Benefits Of Therapeutic Hypothermia Research Articles

Therapeutic hypothermia success for hypoxic-ischaemic encephalopathy in Latin America: Eight-year experience in EpicLatino Neonatal Network.

A study reported that therapeutic hypothermia (TH) did not reduce the combined prognosis of mortality and disability at 18 months, in low- and middle-income countries for patients with hypoxic ischaemic encephalopathy (HIE) who received TH, suggesting its no implementation in these regions. We described characteristics, mortality, and neurological response before and after the use of TH in newborns with HIE within the EpicLatino Neonatal Network (ENN) and described the population of infants with HIE treated and not treated with TH. Data were collected from 2015 to 2022 for patients with HIE. Mortality rates and Sarnat scores were compared before and after TH. The Wilcoxon Signed-Rank Test was used for comparisons. In this observational study 518 neonates of our total population of 26 970, had HIE (1.92%) of whom 150 underwent TH. Ten out of 21 neonatal intensive care units (NICUs) provided TH. The Wilcoxon Signed Rank Test for 138 cases with complete data showed a significant difference. The findings support the benefits of TH in HIE within this cohort. TH should not be withheld solely due to the economic status of the country. A strict patient selection and TH protocol are essential.

Clinical and prognostic significance of neurosonography of lateral ventricles for infants treated with therapeutic hypothermia during the early neonatal period

Background. Currently, therapeutic hypothermia (TH) is the only approved method for treating hypoxic-ischemic encephalopathy (HIE) that helps improve outcomes. However, it also has significant drawbacks, including the necessity for expensive equipment and treatment technologies, poorly understood pathophysiological mechanisms, and, most importantly, not always well-understood long-term results. Numerous scientific studies report the potential benefits of TH, but the actual risk/benefit ratio is still unknown. The results of long-term follow-up of children who underwent TH and did not have serious neuromotor or intellectual disorders are variable. It is believed that the correlation between neonatal neuroimaging and the degree of nervous system impairment remains poorly defined. Chronic brain injuries diagnosed after the neonatal period, such as parenchymal volume loss, appear to be more prognostically significant, which may be reflected by moderate enlargement of the ventricular system of the brain. The method for determining the size of the ventricular system using ultrasound can be accessible for infants of the first year of life who had HIE but do not have direct indications for magne­tic resonance imaging. Therefore, this study aimed to explore the characteristics of the cerebral ventricular system in infants of the first year of life who suffered severe asphyxia at birth, depen­ding on the method of post-resuscitation care (with or without TH). Materials and ­methods. The study examined the results of neurosonographic examinations of 309 infants during their first year of life. Inclusion criteria were gestational age at birth ≥ 36 weeks and birth weight ≥ 2000 g, manifestations of HIE in the early neonatal period without adverse short-term outcomes (at the time of discharge from the neonatal hospital, the children showed no signs of destructive hypoxic-ischemic lesions of the central nervous system (CNS), seizures, or pathological muscle tone, and had full oral feeding). Exclusion criteria were diagnosed congenital CNS abnormalities, neuroinfections, psychomotor development delay of more than 3 months during the first years of life, progressive obstructive ventriculomegaly or ventriculomegaly associated with non-atrophic subarachnomegaly. The children were divided into three groups: hypothermia group — 19 infants who underwent TH after birth; normothermia group — 14 children who conditio­nally had indications for TH but did not undergo it; comparison group — 276 children in their first year of life who did not require TH (Apgar score > 5 at 10 minutes of life, manifestations of mild or moderate HIE (according to the Sarnat scale) during the first days of life). Neurosonographic examinations were conducted at the age of 2–7 months (mean of 2.12 ± 0.07 months). The sizes of the lateral ventricles were assessed in comparison with the results from the control group of infants of the same age (34 healthy children with no recorded factors of complicated perinatal period, no signs of neurological dysfunction during the neonatal period, and the seven-month observation). Enlargement of the lateral ventricles was recorded when the size of the anterior horn or body of the ventricle in the parasagittal projection exceeded the 95th percentile of the corresponding measurements from the control group. Results. Enlargement of the lateral ventricles during the neurosonographic examination was detected in 36.8 % of children in the hypothermia group, 14.3 % in the normothermia group, and 8.0 % of children in the comparison group. Significant differences were registered only when comparing the results of the hypothermia group with the comparison group (p < 0.05, Fisher’s exact test). Significant correlations (p < 0.05) were found between the size of the lateral ventricles and clinical signs such as sleep disturbances, decreased muscle tone in the arms, increased tendon reflexes, delayed motor development, increased muscle tone in a pyramidal pattern, and diffuse muscle hypotonia. Conclusions. Thus, infants who had severe asphyxia at birth and underwent TH significantly more often had enlargement of the cerebral ventri­cular system (versus the comparison group). Therefore, although therapeutic hypothermia improves outcomes for the development of the nervous system in children who have moderate and severe hypoxic-ischemic encephalopathy, brain morphology (particularly the state of the ventricular system) may still be altered in infants during the first year of life. And the presence of significant correlations between the size of the lateral ventricles and clinical signs of neurological dysfunction argues for further clinical monitoring of children after therapeutic hypothermia throughout the first years of life and in the absence of short-term adverse outcomes of HIE or significant delays in psychomotor development during the first year of life.

Clinical Insights and Future Directions in Hypothermia for Severe Traumatic Brain Injury: A Narrative Review.

Fever control is essential in patients with severe traumatic brain injury (TBI). The efficacy of therapeutic hypothermia (TH) in severe TBI has been investigated over the last few decades; however, in contrast to experimental studies showing benefits, no evidence of efficacy has been demonstrated in clinical practice. In this review, the mechanisms and history of hypothermia were briefly outlined, while the results of major randomized controlled trials (RCTs) and meta-analyses investigating TH for adult TBI were introduced and discussed. The retrieved meta-analyses showed conflicting results, with a limited number of studies indicating the benefits of TH. Some studies have shown the benefits of long-term TH compared with short-term TH. Although TH is effective at lowering elevated intracranial pressure (ICP), reduced ICP does not lead to favorable outcomes. Low-quality RCTs overestimated the benefits of TH, while high-quality RCTs showed no difference or worse outcomes with TH. RCTs assessing standardized TH quality demonstrated the benefits of TH. As TBI has heterogeneous and complicated pathologies, applying a uniform treatment may not be ideal. A meta-analysis of young patients who underwent early cooling and hematoma removal showed better TH results. TH should not be abandoned, and its optimal usage should be advocated on an individual basis.

Therapeutic Hypothermia Compared with Normothermia in Adults with Traumatic Brain Injury; Functional Outcome, Mortality, and Adverse Effects: A Systematic Review and Meta-Analysis.

The main focus of traumatic brain injury (TBI) management is prevention of secondary injury. Therapeutic hypothermia (TH), the induction of a targeted low core body temperature, has been explored as a potential neuroprotectant in TBI. The aim of this article is to synthesize the available clinical data comparing the use of TH with the use of normothermia in TBI. A systematic search was conducted through MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized clinical trials including one or more outcome of interest associated with TH use in TBI. Independent reviewers evaluated quality of the studies and extracted data on patients with TBI undergoing TH treatment compared with those undergoing normothermia treatment. Pooled estimates, confidence intervals (CIs), and risk ratios (RRs) or odds ratios were calculated for all outcomes. A total of 3,909 patients from 32 studies were eligible for analysis. Pooled analysis revealed a significant benefit of TH on mortality and functional outcome (RR 0.81, 95% CI 0.68-0.96, I2 = 41%; and RR 0.77; 95% CI 0.67-0.88, I2 = 68%, respectively). However, subgroup analysis based on risk of bias showed that only studies with a high risk of bias maintained this benefit. When divided by cooling method, reduced poor functional outcome was seen in the systemic surface cooling and cranial cooling groups (RR 0.68, 95% CI 0.59-0.79, I2 = 35%; and RR 0.44, 95% CI 0.29-0.67, I2 = 0%), and no difference was seen for the systemic intravenous or gastric cooling group. Reduced mortality was only seen in the systemic surface cooling group (RR 0.63, 95% CI 0.53-0.75, I2 = 0%,); however, this group had mostly high risk of bias studies. TH had an increased rate of pneumonia (RR 1.24, 95% CI 1.10-1.40, I2 = 32%), coagulation abnormalities (RR 1.63, 95% CI 1.09-2.44, I2 = 55%), and cardiac arrhythmias (RR 1.78, 95% CI 1.05-3.01, I2 = 21%). Once separated by low and high risk of bias, we saw no difference in these complications in the groups with low risk of bias. Overall quality of the evidence was moderate for mortality, functional outcome, and pneumonia and was low for coagulation abnormalities and cardiac arrhythmias. With the addition of several recent randomized clinical trials and a thorough quality assessment, we have provided an updated systematic review and meta-analysis that concludes that TH does not show any benefit over normothermia in terms of mortality and functional outcome.

Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy.

Therapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO2) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO2's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO2 and temperature during TH. This was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates ≥34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15). Data quality for 58 neonates was sufficient for analysis. CMRO2 changed by 14.4% per °C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per °C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (β (SE)=4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10moL/dl×mm2/s, P=0.009 and P=0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes. Point of care measures of CMRO2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE. This clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258).

The Short Term Outcome of Therapeutic Hypothermia Compared with Standard Treatment among Asphyxiated Newborns Presenting after 6 hours of Life

Objectives: To compare the short term outcome of therapeutic hypothermia in asphyxiated newborn with standard treatment presenting after 6 hours of life. Methodology: It was Randomized controlled trial conducted in the department of Pediatric Medicine, Bahawal Victoria Hospital, Bahawalpur from December 2018 to June 2019 after taking ethical approval from institutional ethical review committee and informed written consent from parents of patients. Confidentiality of the data was maintained and it was assured that no harm to study participants is done. A total of 108 term neonates with moderate to severe HIE presenting >6 hours of life were included. Preterm infants, major congenital anomaly and overt bleeding were excluded. Then selected patients were placed randomly into Group A (hypothermia group) & Group B (conservative group), by using lottery method. Outcome variable like mortality within 1st week was noted. There was no conflict of interest in the study and funding was done by the authors. Results: The mean age of patients in group A was 17.69 ± 6.68 hours and in group B was 17.60 ± 6.65 hours. Out of 108 patients, 62 (57.41%) were males and 46 (42.59%) were females with male to female ration of 1.3:1. There was mortality within one week (short term outcome) in 07 (12.96%) patients in Group A (hypothermia group) while in Group B (conservative group), it was seen in 16 (29.63%) patients. Conclusion: This study concluded that there is benefit of therapeutic hypothermia in asphyxiated newborns after 6 hours of life and short term outcome is better after therapeutic hypothermia in asphyxiated newborns. Keywords: Asphyxia, Encephalopathy, Mortality, Cooling.

Abstract 14498: Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK)

Introduction: Despite advances in revascularization and mechanical support, cardiogenic shock (CS) remains a highly morbid clinical state with 30-day mortality approaching 50%. Therapeutic hypothermia (TH) has been demonstrated to improve hemodynamics and reduce inflammation in small studies, but prospective randomized data is limited. We aimed to assess the safety and hemodynamic effects of TH (33 °C for 24 hours) in patients with CS. Methods: A total of 20 patients in CS were randomized to either TH plus standard therapy or standard therapy alone in this pilot study. Patients randomized to TH were cooled and rewarmed via intravenous cooling catheter. The primary safety endpoint was a composite of bradycardia requiring treatment, bleeding requiring transfusion as a result of catheter placement or secondary to resulting coagulopathy, shivering, hyperglycemia requiring insulin for non-diabetic patients, electrolyte derangement unexplained by other therapies, and complications from cooling catheter insertion. Secondary endpoints included hemodynamic parameters (cardiac output, pulmonary artery pressure, systemic vascular resistance, and cardiac power index). Results: There were no statistically significant differences in the composite analysis of prespecified safety outcomes (3 events in TH group vs 0 events in control group, p = 0.24). Patients randomized to TH demonstrated a statistically significant increase in cardiac index (3.6 [3.1, 3.9] L/min/m 2 vs 2.6 [2.5, 3.2] L/min/m 2 , p = 0.03) and cardiac power index (0.61 [0.55, 0.70] W/m 2 vs 0.53 [0.44, 0.57] W/m 2 , p = 0.03) compared to the control group at 48-96 hours after randomization. There were no statistically significant differences between the two groups for other collected hemodynamic variables. Conclusions: TH is a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters. Larger studies are necessary to better understand the clinical benefits of TH in patients presenting with CS.

Abstract 10566: Hypothermia as an Adjunctive Therapy to Percutaneous Intervention in St-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Control Trials

Introduction: In the setting of acute ST-elevation myocardial infarction (STEMI), several randomized control trials (RCTs) suggested a potential benefit with the use of Therapeutic hypothermia (TH). However, results from previous studies are contradictory. Method: We performed a comprehensive literature search for studies that evaluated the efficacy and safety of adjunctive TH compared to the standard percutaneous coronary intervention (PCI) in awake patients with STEMI. The primary outcome was the infarct size (IS) and microvascular obstruction (MVO) assessed by cardiac imaging at the end of follow-up. The secondary outcomes were major adverse cardiovascular events (MACE), procedure-related complications, and door to balloon time. Relative risk (RR) or the mean difference (MD) and corresponding 95% confidence intervals (CIs) were calculated using the random-effects model. Results: A total of 10 RCTs, including 706 patients (mean age: 58±9.6 years, 364 patients managed with adjunctive TH vs. 342 with standard PCI), were included. As compared to standard PCI, TH was not associated with a statistically significant improvement in the IS (MD: -0.87 %, 95%CI: -2.97, 1.23; P = 0.42) or in the MVO (MD: 0.11 %, 95%CI: -0.06, 0.27; P = 0.21). MACE and its individual components were comparable between the two groups. However, the TH approach was associated with an increased risk of infection and prolonged door to balloon time. Furthermore, there was a trend in the TH group toward an increased incidence of stent thrombosis and paroxysmal atrial fibrillation. Conclusions: According to our meta-analysis of published RCTs, the benefit of TH in STEMI patients is modest, with a marginal safety profile and potential for care delays. Larger-scale RCTs are needed to further clarify our results.

Therapeutic hypothermia in neonatal hypoxic encephalopathy: A systematic review and meta-analysis.

BackgroundTherapeutic hypothermia (TH) is regarded as the most efficacious therapy for neonatal hypoxic encephalopathy. However, limitations in previous systematic reviews and the publication of new data necessitate updating the evidence. We conducted this up-to-date systematic review to evaluate the effects of TH in neonatal encephalopathy on clinical outcomes.MethodsIn this systematic review and meta-analysis, we searched Medline, Cochrane Library, Embase, LIVIVO, Web of Science, Scopus, CINAHL, major trial registries, and grey literature (from inception to October 31, 2021), for randomized controlled trials (RCT) comparing TH vs normothermia in neonatal encephalopathy. We included RCTs enrolling neonates (gestation ≥35 weeks) with perinatal asphyxia and encephalopathy, who received either TH (temperature ≤34°C) initiated within 6 hours of birth for ≥48 hours, vs no cooling. We excluded non-RCTs, those with delayed cooling, or cooling to >34°C. Two authors independently appraised risk-of-bias and extracted data on mortality and neurologic disability at four time points: neonatal (from randomization to discharge/death), infancy (18-24 months), childhood (5-10 years), and long-term (>10 years). Other outcomes included seizures, EEG abnormalities, and MRI findings. Summary data from published RCTs were pooled through fixed-effect meta-analysis.ResultsWe identified 36 863 citations and included 39 publications representing 29 RCTs with 2926 participants. Thirteen studies each had low, moderate, and high risk-of-bias. The pooled risk ratios (95% confidence interval, CI) were as follows: neonatal mortality: 0.87 (95% CI = 0.75, 1.00), n = 2434, I2 = 38%; mortality at 18-24 months: 0.88 (95% CI = 0.78, 1.01), n = 2042, I2 = 51%; mortality at 5-10 years: 0.81 (95% CI = 0.62, 1.04), n = 515, I2 = 59%; disability at 18-24 months: 0.62 (95% CI = 0.52, 0.75), n = 1440, I2 = 26%; disability at 5-10 years: 0.68 (95% CI = 0.52, 0.90), n = 442, I2 = 3%; mortality or disability at 18-24 months: 0.78 (95% CI = 0.72, 0.86), n = 1914, I2 = 54%; cerebral palsy at 18-24 months: 0.63 (95% CI = 0.50, 0.78), n = 1136, I2 = 39%; and childhood cerebral palsy: 0.63 (95% CI = 0.46, 0.85), n = 449, I2 = 0%. Some outcomes showed significant differences by study-setting; the risk ratio (95% CI) for mortality at 18-24 months was 0.79 (95% CI = 0.66,0.93), n = 1212, I2 = 7% in high-income countries, 0.67 (95% CI = 0.41, 1.09), n = 276, I2 = 0% in upper-middle-income countries, and 1.18 (95% CI = 0.94, 1.47), n = 554, I2 = 75% in lower-middle-income countries. The corresponding pooled risk ratios for ‘mortality or disability at 18-24 months’ were 0.77 (95% CI = 0.69, 0.86), n = 1089, I2 = 0%; 0.56 (95% CI = 0.41, 0.78), n = 276, I2 = 30%; and 0.92 (95% CI = 0.77, 1.09), n = 549, I2 = 86% respectively. Trials with low risk of bias showed risk ratio of 0.97 (95% CI = 0.80, 1.16, n = 1475, I2 = 62%) for neonatal mortality, whereas trials with higher risk of bias showed 0.71 (95% CI = 0.55, 0.91), n = 959, I2 = 0%. Likewise, risk ratio for mortality at 18-24 months was 0.96 (95% CI = 0.83, 1.13), n = 1336, I2 = 58% among low risk-of-bias trials, but 0.72 (95% CI = 0.56, 0.92), n = 706, I2 = 0%, among higher risk of bias trials.ConclusionsTherapeutic hypothermia for neonatal encephalopathy reduces neurologic disability and cerebral palsy, but its effect on neonatal, infantile and childhood mortality is uncertain. The setting where it is implemented affects the outcomes. Low(er) quality trials overestimated the potential benefit of TH.

Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy.

Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: (1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. (2) Even with possible access for 'local refrigeration', cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4 °C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.

Therapeutic Hypothermia Is Associated With a Decrease in All-cause Mortality in Cardiac Arrest Due to Shockable Rhythm.

The benefits of therapeutic hypothermia (TH) in comatose patients postcardiac arrest remain uncertain. While some studies have shown benefit, others have shown equivocal results. We pooled data from randomized controlled trials to better study the outcomes of TH. Electronic research databases were queried up till September 21, 2021. Randomized controlled trials comparing TH (32-34 °C) with control (normothermia or temperature ≥36 °C) in comatose postcardiac arrest patients were included. The study included 10 randomized controlled trials with 3988 subjects (1999 in the TH arm and 1989 in the control arm). There was no difference in all-cause mortality between TH and control (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.66-1.05; P = 0.08; I2 = 41%). There was no difference in the odds of poor neurological outcomes (OR, 0.78; 95% CI, 0.61-1.01; P = 0.07; I2 = 43%). Subgroup analysis showed a decrease in all-cause mortality and poor neurological outcomes with TH in shockable rhythms (OR, 0.55; 95% CI, 0.37-0.80; P = 1.00; I2 = 0% and OR, 0.48; 95% CI, 0.32-0.72; P = 0.92; I2 = 0%, respectively). TH may be beneficial in reducing mortality and poor neurological outcomes in comatose postcardiac arrest patients with shockable rhythms.

Therapeutic hypothermia after resuscitated cardiac arrest: benefits in survival and neurological outcome

Abstract Introduction The benefits of therapeutic hypothermia in patients remaining in coma after resuscitated cardiac arrest are still controversial, specially for nonshockable rhythm. This study aims to assess the effects of this technique in survival and neurological outcome in comatous patients after resuscitated cardiac arrest. Methods Retrospective analysis of patients admitted to a Coronary Care Unit from 2006 to 2020 who remained in coma (Glasgow Coma Scale ≤10) after resuscitated cardiac arrest. We compared intrahospital mortality and neurological outcome at discharge between patients who were treated with therapeutic hypothermia and those who weren't. We used intravascular cooling catheter with a target core temperature of 33°C, which was maintained for 24 hours. We performed a subgroup analysis to compare shockable and nonshockable rhythm. Neurological outcome was evaluated with the Cerebral Performance Categories Scale (CPC), which considers survival without limiting disability (CPC 1–2) as favourable neurological outcome. Results A total of 272 patients were admitted at our Coronary Care Unit after resuscitated cardiac arrest. 182 patients remained in coma after cardiac arrest. The median age was 65.83±0.98 years and 29.1% were women. 70 patients (38.46%) were treated with therapeutic hypothermia – 44 (62.85%) of them had shockable rhythm at presentation and 26 (37.14%), nonshockable rhythm. When we analysed all patients with shockable rhythm, mortality was significantly lower in those treated with therapeutic hypothermia (25% vs 53.8%, p=0.004). In nonshockable rhythm, there was a tendency for lower mortality in the hypothermia group (73.1% vs. 85%, p=0.19). Regarding neurological outcomes, we observed that therapeutic hypothermia also improved neurological outcome at discharge in patients with initial shockable rhythm (CPC 1–2 in 68.2% vs. 26.9%, p<0.001). On the other hand, more patients with nonshockable rhythm had a CPC 1–2 with this technique, although these results didn't reach statistical significance (19.2% vs. 10%, p=0.24). Conclusions According to our experience, therapeutic hypothermia in patients who remained in coma after resuscitated cardiac arrest showed favourable results in survival and neurological outcome both in shockable and nonshockable rhythm. Funding Acknowledgement Type of funding sources: None. Intrahospital MortalityGood neurological outcome at discharge

Long-Term Outcome after Asphyxia and Therapeutic Hypothermia in Late Preterm Infants: A Pilot Study.

Therapeutic hypothermia (THT) is the recommended treatment for neuroprotection in (near) term newborns that experience perinatal asphyxia with hypoxic-ischemic encephalopathy. The benefit of THT in preterm newborns is unknown. This pilot study aims to investigate long-term outcomes of late preterm asphyctic infants with and without THT compared to term infants. The single-center, retrospective analysis examined medical charts of infants with perinatal asphyxia born between 2008 and 2015. Long-term outcome was assessed using the Bayley Scales of Infant Development 2 at the age of (corrected) 24 months. Term (n = 31) and preterm (n = 8) infants with THT showed no differences regarding their long-term outcomes of psychomotor development (Psychomotor Developmental Index 101 ± 16 vs. 105 ± 11, p = 0.570), whereas preterm infants had a better mental outcome (Mental Developmental Index 105 ± 13 vs. 93 ± 18, p = 0.048). Preterm infants with and without (n = 69) THT showed a similar mental and psychomotor development (Mental Developmental Index 105 ± 13 vs. 96 ± 20, p = 0.527; Psychomotor Developmental Index 105 ± 11 vs. 105 ± 15, p = 0.927). The study highlights the importance of studying THT in asphyctic preterm infants. However, this study shows limitations and should not be used as a basis for decision-making in the clinical context. Results of a multicenter trial of THT for preterm infants (ID No.: CN-01540535) have to be awaited.

POLAR Study Revisited: Therapeutic Hypothermia in Severe Brain Trauma Should Not Be Abandoned.

The benefits of therapeutic hypothermia (TH) in severe traumatic brain injury (sTBI) have been long debated. In 2018, the POLAR study, a high-quality international trial, appeared to end the debate by showing that TH did not improve mortality in sTBI. However, the POLAR-based recommendation to abandon TH was challenged by different investigators. In our recent meta-analysis, we introduced the cooling index (COIN) to assess the extent of cooling and showed that TH is beneficial in sTBI, but only when the COIN is sufficiently high. In the present study, we calculated the COIN for the POLAR study and ran a new meta-analysis, which included the POLAR data and accounted for the cooling extent. The POLAR study targeted a high cooling extent (COIN of 276°C × h; calculated for 72 h), but the achieved cooling was much lower (COIN of 193°C × h)-because of deviations from the protocol. When the POLAR data were included in the COIN-based meta-analysis, TH had an overall effect of reducing death (odds rate of 0.686; p = 0.007). Among the subgroups with different COIN levels, the only significantly decreased odds rate (i.e., beneficial effect of TH) was observed in the subgroup with high COIN (0.470; p = 0.013). We conclude that, because of deviations from the targeted cooling protocol, the overall cooling extent was not sufficiently high in the POLAR study, thus masking the beneficial effects of TH. The current analysis shows that TH is beneficial in sTBI, but only when the COIN is high. Abandoning the use of TH in sTBI may be premature.

Case series of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy during extracorporeal life support

Therapeutic hypothermia initiated within 6 hours of birth is currently the standard of care for the management of neonates with hypoxic-ischemic encephalopathy. Neonates undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy are also at risk for severe respiratory failure and need for extracorporeal life support. The risks and benefits of therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support are still not well defined. We report our experience of a case series of six neonates who underwent therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support. We also report long-term neurodevelopmental follow-up from 6 to 24 months and add to the current body of evidence regarding feasibility, clinical experience, and short-term complications.

Neuroprotection in neurocritical care

In intensive care medicine neuroprotection is understood mostly as various measures to avoid secondary brain damage after initial trauma, as in stroke, intracranial hemorrhage and resuscitation. Every brain trauma differs in the damage pattern and dynamics depending on the primary form of injury. Therefore, there are targeted treatment approaches depending on the pathophysiology of the medical condition. In addition, neuroprotective methods are desirable that are effective in the majority of patients with acute brain injury. In actual fact, in all forms of acute brain injury certain pathophysiological courses are encountered, which can lead to secondary brain damage depending on the intensity, e.g. reperfusion injury, damage to the blood-brain barrier and excitotoxicity. There is evidence to suggest that the creation of physiologically normal conditions leads to a favorable situation for the damaged brain. This article firstly describes the relevance of neuroprotective measures in neurocritical care medicine. Subsequently, general pathophysiological mechanisms in brain trauma are described. Following this, the pathophysiology and treatment options in brain pressure crises (reduction of intracranial pressure), anemia (transfusion management), hyperglycemia and hypoglycemia (adjustment of the blood sugar level) are dealt with. Finally, the use and benefits of therapeutic hypothermia are discussed. This has a special position as the only clinically effective individual measure for neuroprotection. The focus here is on the application following circulatory and cardiac arrest and resuscitation.

Decreased body temperature during anoxia affects the endogenous BDNF level in tertiary phase of injury

Asphyxia before, during, or after birth is an important cause of perinatal mortality and morbidity. The mechanism underlying neurological damage resulting from anoxia episode is complex and is not limited to the anoxia episode. Although the benefits of therapeutic hypothermia in secondary failure of oxidative metabolism have long been known, the principle of this therapy in tertiary phase of repair and reorganization have not yet to be fully elucidated. Currently brain-derived neurotrophic factor (BDNF) is also considered to be beneficial to neuronal survival.Therefore, our experiments aimed at determining the effects of low body temperature during simulated perinatal anoxia on the level of the neurotrophic brain-derived factor (BDNF) and on the correlation between the level of BDNF (proBDNF and mBDNF) and the level of active caspase-3 (marker of apoptosis) in developing brain in tertiary phase after exposure.The results demonstrated that the ability of BDNF to inhibit caspase-3 activation and subsequent apoptosis likely accounts in large part for its protection against neuronal damage only in rats maintaining the low body temperature.

Therapeutic hypothermia in children: Which indications remain in 2018?

Experimental studies on therapeutic hypothermia in acute brain injury reported positive outcomes and identified two potential benefits, namely, reduction in seizure incidence and in intracranial pressure. Translating this evidence to humans is challenging, especially for conditions in pediatric patients, such as cardiac arrest, traumatic brain injury, and status epilepticus, among others. This narrative review aimed to discuss the current indications and benefits of therapeutic hypothermia in acute brain injury in the pediatric population (i.e., beyond the neonatal period) by analyzing the neurologic outcome and mortality data obtained from previous studies.

Analysis of using of citicoline in term newborns during the acute period of hypoxic ischemic encephalopathy

Hypoxic ischemic encephalopathy occurs in 1.5 to 4 per 1,000 births in developed countries, and in as many as 26 per 1,000 live births in resource-limited settings. Therapeutic hypothermia significantly reduces the combined outcome of death or severe neurodevelopmental impairment from 65% to 40-50%. While the benefits of therapeutic hypothermia provide proof of concept that outcomes can be improved, additional pharmacological agents for neonatal neuroprotection for further improve outcomes of hypoxic ischemic encephalopathy are needed.Objective.To determine the potential neuroprotective influence of citicoline interm neonatesduring the acute period of hypoxic-ischemic encephalopathy.Materials and methods.A prospective, single-centered, randomized, controlled study of the citicolineimpact on acute period after perinatal hypoxia-ischemia performed in 205 full-term infant, were treated in the neonatal intensive care unit inbabiessustained of hypoxic ischemic encephalopathy in 2012-2017. Citicoline was administered basingon simple randomization in dose of 200 mg once daily intravenously for the first 5 days of treatment. Endpoints included indicators such as duration of positive pressure ventilation, total days of intensive care and the morbidity of cerebral leukomalacia, as well as frequency of the development of seizures. During all the days of the study, a standard neurosonography was performedtoevaluateresistant and pulsatile indexes in the anterior cerebral artery.Results.After randomization 31 babieswere collectedinthe groupof citicoline, remaining 174 infants were at the control group. The obtained data showed no significant differences between citicoline and control groupsin Doppler indexes on the first day of treatment, mean blood pressure, terms of extubation, and the total duration of respiratory support, both invasive and non-invasive. Interestingly, there was a significant difference on the 3rd day of treatment with the resistantindex (p=0.026) and pulsatile index (p = 0.036) measured in the anterior cerebral arteries. However, despite the more prognostic, more positive values in the citicoline group, this did not lead to a decrease in the incidence of cerebral leukomalacia, which was even lower in the control group (10.9% vs. 19.4%), but this difference was not reliable (p=0.186). On the other hand, we paid our attention to the higher frequency of the development of seizuresin the citicoline group on the 1st(p=0.005) and 2nd(p <0.001) and 3rd days of the study (p=0.003).Conclusions.Among term neonates the use of citicoline duringthe acute period of HIEdid not show neuroprotective properties.

Impact of Education on Hypothermia Delivery during Neonatal Transport

Background: Moderate therapeutic hypothermia (TH) initiated within 6 h of life reduces adverse neurodevelopmental outcomes in infants after perinatal hypoxic ischaemic insult. For infants born in non-tertiary centres, TH may be initiated manually en route to a neonatal intensive care unit (NICU). However, both over- and undercooling is reported with this strategy, precluding some infants from the benefits of TH. Objectives: To evaluate the impact of a region-wide educational programme on the safety and efficacy of manual cooling administered by the Wellington Neonatal Transport Service (NeTS). Methods: Clinical records of infants with hypoxic ischaemic encephalopathy (HIE) retrieved by the Wellington NeTS for TH between January 2012 and June 2017 were reviewed retrospectively. Temperature outcomes of infants retrieved before and after the education programme were compared. Results: A total of 101 infants were cooled manually by Wellington NeTS for TH during the study period. Education and training significantly reduced the rate of overcooling to ≤32.0°C (4/43 [9%] vs. 0/58, p = 0.02). However, there was no difference in the proportion of infants who achieved target rectal temperature within 6 h of life (29/43 [65%] vs. 35/58 [60%], p = 0.57). Conclusions: Introduction of a region-wide educational programme may have improved the safety of manual cooling during neonatal transport but it had a negligible impact on its efficacy. The use of servo-controlled cooling during transport should therefore be considered to improve access to the optimal neuroprotective benefits of TH for outborn infants with HIE.