Early neonatal heart rate variability patterns in different subtypes of perinatal hypoxic-ischemic brain injury.

BACKGROUND: This study aims to compare the longitudinal changes in heart rate variability (HRV) during therapeutic hypothermia in neonates with different subtypes of hypoxic-ischemic brain injury. METHODS: HRV was computed from 1 hour time-epochs q6 hours for the first 48 hours. Primary outcome was brain-injury pattern on MRI at 4(3-5) days. We fitted linear mixed-effect regression models with HRV metric, brain injury subtype and postnatal age. RESULTS: Among 89 term neonates, 40 neonates had abnormal brain MRI (focal infarct 15 (38%), basal-ganglia predominant 8 (20%), watershed-predominant 5 (13%), and mixed pattern 12 (30%)). There was no significant difference in the HRV metrics between neonates with normal MRI, focal infarcts and basal ganglia pattern. At any given postnatal age, the degree of HRV suppression (HRV measure in the brain-injury subtype group/HRV measure in Normal MRI group) was significant in neonates with watershed pattern (SDNN(0.63, p = 0.08), RMSSD(0.74, p = 0.04)) and mixed pattern injury (SDNN (0.64, p < 0.001), RMSSD (0.75, p = 0.02)). HRV suppression was most profound at the postnatal age of 24-30 h in all brain injury subtypes. CONCLUSION: Neonates with underlying watershed injury with or without basal-ganglia injury demonstrates significant HRV suppression during first 48 hour of hypothermia therapy. IMPACT: Our study suggests that suppression of heart rate variability in neonates during therapeutic hypothermia varies according to the pattern of underlying hypoxic-ischemic brain injury. Neonates with watershed predominant pattern and mixed pattern of brain injury have the most severe suppression of heart rate variability measures. Heart rate variability monitoring may provide early insights into the pattern of hypoxic-ischemic brain injury in neonates undergoing therapeutic hypothermia earlier than routine clinical MRI.

Predictors of Long-Term Neurodevelopmental Outcome of Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia.

Hypoxic-ischemic encephalopathy (HIE) is a manifestation of perinatal asphyxial insult that continues to evolve over days to weeks following the initial injury. Therapeutic hypothermia has demonstrated that a proportion of this secondary brain injury may indeed be preventable. However, therapeutic hypothermia has also altered the prognostic utility of many bedside tools that are commonly used as predictors of long-term neurodevelopmental outcome in HIE. Clinicians are often confronted with uncertainty when assessing the prognosis of infants with HIE. Improved understanding of the implications and limitations of individual investigations may inform clinical decisions and allow for timely intervention. This review summarizes the predictive value of currently available prognostic markers in HIE infants in the therapeutic hypothermia era, including clinical, biochemical, neurophysiological, physiological, and neuroimaging predictors.

Introduction of Continuous Video EEG Monitoring into 2 Different NICU Models by Training Neonatal Nurses.

BACKGROUND: Continuous video electroencephalographic (EEG) (cvEEG) monitoring is emerging as the standard of care for diagnosis and management of neonatal seizures. However, cvEEG is labor-intensive and the need to initiate and interpret studies on a 24-hour basis is a major limitation. PURPOSE: This study aims at establishing consistency in monitoring of newborns admitted to 2 different neonatal intensive care units (NICUs) managed by the same neurocritical care team. METHODS: Neonatal nurses were trained to apply scalp electrodes, troubleshoot technical issues, and identify amplitude-integrated EEG abnormalities. Guidelines, checklists, and visual training modules were developed. A central network system allowed remote access to the cvEEGs by the epileptologist for timely interpretation and feedback. A cohort of 100 infants with moderate to severe hypoxic-ischemic encephalopathy before and after the training program was compared. RESULTS: During the study period, 192 cvEEGs were obtained. The time to initiate brain monitoring decreased by 31.5 hours posttraining; this, in turn, led to an increase in electrographic seizure detection (20% before vs 34% after), decrease in seizure clinical misdiagnosis (65% before and 36% after), and reduction in antiseizure medication burden. IMPLICATIONS FOR PRACTICE: Training experienced NICU nurses to set up, start, and monitor cvEEGs can decrease the time to initiate cvEEGs, which may lead to better seizure diagnosis and management. IMPLICATIONS FOR RESEARCH: Further understanding of practice bundles for best supporting infants at risk and being treated for seizures needs to be evaluated for integration into practice.Video Abstract Available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx.

Current practice of neonatal resuscitation documentation in North America: a multi-center retrospective chart review.

BACKGROUND: To determine the comprehensiveness of neonatal resuscitation documentation and to determine the association of various patient, provider and institutional factors with completeness of neonatal documentation. METHODS: Multi-center retrospective chart review of a sequential sample of very low birth weight infants born in 2013. The description of resuscitation in each infant's record was evaluated for the presence of 29 Resuscitation Data Items and assigned a Number of items documented per record. Covariates associated with this Assessment were identified. RESULTS: Charts of 263 infants were reviewed. The mean gestational age was 28.4 weeks, and the mean birth weight 1050 g. Of the infants, 69 % were singletons, and 74 % were delivered by Cesarean section. A mean of 13.2 (SD 3.5) of the 29 Resuscitation Data Items were registered for each birth. Items most frequently present were; review of obstetric history (98 %), Apgar scores (96 %), oxygen use (77 %), suctioning (71 %), and stimulation (62 %). In our model adjusted for measured covariates, the institution was significantly associated with documentation. CONCLUSIONS: Neonatal resuscitation documentation is not standardized and has significant variation. Variation in documentation was mostly dependent on institutional factors, not infant or provider characteristics. Understanding this variation may lead to efforts to standardize documentation of neonatal resuscitation.

Integrating Clinical and Neuroimaging Markers to Predict the Onset of Posthemorrhagic Ventricular Dilatation in Preterm Neonates.

BACKGROUND: Posthemorrhagic ventricular dilatation (PHVD) is a major complication of intraventricular hemorrhage (IVH); it is associated with high risks of cerebral palsy and cognitive deficits compared with infants without PHVD. This study aims to explore the early perinatal risk factors-associated with the risk of progressive PHVD. METHODS: Neonates ≤29 weeks gestational age (GA) with Grade II-III IVH and periventricular hemorrhagic infarct (PVHI) between 2015 and 2021 were retrospectively reviewed. All cranial ultrasounds done within 14 days postnatal age (PNA) were assessed for grade of IVH, anterior horn width (AHW), ventricular index (VI), and thalamo-occipital index (TOD). The outcome was defined as death of any cause or VI and/or AHW and/or TOD ≥ moderate-risk zone based on an ultrasound done beyond two weeks PNA. RESULTS: A total of 146 infants with a mean GA of 26 ± 1.8 weeks, birth weight 900 ± 234 g were included, 46% were females. The primary outcome occurred in 56 (39%) infants; among them 17 (30%) and 11 (20%) needed ventricular reservoir and shunt insertion, respectively. The risk factors present within 14 days PNA that significantly increased the odds of developing PHVD were hemodynamically significant patent ductus arteriosus (odds ratio [OR] 6.1, 95% confidence interval [CI] 1.9 to 22), culture-proven sepsis (OR 5.4, 95% CI 1.8 to 18), Grade III IVH (OR 4.6, 95% CI 1.1 to 22), PVHI (OR 3.0, 95% CI 0.9 to 10), and VI (OR 2.1, 95% CI 1.6 to 2.9). CONCLUSIONS: Clinical predictors such as significant ductus arteriosus and bacterial septicemia, along with risk levels of AHW and VI measured with early cranial ultrasounds, are potential predictors of subsequent onset of PHVD.

An Exploratory Analysis of Gastrointestinal Morbidities and Feeding Outcomes Associated with Neonatal Hypoxic-Ischemic Encephalopathy With or Without Hypothermia Therapy.

This study investigates the clinical profile and predictors of gastrointestinal/hepatic morbidities and feeding outcomes among neonates with hypoxic-ischemic encephalopathy (HIE). A single-center retrospective chart review of consecutive neonates >35 weeks of gestation admitted with a diagnosis of HIE between January 1, 2015, and December 31, 2020, and treated with therapeutic hypothermia, if met the institutional eligibility criteria. Outcomes assessed included necrotizing enterocolitis (NEC), conjugated hyperbilirubinemia, hepatic dysfunction, assisted feeding at discharge, and time to reach full enteral and oral feeds. Among 240 eligible neonates (gestational age 38.7 [1.7] weeks, birth weight 3279 [551] g), 148 (62%) received hypothermia therapy, and 7 (3%) and 5 (2%) were diagnosed with stage 1 NEC and stage 2-3 NEC, respectively. Twenty-nine (12%) were discharged home with a gastrostomy/gavage tube, conjugated hyperbilirubinemia (first week 22 [9%], at discharge 19 [8%]), and hepatic dysfunction (74 [31%]). Time to reach full oral feeds was significantly longer in hypothermic neonates compared with neonates who did not receive hypothermia (9 [7-12] days vs. 4.5 [3-9] days, p < 0.0001). Factors significantly associated with NEC were renal failure (odds ratio [OR] 9.24, 95% confidence interval [CI] 2.7-33), hepatic dysfunction (OR 5.69, 95% CI 1.6-26), and thrombocytopenia (OR 3.6, 95% CI 1.1-12), but no significant association with hypothermia, severity of brain injury, or stage of encephalopathy. Transient conjugated hyperbilirubinemia, hepatic dysfunction within first week of life, and need for assistive feeding are more common than NEC in HIE. Risk of NEC was associated with the severity of end-organ dysfunction in the first week of life, rather than severity of brain injury and hypothermia therapy per se.

Analgesia and sedation strategies in neonates undergoing whole-body therapeutic hypothermia: A scoping review.

BACKGROUND: Therapeutic hypothermia (TH) is a widely practiced neuroprotective strategy for neonates with hypoxic-ischemic encephalopathy. Induced hypothermia is associated with shivering, cold pain, agitation, and distress. OBJECTIVE: This scoping review determines the breadth of research undertaken for pain and stress management in neonates undergoing hypothermia therapy, the pharmacokinetics of analgesic and sedative medications during hypothermia and the effect of such medication on short- and long-term neurological outcomes. METHODS: We searched the following online databases namely, (i) MEDLINE, (ii) Web of Science, (iii) Cochrane Library, (iv) Scopus, (v) CINAHL, and (vi) EMBASE to identify published original articles between January 2005 and December 2022. We included only English full-text articles on neonates treated with TH and reported the sedation/analgesia strategy used. We excluded articles that reported TH on transport or extracorporeal membrane oxygenation, did not report the intervention strategies for sedation/analgesia, and reported hypoxic-ischemic encephalopathy in which hypothermia was not applied. RESULTS: The eligible publications (n = 97) included cohort studies (n = 72), non-randomized experimental studies (n = 2), pharmacokinetic studies (n = 4), dose escalation feasibility trial (n = 1), cross-sectional surveys (n = 5), and randomized control trials (n = 13). Neonatal Pain, Agitation, and Sedation Scale (NPASS) is the most frequently used pain assessment tool in this cohort. The most frequently used pharmacological agents are opioids (Morphine, Fentanyl), benzodiazepine (Midazolam) and Alpha2 agonists (Dexmedetomidine). The proportion of neonates receiving routine sedation-analgesia during TH is center-specific and varies from 40-100% worldwide. TH alters most drugs' metabolic rate and clearance, except for Midazolam. Dexmedetomidine has additional benefits of thermal tolerance, neuroprotection, faster recovery, and less likelihood of seizures. There is a wide inter-individual variability in serum drug levels due to the impact of temperature, end-organ dysfunction, postnatal age, and body weight on drug metabolism. CONCLUSIONS: No multidimensional pain scale has been tested for reliability and construct validity in hypothermic encephalopathic neonates. There is an increasing trend towards using routine sedation/analgesia during TH worldwide. Wide variability in the type of medication used, administration (bolus versus infusion), and dose ranges used emphasizes the urgent need for standardized practice recommendations and guidelines. There is insufficient data on the long-term neurological outcomes of exposure to these medications, adjusted for underlying brain injury and severity of encephalopathy. Future studies will need to develop framework tools to enable precise control of sedation/analgesia drug exposure customized to individual patient needs.

Prevalence and Implications of Low Reticulocyte-Hemoglobin Levels among Extreme Preterm Neonates: A Single-Center Retrospective Study.

This retrospective cohort study aims to determine the epidemiology of iron deficiency among extreme preterm neonates and the association of iron-deficient status during the NICU stay with neurodevelopmental outcomes at 18−24 months. Neonates ≤29 weeks gestational age (GA) born between June 2016 and December 2019, who received routine iron supplementation were enrolled. Iron deficiency was defined as reticulocyte−hemoglobin (Ret-Hb) levels ≤ 29 pg at 36 weeks corrected age. A subcohort of neonates completed standardized developmental assessment at 18−24 months corrected age. Significant neurodevelopmental impairment (sNDI) was defined as either Bayley Scales of Infant Development score < 70 or cerebral palsy or blindness or hearing aided. Among a cohort of 215 neonates [GA 25.8 (1.7) weeks, birthweight 885 (232) g], prevalence of iron deficiency was 55%, 21%, 26%, and 13%, in neonates <24 weeks, 24−25 + 6 weeks, 26−27 + 6 weeks, and ≥ 28 weeks GA, respectively. Male sex and receipt of corticosteroid therapy were associated with iron-deficiency. In the subcohort analysis (n = 69), there was no statistically significant association between Ret-Hb levels at 36 weeks corrected age and the risk of sNDI [OR 0.99 (95% CI 0.85−1.2)]. Male infants and those who received postnatal corticosteroids are likely to have iron-limited erythropoiesis at corrected term despite routine iron-supplementation; however, low Ret-Hb levels during the neonatal period were not associated with significant neurological disability in early childhood.

Early transient dysautonomia predicts the risk of infantile epileptic spasm syndrome onset: A prospective cohort study.

Background: Infantile epileptic spasm syndrome (IESS) is an age-dependent epileptic encephalopathy with a significant risk of developmental regression. This study investigates the association between heart rate variability (HRV) in infants at risk of IESS and the clinical onset of IESS. Methods: Sixty neonates at risk of IESS were prospectively followed from birth to 12 months with simultaneous electroencephalogram (EEG) and electrocardiogram recordings for 60 min at every 2-month interval. HRV metrics were calculated from 5 min time-epoch during sleep including frequency domain measures, Poincare analysis including cardiac vagal index (CVI) and cardiac sympathetic index (CSI), and detrended fluctuation analysis (DFA α1, DFA α2). To assess the effect of each HRV metric at the 2-month baseline on the time until the first occurrence of either hypsarrhythmia on EEG and/or clinical spasm, univariate cox-proportional hazard models were fitted for each HRV metric. Results: Infantile epileptic spasm syndrome was diagnosed in 20/60 (33%) of the cohort in a 12-month follow-up and 3 (5%) were lost to follow-up. The median age of developing hypsarrhythmia was 25 (7-53) weeks and clinical spasms at 24 (8-40) weeks. Three (5%) patients had clinical spasms without hypsarrhythmia, and 5 (8%) patients had hypsarrhythmia before clinical spasms at the initial presentation. The infants with high CSI (hazard ratio 2.5, 95% CI 1.2-5.2, P = 0.01) and high DFA α1 (hazard ratio 16, 95% CI 1.1-240, P = 0.04) at 2 months were more likely to develop hypsarrhythmia by the first year of age. There was a trend toward decreasing CSI and DFA α1 and increasing CVI in the first 8 months of age. Conclusion: Our data suggest that relative sympathetic predominance at an early age of 2 months may be a potential predictor for developing IESS. Hence, early HRV patterns may provide valuable prognostic information in children at risk of IESS allowing early detection and optimization of cognitive outcomes. Whether early intervention to restore sympathovagal balance per se would provide clinical benefit must be addressed by future studies.

Metabolic acidosis rather than hypo/hypercapnia in the first 72 hours of life associated with intraventricular hemorrhage in preterm neonates.

AIM: Safe limits of arterial partial pressure of carbon dioxide (PaCO2) and acidosis in premature infants are not well defined. Both respiratory and systemic illness along with center-specific ventilation strategies contribute to PaCO2 fluctuations and acid-base imbalances during the critical time period of first 72 h of life. This study evaluated the association between early blood gas parameters and intraventricular hemorrhage (IVH) in preterm infants. METHODS: This retrospective observational study included neonates with a gestational age (GA) of ≤29 wks, who had at least 7 blood gas analysis done within the first 72 h of life. By adjusting for known variables that predispose to IVH, multivariable logistic regression analysis was used to study the association of PaCO2 and acid-base measures with the risk of IVH. RESULTS: Between 2013-2016, among 272 neonates who met inclusion criteria and were assessed for IVH on cranial ultrasound within first week of life, 101 neonates [mean GA of 25 ± 1.5 wks] had IVH and 171 neonates [mean GA of 25 ± 1.6 wks] had normal scans. After adjustment for confounding variables, higher values of maximum lactate (OR = 1.18, 95% CI = 1.1-1.3, p < .0001) and maximum base deficit (OR = 1.19, 95% CI = 1.1-1.2, p < .0001) within 72 h of life increased the likelihood of any grade of IVH. However, time-weighted average PaCO2, maximum and minimum PaCO2 had no statistically significant effect on the risk of IVH. The relationship remained unchanged even when moderate-severe IVH was considered as the primary outcome. CONCLUSION: Severe metabolic acidosis rather than hypo/hypercapnia during the first 72 h of life was associated with higher odds of IVH in infants born at ≤29 wks of gestation. Future studies determining levels of PaCO2 that is safe for premature brain would need to control for the metabolic component of acidosis.

Improving Compliance and Quality of Documentation of Cerebral Function Monitoring in a Neonatal Neurocritical Care Unit.

INTRODUCTION: Neonates admitted to neurocritical care units frequently undergo continuous bedside cerebral function monitoring (CFM). Documentation of CFM findings that are complete and accurate can augment the quality of care through improved communication. We aimed to increase the compliance with and quality of CFM documentation in the electronic medical records by 50% in our neonatal intensive care unit over 6 months. METHODS: We used the Plan-Do-Study-Act methodology, process mapping, and fishbone analysis. We implemented interventions, including the development of standardized EMR templates, face-to-face reminders at staff meetings and clinical handover sessions, and teaching on CFM interpretation. RESULTS: We evaluated 50 and 161 charts pre (August-October 2018) and postintervention (December 2018-July 2019), respectively. We improved compliance with documentation from 72% to 89% (P = 0.004); and the quality of documentation from 10% to 61% (P < 0.001). Multimodal reminders to document and educational sessions to increase familiarity with CFM interpretation effectively improved the quality of documentation. CONCLUSIONS: We improved the compliance with and the quality of CFM documentation using targeted quality improvement interventions with case-focused educational sessions, reference tools, and standardized templates. Barriers to compliance with documentation were adverse effects on the workflow that changes in the EMR system may address. A significant challenge to sustainability was the high frequency of rotating trainees. We addressed this challenge by developing mandatory electronic teaching modules that include reminders to document and a case-focused teaching curriculum; to increase awareness of the importance of CFM documentation and increase confidence in CFM interpretation.

Characteristics and short-term outcomes of neonates with mild hypoxic-ischemic encephalopathy treated with hypothermia.

OBJECTIVE: To compare the characteristics and outcomes of neonates with mild hypoxic-ischemic encephalopathy (HIE) who received hypothermia versus standard care. STUDY DESIGN: We conducted a retrospective cohort study of neonates ≥35 weeks' gestation and ≥1800 g admitted with a diagnosis of Sarnat stage 1 encephalopathy. We evaluated length of hospital stay, duration of ventilation, evidence of brain injury on MRI, and neonatal morbidities. RESULTS: Of 1089 eligible neonates, 393 (36%) received hypothermia and 595 (55%) had neuroimaging. The hypothermia group was more likely to be outborn, born via C-section, had lower Apgar scores, and required extensive resuscitation. They had longer durations of stay (9 vs. 6 days, P < 0.001), respiratory support (3 vs. 2 days, P < 0.001), but lower odds of brain injury on MRI (adjusted odds ratio 0.33, 95% CI: 0.22-0.52) compared with standard care group. CONCLUSION: Despite prolongation of hospital stay, hypothermia may be potentially beneficial in neonates with mild HIE; however, selection bias cannot be ruled out.

Length Normalized Indices for Fat Mass and Fat-Free Mass in Preterm and Term Infants during the First Six Months of Life.

OBJECTIVE: Postnatal tissue accretion in preterm infants differs from those in utero, affecting body composition (BC) and lifelong morbidity. Length normalized BC data allows infants with different body lengths to be compared and followed longitudinally. This study aims to analyze BC of preterm and term infants during the first six months of life. METHODS: The BC data, measured using dual energy X-ray absorptiometry, of 389 preterm and 132 term infants from four longitudinal studies were combined. Fat-mass/length² (FMI) and fat-free mass/length² (FFMI) for postmenstrual age were calculated after reaching full enteral feeding, at term and two further time points up to six months corrected age. RESULTS: Median FMI (preterm) increased from 0.4 kg/m² at 30 weeks to 2.5, 4.3, and 4.8 kg/m² compared to 1.7, 4.7, and 6 kg/m² in term infants at 40, 52, and 64 weeks, respectively. Median FFMI (preterm) increased from 8.5 kg/m² (30 weeks) to 11.4 kg/m² (45 weeks) and remained constant thereafter, whereas term FFMI remained constant at 11 kg/m² throughout the tested time points. CONCLUSION: The study provides a large dataset of length normalized BC indices. Followed longitudinally, term and preterm infants differ considerably during early infancy in the pattern of change in FMI and FFMI for age.

Can the special care neonatal unit admission cut-off be lowered down to 1500g babies?

OBJECTIVE: The study was conducted to find out whether there is any significant difference in outcome if low birth weight babies weighing between 1500g and 1800g are managed by keeping them with their mothers, i.e., without special care neonatal unit (SCNU) admission. METHODS: It was a retrospective study for which data was collected from past medical record section of 6 months duration from 01.07.06 to 31.12.06, Medical College, Kolkata. The subject of the study was babies born with weight between 1500g and 2000g, divided into 2 groups. Group A representing babies born between weight 1500g and 1800g, groups B representing babies born between 1801g and 2000g. The groups were compared with regard to four variable namely average material age, sex of the babies, singleton or twin pregnancy, mode of delivery and gestational maturity. Test of one proportion was used for statistical analysis of outcome. RESULTS: Total number of live born babies in group A were 198 and in group B 223. Two group were comparable with respect to average maternal age (23.7 yr), sex distribution, singleton or twin pregnancy and number of cesarian section or vaginal delivery and proportion of small for gestational age (SGA) babies. In both the group 13 babies required SCNU admission after being given to their mothers in the postnatal ward. No significant difference in outcome was observed between the groups. CONCLUSION: We conclude that the recommended guidelines for giving institutional care to babies below 1800g may be lowered down to 1500g. However, more babies should be evaluated prospectively, over a longer duration of time, before changing the standard guidelines.