Professional Documents
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Principal author(s)
Brigitte Lemyre, Vann Chau
; Canadian Paediatric Society, Fetus and Newborn Committee
(https://cps.ca/en/documents/authors-auteurs/fetus-and-newborn-committee)
Abstract
Therapeutic hypothermia is a standard of care for infants ≥36 weeks gestational age (GA) with moderate-to-severe
hypoxic-ischemic encephalopathy. Because some studies included infants born at 35 weeks GA, hypothermia should be
considered if they meet other criteria. Cooling for infants <35 weeks GA is not recommended. Passive cooling should be
started promptly in community centres, in consultation with a tertiary care centre neonatologist, while closely
monitoring the infant’s temperature. Best evidence suggests that maintaining core body temperature between 33°C and
34°C for 72 hours, followed by a period of rewarming of 6 to 12 hours, is optimal. Antiepileptic medications should be
used when clinical or electrographic seizures are present. Maintaining serum electrolytes and glucose within normal
ranges, and avoiding hypo- or hypercarbia and hyperoxia, are important adjunct treatments. A brain magnetic
resonance image (MRI) is advised shortly after rewarming and, in cases where earlier findings do not match the clinical
picture, a repeat MRI after 10 days of life is suggested. Multidisciplinary neurodevelopmental follow-up is
recommended.
BACKGROUND
Neonatal encephalopathy is a clinical syndrome of disturbed neurological function that presents early in life, with an
incidence of approximately 1/1000 to 6/1000 live births [1]. Hypoxic-ischemic encephalopathy (HIE) accounts for a significant
proportion of encephalopathic newborns. Despite advances in perinatal care, moderate-to-severe acute perinatal HIE in late
preterm and term infants remains an important cause of mortality, acute neurological injury and subsequent long-term
neurodevelopmental disability [1]. Impaired cerebral blood flow, in the setting of hypoxia, is the main mechanism causing
brain injury following intrapartum hypoxia-ischemia.
At the cellular level, hypoxia-ischemia results in two phases of energy failure. The primary phase follows the reduction in
blood flow and oxygen supply, with a fall in adenosine triphosphate (ATP), failure of the sodium (Na+)/potassium (K+) pump,
depolarization of cells, lactic acidosis, release of excitatory amino acids, calcium entry into the cell and, when severe, cell
necrosis [2]. Following resuscitation and reperfusion, there is a latent period of 1 to 6 hours where the impairment of cerebral
oxidative metabolism can at least partially recover, before irreversible failure of mitochondrial function [2]. This latent phase
is the therapeutic window for neuroprotective interventions [2][3].
The risk for disability and impaired cognitive development correlates with the severity of HIE [4][5]. A mild reduction in brain
temperature of 2°C to 4°C, initiated within 6 hours after birth, was the first therapy to demonstrate neuroprotection in
newborn animals [6]. The neuroprotective mechanism of therapeutic hypothermia is multifactorial and attributable to broad
inhibitory activity against a variety of harmful cell processes.
HIE is often unanticipated, and many infants are initially cared for in community hospitals. It is important, therefore, that
professionals involved in caring for these infants—family physicians, obstetricians, midwives, nurses, community
paediatricians and neonatologists—recognize when cooling may be beneficial. This position statement summarizes the
current evidence pertaining to therapeutic hypothermia for the neuroprotection of neonates with HIE and provides guidance
for clinicians regarding this therapy.
STATEMENT DEVELOPMENT
A search of MEDLINE, including ‘in-process and other non-indexed citations’ (1946 to May 6, 2016), Embase (1974 to May 6,
2016), and the Cochrane Central Register of Controlled Trials (CENTRAL, April 2016) was performed by a certified librarian,
using the OVID interface [7]. Search terms included: ‘hypothermia, induced’, ‘hypother* or cooling’, ‘hypoxia-ischemia, brain’,
‘hypox*or ischem*’, ‘newborn infant’, and ‘infan* or newborn* or newborn* or neonat*’. Reference lists of publications were
reviewed. A total of 1511 references were retrieved, of which full text articles and Cochrane reviews were reviewed.
The hierarchy of evidence from the Centre for Evidence-Based Medicine (www.cebm.net) was applied to the publications
identified. Recommendations are based on the format developed by Shekelle et al. [8].
Therapeutic hypothermia is therefore considered to be the standard of care for infants with moderate-to-severe HIE who
meet inclusion criteria. Level of evidence: 1a
B. pH 7.01 to 7.15 or base deficit −10 to −15.9 on cord gas or blood gas within 1 h AND
1.
History of acute perinatal event (such as but not limited to cord prolapse, placental abruption or uterine rupture) AND
2. Apgar score ≤5 at 10 minutes or at least 10 minutes of
positive-pressure ventilation
C. Evidence of moderate-to-severe encephalopathy, demonstrated by the presence of seizures OR at least one sign in three or
more of the six categories shown in Table 1.
When available, assessment with an amplitude-integrated electroencephalogram (aEEG) for at least 20 minutes to document
abnormal tracings or seizures, particularly for infants with moderate encephalopathy, may be useful for determining
eligibility. A normal aEEG does not predict a normal MRI or favourable acute outcome [21]. The use of continuous EEG (when
available) or aEEG within the first 48 hours postbirth may be useful for detecting electrical seizures or mild HIE [22]. Recent
retrospective studies suggest that infants with mild HIE may have sequelae and perhaps should be considered for therapeutic
hypothermia [23]–[25]. However, at this point, there are insufficient data to make this recommendation.
Table 1. Criteria for defining moderate and severe encephalopathy
3. Posture Distal flexion, full Decerebrate (arms extended and internally rotated, legs
extension extended with feet in forced plantar flexion)
5. Primitive reflexes
6. Autonomic system
All infants who are depressed at birth should be assessed to determine whether they fulfill criteria A or B. Infants who fulfill
criteria A or B should then undergo a careful neurological examination to determine whether they fulfill criteria C. Infants
who meet criteria A and C or B and C should be offered hypothermia. Some cases are difficult to categorize and require
discussion with a tertiary care neonatologist. As preparations for cooling are made, if an infant’s neurological status has fully
returned to normal (within 30 to 45 minutes after birth), cooling may be deferred with careful ongoing observation for signs
of returning encephalopathy. Level of evidence: 1a
Selective head cooling can be achieved with cooling caps fitted around an infant’s head, with the aim of maintaining
fontanelle temperature below 30°C. A rectal temperature of 34°C ± 0.5°C is maintained using a servo-controlled radiant heater.
This system is expensive and labour-intensive, and may produce scalp edema or skin breakdown. It is also more difficult to
maintain rectal temperature and there is limited access for EEG leads. Whole body cooling to a rectal temperature of 33.5°C ±
0.5°C can be achieved with passive cooling, cool packs and/or commercially available cooling blankets. Servo-controlled
cooling blankets produce more consistent target temperatures [31].
Whole body cooling is recommended preferentially because it is easier to set up and use, less expensive, provides better
access to EEGs and is more readily available. Level of evidence: 1b
The earlier passive cooling is initiated, the earlier target temperature will be reached [33]. The use of ice packs or cool gels by
untrained personnel, which can lead to severe hypothermia, is not recommended. Level of evidence: 2b
Similarly, antiepileptic drugs should be used with caution in newborns with HIE, due to their known neurotoxicity [44].
Despite this proviso, experts recommend to treat neonatal seizures, which are common in HIE and suspected to be an
independent cause of brain injury [22][45][46]. Obtaining serum levels of antiepileptics, particularly in the first 72 hours if
redosing is needed, should be strongly considered. Level of evidence: 4
Early minimal enteral feeding (10 mL/kg/day to 20 mL/kg/ day) during hypothermia, initiated during the first few days of life,
is safe and feasible for newborns with HIE [47]. In fact, whole body hypothermia may even have beneficial effects on
gastrointestinal morbidity and feeding tolerance [48]. However, more than minimal feeds is not as safe because gut perfusion
may be decreased during cooling [49].
Minimizing fluctuations in blood carbon dioxide levels, avoiding hyperoxia, ensuring adequate tissue perfusion with
appropriate use of vasopressors or inotropic agents, maintaining normal serum glucose, treating hyperbilirubinemia, and
minimizing unnecessary stimulation or handling are additional management strategies to optimize outcome [50]–[53].
There has been considerable interest and ongoing research in evaluating the neuroprotective efficacy of different agents
(allopurinol, xenon, melatonin, erythropoietin, neural stem cells and magnesium sulphate) in combination with hypothermia
[54]–[60], but there is insufficient evidence to recommend their use at this time.
Performing an MRI in an infant undergoing active cooling is a challenge, due to the needs to maintain a steady temperature
and compatibility of thermoregulation equipment with MRI. In the absence of an MRI-compatible isolette and other
specialized equipment, it is recommended to obtain an MRI once rewarming has taken place, on day of life 4 or 5. Imaging can
usually be done with the infant swaddled and after a feed, as opposed to under general anaesthesia. Centres should attempt to
perform such MRIs on the same day of life for all patients, to increase local expertise in reading and interpreting findings.
Consider a repeat MRI between days 10 and 14 of life when the imaging and clinical features are discordant or when
diagnostic ambiguity persists [65]. Level of evidence: 3
WHAT FOLLOW-UP SHOULD BE ORGANIZED FOR INFANTS WHO RECEIVE
HYPOTHERMIA?
Cerebral palsy or severe disability occurs in more than 30% of HIE-affected newborns, and is most common in infants with
severe encephalopathy [66]. There is increasing recognition that cognitive deficits may be prominent, even in the absence of
cerebral palsy [67]. Severe visual impairment or blindness occurs in up to 25% of children after moderate or severe
encephalopathy, especially in the setting of hypoglycemia. Decreased visual acuity, visual fields or stereopsis are also
described [68]. Sensorineural hearing loss, likely secondary to brainstem injury, affects up to 18% of survivors of moderate
encephalopathy without cerebral palsy [69]. Cognitive deficits, particularly difficulties with reading, spelling and arithmetic,
are seen in 30% to 50% of childhood survivors of moderate HIE [70]. Behavioural difficulties, such as hyperactivity and
emotional problems, should also be considered even in survivors who do not experience motor disability [71]. In neonates
with moderate-to-severe HIE treated with therapeutic hypothermia, childhood epilepsy is identified in 13% of survivors, with
7% necessitating an antiepileptic medication in school age [72].
Follow-up at 18 to 24 months has been the standard of care in hypothermia trials. However, given the broad spectrum of
neurodevelopmental impairments following hypoxic-ischemic brain encephalopathy and individual heterogeneity, following
affected newborns closely through infancy and into later childhood is important. Multidisciplinary follow-up could involve a
neonatologist or paediatrician, nurse, physiotherapy, occupational therapy, psychology, an infant development program,
neurology, developmental paediatrician, ophthalmology and audiology. Specialists working together to assess long-term
motor, psycho-educational, auditory and cognitive outcomes is an important care component for infants who have received
therapeutic hypothermia. Level of evidence: 2b
CONCLUSION
Mild therapeutic hypothermia to a core rectal temperature of 33.5°C ± 0.5°C, initiated as soon as possible within the first 6
hours of life, decreases mortality and or severe long-term neurodevelopmental disabilities in infants with moderate-to-severe
HIE, without increasing the incidence of disability in survivors. Therapeutic hypothermia should be provided in tertiary
neonatal units and initiated in consultation with a level 3 neonatologist before transport. Close surveillance of infants during
the cooling process is needed, given the risk for complications of both HIE and cooling. Long-term, multidisciplinary follow-up
of survivors to assess and address neurocognitive function is essential to quality care.
A SUMMARY OF RECOMMENDATIONS
Infants ≥36 weeks GA with moderate-to-severe HIE who meet inclusion criteria should receive therapeutic
hypothermia. Recommendation grade A.
Infants ≥35 weeks GA with moderate-to-severe HIE who meet other inclusion criteria should be considered for
therapeutic hypothermia. Recommendation grade B.
Therapeutic hypothermia should not be offered for the following patients: moribund infants or infants with major
congenital or genetic abnormalities for whom no further aggressive treatment is planned, infants with severe intra-
uterine growth restriction or clinically significant coagulopathy, or infants with evidence of severe head trauma or
intracranial bleeding. Recommendation grade A.
Community physicians caring for infants with suspected HIE for whom therapeutic hypothermia is considered, should
consult a neonatologist regarding initiation of passive cooling as soon as possible after birth. All infants requiring
therapeutic hypothermia should be transferred to a tertiary care Neonatal Intensive Care Unit with appropriate
expertise and resources. Recommendation grade D.
Both selective head cooling and whole body cooling are effective. Whole body cooling is easier to set up and use, less
expensive and provides access to EEG; it is therefore recommended for centres not currently using selective head
cooling. Recommendation grade B.
Therapeutic hypothermia should be continued for 72 hours, with a target rectal (or esophageal) temperature of 33°C to
34°C for whole body cooling, or 34°C to 35°C for selective head cooling. Rewarming should occur over 6 to 12 hours
(0.5°C every 1 to 2 hours). Recommendation grade A.
Therapeutic hypothermia in infants younger than 35 weeks is not recommended. Recommendation grade C.
Treatment of pain or discomfort during cooling with a low-dose opioid is recommended. Recommendation grade B.
Treatment of seizures, despite limitations of knowledge
about the side effects of antiepileptic medications, is
recommended, because benefits likely outweigh the risks. Recommendation grade D.
Follow-up of infants who received hypothermia to a minimum of 2 years, but ideally until school age, in a neonatal
follow-up clinic, is recommended. Follow-up should be in conjunction with care by a community paediatrician.
Recommendation grade B.
Acknowledgements
This position statement was reviewed by the Community Paediatrics and Acute Care Committees of the Canadian Paediatric
Society.
Members: Mireille Guillot MD, Leonora Hendson MD, Ann Jefferies MD (past Chair), Thierry Lacaze-Masmonteil MD (Chair),
Brigitte Lemyre MD, Michael Narvey MD, Leigh Anne Allwood Newhook MD (Board Representative), Vibhuti Shah MD
Liaisons: Radha Chari MD, The Society of Obstetricians and Gynaecologists of Canada; William Ehman MD, College of Family
Physicians of Canada; Roxanne Laforge RN, Canadian Perinatal Programs Coalition; Chantal Nelson PhD, Public Health
Agency of Canada; Eugene H Ng MD, CPS Neonatal-Perinatal Medicine Section; Doris Sawatzky-Dickson RN, Canadian
Association of Neonatal Nurses; Kristi Watterberg MD, Committee on Fetus and Newborn, American Academy of Pediatrics
References
Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to
be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at
time of publication.