Impact Of Hypothermia Research Articles

Investigating the Safety and Efficacy of Therapeutic Hypothermia in Pediatric Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Prior guidelines recommended maintaining normothermia following traumatic brain injury (TBI), but recent studies suggest therapeutic hypothermia as a viable option in pediatric cases. However, some others demonstrated a higher mortality rate. Hence, the impact of hypothermia on neurological symptoms and overall survival remains contentious. We conducted a systematic review and meta-analysis to evaluate the effects of hypothermia on neurological outcomes in pediatric TBI patients. The PubMed/Medline, Scopus, and Web of Science databases were searched until 1 January 2024 and data were analyzed using appropriate statistical methods. A total of eight studies, comprising nine reports, were included in this analysis. Our meta-analysis did not reveal significant differences in mortality (RR = 1.58; 95% CI = 0.89-2.82, p = 0.055), infection (RR = 0.95: 95% CI = 0.79-1.1, p = 0.6), arrhythmia (RR = 2.85: 95% CI = 0.88-9.2, p = 0.08), hypotension (RR = 1.54: 95% CI = 0.91-2.6, p = 0.10), intracranial pressure (SMD = 5.07: 95% CI = -4.6-14.8, p = 0.30), hospital length of stay (SMD = 0.10; 95% CI = -0.13-0.3, p = 0.39), pediatric intensive care unit length of stay (SMD = 0.04; 95% CI = -0.19-0.28, p = 0.71), hemorrhage (RR = 0.86; 95% CI = 0.34-2.13, p = 0.75), cerebral perfusion pressure (SMD = 0.158: 95% CI = 0.11-0.13, p = 0.172), prothrombin time (SMD = 0.425; 95% CI = -0.037-0.886, p = 0.07), and partial thromboplastin time (SMD = 0.386; 95% CI = -0.074-0.847, p = 0.10) between the hypothermic and non-hypothermic groups. However, the heart rate was significantly lower in the hypothermic group (-1.523 SMD = -1.523: 95% CI = -1.81--1.22 p < 0.001). Our findings challenge the effectiveness of therapeutic hypothermia in pediatric TBI cases. Despite expectations, it did not significantly improve key clinical outcomes. This prompts a critical re-evaluation of hypothermia's role as a standard intervention in pediatric TBI treatment.

The impact of hypothermia in a tertiary hospital neonatal unit

Background. Neonatal hypothermia, defined as a body temperature &lt;36.5°C, is a known contributor to neonatal morbidity and mortality. The admission temperature is an important predictor of neonatal outcomes, and a measure of quality of care. Objectives. This study aims to determine the incidence of and factors associated with hypothermia on admission to the neonatal unit at Steve Biko Academic Hospital (SBAH), a public tertiary hospital in South Africa. Methods. A retrospective, cross-sectional study of infants admitted to the neonatal unit from September 2019 to February 2020 using data from patient records. Results. The overall incidence of hypothermia on admission was 66% (mild 25%, moderate to severe 41%), with a mean (standard deviation (SD)) admission temperature of 35.1 (4.7)°C, and 82% (mild 19%, moderate to severe 62%) in very-low-birthweight infants. Infants remained hypothermic for a mean (SD) of 4.1 (3.9) hours post admission. Birthweight ≤1 500 g (odds ratio (OR) 1.87; p=0.019), admission to the neonatal intensive care unit (OR 1.97; p&lt;0.0001), and admission from the delivery room within the first 60 minutes of life (OR 3.06; p=0.026) were independent risk factors for hypothermia. Hypothermia was associated with increased duration of respiratory support (mean 3.2 (5.6) v. 1.7 (4.5) days; p&lt;0.0001), and longer length of hospital stay (mean 17.9 (18.8) v. 10.9 (12.6) days; p&lt;0.0001). Conclusion. The incidence of hypothermia on admission to the unit is significantly high, and hypothermic infants take a significant length of time to regain normothermia. A standardised protocol for the prevention and management of hypothermia needs to be introduced in the unit.

Impact of accidental hypothermia in trauma patients: A retrospective cohort study

BackgroundTrauma patients with hypothermia have substantial increases in mortality and morbidity. In severely injured patients, hypothermia is common with a rate up to 50% in various geographic areas. This study aims to elucidate the incidence, predictors, and impact of hypothermia on outcomes in severely injured patients. MethodsThis was a retrospective cohort study which included trauma patients with an Injury Severity Score (ISS) ≥ 16 admitted to a level 1 trauma center in the Netherlands between January 1, 2015 and December 31, 2021. Primary outcome was incidence of hypothermia on arrival at the emergency department. Factors associated with hypothermia were identified. Secondary outcomes were transfusion requirement, mortality, and intensive care unit (ICU) admission. Logistic regression analysis was used to identify associations. ResultsA total of 2032 severely injured patients were included of which 257 (12.6%) were hypothermic on hospital arrival. Predictors for hypothermia on hospital arrival included higher ISS, prehospital intubation, cervical spine immobilization, winter months, systolic blood pressure (SBP) < 90 mmHg and Glasgow Coma Scale (GCS) ≤ 8. Hypothermia was independently associated with transfusion requirement (OR, 2.68; 95% CI, 1.94 – 3.73; p < 0.001), mortality (OR, 2.12; 95% CI, 1.40 – 3.19; p < 0.001) and more often ICU admission (OR, 1.81; 95% CI, 1.10 – 2.97, p = 0.019). ConclusionsIn this study, hypothermia was present in 12.6% of severely injured patients. Hypothermia was associated with increased transfusion requirement, mortality, and ICU admission. Identified predictors for hypothermia included the severity of injury, intubation, and immobilization, as well as winter season, SBP < 90 mmHg, and GCS ≤ 8.

131. The Impact of Intraoperative Temperature on Venous Thromboembolism and Flap Pedicle Thrombosis in Patients Undergoing Head and Neck Microsurgical Reconstruction

PURPOSE: In vitro studies on platelet function have shown that lower temperatures encourage aggregation and overexpression of the adhesion molecules. Anesthesia guidelines recommend the prevention of hypothermia (T < 36 º). This study aims to explore the impact of intraoperative body temperature on venous thromboembolism (VTE) and flap pedicle thrombosis within 30 days of microsurgical free tissue transfer surgery to the head and neck. METHODS: All patients who underwent head and neck reconstruction with free tissue transfer from January 2012 through March 2022 in a tertiary center were included in this study. Data were collected from a retrospective and prospective held database. Intraoperative temperature readings were extracted electronically in one-minute intervals for each surgery. Non-physiologic readings less than 30 or more than 42 were discarded. A median was calculated for every five consecutive readings to create a five-minute temperature reading. A median value under 36 º was considered an onset of hypothermia. VTE events and thrombosis of the free flap pedicle (arterial or venous) that require revision surgery were the study outcomes, and they were recorded within 30 days of the index surgery. RESULTS: 895 patients were included, and out of those n=300, 34% were females. The mean intraoperative body temperature and Caprini score for the whole cohort were 36.13 ± 1.08 º and 6.54 ± 1.74. The VTE and pedicle thrombosis rates were (n=37, 4.0%) and (n=58, 6%), respectively. The incidence of patients developing at least one onset of hypothermia was (n=720, 80%). The mean number of hypothermia onsets and the mean length of surgery were 52.40 ± 84.80 and 685.12 ± 144.31 minutes, respectively. The mean for Caprini score in those who developed at least one onset of hypothermia did not differ significantly from those who were normothermic (≥ 36 º) for the whole surgery (6.55±1.76 vs. 6.46±1.60, p=0.533). The rate of VTE in those who experienced at least one onset of hypothermia was significantly higher than in those who were normothermic for the whole surgery (n=35/720, 3.9% vs. n=2/175, 0.22%, p=0.026). This association persisted even after controlling for the Caprini score, the number of hypothermic onsets, and the length of surgery in a multivariable regression model (OR, 5.478, 95%CI: 1.222-24.557). In contrast, the rate of free flap pedicle thrombosis was lower in patients who experienced hypothermia than others in the cohort (n=9/175, 1.01% vs. n=49/720, 5.47%). However, the difference failed to reach a statistical significance (p=0.422). CONCLUSIONS: Hypothermia onset is associated with an increased rate of VTE postoperative, even after controlling for the number of hypothermia onsets, Caprini score, and length of surgery. Patients who experienced hypothermia during surgery had a lower incidence of free flap pedicle thrombosis than those who were normothermic throughout the surgery. However, no conclusion can be made about the impact of hypothermia on pedicle thrombosis since the difference failed to reach statistical significance.

Hypothermia and its role in patients with ST-segment-elevation myocardial infarction and cardiac arrest.

Patients suffering cardiac arrest resulting from ST-segment-elevation myocardial infarction (STEMI) are at very high risk of death. In addition to reperfusion strategies, therapeutic hypothermia is recommended for cardiac arrest patients who remain unconscious after resuscitation. However, data analysis of the impact of therapeutic hypothermia on survival showed inconsistent results. We aimed to investigate the benefits of therapeutic hypothermia in STEMI patients after cardiopulmonary resuscitation (CPR). Patients with STEMI who received CPR were identified after nationwide German inpatient data (2005-2019) were screened. These patients were stratified for therapeutic hypothermia. The impact of hypothermia on mortality and adverse in-hospital outcomes was analyzed. Overall, 133,070 inpatients with STEMI and CPR (53.3% aged ≥70 years; 34% females) were recorded in Germany between 2005 and 2019, of which 12.3% (16,386 patients) underwent therapeutic hypothermia. Females (23.8 vs. 35.4%, p < 0.001) and patients aged ≥70 years (34.9 vs. 55.9%, p < 0.001) were less frequently treated with therapeutic hypothermia. The in-hospital case fatality rate was lower for STEMI with CPR and subsequent therapeutic hypothermia than for treatment without therapeutic hypothermia (53.5 vs. 66.7%, p < 0.001). Therapeutic hypothermia was independently associated with a reduced in-hospital case fatality rate {OR 0.83 [95% confidence interval (CI) 0.80-0.86], p < 0.001}. In addition, therapeutic hypothermia was associated with an increased risk for stroke (OR 1.37 [95% CI 1.25-1.49], p < 0.001), pneumonia (OR 1.75 [95% CI 1.68-1.82], p < 0.001), and acute kidney injury (OR 2.21 [95% CI 2.07-2.35], p < 0.001). Therapeutic hypothermia is associated with a survival benefit for STEMI patients after cardiac arrest.

A study on hypothermia and associated countermeasures in tsunami disasters: A case study of Miyagi Prefecture during the 2011 great East Japan earthquake

In this study, the impact of hypothermia during tsunami disasters based on casualty data from Miyagi Prefecture during the Great East Japan Earthquake was analyzed. The spatial distribution of the locations in which the corpses of hypothermia victims were found and the effects of age group, location, environmental temperature, and tsunami exposure were examined at the municipal and postal code scales. Hypothermia victims were identified only in coastal areas, indicating an increased risk of hypothermia due to wetting of the body caused by exposure to tsunami water and a cold environment at the evacuation centers. The proportion of older (>70 years) individuals among the hypothermia victims was significantly higher (p > 0.05) compared to the victims of drowning. Based on the findings of this study, a response checklist in evacuation centers and a modified government response flowchart are proposed, assuming response by nonmedical personnel to reduce the risk of hypothermia after a disaster.

Myocardial electrophysiological and mechanical changes caused by moderate hypothermia-A clinical study.

Moderate hypothermia has been used to improve outcomes in comatose out‐of‐hospital cardiac arrest survivors during the past two decades, although the effects remain controversial. We have recently shown in an experimental study that myocardial electrophysiological and mechanical relationships were altered during moderate hypothermia. Electromechanical window positivity increased, and electrical dispersion of repolarization decreased, both of which are changes associated with decreased arrhythmogenicity in clinical conditions. Mechanical dispersion, a parameter also linked to arrhythmic risk, remained unaltered. Whether corresponding electrophysiological and mechanical changes occur in humans during moderate hypothermia, has not been previously explored. Twenty patients with normal left ventricular function were included. Measurements were obtained at 36 and 32°C prior to ascending aortic repair while on partial cardiopulmonary bypass and at 36°C after repair. Registrations were performed in the presence of both spontaneous and comparable paced heart rate during standardized loading conditions. The following electrical and mechanical parameters were explored: (1) Electromechanical window, measured as time difference between mechanical and electrical systole, (2) dispersion of repolarization from ECG T‐wave, and (3) mechanical dispersion, measured as segmental variation in time to peak echocardiographic strain. At moderate hypothermia, mechanical systolic prolongation (425 ± 43–588 ± 67 ms, p < 0.001) exceeded electrical systolic prolongation (397 ± 49–497 ± 79 ms, p < 0.001), whereby, electromechanical window positivity increased (29 ± 30–86 ± 50 ms, p < 0.001). Dispersion of repolarization and mechanical dispersion remained unchanged. Corresponding electrophysiological and mechanical relationships were present at comparable paced heart rates. After rewarming, the increased electromechanical window was reversed in the presence of both spontaneous and paced heart rates. Moderate hypothermia increased electromechanical window positivity, while dispersion of repolarization and mechanical dispersion remained unchanged. This impact of hypothermia may be clinically relevant for selected groups of patients after cardiac arrest.

Staying Cool in Space: A Review of Therapeutic Hypothermia and Potential Application for Space Medicine.

Despite rigorous health screenings, medical incidents during spaceflight missions cannot be avoided. With long-duration exploration flights on the rise, the likelihood of critical medical conditions with no suitable treatment on board will increase. Therapeutic hypothermia (TH) could serve as a bridge treatment in space prolonging survival and reducing neurological damage in ischemic conditions such as stroke and cardiac arrest. We conducted a review of published studies to determine the potential and challenges of TH in space based on its physiological effects, the cooling methods available, and clinical evidence on Earth. Currently, investigators have found that application of low normothermia leads to better outcomes than mild hypothermia. Data on the impact of hypothermia on a favorable neurological outcome are inconclusive due to lack of standardized protocols across hospitals and the heterogeneity of medical conditions. Adverse effects with systemic cooling are widely reported, and could be reduced through selective brain cooling and pharmacological cooling, promising techniques that currently lack clinical evidence. We hypothesize that TH has the potential for application as supportive treatment for multiple medical conditions in space and recommend further investigation of the concept in feasibility studies.

Impact of hypothermia on the biomechanical effect of epithelium-off corneal cross-linking

BackgroundThe corneal cross-linking (CXL) photochemical reaction is essentially dependent on oxygen and hypothermia, which usually leads to higher dissolved oxygen levels in tissues, with potentially greater oxygen availability for treatment. Here, we evaluate whether a reduction of corneal temperature during CXL may increase oxygen availability and therefore enhance the CXL biomechanical stiffening effect in ex vivo porcine corneas.MethodsOne hundred and twelve porcine corneas had their epithelium manually debrided before being soaked with 0.1% hypo-osmolaric riboflavin. These corneas were equally assigned to one of four groups. Groups 2 and 4 underwent accelerated epithelium-off CXL using 9 mW/cm2 irradiance for 10 min, performed either in a cold room temperature (group 2, 4 °C) or at standard room temperature (group 4, 24 °C). Groups 1 and 3 served as non-cross-linked, temperature-matched controls. Using a stress-strain extensometer, the elastic moduli of 5-mm wide corneal strips were analyzed as an indicator of corneal stiffness.ResultsAccelerated epithelium-off CXL led to significant increases in the elastic modulus between 1 and 5% of strain when compared to non-cross-linked controls (P < 0.05), both at 4 °C (1.40 ± 0.22 vs 1.23 ± 0.18 N/mm) and 24 °C (1.42 ± 0.15 vs 1.19 ± 0.11 N/mm). However, no significant difference was found between control groups (P = 0.846) or between groups in which CXL was performed at low or standard room temperature (P = 0.969).ConclusionsAlthough initial oxygen availability should be increased under hypothermic conditions, it does not appear to play a significant role in the biomechanical strengthening effect of epithelium-off CXL accelerated protocols in ex vivo porcine corneas.

Impact of Intraoperative Hypothermia on Microsurgical Free Flap Reconstructions.

Patients requiring microsurgical defect reconstruction are highly susceptible to intraoperative hypothermia, given oftentimes long operative times and exposure of large skin surface areas. While the impact of hypothermia has been extensively studied across various surgical fields, its role in the setting of microsurgical free flap reconstruction remains elusive. This study evaluates the effects of hypothermia on outcomes of free flap reconstructions. Within 7 years, 602 patients underwent 668 microvascular free flap reconstructions. The cases were divided into two groups regarding the minimal core body temperature during free flap surgery: hypothermia (HT; < 36.0°C) versus normothermia (NT; ≥36.0°C). The data were retrospectively screened for patients' demographics, perioperative details, flap survival, surgical complications, and outcomes. Our data revealed no significant difference with regard to the rate of major and minor surgical complications, or the rate of revision surgery between both groups (p > 0.05). However, patients in the HT group showed significantly higher rates of total flap loss (6.6% [HT] vs. 3.0% [NT], p < 0.05) and arterial thrombosis (4.6% [HT] vs. 1.9% [NT], p < 0.05). This translated into a significantly longer hospitalization of patients with reduced core body temperature (HT: mean 16.8 days vs. NT: mean 15.1 days; p < 0.05). Hypothermia increases the risk for arterial thrombosis and total flap loss. While free flap transfer is feasible also in hypothermic patients, surgeons' awareness of core body temperature should increase. Taken together, we suggest that the mean intraoperative minimum temperature should range between 36 and 36.5°C during free flap surgery as a pragmatic guideline.

Impact of Hypothermia on Oxygenation Variables and Metabolism in Survivors of Out-of-Hospital Cardiac Arrest Undergoing Targeted Temperature Management at 33°C Versus 36°C.

Targeted temperature management (TTM) exerts substantial impact on hemodynamic function in out-of-hospital cardiac arrest (OHCA) patients. Whole-body oxygen consumption (VO2) and delivery (DO2) have not previously been investigated in a clinical setting during TTM at different levels of temperature after OHCA. A substudy of 151 patients randomized at a single center in the TTM-trial, where patients were randomly assigned TTM at 33°C (TTM33) or 36°C (TTM36) for 24 hours. We calculated VO2 according to the principle of Fick (VO2 = cardiac output*arteriovenous oxygen content difference). DO2 was calculated as cardiac output*arterial oxygen content. Cardiac output was measured by pulmonary artery catheter with thermodilution. Arteriovenous oxygen content difference was calculated from arterial and mixed venous oxygen saturation and hemoglobin. Oxygen extraction ratio = VO2/DO2. At 24 hours, the VO2 was 169 ± 59 mL O2 per minute in TTM33 and 217 ± 53 mL O2 per minute in TTM36 (p < 0.0001). During 24 hours of TTM, the overall difference was 53 mL O2 minute (95% confidence interval [CI]: 31-74, pgroup < 0.0001). After rewarming at 36 and 48 hours, there was no difference in VO2 between the groups. DO2 was overall 277 mL O2 per minute (95% CI: 175-379, pgroup < 0.0001) higher in the TTM36-group during TTM. Oxygen extraction ratio during TTM was not significantly different between the two groups (2% [95% CI: -0.1 to 5, pgroup = 0.09]). VO2 during the first 36 hours after OHCA correlated significantly with temperature, and VO2 was 19 mL O2 per minute lower per degree reduction in temperature (95% CI: 15-22), p < 0.0001. TTM at 33°C compared to 36°C after OHCA is associated with significantly lower VO2 and DO2, however, oxygen extraction ratio was not significantly different. For each degree lower body temperature, the VO2 fell by 19 mL O2 per minute.

Selective cerebral and coronary perfusion in the correction of coarctation of the aorta with tubular aortic arch hypoplasia (literature review)

This literature review presents the analysis of different techniques for approaches and cerebral and cardiac protection in surgical correction of coarctation of the aorta (CoA) with tubular aortic arch hypoplasia. Various definitions of tubular hypoplasia are reviewed. The attempt is made to bring together theoretical basis and data concerning the results of particular methods. The authors investigate up-to-date literature data based on results using thoracotomy and sternotomy approaches in CoA correction with tubular aortic arch hypoplasia. Literature results of operations using these approaches and authors' rival opinions for different methods are presented. The impact of hypothermia and its physiological effects on the brain and the late neurological outcomes of deep hypothermic circulatory arrest are discussed. Advantages and disadvantages of deep hypothermic circulatory arrest and selective cerebral perfusion and authors' opposite opinions on these techniques are presented. The methods of selective cerebral perfusion control and strategies to assess its adequacy are briefly described. Coronary perfusion peculiarities, hypothermic cardioplegia effects on the myocardium, and disadvantages of hyperkalemic cardioplegia are summarized. Based on literature data, the authors justify the implementation of selective coronary perfusion for the correction of CoA with tubular aortic arch hypoplasia.

Impact of hypothermia on cardiac performance during targeted temperature management after cardiac arrest

IntroductionTargeted temperature management (TTM) is a well-accepted neuro-protective intervention in the management of comatose survivors of cardiac arrest (CA). However, the impact of TTM on cardiac performance has not been adequately evaluated. MethodsWe reviewed data on consecutive CA survivors undergoing TTM at a quaternary cardiac intensive care unit between January 2015 and June 2017. Enrollment was restricted to cases with invasive hemodynamics (iHDs) at TTM initiation, every 8 h at target temperature (32–34 °C) and at completion of rewarming (>36 °C), unless precluded by mortality. Cardiac index and cardiac index-derived variables were adjusted for a decreased oxygen consumption during hypothermia. We assessed the serial impact of cooling on iHDs and cardiac performance utilizing longitudinal data analysis accounting for the effects of time as surrogate for the expected change from the post arrest syndrome and instituted treatments. A Frank–Starling construct was used to evaluate changes in cardiac contractility. ResultsWe evaluated the effects of cooling on iHDs and cardiac performance in 46 CA survivors. Heart rate decreased with cooling (p < 0.001), to return to baseline after rewarming (p = 0.6). Mean arterial pressure and pulmonary wedge pressure decreased by cooling (p < 0.001 for both), with sustained improvement after rewarming (p < 0.001 for both). Systemic vascular resistance was unaffected by hypothermia (p > 0.05). Left stroke work index increased with cooling (p < 0.001), with return to baseline after rewarming (p = 0.6). Cooling was associated with a left-upward shift in the Frank–Starling curve indicative of increased contractility. ConclusionMild hypothermia in CA survivors appears associated to positive changes in iHDs and cardiac performance, including a potential increase in cardiac contractility. Larger studies are needed to conclusively confirm these findings.

The impact of hypothermia on outcomes in massively transfused patients.

Hypothermia is associated with poor outcomes after injury. The relationship between hypothermia during contemporary large volume resuscitation and blood product consumption is unknown. We evaluated this association, and the predictive value of hypothermia on mortality. Patients predicted to receive massive transfusion at 12 level 1 trauma centers were randomized in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial and were grouped into those who were hypothermic (<36°C) or normothermic (36-38.5°C) within the first 6 hours of emergency department arrival. The impact of hypothermia or normothermia on the volume of blood product required during the first 24 hours was determined via negative binomial regression, adjusting for treatment arm, injury severity score, mechanism, demographics, pre-emergency department fluid volume, blood administered before becoming hypothermic, pulse and systolic blood pressure on arrival, and the time exposed to hypothermic or normothermic temperatures. Of 680 patients, 590 had a temperature measured during the first 6 hours in hospital, and 399 experienced hypothermia. The mean number of red blood cell (RBC) units given to all patients in the first 24 hours of admission was 8.8 (95% confidence interval [CI], 7.9-9.6). In multivariable analysis, every 1°C decrease in temperature below 36.0°C was associated with a 10% increase (incidence rate ratio, 0.90; 95% CI, 0.89-0.92; p < 0.00) in consumption of RBCs during the first 24 hours of admission. There was no association between RBC administration and a temperature above 36°C. Hypothermia on arrival was an independent predictor of mortality, with an adjusted odds ratio of 2.7 (95% CI, 1.7-4.5; p < 0.00) for 24-hour mortality and 1.8 (95% CI, 1.3-2.4; p < 0.00) for 30-day mortality. Hypothermia is associated with increase in blood product consumption and mortality. These findings support the maintenance of normothermia in trauma patients and suggest that further investigation on the impact of cooling or rewarming during massive transfusion is warranted. Prognostic, level III.

Impact of Hypothermia on Differentiation and Maturation of Neutrophils

Accumulating evidence has suggested that low body temperature is associated with the risk of infection. Unintentional drops in the body temperature known as “accidental hypothermia” are occasionally accompanied with infections. Patients under therapeutic hypothermia for post-cardiac arrest care are also susceptible to infections. In addition, secondary hypothermia caused by severe sepsis is significantly associated with higher mortality. These observations suggest the negative impact of hypothermia on host defense. Neutrophils are continuously produced in the bone marrow (BM) and supplied to the peripheral blood (PB) or tissues, where they fight against microorganisms. In addition to the neutrophil functions, sufficient supply of neutrophils is a critical determinant of host defense. However, little is known about the impact of hypothermia on granulopoiesis, the process of neutrophil production in the BM. In this study, we investigated the changes in granulopoiesis under hypothermic conditions.We first analyzed the neutrophils in the PB of mice exposed to low environmental temperature (4 °C). Under this condition, rectal temperature of the mice significantly declined from 36.7±0.4 °C to 35.5±0.4 °C. After 72-hour exposure to the low environmental temperature, PB neutrophil counts were significantly decreased. In order to understand the reason for the decrease, we analyzed their BMs by flow cytometry. Previously we developed a unique strategy to divide cells undergoing granulopoiesis into 5 subpopulations based on the expression of c-kit and Ly6G, which reflect successive differentiation/maturation from #1 (c-kithi Ly6G-) to #5 (c-kit- Ly6Ghi) (Satake S and Hirai H et al. J Immunol, 2012). In BM cells of the mice exposed to the low environmental temperature, a significant decrease in mature neutrophils (#5) and a significant increase in cellular intermediates (#3 and #4) were observed, while total BM cell numbers were unchanged. In order to clarify whether these changes were cell-intrinsic or -extrinsic, total BM cells were cultured in vitro at either 35 °C or 37 °C in the presence of G-CSF. Flow cytometric analysis of these cultured BM cells at 72 hours revealed the increase in the intermediates (#2 to #4) and a decrease in the mature subpopulation (#5), suggesting that these alterations were cell-intrinsic phenomena.When neutrophil precursors (#1 or #2) were purified by cell sorter and subjected to in vitro culture at 35 °C for 48 hours, the number of resultant mature neutrophils (#5) were significantly less than those induced at 37 °C. These results clearly indicate that hypothermia delayed neutrophil differentiation/maturation.Interestingly, mice with sepsis induced by cecal ligation and puncture (CLP) accompanied with lower body temperature revealed significantly fewer PB granulocytes and shorter survival when compared to those mice which maintained normal body temperature after CLP.In order to understand the molecular mechanisms underlying the differentiation/maturation delay induced by hypothermia, we performed RNA sequencing of purified neutrophil precursors (#2) after 24-hour culture either at 35 °C or 37 °C. Interestingly, we found alterations in amino acid metabolic pathways and target genes of C/EBP, which is the transcription factor family required for granulopoiesis and cellular metabolism.Collectively, these results indicate hypothermia causes neutropenia through delayed neutrophil differentiation/maturation. We are currently analyzing metabolic changes to understand more precise molecular mechanisms by which hypothermia regulates granulopoiesis. This study will facilitate the understanding of host defense at low body temperature, and shed novel insight into the management of hypothermia in patients. DisclosuresKashiwagi:Takara Bio Inc.: Employment. Hirai:Kyowa Hakko Kirin: Research Funding; Novartis Pharma: Research Funding.

Impact of Hypothermia and Oxygen Deprivation on the Cytoskeleton in Organ Preservation Models.

Ischemia reperfusion (IR) lesions are an unavoidable consequence of organ transplantation. Researching new therapeutics against these lesions requires the definition of early mechanisms. The cytoskeleton is composed of 3 types of filaments: microfilaments, intermediate filaments, and microtubules. We aimed to characterize the influence of preservation on their phenotype. In an in vitro model using primary human endothelial cells reproducing the conditions of organ preservation, two aspects were explored: (a) the impact of IR and cold ischemia time on each filament type, evaluating the roles of temperature, solution, and oxygen; and (b) the potential of cytoskeleton-mediated therapy to alleviate cell death. Results showed that intermediary filaments were unaffected, while microfilaments showed radical changes with disappearance of the structure replaced by a disorganized array of nodules; moreover, microtubules almost completely disappeared with time. Furthermore, temperature, and not oxygen deprivation or the solution, was the determining factor of the cytoskeleton's loss of integrity during preservation. Finally, pharmaceutical intervention could indeed preserve fiber structure but did not alter survival. Our work shows that improvement of preservation must include a more adapted temperature before considering oxygen, as it could profoundly improve cytoskeleton organization and thus cell fate. This highlights the importance of this structure for the development of new therapeutics and the definition of graft quality biomarkers.

INDISCRIMINATE USE OF HYPOTHERMIA COULD BE DELETERIOUS IN HEART FAILURE PATIENTS WITH CARDIAC ARREST

The use of hypothermia, post cardiac arrest increases peripheral vascular constriction and myocardial load in Heart Failure patients in whom perfusion is already compromised. We hypothesized that there is differential impact of hypothermia in patients with and without Congestive Heart Failure(CHF)

Chapter 44 - Hypothermia as a risk factor for Alzheimer disease

Alzheimer disease (AD), which is associated with chronic and progressive neurodegeneration, is the most prevalent cause of dementia linked to aging. Among the risk factors for AD, age stands as the greatest one, with the vast majority of people with AD being 65 years of age or older. Nevertheless, the pathophysiologic mechanisms underlying the link between aging and the development of AD, although not completely understood, might reveal important aspects for the understanding of this pathology. Thus, there is significant evidence that the impaired thermal homeostasis associated with normal aging leads to a variety of metabolic changes that could be associated with AD development. In this chapter, we assess the clinical and biochemical evidence implicating hypothermia as a risk factor for the development of AD and the impact of hypothermia on the two pathologic hallmarks of AD: accumulation of senile plaques of amyloid-beta and neurofibrillary tangles of aberrant hyperphosphorylated tau protein.

Moderate hypothermia increased the incidence of delayed paralysis through activation of the spinal microglia in an aortic cross-clamping rat model

BackgroundHypothermia reduces immediate paralysis during surgical repair of aortic aneurysms. However, it is unknown what the impact of hypothermia is on delayed paralysis, a serious complication of this type of surgery. MethodsSprague-Dawley rats were subjected to occlusion of the descending aorta at different duration under normothermia (38.0±0.5) or hypothermia (33.0±0.5°). Neurologic function was assessed. Motor neuron number, glial activation, and cytokine expression in the spinal cord were examined. Minocycline was administered perioperatively by intraperitoneal injection in the rats subjected to the aorta occlusion. ResultsIn contrast to normothermia conditions at which immediate paralysis occurred when the duration of aorta occlusion exceeded 11.5min, hypothermia did not induce immediate paralysis if the duration of aorta occlusion was less than 41min. However, delayed paralysis was developed when the duration of aorta occlusion exceeded 18min, and reached peak level when the duration of aorta occlusion was 40min at hypothermia condition. The number of motoneurons was significantly decreased (P<0.05) at 30h postoperation. In addition, microglia was activated, and interleukin-1β and interleukin-6 levels were upregulated, both of which were co-localized in microglia at 24h postoperation in the hypothermia group. Minocycline treatment attenuated the incidence and degree of paralysis but did not decrease the mortality. ConclusionsHypothermia, a neuroprotective strategy in cardiothoracic surgery, increased the incidence of delayed paralysis through activation of spinal microglia and cytokines. Blocking the activated microglia may be a potential intervention to prevent the incidence of delayed paralysis.

Long-Term Effects of Induced Hypothermia on Local and Systemic Inflammation - Results from a Porcine Long-Term Trauma Model.

BackgroundHypothermia has been discussed as playing a role in improving the early phase of systemic inflammation. However, information on the impact of hypothermia on the local inflammatory response is sparse. We therefore investigated the kinetics of local and systemic inflammation in the late posttraumatic phase after induction of hypothermia in an established porcine long-term model of combined trauma.Materials & MethodsMale pigs (35 ± 5kg) were mechanically ventilated and monitored over the study period of 48 h. Combined trauma included tibia fracture, lung contusion, liver laceration and pressure-controlled hemorrhagic shock (MAP < 30 ± 5 mmHg for 90 min). After resuscitation, hypothermia (33°C) was induced for a period of 12 h (HT-T group) with subsequent re-warming over a period of 10 h. The NT-T group was kept normothermic. Systemic and local (fracture hematoma) cytokine levels (IL-6, -8, -10) and alarmins (HMGB1, HSP70) were measured via ELISA.ResultsSevere signs of shock as well as systemic and local increases of pro-inflammatory mediators were observed in both trauma groups. In general the local increase of pro- and anti-inflammatory mediator levels was significantly higher and prolonged compared to systemic concentrations. Induction of hypothermia resulted in a significantly prolonged elevation of both systemic and local HMGB1 levels at 48 h compared to the NT-T group. Correspondingly, local IL-6 levels demonstrated a significantly prolonged increase in the HT-T group at 48 h.ConclusionA prolonged inflammatory response might reduce the well-described protective effects on organ and immune function observed in the early phase after hypothermia induction. Furthermore, local immune response also seems to be affected. Future studies should aim to investigate the use of therapeutic hypothermia at different degrees and duration of application.