Early Transient Hypoglycemia and Test Performance in At-Risk Newborns.

OBJECTIVE: This study aimed to evaluate if early (within the first 3 hours after birth) transient neonatal hypoglycemia (TNH) is associated with poor academic performance in infants at-risk for hypoglycemia. STUDY DESIGN: This was a retrospective cohort study of at risk-infants (late preterm infants, small and large for gestational age infants, and infants of diabetic mothers [IDMs]) who were born in 1998 and 1999 at the University of Arkansas for Medical Sciences and had ≥1 recorded glucose concentration. The outcome measure was proficiency on 4th grade literacy and mathematics achievement tests. Three glucose concentration cutoffs for defining hypoglycemia (<35, <40, and <45 mg/dL) were investigated. Logistic regression models were developed to examine the association between early TNH and achievement test proficiency based on perinatal factors. RESULTS: Among 726 infants, 472 had one, 233 had two, and 21 had three risk factor(s). Early TNH (glucose concentration <35, <40, and <45 mg/dL) was observed in 6.3, 11.6, and 20.5% of the study cohort, respectively. Irrespective of the cutoff used, the frequency of early TNH (number of patients with early TNH in a risk category divided by the total number of patients in that category) was significantly greater among infants with multiple risk factors. After controlling for perinatal factors, early TNH (cutoffs <35 and <40 mg/dL) was significantly associated with decreased probability of proficiency in literacy but not mathematics. Despite that early TNH was more common in IDMs and infants with three risk factors, the category or number of risk factors did not impact academic proficiency. CONCLUSION: Early TNH (<35 and <40 mg/dL) was associated with lower adjusted probability of proficiency on 4th grade literacy achievement tests in at-risk infants. The impact of early TNH on academic performance was similar irrespective of category or number of risk factors. KEY POINTS: · Transient hypoglycemia was associated with lower proficiency on 4th grade tests in at-risk infants.. · The category of risk factors among at-risk infants did not impact 4th grade academic proficiency.. · The number of risk factors among at-risk infants did not impact 4th grade academic proficiency..

Childhood Educational Outcomes of Children Born with Gastroschisis.

OBJECTIVE: To compare third grade literacy and mathematics test proficiency among children born with gastroschisis vs unaffected controls and identify predictors of academic proficiency among these children. STUDY DESIGN: Infants born with gastroschisis (2000-2005) were identified from the Arkansas Reproductive Health Monitoring System. For each case, 2 controls were selected at random from birth certificates and matched for hospital and month of birth, sex, and race/ethnicity. Data on rehospitalization within the first 6 years and payer data were abstracted from the Arkansas Hospital Inpatient Discharge database. Surviving cases and controls were linked to the Arkansas Department of Education database containing achievement test scores. The primary outcome was proficiency, defined as performance at or above grade level, on third grade achievement tests. Cases and controls who did not attend public schools could not be linked to education records. Multivariable logistic regression models evaluated the association between study characteristics and academic proficiency. RESULTS: The final study cohort included 47 cases and 63 controls. There was no statistically significant difference in the rate of literacy (68% vs 81%; P = .65) or mathematics proficiency (89% vs 87%; P = .15) between cases and controls. On multivariable analysis, a complex gastroschisis (defined as atresia, volvulus, necrosis, or perforation of the bowel) was associated with lower proficiency in literacy (aOR, 0.1; 95% CI, 0.02-0.58; P = .01). No neonatal or maternal characteristics predictive of lower proficiency in mathematics were identified. CONCLUSIONS: Among children born with gastroschisis, the presence of a complex gastroschisis was associated with lower proficiency on third grade literacy achievement tests.

Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy.

PURPOSE: Maternal diabetes is a known teratogen that can cause a wide spectrum of birth defects, collectively referred to as diabetic embryopathy (DE). However, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests to establish the diagnosis. Here, we explore the potential of DNA methylation as a diagnostic biomarker for DE and to inform disease pathogenesis. METHODS: Bisulfite sequencing was used to identify gene regions with differential methylation between DE neonates and healthy infants born with or without prenatal exposure to maternal diabetes, and to investigate the role of allele-specific methylation at implicated sites. RESULTS: We identified a methylation signature consisting of 237 differentially methylated loci that distinguished infants with DE from control infants. These loci were found proximal to genes associated with Mendelian syndromes that overlap the DE phenotype (e.g., CACNA1C, TRIO, ANKRD11) or genes known to influence embryonic development (e.g., BRAX1, RASA3). Further, we identified allele-specific methylation (ASM) at 11 of these loci, within which 61.5% of ASM single-nucleotide variants are known expression quantitative trait loci (eQTLs). CONCLUSIONS: Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.

Observed and calculated cerebral critical closing pressure are highly correlated in preterm infants.

BACKGROUND: Cerebrovascular critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow ceases. Preterm ABP is low and close to CrCP. The diastolic closing margin (diastolic ABP minus CrCP) has been associated with intraventricular hemorrhage in preterm infants. CrCP is estimated from middle cerebral artery cerebral blood flow velocity (CBFV) and ABP waveforms. However, these estimations have not been validated due to a lack of gold standard. Direct observation of the CrCP in preterm infants with hypotension is an opportunity to validate synchronously estimated CrCP. METHODS: ABP and CBFV tracings were obtained from 24 extremely low birth weight infants. Recordings where diastolic CBFV was zero were identified. The gold standard CrCP was delineated using piecewise regression of ABP and CBFV values paired by rank ordering and then estimated using a published formula. The measured and estimated values were compared using linear regression and Bland-Altman analysis. RESULTS: Linear regression showed a high degree of correlation between measured and calculated CrCP (r2 = 0.93). CONCLUSIONS: This is the first study to validate a calculated CrCP by comparing it to direct measurements of CrCP from preterm infants when ABP is lower than CrCP.

Practice variation in anti-epileptic drug use for neonatal hypoxic-ischemic encephalopathy among regional NICUs.

BACKGROUND: While intercenter variation (ICV) in anti-epileptic drug (AED) use in neonates with seizures has been previously reported, variation in AED practices across regional NICUs has not been specifically and systematically evaluated. This is important as these centers typically have multidisciplinary neonatal neurocritical care teams and protocolized approaches to treating conditions such as hypoxic ischemic encephalopathy (HIE), a population at high risk for neonatal seizures. To identify opportunities for quality improvement (QI), we evaluated ICV in AED utilization for neonates with HIE treated with therapeutic hypothermia (TH) across regional NICUs in the US. METHODS: Children's Hospital Neonatal Database and Pediatric Health Information Systems data were linked for 1658 neonates ≥36 weeks' gestation, > 1800 g birthweight, with HIE treated with TH, from 20 NICUs, between 2010 and 2016. ICV in AED use was evaluated using a mixed-effect regression model. Rates of AED exposure, duration, prescription at discharge and standardized AED costs per patient were calculated as different measures of utilization. RESULTS: Ninety-five percent (range: 83-100%) of patients with electrographic seizures, and 26% (0-81%) without electrographic seizures, received AEDs. Phenobarbital was most frequently used (97.6%), followed by levetiracetam (16.9%), phenytoin/fosphenytoin (15.6%) and others (2.4%; oxcarbazepine, topiramate and valproate). There was significant ICV in all measures of AED utilization. Median cost of AEDs per patient was $89.90 (IQR $24.52,$258.58). CONCLUSIONS: Amongst Children's Hospitals, there is marked ICV in AED utilization for neonatal HIE. Variation was particularly notable for HIE patients without electrographic seizures, indicating that this population may be an appropriate target for QI processes to harmonize neuromonitoring and AED practices across centers.

Early proton magnetic resonance spectroscopy during and after therapeutic hypothermia in perinatal hypoxic-ischemic encephalopathy.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) remains a significant cause of mortality and neurodevelopmental impairment despite treatment with therapeutic hypothermia. Magnetic resonance H1-spectroscopy measures concentrations of cerebral metabolites to detect derangements in aerobic metabolism. OBJECTIVE: We assessed MR spectroscopy in neonates with HIE within 18-24 h of initiating therapeutic hypothermia and at 5-6 days post therapeutic hypothermia. MATERIALS AND METHODS: Eleven neonates with HIE underwent MR spectroscopy of the basal ganglia and white matter. We compared metabolite concentrations during therapeutic hypothermia and post-therapeutic hypothermia and between moderate and severe HIE. RESULTS: During therapeutic hypothermia, neonates with severe HIE had decreased basal ganglia N-acetylaspartate (NAA; 0.62±0.08 vs. 0.72±0.05; P=0.02), NAA + N-acetylaspartylglutamate (NAAG; 0.66±0.11 vs. 0.77±0.06; P=0.05), glycerophosphorylcholine + phosphatidylcholine (GPC+PCh; 0.28±0.05 vs. 0.38±0.06; P=0.02) and decreased white matter GPC+PCh (0.35±0.13 vs. 0.48±0.04; P=0.02) compared to neonates with moderate HIE. For all subjects, basal ganglia NAA decreased (-0.08±0.07; P=0.01), whereas white matter GPC+PCh increased (0.03±0.04; P=0.04) from therapeutic hypothermia MRI to post-therapeutic-hypothermia MRI. All metabolite values are expressed in mmol/L. CONCLUSION: Decreased NAA and GPC+PCh were associated with greater HIE severity and could distinguish neonates who might benefit most from targeted additional neuroprotective therapies.

Cerebral oxygen metabolism during and after therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy: a feasibility study using magnetic resonance imaging.

BACKGROUND: Therapeutic hypothermia is the standard-of-care treatment for infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). MRI for assessing brain injury is usually performed after hypothermia because of logistical challenges in bringing acutely sick infants receiving hypothermia from the neonatal intensive care unit (NICU) to the MRI suite. Perhaps examining and comparing early cerebral oxygen metabolism disturbances to those after rewarming will lead to a better understanding of the mechanisms of brain injury in HIE and the effects of therapeutic hypothermia. OBJECTIVE: The objectives were to assess the feasibility of performing a novel T2-relaxation under spin tagging (TRUST) MRI technique to measure venous oxygen saturation very early in the time course of treatment, 18-24 h after the initiation of therapeutic hypothermia, to provide a framework to measure neonatal cerebral oxygen metabolism noninvasively, and to compare parameters between early and post-hypothermia MRIs. MATERIALS AND METHODS: Early (18-24 h after initiating hypothermia) MRIs were performed during hypothermia treatment in nine infants with HIE (six with moderate and three with severe HIE). Six infants subsequently had an MRI after hypothermia. Mean values of cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen from MRIs during hypothermia were compared between infants with moderate and severe HIE; and in those with moderate HIE, we compared cerebral oxygen metabolism parameters between MRIs performed during and after hypothermia. RESULTS: During the initial hypothermia MRI at 23.5±5.2 h after birth, infants with severe HIE had lower oxygen extraction fraction (P=0.04) and cerebral metabolic rate of oxygen (P=0.03) and a trend toward lower cerebral blood flow (P=0.33) compared to infants with moderate HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between MRIs during and after hypothermia (although not significantly); cerebral metabolic rate of oxygen (P=0.93) was not different. CONCLUSION: Early MRIs were technically feasible while maintaining hypothermic goal temperatures in infants with HIE. Cerebral oxygen metabolism early during hypothermia is more disturbed in severe HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between early and post-hypothermia scans. A comparison of cerebral oxygen metabolism parameters between early and post-hypothermia MRIs might improve our understanding of the evolution of HIE and the benefits of hypothermia. This approach could guide the use of adjunctive neuroprotective strategies in affected infants.

Prophylactic Dextrose Gel Does Not Prevent Neonatal Hypoglycemia: A Quasi-Experimental Pilot Study.

OBJECTIVE: To test the hypothesis that prophylactic dextrose gel administered to newborn infants at risk for hypoglycemia will increase the initial blood glucose concentration after the first feeding and decrease neonatal intensive care unit (NICU) admissions for treatment of asymptomatic neonatal hypoglycemia compared with feedings alone. STUDY DESIGN: This quasi-experimental study allocated asymptomatic at-risk newborn infants (late preterm, birth weight <2500 or >4000 g, and infants of mothers with diabetes) to receive prophylactic dextrose gel (Insta-Glucose; Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey); other at-risk infants formed the control group. After the initial feeding, the prophylactic group received dextrose gel (0.5 mL/kg) rubbed into the buccal mucosa. The blood glucose concentration was checked 30 minutes later. Initial glucose concentrations and rate of NICU admissions were compared between the prophylactic group and controls using bivariate analyses. A multivariable linear regression compared first glucose concentrations between groups, adjusting for at-risk categories and age at first glucose concentration. RESULTS: There were 236 subjects (72 prophylactic, 164 controls). The first glucose concentration was not different between the prophylactic and control groups in bivariate analysis (52.1 ± 17.1 vs 50.5 ± 15.3 mg/dL, P = .69) and after adjusting for covariates (P = .18). Rates of NICU admission for treatment of transient neonatal hypoglycemia were 9.7% and 14.6%, respectively (P = .40). CONCLUSIONS: Prophylactic dextrose gel did not reduce transient neonatal hypoglycemia or NICU admissions for hypoglycemia. The carbohydrate concentration of Insta-Glucose (77%) may have caused a hyperinsulinemic response, or alternatively, exogenous enteral dextrose influences glucose homeostasis minimally during the first few hours when counter-regulatory mechanisms are especially active. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02523222.

Early Glycemic Profile Is Associated with Brain Injury Patterns on Magnetic Resonance Imaging in Hypoxic Ischemic Encephalopathy.

OBJECTIVE: To investigate whether the early glycemic profile in infants with hypoxic ischemic encephalopathy is associated with distinct patterns of brain injury on magnetic resonance imaging (MRI). STUDY DESIGN: We performed a secondary analysis of 178 prospectively enrolled infants who received therapeutic hypothermia for hypoxic ischemic encephalopathy. Glycemic profiles were identified by glucose concentrations within 24 hours after birth: normoglycemia (all glucose concentrations of >47 to ≤150 mg/dL; n = 62); hypoglycemia (≥1 concentration ≤47 mg/dL; n = 17); hyperglycemia (≥1 concentration >150 mg/dL; n = 76); and labile glucose (both hypoglycemia and hyperglycemia; n = 23). Patterns of brain injury were identified for 151 infants based on Barkovich scores from the postrewarming brain MRIs at a median age of 9 days. RESULTS: A normal brain MRI was reported in 37 of 62 infants (60%) with normal blood glucose values compared with 37 of 116 infants (32%) with an abnormal glucose profile (adjusted for Sarnat stage of encephalopathy and Apgar score at 5 minutes; P = .02). The distribution of MRI patterns of brain injury differed among the glycemic groups (P = .03). The odds of predominant watershed or focal-multifocal injury was higher in infants with hypoglycemia (aOR, 6; 95% CI, 1.5-24.2) and labile glucose (6.6; 95% CI, 1.6-27) compared with infants with normoglycemia. Infants with labile glucose had higher odds (5.6; 95% CI, 1.1-29.3) of predominant basal ganglia or global injury compared with infants with normal blood glucose values. CONCLUSIONS: The early glycemic profile in infants with hypoxic ischemic encephalopathy is associated with specific patterns of brain injury on MRI. Further investigation is needed to explore its prognostic significance and role as a phenotype biomarker.

Bleeding Complications and Mortality in Neonates Receiving Therapeutic Hypothermia and Extracorporeal Membrane Oxygenation.

OBJECTIVE: The objective of this study was to compare complications and mortality in neonates with hypoxic ischemic encephalopathy (HIE) on extracorporeal membrane oxygenation (ECMO) who did and did not receive therapeutic hypothermia (TH). STUDY DESIGN: The Extracorporeal Life Support Organization registry was queried from 2005 to 2013 to identified infants with HIE. Infants ≤30 days of age with HIE on respiratory ECMO were included. Fisher's exact test and the Wilcoxon's rank-sum test were used to compare neonates with and without TH. Logistic regression was used to examine the association of TH with complications and mortality. RESULTS: There were no difference between neonates with HIE who did (n = 78) and did not (n = 109) receive TH in demographics, severity of illness, complications, and mortality (p = 0.21). CONCLUSION: No differences in complications or mortality in neonates with HIE and respiratory ECMO were observed between those who did and did not receive TH. We suggest that for neonates requiring respiratory ECMO who also have HIE, TH is not contraindicated.

The Effect of Early Feeding on Initial Glucose Concentrations in Term Newborns.

OBJECTIVE: To evaluate the influence of early feeding on initial glucose concentrations in healthy term newborns who were not at risk for hypoglycemia. STUDY DESIGN: This retrospective observational study was conducted at the University of Arkansas for Medical Sciences where universal early glucose screening was standard of care for newborn infants. Plasma glucose concentrations were compared in term infants born in 2008 who were not at risk for neonatal hypoglycemia and who were fed before (early feeders) and after (late feeders) their initial glucose screens. Multiple linear regression models were built to determine whether glucose concentrations differed significantly between early vs late feeders. RESULTS: In the 315 early and 572 late feeders, the mean (SD) age of first feeding was 0.9 (0.6) and 3.8 (2.0) hours, respectively. The age at initial glucose specimen collection was 2.2 (1.1) and 1.8 (0.8) hours, respectively. The initial glucose concentration was not higher in early vs late feeders (51.8 ± 11.9 vs 55.5 ± 13.3 mg/dL; P < .001). In linear regression analyses of all infants, the mean initial glucose concentration was 3.61 (95% CI 1.75-5.48) mg/dL lower in early vs late feeders. CONCLUSIONS: Early feeding in otherwise healthy term newborns did not increase initial glucose concentrations compared with newborns who fed later (ie, fasted). Before direct evidence is available, these observations may be instructive for managing early asymptomatic hypoglycemia in at-risk newborns.

Preventing Pressure Injuries in Neonates Undergoing Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: An Interprofessional Quality Improvement Project.

BACKGROUND: Hospital-acquired pressure injuries (HAPIs) can be caused by multiple factors including pressure, shear, friction, moisture/incontinence, device-related pressure, immobility, inactivity, and nutritional deficits. Along with immobility, medical device-related (MDR) HAPIs are a primary cause of pressure injury in neonates, as the clinical practice setting has become increasingly technologically advanced. It is estimated that up to 50% of HAPIs are MDR in pediatric patients. Neonates are at particular risk for HAPI because of their specific anatomical, physiological, and developmental vulnerabilities. A specific example of confluent factors that may increase risk for HAPI is the application of therapeutic hypothermia (TH) and continuous electroencephalography monitoring for neonates with hypoxic-ischemic encephalopathy (HIE). INTERVENTIONS: An interprofessional team collaborated to expand upon existing evidence-based standards of care to address the needs of this specific population within the neonatal intensive care unit (NICU). Interventions centered on revision of current protocols, with efforts to optimize product selection, hardwire assessment practices, and refine documentation of patient care and outcomes. METHODS: The team primarily utilized plan-do-study-act (PDSA) cycles to test and refine specific methods and strategies to reduce HAPIs. Tested solutions were adopted, adapted, or abandoned. RESULTS: A sustained zero HAPI rate in the HIE population resulted. The team continues to collect, report, and utilize near-miss data to continue to refine the process as new risks are identified. IMPLICATIONS FOR PRACTICE: Recognizing the unique skin protection needs of special populations within the NICU, such as those undergoing TH, is crucial. When evidence-based standards of care fail to adequately meet such needs, a collaborative approach to identifying, testing, and implementing population-specific solutions is essential. IMPLICATIONS FOR RESEARCH: A paucity of literature regarding the unique skin protection needs for babies undergoing TH exists. Work should be done to better describe the influence of TH on skin integrity, with the goal of identifying population-specific protective measures.

School-Age Test Proficiency and Special Education After Congenital Heart Disease Surgery in Infancy.

OBJECTIVE: To evaluate test proficiency and the receipt of special education services in school-age children who had undergone surgery for congenital heart disease (CHD) at age <1 year. STUDY DESIGN: Data from Arkansas-born children who underwent surgery for CHD at Arkansas Children's Hospital at age <1 year between 1996 and 2004 were linked to state birth certificates and the Arkansas Department of Education longitudinal database containing achievement test scores in literacy and mathematics for grades 3-4 and special education codes. The primary negative outcome was not achieving grade-level proficiency on achievement tests. Logistic regression accounting for repeated measures was used to evaluate for associations between achieving proficiency and demographic data, maternal education, and clinical factors. RESULTS: A total of 362 of 458 (79%) children who underwent surgery for CHD were matched to the Arkansas Department of Education database, 285 of whom had grade 3 and/or 4 achievement tests scores. Fewer students with CHD achieved proficiency in literacy and mathematics (P < .05) compared with grade-matched state students. Higher 5-minute Apgar score, shorter duration of hospitalization, and higher maternal education predicted proficiency in literacy (P < .05). White race, no cardiopulmonary bypass, and shorter hospitalization predicted proficiency in mathematics (P < .05). Sex, gestational age, age at surgery, CHD diagnosis, and type and number of surgeries did not predict test proficiency. Compared with all public school students, more children with CHD received special education services (26.9% vs 11.6%; P < .001). CONCLUSION: Children with CHD had poorer academic achievement and were more likely to receive special education services than all state students. Results from this study support the need for neurodevelopmental evaluations as standard practice in children with CHD.

Elevated Diastolic Closing Margin Is Associated with Intraventricular Hemorrhage in Premature Infants.

OBJECTIVE: To determine whether the diastolic closing margin (DCM), defined as diastolic blood pressure minus critical closing pressure, is associated with the development of early severe intraventricular hemorrhage (IVH). STUDY DESIGN: A reanalysis of prospectively collected data was conducted. Premature infants (gestational age 23-31 weeks) receiving mechanical ventilation (n = 185) had ∼1-hour continuous recordings of umbilical arterial blood pressure, middle cerebral artery cerebral blood flow velocity, and PaCO2 during the first week of life. Models using multivariate generalized linear regression and purposeful selection were used to determine associations with severe IVH. RESULTS: Severe IVH (grades 3-4) was observed in 14.6% of the infants. Irrespective of the model used, Apgar score at 5 minutes and DCM were significantly associated with severe IVH. A clinically relevant 5-mm Hg increase in DCM was associated with a 1.83- to 1.89-fold increased odds of developing severe IVH. CONCLUSION: Elevated DCM was associated with severe IVH, consistent with previous animal data showing that IVH is associated with hyperperfusion. Measurement of DCM may be more useful than blood pressure in defining cerebral perfusion in premature infants.

Relationship between PCO2 and unfavorable outcome in infants with moderate-to-severe hypoxic ischemic encephalopathy.

BACKGROUND: Abnormal PCO2 is common in infants with hypoxic ischemic encephalopathy (HIE). The objective was to determine whether hypocapnia was independently associated with unfavorable outcome (death or severe neurodevelopmental disability at 18 mo) in infants with moderate-to-severe HIE. METHODS: This was a post hoc analysis of the CoolCap Study in which infants were randomized to head cooling or standard care. Blood gases were measured at prespecified times after randomization. PCO2 and follow-up data were available for 196 of 234 infants. Analyses were performed to investigate the relationship between hypocapnia in the first 72 h after randomization and unfavorable outcome. RESULTS: After adjusting for pH, amplitude-integrated electroencephalogram background and seizures, birth weight, Apgar score at 5 min, cooling status, and Sarnat stage, PCO2 was inversely associated with unfavorable outcome (P < 0.001). The probability of unfavorable outcome was 0.20 ± 0.1 (point estimate ± SE), 0.53 ± 0.23 and 0.89 ± 0.16 for a PCO2 of 40, 30, and 20 mm Hg respectively and was greater in infants with severe HIE than with moderate HIE. CONCLUSIONS: Hypocapnia in infants with moderate-to-severe HIE was independently associated with unfavorable outcome. Future studies of controlled normocapnia will be important.

The Ontogeny of Cerebrovascular Pressure Autoregulation in Premature Infants.

Our objective was to quantify cerebrovascular autoregulation as a function of gestational age (GA) and across the phases of the cardiac cycle. One hundred eighty-six premature infants, with a GA range of 23-33 weeks, were monitored using umbilical artery catheters and transcranial Doppler insonation of middle cerebral artery flow velocity (FV) for 1-h sessions over the first week of life. Autoregulation was quantified as a moving correlation coefficient between systolic arterial blood pressure (ABP) and systolic FV (Sx); mean ABP and mean FV (Mx); diastolic ABP and diastolic FV (Dx). Autoregulation was compared across GAs for each aspect of the cardiac cycle. Systolic FV was pressure-passive in infants with the lowest GA, and Sx decreased with increased GA (r = -0.3; p < 0.001). By contrast, Dx was elevated in all subjects, and showed minimal change with increased GA (r = -0.06; p = 0.05). Multivariate analysis confirmed that GA (p < 0.001) and the "closing margin" (p < 0.01) were associated with Sx. Premature infants have low and almost always pressure-passive diastolic cerebral blood FV. Conversely, the regulation of systolic cerebral blood FV by autoregulation was manifested in this cohort at a GA of between 23 and 33 weeks.

The Diastolic Closing Margin Is Associated with Intraventricular Hemorrhage in Premature Infants.

Premature infants are at an increased risk of intraventricular hemorrhage (IVH). The roles of hypotension and hyperemia are still debated. Critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow (CBF) ceases. When diastolic ABP is equal to CrCP, CBF occurs only during systole. The difference between diastolic ABP and CrCP is the diastolic closing margin (DCM). We hypothesized that a low DCM was associated with IVH. One hundred eighty-six premature infants, with a gestational age (GA) range of 23-33 weeks, were monitored with umbilical artery catheters and transcranial Doppler insonation of middle cerebral artery flow velocity for 1-h sessions over the first week of life. CrCP was calculated linearly and using an impedance model. A multivariate generalized linear regression model was used to determine associations with severe IVH (grades 3-4). An elevated DCM by either method was associated with IVH (p < 0.0001 for the linear method; p < 0.001 for the impedance model). Lower 5-min Apgar scores, elevated mean CBF velocity, and lower mean ABP were also associated with IVH (p < 0.0001). Elevated DCM, not low DCM, was associated with severe IVH in this cohort.

The Ontogeny of Cerebrovascular Critical Closing Pressure.

Premature infants are at risk of vascular neurological insults. Hypotension and hypertension are considered injurious, but neither condition is defined with consensus. Critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow ceases. CrCP may serve to define subject-specific low or high ABP. Our objective was to quantify CrCP as a function of gestational age (GA). One hundred eighty-six premature infants with a GA range of 23-33 weeks, were monitored with umbilical artery catheters and transcranial Doppler insonation of middle cerebral artery flow velocity (FV) for 1-h sessions over the first week of life. CrCP was calculated using an impedance model derivation with Doppler-based estimations of cerebrovascular resistance and compliance. CrCP increased significantly with GA (r = 0.47; slope = 1.4 mmHg/week gestation), an association that persisted with multivariate analysis (p < 0.001). Higher diastolic ABP and higher GA were associated with increased CrCP (p <0.001 for both). CrCP increases significantly at the end of the second and beginning of the third trimester. The low CrCP observed in premature infants may explain their ability to tolerate low ABP without global cerebral infarct or hemorrhage.

Vasopressin versus dopamine for treatment of hypotension in extremely low birth weight infants: a randomized, blinded pilot study.

OBJECTIVE: To evaluate vasopressin vs dopamine as initial therapy in extremely low birth weight (ELBW) infants with hypotension during the first 24 hours of life. STUDY DESIGN: ELBW infants with hypertension ≤ 30 weeks' gestation and ≤ 24 hours old randomly received treatment with vasopressin or dopamine in a blinded fashion. Normotensive infants not receiving vasopressor support served as a comparison group. RESULTS: Twenty ELBW infants with hypertension received vasopressin (n = 10) or dopamine (n = 10), and 50 were enrolled for comparison. Mean gestational age was 25.6 ± 1.4 weeks and birth weight 705 ± 154 g. Response to vasopressin paralleled that of dopamine in time to adequate mean blood pressure (Kaplan-Meier curve, P = .986); 90% of infants in each treatment group responded with adequate blood pressure. The vasopressin group received fewer doses of surfactant (P < .05), had lower PaCO2 values (P < .05), and were not tachycardic (P < .001) during vasopressin administration, compared with the dopamine group. CONCLUSIONS: Vasopressin in ELBW infants as the initial agent for early hypotension appeared safe. This pilot study supports a larger randomized controlled trial of vasopressin vs dopamine therapy in ELBW infants with hypotension.