An Assessment of Physical and N6-Cyclohexyladenosine-Induced Hypothermia in Rodent Distal Focal Ischemic Stroke.

Therapeutic hypothermia (TH) mitigates damage in ischemic stroke models. However, safer and easier TH methods (e.g., pharmacological) are needed to circumvent physical cooling complications. This study evaluated systemic and pharmacologically induced TH using the adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), with control groups in male Sprague-Dawley rats. CHA was administered intraperitoneally 10 minutes following a 2-hour intraluminal middle cerebral artery occlusion. We used a 1.5 mg/kg induction dose, followed by three 1.0 mg/kg doses every 6 hours for a total of 4 doses, causing 20-24 hours of hypothermia. Animals assigned to physical hypothermia and CHA-hypothermia had similar induction rates and nadir temperatures, but forced cooling lasted ∼6 hours longer compared with CHA-treated animals. The divergence is likely attributable to individual differences in CHA metabolism, which led to varied durations at nadir, whereas physical hypothermia was better regulated. Physical hypothermia significantly reduced infarction (primary endpoint) on day 7 (mean reduction of 36.8 mm3 or 39% reduction; p = 0.021 vs. normothermic animals; Cohen's d = 0.75), whereas CHA-induced hypothermia did not (p = 0.33). Similarly, physical cooling improved neurological function (physical hypothermia median = 0, physical normothermia median = 2; p = 0.008) and CHA-induced cooling did not (p > 0.99). Our findings demonstrate that forced cooling was neuroprotective compared with controls, but prolonged CHA-induced cooling was not neuroprotective.

Variation in the Use of Targeted Temperature Management for Cardiac Arrest.

Targeted temperature management (TTM) is recommended for patients who do not respond after return of spontaneous circulation after cardiac arrest. However, the degree to which patients with cardiac arrest have access to this therapy on a national level is not known. Understanding hospital- and patient-level factors associated with receipt of TTM could inform interventions to improve access to this treatment among appropriate patients. Therefore, we performed a retrospective analysis using National Inpatient Sample data from 2016 to 2019. We used International Classification of Diseases, Tenth Edition diagnosis and procedure codes to identify adult patients with in-hospital and out-of-hospital cardiac arrest and receipt of TTM. We evaluated patient and hospital factors associated with receiving TTM. We identified 478,419 patients with cardiac arrest. Of those, 4,088 (0.85%) received TTM. Hospital use of TTM was driven by large, nonprofit, urban, teaching hospitals, with less use at other hospital types. There was significant regional variation in TTM capabilities, with the proportion of hospitals providing TTM ranging from >21% in the Mid-Atlantic region to <11% in the East and West South Central and Mountain regions. At the patient level, age >74 years (odds ratio [OR] 0.54, p <0.001), female gender (OR 0.89, p >0.001), and Hispanic ethnicity (OR 0.74, p <0.001) were all associated with decreased odds of receiving TTM. Patients with Medicare (OR 0.75, p <0.001) and Medicaid (OR 0.89, p = 0.027) were less likely than patients with private insurance to receive TTM. Part of these differences was driven by inequitable access to TTM-capable hospitals. In conclusion, TTM is rarely used after cardiac arrest. Hospital use of TTM is predominately limited to a subset of academic hospitals with substantial regional variation. Older age, female gender, Hispanic ethnicity, and Medicare or Medicaid insurance are all associated with a decreased likelihood of receiving TTM.

Adrenal congestion in perinatal hypoxia: Sonographic assessment and relationship with hypoxic ischemic encephalopathy.

BACKGROUND: During hypoxia, blood flow to the brain, myocardium, and adrenal glands is preserved or even increased to maintain homeostasis. Adrenal congestion occurs when venous return remains insufficient. Several different ultrasound measurements of adrenal glands in neonates have been reported in the literature. However, there is no data related on adrenal gland size in neonates with perinatal hypoxia. AIMS: To evaluate the adrenal congestion using by ultrasound (US) measurements in perinatal hypoxia, and to reveal the relationship of adrenal congestion with hypoxic-ischemic encephalopathy (HIE) grades and magnetic resonance imaging (MRI) findings. STUDY DESIGN: Prospective cohort study. SUBJECTS: Infants with perinatal hypoxia who met therapeutic hypothermia criteria and were being cooled were included in the present study. The control group was established from healthy neonates admitted to our center during the recruitment. OUTCOME MEASURES: The gland area was measured by tracing, and both the corpus and crura widths were measured. RESULTS: We reported adrenal gland area data of 110 newborns with HIE and compared them with 56 normal neonates. The adrenal size was significantly higher in the HIE group than in the control group (p<0,01). The frequency of adrenal congestion was 72.7% based on the selected cut-off values. The adrenal gland measurements were increased in the patients with perinatal hypoxia than those of the controls. CONCLUSIONS: In the systemic evaluation of newborns with perinatal hypoxia, additional care should be taken regarding adrenal congestion. The measurement of adrenal size with 2D US will help us to diagnose or confirm adrenal congestion and possible hemorrhagic changes. The morphological data and cut-off values given in our study will be useful for neonatologists and pediatric radiologists to evaluate the patient while managing perinatal hypoxia.

Eficacia y seguridad del electroencefalograma de amplitud integrada para recién nacidos con encefalopatía hipóxico-isquémica sometidos a hipotermia terapéutica / Efficacy and safety of amplitude-integrated electroencephalogram for neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen, el cual expone la evaluación de la eficacia y seguridad del electroencefalograma de amplitud integrada (aEEG) para recién nacidos con encefalopatía hipóxico-isquémica (EHI) sometidos a hipotermia terapéutica. ASPECTOS GENERALES: La EHI en el periodo neonatal ha sido descrita al detalle previamente en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 030-DETS-IETSI-2021. Brevemente, se trata de un síndrome heterogéneo clínicamente definido por una disfunción neurológica del recién nacido que se manifiesta con un nivel reducido de conciencia o convulsiones, dificultad para iniciar o mantener la respiración, y por depresión del tono y los reflejos (American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy 2014). Es preciso señalar que la EHI es la causa más común de convulsiones neonatales, lo cual se asocia frecuentemente con una alta carga de morbilidad (Glass et al. 2016). METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de la monitorización de recién nacidos con EHI sometidos a HTCC empleando el aEEG. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) incluyendo el National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Clinical and Economic Review (ICER), el Instituto de Calidad y Eficiencia en la Atención de la Salud (IQWiG, por sus siglas en alemán), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la OMS, el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). RESULTADOS: Luego de la búsqueda bibliográfica hasta marzo del 2022, y la selección de la evidencia se identificaron dos guías de práctica clínica con recomendaciones pertinentes al uso de aEEG o cEEG (Dilena et al. 2021; Ministerio de Sanidad, Servicios Sociales e Igualdad 2015) y dos revisiones sistemáticas cualitativas de estudios observacionales que compararon aEEG frente a cEEG (Kadivar et al. 2019; Rakshasbhuvankar et al. 2015), los cuales fueron considerados para inclusión en el presente documento. CONCLUSIÓN: Por lo expuesto, el IETSI aprueba el uso de electroencefalograma de amplitud integrada para recién nacidos con encefalopatía hipóxico-isquémica sometidos a hipotermia terapêutica.

The blood heat exchanger in intra-arterial selective cooling infusion for acute ischemic stroke: A computational fluid-thermodynamics performance, experimental assessment and evaluation on the brain temperature.

Intra-arterial selective cooling infusion with the autologous blood (IA-SCAI) is a promising therapeutic hypothermia induction method for conferring neuroprotection to acute ischemic stroke (AIS) patients. The blood heat exchanger (BHE) plays a crucial role in IA-SCAI's cooling capacity. However, there are no BHEs currently available that are specifically designed for the IA-SCAI, which requires a low blood flow to be compatible with cerebral hemodynamics. In an effort to develop a BHE for AIS patients, a prototype of a commercial BHE, Medtronic MYOtherm XP®, was mathematically modeled; specifically, computational fluid dynamics (CFD) was used to analyze its hemo- and thermo-dynamic characteristics under low blood flow including temperature distribution, velocity field and shear stress. Our numerical model predicted the hemolysis index to be 0.0041%-0.0581% inside the BHE with blood flows rates of 10 ml min-1-50 ml min-1. The in vitro heat transfer experiment showed that the BHE efficiently cooled the simulated blood from the initial 37 °C-5.8 °C within 150 s by using cold water (200 ml·min-1, 0 °C). The cooled simulated blood was able to cool the simulated blood in the middle cerebral artery of an artificial circulating system from 37 °C to 16.8 °C-33.7 °C depending on the blood perfusion rate (10-50 ml/min). A biological heat transfer mathematical model showed that brain tissue could be cooled by 2 °C within the initial 1min of infusion. This study verified the feasibility of using a commercial BHE for IA-SCAI and provided insights into its cooling capacity for therapeutic hypothermia.

Cost-effectiveness of the TherMax blood warmer during continuous renal replacement therapy.

Hypothermia is a common adverse event during continuous renal replacement therapy (CRRT), affecting multiple organ systems and increasing risk of poor health outcomes among patients with acute kidney injury (AKI) undergoing CRRT. TheraMax blood warmers are the next generation of extracorporeal blood warmers which reduce risk of hypothermia during CRRT. The purpose of this study is to elucidate the potential health economic impacts of avoiding CRRT-induced hypothermia by using the novel TherMax blood warming device. This study compares health care costs associated with use of the new TherMax blood warmer unit integrated with the PrisMax system compared to CRRT with a standalone blood warming device to avoid hypothermia in continuous renal replacement therapy (CRRT). An economic model was developed in which relevant health states for each intervention were normothermia, hypothermia, discharge, and death. Clinical inputs and costs were obtained from a combination of retrospective chart review and publicly available summary estimates. The proportion of AKI patients treated with CRRT who became hypothermic (<36°C) during CRRT treatment was 34.5% in the TherMax group compared to 71.9% in the 'standalone warmer' group. Given the 78.7-year average life expectancy in the US and the assumed average patient age at discharge/death of 65.4 years, the total life-years gained by avoiding mortality related to hypothermia was 9.0 in the TherMax group compared to 8.0 in the 'standalone warmer' group. Cost per life-year gained was $8,615 in the TherMax group versus $10,115 in the 'standalone warmer' group for a difference of -$1,501 favoring TherMax. The incremental cost-effectiveness ratio was negative, indicating superior cost-effectiveness for TherMax versus 'standalone warmer'. The TherMax blood warming device used with the PrisMax system is associated with lower risk of hypothermia, which our model indicates leads to lower costs, lower risk of mortality due to hypothermia, and superior cost-effectiveness.

Eficacia y seguridad de hipotermia terapéutica de cuerpo completo con mantas térmicas en recien nacidos de 35 semanas o más con asfixia perinatal y encefalopatía hipóxico-isquémica moderada o severa / Efficacy and safety of whole body therapeutic hypothermia with heating blankets in newborns 35 weeks or older with perinatal asphyxia and moderate or severe hypoxic-ischemic encephalopathy

INTRODUCCIÓN: El presente documento de evaluación de tecnología sanitaria (ETS) expone la evaluación de la eficacia y seguridad del equipo de hipotermia terapéutica de cuerpo completo (HTCC) con mantas térmicas en comparación al tratamiento de soporte estándar en la unidad de cuidados intensivos neonatales (UCIN) en recién nacidos de 35 semanas o más con asfixia perinatal (AP) y encefalopatía hipóxico-isquémica (EHI) moderada o severa sin malformaciones congénitas mayores, cromosomopatías incompatibles con la vida, retardo en crecimiento intrauterino severo (<1,8 kg), patologías quirúrgicas severas, o con criterios de severidad (bradicardia mantenida, midriasis paralítica, ausencia de reflejo corneal). La encefalopatía neonatal es un estado de alteración de la función neurológica del recién nacido. Esta patología se asocia a convulsiones y dificultad para iniciar o mantener la respiración; acarreando una alta morbilidad y mortalidad neonatal. La encefalopatía hipóxico-isquémica (EHI), producida por un cuadro de asfixia perinatal (AP), es uno de los principales subtipos de encefalopatía neonatal. En el Perú, un informe de la Dirección de Epidemiología del Ministerio de Salud reportó que la AP fue la tercera causa de muerte neonatal entre los años 2011 y 2012. Además, reportes del servicio de neonatología del Hospital Nacional Edgardo Rebagliati Martins (HNERM) del periodo 2015 - 2016 estimaron la incidencia de EHI en 2.5 casos por cada 1000 nacidos vivos. Diversos estudios han reportado que la neuroprotección mediante la hipotermia terapéutica (HT) disminuye la morbilidad y mortalidad en neonatos con EHI moderada o severa. Para la inducción de HT se utilizan, principalmente, dos tecnologías: 1) la HT de cuerpo completo (HTCC) y 2) la HT selectiva de cabeza (HTSC). Las unidades de cuidados intensivos neonatales (UCIN) de EsSalud brindan terapia de soporte a los recién nacidos con EHI consistente en monitoreo de signos vitales y atención oportuna frente a disfunciones orgánicas, además de reducción de la temperatura mediante el apagado de calefactor en la incubadora, pero no cuentan con equipos específicos que aseguren que el neonato alcance temperaturas de enfriamiento óptimas. Por ello, los especialistas en neonatología del HNERM solicitan la incorporación de la tecnología de HTCC con mantas térmicas con la finalidad de disminuir la mortalidad y discapacidad severa de los neonatos con EHI moderada o severa. En este sentido, el objetivo del presente dictamen preliminar fue evaluar la eficacia y seguridad de la hipotermia terapéutica de cuerpo completo con mantas térmicas en recién nacidos de 35 semanas o más con asfixia perinatal y encefalopatía hipóxico-isquémica moderada o severa. METODOLOGÍA: Se realizó una búsqueda sistemática para identificar la evidencia disponible a abril de 2021 sobre la eficacia y seguridad del procedimiento de hipotermia terapéutica de cuerpo completo en recién nacidos de 35 semanas o más con asfixia neonatal y encefalopatía hipóxico-isquémica moderada o severa. Se indagó en las bases de datos PubMed, Cochrane Library y LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud) y se creó una alerta semanas en PubMed que informara si surgiera nueva evidencia sobre el tema. Adicionalmente, se realizó una búsqueda manual de literatura gris mediante el motor de búsqueda Google. Se buscaron GPC y ETS que pudieran haber sido omitidas en la revisión sistemática por no encontrarse indixadas en las bases de datos consultadas. De igual forma, se consultaron las páginas oficiales de grupos conocidos por realizar ETS y GPC que incluyó el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualitát und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) y la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), además de sociedades especializadas en manejo de pacientes pediátricos con patologías perinatales (sociedad británica de medicina perinatal (BAPM), la asociación americana del corazón, y la sociedad canadiense de pediatría). RESULTADOS: La presente sinopsis describe la evidencia disponible sobre la eficacia y seguridad de la HTCC con mantas térmicas en recién nacidos de 35 semanas o más con AP y EHI moderada o severa, según el tipo de publicación. CONCLUSIONES: El objetivo del presente dictamen preliminar es evaluar la eficacia y seguridad de la hipotermia terapéutica de cuerpo completo con mantas térmicas en recién nacidos de 35 semanas o más de gestación, con asfixia perinatal y encefalopatía hipóxico-isquémica moderada o severa. Se identificaron seis GPC American Heart Association (AHA), 2020; Ministerio de Salud Pública del Ecuador (MSP), 2019; Canadian Paediatric Society (CPS), 2018; Instituto Mexicano del Seguro Social (IMSS), 2017; Ministerio de Sanidad, Servicio Social e Igualdad de España (MSSSI), 2015; y Ministerio de Salud y Protección Social de Colombia (MinSalud), 2013) y siete publicaciones de cuatro ensayos clínicos aleatorizados (ECA) (HELIX: Thayyil et al., 2021; TOBY: Azzopardi et al., 2014, 2009; NICHD: Shankaran et al., 2012, 2008, 2005; y neo.nEURO.network: Simbruner et al., 2010). No existe evidencia de una mayor eficacia en el uso de HTCC frente a la HTSC. Pese a ello, en centros asistenciales que no han implementado aún un método de HT, las recomendaciones de las GPC indican que debería implementarse equipos de HTCC debido a su facilidad de uso, menor costo y facilidad de acceso para la utilización de otros equipos como el electroencefalograma. Entre las GPC, existe un consenso en que la aplicación de HTCC debe realizarse bajo protocolos similares a los utilizados en los principales ECA. La eficacia de la HTCC con mantas térmicas en infantes de 36 semanas o más de gestación con EIH moderada a severa es consistente en cuanto a la reducción de morbilidad, pero no en mortalidad. Los ECA más grandes en el tema han reportado beneficios clínicos, tanto en indicadores de desarrollo mental y psicomotor, como en ocurrencia de parálisis cerebral a los 18 - 22 meses y 6 - 7 años de vida. Pese a que uno de los ECA evaluados (HELIX) reporta mayor riesgo de muerte y ocurrencia de eventos adversos en los pacientes intervenidos con HTCC, esto se puede explicar debido a factores poblacionales que modificaron el efecto de la intervención. Por lo expuesto, el IETSI aprueba el uso de equipos de HTCC con mantas térmicas en recién nacidos de 36 semanas o más de edad gestacional, con AP y EHI moderada o severa, según lo establecido en el Anexo N°1. Debido a la falta de evidencia, no se aprueba su uso en recién nacidos con menos de 36 semanas de edad gestacional. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación.

Thermal Index for early non-invasive assessment of brain injury in newborns treated with therapeutic hypothermia: preliminary report.

Perinatal asphyxia (PA) is the 3rd most common cause of neonatal death and one of the most common causes of severe neurological impairments in children. Current tools and measurements mainly based on the analysis of clinical evaluation and laboratory and electrophysiological tests do not give consistent data allowing to predict the severity of hypoxic-ischemic encephalopathy (HIE) until a magnetic resonance imaging (MRI) score is performed. The aim of this work is to evaluate the usefulness of the new index, called Thermal Index (TI) in the assessment of the degree of brain damage in newborns in the course of therapeutic hypothermia (TH) due to PA. This was a prospective, observational, pilot study which did not require any changes in the applicable procedures. Analysis has been applied to six newborn babies treated with TH in Neonatal/Paediatric ICU in University Hospital in Opole in 2018 due to PA. They all met criteria for TH according to the current recommendations. Brain MRI was performed after the end of TH when the children were brought back to normal temperature, with the use of a 1.5 T scanner, using T1-, T2-weighted images, fluid-attenuated inversion recovery (FLAIR), inversion recovery (IR), susceptibility-weighted imaging (SWI), and diffusion-weighted imaging (DWI). The images were assessed using MRI score according to the scoring system proposed by Weeke et al. The Thermal Index assessing endogenous heat production was calculated according to the formula proposed in this paper. A high, statistically significant positive correlation was found between MRI scores and TI values (0.98; p = 0.0003) in the 1st hour of therapy. High correlation with MRI assessment, the non-invasiveness of measurements and the availability of results within the first few hours of treatment, allow authors to propose the Thermal Index as a tool for early evaluating of the brain injury in newborns treated with TH. Further research is required to confirm the usefulness of the proposed method.

Effectiveness of reaching and maintaining therapeutic hypothermia target temperature using low-cost devices in newborns with hypoxic-ischemic encephalopathy.

Therapeutic hypothermia (TH) using servo-controlled cooling devices has proved to be a safe and effective method to reduce mortality and sequelae in neonates with hypoxic-ischemic encephalopathy (HIE). However, such cooling devices can be expensive and have limited availability in low- and middle-income countries. To evaluate the feasibility and effectiveness of low-cost cooling devices (ice packs) to reach and maintain the target temperature in newborns with moderate or severe HIE. Descriptive retrospective cross-sectional study, including newborns with gestational age ≥35 weeks, weight ≥1800 g, with diagnosis of moderate or severe HIE, submitted to whole body hypothermia using ice packs for 72 hr. Data was obtained from medical records and databases. The thermal curves of each patient, time spent at the target temperature and rewarming time were evaluated. Complications directly related to therapeutic hypothermia, evolution, and early outcomes before hospital discharge were analyzed. Seventy-one newborns met the criteria for TH, and 61 completed the entire cooling period and were included in the final analysis. The average time to reach the target temperature was 1.50 ± 1.3 hr. The mean temperature during the cooling period was 33.5°C (±0.62). 82.32% of the measurements were within the target temperature range (from 33 to 34°C). The following adverse events were observed during TH: pulmonary hypertension 11.3%, arrhythmia 4.2%, and coagulopathy 26.7%. Whole body hypothermia using low-cost devices proved to be an effective method in the absence of availability of servo-controlled devices, representing a plausible option in restricted resource settings.

Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

BACKGROUND: Theophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies. METHODS: A population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined. RESULTS: Birth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates. CONCLUSIONS: In neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population. IMPACT: Theophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.

Rigor of Neurovascular Coupling (NVC) Assessment in Newborns Using Different Amplitude EEG Algorithms.

Birth asphyxia constitutes a major global public health burden for millions of infants with a critical need for real time physiological biomarkers. This proof of concept study targets the translational rigor of such biomarkers and aims to examine whether the variability in the amplitude-integrated EEG (aEEG) outputs impact the determination of neurovascular coupling (NVC) in newborns with encephalopathy. A convenience sample with neonatal asphyxia were monitored for twenty hours in the first day of life with EEG and near infrared spectroscopy (NIRS)-based cerebral tissue oxygen saturation (SctO2). NVC between aEEG and NIRS-SctO2 was assessed using wavelet transform coherence (WTC) analysis, specifically by the wavelet total pixel number of significant coherences within 95% confidence interval. The raw EEG was converted to aEEG using three different methods: Method (M1) derives from the algorithm by Zhang and Ding. Method (M2) uses a Neonatal EEG Analysis Toolbox (WU-NEAT). Method (M3) extracts output directly from a commercial platform with an undisclosed algorithm. Our results demonstrate excellent agreement with Bland Altman comparisons for WTC-based NVC irrespective of the algorithms used, despite significant heterogeneities in the aEEG tracings produced by three algorithms. Our findings confirm the robustness of NVC wavelet analysis in Neonatal Encephalopathy related to HIE.

Hemodynamic Instability in Hypoxic Ischemic Encephalopathy: More Than Just Brain Injury-Understanding Physiology, Assessment, and Management.

Hypoxic-ischemic encephalopathy (HIE) can have both transient and long-lasting effects on the neonate, including neurologic, renal, cardiac, hepatic, and hematologic. Both the disease process and the treatment option of therapeutic hypothermia can result in hemodynamic instability. Understanding the effects of HIE on the neonatal myocardium, pulmonary vascular bed, and the cardiac dysfunction that can occur is key to managing infants with HIE. This article focuses on causes of hemodynamic instability in neonates following perinatal asphyxia and how to recognize hemodynamic compromise. It reviews the underlying pathophysiology and associated management strategies to improve hemodynamics and potentially improve outcomes.

Comprehensive assessment of deceased donor kidneys with clinical characteristics, pre-implant biopsy histopathology and hypothermic mechanical perfusion parameters is highly predictive of delayed graft function.

Background: Due to the current high demand for transplant tissue, an increasing proportion of kidney donors are considered extended criteria donors, which results in a higher incidence of delayed graft function (DGF) in organ recipients. Therefore, it is important to fully investigate the risk factors of DGF, and establish a prediction system to assess donor kidney quality before transplantation.Methods: A total of 333 donation after cardiac death kidney transplant recipients were included in this retrospective study. Both univariate and multivariate analyses were used to analyze the risk factors of DGF occurrence. Receiver operating characteristic (ROC) curves were used to analyze the predictive value of variables on DGF posttransplant.Results: The donor clinical scores, kidney histopathologic Remuzzi scores and hypothermic mechanical perfusion (HMP) parameters (flow and resistance index) were all correlated. 46 recipients developed DGF postoperatively, with an incidence of 13.8% (46/333). Multivariate logistic regression analysis of the kidney transplants revealed that the independent risk factors of DGF occurrence post-transplantation included donor score (OR = 1.12, 95% CI 1.06-1.19, p < 0.001), Remuzzi score (OR = 1.21, 95% CI 1.02-1.43, p = 0.029) and acute tubular injury (ATI) score (OR = 4.72, 95% CI 2.32-9.60, p < 0.001). Prediction of DGF with ROC curve showed that the area under the curve was increased to 0.89 when all variables (donor score, Remuzzi score, ATI score and HMP resistance index) were considered together.Conclusions: Combination of donor clinical information, kidney pre-implant histopathology and HMP parameters provide a more accurate prediction of DGF occurrence post-transplantation than any of the measures alone.

Prognostic Value of Knowledge of Cancer and Used Unconventional Therapy Methods on Quality of Life in Advanced, Metastatic Colorectal Cancer in Clinical Practice.

Colorectal cancer (CRC) is the third most common malignancy in the world and the second cause of cancer-related deaths. Despite the search for new therapeutic agents, there are still many doubts concerning the quality of life (QOL) improvement in palliative patients. In this study, we assessed the impact of oncology knowledge on QOL and the relationship between QOL and various environmental factors and unconventional treatment methods in patients with CRC treated with chemotherapy and targeted therapy. The results of first-line palliative chemotherapy in 330 patients with colorectal cancer treated between January 2010 and December 2016 in two centers were analyzed. The average age of patients was 66 ± 11.7 years. Median survival time was 25 months. In multivariate analysis, the performance status and response to treatment had a significant effect on survival time. A trend towards shorter survival was also observed in patients receiving 5-FU monotherapy, in elderly patients and in patients with less oncology knowledge. A relationship between general quality of life and performance status (PS 0 vs. PS > 0), response to treatment and oncology knowledge was found. Patients with limited oncology knowledge more often used unconventional therapy methods in parallel with the treatment. In patients over 70 years of age and in patients with worse overall condition, 5-FU monotherapy was more commonly used (p < 0.01). The level of oncology knowledge of the treated patients observed in everyday clinical practice may be related to some parameters of treatment effectiveness assessment, such as QOL and may be related to the use of unconventional treatment methods. Those, in turn may have an impact on the QOL of the treated patients.

Cooled radiofrequency ablation of the genicular nerves for chronic pain due to osteoarthritis of the knee: a cost-effectiveness analysis based on trial data.

BACKGROUND: For patients with painful knee osteoarthritis, long-term symptomatic relief may improve quality of life. Cooled radiofrequency ablation (CRFA) has demonstrated significant improvements in pain, physical function and health-related quality of life compared with conservative therapy with intra-articular steroid (IAS) injections. This study aimed to establish the cost-effectiveness of CRFA compared with IAS for managing moderate to severe osteoarthritis-related knee pain, from the US Medicare system perspective. METHODS: We conducted a cost-effectiveness analysis utilizing efficacy data (Oxford Knee Scores) from a randomized, crossover trial on CRFA (NCT02343003), which compared CRFA with IAS out to 6 and 12 months, and with IAS patients who subsequently crossed over to receive CRFA after 6 months. Outcomes included health benefits (quality-adjusted life-years [QALYs]), costs and cost-effectiveness (expressed as cost per QALY gained). QALYs were estimated by mapping Oxford Knee Scores to the EQ-5D generic utility measure using a validated algorithm. Secondary analyses explored differences in the settings of care and procedures used in-trial versus real-world clinical practice. RESULTS: CRFA resulted in an incremental QALY gain of 0.091 at an incremental cost of $1711, equating to a cost of US$18,773 per QALY gained over a 6-month time horizon versus IAS. Over a 12-month time horizon, the incremental QALY gain was 0.229 at the same incremental cost, equating to a cost of US$7462 per QALY gained versus IAS. Real-world cost assumptions resulted in modest increases in the cost per QALY gained to a maximum of US$21,166 and US$8296 at 6 and 12 months, respectively. Sensitivity analyses demonstrated that findings were robust to variations in efficacy and cost parameters. CONCLUSIONS: CRFA is a highly cost-effective treatment option for patients with osteoarthritis-related knee pain, compared with the US$100,000/QALY threshold typically used in the US.

A functional assessment of the circle of Willis before aortic arch surgery using transcranial Doppler.

BACKGROUND: Antegrade selective cerebral perfusion (ASCP) with systemic moderate hypothermia is routinely used as brain protection during aortic arch surgery. Whether ASCP should be delivered unilaterally (u-ASCP) or bilaterally (bi-ASCP) remains controversial. METHODS: We routinely studied the functional anatomy of the circle of Willis (CoW in all patients scheduled for arch surgery using transcranial color-coded Doppler over a decade. On the basis of these data, we classified observed functional variants as being "safe," "moderately safe," or "unsafe" for u-ASCP. RESULTS: From January 2005 to June 2015, 1119 patients underwent aortic arch surgery in our institution. Of these, 636 patients had elective surgery performed with ASCP. Preoperative full functional assessment of the CoW was possible in 61% of patients. A functionally complete CoW was found in only 27%. Of all variants, 72% were classified as being safe for u-ASCP, whereas 18% were moderately safe for u-ASCP, and 10% unsafe. Unsafe variants for bi-ASCP were observed in 0.5% of patients. CONCLUSIONS: The risk of ischemic brain damage due to malperfusion is estimated to be substantially higher during right u-ASCP than during bi-ASCP. Bi-ASCP is therefore highly preferable over u-ASCP if the function of the CoW is unknown. We propose a tailored approach using this full functional assessment preoperatively by applying u-ASCP via the right subclavian artery when considered safely possible, and bi-ASCP when considered a necessity to prevent cerebral malperfusion, and thus thereby try to reduce the embolic stroke risk of ostial instrumentation in bi-ASCP.

Association of health insurance with post-resuscitation care and neurological outcomes after return of spontaneous circulation in out-of-hospital cardiac arrest patients in Korea.

BACKGROUND: We investigated the association of health insurance status with post-resuscitation care and neurological recovery in out-of-hospital cardiac arrest (OHCA) and whether the effects changed with age or gender. METHODS: Adult OHCAs with presumed cardiac etiology who had sustained ROSC from 2013 to 2016 were enrolled from the nationwide OHCA registry of Korea. Insurance status was categorized into 2 groups: National Health Insurance (NHI) and Medical Aid (MA). The endpoints were post-resuscitation coronary reperfusion therapy (CRT), targeted temperature management (TTM), and good neurological recovery (cerebral performance category of 1 or 2). Multivariable logistic regression models and interaction analyses (insurance × age and insurance × gender) were conducted for adjusted odds ratios (aORs) and 95% confidence intervals (CI). RESULTS: Of a total of 19,865 eligible OHCA patients, 18,119 (91.2%) were covered by NHI and 1746 (8.8%) by MA. The MA group was less likely to receive post-resuscitation CRT and TTM (aOR (95% CI): 0.75 (0.59-0.96) for CRT; 0.71 (0.57-0.89) for TTM) and had worse neurological outcomes (0.71 (0.57-0.89)) compared with the NHI group. In the interaction analyses, MA was associated with less CRT and good neurological recovery in the 45-64 year old group (0.54 (0.37-0.77) for CRT; 0.70 (0.51-0.95) for neurological outcome) and in the male group (0.69 (0.52-0.91) for CRT; 0.77 (0.61-0.97) for TTM; 0.70 (0.53-0.92)) for neurological outcome). CONCLUSIONS: There were disparities in post-resuscitation care and substantial neurological recovery by health insurance status, and the disparities were prominent in middle-aged adults and males. Increasing health insurance coverage for post-resuscitation care should be considered.

Therapeutic hypothermia for moderate and severe hypoxic ischaemic encephalopathy in newborns using low-cost devices - ice packs and phase changing material.

Background: Different methods have been used for therapeutic hypothermia for neonates with moderate-to-severe hypoxic ischaemic encephalopathy (HIE). As standard cooling devices are expensive, there is a need to establish the safety and efficacy of low-cost devices such as ice packs (IP) and phase changing material (PCM). Aim: To assess the efficacy and safety of therapeutic hypothermia (TH) and the clinico-laboratory profile of neonates who underwent cooling with IP or PCM. Methods: The study was retrospective. TH for moderate-to-severe HIE was initiated with IP between 2012 and 2014 and with PCM (MiraCradleTM) from September 2014. A standard protocol for inclusion and management during TH was used for all newborns. All data were collected by means of a local cooling registry. Results: Sixty-two cooled newborns (IP 29, PCM 33) were included in the study. Mean gestational age was 38.6 (1.7) weeks and mean birthweight 2920.6 g (450.7); 66.1% were inborn and 91.9% had moderate encephalopathy. Mean (SD) core temperature during cooling was 33.47°C (0.33) for PCM and 33.44°C (0.34) for IP. Adverse events observed during TH were thrombocytopenia (54.8%), coagulopathy (30.6%), shock (30.6%), skin changes (12.9%) and persistent pulmonary hypertension (8.1%). Forty-nine infants were discharged, two died and 11 were discharged against medical advice. TH was prematurely stopped in seven newborns with serious adverse events such as disseminated intravascular coagulation (DIC), gangrene and arrhythmia (IP 5, PCM 2). Conclusion: Low-cost devices are safe and effective alternatives for maintaining TH in low-resource settings with adequate monitoring. Abbreviations: DAMA, discharged against medical advice; DIC, disseminated intravascular coagulation; HELIX, Hypothermia for Encephalopathy in Low- and Middle-Income Countries Trial; HIE, hypoxic ischaemic encephalopathy; IP, ice packs; LMIC, low- and middle-income countries; NICHD, National Institute of Child Health and Human Development; PCM, phase changing; TH, therapeutic hypothermia (TH); TOBY, total body hypothermia for neonatal encephalopathy.

Hypothermia for perinatal asphyxia: trial-based resource use and costs at 6-7 years.

OBJECTIVE: To assess the impact of hypothermic neural rescue for perinatal asphyxia at birth on healthcare costs of survivors aged 6-7 years, and to quantify the relationship between costs and overall disability levels. DESIGN: 6-7 years follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. SETTING: Community study including a single parental questionnaire to collect information on children's healthcare resource use. PATIENTS: 130 UK children (63 in the control group, 67 in the hypothermia group) whose parents consented and returned the questionnaire. INTERVENTIONS: Intensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone. MAIN OUTCOME MEASURES: Healthcare resource usage and costs over the preceding 6 months. RESULTS: At 6-7 years, mean (SE) healthcare costs per child were £1543 (£361) in the hypothermia group and £2549 (£812) in the control group, giving a saving of -£1005 (95% CI -£2734 to £724). Greater levels of overall disability were associated with progressively higher costs, and more parents in the hypothermia group were employed (64% vs 47%). Results were sensitive to outlying observations. CONCLUSIONS: Cost results although not significant favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. Estimates were however sensitive to the care requirements of two seriously ill children in the control group. A quantification of the relationship between costs and levels of disability experienced will be useful to healthcare professionals, policy makers and health economists contemplating the long-term economic consequences of perinatal asphyxia and hypothermic neural rescue. TRIAL REGISTRATION NUMBER: This study reports on the follow-up of the TOBY clinical trial: ClinicalTrials. gov number NCT01092637.

Effects of Mild Hypothermia on Cardiac and Neurological Function in Piglets Under Pathological and Physiological Stress Conditions.

To investigate the different effects of mild hypothermia on pathological and physiological stress conditions in piglets, 30 pigs were randomized into four groups: cardiac arrest and mild hypothermia (CA-MH group), cardiac arrest and normothermia (CA-NH group), non-CA-MH (NCA-MH group), and a sham operation. The same hypothermia intervention was implemented in both CA-MH and NCA-MH groups. The CA-NH group did not undergo therapeutic hypothermia after resuscitation. The hemodynamic parameters were recorded. Cerebral metabolism variables and neurotransmitters in the extracellular fluid were collected through microdialysis tubes. The serum of venous blood was used to detect levels of inflammatory factors. The cerebral function was evaluated. At 24 and 72 hours after resuscitation, the cerebral performance category and neurological deficit score in the CA-NH group had higher values. Heart rate and cardiac output (CO) in the CA-MH group during cooling were lower than that of the CA-NH group, but CO was higher after rewarming. Glucose was higher during cooling, and extracellular lactate and lactate/pyruvate ratio in the CA-MH group were lower than that of the CA-NH group. Noradrenaline and 5-hydroxytryptamine in the CA-MH and NCA-MH groups were lower than that of the CA-NH group and sham group during cooling, respectively. Inflammatory factor levels, including interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, and tumor necrosis factor-α, in the CA-MH group were lower than that of the CA-NH group at cooling for 12 hours. These values in the NCA-MH group were higher than that of the sham group. Under a light and an electron microscope, the worse pathological results of heart and brain were observed in the two cardiac arrest groups. Mild hypothermia can provide limited organ protection in the specific pathological condition caused by ischemia-reperfusion, but it may produce a negative effect in a normal physiological state.