Neuroprotective mechanisms and translational potential of therapeutic hypothermia in the treatment of ischemic stroke

Stroke is a leading cause of disability and death,yet effective treatments for acute stroke has been very limited.Thus far,tissue plasminogen activator has been the only FDA-approved drug for thrombolytic treatment of ischemic stroke patients,yet its application is only applicable to less than 4–5% of stroke patients due to the narrow therapeutic window（〈 4.5 hours after the onset of stroke） and the high risk of hemorrhagic transformation.Emerging evidence from basic and clinical studies has shown that therapeutic hypothermia,also known as targeted temperature management,can be a promising therapy for patients with different types of stroke.Moreover,the success in animal models using pharmacologically induced hypothermia（PIH） has gained increasing momentum for clinical translation of hypothermic therapy.This review provides an updated overview of the mechanisms and protective effects of therapeutic hypothermia,as well as the recent development and findings behind PIH treatment.It is expected that a safe and effective hypothermic therapy has a high translational potential for clinical treatment of patients with stroke and other CNS injuries.

Induction of therapeutic hypothermia via the esophagus:a proof of concept study

BACKGROUND:Induction of hypothermia(a 4℃decrease from baseline)improves outcomes in adult cardiac arrest and neonatal hypoxic ischemic encephalopathy,and may benefit other conditions as well.Methods used to implement or prevent hypothermia typically require skin contact with blankets or pads or intravascular access with catheter devices.The study was to evaluate the potential to induce mild therapeutic hypothermia via an esophageal route in a porcine model.METHODS:Single-animal proof-of-concept study of a prototype esophageal device in a 70 kg Yorkshire swine.We measured the rate of temperature change after placement of a prototype device to induce hypothermia via the esophagus,and compared this rate to known temperature changes that occur under similar laboratory conditions without a hypothermic device.RESULTS:Swine temperature decreased from a starting temperature of 37.8℃to 33.8℃(achieving the goal of a 4℃decrease)in 175 minutes,resulting in a cooling rate of 1.37℃/h.Histopathology of the esophagus showed normal tissue without evidence of injury.CONCLUSION:A prototype of an esophageal cooling device induced hypothermia effectively in a large single-swine model.

The utility of therapeutic hypothermia on cerebral autoregulation

Cerebral autoregulation(CA)dysfunction is a strong predictor of clinical outcome in patients with acute brain injury(ABI).CA dysfunction is a potential pathologic defect that may lead to secondary injury and worse functional outcomes.Early therapeutic hypothermia(TH)in patients with ABI is controversial.Many factors,including patient selection,timing,treatment depth,duration,and rewarming strategy,impact its clinical efficacy.Therefore,optimizing the benefit of TH is an important issue.This paper reviews the state of current research on the impact of TH on CA function,which may provide the basis and direction for CA-oriented target temperature management.

Epileptic Seizures in Neonates Treated with Hypothermia for Hypoxo-Ischemic Encephalopathy in Brazzaville, Congo: Types and Evolution

Background: Moderate to severe hypoxic-ischemic encephalopathy (HIE) in neonates is often treated with hypothermia. However, some neonates may experience epileptic seizures during therapeutic hypothermia (TH). Data on the electrophysiologic and evolutionary aspects of these seizures are scarce in African countries. Objectives: To determine the types of epileptic seizures caused by HIE in neonates in Brazzaville;to describe the evolution of background EEG activities during TH and rewarming;to report the evolution of epileptic seizures. Methods: This was a cross-sectional, descriptive study conducted from January 2020 to July 2022. It took place in Brazzaville in the Neonatology Department of the Blanche Gomez Mother and Child Hospital. It focused on term neonates suffering from moderate or severe HIE. They were treated with hypothermia combined with phenobarbital for 72 hours. Results: Among 36 neonates meeting inclusion criteria, there were 18 boys and 18 girls. Thirty-one (86.1%) neonates had grade 2 and 5 (13.9%) grade 3 HIE. In our neonates, HIE had induced isolated electrographic seizures (n = 11;30.6%), electroclinical seizures (n = 25;69.4%), and 6 types of background EEG activity. During TH and rewarming, there were 52.8% of patients with improved background EEG activity, 41.7% of patients with unchanged background EEG activity, and 5.5% of patients with worsened background EEG activity. At the end of rewarming, only 9 (25%) patients still had seizures. Conclusion: Isolated electrographic and electroclinical seizures are the only pathological entities found in our studied population. In neonates with moderate HIE, the applied therapeutic strategy positively influences the evolution of both seizures and background EEG activity. On the other hand, in neonates with severe HIE, the same therapeutic strategy is ineffective. .

Mild hypothermia as a treatment for central nervous system injuries Positive or negative effects?

Besides local neuronal damage caused by the primary insult, central nervous system injuries may secondarily cause a progressive cascade of related events including brain edema, ischemia, oxida- tive stress, excitotoxicity, and dysregulation of calcium homeostasis. Hypothermia is a beneficial strategy in a variety of acute central nervous system injuries. Mild hypothermia can treat high in- tracranial pressure following traumatic brain injuries in adults. It is a new treatment that increases survival and quality of life for patients suffering from ischemic insults such as cardiac arrest, stroke, and neurogenic fever following brain trauma. Therapeutic hypothermia decreases free radical pro- duction, inflammation, excitotoxicity and intracranial pressure, and improves cerebral metabolism after traumatic brain injury and cerebral ischemia, thus protecting against central nervous system damage. Although a series of pathological and physiological changes as well as potential side ef- fects are observed during hypothermia treatment, it remains a potential therapeutic strategy for central nervous system injuries and deserves further study.

Challenges in developing therapeutic strategies for mild neonatal encephalopathy

There is increasing evidence that infants with mild neonatal encephalopathy(NE) have significant risks of mortality, brain injury and adverse neurodevelopmental outcomes. In the era of therapeutic hypothermia, infants need to be diagnosed within 6 hours of birth, corresponding with the window of opportunity for treatment of moderate to severe NE, compared to the retrospective grading over 2 to 3 days, typically with imaging and formal electroencephalographic assessment in the pre-hypothermia era. This shift in diagnosis may have increased the apparent prevalence of brain damage and poor neurological outcomes seen in infants with mild NE in the era of hypothermia. Abnormal short term outcomes observed in infants with mild NE include seizures, abnormal neurologic examination at discharge, abnormal brain magnetic resonance imaging and difficulty feeding. At 2 to 3 years of age, mild NE has been associated with an increased risk of autism, language and cognitive deficits. There are no approved treatment strategies for these infants as they were not included in the initial randomized controlled trials for therapeutic hypothermia. However, there is already therapeutic creep, with many centers treating infants with mild NE despite the limited evidence for its safety and efficacy. The optimal duration of treatment and therapeutic window of opportunity for effective treatment need to be specifically established for mild NE as the evolution of injury is likely to be slower, based on preclinical data. Randomized controlled trials of therapeutic hypothermia for infants with mild NE are urgently required to establish the safety and efficacy of treatment. This review will examine the evidence for adverse outcomes after mild NE and dissect some of the challenges in developing therapeutic strategies for mild NE, before analyzing the evidence for therapeutic hypothermia and other strategies for treatment of these infants.

Effects of hypothermia on the liver in a swine model of cardiopulmonary resuscitation

BACKGROUND:The study aimed to explore the effects of hypothermia state induced by4 ℃ normal saline(NS) on liver biochemistry,enzymology and morphology after restoration of spontaneous circulation(ROSC) by cardiopulmonary resuscitation(CPR) in swine.METHODS:After 4 minutes of ventricular fibrillation(VF),standard CPR was carried out.Then the survivors were divided into two groups:low temperature group and normal temperature group.The low temperature(LT) group(n-5) received continuously 4 °C NS at the speed of 1.33 mL/kg per minute for 22 minutes,then at the speed lowering to 10 mL/kg per hour.The normal temperature(NT) group(n-5) received NS with normal room temperature at the same speed of the LT group.Hemodynamic status and oxygen metabolism were monitored and the levels of serum alanine aminotransferase(ALT),aspartate aminotransferase(AST) and lactate dehydrogenase(LDH) were measured in blood samples obtained at baseline and at 10 minutes,2 hours and 4 hours after ROSC.At 24 hours after ROSC,the animals were killed and the liver was removed to determine the Na^+-K^+-ATPase and Ca^(2+)-ATPase enzyme activities and histological changes under a light or electron microscope.RESULTS:Core temperature was decreased in the LT group(P<0.05),while HR,MAP and CPP were not significantly decreased(P>0.05) compared with the NT group(P>0.05).The oxygen extraction ratio was lower in the LT group than in the NT group(P<0.05).The serum levels of ALT,AST and LDH increased in both groups but not significantly in the LT group.The enzyme activity of liver ATP was much higher in the LT group(Na^+-K^+-ATP enzyme:8.64±3.32 U vs.3.28±0.71 U;Ca^(2+)-ATP enzyme:10.92±2.12 U vs.2.75±0.78 U,P<0.05).The LT group showed less cellular edema,inflammation and few damaged mitochondria as compared with the NT group.CONCLUSION:These data suggested that infusing 4 °C NS continuously after ROSC could quickly lower the core body temperature,while maintaining a stable hemodynamic state and balancing oxygen metabolism,which protect the liver in terms of biochemistry,enzymology and histology after CPR.

Comments on"Neonatal infratentorial subdural hematoma contributing to obstructive hydrocephalus in the setting of therapeutic cooling:A case report"

Although therapeutic hypothermia(TH)contributes significantly in the treatment of hypoxic ischemic encephalopathy(HIE),it could result in devastating complications such as intracranial hemorrhages.Laboratory examinations for possible coagulation disorders and early brain imaging can detect all these cases that are amenable to aggravation of HIE after the initiation of TH.

Neonatal infratentorial subdural hematoma contributing to obstructive hydrocephalus in the setting of therapeutic cooling: A case report

BACKGROUND Symptomatic neonatal subdural hematomas usually result from head trauma incurred during vaginal delivery,most commonly during instrument assistance.Symptomatic subdural hematomas are rare in C-section deliveries that were not preceded by assisted delivery techniques.Although the literature is inconclusive,another possible cause of subdural hematomas is therapeutic hypothermia.CASE SUMMARY We present a case of a term neonate who underwent therapeutic whole-body cooling for hypoxic ischemic encephalopathy following an emergent C-section delivery for prolonged decelerations.Head ultrasound on day of life 3 demonstrated a rounded mass in the posterior fossa.A follow-up brain magnetic resonance imaging confirmed hypoxic ischemic encephalopathy and clarified the subdural hematomas in the posterior fossa causing mass effect and obstructive hydrocephalus.CONCLUSION The aim of this report is to highlight the rarity and importance of mass-like subdural hematomas causing obstructive hydrocephalus,particularly in the setting of hypoxic ischemic encephalopathy and therapeutic whole-body cooling.

Mechanism Interpretation of the Biological Brain Cooling and Its Inspiration on Bionic Engineering

The brain is one of the most important organs in a biological body which can only work in a relatively stable temperature range. However, many environmental factors in biosphere would cause cerebral temperature fluctuations. To sustain and regulate the brain temperature, many mechanisms of biological brain cooling have been evolved, including Selective Brain Cooling （SBC）, cooling through surface water evaporation, respiration, behavior response and using special anatomical ap- pendages. This article is dedicated to present a summarization and systematic interpretation on brain cooling strategies devel- oped in animals by classifying and comparatively analyzing each typical biological brain cooling mechanism from the per- spective of bio-heat transfer. Meanwhile, inspirations from such cooling in nature were proposed for developing advanced bionic engineering technologies especially with two focuses on therapeutic hypothermia and computer chip cooling areas. It is expected that many innovations can be achieved along this way to find out new cooling methodologies for a wide variety of industrial applications which will be highly efficient, energy saving, flexible or even intelligent.

Modeling and Simulation of an Invasive Mild Hypothermic Blood Cooling System

Nowadays,mild hypothermia is widely used in the fields of post-cardiac arrest resuscitation,stroke,cerebral hemorrhage,large-scale cerebral infarction,and craniocerebral injury.In this paper,a locally mixed sub-low temperature device is designed,and the cold and hot water mixing experiment is used to simulate the human blood transfer process.To set a foundation for the optimization of the heat transfer system,the static characteristics are analyzed by building the mathematic model and setting up the experimental station.In addition,the affection of several key structure parameters is researched.Through experimental and simulation studies,it can be concluded that,firstly,the mathematical model proved to be effective.Secondly,the results of simulation experiments show that 14.52℃ refrigeration can reduce the original temperature of 33.42℃ to 32.02℃,and the temperature of refrigerated blood rises to 18.64℃,and the average error is about 0.3℃.Thirdly,as the thermal conductivity of the vascular sheath increases,the efficiency of the heat exchange system also increases significantly.Finally,as the input cold blood flow rate increases,the mass increases and the temperature of the mixed blood temperature decreases.It provides a research basis for subsequent research on local fixed-point sub-low temperature control technology.

Unraveling quad fever:Severe hyperthermia after traumatic cervical spinal cord injury

Purpose:There are many infectious and inflammatory causes for elevated core-body temperatures,though they rarely pass 40℃(104℉).The term"quad fever"is used for extreme hyperpyrexia in the setting of acute cervical spinal cord injuries(SCIs).The traditional methods of treating hyperpyrexia are often ineffective and reported morbidity and mortality rates approach 100%.This study aims to identify the incidence of elevated temperatures in SCIs at our institution and assess the effectiveness of using a non-invasive dry water temperature management system as a treatment modality with mortality.Methods:A retrospective analysis of acute SCI patients requiring surgical intensive care unit admission who experienced fevers≥40℃(104℉)were compared to patients with maximum temperatures<40℃.Patients≥18 years old who sustained an acute traumatic SCI were included in this study.Patients who expired in the emergency department;had a SCI without radiologic abnormality;had neuropraxia;were admitted to any location other than the surgical intensive care unit;or had positive blood cultures were excluded.SAS 9.4 was used to conduct statistical analysis.Results:Over the 9-year study period,35 patients were admitted to the surgical intensive care unit with a verified SCI.Seven patients experienced maximum temperatures of≥40℃.Six of those patients were treated with the dry water temperature management system with an overall mortality of 57.1%in this subgroup.The mortality rate for the 28 patients who experienced a maximum temperature of≤40℃was 21.4%(p=0.16).Conclusion:The diagnosis of quad fever should be considered in patients with cervical SCI in the presence of hyperthermia.In this study,there was no significant difference in mortality between quad fever patients treated with a dry water temperature management system versus SCI patients without quad fever.The early use of a dry water temperature management system appears to decrease the mortality rate of quad fever.