questions about hypothermia

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Cooling babies who do not meet “criteria”

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Smit, E., Liu, X., Jary, S., Cowan, F. & Thoresen, M. Cooling neonates who do not fulfil the standard cooling criteria - short- and long-term outcomes. Acta Paediatr 104, 138--145 (2015).

This study from the UK looked at the effects of cooling babies who did not meet criteria. This is such an important concept because we tend to think that cooling is this benign therapy with almost no side effects but we often fail to consider the potential adverse events this could cause in more vulnerable populations. So this group reviewed data from 2006 to 2012 and identified the babies who were cooled and had not met usual criteria.
They identified 36 infants, ˜22% of infants cooled during that time.
These patients included the following: cooled >6 postnatal hours, late preterm infants, and infants with postnatal collapse, major cranial haemorrhage, congenital cardiac disease and surgical conditions.
What they found was that complication rates and long-term outcomes did not significantly differ between the two groups.
However, infants with major cranial hemorrhage had significantly higher rates of coagulopathy and much worse outcomes (80% death/disability). This study is a good reminder that coagulopathy is significantly associated with cooling and should be in the back of our minds when deciding to proceed with TH.

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Cooling babies longer and deeper

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Shankaran, S. et al. Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA 312, (2014).

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Shankaran, S. et al. Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. Jama 318, 57–67 (2017).

The follow up paper published a few years later looking at neurodevelopmental data showed that among 347 infants with primary outcome data death or disability occurred in 31.8% cooled for 72 hours and 31.6% cooled for 120 hours, and in 31.9% cooled to 33.5°C and 31.5% cooled to 32.0°C.
The trial was underpowered because it was stopped early and a significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. Whether this would have translated to significant outcomes if the trial had continued is an interesting question but one that will most likely not be investigated considered the safety issues related to mortality. [3]

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Can you start cooling after 6hrs?

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Laptook, A. R. et al. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. Jama 318, 1550–1560 (2017)

Another interesting paper, published in JAMA also in 2017 titled: Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy A Randomized Clinical Trial asks the interesting question of what would happen if you started cooling past the 6hr mark.
Laptook and colleague for the NICHD NRN assessed whether cooling an HIE baby between 6-24hours of life could reduce the risk of death or disability at 18-22mo of age.
They had ˜80 patients in the study group and ˜80 in the control group, ie. not cooled.
Results for the primary outcome showed that death or disability at 18-22mo occured in 24.4% of cooled infants vs 27.9% of controls (not cooled).
Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group. Which meant that there was an effect on the outcome but some uncertainty of its effectiveness remains.

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Therapeutic Hypothermia for mild HIE…

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#1 The definition of mild HIE is not perfect

#2 There is not yet sufficient evidence to answer this question

#3 Mild HIE does have some neurodevelopmental impact

Mild HIE was associated with worse outcomes. The PRIME study found that disability occurred in 16% of infants at 18–22months follow-up. DuPont et al. demonstrated that 20% of newborns with perinatal acidemia and a neurologic exam consistent with mild HIE had abnormal short-term outcomes attributable to their encephalopathy, such as seizures, death from progressive asphyxia insult, and abnormal MRI find- ings consistent with HIE. A retrospective study by Walsh et al. had found that 54% of infants with mild HIE had an abnormal MRI. And so, this evidence published between 2013-2017 has led to what is know as a therapeutic "creep" where clinicians started cooling babies with mild HIE. Data from the Vermont Oxford Network shows that 40% of patients undergoing TH had neither moderate nor severe HIE.

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Kariholu, U. et al. Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and meta-analysis. Archives Dis Child - Fetal Neonatal Ed 105, 225 (2018).

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Perretta, L., Reed, R., Ross, G. & Perlman, J. Is there a role for therapeutic hypothermia administration in term infants with mild neonatal encephalopathy? J Perinatol 40, 522–529 (2019).

Two more trials that were more recently published on this subject are worth mentioning. First, a study by Perretta et al. called Is there a role for therapeutic hypothermia administration in term infants with mild neonatal encephalopathy? was published in the journal of perinatology in 2019.

In this retrospective study comparing the outcomes of 37 infants with moderate HIE to 11 babies with mild HIE, both groups were cooled.
This was an odd comparison, I admit, and overall the outcomes of the 11 babies in the Mild HIE group were quite good and obviously better than the ones in the moderate HIE group without reaching statistical significance

What was interesting though was that the authors report that 7/11, or 64%, infants with mild HIE progressed to moderate HIE as evidenced by EEG seizures (n = 7) ± clinical seizures (n = 4). This is quite frightening considering that most of us will have to make some decision regarding cooling within the narrow window of 6hrs.

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Montaldo, P. et al. Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic-ischaemic encephalopathy: a non-randomised cohort study. Archives Dis Child Fetal Neonatal Ed 104, F515–F520 (2019).

Last paper is called Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic-ischaemic encephalopathy: a non-randomised cohort study and was published in the Archives by Montaldo and colleagues in 2019.

This trial involved 8 units in the UK and looked at 47 newborns w Mild HIE. 32/47 were cooled and the remaining 15 were not (5 were cooled for <12h).

They looked at MRI data at 2 weeks and neurodevelopmental outcomes at 2 years.

Outcomes were, to me, impressive. Mean (SD) thalamic N-AcetylAspartate/Creatinine ratio was HIGHER in cooled babies, so was the NAA/Cho ratios on MR spectroscopy.

Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02).

Four (27%) non-cooled babies with mild HIE developed seizures after 6hours of age, while none of the cooled babies developed seizures (p=0.008).

Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies.
Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09).

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Is passive cooling a thing?

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Lemyre, B. et al. Initiation of passive cooling at referring centre is most predictive of achieving early therapeutic hypothermia in asphyxiated newborns. Paediatr Child Healt 22, 264–268 (2017).

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Summary

Therapeutic hypothermia was first tried on asphyxiated neonates in the 1960s.
The cooling trials published in the early 2000’s showed a significant reduction in death or moderate-severe neurodevelopmental disability in patients with moderate to severe HIE.
Therapeutic hypothermia initiated within the therapeutic window can reduce the impact of the secondary energy failure that normally leads to cell death
The use of hypothermia outside of the usual indications (after 6hrs, mild HIE, etc) remains debated and warrants more evidence.

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Thank You