Growth trajectories and need for oral feeding support among infants with neonatal encephalopathy treated with therapeutic hypothermia.

OBJECTIVE: Identify feeding supports required among infants with neonatal encephalopathy and determine growth trajectories to 3 years. STUDY DESIGN: Single-center retrospective cohort study of 120 infants undergoing therapeutic hypothermia. Logistic regression and stratified analyses identified whether clinical factors, EEG-determined encephalopathy severity, and MRI-based brain injury predict feeding supports (nasogastric tube, oral feeding compensations) and growth. RESULTS: 50.8% of infants required feeding supports in the hospital, decreasing to 14% at discharge. Moderate-to-severe encephalopathy and basal ganglia injury predicted feeding support needs. Yet, 35% of mildly encephalopathic infants required gavage tubes. Growth trajectories approximated expected growth of healthy infants. CONCLUSION: Infants with neonatal encephalopathy-even if mild-frequently experience feeding difficulties during initial hospitalization. With support, most achieve full oral feeds by discharge and adequate early childhood growth. Clinical factors may help identify infants requiring feeding support, but do not detect all at-risk infants, supporting routine screening of this high-risk population.

The predictive value of MRI scores for neurodevelopmental outcome in infants with neonatal encephalopathy.

BACKGROUND: MRI scoring systems are utilized to quantify brain injury and predict outcome in infants with neonatal encephalopathy (NE). Our aim was to evaluate the predictive accuracy of total scores, white matter (WM) and grey matter (GM) subscores of Barkovich and Weeke scoring systems for neurodevelopmental outcome at 2 years of age in infants receiving therapeutic hypothermia for NE. METHODS: Data of 162 infants were analyzed in this retrospective cohort study. DeLong tests were used to compare areas under the curve of corresponding items of the two scoring systems. LASSO logistic regression was carried out to evaluate the association between MRI scores and adverse composite (death or severe disabilities), motor and cognitive outcomes (Bayley developmental index <70). RESULTS: Weeke scores predicted each outcome measure with greater accuracy than the corresponding items of Barkovich system (DeLong tests p < 0.03). Total scores, GM and cerebellum involvement were associated with increased odds for adverse outcomes, in contrast to WM injury, after adjustment to 5' Apgar score, first postnatal lactate and aEEG normalization within 48 h. CONCLUSION: A more detailed scoring system had better predictive value for adverse outcome. GM injury graded on both scoring systems was an independent predictor of each outcome measure. IMPACT STATEMENTS: A more detailed MRI scoring system had a better predictive value for motor, cognitive and composite outcomes. While hypoxic-ischemic brain injuries in the deep grey matter and cerebellum were predictive of adverse outcome, white matter injury including cortical involvement was not associated with any of the outcome measures at 2 years of age. Structured MRI evaluation based on validated scores may aid future clinical research, as well as inform parents and caregivers to optimize care beyond the neonatal period.

Higher parental education was associated with good cognitive outcomes in infants with hypoxic-ischaemic encephalopathy.

AIM: Predicting neurodevelopmental outcomes in hypoxic-ischaemic encephalopathy (HIE) remains imprecise, despite advanced imaging and neurophysiological tests. We explored the predictive value of socio-economic status (SES). METHODS: The cohort comprised 93 infants (59% male) with HIE, who had received therapeutic hypothermia. Patients underwent magnetic resonance imaging, and brain injuries were quantified using the Barkovich scoring system. Family SES was self-reported using a questionnaire. Adverse outcomes were defined as mild to severely delayed development with a score of ≤85 in any domain at 2 years of age, based on the Bayley Scales of Infant Development, Second Edition. Data are presented as odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Multiple regression modelling revealed that higher parental education was strongly associated with good cognitive development, when adjusted for gestational age, serum lactate and brain injuries (OR 2.20, 95% CI 1.16-4.36). The effect size of parental education (ß = 0.786) was higher than one score for any brain injury using the Barkovich scoring system (ß = -0.356). The literacy environment had a significant effect on cognitive development in the 21 infants who had brain injuries (OR 40, 95% CI 3.70-1352). CONCLUSION: Parental education and the literacy environment influenced cognitive outcomes in patients with HIE.

Neuromonitoring in neonatal critical care part II: extremely premature infants and critically ill neonates.

Neonatal intensive care has expanded from cardiorespiratory care to a holistic approach emphasizing brain health. To best understand and monitor brain function and physiology in the neonatal intensive care unit (NICU), the most commonly used tools are amplitude-integrated EEG, full multichannel continuous EEG, and near-infrared spectroscopy. Each of these modalities has unique characteristics and functions. While some of these tools have been the subject of expert consensus statements or guidelines, there is no overarching agreement on the optimal approach to neuromonitoring in the NICU. This work reviews current evidence to assist decision making for the best utilization of these neuromonitoring tools to promote neuroprotective care in extremely premature infants and in critically ill neonates. Neuromonitoring approaches in neonatal encephalopathy and neonates with possible seizures are discussed separately in the companion paper. IMPACT: For extremely premature infants, NIRS monitoring has a potential role in individualized brain-oriented care, and selective use of aEEG and cEEG can assist in seizure detection and prognostication. For critically ill neonates, NIRS can monitor cerebral perfusion, oxygen delivery, and extraction associated with disease processes as well as respiratory and hypodynamic management. Selective use of aEEG and cEEG is important in those with a high risk of seizures and brain injury. Continuous multimodal monitoring as well as monitoring of sleep, sleep-wake cycling, and autonomic nervous system have a promising role in neonatal neurocritical care.

Magnetic resonance venography to evaluate cerebral sinovenous thrombosis in infants receiving therapeutic hypothermia.

BACKGROUND: The incidence of cerebral sinovenous thrombosis (CSVT) in infants receiving therapeutic hypothermia for neonatal encephalopathy remains controversial. The aim of this study was to identify if the routine use of magnetic resonance venography (MRV) in term-born infants receiving hypothermia is associated with diagnostic identification of CSVT. METHODS: We performed a retrospective review of 291 infants who received therapeutic hypothermia from January 2014 to March 2020. Demographic and clinical data, as well as the incidence of CSVT, were compared between infants born before and after adding routine MRV to post-rewarming magnetic resonance imaging (MRI). RESULTS: Before routine inclusion of MRV, 209 babies were cooled, and 25 (12%) underwent MRV. Only one baby (0.5%) was diagnosed with CSVT in that period, and it was detected by structural MRI, then confirmed with MRV. After the inclusion of routine MRV, 82 infants were cooled. Of these, 74 (90%) had MRV and none were diagnosed with CSVT. CONCLUSION: CSVT is uncommon in our cohort of infants receiving therapeutic hypothermia for neonatal encephalopathy. Inclusion of routine MRV in the post-rewarming imaging protocol was not associated with increased detection of CSVT in this population. IMPACT: Cerebral sinovenous thrombosis (CSVT) in infants with NE receiving TH may not be as common as previously indicated. The addition of MRV to routine post-rewarming imaging protocol did not lead to increased detection of CSVT in infants with NE. Asymmetry on MRV of the transverse sinus is a common anatomic variant. MRI alone may be sufficient in indicating the presence of CSVT.

Hypocapnia in early hours of life is associated with brain injury in moderate to severe neonatal encephalopathy.

OBJECTIVE: To evaluate the association between hypocapnia within the first 24 h of life and brain injury assessed by a detailed MRI scoring system in infants receiving therapeutic hypothermia (TH) for neonatal encephalopathy (NE) stratified by the stage of NE. STUDY DESIGN: This retrospective cohort study included infants who received TH for mild to severe NE. RESULTS: 188 infants were included in the study with 48% having mild and 52% moderate-severe NE. Infants with moderate-severe NE spent more time in hypocapnia (PCO2 ≤ 35 mmHg) and presented with more severe brain injury on MRI compared to mild cases. The MRI injury score increased by 6% for each extra hour spent in hypocapnic range in infants with moderate-severe NE. There was no association between hypocapnia and injury scores in mild cases. CONCLUSION: In infants with moderate-severe NE, the hours spent in hypocapnia was an independent predictor of brain injury.

Longitudinal Analysis of Amplitude-Integrated Electroencephalography for Outcome Prediction in Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To investigate the prognostic accuracy of longitudinal analysis of amplitude-integrated electroencephalography (aEEG) background activity to predict long-term neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia. STUDY DESIGN: This single-center observational study included 149 neonates for derivation and 55 neonates for validation with moderate-severe HIE and of gestational age ≥35 weeks at a tertiary neonatal intensive care unit. Single-channel aEEG background pattern, sleep-wake cycling, and seizure activity were monitored over 84 hours during therapeutic hypothermia and rewarming, then scored for each 6-hour interval. Neurodevelopmental outcome was assessed using the Bayley Scales of Infant Development, Second Edition. Favorable outcome was defined as having both a Mental Development Index (MDI) score and Psychomotor Development Index (PDI) score ≥70, and adverse outcome was defined as either an MDI or a PDI <70 or death. Regression modeling for longitudinal analysis of repeatedly measured data was applied, and area under the receiver operating characteristic curve (AUC) was calculated. RESULTS: Longitudinal aEEG background analysis combined with sleep-wake cycling score had excellent predictive value (AUC, 0.90; 95% CI, 0.85-0.95), better than single aEEG scores at any individual time point. The model performed well in the independent validation cohort (AUC, 0.87; 95% CI, 0.62-1.00). The reclassification rate of this model compared with the conventional analysis of aEEG background at 48 hours was 18% (24 patients); 14% (18 patients) were reclassified correctly. Our results were used to develop a user-friendly online outcome prediction tool. CONCLUSIONS: Longitudinal analysis of aEEG background activity and sleep-wake cycling is a valuable and accurate prognostic tool.

Challenges in respiratory management during therapeutic hypothermia for neonatal encephalopathy.

Neonatal encephalopathy (NE) is a serious condition with devastating neurological outcomes that can impact oxygenation and ventilation. The currently recommended therapeutic hypothermia (TH) for these infants may also has several respiratory implications. It decreases metabolic rate and oxygen demands; however, it increases oxygen solubility in the blood and impacts its release to peripheral tissue including the brain. Respiratory management of infants treated with TH should aim for minimizing exposure to hypocapnia or hyperoxia. Inspiratory gas should be heated to 37 °C and humidified to prevent airway and alveolar injury. Blood gas values should be corrected to the core temperature during TH and the use of alkaline buffers is discouraged. While mild sedation/analgesia may ameliorate the discomfort related to cooling, paralytic agents/heavy sedation should be used with caution considering their side effects. Finally, the use of caffeine still needs careful investigation in this population.

Blood gas measures as predictors for neonatal encephalopathy severity.

OBJECTIVE: To correlate arterial umbilical cord gas (aUCG) and infant blood gas with severity of neurological injury. STUDY DESIGN: Retrospective single-site study of infants evaluated for therapeutic hypothermia. Clinical neurological examination and a validated MRI scoring system were used to assess injury severity. RESULTS: Sixty-eight infants were included. aUCG base deficit (BD) and lactate correlated with infant blood gas counterparts (r = 0.43 and r = 0.56, respectively). aUCG and infant pH did not correlate. Infant blood gas lactate (RADJ2 = 0.40), infant BD (RADJ2 = 0.26), infant pH (RADJ2 = 0.17), aUCG base deficit (RADJ2 = 0.08), and aUCG lactate (RADJ2 = 0.11) were associated with clinical neurological examination severity. aUCG and infant blood gas measures were not correlated with MRI score. CONCLUSION: Metabolic measures from initial infant blood gases were most associated with the clinical neurological examination severity and can be used to evaluate hypoxic-ischemic cerebral injury risk.

Association between cerebral oxygen saturation and brain injury in neonates receiving therapeutic hypothermia for neonatal encephalopathy.

OBJECTIVE: To assess the association of cerebral oxygen saturation (CrSO2) collected by near infrared spectroscopy (NIRS) during therapeutic hypothermia (TH) and rewarming with evidence of brain injury on post-rewarming MRI. STUDY DESIGN: This retrospective cohort study included 49 infants, who received TH for mild to severe neonatal encephalopathy. Of those, 26 presented with brain injury assessed by a novel MRI grading system, whereas 23 had normal MRI scans. RESULTS: CrSO2 increased significantly from the first to the second day of TH in infants with brain injury, whereas it remained stable in patients with normal MRI. Increasing mean CrSO2 values during rewarming was associated with brain injury (aOR 1.14; 95% CI 1.00-1.28), specifically with gray matter (GM) injury (aOR 1.23; 95% CI 1.02-1.49). The area under the ROC curve showed an excellent discrimination for GM involvement. CONCLUSION: Clinically applied NIRS during TH and rewarming can assist in identifying the risk for brain injury.

Cerebral oxygenation in preterm infants during maternal singing combined with skin-to-skin care.

BACKGROUND: Our aim was to investigate the effect of music therapy in combination with skin-to-skin care (SSC) on regional cerebral oxygenation (rSO2) measured with near-infrared spectroscopy (NIRS) in premature infants and to study physiological stability during the interventions. METHODS: This was a prospective single-center observational cohort study conducted in a tertiary neonatal intensive care unit. The study consisted of four phases: (1) baseline measurements in an incubator for 30 min; (2) quiet SSC for 30 min (SSC-Pre); (3) SSC with live maternal singing accompanied by live guitar music for 20 min (SSC-Music); (4) final quiet SSC for another 30 min (SSC-Post). RESULTS: The primary outcome measure of mean rSO2 for the 31 preterm infants analyzed showed a significant increase from baseline during SSC-Music (76.87% vs 77.74%, p = 0.04) and SSC-Post (76.87% vs 78.0%, p = 0.03) phases. There were no significant changes observed in heart rate (HR), peripheral oxygen saturation (SpO2), and cerebral fractional tissue oxygen extraction (cFTOE). The coefficient of variation (CV) of rSO2 and SpO2 decreased during each intervention phase. CONCLUSION: Combining music therapy with SSC appears to be safe in preterm neonates. The impact of the small increase in rSO2 and reduced variability of SpO2 and rSO2 warrants further investigation. IMPACT: Music therapy combined with skin-to-skin care (SSC) is safe in clinically stable premature infants and could be encouraged as part of developmental care. This is the first report where near-infrared spectroscopy (NIRS) was used to detect the simultaneous effect of music therapy and SSC on cerebral rSO2 in preterm infants. Music therapy with SSC caused a modest increase in rSO2 and decreased the coefficient of variation of rSO2 and peripheral oxygen saturation (SpO2), which suggest short-term benefits for preterm infants.

Effect of pressure rise time on ventilator parameters and gas exchange during neonatal ventilation.

BACKGROUND: Pressure rise time (PRT), also known as slope time to the peak inflating pressure can be set on some modern neonatal ventilators. On other ventilators, PRT is determined by the set circuit flow. Changing slope time can affect mean airway pressure (MAP), oxygenation, and carbon dioxide elimination. Our aim was to investigate the effect of PRT on ventilator parameters and gas exchange during volume-guaranteed ventilation. METHODS: In a crossover study, 12 infants weighing greater than 2 kg were ventilated using a Dräger Babylog VN500 ventilator with synchronized intermittent positive pressure ventilation with volume guarantee (SIPPV-VG) and pressure support ventilation with volume guarantee (PSV-VG). During both modes PRTs between 0.08 and 0.40 seconds were used in 15-minute epochs. Data from the ventilator and patient monitors were downloaded with 1- and 100-Hz sampling rate and analyzed using the Python computer language. RESULTS: During PSV-VG, longer PRTs were associated with longer inspiratory time (P < .0001) and with lower peak inflating pressure (PIP; P = .003), but the MAP was similar. During SIPPV-VG the PIP was not significantly different; however, MAP was lower with longer PRT (P = .001). With a short PRT (0.08 seconds), the PIP was higher during PSV-VG than during SIPPV-VG (19.8 vs 16.5 mbar; P = .042). There were no significant differences in tidal volume delivery, respiratory rate, minute volume, oxygen saturations, or end-tidal CO2 with different PRTs in either mode. CONCLUSIONS: During SIPPV-VG or PSV-VG, using short or long PRTs affects some ventilation parameters but does not significantly change oxygenation or carbon dioxide elimination.

Late onset oxygen requirement following neonatal therapeutic hypothermia.

AIM: To investigate the characteristics of infants with neonatal encephalopathy (NE) receiving therapeutic hypothermia (TH) who developed late onset oxygen requirement during or after rewarming. METHODS: Infants were stratified by receiving (a) new onset isolated oxygen requirements during or after rewarming; (b) no respiratory support during hospital stay; and (c) invasive and/or non-invasive respiratory support before or during cooling. RESULTS: Of 136 infants treated with TH, 49 (36%) did not require any respiratory support, and 78 (57.4%) received invasive or non-invasive support before or during cooling. Nine infants (6.6%) developed late onset oxygen requirement. The late onset oxygen requirement started at median age of 3.8 days (IQR 3.6-5.2) and ended at median 7.5 days (IQR 5.8-12.7). Total hours of O2 exposure were median 62.0 (IQR 24.4-112.6). Maximum support was low-flow nasal cannula from 100% oxygen source with a flow rate of 40-250 mL/min. Infants in this group had higher Apgar scores, milder metabolic acidosis and no seizures. Three infants had diagnostic investigations without significant findings. CONCLUSION: A small percentage of neonates with NE developed late onset oxygen requirement during or after rewarming. Late oxygen requirement was associated with evidence of less severe perinatal hypoxia-ischaemia.

Neonatal encephalopathy therapy optimization for better neuroprotection with inhalation of CO2: the HENRIC feasibility and safety trial.

BACKGROUND: There is an association between hypocapnia and adverse neurodevelopmental outcome in infants with neonatal encephalopathy (NE). Our aim was to test the safety and feasibility of 5% CO2 and 95% air inhalation to correct hypocapnia in mechanically ventilated infants with NE undergoing therapeutic hypothermia. METHODS: Ten infants were assigned to this open-label, single-center trial. The gas mixture of 5% CO2 and 95% air was administered through patient circuits if the temperature-corrected PCO2 ≤40 mm Hg. The CO2 inhalation was continued for 12 h or was stopped earlier if the base deficit (BD) level decreased <5 mmol/L. Follow-up was performed using Bayley Scales of Infant Development II. RESULTS: The patients spent a median 95.1% (range 44.6-98.5%) of time in the desired PCO2 range (40-60 mm Hg) during the inhalation. All PCO2 values were >40 mm Hg, the lower value of the target range. Regression modeling revealed that BD and lactate had a tendency to decrease during the intervention (by 0.61 and 0.55 mmol/L/h, respectively), whereas pH remained stable. The rate of moderate disabilities and normal outcome was 50%. CONCLUSIONS: Our results suggest that inhaled 5% CO2 administration is a feasible and safe intervention for correcting hypocapnia.

A Randomized Controlled Study of Low-Dose Hydrocortisone Versus Placebo in Dopamine-Treated Hypotensive Neonates Undergoing Hypothermia Treatment for Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To investigate whether hydrocortisone supplementation increases blood pressure and decreases inotrope requirements compared with placebo in cooled, asphyxiated neonates with volume-resistant hypotension. STUDY DESIGN: A double-blind, randomized, placebo-controlled clinical trial was conducted in a Level III neonatal intensive care unit in 2016-2017. Thirty-five asphyxiated neonates with volume-resistant hypotension (defined as a mean arterial pressure [MAP] < gestational age in weeks) were randomly assigned to receive 0.5 mg/kg/6 hours of hydrocortisone or placebo in addition to standard dopamine treatment during hypothermia. RESULTS: More patients reached the target of at least 5-mm Hg increment of MAP in 2 hours after randomization in the hydrocortisone group, compared with the placebo group (94% vs 58%, P = .02, intention-to-treat analysis). The duration of cardiovascular support (P = .001) as well as cumulative (P < .001) and peak inotrope dosage (P < .001) were lower in the hydrocortisone group. In a per-protocol analysis, regression modeling predicted that a 4-mm Hg increase in MAP in response to hydrocortisone treatment was comparable with the effect of 15 µg/kg/min of dopamine in this patient population. Serum cortisol concentrations were low before randomization in both the hydrocortisone and placebo groups (median 3.5 and 3.3 µg/dL, P = .87; respectively), suggesting inappropriate adrenal function. Short-term clinical outcomes were similar in the 2 groups. CONCLUSIONS: Hydrocortisone administration was effective in raising the blood pressure and decreasing inotrope requirement in asphyxiated neonates with volume-resistant hypotension during hypothermia treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02700828.

Correction: Respiratory management during therapeutic hypothermia for hypoxic-ischemic encephalopathy.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Respiratory management during therapeutic hypothermia for hypoxic-ischemic encephalopathy.

Therapeutic hypothermia (TH) has become the standard of care treatment to improve morbidity and mortality in infants with hypoxic-ischemic encephalopathy (HIE). Although TH has clearly proven to be beneficial, recent studies suggest optimization of respiratory management as an approach to prevent further damage and improve neurodevelopmental outcome. The ventilatory management of asphyxiated neonates presents a challenge because both the hypoxic insult and TH have an impact on respiratory functions. Although the danger of recurrence of hypocapnia is well recognized, a brief period of severe hyperoxia also can be detrimental to the previously compromised brain and have been shown to increase the risk of adverse neurodevelopmental outcomes. Therefore, judicious ventilatory management with rigorous monitoring is of particular importance in patients with HIE. In the present review, we provide an overview of the currently available evidence on pulmonary function, respiratory morbidities, and ventilation strategies in HIE and we highlight possible future research directions.

Analysis of peak inflating pressure and inflating pressure limit during neonatal volume guaranteed ventilation.

OBJECTIVES: To report how peak inflating pressure (PIP), tidal volume (VT) and low-tidal volume alarms are affected by maximum allowed inflating pressure (Pmax) during volume guarantee (VG) ventilation. STUDY DESIGN: Ventilation data were analysed with 1 Hz sampling rate from 25 neonates receiving synchronised intermittent positive pressure ventilation with VG for >12 h. RESULTS: The difference between Pmax and PIP (Pdiff) ranged between 5 and 20 mbar (median = 11 mbar) despite a protocol to keep Pmax 5 mbar above the "working PIP". Pmax was reached in 5.2% of inflations. Computational modelling demonstrated that had Pdiff been kept at 5 mbar more consistently, >10% of inflations would have reached Pmax. The frequency of low-tidal volume alarms showed inverse correlation with Pdiff. CONCLUSIONS: It is difficult to implement a simple Pmax strategy due to variability of PIP. Setting Pmax close to the "working PIP" limits VT delivery and triggers frequent alarms.