Neonatal Hypothermia

A Method to Provide Neuroprotection After Hypoxic Ischemic Encephalopathy

Katherine M. Newnam, MS, RN, CPNP, NNP-BC; Donna L. DeLoach, MS, RN, CPNP, NNP-BC

NAINR. 2011;11(3):113-124.

Rewarming: Slowly Achieving a Normothermic Temperature

Although the risk for seizures increases with rewarming, a discussion is warranted to review other risk factors associated with this process. Rewarming may cause peripheral vasodilatation, and the intravascular blood volume increases.^[30] Hypotension occurs if the vascular bed is underfilled. Alteration in the cardiac function as a result of the initial hypoxic event may play a contributing role.^[42] Apnea may also occur during rewarming, which requires rapid intervention. In experimental models, a mismatch between oxygen delivery and the consumption of oxygen has been demonstrated during the rewarming process.^[30] In the clinical setting, this mismatch can be measured by serial plasma lactate levels; baseline and serial levels should be considered.

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Table 1. Summary of Initial Clinical Trials; Seminal Work From 3 Primary Research Teams
Citation	Sample Size/Inclusion Criteria	Method/Duration of Cooling	Follow-up	Findings
27	234 term infants; 116 randomly selected for cooling and 118 selected for control. Sixteen infants were lost to follow-up at 18 months with final reported sample; cooled, n = 108 and control, n = 110.Clinical inclusion criteria: Apgar score of five or less at 10 minutes after birth; continued need for resuscitation at 10 minutes after birth; pH <7 or base deficit of 16 mmol/L and evidence of moderate or severe encephalopathy (Sarnet score) and aEEG recording used to control for the severity of injury.	Method: Head cooling with cooling cap within 6 hours of birth. Duration of cooling: 72 hours at 34°C–35°C (measured rectally).	Followed up infants until 18 months of age with neurologic, visual, auditory, and neurodevelopmental assessments by a developmental specialist using the Bayley II scale.	No differences were reported in the frequency of clinically significant complications. Head cooling in the most severely affected infants had little effect on mortality rates as well as measured short- and long-term outcomes. The most significant improvements in the rates of mortality and short- and long-term neurodevelopmental outcomes were noted in the moderately affected infants.
31	Six participating sites enrolled a total of 65 infants; randomized patients to groups: 32 to hypothermia (treatment) and 33 to normothermia (control).A total of five patients were withdrawn from the study (three from treatment and two from control). Inclusion criteria included infants >35 weeks gestation and >2 kg birth weight and within 6 hours of birth who exhibited one clinical sign (acidosis, Apgar, prolonged resuscitation, bradycardia >15 minutes) of HIE and two neurologic findings (posturing, seizures, tone abnormalities orchanges in level of consciousness [LOC]).	Method: Whole body cooling with infant cooling blanket within 6 hours of birth. Duration of cooling: 72 hours at 34°C–35°C (measured rectally).	Primary outcome variables were death or abnormal neurodevelopmental scores (Bayley II), Cognitive Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS), or Vineland examinations up to and including 12 months of age.	77% of all infants enrolled were classified as Sarnat III (severe). The death rate was 31% in the treatment group and 42% in the control group (P = .35). The patients evaluated at 12 months (17 treatment and 12 control patients ) had neurodevelopmental testing, which showed that 24% of the treatment group had severely abnormal index scores compared with 64% of the control group. Length of hospitalization was not significantly different between the groups.
14	Hypothermia group, n = 106; control group, n = 102 of 239 eligible infants; and three infants from the control group were lost to follow-up.Infants >36 weeks gestation admitted to the hospital by 6 hours of age who demonstrated severe acidosis (pH ≤7, cord or infant blood analysis with base deficit of 16 mmol/L and/or 10 minutes Apgar score ≤5 with prolonged resuscitation requirement at delivery. Neurologic evaluation for moderate or severe (modified Sarnat) encephalopathy was used. Exclusion criteria: admission >6 hours, major congenital abnormality, intrauterine growth restriction (IUGR), low birth weight <1800 grams, or parental/attending physician refusal.	Method: Whole body cooling with infant cooling blanket within 6 hours of birth. Duration of cooling: 72 hours at 33.5°C (target temp) (measured with esophageal and skin probes). Rewarming process; increased infant's temperature by 0.5°C per hour until goal temperature of 36.5°C.	Followed up infants until 18–22 months of age with an assessment of neuromotor disability based on the presence of cerebral palsy (CP) and functional disability graded according to the Gross Motor Function Classification System. Cognitive outcome assessment was completed with the Bayley Scales of Infant Development II.Moderate disability was defined as Gross Motor Function Classification System (GMFCS) grade of level 2, hearing impairment, or persistent seizure disorder.	Primary outcome was death or disability (moderate or severe). There was no increased risk of death or disability as a result of the treatment protocol. There was no increased rate of moderate or severe disability at 18–22 months of age with the rate of CP among the hypothermia group, 19%, and control group, 30%. The Bayley II index less than 70 was 25% in the hypothermia group and 39% in the control group. Whole body hypothermia reduced the risk of death or disability in those infants who were identified as moderate or severe classification of HIE. The safety of this treatment (whole-body hypothermia) was also proven.

Eicher, Wagner et al. 2005; Gluckman, Wyatt et al. 2005; Shankaran, Laptook et al. 2005.

Table 2. Stages of Injury Based on Clinical Evaluation After HIE
	Stage I (Mild)	Stage II (Moderate)	Stage III (Severe)
Level of consciousness	Hyperalert	Lethargy	Stupor
Neuromuscular
Tone	Normal	Hypotonia (mild/moderate)	Flaccid
Posture	Mild flexion	Strong flexion	Decerebrate
Reflexes	Hyperactive	Hyperactive	Decreased/absent
Suck	Weak	Weak or absent	Absent
Moro	Strong	Weak	Absent
Tonic neck	Slight	Strong	Absent
Autonomic function	Sympathetic depressed	Parasympathetic depressed	Both depressed
Pupillary response	Dilated (mydriasis)	Pinpoint (miosis)	Unequal/poor response
Heart rate	Tachycardia	Bradycardia	Both
GI motility	Normal or slowed	Increased/diarrhea	Both
Seizure activity	None	Common: Focal/multifocal	Uncommon/decerebrate
EEG findings	Normal	Intermittent spike/seizure	Isopotential/depressed
Typical duration	<24 hours	2–14 days	Hours to weeks

Information adapted by the authors from Sarnat's original work with revisions described during early clinical trials 14,26,27,28.
*May have findings in various stages.

Table 3. Recommended Inclusion/Exclusion Criteria for Hypothermia Treatment After HIE
Inclusion Criteria:
Infants >36 weeks of age Infants who have been evaluated as moderate or severe HIE/Sarnat stages II or III (see Table 2) Blood gas pH <7 and/or base deficit of >16 (cord gas or initial blood gas) History of acute perinatal event and/or Apgar score at 10 minutes of <5 Need for continued respiratory support through ventilation
Exclusion criteria
Infants with birth weight <2 kg Infants who have been evaluated as mild HIE/Sarnat stage I (see Table 2) Life-threatening coagulopathy Longer than (>) 6 hours from birth Medical team exclusion for other reasons (may include family request or other physical/genetic anomalies)

Eicher et al, 2005; Gluckman et al, 2005; Shankaran et al, 2005.

Table 4. Observed Signs and Symptoms of Adverse Effects of Hypoxia and/or Hypothermia
Physiologic System	Hypoxia/Hypothermia/Both
Neurologic
Seizures	Hypoxia
CNS bleeds	Hypoxia
CNS infarcts	Hypoxia
Difficulties in temperature control	Both
Encephalopathy	Hypoxia
Respiratory
Respiratory insufficiency or failure	Both (especially with rewarming)
Respiratory acidosis	Both
Pulmonary hemorrhage	Hypoxia
Persistent pulmonary hypertension	Hypoxia
Cardiovascular
Bradycardia	Both
Cardiac arrhythmia	Both
Coagulopathy/bleeding	Hypoxia
Microembolism	Both
Hypotension	Both
Thrombocytopenia	Both
Hyperviscosity	Hyperthermia
Gastrointestinal
Slowed gastric motility	Both
Hypoglycemia	Both
Renal
Oliguria	Hypoxia
Anuria	Hypoxia
Integument
Skin changes	Both
Subcutaneous fat necrosis	Both
Hepatic/endocrine
Metabolic acidosis	Both (especially with rewarming)
Hepatic dysfunction	Hypoxia
Hypocalcaemia	Hypoxia
Hypercalcemia	Both
Hyponatremia	Hypoxia
Infections
Sepsis (viral/bacterial)	Independent of either

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Neonatal Hypothermia

A Method to Provide Neuroprotection After Hypoxic Ischemic Encephalopathy

Rewarming: Slowly Achieving a Normothermic Temperature

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