The evolution of hypothermia for neuroprotection after cardiac arrest: a history in the making.

While much has been observed regarding hypothermia by way of environmental exposure, it is modern day medicine that deployed hypothermia as a therapeutic. From the early 1930s, when Temple Fay deployed "refrigeration" to treat pain, to the work of Wilfred Bigelow and Charles Drew, who utilized hypothermia in open heart surgery-the opportunities seemed endless. However, questions arose surrounding appropriate temperatures to achieve best outcomes and how to minimize adverse events, such as coagulopathy and infection. In the 1980s, hypothermia underwent a resurgence through Peter Safar's critical studies in large animals, which quickly translated into feasibility studies and the landmark trials of 2002 that paved the way for postcardiac arrest care as we currently know it. Through clinical and observational trials, modern-day targeted temperature management continues to adapt, striving to improve patient outcomes. While hypothermia has come a long way from the writings of Hippocrates, the ideal therapy has not yet been defined, and more work is needed. While the history is long, there is more to be written and advances to be achieved as we optimize the neuroprotective effects of hypothermia for comatose survivors of cardiac arrest.

Prognostic value of neonatal EEG following therapeutic hypothermia in survivors of hypoxic-ischemic encephalopathy.

OBJECTIVE: Early prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes. METHODS: We identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings. RESULTS: Higher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings. CONCLUSIONS: Clinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy. SIGNIFICANCE: These findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future.

Treating Seizures after Hypoxic-Ischemic Encephalopathy-Current Controversies and Future Directions.

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.

Research Progress of the Application of Hypothermia in the Eye.

Hypothermia is widely used in the medical field to protect organs or tissues from damage. Different research fields have different explanations of the protection mechanism of hypothermia. Hypothermia is also widely used in the field of ophthalmology, for example, in the eye bank, the preservation of corneal tissue and the preservation of the eyeball. Low temperature can also be applied to some ophthalmic diseases, such as allergic conjunctivitis, retinal ischemia, and retinal hypoxia. It is used to relieve eye symptoms or reduce tissue damage. Hypothermic techniques have important applications in ophthalmic surgery, such as corneal refractive surgery, vitrectomy surgery, and ciliary body cryotherapy for end-stage glaucoma. Hypothermia can reduce the inflammation of the cornea and protect the retinal tissue. The eyeball is a complex organ, including collagen tissue of the eyeball wall and retinal nerve tissue and retinal blood vessels. The mechanism of low temperature protecting eye tissue is complicated. It is important to understand the mechanism of hypothermia and its applications in ophthalmology. This review introduces the mechanism of hypothermia and its application in the eye banks, eye diseases (allergic conjunctivitis, retinal ischemia, and hypoxia), and eye surgeries (corneal transplant surgery, corneal refractive surgery, and vitrectomy).

Implementation of Targeted Temperature Management After Out-of-Hospital Cardiac Arrest: Observations From the Los Angeles County Regional System.

Background Despite the benefits of targeted temperature management (TTM) for out-of-hospital cardiac arrest), implementation within the United States remains low. The objective of this study was to evaluate the prevalence and factors associated with TTM use in a large, urban-suburban regional system of care. Methods and Results This was a retrospective analysis from the Los Angeles County regional cardiac system of care serving a population of >10 million residents. All adult patients aged ≥18 years with non-traumatic out-of-hospital cardiac arrest transported to a cardiac arrest center from April 2011 to August 2017 were included. Patients awake and alert in the emergency department and patients who died in the emergency department before consideration for TTM were excluded. The primary outcome measure was prevalence of TTM use. The secondary analysis were annual trends in TTM use over the study period and factors associated with TTM use. The study population included 8072 patients; 4154 patients (51.5%) received TTM and 3767 patients (46.7%) did not receive TTM. Median age was 67 years, 4780 patients (59.2%) were men, 4645 patients (57.5%) were non-White, and the most common arrest location was personal residence in 4841 patients (60.0%). In the adjusted analysis, younger age, male sex, an initial shockable rhythm, witnessed arrest, and receiving coronary angiography were associated with receiving TTM. Conclusions Within this regional system of care, use of TTM was higher than previously reported in the literature at just over 50%. Use of integrated systems of care may be a novel method to increase TTM use within the United States.

Trends, Predictors and Outcomes After Utilization of Targeted Temperature Management in Cardiac Arrest Patients With Anoxic Brain Injury.

BACKGROUND: Targeted Temperature Management (TTM) is a class I recommendation for the management of sudden cardiac arrest (SCA) patients with presumed brain injury. We aimed to study trends, predictors and outcomes in SCA patients from a nationally represented US population sample. METHODS: We utilized the National Inpatient Sample from years 2005 to 2014 for the purpose of our study. Patients with SCA and anoxic brain injury were selected using relevant ICD-9 codes. Data were analyzed for trends over the years and key outcomes were assessed. Logistic regression analysis was done to determine predictors of TTM utilization in our study population. RESULTS: A total of 78,465 patients with SCA and anoxic brain injury were identified from January 2005 to December 2014. Out of these, approximately 4,481 (5.7%) patients underwent TTM. Patients that underwent TTM were younger compared to patients without TTM utilization (60.67 vs. 63.27 years, P < 0.01). African Americans, Hispanics and women were less likely to undergo TTM. Myocardial infarction, electrolyte disorders and cardiogenic shock were associated with higher odds of TTM utilization. Sepsis, renal failure and diabetes were associated with underutilization of TTM. Inpatient mortality was higher in patients who did not undergo TTM when compared to patients who underwent TTM (67.30% vs. 65.10%, P < 0.01). CONCLUSIONS: Although TTM utilization increased over our study period, the overall application of TTM was still dismal. Factors that circumvent TTM utilization need to be addressed in future studies so more eligible patients could benefit from this life saving therapy.

Therapeutic Hypothermia in Patients with Malignant Ischemic Stroke and Hemicraniectomy-A Systematic Review and Meta-analysis.

BACKGROUND: Therapeutic hypothermia (TH) offers cerebral protection following ischemic stroke and may improve outcomes in conjunction with decompressive hemicraniectomy (DHC). We aimed to assess the effectiveness of TH in patients with malignant ischemic stroke and DHC. METHODS: We performed a meta-analysis in patients with malignant ischemic stroke undergoing DHC comparing TH versus normothermia in studies published up to August 2019. Included studies had ≥10 adults with acute ischemic stroke. Primary outcome was functional independence, and secondary outcomes included complications. Effect size was pooled and described by relative risk (RR) ratios and 95% confidence intervals (CIs). RESULTS: Five studies (n = 269 patients; n = 130 TH, n = 139 controls) were included, 4 of which were prospective (n = 2 randomized controlled trials). Median achieved body temperature of TH was 33.6°C (range 33°C-35°C). Median modified Rankin Scale at the study completion was similar between TH and controls (RR 1.08, 95% CI 0.56-2.07, P = 0.8). Three studies reported individual patient modified Rankin Scale outcomes demonstrated a shift toward worse outcomes with TH (unadjusted common odds ratio 1.74; 95% CI 1.05-2.88, P = 0.01). Overall complications were similar between groups (RR 1.20, 95% CI 0.70-2.05, random effects P = 0.5). A suggestion of higher mortality was seen in TH (RR 1.50, 95% CI 0.97-2.32, P = 0.07). CONCLUSIONS: Clinical and functional outcomes were not overall different between patients undergoing systemic TH and controls following DHC despite the shift toward worse outcomes with TH observed in some studies.

Characteristics and short-term outcomes of neonates with mild hypoxic-ischemic encephalopathy treated with hypothermia.

OBJECTIVE: To compare the characteristics and outcomes of neonates with mild hypoxic-ischemic encephalopathy (HIE) who received hypothermia versus standard care. STUDY DESIGN: We conducted a retrospective cohort study of neonates ≥35 weeks' gestation and ≥1800 g admitted with a diagnosis of Sarnat stage 1 encephalopathy. We evaluated length of hospital stay, duration of ventilation, evidence of brain injury on MRI, and neonatal morbidities. RESULTS: Of 1089 eligible neonates, 393 (36%) received hypothermia and 595 (55%) had neuroimaging. The hypothermia group was more likely to be outborn, born via C-section, had lower Apgar scores, and required extensive resuscitation. They had longer durations of stay (9 vs. 6 days, P < 0.001), respiratory support (3 vs. 2 days, P < 0.001), but lower odds of brain injury on MRI (adjusted odds ratio 0.33, 95% CI: 0.22-0.52) compared with standard care group. CONCLUSION: Despite prolongation of hospital stay, hypothermia may be potentially beneficial in neonates with mild HIE; however, selection bias cannot be ruled out.

SSEP retains its value as predictor of poor outcome following cardiac arrest in the era of therapeutic hypothermia.

OBJECTIVES: To re-evaluate the role of median nerve somatosensory evoked potentials (SSEPs) and bilateral loss of the N20 cortical wave as a predictor of unfavorable outcome in comatose patients following cardiac arrest (CA) in the therapeutic hypothermia (TH) era. METHODS: Review the results and conclusions drawn from isolated case reports and small series of comatose patients following CA in which the bilateral absence of N20 response has been associated with recovery, and evaluate the proposal that SSEP can no longer be considered a reliable and accurate predictor of unfavorable neurologic outcome. RESULTS: There are many methodological limitations in those patients reported in the literature with severe post anoxic encephalopathy who recover despite having lost their N20 cortical potential. These limitations include lack of sufficient clinical and neurologic data, severe core body hypothermia, specifics of electrophysiologic testing, technical issues such as background noise artifacts, flawed interpretations sometimes related to interobserver inconsistency, and the extreme variability in interpretation and quality of SSEP analysis among different clinicians and hospitals. CONCLUSIONS: The absence of the SSEP N20 cortical wave remains one of the most reliable early prognostic tools for identifying unfavorable neurologic outcome in the evaluation of patients with severe anoxic-ischemic encephalopathy whether or not they have been treated with TH. When confounding factors are eliminated the false positive rate (FPR) approaches zero.

Renal function after out-of-hospital cardiac arrest; the influence of temperature management and coronary angiography, a post hoc study of the target temperature management trial.

BACKGROUND: To elucidate the incidence of acute kidney injury (AKI) after out-of-hospital cardiac arrest (OHCA) and to examine the impact of target temperature management (TTM) and early coronary angiography on renal function. METHODS: Post hoc analysis of the TTM trial, a multinational randomised controlled trial comparing target temperature of 33 °C versus 36 °C in patients with return of spontaneous circulation after OHCA. The impact of TTM and early angiography (within 6 h of OHCA) versus late or no angiography on the development of AKI during the 7-day period after OHCA was analysed. AKI was defined according to modified KDIGO criteria in patients surviving beyond day 2 after OHCA. RESULTS: Following exclusions, 853 of 939 patients enrolled in the main trial were analysed. Unadjusted analysis showed that significantly more patients in the 33 °C group had AKI compared to the 36 °C group [211/431 (49%) versus 170/422 (40%) p = 0.01], with a worse severity (p = 0.018). After multivariable adjustment, the difference was not significant (odds ratio 0.75, 95% confidence interval 0.54-1.06, p = 0.10]. Five hundred seventeen patients underwent early coronary angiography. Although the unadjusted analysis showed less AKI and less severe AKI in patients who underwent early angiography compared to patients with late or no angiography, in adjusted analyses, early angiography was not an independent risk factor for AKI (odds ratio 0.73, 95% confidence interval 0.50-1.05, p = 0.09). CONCLUSIONS: In OHCA survivors, TTM at 33 °C compared to management at 36 °C did not show different rates of AKI and early angiography was not associated with an increased risk of AKI. TRIAL REGISTRATION: NCT01020916 . Registered on www.ClinicalTrials.gov 26 November 2009 (main trial).

Hypothermia as a treatment in status epilepticus: A narrative review.

Status epilepticus (SE) is associated with high mortality and morbidity rates, notably in its refractory and super-refractory forms. This narrative review discusses recent data on the potential benefits of targeted temperature management. In studies of patients with cerebral injury due to various factors, therapeutic hypothermia had variable effects on survival and functional outcomes. Sources of this variability may include the underlying etiology, whether hypothermia was used for prophylaxis or treatment, the degree and duration of hypothermia, and the hypothermia application modalities. Data from animal studies strongly suggest benefits from therapeutic hypothermia in SE. In humans, beneficial effects have been described in anecdotal case reports and small case series, but the level of evidence is low. A randomized controlled trial found no evidence that moderate hypothermia (32-34 °C) was neuroprotective in critically ill patients with convulsive SE. Nevertheless, some promising effects were noted, suggesting that therapeutic hypothermia might have a role as an adjuvant to anticonvulsant drug therapy in patients with refractory or super-refractory SE. This article is part of a Special Issue entitled "Status Epilepticus". This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Toward Understanding Cerebral Blood Flow during Cardiopulmonary Bypass: Implications for the Central Nervous System.

Factors and Their Influence on Regional Cerebral Blood Flow during Nonpulsatile Cardiopulmonary Bypass. By Govier AV, Reves JG, McKay RD, Karp RB, Zorn GL, Morawetz RB, Smith LR, Adams M, and Freeman AM. Ann Thorac Surg. 1984; 38:609-13. Reprinted with permission.In this study, we examined the relationship of regional cerebral blood flow (CBF) to mean arterial pressure, systemic blood flow, partial pressure of arterial carbon dioxide (PaCO2), nasopharyngeal temperature, and hemoglobin during hypothermic nonpulsatile cardiopulmonary bypass (CPB). Regional CBF was determined by clearance of xenon 133 in 67 patients undergoing coronary bypass grafting procedures. There was a significant decrease in regional CBF (55% decrease) during CPB, with nasopharyngeal temperature and PaCO2 being the only two significant factors (p < 0.05). In a subgroup of 10 patients, variation of pump flow between 1.0 and 2.0 L/min/m2 did not significantly affect regional CBF. We conclude that cerebral autoregulation is retained during hypothermic CPB. Under the usual conditions of CPB, variations in flow and pressure are not associated with important physiologic or detrimental clinical effects.

A New Vision for Therapeutic Hypothermia in the Era of Targeted Temperature Management: A Speculative Synthesis.

Three decades of animal studies have reproducibly shown that hypothermia is profoundly cerebroprotective during or after a central nervous system (CNS) insult. The success of hypothermia in preclinical acute brain injury has not only fostered continued interest in research on the classic secondary injury mechanisms that are prevented or blunted by hypothermia but has also sparked a surge of new interest in elucidating beneficial signaling molecules that are increased by cooling. Ironically, while research into cold-induced neuroprotection is enjoying newfound interest in chronic neurodegenerative disease, conversely, the scope of the utility of therapeutic hypothermia (TH) across the field of acute brain injury is somewhat controversial and remains to be fully defined. This has led to the era of Targeted Temperature Management, which emphasizes a wider range of temperatures (33-36°C) showing benefit in acute brain injury. In this comprehensive review, we focus on our current understandings of the novel neuroprotective mechanisms activated by TH, and discuss the critical importance of developmental age germane to its clinical efficacy. We review emerging data on four cold stress hormones and three cold shock proteins that have generated new interest in hypothermia in the field of CNS injury, to create a framework for new frontiers in TH research. We make the case that further elucidation of novel cold responsive pathways might lead to major breakthroughs in the treatment of acute brain injury, chronic neurological diseases, and have broad potential implications for medicines of the distant future, including scenarios such as the prevention of adverse effects of long-duration spaceflight, among others. Finally, we introduce several new phrases that readily summarize the essence of the major concepts outlined by this review-namely, Ultramild Hypothermia, the "Responsivity of Cold Stress Pathways," and "Hypothermia in a Syringe."

Trends in Management and Mortality in Adults Hospitalized With Cardiac Arrest in the United States.

BACKGROUND: We sought to examine temporal trends in management (ie, use of extracorporeal membrane oxygenation [ECMO], therapeutic hypothermia [TH], coronary angiogram, and percutaneous coronary intervention [PCI]) and in-hospital mortality in adults hospitalized with cardiac arrest. METHODS: Utilizing the Nationwide Inpatient Sample, medical history, clinical management, and in-hospital mortality were assessed in 942 495 hospitalizations in adults with cardiac arrest (identified through International Classification of Diseases-9 codes) from 2006 to 2012. RESULTS: From 2006 to 2012, there was an overall rise in the use of coronary angiogram (12.8%, 13.0%, 14.7%, 15.0%, 14.3%, 14.7%, and 15.8%), PCI (7.5%, 7.1%, 8.4%, 8.1%, 8.1%, 8.4%, and 8.9%), TH (0.2%, 0.3%, 0.6%, 1.2%, 1.9%, 2.8%, and 3.0%), and ECMO (0.1%, 0.1%, 0.1%, 0.2%, 0.2%, 0.3%, and 0.4%; P < .001 for all). In-hospital mortality significantly decreased over the 7-year study period (65.5%, 63.4%, 59.3%, 57.9%, 57.0%, 56.0%, and 56.3% from 2006 to 2012). In multivariable analysis, a 31% decrease in mortality was accompanied by a concomitant 24% and 27% increase in coronary angiogram and PCI, respectively, during the study period. Therapeutic hypothermia and ECMO were associated with an approximate 11-fold and 7-fold increase, respectively, from 2006 to 2012. The strongest predictors of use of ECMO, TH, coronary angiogram, and PCI were younger age and the presence of coronary artery disease. CONCLUSION: During 2006 to 2012, a decline in mortality was accompanied by a steady rise in the use of ECMO, TH, coronary angiogram, and PCI in adults hospitalized with cardiac arrest. Patients of younger age and with coronary artery disease were more likely to receive these advanced therapies.

Neonatal Encephalopathy: Current Management and Future Trends.

It is well-documented in the literature that infants who suffer from hypoxic ischemic encephalopathy are at high risk for neurologic sequelae or even death. With the addition of therapeutic hypothermia into the treatment regimen for neonatal hypoxic ischemic encephalopathy, newborns afflicted with hypoxic ischemic encephalopathy were given the opportunity for a better outcome. Questions linger as to the most optimal treatment strategy of therapeutic hypothermia for these newborns. The goal of this article is to discuss current management strategies, as well as future trends, for infants with hypoxic ischemic encephalopathy.