Amplitude-Integrated Electroencephalography Improves the Identification of Infants with Encephalopathy for Therapeutic Hypothermia and Predicts Neurodevelopmental Outcomes at 2 Years of Age.

OBJECTIVES: To examine whether using an amplitude-integrated electroencephalography (aEEG) severity pattern as an entry criterion for therapeutic hypothermia better selects infants with hypoxic-ischemic encephalopathy and to assess the time-to-normal trace for aEEG and magnetic resonance imaging (MRI) lesion load as 24-month outcome predictors. STUDY DESIGN: Forty-seven infants meeting Norwegian therapeutic hypothermia guidelines were enrolled prospectively. Eight-channel EEG/aEEG was recorded from 6 hours until after rewarming, and read after discharge. Neonatal MRI brain scans were scored for summated (range 0-11) regional lesion load. A poor outcome at 2 years was defined as death or a Bayley Scales of Infant-Toddler Development cognitive or motor composite score of <85 or severe hearing or visual loss. RESULTS: Three severity groups were defined from the initial aEEG; continuous normal voltage (CNV; n = 15), discontinuous normal voltage (DNV; n = 18), and a severe aEEG voltage pattern (SEVP; n = 14). Any seizure occurrence was 7% CNV, 50% DNV, and 100% SEVP. Infants with SEVP with poor vs good outcome had a significantly longer median (IQR) time-to-normal trace: 58 hours (9-79) vs 18 hours (12-19) and higher MRI lesion load: 10 (3-10) vs 2 (1-5). A poor outcome was noted in 3 of 15 infants with CNV, 4 of 18 infants with DNV, and 8 of 14 infants with SEVP. Using multiple stepwise linear regression analyses including only infants with abnormal aEEG (DNV and SEVP), MRI lesion load significantly predicted cognitive and motor scores. For the SEVP group alone, time-to-normal trace was a stronger outcome predictor than MRI score. No variable predicted outcome in infants with CNV. CONCLUSIONS: Selection of infants with encephalopathy for therapeutic hypothermia after perinatal asphyxia may be improved by including only infants with an early moderate or severely depressed background aEEG trace.

Factors associated with permanent hearing impairment in infants treated with therapeutic hypothermia.

OBJECTIVE: To define the incidence of hearing impairment, document plasma gentamicin concentrations, and identify factors associated with permanent hearing impairment in infants subjected to therapeutic hypothermia for moderate or severe neonatal encephalopathy. STUDY DESIGN: Data were collected prospectively in a regional center providing therapeutic hypothermia. Cooled infants at ≥ 36 weeks gestation with moderate or severe neonatal encephalopathy were analyzed if a full dataset was available (n = 108), including clinical variables and gentamicin trough levels. Infants with hearing impairment were identified, and survivors were followed up with neurodevelopmental evaluation at age 18 months. Stepwise logistic regression identified factors associated with hearing impairment. RESULTS: Nine infants died, and among the survivors, 10.1% developed a permanent hearing impairment. The trough gentamicin level was above the recommended cutoff of 2 mg/L in 37% of the infants in the entire cohort and in 90% of the infants with hearing impairment. Logistic regression analysis identified high trough gentamicin level, low cord pH, and hypoglycemia (<46.8 mg/dL) in the first postnatal hour as significantly associated with hearing impairment. The need for inotropic support was close to significant (P = .055). CONCLUSION: Hearing impairment was a common finding among cooled infants. Plasma gentamicin levels were commonly >2 mg/L. Based on these findings, we propose changes in gentamicin dosing interval and trough level monitoring to minimize the risk of potentially toxic levels in cooled newborns.

Increased inspired oxygen in the first hours of life is associated with adverse outcome in newborns treated for perinatal asphyxia with therapeutic hypothermia.

OBJECTIVE: To assess whether increased inspired oxygen and/or hypocarbia during the first 6 hours of life are associated with adverse outcome at 18 months in term neonates treated with therapeutic hypothermia. STUDY DESIGN: Blood gas values and ventilatory settings were monitored hourly in 61 newborns for 6 hours after birth. We investigated if there was an association between increased inspired oxygen and/or hypocarbia and adverse outcome (death or disability by Bayley Scales of Newborn Development II examination at 18-20 months). RESULTS: Hypothermia was started from 3 hours 45 minutes (10 minutes-10 hours) and median lowest Pco(2) level within the first 6 hours of life was 30 mm Hg (16.5-96 mm Hg). The median highest fraction of inspiratory oxygen within the first hour of life was 0.43 (0.21-1.00). The area under the curve fraction of inspiratory oxygen and Pao(2) for hours 1-6 of life was 0.23 (0.21-1.0) and 86 mm Hg (22-197 mm Hg), respectively. We did not find any association between any measures of hypocapnia and adverse outcome (P > .05), but increased inspired oxygen correlated with adverse outcome, even when excluding newborns with initial oxygenation failure (P < .05). CONCLUSION: Increased fraction of inspired oxygen within the first 6 hours of life was significantly associated with adverse outcome in newborns treated with therapeutic hypothermia following hypoxic ischemic encephalopathy.

Hypothermia after perinatal asphyxia: selection for treatment and cooling protocol.

Three large randomized controlled trials have demonstrated benefits from 3 days of cooling to 33-34°C after perinatal asphyxia. No serious adverse effects were documented. The trials excluded many infants for hypothermia (HT) therapy, including those of age >6 hours and those with prematurity of <36 weeks gestation, abnormal coagulation, persistent pulmonary hypertension, and congenital abnormalities. This article considers whether the foregoing trial exclusion criteria are feasible given current knowledge and evidence. HT affects the validity of some outcome predictors (eg, clinical examination, amplitude-integrated electroencephalography), but not of magnetic resonance imaging. HT is a time-critical emergency treatment after perinatal asphyxia that requires optimal collaboration among local hospitals, transport teams, and cooling centers.

Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy.

OBJECTIVE: To evaluate whether therapeutic hypothermia alters the prognostic value of clinical grading of neonatal encephalopathy. STUDY DESIGN: This study was a secondary analysis of a multicenter study of 234 term infants with neonatal encephalopathy randomized to head cooling for 72 hours starting within 6 hours of birth, with rectal temperature maintained at 34.5 degrees C +/- 0.5 degrees C, followed by re-warming for 4 hours, or standard care at 37.0 degrees C +/- 0.5 degrees C. Severity of encephalopathy was measured pre-randomization and on day 4, after re-warming, in 177 infants; 31 infants died before day 4, and data were missing for 10 infants. The primary outcome was death or severe disability at 18 months of age. RESULTS: Milder pre-randomization encephalopathy, greater improvement in encephalopathy from randomization to day 4, and cooling were associated with favorable outcome in multivariate binary logistic regression. Hypothermia did not affect severity of encephalopathy at day 4, however, in infants with moderate encephalopathy at day 4, those treated with hypothermia had a significantly higher rate of favorable outcome (31/45 infants, 69%, P = .006) compared with standard care (12/33, 36%). CONCLUSION: Infants with moderate encephalopathy on day 4 may have a more favorable prognosis after hypothermia treatment than expected after standard care.