Biomarkers S100B and neuron-specific enolase predict outcome in hypothermia-treated encephalopathic newborns*.

OBJECTIVES: To evaluate if serum S100B protein and neuron-specific enolase measured during therapeutic hypothermia are predictive of neurodevelopmental outcome at 15 months in children with neonatal encephalopathy. DESIGN: Prospective longitudinal cohort study. SETTING: A level IV neonatal ICU in a freestanding children's hospital. PATIENTS: Term newborns with moderate to severe neonatal encephalopathy referred for therapeutic hypothermia during the study period. INTERVENTIONS: Serum neuron-specific enolase and S100B were measured at 0, 12, 24, and 72 hours of hypothermia. MEASUREMENTS AND MAIN RESULTS: Of the 83 infants enrolled, 15 (18%) died in the newborn period. Survivors were evaluated by the Bayley Scales of Infant Development-II at 15 months. Outcomes were assessed in 49 of 68 survivors (72%) at a mean age of 15.2 ± 2.7 months. Neurodevelopmental outcome was classified by Bayley Scales of Infant Development-II Mental Developmental Index and Psychomotor Developmental Index scores, reflecting cognitive and motor outcomes, respectively. Four-level outcome classifications were defined a priori: normal = Mental Developmental Index/Psychomotor Developmental Index within 1 SD (> 85), mild = Mental Developmental Index/Psychomotor Developmental Index less than 1 SD (70-85), moderate/severe = Mental Developmental Index/Psychomotor Developmental Index less than 2 SD (< 70), or died. Elevated serum S100B and neuron-specific enolase levels measured during hypothermia were associated with increasing outcome severity after controlling for baseline and socioeconomic characteristics in ordinal regression models. Adjusted odds ratios for cognitive outcome were 2.5 (95% CI, 1.3-4.8) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase, and for motor outcome, 2.6 (95% CI, 1.2-5.6) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase. CONCLUSIONS: Serum S100B and neuron-specific enolase levels in babies with neonatal encephalopathy are associated with neurodevelopmental outcome at 15 months. These putative biomarkers of brain injury may help direct care during therapeutic hypothermia.

Coagulopathy in newborns with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia: a retrospective case-control study.

BACKGROUND: Newborns with hypoxic ischemic encephalopathy (HIE) are at risk for coagulopathy due to systemic oxygen deprivation. Additionally, therapeutic hypothermia (TH) slows enzymatic activity of the coagulation cascade, leading to constitutive prolongation of routinely assessed coagulation studies. The level of laboratory abnormality that predicts bleeding is unclear, leading to varying transfusion therapy practices. METHODS: HIE infants treated with TH between 2008-2012 were included in this retrospective study. Initial, minimum (min) and maximum (max) values of International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen (Fib) and platelet (PLT) count (measured twice daily during TH) were collected. Bleeding was defined as clinically significant if associated with 1) decreased hemoglobin (Hb) by 2 g/dL in 24 hours, 2) transfusion of blood products for hemostasis, or 3) involvement of a critical organ system. Laboratory data between the bleeding group (BG) and non-bleeding group (NBG) were compared. Variables that differed significantly between groups were evaluated with Receiver Operating Characteristic Curve (ROC) analyses to determine cut-points to predict bleeding. RESULTS: Laboratory and bleeding data were collected from a total of 76 HIE infants with a mean (±SD) birthweight of 3.34 ± 0.67 kg and gestational age of 38.6 ± 1.9 wks. BG included 41 infants. Bleeding sites were intracranial (n = 13), gastrointestinal (n = 19), pulmonary (n = 18), hematuria (n = 11) or other (n = 1). There were no differences between BG and NBG in baseline characteristics (p > 0.05). Both groups demonstrated INR and aPTT values beyond the acceptable reference ranges utilized for full tem newborns. BG had higher initial and max INR, initial aPTT, and lower min PLT and min Fib compared to NBG. ROC analyses revealed that platelet count <130 × 109/L, fib level <1.5 g/L, and INR >2 discriminated BG from NBG. CONCLUSIONS: Laboratory evidence of coagulopathy is universal in HIE babies undergoing TH. Transfusion strategies to maintain PLT counts >130 × 109/L, fib level >1.5 g/L, and INR <2 may prevent clinical bleeding in this high risk population.

Perioperative hypothermia in NICU infants: its occurrence and impact on infant outcomes.

Infants admitted to the neonatal intensive care unit (NICU) often require surgical intervention and maintaining normothermia perioperatively is a major concern. In our preliminary study of 31 normothermic infants undergoing operative procedures in the operating room (OR), 58% (N = 18) returned hypothermic while all 5 undergoing procedures in the NICU remained normothermic (P = .001). To describe perioperative thermal instability (temperatures lower than 36.0°C) and frequency of associated adverse events, support interventions, and diagnostic tests in infants undergoing operative procedures in the OR and the NICU. This prospective, case-control study included 108 infants admitted to the NICU who were sequentially scheduled for an operative procedure in the OR (50.93%; N = 55) or the NICU (49.07%; N = 53). Existing data from the medical record were collected about temperatures and frequency of adverse cardiovascular, respiratory, and metabolic events, associated support interventions, and diagnostic tests during the perioperative period. Analyses examined the relative risks and proportional differences in rates of hypothermia between the OR group and the NICU group and associated adverse events, support interventions, and diagnostic tests between hypothermic and normothermic infants. Hypothermia developed in 40% (N = 43) of infants during the perioperative period. The OR group had a higher rate of perioperative hypothermia (65.45%, N = 36; P < .001) and were 7 times more likely to develop perioperative hypothermia (P = .008) than the NICU group (13.21%, N = 7). Likewise, infants in the OR group were 10 times more likely to develop hypothermia during the intra- and postoperative periods than those in the NICU group (P = .001). The hypothermic group had significantly more respiratory adverse events (P = .025), were 6 times more likely to require thermoregulatory interventions (P < .001), 5 times more likely to require cardiac support interventions (P < .006), and 3 times more likely to require respiratory interventions (P = .02) than normothermic infants. Although infants undergoing operative procedures in the OR experienced significantly higher rates of hypothermia than those undergoing procedures in the NICU, both groups experienced unacceptable rates of clinical hypothermia. Hypothermic infants experienced more adverse events and required more support interventions during the intra- and postoperative periods than normothermic infants, thereby demonstrating the negative sequelae associated with thermal instability. As a result, a translational team of key stakeholders has been created to explore multifaceted strategies based on translation science to implement, embed, and sustain perioperative thermoregulation best practices for the infant, regardless of the operative setting.

Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias.

BACKGROUND: Children with urea cycle disorders (UCDs) or organic acidemias (OAs) and acute hyperammonemia and encephalopathy are at great risk for neurological injury, developmental delay, intellectual disability, and death. Nutritional support, intravenous alternative pathway therapy, and dialysis are used to treat severe hyperammonemia associated with UCDs and nutritional support and dialysis are used to treat severe hyperammonemia in OAs. Brain protective treatment while therapy is initiated may improve neurological and cognitive function for the lifetime of the child. Animal experiments and small clinical trials in hepatic encephalopathy caused by acute liver failure suggest that therapeutic hypothermia provides neuroprotection in hyperammonemia associated encephalopathy. We report results of an ongoing pilot study that assesses if whole body cooling during rescue treatment of neonates with acute hyperammonemia and encephalopathy is feasible and can be conducted safely. METHODS: Adjunct whole body therapeutic hypothermia was conducted in addition to standard treatment in acutely encephalopathic, hyperammonemic neonates with UCDs and OAs requiring dialysis. Therapeutic hypothermia was initiated using cooling blankets as preparations for dialysis were underway. Similar to standard therapeutic hypothermia treatment for neonatal hypoxic ischemic encephalopathy, patients were maintained at 33.5°C±1°C for 72h, they were then slowly rewarmed by 0.5°C every 3h over 18h. In addition data of age-matched historic controls were collected for comparison. RESULTS: Seven patients were cooled using the pilot study protocol and data of seven historic controls were reviewed. All seven patients survived the initial rescue and cooling treatment, 6 patients were discharged home 2-4weeks after hospitalization, five of them feeding orally. The main complication observed in a majority of patients was hypotension. CONCLUSION: Adjunct therapeutic hypothermia for neonates with UCDs and OAs receiving standard treatment was feasible and could be conducted safely in pediatric and neonatal intensive care units experienced in the application of therapeutic hypothermia in critically ill neonates. However, including adjunct therapeutic hypothermia in the already involved treatment regimen of critically ill patients with hyperammonemia and encephalopathy adds to the complexity of care and should not be done unless it is proven efficacious in a randomized clinical trial.

Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia.

OBJECTIVE: To determine if early serum S100B and neuron-specific enolase (NSE) levels are associated with neuroradiographic and clinical evidence of brain injury in newborns with encephalopathy. STUDY DESIGN: Patients who received therapeutic whole-body hypothermia were prospectively enrolled in this observational study. Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. S100B and NSE levels were measured by enzyme linked immunosorbent assay. Magnetic resonance imaging was performed in surviving infants at 7-10 days of life. Standardized neurologic examination was performed by a child neurologist at 14 days of life. Multiple linear regression analyses were performed to evaluate the association between S100B and NSE levels and unfavorable outcome (death or severe magnetic resonance imaging injury/significant neurologic deficit). Cutoff values were determined by receiver operating curve analysis. RESULTS: Newborns with moderate to severe encephalopathy were enrolled (n = 75). Median pH at presentation was 6.9 (range, 6.5-7.35), and median Apgar scores of 1 at 1 minute, 3 at 5 minutes, and 5 at 10 minutes. NSE and S100B levels were higher in patients with unfavorable outcomes across all time points. These results remained statistically significant after controlling for covariables, including encephalopathy grade at presentation, Apgar score at 5 minutes of life, initial pH, and clinical seizures. CONCLUSION: Elevated serum S100B and NSE levels measured during hypothermia were associated with neuroradiographic and clinical evidence of brain injury in encephalopathic newborns. These brain-specific proteins may be useful immediate biomarkers of cerebral injury severity.

Therapeutic hypothermia for neonatal encephalopathy and extracorporeal membrane oxygenation.

This case series describes the clinical management of 5 infants who underwent whole-body cooling during extracorporeal membrane oxygenation (ECMO). In all 5 infants, systemic hypothermia was maintained during ECMO with acceptable clinical outcomes.

Iatrogenic hyperthermia and hypothermia in the neonate.

This article reviews the physiology of thermoregulation, hypothermia, and hyperthermia. The differential diagnosis of hypothermia and hyperthermia is discussed. The benefits of hypothermia following hypoxic-ischemic injury are discussed; however, both hypothermia and hyperthermia, in the extreme, are potentially harmful to the newborn. Recommendations for the prevention of these problems are discussed, as well as available treatments.

Serial head ultrasound studies in preterm infants: how many normal studies does one infant need to exclude significant abnormalities?

OBJECTIVE: We hypothesized that preterm infants with two normal head ultrasound (HUS) screening studies > or = 7 days apart would have subsequently normal follow-up studies. POPULATION: We reviewed reports of all HUS studies performed in preterm infants < or = 32 weeks gestation admitted to our nursery between January 1998 and July 2000. SETTING: Regional perinatal referral center. DESIGN: A normal HUS screening study was defined as either no findings; or grade I intraventricular hemorrhage (IVH) (Papile classification), germinal matrix irregularity or cyst, or normal but unequal ventricular size. An abnormal study was defined as any with IVH > or = grade II, periventricular leukomalacia (PVL), ventriculomegaly (VM), or periventricular echogenicity (PVE). RESULTS: Of 98 infants, 92 infants (94%) who had two normal HUS studies > or = 7 days apart had normal repeat studies subsequently, and six (6%) were abnormal. Four of the six abnormal infants were <25 weeks gestation at birth. One infant (27 weeks) became abnormal after culture-positive bacterial sepsis and necrotizing enterocolitis with bowel perforation requiring surgery. The remaining infant (29 weeks) had a question of PVE, and a normal repeat study. The positive predictive value for having a normal HUS after two previously normal studies > or = 7 days apart was 94% with a specificity of 86%. CONCLUSION: Stable premature infants > or = 25 weeks gestation without intervening deterioration may not need repeat screening HUSs after having had two normal studies > or = 7 days apart. Unstable or extremely premature infants <25 weeks gestation may be subject to late severe IVH, VM, and PVL, and therefore need a repeat study before hospital discharge, even if two initial studies > or = 7 days apart were normal.

Handheld, portable ultrasound in the neonatal intensive care nursery: a new, inexpensive tool for the rapid diagnosis of common neonatal problems.

The use of ultrasound imaging in the neonatal intensive care unit (NICU) has become an essential part of the evaluation and delivery of care for most neonates. Until recently, ultrasound machines were large, expensive, and often not immediately available, particularly at night and during weekends. Additionally, serial studies to define the evolution of an acute clinical situation were often not practical because of the dedicated time required and the expense involved. The recent introduction into our NICU of a high-quality, reasonably priced, and completely portable neonatal ultrasound unit (Sonosite, Bothell, WA) has now made it possible for neonatologists to rapidly obtain the hour-by-hour information that can be extremely helpful in the evaluation of a critically ill neonate. This paper illustrates some of the capabilities of this simplified device, and the value of having continuous on-site ultrasound availability in the NICU.

Metabolic and mitochondrial effects of antiretroviral drug exposure in pregnancy and postpartum: implications for fetal and future health.

Antiretroviral drugs (ARVs) are indispensable in the treatment and prevention of human immunodeficiency virus infection. Although their use before, during and after pregnancy is considered safe for mother and child, there are still lingering concerns about their long-term health consequences and the ramifications of their effects on lipid, glucose, intermediary and mitochondrial metabolism. This article reviews the known effects of ARVs on macromolecular and mitochondrial metabolism as well as the potential maternal, fetal, neonatal and adult health risks associated with abnormal energy metabolism during gestation. Recommendations about enhanced monitoring for these risks in affected populations are being provided.

aEEG evolution during therapeutic hypothermia and prediction of NICU outcome in encephalopathic neonates.

BACKGROUND: Initial aEEG background pattern has been used as a predictor of neurological outcome after asphyxia and has been used as inclusion criterion for trials evaluating efficacy of therapeutic hypothermia in encephalopathic newborns. The utility of continuous aEEG monitoring during hypothermia has not been well described. OBJECTIVES: (1) To describe the evolution of aEEG during therapeutic hypothermia in newborns with encephalopathy, and (2) to evaluate the utility of continuous aEEG monitoring during therapeutic hypothermia. METHODS: This is a retrospective review of continuous aEEG data from encephalopathic newborns treated with whole-body hypothermia. aEEG segments were scored for background and sleep-wake cycling (SWC). Sensitivity and specificity calculations and logistic regression analyses were performed to evaluate the ability of aEEG to predict death or severe MRI abnormality/significant neurological deficit at discharge. RESULTS: aEEG data from 75 encephalopathic newborns were reviewed. Abnormal aEEG background was predictive of adverse outcome with increasing positive predictive value over the course of hypothermia. Few patients (5%) had early SWC, but 58% developed SWC by rewarming and all had favorable outcome. CONCLUSIONS: Persisting aEEG background abnormality beyond 48 h of life and lack of SWC over the course of hypothermia is predictive of adverse NICU outcome in encephalopathic newborns.

Cerebral function monitoring: a new scoring system for the evaluation of brain maturation in neonates.

OBJECTIVE: Cerebral function monitoring (CFM), using compressed single-channel amplitude-integrated electroencephalogram recorded from 2 biparietal electrodes, has been shown previously to be a simple bedside tool for monitoring neonatal central nervous system (CNS) status. As the pattern of the CFM changes with gestational age, the technique can be used to assess brain maturation in premature infants. We have developed a new scoring system for the interpretation of neonatal CFM recordings. The objective of this study was to evaluate CFM tracings at increasing gestational and postnatal ages to develop a scoring system to quantify CFM pattern changes. METHODS: Term and preterm neonates were studied with CFM at 12 to 24 hours of life, 48 to 72 hours of life, and then weekly or biweekly until hospital discharge. Each study comprised 8 to 24 hours of continuous CFM recording. CFM recordings were evaluated using the scoring system for record continuity, presence of cyclic changes in electrical activity, degree of voltage amplitude depression, and bandwidth. Each variable was scored for each recording. All variables were summed to yield a total score (minimum 0, maximum 13). Total scores were correlated with gestational and postconceptional ages. RESULTS: Thirty infants were studied with gestational ages at birth that ranged from 24 to 39 weeks and birth weights that varied between 450 and 3850 g. A total of 146 CFM tracings were analyzed. With advancing gestational and postconceptional age, scores for each variable as well as total scores progressively increased with CNS maturation. The highest scores were attained at 35 to 36 weeks' postconceptional age, which corresponded to previously reported subjective observations performed by visual description of CFM patterns. Of the 4 component variables that we analyzed, the most sensitive indicators of CNS maturity were 1) the presence of a cycling pattern, 2) the continuity of the record pattern, and 3) the CFM recording bandwidth. CONCLUSIONS: Our proposed scoring system may be a valuable tool to quantify changes during CFM more objectively, reflecting variations in CNS activity in newborn infants and allowing for better statistical comparisons between amplitude-integrated electroencephalogram tracings from different patients as well as from the same patient at different points of time.