Moderate-severe Hypoxic-ischemic Encephalopathy Research Articles

Trends in HIE and Use of Hypothermia in California: Opportunities forImprovement.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal morbidity and mortality. Therapeutic hypothermia (TH), a proven treatment of moderate-severe HIE, was first used clinically after 2006. We describe trends in HIE diagnosis and use of TH over a 10-year period in California. We identified 62 888 infants,≥36 weeks gestation, who were cared for in California Perinatal Quality Care Collaborative-participating NICUs between 2010 and 2019, and linked them to birth certificate data. We evaluated trends in HIE diagnosis and use of TH. Over time, rates of HIE diagnosis increased from 0.6 to 1.7 per 1000 live births, and use of TH increased from 26.5 to 83.0 per 1000 infants. Rates of moderate HIE increased more than mild or severe, although use of TH for mild HIE increased more than for moderate. Of those with moderate-severe HIE, 25% remain untreated. Treatment varied by NICU level of care. The rates of HIE and TH increased steadily. Some infants with moderate-severe HIE remain untreated, suggesting a need for ongoing education. Further evaluation of systems of care is needed to assure all qualifying infants are treated.

Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study

ObjectiveTo evaluate associations between neurologic outcomes and early measurements of basal ganglia (BG) and thalamic (Th) perfusion using color Doppler ultrasonography (CDUS) in infants with hypoxic-ischemic encephalopathy (HIE). Study designProspective study of infants with mild (n=18), moderate (n=17), and severe HIE (n=14) and controls (n=17). Infants with moderate-severe HIE received therapeutic hypothermia (TH). CDUS was performed at 24-36h and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5 to 5 years. The primary outcome was the association between BG and Th perfusion and brain MRI injury. Secondary analyses focused on associations between perfusion measurements and admission neurologic examinations, MRI scores in infants treated with TH, and motor and sensory disability, or death. An exploratory analysis assessed the accuracy of BG and Th perfusion to predict brain MRI injury in infants treated with TH. ResultsIncreased BG and Th perfusion on CDUS was observed in infants with severe MRI scores and those with significant motor and neurosensory disability or death through 2.5 to 5 years (p<0.05). Infants with severe HIE showed increased BG and Th perfusion (p< .005) compared with infants with moderate HIE. No differences were identified between the between the control and mild HIE groups. Th perfusion ≥ 0.237 cm/sec (AUC of 0.824) correctly classified 80% of infants with severe MRI scores. ConclusionEarly dynamic CDUS of the BG and Th is a potential biomarker of severe brain injury in infants with HIE and may be a useful adjunct to currently used assessments.

Incidence of encephalopathy and comorbidity in infants with perinatal asphyxia: a comparative prospective cohort study.

Programs that aim to improve the detection hypoxic-ischemic encephalopathy (HIE) should establish which neonates suffering from perinatal asphyxia need to be monitored within the first 6 h of life. An observational prospective cohort study of infants with gestational age ≥35 weeks, and above 1,800g, were included according to their arterial cord pH value (ApH): ≤7.00 vs. 7.01-7.10. Data was collected including obstetrical history, as well as neonatal comorbidities, including the presence of HIE, that happened within 6 h of life. A standardized neurological exam was performed at discharge. There were 9,537 births; 176 infants with ApH 7.01-7.10 and 117 infants with ApH ≤7.00. All 9 cases with moderate-to-severe HIE occurred among infants with ApH ≤7.00. The incidence of global and moderate-severe HIE was 3/1,000 and 1/1,000 births, respectively. Outcome at discharge (abnormal exam or death) showed an OR 12.03 (95% CI 1.53, 94.96) in infants with ApH ≤7.00 compared to ApH 7.01-7.10 cohort. Ventilation support was 5.1 times (95% CI 2.87, 9.03) more likely to be needed by those with cord ApH ≤7.00 compared to those with ApH 7.01-7.10, as well as hypoglycemia (37% vs. 25%; p = 0.026). In 55%, hypoglycemia occurred despite oral and/or intravenous glucose administration had been already initiated. Cord pH 7.00 might be a safe pH cut-off point when developing protocols to monitor infants born with acidemia in order to identify infants with moderate or severe HIE early on. There is non-negligible comorbidity in the ApH ≤7.00 cohort, but also in the 7.01-7.10 cohort.

Early Hyperoxemia and 2-year Outcomes in Infants with Hypoxic-ischemic Encephalopathy: A Secondary Analysis of the Infant Cooling Evaluation Trial

ObjectiveTo determine the causal relationship between exposure to early hyperoxemia and death or major disability in infants with hypoxic-ischemic encephalopathy (HIE). Study designWe analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns ≥35 weeks' gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 hours of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. ResultsAmong 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death or major disability. Among hyperoxemic infants (pO2 100–500 mmHg) the proportion with death or major disability was 40/58 (0.69), while the proportion in normoxemic infants (pO2 40 – 99mmHg) was 20/48 (0.42). In the adjusted model, hyperoxemia increased the risk of death or major disability (adjusted risk ratio 1.61, 95% CI 1.07 – 2.00, p= 0.03) in relation to normoxemia. ConclusionEarly hyperoxemia increased the risk of death or major disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.

Hearing impairment after asphyxia and neonatal encephalopathy: a Norwegian population-based study.

The purpose of this study is to evaluate the association between perinatal asphyxia, neonatal encephalopathy, and childhood hearing impairment. This is a population-basedstudy including all Norwegian infants born ≥ 36weeks gestation between 1999 and 2014 and alive at 2years (n = 866,232). Data was linked from five national health registries with follow-up through 2019. Perinatal asphyxia was defined as need for neonatal intensive care unit (NICU) admission and an Apgar 5-min score of 4-6 (moderate) or 0-3 (severe). We coined infants with seizures and an Apgar 5-min score < 7 as neonatal encephalopathy with seizures. Infants who received therapeutic hypothermia were considered to have moderate-severe hypoxic-ischemic encephalopathy (HIE). The reference group for comparisons were non-admitted infants with Apgar 5-min score ≥ 7. We used logistic regression models and present data as adjusted odds ratios (aORs) with 95% confidence intervals (CI). The aOR for hearing impairment was increased in all infants admitted to NICU: moderate asphyxia aOR 2.2 (95% CI 1.7-2.9), severe asphyxia aOR 5.2 (95% CI 3.6-7.5), neonatal encephalopathy with seizures aOR 7.0 (95% CI 2.6-19.0), and moderate-severe HIE aOR 10.7 (95% CI 5.3-22.0). However, non-admitted infants with Apgar 5-min scores < 7 did not have increased OR of hearing impairment. The aOR for hearing impairment for individual Apgar 5-min scores in NICU infants increased with decreasing Apgar scores and was 13.6 (95% CI 5.9-31.3) when the score was 0. Conclusions: An Apgar 5-min score < 7 in combination with NICU admission is an independent risk factor for hearing impairment. Children with moderate-severe HIE had the highest risk for hearing impairment. What is Known: • Perinatal asphyxia and neonatal encephalopathy are associated with an increased risk of hearing impairment. • The strength of the association, and how other co-morbidities affect the risk of hearing impairment, is poorly defined. What is New: • Among neonates admitted to a neonatal intensive care unit (NICU), decreased Apgar 5-min scores, and increased severity of neonatal encephalopathy, were associated with a gradual rise in risk of hearing impairment. • Neonates with an Apgar 5-min score 7, but without NICU admission, did not have an increased risk of hearing impairment.

Renal artery flow alterations in neonates with hypoxic ischemic encephalopathy.

To compare kidney blood flow and kidney function tests in infants with hypoxic ischemic encephalopathy (HIE), and the effects of therapeutic hypothermia (TH) during the first 7days of life. Fifty-nine infants with HIE were prospectively evaluated. Infants with moderate-severe HIE who required TH were classified as group 1 (n = 36), infants with mild HIE were classified as group 2 (n = 23), and healthy infants were classified as group 3 (n = 60). Kidney function tests were evaluated on the sixth hour, third and seventh days of life in Group 1 and Group 2, and on the sixth hour and third day of life in group 3. Renal artery (RA) Doppler ultrasonography (dUS) was performed in all infants on the first, third, and seventh days of life. Systolic and end diastolic blood flow in RA tended to increase and RA resistive index (RI) tended to decrease with time in group 1 (p = 0.0001). While end diastolic blood flow rates in RA on the third day were similar in patients with severe HIE and mild HIE, it was lower in patients with mild-moderate-severe HIE than healthy newborns. On the seventh day, all three groups had similar values (p > 0.05). Serum blood urea nitrogen (BUN), creatinine, uric acid, and cystatin C levels gradually decreased and glomerular filtration rate (GFR) gradually increased during TH in group 1 (p = 0.0001). Serum creatinine levels gradually decreased while GFR gradually increased during the study period in group 2. Therapeutic hypothermia seems to help restore renal blood flow and kidney functions during the neonatal adaptive period with its neuroprotective properties.

Newborns with Favourable Outcomes after Perinatal Asphyxia Have Upregulated Glucose Metabolism-Related Proteins in Plasma.

Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality globally. Although mild therapeutic hypothermia (TH) may improve outcomes in selected babies, the mechanism of action is not fully understood. A proteomics discovery study was carried out to analyse proteins in the plasma of newborns with HIE. Proteomic analysis of plasma from 22 newborns with moderate-severe HIE that had initially undergone TH, and relative controls including 10 newborns with mild HIE who did not warrant TH and also cord blood from 10 normal births (non-HIE) were carried out using the isobaric Tandem Mass Tag (TMT®) 10plexTM labelling with tandem mass spectrometry. A total of 7818 unique peptides were identified in all TMT10plexTM samples, translating to 3457 peptides representing 405 proteins, after applying stringent filter criteria. Apart from the unique protein signature from normal cord blood, unsupervised analysis revealed several significantly regulated proteins in the TH-treated moderate-severe HIE group. GO annotation and functional clustering revealed various proteins associated with glucose metabolism: the enzymes fructose-bisphosphate aldolase A, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate mutase 1, phosphoglycerate kinase 1, and pyruvate kinase PKM were upregulated in newborns with favourable (sHIE+) outcomes compared to newborns with unfavourable (sHIE-) outcomes. Those with favourable outcomes had normal MR imaging or mild abnormalities not predictive of adverse outcomes. However, in comparison to mild HIE and the sHIE- groups, the sHIE+ group had the additional glucose metabolism-related enzymes upregulated, including triosephosphate isomerase, α-enolase, 6-phosphogluconate dehydrogenase, transaldolase, and mitochondrial glutathione reductase. In conclusion, our plasma proteomic study demonstrates that TH-treated newborns with favourable outcomes have an upregulation in glucose metabolism. These findings may open new avenues for more effective neuroprotective therapy.

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

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. 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. 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). 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.

Temperature dysregulation during therapeutic hypothermia predicts long-term outcome in neonates with HIE

Few reliable or easily obtainable biomarkers to predict long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) have been identified. We previously showed that mattress temperature (MT), as proxy for disturbed temperature regulation during therapeutic hypothermia (TH), predicts injury on early MRI and holds promise as physiologic biomarker. To determine whether MT in neonates treated with TH for moderate-severe HIE is associated with long-term outcome at 18–22 months, we performed a secondary analysis of the Optimizing Cooling trial using MT data from 167 infants treated at a core temperature of 33.5°C. Median MTs from four time-epochs (0–6 h, 6–24 h, 24–48 h, and 48–72 h of TH) were used to predict death or moderate-severe neurodevelopmental impairment (NDI), using epoch-specific derived and validated MT cutoffs. Median MT of infants who died or survived with NDI was consistently 1.5–3.0°C higher throughout TH. Infants requiring a median MT above the derived cut-offs had a significantly increased odds of death or NDI, most notably at 0–6 h (aOR 17.0, 95%CI 4.3–67.4). By contrast, infants who remained below cut-offs across all epochs had 100% NDI-free survival. MTs in neonates with moderate-severe HIE during TH are highly predictive of long-term outcome and can be used as physiologic biomarker.

Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild-Moderate Neonatal Hypoxia-Ischemia Brain Injury Model.

Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2–3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3–10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate–severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild–moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild–moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild–moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild–moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild–moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.

Concentration of Serum Biomarkers of Brain Injury in Neonates With a Low Cord pH With or Without Mild Hypoxic-Ischemic Encephalopathy.

ObjectiveTo determine the concentrations of four neuroprotein biomarkers and 68 miRNAs in neonates with low cord pH and/or mild hypoxic-ischemic encephalopathy (HIE).Study DesignA prospective cohort study enrolled neonates with low cord pH (n = 18), moderate-severe HIE (n = 40), and healthy controls (n = 38). Groups provided serum samples at 0–6 h of life. The concentrations of biomarkers and miRNAs were compared between cohorts.ResultThe low cord pH and moderate-severe HIE groups had increased concentrations of GFAP, NFL and Tau compared to controls (P < 0.05, P < 0.001, respectively). NFL concentrations in mild HIE was higher than controls (P < 0.05) but less than moderate-severe HIE (P < 0.001). Of 68 miRNAs, 36 in low cord pH group and 40 in moderate-severe HIE were upregulated compared to controls (P < 0.05). Five miRNAs in low cord pH group (P < 0.05) and 3 in moderate-severe HIE were downregulated compared to controls (P < 0.05).ConclusionA biomarker panel in neonates with low cord pH may help clinicians make real-time decisions.

Diastolic Dysfunction in Neonates With Hypoxic-Ischemic Encephalopathy During Therapeutic Hypothermia: A Tissue Doppler Study.

Diastolic dysfunction often complicates myocardial ischemia with increased mortality rates. However, less is known about diastolic function after perinatal asphyxia in neonates with hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia (TH) and rewarming.AimThe aim of this study was to assess diastolic function with tissue Doppler imaging (TDI) in neonates with moderate–severe HIE during TH and rewarming.MethodNewborns at >36 weeks' gestation with moderate–severe HIE treated with TH were evaluated with targeted neonatal echocardiography (TNE), including TDI, within 24 h of TH initiation (T1), at 48–72 h of treatment (T2), and after rewarming (T3). These retrospective data were collected and compared with a control group of healthy babies at >36 weeks' gestation that was prospectively evaluated following the same protocol.ResultsA total of 21 patients with HIE + TH and 15 controls were included in the study. Myocardial relaxation before the onset of biventricular filling was prolonged in the HIE + TH group during TH with significantly longer isovolumic relaxation time (IVRT') in the left ventricle (LV), the septum, and the right ventricle (RV). This was associated with slower RV early diastolic velocity (e') and prolonged filling on T1. Total isovolumic time (t-IVT; isovolumic contraction time [IVCT'] + IVRT') and myocardial performance index (MPI') were globally increased in asphyxiated neonates. All these differences persisted after correction for heart rate (HR) and normalized after rewarming. TDI parameters assessing late diastole (a' velocity or e'/a' and E/e' ratios) did not differ between groups.ConclusionTDI evaluation in our study demonstrated a pattern of early diastolic dysfunction during TH that normalized after rewarming, whereas late diastole seemed to be preserved. Our data also suggest a possible involvement of impaired twist/untwist motion and dyssynchrony. More studies are needed to investigate the impact and therapeutic implication of diastolic dysfunction in these babies, as well as to clarify the role of TH in these findings.

Uterine activity in labour and the risk of neonatal encephalopathy: a case control study

ObjectiveTo determine the relationship between intrapartum contraction frequency, rest interval duration, and cervical dilation speed and the risk of neonatal hypoxic-ischemic encephalopathy (HIE). Study DesignThis was a retrospective case-control study conducted in a maternity hospital in Dublin, Ireland. Babies born without major congenital anomalies between September 2006 and November 2017 at ≥ 35 + 0 weeks’ gestational age were eligible. Cases were diagnosed with moderate-severe HIE. The controls were the first eligible baby born before and after each case with normal Apgar scores and not admitted to the neonatal unit.Intrapartum uterine activity was assessed by automated analysis of external tocography recordings. Cervical dilation was assessed by linear interpolation between vaginal examination measurements. The speed of cervical dilation was expressed as the times from 4 to 6 cm, >6 cm to the start of pushing, and from pushing to delivery. ResultsIntrapartum tocographs results were available in 49 of 88 cases and 121 of 176 controls. The median contraction rate in cases was 7.7 (Interquartile range [IQR]: 6.6–9.0) compared to 7.0 in controls (IQR: 6.2–7.9) (p = 0.021). The median rest interval duration was 56 s (IQR: 38–76) in cases and 62 s (IQR: 50–79) in controls (p = 0.058). Cases took longer to progress from > 6 cm to the start of pushing (cases: 02:58 [01:14–04:49], controls: 01:48 [00:51–03:34], p = 0.020) and from pushing to delivery (cases: 00:34 [00:24–01:10], controls: 00:27 [00:13–00:56], p = 0.036). ConclusionsHigher contraction frequencies and slower progress towards the end of labour are both independently associated with the risk of moderate-severe HIE. Inter-contraction rest interval duration as measured by external tocography does not provide additional accuracy.

Relationship Between Placental Weight and Placental Pathology With MRI Findings in Mild to Moderate Hypoxic Ischemic Encephalopathy.

IntroductionThe placenta plays a critical role in fetal growth and development. Examination of the placenta may provide information on the timing and extent of adverse prenatal and perinatal events. Multiple studies demonstrate an association between placental changes and hypoxic-ischemic encephalopathy (HIE), but there are limited data on the association between placental pathology and MRI changes in HIE. This study assesses the relationship between placental pathology and MRI abnormalities in infants with HIE after receiving therapeutic hypothermia.MethodsA retrospective study of 138 full-term infants who underwent therapeutic hypothermia for HIE at a single delivery center. Using logistic regression models, placental pathology and MRI results were analyzed to determine if placental abnormalities are associated with more significant MRI abnormalities. Placentas matched by gestational age and birthweight from a sample of convenience were included for comparison.ResultsOf the 138 infants who underwent therapeutic hypothermia for HIE, 84 had placental pathology and MRIs available. Of these, 30 had normal, and 54 had abnormal MRIs. Placental changes are not observed more frequently in the HIE cohort with abnormal MRI. Increased placenta weight: birthweight ratio is independently associated with increased odds of moderate-severe HIE compared to a convenient sample.ConclusionIn a study sample of babies with HIE, placental pathology was not associated with subsequent abnormal MRI findings. Compared to matched controls, babies with HIE had an elevation in placental weight/birthweight.

No pain, neurodevelopmental gain: Time to avoid painful placebo injections in neonatal research.

No pain, neurodevelopmental gain: Time to avoid painful placebo injections in neonatal research.

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

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. This single-center observational study included 149 neonates for derivation and 55 neonates for validation with moderate-severe HIE and of gestational age ≥35weeks at a tertiary neonatal intensive care unit. Single-channel aEEG background pattern, sleep-wake cycling, and seizure activity were monitored over 84hours 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. 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 48hours was 18% (24 patients); 14% (18 patients) were reclassified correctly. Our results were used to develop a user-friendly online outcome prediction tool. Longitudinal analysis of aEEG background activity and sleep-wake cycling is a valuable and accurate prognostic tool.

Mortality related factors on hypoxic ischemic encephalopathic patients treated with therapeutic hypothermia: an 11-year single-center experience.

Hypoxic-ischemic encephalopathy (HIE) is a condition that may cause multiple organ dysfunction and has a high rate of mortality and morbidity. Therapeutic hypothermia is the only proven treatment that decreases the sequel and mortality rate of neonates that are born after 36 weeks of pregnancy and have moderate-severe HIE. Our study was a single-center, retrospective study that includes newborns (gestational age ≥ 36 weeks) who underwent therapeutic hypothermia due to hypoxic-ischemic encephalopathy between 2010 and 2020. We evaluated 125 patients who were diagnosed with moderate to severe HIE and received therapeutic hypothermia. Demographic and clinical data were obtained from electronic medical records and patient files. The patients were separated into two groups as exitus group (n = 39) and discharged group (n = 86). We aimed to evaluate factors affecting mortality. We determined that the median resuscitation times were longer in the delivery room [retrospectively, 10th minutes (0-30) vs. 1 min (0-20), p < 0.05], the tenth min APGAR scores were lower [respectively, 4 (0-7) vs. 6 (3-10), p < 0.05], and the median pH value in the first blood gas taken was lower [respectively, 6.87 (6.4-7.14) vs. 6.90 (6.58-7.12), p < 0.05] in the exitus group. We also determined that multiple organ dysfunction is seen more often in the exitus group. This study demonstrated that the depth of acidosis in the blood gas, multiple organ dysfunction, and the existence of early-onset seizures are the signs of poor prognosis. Therefore, physicians need to be aware of such prognostic factors to follow these patients more closely in terms of possible complications and to inform their parents.

Lipid Profiles from Dried Blood Spots Reveal Lipidomic Signatures of Newborns Undergoing Mild Therapeutic Hypothermia after Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is associated with perinatal brain injury, which may lead to disability or death. As the brain is a lipid-rich organ, various lipid species can be significantly impacted by HIE and these correlate with specific changes to the lipidomic profile in the circulation. Objective: To investigate the peripheral blood lipidomic signature in dried blood spots (DBS) from newborns with HIE. Using univariate analysis, multivariate analysis and sPLS-DA modelling, we show that newborns with moderate–severe HIE (n = 46) who underwent therapeutic hypothermia (TH) displayed a robust peripheral blood lipidomic signature comprising 29 lipid species in four lipid classes; namely phosphatidylcholine (PC), lysophosphatidylcholine (LPC), triglyceride (TG) and sphingomyelin (SM) when compared with newborns with mild HIE (n = 18). In sPLS-DA modelling, the three most discriminant lipid species were TG 50:3, TG 54:5, and PC 36:5. We report a reduction in plasma TG and SM and an increase in plasma PC and LPC species during the course of TH in newborns with moderate–severe HIE, compared to a single specimen from newborns with mild HIE. These findings may guide the research in nutrition-based intervention strategies after HIE in synergy with TH to enhance neuroprotection.

Cooling and immunomodulation for treating hypoxic-ischemic brain injury.

Therapeutic hypothermia is now well established to partially reduce disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Preclinical and clinical studies have confirmed that current protocols for therapeutic hypothermia are near optimal. The challenge is now to identify complementary therapies that can further improve outcomes, in combination with therapeutic hypothermia. Overall, anti-excitatory and anti-apoptotic agents have shown variable or even no benefit in combination with hypothermia, suggesting overlapping mechanisms of neuroprotection. Inflammation appears to play a critical role in the pathogenesis of injury in the neonatal brain, and thus, there is potential for drugs with immunomodulatory properties that target inflammation to be used as a therapy in neonates. In this review, we examine the evidence for neuroprotection with immunomodulation after hypoxia-ischemia. For example, stemcell therapy can reduce inflammation, increase cell survival, and promote cell maturation and repair. There are also encouraging preclinical data from small animals suggesting that stemcell therapy can augment hypothermic neuroprotection. However, there is conflicting evidence, and rigorous testing in translational animal models is now needed.

Cerebral blood flow velocity and oxygenation correlate predominantly with right ventricular function in cooled neonates with moderate-severe hypoxic-ischemic encephalopathy.

The relationship between right ventricular (RV) function and cerebral blood flow (CBF) velocity and cerebral oxygenation was assessed in neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). Echocardiographic, transcranial Doppler, and hemodynamic data from 37 neonates with moderate-severe HIE + TH were reviewed. Twenty healthy newborns served as controls. Cardiac dysfunction in HIE + TH was characterized by a predominant RV dysfunction, with concomitantly reduced CBF velocity. A significant correlation was found between CBF velocity and tricuspid annular plane systolic excursion (TAPSE), RV output (RVO), and stroke volume (SVRV), as well as with left ventricular output and stroke volume. Brain oxygenation (rSO2) correlated significantly with RVO, SVRV, TAPSE, ejection fraction, and fractional shortening, whereas cerebral fractional tissue oxygen extraction (FTOEc) correlated with RVO, SVRV, RV myocardial performance index, and superior vena cava flow. CBF velocity and cerebral NIRS correlations were stronger with parameters of right ventricular performance.Conclusion: CBF velocity and brain oxygenation correlate predominantly with RV function in HIE + TH. This suggests a preferential contribution of RV performance to cerebral hemodynamics in this context. What is Known: • Neonates with hypoxic ischemic encephalopathy frequently exhibit alterations of cardiac function and cerebral blood flow. • These are considered organ-specific consequences of perinatal asphyxia. What is New: • We show that cerebral blood flow velocity and brain oxygenation are correlated predominantly with right ventricular function during therapeutic hypothermia. • This suggests a potential direct contribution of right ventricular performance to cerebral hemodynamics in this context.