Prediction of the outcomes of post-asphyxial brain injury in infants undergoing therapeutic hypothermia

Subclinical Left Ventricular Systolic Dysfunction due to Coronary Arterial Thrombosis in a Neonate with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia

Background Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal mortality and morbidity, yet no validated biomarkers currently exist to predict long-term outcomes. We investigated the potential of the neonatal urinary metabolomic profile as a predictor of long-term neurodevelopmental outcomes in HIE newborns treated with therapeutic hypothermia (TH).Methods We conducted a longitudinal study in neonates with HIE undergoing TH. Urine samples collected during TH were analyzed using untargeted metabolomics via mass spectrometry. Based on long-term follow-up outcomes, patients were categorized into two groups: the adverse outcome (AO) group, defined by perinatal death, cerebral palsy, and/or an intelligence quotient (IQ) < 70, and the favourable outcome (FO) group, defined as absence of CP and IQ ≥ 70. Additionally, we assessed the predictive value of early neonatal brain magnetic resonance imaging (MRI) in relation to the aforementioned outcomes.Results Among 53 newborns treated with TH for HIE, long-term follow-up outcomes were available for 40; 29 were classified as FO and 11 as AO group. To mitigate bias, 11 FO patients were matched with 11 AO patients based on similar perinatal characteristics. Metabolomic analysis identified 21 metabolites distinguishing the two groups, with γ-butyrolactone, N-acetyl-galactosamine/glucosamine, Aldosterone, and Creatinine showing independent discriminative capability among groups. Brain MRI demonstrated a 67% positive and 96% negative predictive value for adverse outcomes.Conclusions The identified metabolites are implicated in neuromodulation and neuronal susceptibility to damage, suggesting their potential as prognostic markers for long-term outcomes in HIE and warranting further investigation. This is the first study linking the acute-phase metabolomic profile with long-term neurodevelopmental outcomes in HIE neonates, supporting its prognostic potential.

Objectives: Targeted temperature management (TTM) is the core post-resuscitation care to minimize neurologic deficit after out-of-hospital cardiac arrest (OHCA). Uncontrolled body temperature of patients may reflect the thermoregulation ability which can be associated with neurologic damage during arrest. The aim of this study was to investigate the association between initial body temperature (BT) and neurologic outcomes in OHCA patients who underwent TTM. Methods: We used nationwide OHCA database from January 2016 to December 2017. Adult OHCA patients with presumed cardiac etiology who underwent TTM after return-of-spontaneous circulation (ROSC) were included. The main exposure was a BT at initiation of TTM which was categorized into 3 groups: low (-35.5°c), middle(35.6°c-37.4°c), and high BT (37.5°c-). The primary outcome was good neurologic outcome (cerebral performance categories (CPC) 1 or 2). Adjusted ratios (AORs) and 95% confidence intervals (CIs) were estimated to evaluate association between initial BT of TTM and outcome in multivariable logistic regression model. Stratified subgroup analyses were according to the target temperature of TTM (hypothermia vs normothermia). Results: Of a total of 744 patients, 208 (28.0%) patients were low initial BT group and 471 (63.3%) patients were normal initial BT group and 65 (8.7%) patients were high initial BT group. Good neurological recovery rate was 13.9% in low initial BT group, 41.8% in middle initial BT group and 36.9% in high initial BT group. The adjusted odds ratios for good neurologic recovery were 0.281 (95% confidence interval [CI] 0.17-0.47) in low BT group and 0.65 (95% CI 0.34-1.27) in high BT group compared with normal initial BT group. Similar results were also found regardless of target temperature of TTM. Conclusion: Low initial BT of TTM was associated with unfavorable neurologic recovery for OHCA patients who underwent TTM after ROSC.

Out-of-hospital cardiac arrest (OHCA) is a common initial presentation of cardiovascular disease, affecting up to 325 000 people in the United States each year.1 In a recent meta-analysis of >140 000 patients with OHCA, survival to hospital admission was 23.8%, and survival to hospital discharge was only 7.6%.2 In patients who initially achieve return of spontaneous circulation (ROSC) after OHCA, the significant subsequent morbidity and mortality are due largely to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia. This syndrome, called the post cardiac arrest syndrome, comprises anoxic brain injury, post cardiac arrest myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathology3,4 (Table 1). The contribution of each of these components in an individual patient depends on various factors, including prearrest comorbidities, duration of the ischemic insult, and cause of the cardiac arrest. This review focuses on therapeutic strategies and recent developments in managing patients who are initially resuscitated from cardiac arrest. View this table: Table 1. Post Cardiac Arrest Syndrome: Pathophysiology and Potential Treatment Strategies There are 3 major aspects that require consideration in the management of the post cardiac arrest patient. After resuscitation, a decision must be made in relation to the appropriate triage of the OHCA patient. The next phase of management concerns the in-hospital treatment, which must address each component of the postarrest syndrome as appropriate for the individual patient. Finally, there are issues relating to prognostication and the deployment of various secondary prevention measures. Our recommended treatment algorithm is summarized in the Figure. This ideally follows from the implementation of basic and advanced life support measures, including effective cardiopulmonary resuscitation and defibrillation when appropriate, which are major determinants of outcome.2 Such an approach to care may be further modified according to the presence of other comorbidities and precipitating factors, which should be assessed …

The Thompson Encephalopathy Score and Short-Term Outcomes in Asphyxiated Newborns Treated With Therapeutic Hypothermia

Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial

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

AimEarly outcome prediction in neonates with perinatal asphyxia receiving therapeutic hypothermia (TH) remains difficult. Although several studies have explored prognostic markers and proposed scoring systems, none of these tools has been adopted for routine bedside use to date. The present retrospective study aimed to design an early prognostic outcome score (EPO-Score). The score serves to identify patients at discharge, predicting severe adverse outcomes according to the Griffiths Mental Development Scales (GMDS) with one year.MethodsPerinatal data was collected from 44 infants with perinatal asphyxia who had received therapeutic hypothermia between 2010 and 2020 at the University Hospital Erlangen, Germany. 27 predictive variables were analyzed regarding their prognostic significance. Analysis showed significant correlations between 15 variables and their outcome. Outcome at one year was classified as favorable (GMDS DQ > 78) or severe adverse (DQ < 78, cerebral palsy, or death). We combined related variables into four indices: systemic injury, neurologic, liver and renal damage. A forward-looking step-by-step analysis revealed a model, explaining 62.1% of the variance in the outcome (R2 = 0.621; p < 0.001). Based on these results, we developed the EPO-Score and correlated the score to the follow-up assessment at one year.ResultsA total of 32 (out of 44) infants met the inclusion criteria. 25 infants experienced a favorable outcome, 7 infants a severe adverse outcome. The EPO-Score integrates eight routine predictors. Average EPO-Score among all infants was 11 points (range 0–24). The EPO-Score showed significant association with the developmental outcome at one year of age (R2 = 0.421, p < 0.001). ROC-analysis demonstrated the EPO-Score's ability to distinguish between favorable and severe adverse developmental outcome, with a cut-off value of 13.5 (AUC = 0.926; 95% CI 0.831–1.00). Infants with a score of 14 or higher were classified as high-risk.ConclusionEPO-Score underlines the correlation between the severity of early multi-organ involvement and severe adverse outcome, demonstrating a high predictive value within our study population. Early identification of patients with severe adverse outcome is important for optimizing neurodevelopmental therapies and providing family support. Nevertheless, external validation is required before the score can be implemented in routine clinical care.

Background:Neonatal encephalopathy (NE) is a major cause of long-term neurodevelopmental disability in neonates. We evaluated the ability of serially measured biomarkers of brain injury to predict adverse neurological outcomes in this population.Methods:Circulating brain injury biomarkers including BDNF, IL-6, IL-8, IL-10, VEGF, Tau, GFAP, and NRGN were measured at 0, 12, 24, 48, 72, and 96 hours of cooling from 103 infants with NE undergoing TH. The biomarkers’ individual and combinative ability to predict death or severe brain injury and adverse neurodevelopmental outcomes beyond 1 year of age was assessed.Results:Early measurements of inflammatory cytokines IL-6, 8, and 10 within 24 HOL (AUC=0.826) and late measurements of Tau from 72–96 HOL (AUC=0.883, OR 4.37) were accurate in predicting severe brain injury seen on MRI. Late measurements of Tau were predictive of adverse neurodevelopmental outcomes (AUC=0.81, OR 2.59).Conclusions:Tau was consistently a predictive marker for brain injury in neonates with NE. However, in the first 24 HOL, IL-6, 8, and 10 in combination were most predictive of death or severe brain injury. The results of this study support the use of a serial biomarker panel to assess brain injury over the time course of disease in NE.

BackgroundHemodynamic instability in neonatal hypoxic-ischemic encephalopathy (HIE) can contribute to brain injury but long-term neurodevelopmental data is limited. Our objective was to compare the effect of hemodynamic instability requiring vasoactive support on radiologic brain injury and neurodevelopmental outcomes in HIE with therapeutic hypothermia (TH).MethodsThis retrospective cohort study compared infants with HIE post-TH who did not require (Group I) versus those who required vasoactive medications (Group II). The association between hemodynamic instability and MRI brain injury or Bayley Scales of Infant Development III (BSID-III) was evaluated by logistic regression.ResultsAmong 185 infants, group II had higher adjusted odds of moderate-severe grey matter injury [odds ratio 5.54; 95% confidence interval 1.70 - 18.05; p < 0.001] than group I, with no differences in adjusted 18–24-month BSID-III scores.ConclusionHemodynamic instability requiring vasoactive support in HIE with TH was associated with higher odds of radiologic brain injury but no difference in neurodevelopmental outcomes.

To evaluate multi-organ dysfunction (MOD) in newborns treated with therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE), and to compare MOD in those with normal/mild magnetic resonance imaging (MRI) findings to those with moderate to severe MRI findings or death. Retrospective single-center observational study of infants treated with TH. A total of 16 parameters across 7 organ systems were analyzed. Primary outcome was death or moderate to severe brain injury on MRI. Of 157 infants treated with TH, 77% had ≥2 organ systems with dysfunction. The number of organ systems with dysfunction was strongly associated with death or moderate-to-severe brain injury (p < 0.0001). Hematologic (68%) and hepatic (65%) dysfunction were most common. Neurologic and renal dysfunction were most strongly associated with the primary outcome (OR 13.5 [6.1-29.8] and 11.2 [4.1-30.3], respectively), while pulmonary hypertension was not. MOD is prevalent in infants undergoing TH for HIE, and the association between MOD and adverse outcomes may impact clinical care and counseling.

Persistent pulmonary hypertension of the newborn (PPHN) affects systemic oxygenation and may worsen brain injury in infants with neonatal encephalopathy (NE). Evidence suggests that higher cerebral regional oxygenation (crSO2) indicates derangement in cerebral autoregulation, energy metabolism, and blood flow following NE. Our aim was to evaluate the impact of PPHN on crSO2, in infants with NE treated with therapeutic hypothermia (TH). We retrospectively evaluated infants with NE and PPHN vs without PPHN, between 2018-2022. Linear regression analysis was performed to evaluate the impact of PPHN on crSO2 and total MRI score, adjusted for perinatal factors. 164 infants were analyzed, including 19(12%) with PPHN and 145(88%) without. PPHN-infants had significantly higher crSO2 during rewarming and post-rewarming compared to non-PPHN infants (87 ± 6 vs 80 ± 6, p = 0.001; 87 ± 5 vs 80 ± 7, p = 0.008, respectively), and a significantly higher total MRI score [7(2-19) vs 1(0-3), p < 0.001]. PPHN was significantly associated with higher crSO2 during rewarming (b = 6.21, 95% CI 2.37-10.04, p = 0.002) and post-rewarming (b = 8.60, 95% CI 2.28-14.91, p = 0.009), and total MRI score (b = 7.42, 95% CI 4.88-9.95, p < 0.001). PPHN was associated with higher crSO2 during and after rewarming, and worse brain MRI score, indicating a significant impact of PPHN on brain injury in infants with NE undergoing TH. Cerebral oxygenation was significantly higher in infants with neonatal encephalopathy (NE) and persistent pulmonary hypertension (PPHN) compared to infants without PPHN, during the rewarming and post-rewarming periods of therapeutic hypothermia (TH). PPHN is associated with brain injury in infants with NE undergoing TH. In infants with NE and PPHN, monitoring of cerebral oxygenation would help detect infants at higher risk of adverse outcomes.

Introduction: Prolonged time to Return of Spontaneous Circulation (ttROSC) after Out of Hospital Cardiac Arrest (OHCA) has consistently been associated with adverse outcome by a plausible direct relation to severity of anoxic injury. Hypothesis: Target temperature management (TTM) is assumed effective against anoxic brain injury and we hypothesized that TTM at 33 degrees would be more beneficial with prolonged time to ROSC compared to 36 degrees. Methods: In a post hoc analysis of the TTM trial, which showed no overall benefit of targeting 33 °C over 36 in 939 patients (NEJM 2013), we investigated the relation of time to ROSC and mortality and neurological outcome as assessed by the Cerebral Performance Category (CPC) and Modified Ranking Scale (mRS) after 180 days. Results: Prolonged ttROSC was significantly and independently associated with increased mortality, p&lt;0.001 (figure), with Hazard Ratio (HR) of 1.02 (95% CI 1.01-1.02, p&lt;0.001) per minute increase and level of TTM did not modify this association, p interaction =0.85. In survivors prolonged ttROSC was associated with increased odds of surviving with an unfavorable neurological outcome for CPC (p=0.008 for CPC 3-4) and a similar trend, albeit not statistically significant was observed for mRS (p=0.17, mRS 4-5). Odds for unfavorable neurological outcome (CPC&gt;2, mRS&gt;3) was not modified by levels of TTM overall. Conclusion: Time to ROSC remains a significant prognostic factor in comatose patients resuscitated from OHCA with regards to risk of death and risk of adverse neurological outcome in survivors. TTM at 33 degrees offers no advantage over targeting 36 degrees with regards to mortality or neurological outcome in patients with prolonged time to ROSC. Figure: Mortality rates stratified by quartiles of tome to ROSC and by TTM level. Differences tested by log rank test in between TTM in strata

Electrocardiographic and echocardiographic changes during therapeutic hypothermia in encephalopathic infants with long-term adverse outcome

Racial and Ethnic Inequities in Therapeutic Hypothermia and Neonatal Hypoxic–Ischemic Encephalopathy: A Retrospective Cohort Study