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.

Airway management may influence postoperative ventilation need in preterm infants after laser eye treatment.

BACKGROUND: Retinopathy of prematurity is treated with laser photocoagulation under general anaesthesia with intubation using endotracheal tube (ETT), which carries a risk for postoperative mechanical ventilation (MV). Laryngeal mask airway (LMA) may provide a safe alternative. We assessed the need for postoperative MV in preterm infants who received LMA versus ETT. METHODS: In this single-centre, retrospective cohort study, preterm infants who underwent laser photocoagulation between 2014-2021 were enroled. For airway management, patients received either LMA (n = 224) or ETT (n = 47). The outcome was the rate of postoperative MV. RESULTS: Patients' age were 37 [35;39] weeks of postmenstrual age, median bodyweight of Group LMA was higher than Group ETT's (2110 [1800;2780] g versus 1350 [1230;1610] g, respectively, p < 0.0001). After laser photocoagulation, 8% of Group LMA and 74% of Group ETT left the operating theatre requiring MV. Multiple logistic regression revealed that the use of LMA and every 100 g increase in bodyweight significantly decreased the odds of mechanical ventilation (OR 0.21 [95% CI 0.07-0.60], and 0.73 [95% CI 0.63-0.84], respectively). Propensity score matching confirmed that LMA decreased the odds of postoperative MV (OR 0.30 [95% CI 0.11-0.70]). CONCLUSION: The use of LMA is associated with a reduced need for postoperative MV. IMPACT: Using laryngeal mask airway instead of endotracheal tube for airway management in preterm infants undergoing general anaesthesia for laser photocoagulation for treating retinopathy of prematurity could significantly decrease the postoperative need for mechanical ventilation. According to our current understanding, this has been the largest study investigating the effect of laryngeal mask airway during general anaesthesia in preterm infants. Our study suggests that the use of laryngeal mask airway is a viable alternative to intubation in the vulnerable population of preterm infants in need of laser treatment.

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.

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.

Predictive performance and metabolite dynamics of proton MR spectroscopy in neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Prognostic value of proton MR spectroscopy (H-MRS) in hypoxic-ischemic encephalopathy (HIE) is acknowledged; however, effects of gestational age (GA) and postnatal age (PA) on prediction and metabolite levels are unknown. METHODS: One hundred and sixty-nine newborns with moderate-to-severe HIE were studied, having ≥1 H-MRS scan during postnatal days 0-14 and known neurodevelopmental outcome (Bayley-II score/cerebral palsy/death). Initial scans were categorized by PA (day 1-3/4-6/≥7), and metabolite ratios were compared by predictive value. Metabolite dynamics were assessed in a total of 214 scans performed in the study population, using regression modeling, with predictors GA, PA, and outcome. RESULTS: N-acetyl-aspartate (NAA)/creatine (Cr) and myo-inositol (mI)/NAA height ratios were consistently associated with outcome throughout the first 14 days, with the highest predictive value in the late (≥7 days) period (AUC = 0.963 and 0.816, respectively). Neither GA nor PA had an overall effect on these metabolite ratios, which showed strongest association with outcome (p < 0.001). Assessed separately in patients with good outcome, GA became a significant covariate for metabolite ratios (p = 0.0058 and 0.0002, respectively). However, this association disappeared in the poor outcome group. CONCLUSIONS: In HIE, NAA/Cr and mI/NAA give most accurate outcome prediction throughout postnatal days 0-14. GA only affected metabolite levels in the good outcome group. IMPACT: Proton MR spectroscopy metabolite ratios N-acetyl-aspartate/creatine and myo-inositol/N-acetyl-aspartate have persistently high predictive value throughout postnatal days 0-14 in newborns with hypoxic-ischemic encephalopathy, with the highest predictive power between postnatal days 7 and 14. Overall, neither metabolite ratio was affected by gestational age nor by postnatal age, while they showed the strongest association with neurological outcome. However, in newborns facing good outcome, metabolite ratios were associated with gestational age, whereas in cases facing poor outcome, this association disappeared. Proton MR spectroscopy provides valuable prognostic information in neonatal hypoxic-ischemic encephalopathy throughout the first 2 weeks of life, irrespective of the timing of MR scan.

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.

Neurodevelopmental effect of intracranial hemorrhage observed in hypoxic ischemic brain injury in hypothermia-treated asphyxiated neonates - an MRI study.

BACKGROUND: Identification of early signs of hypoxic ischemic encephalopathy (HIE) with magnetic resonance imaging (MRI) has proven of prognostic significance. Yet, the importance of intracranial hemorrhage (ICH), being present concomitantly had not been investigated yet, despite the known influence of hypothermia on hemostasis. We aimed to determine whether presence of ICH on MRI alongside the signs of HIE have an impact on prognosis in neonates with the clinical diagnosis of HIE. METHODS: A retrospective study of consecutively sampled 108 asphyxiated term infants admitted to a tertiary neonatal intensive care unit (between 2007 and 2016), treated with whole body hypothermia and having brain MRI within 1 week of life was conducted. Presence or absence of HIE signs on MRI (basal ganglia-thalamus, watershed pattern and total brain injury) and on MR spectroscopy (lactate peak with decreased normal metabolites measured by Lac/NAA ratio) and/or of the five major types of ICH were recorded. Neurodevelopmental outcome was measured with Bayley Scales of Infant Development-II (BSID-II) test. Death or abnormal neurodevelopment (BSID-II score < 85) was defined as poor outcome in Chi-square test. Multivariate logistic regression analysis was performed on survivors. RESULTS: MRI and MR-spectroscopy (MRS) signs of HIE were present in 72% (n = 78). 36% (n = 39) of neonates had ICH, being mainly small in size. Chi-square test showed a relationship between neurodevelopmental outcome and initial MRI. Unadjusted logistic regression showed that neonates presenting MRI and MRS signs of HIE have 6.23 times higher odds for delayed mental development (OR = 6.2292; CI95% = [1.2642; 30.6934], p = 0.0246), than infants without imaging alterations; with no ICH effect on outcome. Adjustment for clinical and imaging parameters did not change the pattern of results, i.e. HIE remained an independent risk factor for delayed neurodevelopment (OR = 6.2496; CI95% = [1.2018; 32.4983], p = 0.0294), while ICH remained to have no significant effect. CONCLUSION: HIE related MRI abnormalities proved to be important prognostic factors of poor outcome in cooled asphyxiated infants when present, suggesting that early MRI with MRS is beneficial for prognostication. Interestingly, ICHs present in about one third of all cases had no significant effect on neurodevelopmental outcome, despite the known hemostasis altering effects of hypothermia.

Association between interferon-induced helicase (IFIH1) rs1990760 polymorphism and seasonal variation in the onset of type 1 diabetes mellitus.

BACKGROUND: Infections, mostly of viral origin, may contribute to the seasonal variation in the onset of type 1 diabetes mellitus (T1DM). The rs1990760 (A>G, Ala946Thr) polymorphism (GG genotype) of the interferon induced helicase (IFIH1), a virus recognition receptor, confers a modest protection for T1DM. The aim of our study was to evaluate a possible association between this IFIH1 polymorphism and the seasonal variation in the onset of T1DM. MATERIALS AND METHODS: The IFIH1 rs1990760 polymorphism was genotyped in 1055 patients of Central-Eastern European ancestry with T1DM (median age at diagnosis: 8.2 [interquartile range, IQR 4.8-11.8] years). T1DM onset was recorded in monthly intervals. RESULTS: The IFIH1 genotype distribution was the following: 436 patients (41.3%) had AA genotype, 483 patients (45.8%) had AG genotype, and 136 patients (12.9%) had GG genotype. Significant seasonal variation in manifestation of T1DM (highest rate in winter and lowest rate in summer period) was observed in the total cohort (n = 1055), irrespective of gender. The disease predisposing AA genotype was more frequently found among new cases with onset in summer vs in those with onset in winter (44.3% vs 37.9%); conversely, the protective GG genotype was less frequent (9.3% vs 12.9%, respectively; P = .0268 for trend). Significant effect of genotype (P = .0418) was found on the seasonal variability of T1DM onset in the total cohort. CONCLUSIONS: The IFIH1 rs1990760 polymorphism seems to be associated with the seasonal manifestation of T1DM. Our findings suggest that this virus receptor gene may contribute to T1DM manifestation primarily in the summer period.

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.

[Clinical application of the electric cardiometry based non-invasive ICON® hemodynamic monitor]. / Az ICON® elektromos kardiometrián alapuló nem invazív hemodinamikai monitor használata a klinikumban.

Establishment of a proper hemodynamic monitoring system in order to achieve optimal care among critically ill patients is fundamental. In contrast to invasive patient-checking systems, which were introduced decades ago and used in both adult and pediatric intensive care, the non-invasive methods have become more popular in recent years due to technical advancements in intensive care and patient monitoring. This increase in popularity can be attributed to the higher degree of safety and reduced complication rates as well as to its being more economical. Our summary focuses on the ICON® patient monitoring system. This newly engineered, non-invasive tool is based on electrical cardiometry, and uses hemodynamic parameters in both neonatal and pediatric care as well as in adults. The operating principle is simple: the conductivity of the blood in the aorta shows time-dependent changes. Prior to the opening of the aortic valve, the orientation of the red blood cells (RBCs) is random, and it is not until the contraction of the aorta that the RBCs and the opening of the aortic valve achieve a parallel position. The tool senses the conductivity between four placed electrodes, and measures the stroke volume (SV) and cardiac output (CO), before calculating other additional parameters (eg.: systemic vascular resistance) by tracing the variation of bioimpedance according to changes in the heart cycle. The most important advantages of ICON® are the measurements that are made available immediately as well as continuously, and the low complication rate that originates from its non-invasive operation. ICON® is a new, promising hemodynamic device in the tool belt of intensive care. Due to the nature of the device, it is possible to evaluate the status of the patient on a continuous basis, allowing for optimal care. To identify the more accurate clinical indications further measures will be necessary. Orv Hetil. 2018; 159(44): 1775-1781.

Novel structured MRI reporting system in neonatal hypoxic-ischemic encephalopathy - issues of development and first use experiences.

BACKGROUND AND PURPOSE: To develop an evidence-based, standardized structured reporting (SR) method for brain MRI examinations in neonatal hypoxic-ischemic encephalopathy (HIE) suitable both for clinical and research use. METHODS: SR template development was based on comprehensive review of the pertinent literature with the basic sections and subdivisions of the template defined according to MRI sequences (both conventional and diffusion-weighted, MR-spectroscopy (MRS), and T2*-weighted imaging), and the items targeted on age-related imaging patterns of HIE. In order to evaluate the usability of the proposed SR template we compared data obtained from the brain MR image analysis of 87 term and 19 preterm neonates with the literature. The enrolled 106 infants were born between 2013 and 2015, went through therapeutic hypothermia according to the TOBY criteria due to moderate to severe asphyxia and had at least one brain MRI examination within the first two weeks of life. Ethical approval was obtained for this retrospective study. Descriptive statistical analysis was also performed on data exported from the structured reporting system as feasibility test. RESULTS: The mean gestational age of the study population was 38.3±2.2 weeks; brain MRI was performed on 5.8±2.9 day of life, hence in 78% of our patients after the conclusion of therapeutic hypothermia. Our main imaging findings were concordant to the pertinent literature. Moreover, we identified a characteristic temporal evolution of diffusion changes. Interestingly 18% (n=19/106) of the clinically asphyxiated infants had isolated axial-extraaxial haemorrhage without any imaging sign of HIE. CONCLUSION: In this article our approach of reporting HIE cases with our novel SR template is described. The SR template was found suitable for reporting HIE cases, moreover it uncovered time and location dependent evolution of diffusion abnormalities (and pseudonormalization, as well), suggesting its usefulness in clinical research applications. The high number of isolated intracranial haemorrhages, and the changing diffusion pattern emphasizes the importance of early imaging in HIE.

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.

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.

AIMS/HYPOTHESIS: Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. METHODS: Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. RESULTS: We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells. CONCLUSIONS/INTERPRETATION: Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.

Rational design of α-helix-stabilized exendin-4 analogues.

Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both (15)N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties.

Low inflating pressures during neonatal tidal volume targeted ventilation: occurrence and significance.

OBJECTIVES: We investigated the inflating pressures (Pinfl, the difference between peak inspiratory pressure and positive end-expiratory pressure) in infants receiving volume targeted ventilation. METHODS: Data were collected and analysed from 195 infants. Median Pinfl was determined before each blood gas (n = 3425). Ventilator parameters and blood gases were compared between periods when Pinfl was <5 mbar and periods when it was higher. RESULTS: 1-hour periods when median Pinfl was <5 mbar occurred in 30% of the babies and were associated with similar tidal volumes and minutes ventilation as periods with higher Pinfl. Babies triggered more ventilator inflations, had more spontaneous breaths and lower oxygen requirement when Pinfl was low. There was no difference in blood gases when Pinfl was <5 mbar or when it was higher. CONCLUSIONS: Episodes of low inflating pressure occur frequently in babies receiving volume targeted ventilation, but they do not lead to changes in blood gases.

Time series analysis of non-invasive hemodynamic monitoring data in neonates with hypoxic-ischemic encephalopathy.

Background and aims: Hemodynamic instability is common in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Rewarming is a critical period and non-invasive circulatory monitoring may help guide cardiovascular supportive therapy. The aim of the study was to provide a comprehensive analysis of cardiac function parameters during TH and its relation to neurodevelopmental outcome. Methods: In a prospective, observational study, 26 neonates with moderate-severe HIE were enrolled, born between 2016 and 2019. A hemodynamic monitor based on electrical velocimetry (ICON, Osypka Medical GmbH, Berlin, Germany) was used. Heart rate (HR), stroke volume (SV), cardiac output (CO) data were recorded continuously throughout TH and rewarming. Neurological outcome was assessed at 2 years of age using the Bayley Scales of Infant Development II. edition. Favorable outcome was defined as >70 points on both the psychomotor and mental scales. Time-series analysis was used and features of cardiac function were described to perform logistic regression modeling for outcome prediction. Results: Fourteen (54%) patients had favorable and 12 (46%) had adverse outcome. Data collection started from median [IQR] of 11.8 [7.0; 24.3] hours (h) of life and lasted until 84.0. [81.8; 87.0] h. During TH, the mean HR of the favorable outcome group was significantly lower than that of the adverse outcome group (86 ± 13/min vs. 104 ± 18/min, p = 0.01). During rewarming HR increased similarly in both groups. SV was unaffected by rewarming, and showed a slowly increasing trend. SV of the favorable outcome group was significantly higher compared to the adverse outcome group (1.55 ± 0.23 ml/kg vs. 1.29 ± 0.30 ml/kg, p = 0.035). In line with this, CO was similar in both groups (136 ± 27 ml/kg/min vs. 134 ± 36 ml/kg/min), and a significant 25% increase in CO was observed during rewarming. Based on multiple regression modeling, HR during TH was independently associated with neurological outcome (p = 0.023). Conclusion: Based on continuous hemodynamic monitoring, patients with adverse outcome have lower SV and higher HR to achieve similar CO to patients with favorable outcome during TH. HR during hypothermia is independently associated with the neurodevelopmental outcome.