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A feasibility study was performed to compare an investigational drug, HBN-1, to forced cooling to induce hypothermia after resuscitation in a translation model of asphyxial cardiac arrest in swine. Serum and cerebral spinal fluid neuron-specific enolase activity (sNSE and csfNSE) were measured after cardiac arrest as surrogate markers of brain injury. In a block design, swine resuscitated from 10 minutes of asphyxial cardiac arrest were infused intravenously with HBN-1 or iced saline vehicle (forced hypothermia [FH]) 5 to 45 minutes after return of spontaneous circulation (ROSC). External cooling in both groups was added 45 minutes after ROSC until hypothermia (T=4°C below baseline) was attained. Esophageal (core) temperature, shivering, cardiopulmonary parameters, and time to hypothermia after ROSC were monitored. sNSE and csfNSE were measured 180 minutes after ROSC. HBN-1 induced hypothermia significantly lowered temperature compared to FH 5-45 minutes after ROSC (p

Background Vasoconstriction, an inherent property of Hemoglobin Based Oxygen Carriers (HBOC) potentially due to nitric oxide (NO) scavenging, may increase cardiovascular complications in HBOC resuscitated trauma patients. The purpose of this study was to determine if co-administration of a weak NO donor, intravenous nitroglycerin (NTG), with HBOC-201 during resuscitation from hemorrhagic shock could safely attenuate HBOC-201 vasoconstriction. Methods and results Hemorrhagic shock was induced in 44 swine randomized to receive fluid resuscitation with HBOC, HBOC+NTG10mcg/kg/min, HBOC+NTG20mcg/kg/min, HBOC+NTG40mcg/kg/min, Hetastarch (HES), HES+NTG20mcg/kg/min, NTG20mcg/kg/min and Lactated Ringers (LR). HBOC resuscitation from hemorrhagic shock increased mean arterial pressure (MAP=94±33mmHg), mean pulmonary artery pressure (MPAP=29±11mmHg) and systemic vascular resistance (SVR=2684±871dyns/cm 5 ) in comparison to HES. Co-administration of NTG during HBOC resuscitation attenuated vasoconstriction with HBOC+40mcg/kg/min demonstrating the most robust reduction in vasoconstriction (MAP=59±23mmHg, MPAP=18±7mmHg, and SVR=1827±511dyns/cm 5 ), although the effects were transient. Co-administration of NTG with HBOC did not alter base deficit, lactate, methemoglobin levels, nor cause profound hypotension during resuscitation. Conclusion Nitroglycerin attenuates vasoconstrictive properties of HBOC when co-administered during resuscitation in this swine model of hemorrhagic shock. Translational survival studies are required to determine if this strategy of attenuation of the vasoconstriction of HBOC-201 reduces cardiovascular complications and improves outcome with HBOC fluid resuscitation for hemorrhagic shock.

Hypothermia is recommended by international guidelines for treatment of unconscious survivors of cardiac arrest to improve neurologic outcomes. However, temperature management is often underutilized because it may be difficult to implement. The present study evaluated the efficacy of pharmacologically induced hypothermia on survival and neurological outcome in rats resuscitated from cardiac arrest.Cardiac arrest was induced for 10 min in 120 rats. Sixty-one rats were resuscitated and randomized to normothermia, physical cooling or pharmacological hypothermia 5 min after resuscitation. Pharmacological hypothermia rats received a combination of ethanol, vasopressin and lidocaine (HBN-1). Physical hypothermia rats were cooled with intravenous iced saline and cooling pads. Rats in the pharmacological hypothermia group received HBN-1 at ambient temperature (20 °C). Normothermic rats were maintained at 37.3 ± 0.2 °C.HBN-1 (p0.0001) shortened the time (85 ± 71 min) to target temperature (33.5 °C) versus physical hypothermia (247 ± 142 min). The duration of hypothermia was 17.0 ± 6.8h in the HBN-1 group and 17.3 ± 7.5h in the physical hypothermia group (p = 0.918). Survival (p = 0.034), neurological deficit scores (p0.0001) and Morris Water Maze performance after resuscitation (p = 0.041) was improved in the HBN-1 versus the normothermic group. HBN-1 improved survival and early neurological outcome compared to the physical hypothermia group while there was no significant difference in performance in the Morris water maze.HBN-1 induced rapid and prolonged hypothermia improved survival with good neurological outcomes after cardiac arrest suggesting that pharmacologically induced regulated hypothermia may provide a practical alternative to physical cooling.

Objective This study evaluates the effect of early administration of an empirical (1 mEq/kg) sodium bicarbonate dose on survival from prehospital cardiac arrest within brief ( 15 minutes) down time. Methods Prospective randomized, double-blinded clinical intervention trial that enrolled 874 prehospital cardiopulmonary arrest patients managed by prehospital, suburban, and rural regional emergency medical services. Over a 4-year period, the randomized experimental group received an empirical dose of bicarbonate (1 mEq/kg) after standard advanced cardiac life support interventions. Outcome was measured as survival to emergency department, as this was a prehospital study. Results The overall survival rate was 13.9% (110/792) for prehospital arrest patients. There was no difference in the amount of sodium bicarbonate administered to nonsurvivors (0.859 ± 0.284 mEq/kg) and survivors (0.8683 ± 0.284 mEq/kg) ( P = .199). Overall, there was no difference in survival in those who received bicarbonate (7.4% [58/420]), compared with those who received placebo (6.7% [52/372]) ( P = .88; risk ratio, 1.0236; 0.142-0.1387). There was, however, a trend toward improved outcome with bicarbonate in prolonged (>15 minute) arrest with a 2-fold increase in survival (32.8% vs 15.4%; P = .007). Conclusion The empirical early administration of sodium bicarbonate (1 mEq/kg) has no effect on the overall outcome in prehospital cardiac arrest. However, a trend toward improvement in prolonged (>15 minutes) arrest outcome was noted.

Study Objective: Controversy surrounds the use of buffers during cardiac arrest to correct acidosis. The objective of this study was to determine whether attenuation or neutralization of cerebral acidosis by Carbicarb alters hippocampal glutamate levels, neuronal cell death, and neurologic deficits after reperfusion from asphyxial cardiac arrest in rats. Methods: Rats were prospectively randomized to either a control (n=45), low-dose Carbicarb (LDC; 3 mL/kg, n=45), or high-dose Carbicarb (HDC; 6 mL/kg, n=45) group in a blinded fashion during resuscitation after 8 minutes of asphyxial cardiac arrest. Microdialysis was used to assess brain pH and glutamate. A neurologic deficit score and neuronal cell death in the hippocampus were determined at day 7. Results: Resuscitation was greatest in LDC rats (42/45) and least in HDC rats (28/45) versus that in control rats (34/45). Brain pH was higher in the LDC and HDC rats 10 minutes after resuscitation and remained higher than that of control rats for 120 minutes after resuscitation. Glutamate levels at 10 to 120 minutes after reperfusion were lowest in the LDC rats. LDC rats had the lowest neurologic deficit score (1±2) versus that of control rats (13±8) and HDC rats (19±6). Hippocampal neuronal cell death was lowest in LDC rats (30±20) versus that in control rats (86±47) and HDC rats (233±85). Conclusion: LDC administered during resuscitation from asphyxial cardiac arrest attenuated acidosis, improved resuscitation, and reduced neurologic deficits and the number of dead hippocampal neurons. Neutralization of cerebral acidosis with HDC increased the number of dead hippocampal neurons and neurologic deficits after resuscitation from cardiac arrest in rats. [Katz LM, Wang Y, Rockoff S, Bouldin TW. Low-dose Carbicarb improves cerebral outcome after asphyxial cardiac arrest in rats. Ann Emerg Med. April 2002;39:359-365.]

OBJECTIVE To determine whether the neurotensin analog NT69L, administered systemically, could induce mild brain hypothermia after asphyxial cardiac arrest (ACA) in rats. METHODS The study design was experimental, blinded, randomized, and approved by the animal use committee. All rats had continuous monitoring of brain temperature and sustained 8 minutes of ACA, resuscitation, and either saline or NT69L intravenously after return of spontaneous circulation (ROSC). Rats surviving 14 days after ACA had a neurological deficit score (NDS) and a Morris Water Maze (MWM) test. RESULTS Seven of eight rats in each group survived 14 days. Brain temperature was less than 35 degrees C 13.1 +/- 3 minutes (mean +/- standard deviation) after NT69L vs controls that remained 37.5 degrees C at the same ambient temperature (p < 0.05 ANOVA). The NT69L group remained below 35 degrees C for 300 +/- 100 minutes while the controls remained at 37.5 +/- 0.5 degrees C. The NDS in the NT69L rats was 3 +/- 3% vs controls 26 +/- 8% (p < 0.05, Kruskal-Wallis, 0% = normal, 100% = brain dead). The NT69L rats performed better on the MWM vs the controls (22 +/- 8 sec vs 45 +/- 26 sec, respectively, p < 0.05 ANOVA). CONCLUSIONS NT69L induced rapid and prolonged mild brain hypothermia after ACA in this rat model and reduced neurological deficits.

Recovery of normal brain energetic conditions during and after resuscitation from cardiac arrest is critical for survival and good neurologic outcome. This review emphasizes the glucose-driven metabolic processes during and after ischemia and on the post-resuscitation development of secondary energy derangements. It also explores some potential therapeutic interventions designed to attenuate these energy derangements. The article summarizes some bench research and is not intended to provide treatment strategies for clinical application.

Over the past four decades, closed-chest cardiopulmonary resuscitation (CPR) and advanced cardiac life support (ACLS) interventions have saved many lives, but overall survival after cardiac arrest remains quite low, with survival rates of less than 5% reported in most studies. 3,15 The poor survival rates can be attributed to one or more of the following factors: (1) use of aggressive resuscitative measures in patients with end-stage disease processes for whom even optimal resuscitative efforts are unlikely to prove successful, (2) delays in initiation of effective therapies within the critical therapeutic window, and (3) ineffective or suboptimal therapeutic interventions. The first factor is complex and involves clinical judgment, advanced directives, medicolegal concerns, and societal expectations that are beyond the scope of this article. The second factor is primarily a problem for out-of-hospital victims and for nonmonitored in-hospital patients. The third factor is an ongoing challenge for the resuscitation research community. Resuscitative interventions can be classified as electrical therapy, artificial ventilation, artificial perfusion, or pharmacologic therapies. Although advances continue to be made in the areas of electrical therapy and artificial ventilation, presently available interventions are highly effective if they can be initiated in a timely manner. Thus, electrical therapy and artificial ventilation are usually not the limiting factors in a resuscitation. Pharmacologic agents given during cardiac arrest are primarily directed toward reversing the adverse effects of tissue hypoperfusion. The principal therapeutic effect of vasoconstrictor agents, traditionally epinephrine, is to restore peripheral arterial resistance to improve blood flow generated by closed-chest CPR. 29,38 The contributions of adrenergic agents and other drugs to improving survival from cardiac arrest have not been clearly demonstrated. Artificial perfusion is the principal weak link in the resuscitation armamentarium. Closed-chest CPR has been shown to generate blood flow equivalent to about 25% to 33% of normal cardiac output under optimal conditions. 4,13 If there is any time delay before the initiation of CPR, as commonly occurs, the progressive loss of peripheral arterial resistance substantially decreases the blood flow generated by CPR, even if performed well technically. 25 Thus, one of the greatest challenges in the development of better resuscitative interventions is to develop more effective methods of artificial perfusion support that can be initiated within the criticial time window allowing for return of spontaneous circulation (ROSC) with good neurologic recovery. Therefore, interventions to improve vital organ perfusion during cardiac arrest are the major focus of this article. Although significant underlying disease is prevalent in the general population of patients suffering cardiac arrest, this is especially true for patients in the intensive care unit setting. Myocardial dysfunction, pulmonary disease, metabolic disturbances, and sepsis only serve to complicate the task of the intensivist who is attempting to resuscitate patients in cardiac arrest. The monitoring sophistication of the ICU provides for early recognition of lethal dysrhythmias or other acute cardiovascular decompensation events. Also, patients in the ICU frequently have monitoring parameters available that can be used to guide the resuscitation. These parameters include arterial pressure, central venous pressure, central venous oximetry, and end-tidal carbon dioxide. This article discusses how these parameters can be used to optimize CPR techniques and to assess the effect of pharmacologic agents administered.

In the setting of rapidly exsanguinating hemorrhage, resuscitation with intravenous (i.v.) crystalloid solution may not sustain survival before availability of allogenic blood transfusion and surgery. This study tested the hypothesis that bovine hemoglobin-based oxygen carrier, HBOC-201, would improve resuscitation and extend early survival from exsanguinating hemorrhage. This study simulated the prehospital scenario of rapidly exsanguinating hemorrhage with prolonged prehospital time and lack of blood availability. Severe hemorrhagic shock was induced in swine by using multiple liver lacerations. At 9 min after the onset of bleeding, swine were randomized to receive approximately 10 mL/kg/min of i.v. lactated Ringer's solution (n = 10) or HBOC-201 (n = 7) to achieve a mean aortic pressure (MAP) of 60 mmHg. Thereafter, infusion rate was adjusted to maintain MAP at 60 mmHg for up to 2 h. All animals were initially successfully resuscitated. The results showed 2-h survival was 1 of 10 with lactated Ringer's and 7 of 7 with HBOC-201 (P = 0.0004). Nine lactated Ringer's swine had cardiovascular collapse at 36 +/- 10 min. Lactate at 30 min was 18 +/- 3 mmol/L with lactated Ringer's and 12 +/- 2 mmol/L with HBOC-201 (P < 0.05). Hematocrit was

The incidence and distribution of ischemic (necrotic) neurons in the brains of rats 72 hr after hypoxic ischemia induced via asphyxiation is described and scored. Anesthetized Sprague-Dawley rats (10/group) were endotracheally intubated and had their airways occluded for 6, 8, or 10 min, which resulted, respectively, in approximately 3, 5, or 7 min of pulselessness (MABP < 10 mm Hg). Survival was 10/10, 9/10, and 6/10 in the 6-, 8-, and 10-min groups: deaths occurred within 1 hr after resuscitation. At 72 hr, rats were reanesthetized and their brains were perfusion-fixed with 3% buffered paraformaldehyde. Paraffin-embedded, 5-μm-thick, H&E-stained sections at 5 coronal levels of the brain had shrunken, hypereosinophilic ischemic neurons in 12 anatomic regions. Ischemic neurons were most consistently found in the lateral reticular thalamic nucleus; lateral caudoputamen; CA1 region of the hippocampus; subiculum; and, with longer asphyxia times, among cerebellar Purkinje neurons. Categorical histologic damage scores were assigned to affected regions on the basis of manual counts of ischemic neurons and summed for the whole brain. Brain histologic damage scores were significantly (p < 0.01) different for the 6-, 8-, and 10-min groups (means of 8 ± 2; 14 ± 4; and 22 ± 4). Brain regions where both the number of rats affected and ranked categorical scores for ischemic neurons increased with asphyxia time were the lateral caudoputamen and cerebellar Purkinje neurons.

Although high-dose epinephrine during CPR improves coronary perfusion pressure (CoPP) and rate of return of spontaneous circulation (ROSC) in some models, its impact on long term outcome (> or = 72 h) has not been evaluated. Previous studies of sodium bicarbonate (NaHCO3) therapy during CPR indicate that beneficial effects may be dependent on epinephrine (EPI) dose. We hypothesized that EPI and NaHCO3 given during CPR have a significant impact on long term outcome. One hundred male Sprague-Dawley rats were prospectively studied in a block randomized placebo controlled trial. Rats were anesthetized, paralyzed, mechanically ventilated, instrumented, and each underwent 10 min of asphyxia, resulting in 6.8 +/- 0.4 min of circulatory arrest. Resuscitation was performed by mechanical ventilation and manual external chest compressions. EPI 0.0 (placebo), 0.01, 0.1, or 1.0 mg/kg IV was given at the onset of CPR, followed by NaHCO3 0.0 (placebo) or 1.0 mEq/kg IV. Successfully resuscitated rats were monitored and ventilated for 1 h without hemodynamic support. Neurologic deficit scores (NDS), cerebral histopathologic damage scores (CHDS) and myocardial histopathologic damage scores (MHDS) were determined in rats that survived 72 h. EPI improved CoPP and ROSC in a dose-dependent manner up to 0.1 mg/kg. Rats receiving EPI 0.1 and 1.0 mg/kg during CPR exhibited prolonged post-ROSC hypertension and metabolic acidemia, increased A-a O2 gradient, and an increased incidence of post-ROSC ventricular tachycardia or fibrillation. Overall survival was lower with EPI 0.1 and 1.0 mg/kg compared to 0.01 mg/kg. Although NDS was significantly less with EPI 0.1 mg/kg compared to placebo, there was no difference in CHDS between groups. In contrast, MDS was significantly higher with EPI 0.1 mg/kg compared to placebo or EPI 0.01 mg/kg. There was an overall trend toward improved survival at 72 h in rats that received NaHCO3 which was most evident in the EPI 0.1 mg/kg group. We conclude that (1) EPI during CPR has a biphasic dose/response curve in terms of survival, when post-resuscitation effects are left untreated and (2) NaHCO3 doses greater than 1.0 mEq/kg may be necessary to treat the side-effects of high-dose EPI. Further work is needed to determine if treating the immediate post-resuscitation effects of high-dose EPI can prevent detrimental effects on long-term outcome.

Item does not contain fulltext Drowning is a leading cause of accidental death. Survivors may sustain severe neurologic morbidity. There is negligible research specific to brain injury in drowning making current clinical management non-specific to this disorder. This review represents an evidence-based consensus effort to provide recommendations for management and investigation of the drowning victim. Epidemiology, brain-oriented prehospital and intensive care, therapeutic hypothermia, neuroimaging/monitoring, biomarkers, and neuroresuscitative pharmacology are addressed. When cardiac arrest is present, chest compressions with rescue breathing are recommended due to the asphyxial insult. In the comatose patient with restoration of spontaneous circulation, hypoxemia and hyperoxemia should be avoided, hyperthermia treated, and induced hypothermia (32-34 degrees C) considered. Arterial hypotension/hypertension should be recognized and treated. Prevent hypoglycemia and treat hyperglycemia. Treat clinical seizures and consider treating non-convulsive status epilepticus. Serial neurologic examinations should be provided. Brain imaging and serial biomarker measurement may aid prognostication. Continuous electroencephalography and N20 somatosensory evoked potential monitoring may be considered. Serial biomarker measurement (e.g., neuron specific enolase) may aid prognostication. There is insufficient evidence to recommend use of any specific brain-oriented neuroresuscitative pharmacologic therapy other than that required to restore and maintain normal physiology. Following initial stabilization, victims should be transferred to centers with expertise in age-specific post-resuscitation neurocritical care. Care should be documented, reviewed, and quality improvement assessment performed. Preclinical research should focus on models of asphyxial cardiac arrest. Clinical research should focus on improved cardiopulmonary resuscitation, re-oxygenation/reperfusion strategies, therapeutic hypothermia, neuroprotection, neurorehabilitation, and consideration of drowning in advances made in treatment of other central nervous system disorders.

OBJECTIVE Early compartment syndrome is difficult to diagnose, and a delay in the diagnosis can result in amputation or death. Our objective was to explore the potential of infrared imaging, a portable and noninvasive technology, for detecting compartment syndrome in the legs of patients with multiple trauma. We hypothesized that development of compartment syndrome is associated with a reduction in surface temperature in the involved leg and that the temperature reduction can be detected by infrared imaging. DESIGN Observational clinical study. SETTING Level I trauma center between July 2006 and July 2007. PATIENTS Trauma patients presenting to the emergency department. INTERVENTIONS Average temperature of the anterior surface of the proximal and distal region of each leg was measured in the emergency department with a radiometrically calibrated, 320 x 240, uncooled microbolometer infrared camera. MEASUREMENTS AND MAIN RESULTS The difference in surface temperature between the thigh and foot regions (thigh-foot index) of the legs in trauma patients was determined by investigators blinded to injury pattern using thermographic image analysis software. The diagnosis of compartment syndrome was made intraoperatively. Thermographic images from 164 patients were analyzed. Eleven patients developed compartment syndrome, and four of those patients had bilateral compartment syndrome. Legs that developed compartment syndrome had a greater difference in proximal vs. distal surface temperature (8.80 +/- 2.05 degrees C) vs. legs without compartment syndrome (1.22 +/- 0.88 degrees C) (analysis of variance p < .01). Patients who developed unilateral compartment syndrome had a greater proximal vs. distal temperature difference in the leg with (8.57 +/- 2.37 degrees C) vs. the contralateral leg without (1.80 +/- 1.60 degrees C) development of compartment syndrome (analysis of variance p < .01). CONCLUSIONS Infrared imaging detected a difference in surface temperature between the proximal and distal leg of patients who developed compartment syndrome. This technology holds promise as a supportive tool for the early detection of acute compartment syndrome in trauma patients.

Regulated hypothermia produces a decrease in core temperature by lowering the brain's temperature set-point while maintaining thermoregulation at that lower set point. In contrast, forced hypothermia lowers core temperature by overwhelming the body's capacity to thermoregulate, but does not change the set-point. Regulated hypothermia has been shown to be cerebral protective in hibernating mammals. The effect of regulated hypothermia on the brain during reperfusion from hypoxic-ischemia has not been well studied. We induced regulated hypothermia with a neurotensin analogue (NT77) to determine whether it could reduce oxidative stress in the brain during reperfusion from asphyxial cardiac arrest (ACA) in rats. Mild hypothermia (32–34 °C) was induced by brief (4 h) external cooling (BC), NT77 or prolonged external cooling (24 h) (PC) 30 min after resuscitation from 8 min of ACA in rats. Malondialdehyde (MDA) levels in the brain were measured during reperfusion to quantitate oxidative stress. Results: MDA levels in the hippocampus were elevated at 16 h of normothermic reperfusion versus 48 h with BC reperfusion. There was no increase in hippocampal MDA levels in the NT77 and PC groups at 24–72 h of reperfusion. Regulated hypothermia induced by NT77 reduced oxidative stress in the hippocampus during reperfusion from hypoxic-ischemia in comparison to forced brief external cooling of the same duration. In addition, the duration of external cooling after resuscitation also alters oxidative stress in the brain during reperfusion.

External cooling is commonly used to force induction of mild hypothermia but requires equipment, has a slow onset of action, and must be prolonged to provide permanent neurologic benefits after hypoxic-ischemia. It is unknown whether the method for inducing mild hypothermia affects neurologic outcome after near-drowning. The objective of the study was to induce mild hypothermia with neurotensin analog NT77 or external cooling in a rat model of near-drowning. We hypothesize that NT77 would be more effective for improving neurologic outcome than external cooling of the same duration.Rats were randomized to a normothermic control, neurotensin-induced hypothermia, brief external cooling, or prolonged external cooling group after asphyxial cardiac arrest.Laboratory investigation.Forty-eight rats.Mild hypothermia was induced by external cooling for 4 hrs (brief external cooling) or 24 hrs (prolonged external cooling) or by neurotensin-induced hypothermia administration 30 mins after asphyxial cardiac arrest in rats.Outcome was assessed by a neurologic deficit score, the Morris water maze, and CA1 hippocampus histology 15 days after resuscitation.Neurologic deficit score at 72 hrs after asphyxial cardiac arrest was lower with neurotensin-induced hypothermia (score, 0) and prolonged external cooling (score, 0) vs. normothermic control (score, 20) and brief external cooling (score, 18; p.05). Latency time in the Morris water maze 15 days after asphyxial cardiac arrest was decreased with neurotensin-induced hypothermia (14+/-11 secs) and prolonged external cooling (18+/-9 secs) vs. normothermic control (74+/-17 secs) and brief external cooling (78+/-18 secs, p.05). There was less ischemic neuronal damage with neurotensin-induced hypothermia (28+/-24%) and prolonged external cooling (21+/-14%) vs. normothermic control (61+/-32%) and brief external cooling (51+/-32%).Neurotensin-induced hypothermia improved neurologic outcome after asphyxial cardiac arrest in rats vs. brief external cooling but was comparable to prolonged external cooling.

Blunt abdominal trauma that leads to hemorrhagic shock and cardiac arrest is almost always fatal in the prehospital setting. The current study investigated whether a hemoglobin-based oxygen carrier (HBOC-201) could maintain organ viability during an exsanguinating liver injury and allow for prolonged survival. This hypothesis was tested in a large animal model that simulated blunt abdominal trauma with major organ injury.Swine underwent a liver crush, laceration and 50 ml/kg initial blood loss. The liver bled at 3 ml/kg per min during the resuscitation phase. No fluid (NF=6), hetastarch (HES=8), or HBOC-201 (HBOC=8) was given during the resuscitation phase. Swine alive 60 min after the initial injury underwent liver repair and 96 h observation.All HBOC swine survived 60 min versus none of the NF or HES swine (P0.05). All HBOC swine survived 24 h and 7/8 survived 96 h with good functional recovery.HBOC resuscitation during liver bleeding in a swine model of hemorrhagic shock and liver injury allowed for 96 h survival. No fluid or HES in the same model was fatal.

Hypothermia during brain ischemia can improve neurological outcome. This study tested whether local cranial cooling during the low-flow state of cardiopulmonary resuscitation (CPR) could produce clinically significant cerebral cooling. Ice was applied to the heads and necks of subjects (hypothermia group) with out-of-hospital cardiac arrest (OOHCA) during CPR. Nasopharyngeal and tympanic temperatures were measured as surrogates for cerebral temperature. The rate of cranial cooling in the hypothermia group (-0.06 +/- 0.06 degrees C/min) was not significantly increased compared with a control group without ice (-0.04 +/- 0.07 degrees C/min), although older age was associated with more rapid cranial cooling. Of note, many subjects with OOHCA are already mildly hypothermic (mean cranial temperature= 35.0 +/- 1.2 degrees C) when they are first encountered in the field. This study suggests that brief cranial cooling is ineffective for rapidly lowering brain temperature. However, most cardiac arrest victims are spontaneously mildly hypothermic and preventing rewarming may provide some of the desired benefits of cerebral hypothermia.

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.

Apneic asphyxia to cardiac arrest (CA) in rats of 10 min was reversed by cardiopulmonary resuscitation (CPR), and after controlled ventilation and controlled normotension for 20 min, was followed by decapitation and brain freezing, and determination of brain concentrations of cytosolic and lysosomal enzymes. Normal values came from a control group of 10 rats without CA. In 20 rats with CA brain cytosolic enzymes CK, LD, and ASAT decreased postarrest, while lysosomal enzyme changes were variable (Table D. Brain lactate increased 8–10-fold post-CA. To test the model, effect of methylprednisolone (MP) was studied. The 20 rats with CA were divided into 4 groups: Group I, received placebo pre-CA; Group II, MP 30 mg/kg i.v. pre-CA; Group III, placebo post-CA; and Group IV, MP post-CA. The post-CA MP Group IV was the only one without norepinephrine requirement and with return of EEG activity at 20 min. Brain CK, LD, and ASAT losses post-CA were not different between groups; and showed no differences between MP groups II and IV vs. placebo Groups I and III. When comparing both pre-CA Groups (I and II) with both post-CA Groups (III and IV), post-CA CK and ASAT levels were the same, but LD was higher in the post-CA treatment group. The lysosomal enzymes acid phosphatase, mannosidase, β-glucuronidase and hexosamidase showed variable concentration changes post-CA in the four groups, with a trend toward a lesser increase of some after MP or after post-treatment. Brain enzyme changes in our asphyxial CA rat model can serve as markers of brain damage. MP post-CA might enhance cardiovascular and EEG recovery, but does not seem to influence brain enzyme levels at 20 min post-CA.