Ensuring signal quality of cerebral near infrared spectroscopy during continuous longterm monitoring.

BACKGROUND: Near infrared spectroscopy (NIRS) derived hemoglobin difference (HbD: oxygenated [HbO2] - reduced hemoglobin [Hb]) and total hemoglobin (HbT: HbO2+Hb) have been used as surrogate measures of cerebral blood flow and volume, respectively. Statistically, a lack of HbD-blood pressure (BP) or negative HbT-BP association is regarded as a state of intact cerebral pressure autoregulation (CPA). In contrast, a co-variation of HbD/HbT and systemic blood pressure (BP) in the same direction is thought of as a failure of CPA. If the quality of one (NIRS/BP) or both signals is compromised, the reliability of the results may be adversely affected. In this work, we develop an analytic approach to assess the quality of the NIRS signals. NEW METHOD: Given that cardiac pulses cause hemodynamic changes that are transmitted through the peripheral vasculature, cerebral NIRS signals should exhibit cyclical changes at the pulse frequency. Therefore, we propose that an association between HbD/HbT and electrocardiogram (EKG) signals would be an indicator of NIRS quality. We demonstrate the application of this approach with data collected from six newborns undergoing therapeutic hypothermia for neonatal encephalopathy. RESULTS: We observed an intermittent lack of association between NIRS signals and EKG data over the course of several hours of continuous records, indicating a loss in the strength in NIRS signals. COMPARISON WITH EXISTING METHOD: Existing CPA characterization suffers from Type-II error which the current preprocessing approach can mitigate. CONCLUSIONS: The proposed approach will allow for real-time assessment of NIRS signal quality that is essential for accurate CPA monitoring.

Impact of prenatal diagnosis of fetus-in-fetu.

Fetus in fetu (FIF) is an extremely rare condition (1/500,000 live births) in which a fetiform structure is incorporated into the body of its twin. FIF can be a diagnostic dilemma due to its similarity to a teratoma, but identification of FIF is important for subsequent medical and surgical management. We compare two cases of fetal masses diagnosed on prenatal imaging that were later identified as FIF through further radiological, surgical, and pathologic evaluation. We use these cases to illustrate key pre- and postnatal features of FIF and highlight the benefits of prenatal detection and follow-up for postnatal management.

Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy.

OBJECTIVE: To determine whether systemic inflammation-modulating cytokine expression is related to heart rate variability (HRV) in newborns with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: The data from 30 newborns with HIE were analyzed. Cytokine levels (IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-1ß, TNF-α, IFN-λ) were measured either at 24 h of cooling (n=5), 72 h of cooling (n=4) or at both timepoints (n=21). The following HRV metrics were quantified in the time domain: alpha_S, alpha_L, root mean square (RMS) at short time scales (RMS_S), RMS at long time scales (RMS_L), while low-frequency power (LF) and high-frequency power (HF) were quantified in the frequency domain. The relationships between HRV metrics and cytokines were evaluated using mixed-models. RESULT: IL-6, IL-8, IL-10, and IL-13 levels were inversely related to selected HRV metrics. CONCLUSION: Inflammation-modulating cytokines may be important mediators in the autonomic dysfunction observed in newborns with HIE.

Patterns of Brain Injury in Newborns Treated with Extracorporeal Membrane Oxygenation.

BACKGROUND AND PURPOSE: Neonates treated with extracorporeal membrane oxygenation are at risk for brain injury and subsequent neurodevelopmental compromise. Advances in MR imaging and improved accessibility have led to the increased use of routine MR imaging after extracorporeal membrane oxygenation. Our objective was to describe the frequency and patterns of extracorporeal membrane oxygenation-related brain injury based on MR imaging findings in a large contemporary cohort of neonates treated with extracorporeal membrane oxygenation. MATERIALS AND METHODS: This was a retrospective study of neonatal patients treated with extracorporeal membrane oxygenation from 2005-2015 who underwent MR imaging before discharge. MR imaging and ultrasound studies were reviewed for location and type of parenchymal injury, ventricular abnormalities, and increased subarachnoid spaces. Parenchymal injury frequencies between patients treated with venoarterial and venovenous extracorporeal membrane oxygenation were compared by χ2 tests. RESULTS: Of 81 neonates studied, 46% demonstrated parenchymal injury; 6% showed infarction, mostly in vascular territories (5% anterior cerebral artery, 5% MCA, 1% posterior cerebral artery); and 20% had hemorrhagic lesions. The highest frequency of injury occurred in the frontal (right, 24%; left, 25%) and temporoparietal (right, 14%; left, 19%) white matter. Sonography had low sensitivity for these lesions. Other MR imaging findings included volume loss (35%), increased subarachnoid spaces (44%), and ventriculomegaly (17% mild, 5% moderate, 1% severe). There were more parenchymal injuries in neonates treated with venoarterial (49%) versus venovenous extracorporeal membrane oxygenation (29%, P = .13), but the pattern of injury was consistent between both modes. CONCLUSIONS: MR imaging identifies brain injury in nearly half of neonates after treatment with extracorporeal membrane oxygenation. The frontal and temporoparietal white matter are most commonly affected, without statistically significant laterality. This pattern of injury is similar between venovenous and venoarterial extracorporeal membrane oxygenation, though the frequency of injury may be higher after venoarterial extracorporeal membrane oxygenation.

Cerebral modulation of the autonomic nervous system in term infants.

OBJECTIVE: Central topography of autonomic nervous system (ANS) function has yet to be fully deciphered. In adults it has been shown to lateralize sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. We examined functional topography of central ANS in newborn subjects utilizing spectral analysis of heart rate variability (HRV), an established measure of ANS function. STUDY DESIGN: We studied newborns with hypoxic-ischemic encephalopathy participating in a prospective study undergoing a therapeutic hypothermia protocol.We included subjects with continuous heart rate data over the first 3 h of normothermia (post rewarming) and brain magnetic resonance imaging, which was reviewed and scored according to a 4 region scheme. HRV was evaluated by spectral analysis in the low-frequency (0.05 to 0.25 Hz) and high-frequency (0.3 to 1 Hz) ranges. The relationship between injured brain regions and HRV was studied using multiple regressions. RESULTS: Forty eight newborns were included. When examined in isolation, right hemisphere injury had a significant negative effect on HRV (-0.088; 95% CI: -0.225,-0.008). The combination of posterior fossa region injury with right hemispheric injury or left hemispheric injury demonstrated significant positive (0.299; 95% CI: 0.065, 0.518) and negative (-0.475; 95% CI: -0.852, -0.128) influences on HRV, respectively. The association between brain injury location and HRV in the high-frequency range did not reach significance. CONCLUSION: Our data support the notion that lateralized cerebral modulation of the ANS, specifically of its sympathetic component, is present in the term newborn, and suggest complex modulation of these tracts by components of the posterior fossa.

Clinical impact of term-equivalent magnetic resonance imaging in extremely low-birth-weight infants at a regional NICU.

OBJECTIVE: To evaluate the clinical impact of routine term-equivalent magnetic resonance imaging (TE-MRI) for extremely low-birth-weight infants at a regional neonatal intensive care unit. STUDY DESIGN: This is a single-center retrospective study evaluating preterm survivors who underwent TE-MRI. MRI abnormalities were compared between infants with and without cranial ultrasonography (CUS) abnormalities. Cost analysis comparing imaging modalities was also performed. RESULTS: TE-MRI use increased from 17% in 2006 to 76% in 2010. MRI detected new findings in nearly half of infants, whether or not they had known ultrasound abnormalities. MRI detected more cerebellar (18% vs 6%, P=0.04) and moderate white matter injury (12% vs 7%, P<0.001), and altered simulated neurological prognosis across developmental domains. The cost of TE-MRI was $1600, which was comparable to serial CUSs. CONCLUSION: TE-MRI detects new abnormalities and impacts developmental prognosis in the extremely low birth weight, which supports its use despite the added financial cost.

Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children's Hospitals Neonatal Consortium HIE focus group.

OBJECTIVE: To characterize infants affected with perinatal hypoxic ischemic encephalopathy (HIE) who were referred to regional neonatal intensive care units (NICUs) and their related short-term outcomes. STUDY DESIGN: This is a descriptive study evaluating the data collected prospectively in the Children's Hospital Neonatal Database, comprised of 27 regional NICUs within their associated children's hospitals. A consecutive sample of 945 referred infants born ⩾36 weeks' gestation with perinatal HIE in the first 3 days of life over approximately 3 years (2010-July 2013) were included. Maternal and infant characteristics are described. Short-term outcomes were evaluated including medical comorbidities, mortality and status of survivors at discharge. RESULT: High relative frequencies of maternal predisposing conditions, cesarean and operative vaginal deliveries were observed. Low Apgar scores, profound metabolic acidosis, extensive resuscitation in the delivery room, clinical and electroencephalographic (EEG) seizures, abnormal EEG background and brain imaging directly correlated with the severity of HIE. Therapeutic hypothermia was provided to 85% of infants, 15% of whom were classified as having mild HIE. Electrographic seizures were observed in 26% of the infants. Rates of complications and morbidities were similar to those reported in prior clinical trials and overall mortality was 15%. CONCLUSION: Within this large contemporary cohort of newborns with perinatal HIE, the application of therapeutic hypothermia and associated neurodiagnostic studies appear to have expanded relative to reported clinical trials. Although seizure incidence and mortality were lower compared with those reported in the trials, it is unclear whether this represented improved outcomes or therapeutic drift with the treatment of milder disease.

Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia.

OBJECTIVE: To evaluate whether heart rate variability (HRV) measures are predictive of neurological outcome in babies with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: This case-control investigation included 20 term encephalopathic newborns treated with systemic hypothermia in a regional neonatal intensive care unit. Electrocardiographic data were collected continuously during hypothermia. Spectral analysis of beat-to-beat heart rate interval was used to quantify HRV. HRV measures were compared between infants with adverse outcome (death or neurodevelopmental impairment at 15 months, n = 10) and those with favorable outcome (survivors without impairment, n = 10). RESULT: HRV differentiated infants by outcome during hypothermia through post-rewarming, with the best distinction between groups at 24 h and after 80 h of life. CONCLUSION: HRV during hypothermia treatment distinguished HIE babies who subsequently died or had neurodevelopmental impairment from intact survivors. This physiological biomarker may identify infants in need of adjuvant neuroprotective interventions. These findings warrant further investigation in a larger population of infants with HIE.

Brain perfusion in encephalopathic newborns after therapeutic hypothermia.

BACKGROUND AND PURPOSE: Cerebral perfusion patterns in neonates with HIE after therapeutic hypothermia have not been well described. The objectives of this study were to compare global and regional perfusion between infants with HIE and neonate controls and to relate measures of cerebral perfusion to brain injury on conventional MR imaging in neonates with HIE. MATERIALS AND METHODS: Term encephalopathic neonates meeting criteria for hypothermia between June 2011 and January 2012 were enrolled in this prospective observational study. MR imaging-ASL was performed in the second week of life. Comparisons were made with data from neonate controls who underwent the same imaging protocol. NIRS measures of cerebral oxygenation during and immediately after hypothermia were also evaluated in a subset of patients. Secondary analyses were performed to assess cerebral perfusion and oxygenation differences by pattern of injury on qualitative MR imaging interpretation. RESULTS: We enrolled 18 infants with HIE and 18 control infants. Mean global CBF and regional CBF in the basal ganglia, thalamus, and anterior white matter were higher in cases compared with controls. Infants with HIE with injury on MR imaging, however, had lower CBF (significant in the thalamus) compared with those with normal MR imaging. Decreased FTOE by NIRS further differentiated patients with HIE with injury on MR imaging. CONCLUSIONS: Disturbed cerebral perfusion is observed in the second week of life in some babies with HIE despite treatment with hypothermia. Infants with HIE with injury on MR imaging have lower regional CBF in the thalamus compared with those without injury, possibly representing pseudonormalization of CBF and low metabolic demand after progression to irreversible brain injury.

Neurobehavioral assessment as a predictor of neurodevelopmental outcome in preterm infants.

OBJECTIVE: Preterm infants are at risk for neurodevelopmental impairment. The Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) is a standardized assessment for the neurobehavioral integrity of the newborn. The use of NNNS as a prognostic tool is still emerging. We hypothesized that the NNNS examination performed at term equivalent can detect neurobehavioral alterations in very low birth weight infants and can help in predicting their neurodevelopmental outcome at 18 months corrected age (CA). STUDY DESIGN: This is a prospective study that included preterm infants with birth weight <1500 g and gestational age ≤ 34 weeks. They were evaluated with NNNS at term-equivalent and 12 summary scores were assigned. Infants who had 2 or more NNNS summary scores that were 2 s.d. beyond the mean of the study group were categorized as having abnormal NNNS. Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) of Bayley Scales of Infant Development (BSID-II) were determined at 18 months CA. Multiple linear regression models were used to examine the predictivity of the NNNS summary scores for both MDI and PDI. RESULT: A total of 41 infants were evaluated at term and at 18 months CA. The average MDI was 78±15 and the average PDI was 80 ± 14. Significant neurodevelopmental delay was observed in 50% and 31% of infants with abnormal and normal NNNS, respectively. Using multiple linear regression, NNNS was predictive for both MDI (P=0.011, adjusted R (2)=0.295) and PDI (P=0.002, adjusted R (2)=0.441). Lower MDI was associated with less regulation and more nonoptimal reflexes, whereas lower PDI was associated with less regulation, more nonoptimal reflexes, hypertonicity and handling. CONCLUSION: NNNS at term-equivalent age can detect neurobehavioral alterations in very low birth weight infants. Individual summary scores showed significant correlation with both the MDI and PDI at 18 months CA.

Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants.

OBJECTIVE: Preliminary studies suggested an association between red blood cell (RBC) transfusion and necrotizing enterocolitis (NEC) in premature neonates. An advantageous effect of withholding feeds during transfusion has never been studied. We aimed, first, to determine whether preterm infants who developed NEC were more likely to be transfused in the 48 to 72 h before the diagnosis of NEC; second, to test if a strict policy of withholding feeds during transfusion would decrease the incidence of transfusion-associated NEC. STUDY DESIGN: The study was conducted in two phases. Phase 1: a retrospective case-control study of premature low-birth weight (<32 weeks and <2500 g) infants who developed NEC over a 6-year period. Phase 2: a comparison study of the incidence of NEC during the 18-months preceding, and the 18 months following the change of practice to withholding feeds during RBC transfusion. RESULT: In the case-control study (25 infants with NEC and 25 controls), more infants in the NEC group received transfusions in the 48 and 72 h preceding diagnosis (56 vs 20% within 48 h, P=0.019; and 64 vs 24% within 72 h, P=0.01). The total number of transfusions and age of RBCs were not different between the two groups. Implementing the policy of withholding feeds during transfusion was associated with a decrease in the incidence of NEC from 5.3 to 1.3% (P=0.047). CONCLUSION: Infants who developed NEC frequently received RBC transfusions in the 48 and 72 h preceding presentation of NEC. A strict policy of withholding feeds during transfusion may have a protective effect from NEC.

Predictors of survival in congenital diaphragmatic hernia patients requiring extracorporeal membrane oxygenation: CNMC 15-year experience.

OBJECTIVE: To review outcomes of patients with congenital diaphragmatic hernia (CDH) requiring extracorporeal membrane oxygenation (ECMO) at a level IIIC neonatal intensive care unit and to determine if pre-ECMO respiratory status can help predict mortality. STUDY DESIGN: A single-center retrospective chart review was conducted on all infants with CDH treated with ECMO in the past 15 years. Demographic and clinical information, including pre-ECMO ventilatory and blood gas data, was collected. Differences between survivors and non-survivors were evaluated using independent samples t-/Mann-Whitney U-and Fisher's exact/chi (2)-tests for continuous and categorical data, respectively. Cox regression analysis was performed to evaluate predictors of survival while controlling for covariates. Significant predictors were further explored with receiver operating characteristic (ROC) curve and Kaplan-Meier survival analysis. RESULT: Overall survival of the population of 62 patients treated with ECMO was 50%. Survivor and non-survivors were similar in birth weight, gestational age, gender, race and Apgar scores. Approximately 80% of patients in both groups had a left-sided defect. Less than half of patients were prenatally diagnosed in either group. Patients in the non-survivor group had associated anomalies (42 vs 23% for survivors) but this was not statistically significant (P=0.303). Non-survivors were more likely to be put on ECMO earlier, stay on ECMO longer and be operated upon later. On pre-ECMO blood gas analyses, survivors had higher pH and PaO(2), and lower oxygenation index and PaCO(2) compared with non-survivors. After controlling for covariates, a lower minimum PaCO(2) and side of defect were the only independent predictors of survival. ROC curve for minimum pre-ECMO PaCO(2) had a significant area under the curve (0.72, P=0.003). Survival was 27% in babies unable to achieve a pre-ECMO PaCO(2) <60 mm Hg whereas no patients survived if their lowest pre-ECMO PaCO(2) was >70 mm Hg. CONCLUSION: Minimum achievable pre-ECMO PaCO(2) is an independent predictor of survival in patients with CDH requiring ECMO life support. These data provide useful prognostic information for counseling families and may facilitate direction of care in extreme cases where the degree of pulmonary hypoplasia may be incompatible with life.

Quantitative analysis of magnetic resonance images and neurological outcome in encephalopathic neonates treated with whole-body hypothermia.

OBJECTIVE: To evaluate whether quantitative measures from magnetic resonance imaging (MRI) performed in hypothermia-treated encephalopathic newborns can differentiate patients with unfavorable neurological outcome. STUDY DESIGN: Retrospective analysis of clinical data and MRI studies was performed in 47 full-term infants treated with whole-body hypothermia for neonatal encephalopathy. Apparent diffusion coefficients (ADCs) and T1 and T2 intensity ratios were measured in the basal ganglia and thalamus on axial MRI images. Unfavorable outcome was defined as (1) death or severe neurological deficits at discharge and (2) death or cerebral palsy/severe motor deficit at follow-up through age 9 months. Differences between groups with favorable versus unfavorable neurological outcome at each time point were compared. Optimal cutoff values for significant MR variables were determined with receiver operating curve analyses. Sensitivity and specificity of these cutoff values for predicting unfavorable outcome were calculated and results were compared with qualitative MRI interpretation. RESULT: Infants presented with a median pH of 6.86, base deficit of 20 and Apgar scores of 1, 3 and 4 at 1, 5 and 10 min, respectively. Severe encephalopathy was present in 38%. Unfavorable outcome was present in 9 patients at discharge and in 13 of 26 patients with available follow-up data through 9 months. ADC values and T1 ratios were not significantly different between groups at either time point. T2 ratios in both the basal ganglia and thalamus were significantly higher in patients with unfavorable outcome, both at discharge and in follow-up. T2 intensity ratio in the basal ganglia and thalamus remained significantly associated with death or severe neurological deficit at discharge, after controlling for covariates in logistic regression analysis. Sensitivity and specificity of T2 intensity ratio for predicting unfavorable outcome at discharge were comparable to qualitative grading of injury in the basal ganglia and thalamus by a neuroradiologist. CONCLUSION: Increased T2 signal intensity in the basal ganglia or thalamus in patients with hypothermia-treated neonatal encephalopathy is associated with unfavorable neurological outcome at discharge and later with motor deficit/cerebral palsy. Quantitative methods to assess MRI evidence of brain injury are important for providing objective measures to predict outcome in this high-risk population.

Massage with kinesthetic stimulation improves weight gain in preterm infants.

OBJECTIVE: The aim of this study was to evaluate the effects of massage with or without kinesthetic stimulation on weight gain and length of hospital stay in the preterm infant. STUDY DESIGN: A prospective randomized clinical trial was conducted evaluating the effects of massage with or without kinesthetic stimulation (KS) on weight gain and length of stay (LOS) in medically stable premature (<1500 g and/or and <1000 g) was also performed. RESULT: A total of 60 premature infants were recruited for this study; 20 infants in each group. Average daily weight gain and LOS were similar between the groups after controlling for covariates. For infants with BW>1000 g, average daily weight gain was increased in the intervention groups compared to control. This effect was mainly attributable to the M/KS group. CONCLUSION: Massage with KS is a relatively simple and inexpensive intervention that can improve weight gain in selected preterm infants. Length of hospital stay is not impacted by massage with or without KS. Further studies are needed to evaluate the effect of massage in the extremely low BW(<1000 g) infant.

Can delivery room management impact the length of hospital stay in premature infants?

OBJECTIVES: To evaluate the impact of initiating early nasal continuous positive airway pressure (ENCPAP) on the length of hospital stay (LOS) for the very low birth weight (VLBW) infants. STUDY DESIGN: LOS at the George Washington University Hospital (GW) after the institution of ENCPAP policy was compared to benchmark values using two-tail t-tests. The incidence of neonatal morbidity was calculated using Bonferroni corrected 95% confidence interval as compared to benchmark rates (alpha=0.001). Comparisons were repeated after stratification of the population into four birth weight subcategories: group A (GrpA) (501 to 750 g), GrpB (751 to 1000 g), GrpC (1001 to 1250 g) and GrpD (1251 to 1500 g). RESULTS: We studied 228 consecutive VLBW infants (birth weight: 995+/-294 g and gestational age: 27.7+/-2.7 weeks). Compared to benchmark values, the GW experience was associated with a significant reduction of 5.1 days in LOS (55.9+/-25.2 vs 61+/-32 days; P=0.04). The decrease in LOS was consistent in all subgroups, but was most noticeable in infants of the smallest weight subcategory (LOS in GrpA=86+/-21 vs 104+/-32, P=0.004; in GrpB=69.9+/-16.7 vs 79+/-27, P=0.018; in GrpC=48.2+/-13 vs 56+/-22, P<0.001 and in GrpD=31.7+/-12.5 vs 40+/-19, P=0.003). In the overall population, a lower incidence of chronic lung disease (CLD) (17.8 vs 29%, P<0.001) was also noted. There were no differences in mortality rates (9 vs 14%), or the incidence of necrotizing enterocolitis (NEC) (8 vs 6%) or intraventricular hemorrhage (6.2 vs 9%) between GW and the established benchmark rates. CONCLUSION: ENCPAP may reduce LOS in VLBW infants in our study population. This relatively shorter LOS was associated with a lower incidence of CLD, which may be a contributing factor.