Resuscitative Hypothermia Research Articles

Study on brain protection of mild hypothermia in cardiopulmonary resuscitation

Cardiac arrest (CA) is often followed by postischemic-anoxic encephalopathy. A ventricular fibrillation CA model in dogs was used in this study to understand the effect of oxygen free radical (OFR) and lactate (LA) in the postischemic-anoxic encephalopathy, and to explore the effect and mechanism of mild hypothermia (32-36°C) induced immediately with reperfusion after cardiac arrest (resuscitation).

Mild resuscitative hypothermia and outcome after cardiopul monary resuscitation: J Neurosurg Anesthesiol 1996; 8/1: 88–96

Mild resuscitative hypothermia and outcome after cardiopul monary resuscitation: J Neurosurg Anesthesiol 1996; 8/1: 88–96

Resuscitative hypothermia

Resuscitative (postinsult) hypothermia is less well studied than protective-preservative (pre- and intra-arrest) hypothermia. The latter is in wide clinical use, particularly for protecting the brain during cardiac surgery. Resuscitative hypothermia was explored in the 1950s and then lay dormant until the 1980s when it was revived. This change occurred through the discoveries of brain damage mitigating effects after cardiac arrest in dogs, and after forebrain ischemia in rats, of mild (34 degrees C) hypothermia (which is safe), and of benefits derived from moderate hypothermia (30 degrees C) after traumatic brain injury or focal brain ischemia in various species. The idea that protection-preservation or resuscitation by hypothermia is mainly explained by its ability to reduce cerebral oxygen demand has been replaced by an increasingly documented synergism of many beneficial mechanisms. Deleterious chemical cascades during and after these insults are suppressed even by mild hypothermia. Prolonged moderate hypothermia carries some risks, e.g., arrhythmias, infection and coagulopathies. These side effects need further study. In global brain ischemia, protective-preservative mild hypothermia provides lasting mitigation of brain damage. Resuscitative mild hypothermia, however, may be beneficial in terms of long-term outcome or may merely delay the inevitable loss of selectively vulnerable neurons. Even if the latter is true, mild hypothermia may extend the therapeutic window for other interventions. This extension of the therapeutic window requires further documentation. After normothermic cardiac arrest of 11 mins in dogs, mild resuscitative hypothermia from 15 mins to 12 hours after reperfusion plus cerebral blood flow promotion normalized functional recovery with the least histologic damage seen thus far. Optimal duration of, and rewarming methods from, resuscitative hypothermia need clarification. The earliest possible induction of mild hypothermia after cardiac arrest seems desirable. Head-neck surface cooling alone is too slow. Among many clinically feasible rapid cooling methods, carotid cold flush and peritoneal cooling look promising. After traumatic brain injury or focal brain ischemia, which seem to still benefit from even later cooling, surface cooling methods may be adequate. Resuscitative hypothermia after cardiac arrest, traumatic brain injury, or focal brain ischemia should be considered for clinical trials.

Cerebral resuscitation from cardiac arrest

In 1961, in Pittsburgh, PA, "cerebral" was added to the cardiopulmonary resuscitation system (CPR --> CPCR). Cerebral recovery is dependent on arrest and cardiopulmonary resuscitation times, and numerous factors related to basic, advanced, and prolonged life support. Postischemic-anoxic encephalopathy (the cerebral postresuscitation disease or syndrome) is complex and multifactorial. The prevention or mitigation of this syndrome requires that there be development and trials of special, multifaceted, combination treatments. The selection of therapies to mitigate the postresuscitation syndrome should continue to be based on mechanistic rationale. Therapy based on a single mechanism, however, is unlikely to be maximally effective. For logistic reasons, the limit for neurologic recovery after 5 mins of arrest must be extended to achieve functionally and histologically normal human brains after 10 to 20 mins of circulatory arrest. This goal has been approached, but not quite reached. Treatment effects on process variables give clues, but long-term outcome evaluation is needed for documentation of efficacy and to improve clinical results. Goals have crystallized for clinically relevant cardiac arrest-intensive care outcome models in large animals. These studies are expensive, but essential, because positive treatment effects cannot always be confirmed in the rat forebrain ischemia model. Except for a still-elusive breakthrough effect, randomized clinical trials of CPCR are limited in their ability to statistically document the effectiveness of treatments found to be beneficial in controlled outcome models in large animals. Clinical studies of feasibility, side effects, and acceptability are essential. Hypertensive reperfusion overcomes multifocal no-reflow and improves outcome. Physical combination treatments, such as mild resuscitative (early postarrest) hypothermia (34 degrees C) plus cerebral blood flow promotion (e.g., with hypertension, hemodilution, and normocapnia), each having multiple beneficial effects, achieved complete functional and near-complete histologic recovery of the dog brain after 11 mins of normothermic, ventricular fibrillation cardiac arrest. Calcium entry blockers appear promising as a treatment for postischemic-anoxic encephalopathy. However, the majority of single or multiple drug treatments explored so far have failed to improve neurologic outcome. Assembling and evaluating combination treatments in further animal studies and determining clinical feasibility inside and outside hospitals are challenges for the near future. Treatments without permanent beneficial effects may at least extend the therapeutic window. All of these investigations will require coordinated efforts by multiple research groups, pursuing systematic, multilevel research--from cell cultures to rats, to large animals, and to clinical trials. There are still many gaps in our knowledge about optimizing extracerebral life support for cerebral outcome.

Resuscitation from severe hemorrhage

The potential to be successfully resuscitation from severe traumatic hemorrhagic shock is not only limited by the "golden 1 hr", but also by the "brass (or platinum) 10 mins" for combat casualties and civilian trauma victims with traumatic exsanguination. One research challenge is to determine how best to prevent cardiac arrest during severe hemorrhage, before control of bleeding is possible. Another research challenge is to determine the critical limits of, and optimal treatments for, protracted hemorrhagic hypotension, in order to prevent "delayed" multiple organ failure after hemostasis and all-out resuscitation. Animal research is shifting from the use of unrealistic, pressure-controlled, hemorrhagic shock models and partially realistic, volume-controlled hemorrhagic shock models to more realistic, uncontrolled hemorrhagic shock outcome models. Animal outcome models of combined trauma and shock are needed; a challenge is to find a humane and clinically realistic long-term method for analgesia that does not interfere with cardiovascular responses. Clinical potentials in need of research are shifting from normotensive to hypotensive (limited) fluid resuscitation with plasma substitutes. Topics include optimal temperature, fluid composition, analgesia, and pharmacotherapy. Hypotensive fluid resuscitation in uncontrolled hemorrhagic shock with the addition of moderate resuscitative (28 degrees to 32 degrees C) hypothermia looks promising in the laboratory. Regarding the composition of the resuscitation fluid, despite encouraging results with new preparations of stroma-free hemoglobin and hypertonic salt solutions with colloid, searches for the optimal combination of oxygen-carrying blood substitute, colloid, and electrolyte solution for limited fluid resuscitation with the smallest volume should continue. For titrating treatment of shock, blood lactate concentrations are of questionable value although metabolic acidemia seems helpful for prognostication. Development of devices for early noninvasive monitoring of multiple parameters in the field is indicated. Molecular research applies more to protracted hypovolemic shock followed by the systemic inflammatory response syndrome or septic shock, which were not the major topics of this discussion.

Mild resuscitative hypothermia and outcome after cardiopulmonary resuscitation.

Recovery without residual neurological damage after cardiac arrest with global cerebral ischemia is still a rare event. Severe impairment of bodily or cognitive functions is often the result. The individual, emotional, and social aspects of brain damage and rehabilitation are seldom taken into account. Efforts to improve the prevention of brain damage immediately after successful resuscitation of patients are missing. The efficacy of hypothermia in preserving neurologic function when instituted before and during certain no-flow cardiovascular states has been well documented both clinically and experimentally since the 1950s. Most studies have used moderate (28-33 degrees C) to deep (20-28 degrees C) hypothermia to demonstrate these protective effects. Considering the use of hypothermia for preservation and resuscitation, the lack of controlled outcome trials, the long period of time required to reach therapeutic hypothermia, and the incidence of rewarming complications such as infection, arrhythmia, and coagulopathy have made it difficult to apply these methods to emergency situations such as cardiac arrest. Recent experimental evidence in dogs has shown that hypothermia induced after cardiac arrest does indeed mitigate the effects of the postresuscitation syndrome and improves neurologic function and reduces histologic brain damage. More importantly, such benefits can be demonstrated with mild (34-36 degrees C) hypothermia, thus minimizing complications and requiring less time for induction of hypothermia. Ice water nasal lavage, direct carotid infusion of cold fluids, use of a cooling helmet, and peritoneal cooling are promising techniques for clinical cerebral cooling. External auditory canal temperature (e.g., tympanic membrane temperature changes) could provide an approximation to brain temperatures. For accurate temperature monitoring, however, a central pulmonary artery thermistor probe should be inserted. Temperature monitoring is needed to avoid temperature < 30 degrees C. Mild hypothermia may prove to be an important and secure component for cerebral preservation and resuscitation during and after global ischemia; it may also prove to be a useful method of cerebral resuscitation after global ischemic states, thereby promoting the prevention of neuromental diseases.

Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion.

In past studies, cerebral outcome after normothermic cardiac arrest of 10 or 12.5 minutes in dogs was improved but not normalized by resuscitative (postarrest) treatment with either mild hypothermia or hypertension plus hemodilution. We hypothesized that a multifaceted combination treatment would achieve complete cerebral recovery. With our established dog outcome model, normothermic ventricular fibrillation of 11 minutes (without blood flow) was followed by controlled reperfusion (with brief normothermic cardiopulmonary bypass simulating low flow and low PaO2 of external cardiopulmonary resuscitation) and defibrillation at < 2 minutes. Controlled ventilation was provided to 20 hours and intensive care to 96 hours. Control group 1 (n = 8) was kept normothermic (37.5 degrees C), normotensive, and hypocapnic throughout. Experimental group 2 (n = 8) received mild resuscitative hypothermia (34 degrees C) from about 10 minutes to 12 hours (by external and peritoneal cooling) plus cerebral blood flow promotion with induced moderate hypertension, mild hemodilution, and normocapnia. All 16 dogs in the protocol survived. At 96 hours, all 8 dogs in control group 1 achieved overall performance categories 3 (severe disability) or 4 (coma). In group 2, 6 of 8 dogs achieved overall performance category 1 (normal); 1 dog achieved category 2 (moderate disability), and 1 dog achieved category 3 (P < .001). Final neurological deficit scores (0% [normal] to 100% [brain death]) at 96 hours were 38 +/- 10% (22% to 45%) in group 1 versus 8 +/- 9% (0% to 27%) in group 2 (P < .001). Total brain histopathologic damage scores were 138 +/- 22 (110 to 176) in group 1 versus 43 +/- 9 (32 to 56) in group 2 (P < .001). Regional scores showed similar group differences. After normothermic cardiac arrest of 11 minutes in dogs, resuscitative mild hypothermia plus cerebral blood flow promotion can achieve functional recovery with the least histological brain damage yet observed with the same model and comparable insults.

P156 The role of hypothermia in trauma resuscitation

P156 The role of hypothermia in trauma resuscitation

P67 Mild protective and resuscitative cerebral hypothermia improves outcome after asphyxial cardiac arrest in rats

P67 Mild protective and resuscitative cerebral hypothermia improves outcome after asphyxial cardiac arrest in rats

P56 Mild resuscitative cerebral hypothermia mitigates brain damage after normothermic cardiac arrest in dog outcome models

P56 Mild resuscitative cerebral hypothermia mitigates brain damage after normothermic cardiac arrest in dog outcome models

P69 Moderate resuscitative hypothermia after brain trauma (simulated epidural hematoma) in new intensive care outcome model in dogs

P69 Moderate resuscitative hypothermia after brain trauma (simulated epidural hematoma) in new intensive care outcome model in dogs

O59 Clinically feasible methods for the rapid induction of mild cerebral resuscitative hypothermia in dogs. Efficacy of peritoneal cooling

O59 Clinically feasible methods for the rapid induction of mild cerebral resuscitative hypothermia in dogs. Efficacy of peritoneal cooling

Evaluation of Cold Reperfusion as an Indicator of Viability in Stored Organs: A 31P NMR Study in Rat Liver

Rat livers were studied during hypothermic resuscitation perfusion using 31 P nuclear magnetic resonance (NMR) spectroscopy as a viability index. Livers were stored for 48 h after being flushed either with a synthetic solution containing plasma-equivalent concentrations of cations, plus citrate and including gelatin polypeptides as colloid (GC solution), or with a modified lactobionate/raffinose [University of Wisconsin, (UWC)] solution. After 48 h in either solution, all NMR-detectable ATP plus ADP had disappeared, inorganic phosphate had increased markedly and pH in the livers had become acidotic. During cold reperfusion, ATP was resynthesized, inorganic phosphate declined, and pH returned toward normal values. ATP recovery and decrease in tissue inorganic phosphate were significantly greater ( P < 0.02 and P < 0.005, respectively) after 1 h cold reperfusion with the modified UW compared with reperfusion with the GC. 31P NMR spectroscopy was able to detect differences in the metabolic responses of livers stored in different solutions, and coupled with cold reperfusion may be a useful indicator of viability.

Effect of moderate hypothermia on lipid peroxidation in canine brain tissue after cardiac arrest and resuscitation.

We sought to examine the effect of moderate hypothermia (30 degrees C to 32 degrees C) initiated after resuscitation on the scavenging systems of free radicals and lipid peroxidation in canine brain tissue after cardiac arrest and resuscitation. Twenty-one dogs were divided into four groups: group A, nonischemic controls (shams) (n = 4); group B, 15-minute cardiac arrest without reperfusion (n = 4); group C, 15-minute cardiac arrest and standard resuscitation (n = 6); and group D, 15-minute cardiac arrest and hypothermic resuscitation (n = 7). During the period of 10 to 120 minutes after resuscitation, brain temperature and core temperature in group D remained at 30 degrees C to 32 degrees C and were 4 degrees C to 5 degrees C lower than in group C. For each dog, a sample of right parietal cerebral cortex was obtained from group A, group B, or from group C and group D at 2 hours after resuscitation. The sample was assayed for tissue malondialdehyde (MDA), the content of reduced glutathione (GSH), and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). In group B, a 15-minute cardiac arrest induced an increase in MDA, a significant reduction of GSH, and no change in SOD and GSH-PX activities compared with group A. In group C, there were further increases in MDA and reductions in GSH content and GSH-PX activity compared with group A; SOD activity remained substantially unchanged. The content of MDA was higher in group D than in group A but less elevated in group D than in group C. The GSH content and SOD and GSH-PX activities were significantly higher in group D than in group C. Moderate hypothermia initiated after resuscitation can significantly inhibit the accumulation of lipid peroxidation products and the consumption of free radical scavengers in the brain tissue.

259 Brain Trauma by Epidural Brain Compression Canine Outcome Model: Prolonged Resuscitative Moderate Hypothermia

259 Brain Trauma by Epidural Brain Compression Canine Outcome Model: Prolonged Resuscitative Moderate Hypothermia

196 Evaluation of Rapid Brain Cooling Methods for Induction of Mild Resuscitative Hypothermia

196 Evaluation of Rapid Brain Cooling Methods for Induction of Mild Resuscitative Hypothermia

単純低体温・冠灌流蘇生法による 2 才未満重症心室中隔欠損症の根治手術 : 術中, 術後の経過を中心に

単純低体温・冠灌流蘇生法による 2 才未満重症心室中隔欠損症の根治手術 : 術中, 術後の経過を中心に

HYPOTHERMIA IN RESUSCITATION OF THE NEWBORN.

HYPOTHERMIA IN RESUSCITATION OF THE NEWBORN.

HYPOTHERMIA IN RESUSCITATION OF THE NEWBORN.

HYPOTHERMIA IN RESUSCITATION OF THE NEWBORN.

Resuscitation and Artificial Hypothermia.

Professor Negovskii, as head of the Laboratory of Experimental Physiology of Resuscitation, Academy of Medicine, USSR, has compiled this rather lengthy work on his own researches as well as the researches of other scientists into terminal states. His main efforts have been toward documenting the morphological, biochemical, and physiological changes that occur as death approaches (agony), after cardiac and respiratory arrest (clinical death), and resuscitation. He differentiates clinical death from biological death as reversible versus irreversible. For the most part the experimental animal is the dog, and death is invoked by an exsanguination technique which is very repeatable. Resuscitation is nearly always based on intra-arterial transfusion accompanied by artificial respiration, both internal and external massage, and various other supportive techniques. The discussion of the physiology underlying death as well as the biochemical and morphological explanations are extremely interesting and are brought together and correlated probably for the first time. The