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.

[Focal congenital hyperinsulinism]. / Focalis congenitalis hyperinsulinismus.

In congenital hyperinsulinemic hypoglycemia - the most common cause of persistent hypoglycemia in infancy - a focal lesion can be identified in 50% of the cases. With appropriate medical care based upon early diagnosis, these patients can be cured by the resection of the lesion rendering unnecessary long time medical care, and avoiding serious brain damage from recurrent hypoglycemic episodes. Genetic testing and 18F-fluoro-dihydroxyphenylalanine PET/CT imaging are essential for determining the best possible treatment. We report 2 cases of focal congenital hyperinsulinism - both male infants: 22 and 2 months of age - treated successfully with enucleation of the pancreas lesion (Semmelweis University, Budapest). Both patients had the pathognomonic mutation of the ABCC8 gene of the ATP-sensitive potassium channel. Radiologic imaging and histology confirmed the diagnosis, and after the operation, pharmacological treatment was terminated in both cases. During the follow-up period (5 and 1.5 years, respectively) they are euglycemic, with no morbidities attributed to the operation. We believe that these two operations for focal hyperinsulinism - diagnosed and localised by the above detailed genetic and specific radiological testing - were the first of their kind in Hungary. Based on the acquired experience, every necessary examination can be achieved in our country to improve patient care, reduce morbidity and medical costs. Orv Hetil. 2023; 164(47): 1877-1884.

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.

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.

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.

Prognostic value of early, conventional proton magnetic resonance spectroscopy in cooled asphyxiated infants.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) commonly leads to neurodevelopmental impairment, raising the need for prognostic tools which may guide future therapies in time. Prognostic value of proton MR spectroscopy (H-MRS) between 1 and 46 days of age has been extensively studied; however, the reproducibility and generalizability of these methods are controversial in a general clinical setting. Therefore, we investigated the prognostic performance of conventional H-MRS during first 96 postnatal hours in hypothermia-treated asphyxiated neonates. METHODS: Fifty-one consecutive hypothermia-treated HIE neonates were examined by H-MRS at three echo-times (TE = 35, 144, 288 ms) between 6 and 96 h of age, depending on clinical stability. Patients were divided into favorable (n = 35) and unfavorable (n = 16) outcome groups based on psychomotor and mental developmental index (PDI and MDI, Bayley Scales of Infant Development II) scores (≥ 70 versus < 70 or death, respectively), assessed at 18-26 months of age. Associations between 36 routinely measured metabolite ratios and outcome were studied. Age-dependency of metabolite ratios in whole patient population was assessed. Prognostic performance of metabolite ratios was evaluated by Receiver Operating Characteristics (ROC) analysis. RESULTS: Three metabolite ratios showed significant difference between outcome groups after correction for multiple testing (p < 0.0014): myo-inositol (mIns)/N-acetyl-aspartate (NAA) height, mIns/creatine (Cr) height, both at TE = 35 ms, and NAA/Cr height at TE = 144 ms. Assessment of age-dependency showed that all 3 metabolite ratios (mIns/NAA, NAA/Cr and mIns/Cr) stayed constant during first 96 postnatal hours, rendering them optimal for prediction. ROC analysis revealed that mIns/NAA gives better prediction for outcome than NAA/Cr and mIns/Cr with cut-off values 0.6798 0.6274 and 0.7798, respectively, (AUC 0.9084, 0.8396 and 0.8462, respectively, p < 0.00001); mIns/NAA had the highest specificity (95.24%) and sensitivity (84.62%) for predicting outcome of neonates with HIE any time during the first 96 postnatal hours. CONCLUSIONS: Our findings suggest that during first 96 h of age even conventional H-MRS could be a useful prognostic tool in predicting the outcome of asphyxiated neonates; mIns/NAA was found to be the best and age-independent predictor.

Asphyxiated neonates who received active therapeutic hypothermia during transport had higher rates of hypocapnia than controls.

AIM: We investigated the association between active hypothermia and hypocapnia in neonates with moderate-to-severe hypoxic-ischaemic encephalopathy (HIE) transported after birth. METHODS: This was a retrospective cohort study of neonates with HIE born between 2007 and 2011 and transported to Semmelweis University, Hungary, for hypothermia treatment before and after we introduced active cooling during transport in 2009. Of these, 71 received intensive care plus controlled active hypothermia during transport, while the 46 controls just received standard intensive care. Incident hypocapnia was defined as a partial pressure of carbon-dioxide (pCO2 ) that decreased below 35 mm Hg during transport. Multivariable logistic regression investigated the relationship between hypothermia and incident hypocapnia. RESULTS: Incident hypocapnia was more frequent in the actively cooled transport group (36.6%) than control group (17.4%; p = 0.025). pCO2 decreased from a median of 45 to 35 mm Hg (p < 0.0001) in the intervention group, but remained unchanged in the controls. After adjusting for confounders, hypothermia remained an independent risk factor for hypocapnia with an odds ratio (OR) of 4.23 and 95% confidence interval (95% CI) of 1.30-13.79. Sedation was associated with a reduction in OR of hypocapnia, at 0.35 (95% CI 0.12-0.98). CONCLUSIONS: Hypothermia increased the risk of hypocapnia in neonates with HIE during transport.

Distinct cytokine patterns may regulate the severity of neonatal asphyxia-an observational study.

BACKGROUND: Neuroinflammation and a systemic inflammatory reaction are important features of perinatal asphyxia. Neuroinflammation may have dual aspects being a hindrance, but also a significant help in the recovery of the CNS. We aimed to assess intracellular cytokine levels of T-lymphocytes and plasma cytokine levels in moderate and severe asphyxia in order to identify players of the inflammatory response that may influence patient outcome. METHODS: We analyzed the data of 28 term neonates requiring moderate systemic hypothermia in a single-center observational study. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Neonates were divided into a moderate (n = 17) and a severe (n = 11) group based on neuroradiological and amplitude-integrated EEG characteristics. Peripheral blood mononuclear cells were assessed with flow cytometry. Cytokine plasma levels were measured using Bioplex immunoassays. Components of the kynurenine pathway were assessed by high-performance liquid chromatography. RESULTS: The prevalence and extravasation of IL-1b + CD4 cells were higher in severe than in moderate asphyxia at 6 h. Based on Receiver operator curve analysis, the assessment of the prevalence of CD4+ IL-1ß+ and CD4+ IL-1ß+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. Intracellular levels of TNF-α in CD4 cells were increased at all time points compared to 6 h in both groups. At 1 month, intracellular levels of TNF-α were higher in the severe group. Plasma IL-6 levels were higher at 1 week in the severe group and decreased by 1 month in the moderate group. Intracellular levels of IL-6 peaked at 24 h in both groups. Intracellular TGF-ß levels were increased from 24 h onwards in the moderate group. CONCLUSIONS: IL-1ß and IL-6 appear to play a key role in the early events of the inflammatory response, while TNF-α seems to be responsible for prolonged neuroinflammation, potentially contributing to a worse outcome. The assessment of the prevalence of CD4+ IL-1ß+ and CD4+ IL-1ß+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia.

Feasibility and Safety of Controlled Active Hypothermia Treatment During Transport in Neonates With Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To evaluate the feasibility and safety of controlled active hypothermia versus standard intensive care during neonatal transport in patients with hypoxic-ischemic encephalopathy. DESIGN: Cohort study with a historic control group. SETTING: All infants were transported by Neonatal Emergency & Transport Services to a Level-III neonatal ICU. PATIENTS: Two hundred fourteen term newborns with moderate-to-severe hypoxic-ischemic encephalopathy. An actively cooled group of 136 newborns were compared with a control group of 78 newborns. INTERVENTIONS: Controlled active hypothermia during neonatal transport. MEASUREMENTS AND MAIN RESULTS: Key measured variables were timing of hypothermia initiation, temperature profiles, and vital signs during neonatal transport. Hypothermia was initiated a median 2.58 hours earlier in the actively cooled group compared with the control group (median 1.42 [interquartile range, 0.83-2.07] vs 4.0 [interquartile range, 2.08-5.79] hours after birth, respectively; p < 0.0001), and target temperature was also achieved a median 1.83 hours earlier (median 2.42 [1.58-3.63] vs 4.25 [2.42-6.08] hours after birth, respectively; p < 0.0001). Blood gas values and vital signs were comparable between the two groups with the exception of heart rate, which was significantly lower in the actively cooled group. The number of infants in the target temperature range (33-34°C) on arrival was 79/136 (58.1%) and the rate of overcooling was 16/136 (11.8%) in the actively cooled group. In the overcooled infants, Apgar scores, pH, base deficit, and eventual death rate (7/16; 43.8%) indicated more severe asphyxia suggesting poor temperature control in this subgroup of patients. Adverse events leading to pulmonary or circulatory failure were not observed in either groups during the transport period. CONCLUSIONS: Therapeutic hypothermia during transport is feasible and safe, allowing for significantly earlier initiation and achievement of target temperature, possibly providing further benefit for neonates with hypoxic-ischemic encephalopathy.

[Hypothermia treatment in asphyxiated neonates - a single center experience in Hungary]. / Terápiás hypothermia alkalmazása az asphyxiás újszülöttek kezelésében ­ egy hazai neonatológiai centrum eredményei.

INTRODUCTION AND AIM: We aimed to analyze patient characteristics of term neonates with hypoxic-ischemic encephalopathy treated with hypothermia at the 3rd level Neonatal Intensive Care Unit of the 1st Department of Pediatrics, Semmelweis University. METHOD: We conducted a retrospective cohort analysis between 2013-2015, including 97 asphyxiated neonates with HIE who received hypothermia treatment, using our in-house developed novel registry database. RESULTS: 59.8% of neonates were born with Cesarean section and the first blood gas analysis showed a pH of 7.0 ± 0.2, pCO2 55.9 ± 27.3 mmHg, base deficit 16.7 ± 7.2 mmol/l, and lactate levels of 13.3 ± 4.7 mmol/l (x ± SD). Hypothermia treatment was started during neonatal transport in 93.7% of the cases, at 2.5 ± 0.3 hours of age. Multiorgan failure associated with the perinatal asphyxia was present in 83.2% of the patients. Patients received intensive therapy for a median of 10.8 days, 61.3% of neonates were discharged home directly, 32.2% required further hospital treatment, and 6.5% died. CONCLUSION: Our novel registry database allowed for a quick, user-friendly and time-efficient analysis of patient characteristics in neonates with HIE. This registry could aid institutional audit work and prospective clinical data collection. Orv. Hetil., 2017, 158(9), 331-339.

Severe Hyperinsulinemic Hypoglycemia in a Neonate: Response to Sirolimus Therapy.

Hyperinsulinemic hypoglycemia (HH) is one of the most common causes of persistent hypoglycemic episodes in neonates. Current pharmacologic treatment of neonatal HH includes diazoxide and octreotide, whereas for diffuse, unresponsive cases a subtotal pancreatectomy may be the last resort, with questionable efficacy. Here we report a case of congenital diffuse neonatal HH, first suspected when severe hypoglycemia presented with extremely high serum insulin levels immediately after birth. Functional imaging and genetic tests later confirmed the diagnosis. Failure to respond to a sequence of different treatments and to avoid extensive surgery with predictable morbidity prompted us to introduce a recently suggested alternative therapy with sirolimus, a mammalian target of rapamycin inhibitor. Glucose intake could be reduced gradually while euglycemia was maintained, and we were able to achieve exclusively enteral feeding within 6 weeks. Sirolimus was found to be effective and well tolerated, with no major adverse side effects attributable to its administration.

[Childhood liver tumor in Hungary: two interesting clinical cases] / Gyermekkori májtumor Magyarországon: két rendhagyó klinikai eset.

Hepatic tumors account for 0.5-2% of all childhood tumors in Hungary, based of the data last ten years. More than half of the cases were histologically malignant. The worldwide incidence of malignant hepatic tumors is 1.6 / 1 million. Here we present two patients with hepatoblastoma. In the first case the size of the initially inoperable tumor diminished following the chemotherapy and total surgical resection became possible. No sign of relapse occurred so far. The second case included a congenital hepatic tumor which was remarkable because of its unusual clinical presentation and histology.