Protective Effects Of Therapeutic Hypothermia Research Articles

Abstract 11243: Novel Peptide for Cardiopulmonary Resuscitation

Introduction: While effective for out-of-hospital cardiac arrest, therapeutic hypothermia can be difficult to timely implement clinically. No drugs exist for improving neurologically intact survival. We have developed a novel peptide (TAT-PHLPP) that inhibits PH domain and Leucine rich repeat Protein Phosphatases (PHLPP), leading to Akt activation and mimicking of the protective effects of therapeutic hypothermia without the need of physical cooling. Hypothesis: We hypothesize that when administered intravenously during CPR, TAT-PHLPP improves neurologically intact survival. Methods: We conducted parallel studies in mouse and swine models. In C57BL6 mice (n = 72), we induced a 8 or 12-min asystolic cardiac arrest with KCl, followed by initiation of CPR and blinded randomized administration of TAT-PHLPP (7.5 mg/kg) or saline placebo. The primary outcomes were 4-h and 5-day survival, mean arterial blood pressure (MAP) and cerebral blood flow (CBF). We assessed PHLPP-NHERF1 binding and glucose utilization (via pyruvate dehydrogenase (PDH) phosphorylation and ATP generation). In 16 swine, we induced 5 min of VF followed by ACLS with vest CPR and administered two doses of TAT-PHLPP or saline. Survival (24 h) and neurological function were assessed. Plasma biomarkers taurine and glutamate levels in mice were measured and validated in CA patients (n=68) with a shockable rhythm at the time of hospital arrival, 6, 24, 48, and 72 h post-hospital arrival. Results: In mice, compared to saline, TAT-PHLPP significantly improved 4-h and 5-day survival, increased post-ROSC MAP and CBF, inhibited PHLPP-NHERF1 binding, increased p-Akt, decreased p-PDH (increased activity) at 15 min post-ROSC, enhanced ATP generation in both heart and brain, and reduced plasma taurine and glutamate levels. In swine, TAT-PHLPP improved 24 h neurologically intact survival (1/9 in control vs. 6/7 with peptide, p < 0.01). In patients, taurine levels were higher in non-survivors (n=44) than survivors (n=24) at 6 h of post-hospital arrival (65.9 ± 34.8 vs. 45.6 ±23.7, p< 0.001). Conclusions: TAT-PHLPP has high translational potential as a first-of-class biologic treatment to reproduce critical outcomes of therapeutic hypothermia and improve cardiac arrest survival.

HIF‑1α protein SUMOylation is an important protective mechanism of action of hypothermia in hypoxic cardiomyocytes.

Different degrees of myocardial ischemia‑reperfusion injury during open‑heart surgery are inevitable. Therapeutic hypothermia is an important technique for reducing ischemia‑reperfusion injury; however, there are numerous potential adverse effects. Furthermore, the underlying molecular mechanisms of action of therapeutic hypothermia remain unclear. In the present study, rat hearts were perfused for 30 min and subjected to 30min of regional ischemia, followed by 120min of reperfusion. Animals received intraperitoneal injection of spectomycinB1 at 30min prior to the start of surgery. Total myocardial area, infarct area, myocardial injury, and apoptosis were assessed. H9C2 cells were incubated for 24 h at 34˚C with 5%CO2 to simulate therapeutic hypothermic stress, and cell viability and mitochondrial injury were evaluated. The levels of protein SUMOylation, hypoxia‑inducible factor (HIF)‑1α and vascular endothelial growth factor (VEGF) were determined by western blot analysis. It was demonstrated that hypoxia significantly increased the overall modification by the small ubiquitin‑related modifier protein (SUMO) of various proteins in cardiomyocytes, both invitro and exvivo. In turn, this increased the protein levels of HIF‑1α, continuously stimulated downstream VEGF expression. Therapeutic hypothermia further increased protein SUMOylation, whereas inhibiting the SUMOylation pathway reduced the protective effect of therapeutic hypothermia on hypoxic cardiomyocytes. Overall, these data suggested that increasing SUMOylation of HIF‑1α may be an important molecular mechanism underlying the protective effects of therapeutic hypothermia following hypoxia in myocardial cells. These findings may aid in the use of therapeutic hypothermia for treatment of myocardial ischemia‑reperfusion and help avoid excessive side effects.

Protective effects of therapeutic hypothermia on renal injury in an asphyxial cardiac arrest rat model.

Cardiac arrest (CA) is a leading cause of mortality worldwide. Most of post-resuscitation related deaths are due to post-cardiac arrest syndrome (PCAS). After cardiopulmonary resuscitation (CPR), return of spontaneous circulation (ROSC) leads to renal ischemia-reperfusion injury, also known as PCAS. Many studies have focused on brain and heart injuries after ROSC, but renal failure has largely been ignored. Therefore, we investigated the protective effects of therapeutic hypothermia (TH) on asphyxial CA-induced renal injury in rats. Thirty rats were randomly divided into five groups: 1) the control group (sham); 2) the normothermic CA (nor.); 3) a normothermic CA group that received TH immediately within 2h after CPR (Hypo. 2 hrs); 4) a normothermic CA group that received TH within 4h after CPR (Hypo. 4 hrs); and 5) a normothermia CA group that received TH within 6h after CPR (Hypo. 6h). One day after CPR, all rats were sacrificed. Compared with the normothermic CA group, the TH groups demonstrated significantly increased survival rate (P<0.05); decreased serum blood urea nitrogen, creatinine, and lactate dehydrogenase levels; and lower histological damage degree and malondialdehyde concentration in their renal tissue. Terminal deoxynucleotidyl transferase dUTP nick end labeling stain revealed that the number of apoptotic cells significantly decreased after 4h and 6h of TH compared to the results seen in the normothermic CA group. Moreover, TH downregulated the expression of cyclooxygenase-2 in the renal cortex compared to the normothermic CA group one day after CPR. These results suggest that TH exerts anti-apoptotic, anti-inflammatory, and anti-oxidative effects immediately after ROSC that protect against renal injury.

Textbook of Neuroanesthesia and Neurocritical Care

Neurocritical care (NCC) of the critically ill patient with neurological diseases and conditions is a relatively new medical subspecialty. And although neurologists and neurosurgeons provide the majority of NCC, anesthesiologists are becoming more involved in this area. Indeed, in the United States, subspecialty certification in NCC is also offered by the American Board of Anesthesiology (ABA), and the first ABA examination on this topic will be administered in 2021. The book, “Textbook of Neuroanesthesia and Neurocritical Care: Volume II - Neurocritical Care,” then, is timely. The book has 33 chapters and over 70 authors who come from the United States, as well as Western Europe and Asia; the editors are both from South Asia and are well regarded in the areas of neuroanesthesia and NCC. The book has 9 parts that include fundamentals, intensive care management, neuromonitoring, systemic care, supportive care, pain management, ethical considerations, near misses, and recent advances. In the fundamentals part, the majority of the discussion concerns patient and fluid management of the neurocritically ill patient. The authors suggest that intravenous fluids should be considered as drugs and then go on to discuss fluid management in patients with traumatic brain injury (TBI), acute respiratory distress syndrome (ARDS), acute kidney injury, subarachnoid hemorrhage (SAH), spinal cord injury (SCI), neuroinflammation, cerebral salt wasting syndrome, syndrome of inappropriate antidiuretic hormone secretion, hypo-/hypernatremia, and hypokalemia. Part II entitled “Intensive Care Management” comprises 10 chapters that include a discussion of neurological dysfunction or abnormal conditions such as myasthenia gravis, Guillain–Barré syndrome, neuromuscular disorder, status epilepticus (SE), stroke, SAH, TBI, and traumatic SCI. The chapters in this part have a similar structure: they start with an introduction, then discuss testing, prognosis and/or outcome, treatment, and end with a summary or conclusion. Neuromonitoring is discussed in part III. Multimodal monitoring has become an important component of care of the severely brain-injured patient in the NCC unit. Multimodal monitoring includes cerebral hemodynamics (intracranial pressure, cerebral perfusion pressure, transcranial Doppler), oxygen metabolism (brain tissue oxygen tension [Pbto2], jugular venous bulb oximetry [Sjvo2], near-infrared spectroscopy), microdialysis, functional state (electroencephalogram [EEG], quantitative EEG [qEEG], somatosensory evoked potential), and neuroimaging (computed tomography [CT]: plain CT, CT angiography, CT perfusion; magnetic resonance imaging [MRI]: MR angiography, MR perfusion, MR spectroscopy, functional MRI; positron emission tomography; single photon emission CT). In parts IV through VI, the authors address supportive care, including nutrition and how nutrition changes during critical illness, nursing care, physiotherapy, psychological care, and pain management including both nonpharmacological and pharmacological measures. Issues related to Ethical Considerations are in part VII. In that part, brain death and organ donation are discussed. In part VIII, in the discussion about near-misses in the NCC unit, the authors address common complications including ventilator-associated pneumonia, ARDS, venous thromboembolism (including deep venous thrombosis, pulmonary embolism), fever, sepsis, and cerebral resuscitation after cardiac arrest in NCC. Tables and illustrations are included. Discussion concerning prophylaxis and management help guide readers to manage these issues for patients during their NCC unit stay. At the end of this book, in the Recent Advances part, protective effects of therapeutic hypothermia and “targeted temperature management (TTM)” are discussed. Then, in the book’s closing chapters, evidence-based practice in neuroanesthesia and neurointensive care is described. For example, in a table describing the management of patients with acute ischemic stroke, for each topic, the level of evidence and current recommendations according to the American Heart Association and the American Society of Anesthesiologists are listed. Above all, a successful NCC depends on harmonious collaboration among neurologists, neurosurgeons, intensivists, specially trained nurses, and associated other providers. Not everyone knows everything and the book contains a wealth of useful, practical advice for the neurointensivists and neuroanesthetists. Yet, some areas of discussion are only minimally discussed, such as perioperative myocardial injury, dementia, and neurodegenerative diseases including Alzheimer disease (AD) and idiopathic Parkinson disease (PD). Future editions might cover these areas in more detail. The book is well written. It will serve not only as an invaluable resource for intensivists and NCC physicians but also for residents, fellows, and trainees. Anesthesiologists who are not specifically trained in neuroanesthesia or neurointensive care will also find this book helpful and worth purchasing. ACKNOWLEDGMENTS The authors thank Professor J. Lance Lichtor, MD, for his selfless help in language editing and revising. Meilin Lu, MDDepartment of AnesthesiologyThe First Affiliated Hospital of Kunming Medical UniversityKunming, ChinaLiang He, MDDepartment of AnesthesiologyYan’an Hospital of Kunming CityKunming Medical UniversityKunming, China[email protected]

Faster Hypothermia Induced by Esophageal Cooling Improves EarlyMarkers of Cardiac and Neurological Injury After Cardiac Arrestin Swine.

BackgroundAfter cardiopulmonary resuscitation, the protective effects of therapeutic hypothermia induced by conventional cooling are limited. Recently, esophageal cooling (EC) has been shown to be an effective, easily performed approach to induce therapeutic hypothermia. In this study we investigated the efficacy of EC and its effects on early markers of postresuscitation cardiac and neurological injury in a porcine model of cardiac arrest.Methods and ResultsThirty‐two male domestic swine were randomized into 4 groups: sham control, normothermia, surface cooling, and EC. Sham animals underwent the surgical preparation only. Ventricular fibrillation was induced and untreated for 8 minutes while defibrillation was attempted after 5 minutes of cardiopulmonary resuscitation. At 5 minutes after resuscitation, therapeutic hypothermia was induced by either EC or surface cooling to reach a target temperature of 33°C until 24 hours postresuscitation, followed by a rewarming rate of 1°C/h for 5 hours. The temperature was normally maintained in the control and normothermia groups. After resuscitation, a significantly faster decrease in blood temperature was observed in the EC group than in the surface cooling group (2.8±0.7°C/h versus 1.5±0.4°C/h; P<0.05). During the maintenance and rewarming phases the temperature was maintained at an even level between the 2 groups. Postresuscitation cardiac and neurological damage was significantly improved in the 2 hypothermic groups compared with the normothermia group; however, the protective effects were significantly greater in the EC group.ConclusionsIn a porcine model of cardiac arrest, faster hypothermia successfully induced by EC was significantly better than conventional cooling in improving early markers of postresuscitation cardiac and neurological injury.

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.

0225 : Inhibition of mitochondrial permeability transition pore by therapeutic hypothermia after cardiac arrest: involvement of RISK signaling pathway

Therapeutic hypothermia (TH) is the sole adjuvant therapy to cardiopulmonary resuscitation able to improve neurologic outcomes in Humans. Resuscitated cardiac arrest (CA) initiates the opening of a mitochondrial mega-canal called permeability transition pore (PTP) jeopardizing cell viability. Activation of reperfusion injury salvage kinase (RISK) pathway inhibits PTP opening. We hypothesized that protective effects of TH involved the RISK pathway and thereby inhibit PTP opening in brain. NZW rabbits were subjected to a 15 minute period of asphyxial CA followed by resuscitation and 120 minutes of reperfusion. Five groups of animals (n=4-6/group) were studied: Sham; Control (Ctrl); TH, CA with fast hypothermia induced by external cooling at reperfusion (target temperature: 32°C); NIM: IV bolus, at the onset of reflow, of 2.5 mg/kg NIM811 (a non immunosuppressive derivative of cyclosporine A); TH+NIM, hypothermia and NIM811-treated rabbits. The following measurements were carried out: pupillary response to light, cell damage marker (protein S100β), RISK pathway activation (P-Akt/Akt and P-ERK/ERK ratios) and on isolated mitochondria both calcium retention capacity (CRC, i.e. Ca 2+ amount required for PTP opening) and respiration. The characteristics of CA were similar among groups. Pupillary response to light, impaired after CA, was preserved by TH (p<0.05 vs. Ctrl). The increase in S100β protein was prevented by TH (p<0.05 vs. Ctrl). TH improved the CRC (altered, by CA) and the ADP – stimulated mitochondrial respiration (p<0.05 vs Ctrl). CA did not increase P-Akt/Akt whereas P-ERK/ERK was significantly increased in the control group (p<0.05 vs. SHAM). TH significantly enhanced P-Akt/Akt while preventing increase in P-ERK/ERK (p<0.05 vs Ctrl). Similar results were obtained in NIM and TH+NIM groups (p<0.05 vs Ctrl). In our model, TH promoted activation of Akt and limited CAinduced brain damage by inhibiting PTP. The author hereby declares no conflict of interest

How Low Should We Go?

Current guidelines from the American Heart Association recommend use of therapeutic hypothermia (TH) after witnessed cardiac arrest (CA) to mitigate posthypoxic injuries. This is based on results of 3 randomized, controlled trials (RCTs) enrolling 385 patients, 43 before–after studies enrolling 10 442 patients, and supporting evidence from the field of neonatal asphyxia where 7 RCTs enrolling 1329 patients also demonstrated neuroprotective effects of hypothermia. However, this has been called into question by a recently published RCT enrolling 939 patients, which found no benefit of cooling to 33°C compared with maintaining 36°C. In this article we review the literature, with extra attention for strengths and weaknesses of the recently published RCT. In view of potential weaknesses in the new study (including a possibility of selection bias, long delays before initiation of cooling, a time to target temperature of 10 hours, and a rapid rewarming rate), we conclude that there are sufficient grounds to continue using hypothermia in most patients with witnessed ventricular fibrillation (VF)/ventricular tachycardia (VT) arrest, pending results of further studies which should examine multiple temperature levels (32–36°C) and multiple treatment durations (24–72 hours). The bases for these conclusions are discussed in detail below. The use of TH to mitigate various types of injury, in particular posthypoxic injury to the brain, has been studied since the late 1930s. Interest was initially kindled by reports of survival after prolonged exposure to cold, or submersion in ice-cold water, indicating a possible protective effect of low temperature on hypoxic injuries.1 Use of hypothermia after CA was first described in the late 1950s,2,3 but conclusive proof that hypothermia could improve outcome in these patients remained elusive.4,5 At the time it was thought that protective effects of TH were purely a result of hypothermia-induced lowering of metabolism; therefore, it …

Delayed and prolonged local brain hypothermia combined with decompressive craniectomy: a novel therapeutic strategy that modulates glial dynamics.

Hypothermia is considered a useful intervention for limiting pathophysiological changes after brain injury. Local hypothermia is a relatively safe and convenient intervention that circumvents many of the complications associated with systemic hypothermia. However, successful hypothermia treatment requires careful consideration of several factors including its practicality, feasibility, and associated risks. Here, we review the protective effects-and the cellular mechanisms that underlie them-of delayed and prolonged local hypothermia in rodent and canine brain injury models. The data show that the protective effects of therapeutic hypothermia, which mainly result from the modulation of inflammatory glial dynamics, are limited. We argue that decompressive craniectomy can be used to overcome the limitations of local brain hypothermia without causing histological abnormalities or other detrimental effects to the cooled area. Therefore, delayed and prolonged local brain hypothermia at the site of craniectomy is a promising intervention that may prove effective in the clinical setting.

Protective effects of therapeutic hypothermia in post-resuscitation myocardium

Aim of the studyPost-resuscitation therapeutic hypothermia has been recommended because of its neuroprotective effects. However, a few studies have reported the effects of therapeutic hypothermia on the heart, especially in ventricular fibrillation cardiac arrest. The aim of this study was to determine whether therapeutic hypothermia attenuates post-resuscitation myocardial injury in a swine cardiac arrest model. MethodsA prospective animal study was performed in the university hospital animal research laboratory. Ventricular fibrillation cardiac arrest was induced in domestic pigs weighing 35–40kg. After 6min of no flow time, cardiopulmonary resuscitation was provided to pigs, and the restoration of spontaneous circulation (ROSC) was achieved. The subjects were randomly allocated to a normothermic (NT group, n=5) or hypothermic (HT group, n=5) group. In the HT group, therapeutic hypothermia (core temperature 32–34°C) was maintained for 24h, and rewarming was performed over a period of 8h. In the NT group, core temperature was maintained at 37°C throughout the experiments. Sixty hours after ROSC, blood and myocardial tissues were harvested. ResultsSerum troponin I was not significantly different between the groups. However, myocardial histological damage was attenuated in the HT group. Myocardial ATP contents were higher in the HT group than in the NT group. Immunohistochemistry for apoptosis-related protein showed that survivin expression was higher in the HT group, and XAF1 and cleaved caspase-3 expressions were lower in the HT group than in the NT group. ConclusionsTherapeutic hypothermia attenuated histological myocardial injury in ventricular fibrillation cardiac arrest model of pigs while preserving more ATP and decreased apoptosis.