Neurological recovery after cardiac arrest: clinical feasibility trial of calcium blockers

In order to determine whether the calcium blockers verapamil and/or magnesium sulfate decrease neurological morbidity after cardiac arrest, all out-of-hospital cardiac arrests (290) occurring during a nine-month period in five participating hospitals were retrospectively studied. Twenty-nine patients met the criteria for inclusion in this study. Each had an unwitnessed, out-of-hospital cardiac arrest and was comatose (no purposeful response to pain) 20 minutes after the restoration of spontaneous circulation (ROSC). Eighteen patients (calcium blocker group) received verapamil and/or magnesium sulfate at some point after ROSC, while eleven patients received standard ACLS therapy (control group). Age, arrest time, cardiopulmonary resuscitation (CPR) time, and cerebral ischemic time were comparable in the two groups. In the calcium blocker group, seven of 18 patients regained consciousness, and six of these seven survived. All six survivors appeared neurologically normal upon discharge and at three and six months of follow-up. While no demonstrably adverse effects were seen after the administration of magnesium sulfate, 56% of the patients who received verapamil had a significant drop in blood pressure. In the control group, three of 11 patients regained consciousness and two of the three left the hospital alive. Both survivors were disabled--one severely and one moderately. Follow-up after three and six months revealed no significant improvement in their disability. Overall, six of 18 patients experienced clinically complete neurological recovery in the calcium blocker group, while none of the 11 patients in the control group made a complete neurological recovery (P = 0.06).     

Emergency preservation and resuscitation improve survival after 15 minutes of normovolemic cardiac arrest in pigs

OBJECTIVE: Outcome after prolonged normovolemic cardiac arrest is poor, and new resuscitation strategies have to be found. We hypothesized that the induction of deep hypothermia for emergency preservation and resuscitation (EPR) during prolonged cardiac arrest, before the start of reperfusion, will mitigate the deleterious cascades leading to neuronal death and will thus improve outcome. DESIGN: Prospective experimental study. SETTING: University research laboratory. SUBJECTS: Thirteen pigs, Large White breed (27-37 kg). INTERVENTIONS: After 15 mins of ventricular fibrillation, pigs were subjected to 1) EPR (n = 6), 20 mins of hypothermic stasis induced with a cold saline aortic flush; or 2) 20 mins of conventional resuscitation (n = 7). Then cardiopulmonary bypass was initiated in both groups, followed by defibrillation. Controlled ventilation and mild hypothermia were continued for 20 hrs; survival was for 9 days. For neurologic evaluation, neurologic deficit score (100% = brain dead, 0-10% = normal), overall performance category (1 = normal, 5 = dead or brain dead), and brain histologic damage score were used. MEASUREMENTS AND MAIN RESULTS: In the EPR group, brain temperature decreased from 38.5 degrees C +/- 0.2 degrees C to 16.7 degrees C +/- 2.5 degrees C within 235 +/- 27 secs. Five animals achieved restoration of spontaneous circulation and survived to 9 days: two pigs with overall performance category 2 and three pigs with overall performance category 3. Their neurologic deficit score was 45% (interquartile range 35, 50) and histologic damage score was 142 (interquartile range 109, 159). In the control group, four pigs achieved restoration of spontaneous circulation: one survived to 9 days with overall performance category 3, neurologic deficit score 45%, and histologic damage score 226 (restoration of spontaneous circulation, p = .6; survival, p = .03; overall performance category, p = .02). CONCLUSIONS: EPR is feasible in an experimental pig model and improves survival after prolonged cardiac arrest in pigs. Further experimental studies are needed before this concept can be brought into clinical practice.     

Neurological recovery by EEG bursting after resuscitation from cardiac arrest in rats

INTRODUCTION: The return of neurological function during the early period after resuscitation from cardiac arrest (CA) has not been evaluated systematically. We report the temporal analysis of EEG bursting pattern during the very early periods after resuscitation. DESIGN/METHOD: A balanced group of good and poor outcome animals was selected from a population of rats subjected to either 5 or 7 min of asphyxial cardiac arrest (ACA) on the basis of a single criteria: 24 h neurobehavioral function based on the neurodeficit score (NDS). The EEGs of six consecutive good outcome rats (NDS > or = 60) and six consecutive poor outcome rats (NDS < 60) were selected for the study. The EEGs of these animals were given to two EEG examiners who were blinded to the selection process, the experimental conditions and the neurobehavioral recovery. The EEG bursting characteristics, such as rate, peak and duration of bursting were studied. RESULTS: There was significantly higher EEG bursting in the good outcome animals (P < 0.05) and the burst complexes evolved into continuous activity by 90 min. Lower frequency bursting that persisted and failed to evolve into continuous activity was observed in the poor outcome group. CONCLUSION: Increased EEG bursting during first 30-40 min after resuscitation from moderate to severe ACA was observed in rats with good neurological outcome at 24 h. Early EEG bursting patterns may provide additional prognostication after resuscitation from CA.     

Asphyxia,cardiac arrest and resuscitation in rats. I. Short term recovery

This study was conducted to investigate the degree of insult from asphyxia leading to total body circulatory arrest, as a model for brain resuscitation studies in rats.Of 78 male rats, 68 were anesthetized with halothane in $\text{0}{}_2\text{N}{}_2\text{0}$, controlled ventilated, paralyzed with pancuronium and asphyxiated, 5, 7.5, 10, 12.5 and 15 min, respectively. Asphyxiation led to circulatory arrest in 244 ± 22 s (mean ± S.E.M.). Resuscitation was successful in 65% within 60 s using controlled ventilation with 100% 02, extrathoracic compressions and epinephrine intravenously. Subsequent intensive care to 6, 12 or 24 h was successful in 50% of resuscitated rats.At 6, 12 and 24 h of recovery, neurologic deficit scores and light microscopic neuropathology scores of the brain after in vivo fixation of the total body with intraventricular paraformaldehyde 3%, revealed a large scatter variability without a clear pattern. Lesions were located mostly in the frontal cortex and hippocampus (footplate) with ischemic neuronal change as the most frequent structural change. Brain cell necrosis was not seen after successful resuscitation. It seems that both scores were influenced by postinsult stress, as indicated by paroxysmal hypertension and motor activity, by complications, such as obstruction of the tracheotomy cannula by abundant sputum production, and by partial sedation with N₂O and paralysis with pancuronium.This study indicates the feasibility of an asphyxial insult in rats for use in resuscitation studies of short duration. Although 24 h post-insult recovery is possible, up to 6 h seems most practical, with asphyxia of 7.5–10 min most successful and controllable. Questions are raised about the effects of irritation during the post-insult intensive care on both neurological deficit and neuropathology scores.     

Erythropoietin improved initial resuscitation and increased survival after cardiac arrest in rats

Introduction

Recent data have demonstrated potent cardioprotective and neuroprotective effects of the application of growth hormones like erythropoietin (EPO) after focal cardiac or cerebral ischemia. In order to assess possible benefits regarding survival and resuscitation conditions, EPO was tested against placebo in a model of cardiac arrest in the rat.

Methods

Thirty-four male Wistar rats were randomized into two groups (EPO versus control; n = 17 per group). Under anesthesia, cardiac arrest was induced by asphyxia after neuromuscular blockade. After 6 min of global ischemia, animals were resuscitated by external chest compression combined with epinephrine administration. An intravenous bolus of recombinant human EPO (rhEPO, 3000 UI kg⁻¹ body weight, i.v.) or saline (in control group) was performed 15 min before cardiac arrest, by a blinded investigator. Restoration of spontaneous circulation (ROSC), survival at 1, 24, 48 and 72 h and hemodynamic changes after cardiac arrest were studied.

Results

Survival to 72 h was significantly improved in the EPO group (n = 15/17) compared to the control group (n = 7/17). All the EPO-treated rats were successfully resuscitated whereas only 13 of 17 control animals resuscitated. EPO-treated animals required a significantly smaller dose of epinephrine before resuscitation, compared to control rats. Time course of systolic arterial blood pressure after resuscitation revealed no significant differences between both groups.

Conclusion

EPO, when administrated before cardiac arrest, improved initial resuscitation and increased the duration of post-resuscitation survival.     

Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial

Purpose

We aimed to determine the feasibility of targeting low-normal or high-normal mean arterial pressure (MAP) after out-of-hospital cardiac arrest (OHCA) and its effect on markers of neurological injury.

Methods

In the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial, we used a 2³ factorial design to randomly assign patients after OHCA and resuscitation to low-normal or high-normal levels of arterial carbon dioxide tension, to normoxia or moderate hyperoxia, and to low-normal or high-normal MAP. In this paper we report the results of the low-normal (65–75 mmHg) vs. high-normal (80–100 mmHg) MAP comparison. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest. The feasibility outcome was the difference in MAP between the groups. Secondary outcomes included S100B protein and cardiac troponin (TnT) concentrations, electroencephalography (EEG) findings, cerebral oxygenation and neurological outcome at 6 months after cardiac arrest.

Results

We recruited 123 patients and included 120 in the final analysis. We found a clear separation in MAP between the groups (p?<?0.001). The median (interquartile range) NSE concentration at 48 h was 20.6 µg/L (15.2–34.9 µg/L) in the low-normal MAP group and 22.0 µg/L (13.6–30.9 µg/L) in the high-normal MAP group, p?=?0.522. We found no differences in the secondary outcomes.

Conclusions

Targeting a specific range of MAP was feasible during post-resuscitation intensive care. However, the blood pressure level did not affect the NSE concentration at 48 h after cardiac arrest, nor any secondary outcomes.

     

Treatment with an endothelin type A receptor-antagonist after cardiac arrest and resuscitation improves cerebral hemodynamic and functional recovery in rats

OBJECTIVE: Successful resuscitation of the brain after cardiac arrest requires unimpaired microcirculatory reperfusion. Postischemic cerebral hypoperfusion presumably is mediated through activation of endothelin type A receptors (ET(A)). The effect of the selective ET(A) antagonist BQ123 on cerebral blood flow and function was studied in a rat model of cardiac arrest. DESIGN: Prospective, randomized trial. SETTING: Experimental animal laboratory. SUBJECTS: Twelve male Sprague-Dawley rats (290-350 g). INTERVENTIONS: Cardiac arrest for 12 mins was induced by electrical fibrillation of the heart, followed by standardized cardiopulmonary resuscitation. BQ123 (0.8 mg/kg; n = 6) or its vehicle (saline; n = 6) was injected intravenously at 15 mins after the return of spontaneous circulation. MEASUREMENTS: Cortical blood flow was measured by laser-Doppler flowmetry, electrophysiological function by recording the amplitude of somatosensory evoked potentials, vascular reactivity by ventilation with 6% CO2, and the functional coupling of blood flow by recording the laser-Doppler flow (LDF) changes during somatosensory stimulation. Hemodynamic and functional cerebral recovery was monitored for 3 hrs after the return of spontaneous circulation. MAIN RESULTS: Forty-five minutes after the return of spontaneous circulation, postischemic hypoperfusion developed in both groups, as reflected by a decrease of the LDF signal to about 60% of the preischemic level. In untreated animals, hypoperfusion persisted throughout the observation time, but in animals receiving BQ123, LDF gradually returned to normal. CO2 reactivity in untreated animals was severely reduced for 2-3 hrs after the onset of recirculation, whereas after BQ123 treatment it returned to normal and after 2 hrs even above normal. The ET(A) antagonist also induced a more rapid recovery of the somatosensory evoked potentials amplitude and of the functional blood flow response to somatosensory stimulation, but these parameters did not recover completely within the observation period. CONCLUSIONS: Application of the ET(A) antagonist BQ123 during the early reperfusion period after cardiac arrest shortens postischemic cerebral hypoperfusion and accelerates the restoration of the cerebrovascular CO2 reactivity and the recovery of electrophysiologic function.     

Accidental hypothermia with cardiac arrest: Complete recovery after prolonged resuscitation and rewarming by extracorporeal circulation

A 51-year-old male remained immersed in sea water (6°C) for 40 min. Brought ashore, the ECG showed asystole. Advanced life support was immediately commenced. On arrival in hospital his rectal temperature was 27°C, but continued to fall to 24°C. The ECG remained isoelectric. Cardiopulmonary resuscitation was continued until extracorporeal circulation was established 190 min after rescue. Upon rewarming ventricular fibrillation occurred which was converted to sinus rhythm with a bolus of lignocaine followed by D.C. conversion at 31.5°C. When rewarming was complete after 60 min, signs of severe heart failure became evident. Sternotomy and pericardiotomy were performed to exclude cardiac tamponade. After 60 min of re-perfusion the patient was be weaned from bypass supported by a high-dose vasopressor infusion and nitroglycerine. He was discharged after 13 days with no evidence of any permanent organ damage. Given the advantage of providing circulatory support, extracorporeal circulation may be useful when rewarming hypothermic victims with cardiac arrest.     

Adenosine during cardiac arrest and cardiopulmonary resuscitation: a placebo-controlled, randomized trial.

BACKGROUND AND HYPOTHESIS TESTED: The effects of adenosine (100 micrograms/kg/min; n = 7) were examined during rodent cardiopulmonary resuscitation (CPR). Change in coronary artery perfusion pressure, end-tidal PCO2, and arterial acid-base status of anesthetized, male, Sprague-Dawley rats were compared with CPR controls (0.9% sodium chloride; n = 7) and with sham controls (n = 9). Sustained ventricular fibrillation was induced and precordial chest compression was followed by defibrillation. RESULTS: After 6 mins of cardiac arrest, six (86%) of seven adenosine-treated animals were resuscitated after adenosine infusion and four (57%) of seven control animals were resuscitated after sodium chloride infusion. During chest compression, coronary artery perfusion pressure was 7 +/- 2 mm Hg after adenosine, but was 22 +/- 3 mm Hg in the controls (p less than .01). Parallel decreases were observed in mean aortic pressure. Arterial and end-tidal PCO2 significantly (p less than .01) decreased after adenosine. These changes contrasted with a second control group of nine identically prepared animals which, in the absence of ventricular fibrillation and subsequent chest compression, demonstrated no changes in hemodynamic, respiratory, or blood gas variables. CONCLUSIONS: Adenosine decreased coronary artery perfusion pressure. However, despite marked reductions in coronary artery perfusion pressure, survival was not compromised after adenosine infusion in this rodent model of CPR.     

Exsanguination cardiac arrest in rats treated by 60 min, but not 75 min, emergency preservation and delayed resuscitation is associated with intact outcome

Emergency preservation and resuscitation (EPR) is a new approach for resuscitation of exsanguination cardiac arrest (CA) victims to buy time for surgical hemostasis. EPR uses a cold aortic flush to induce deep hypothermic preservation, followed by resuscitation with cardiopulmonary bypass (CPB). We previously reported that 20 min of EPR was feasible with intact outcome. In this report, we tested the limits for EPR in rats. Adult male isoflurane-anesthetized rats were subjected to rapid hemorrhage (12.5 ml over 5 min), followed by esmolol/KCl-induced CA and 1 min of no-flow. EPR was then induced by perfusion with 270 ml of ice-cold Plasma-Lyte to decrease body temperature to 15 degrees C. After 60 min (n=7) or 75 min (n=7) of EPR, resuscitation was attempted with CPB over 60 min, blood transfusion, correction of acid-base balance and electrolyte disturbances, and mechanical ventilation for 2h. Survival, overall performance category (OPC: 1=normal, 5=death), neurological deficit score (NDS), and histological damage score (HDS) were assessed in survivors on day 3. While all rats after 60 min EPR survived, only two out of seven rats after 75 min EPR survived (p<0.05). All rats after 60 min EPR achieved OPC 1 and normal NDS by day 3. Survivors after 75 min EPR achieved best OPC 3 (p<0.05 vs. 60 min EPR). HDS of either brain or individual viscera was not statistically different after 60 versus 75 min EPR, except for kidneys (0+/-0 vs. 1.9+/-1.3, respectively; p<0.05), with a strong trend toward greater injury in all extracerebral organs in the 75-min EPR group (p<0.06). Histological findings were dominated by cardiac lesions observed in both groups and acute renal tubular and liver necrosis in the 75-min EPR group. In conclusion, we have shown that 60 min of EPR after exsanguination CA is associated with survival and favorable neurological outcome, while 75 min of EPR results in significant mortality and neurological damage in survivors. Surprisingly, extracerebral lesions predominated at 75-min EPR group. This model should serve as a screening model both for testing new pharmacological adjuncts to improve survival after exsanguination CA, and for elucidating the underlying mechanisms of ischemia/reperfusion injury.     

Endothelin type A-antagonist improves long-term neurological recovery after cardiac arrest in rats

OBJECTIVE: Antagonists of endothelin (ET(A)) receptors improve postischemic hypoperfusion. In this study we investigated whether the selective ET(A)-antagonist BQ123 also improves postischemic functional recovery. STUDY DESIGN: Cardiac arrest of 12 mins duration was induced in rats by electrical fibrillation of the heart, followed by advanced cardiopulmonary resuscitation. BQ123 (0.8 mg/kg; n = 9) or its vehicle (saline; n = 9) was injected intravenously at 15 mins after the return of spontaneous circulation. The neurologic deficit was scored daily for 7 days after resuscitation by rating consciousness, various sensory and motor functions, and coordination tests. On day 7, we measured functional coupling of cerebral blood flow under halothane anesthesia by recording laser-Doppler flow during electrical forepaw stimulation, and we measured vascular reactivity to CO2 by measuring the laser-Doppler flow change during ventilation with 6% CO2. The brains were perfusion-fixated with 4% paraformaldehyde, and the histopathologic damage was evaluated in the CA1 sector of hippocampus, in the motor cortex, and in the cerebellum. RESULTS: Treatment with BQ123 had no effect on histopathologic damage, but it significantly improved neurologic recovery. In all nine treated rats, neurologic performance returned to near normal within 2 days whereas four of nine untreated animals developed spastic paralysis of the hind limbs and severe coordination deficits. BQ123 also normalized CO2 reactivity and improved the functional cerebral blood flow response to somatosensory stimulation. CONCLUSIONS: The ET(A)-antagonist BQ123 significantly improves neurologic outcome after 12 mins of cardiac arrest. The apparent restoration of vascular reactivity demonstrates a correlation between hemodynamic factors and functional recovery.     

Myocardial injury in children following resuscitation after cardiac arrest

BACKGROUND: Myocardial dysfunction occurs immediately after successful cardiac resuscitation. Our purpose was to determine whether measurement of cardiac troponin I in children with acute out-of-hospital cardiac arrest predicts the severity of myocardial injury. METHODS AND RESULTS: This prospective, observational study was performed in the Pediatric Intensive Care Unit (PICU) on 24 patients following arrest, ranging in age from 8 months to 17 years. Troponin measurements were obtained on admission, and at 12, 24, and 48 h. Transthoracic echocardiograms were performed within 24 h after admission. Survival to hospital discharge was 29% (7/24). The mean age was 5.9+/-4.6 years for survivors and 4.2+/-5.3 years for non-survivors. The median (range) duration of cardiac arrest times for survivors was 6 min (3 to 63 min) versus 34 min (4 to 70 min) for nonsurvivors (P=0.02). Survivors received 1.3+/-2.2 doses of epinephrine (adrenaline) compared with 2.9+/-1.6 doses for non-survivors (P=0.02). Only one patient had ventricular fibrillation and defibrillation was unsuccessful. The ejection fraction for survivors averaged 73.2+/-11.2%, but for nonsurvivors only 55.4+/-19.8% (P=0.04). Ejection fraction correlated inversely with troponin at 12 h (r=-0.54, P=0.01) and at 24 h (r=-0.59, P=0.02). Circumferential fiber shortening for survivors was 37.5+/-7.8 and 25.5+/-10.7% for nonsurvivors (P=0.02). It also correlated inversely with troponin (r=-0.46, P=0.03 for survivors and r=-0.65, P=0.01, for nonsurvivors). CONCLUSION: After cardiac arrest and resuscitation in pediatric patients, the severity of myocardial dysfunction was reflected in troponin I levels.     

Cardiopulmonary resuscitation for cardiac arrest: the importance of uninterrupted chest compressions in cardiac arrest resuscitation

Over the last decade, the importance of delivering high-quality cardiopulmonary resuscitation (CPR) for cardiac arrest patients has become increasingly emphasized. Many experts are in agreement concerning the appropriate compression rate, depth, and amount of chest recoil necessary for high-quality CPR. In addition to these factors, there is a growing body of evidence supporting continuous or uninterrupted chest compressions as an equally important aspect of high-quality CPR. An innovative resuscitation protocol, called cardiocerebral resuscitation, emphasizes uninterrupted chest compressions and has been associated with superior rates of survival when compared with traditional CPR with standard advanced life support. Interruptions in chest compressions during CPR can negatively impact outcome in cardiac arrest; these interruptions occur for a range of reasons, including pulse determinations, cardiac rhythm analysis, electrical defibrillation, airway management, and vascular access. In addition to comparing cardiocerebral resuscitation to CPR, this review article also discusses possibilities to reduce interruptions in chest compressions without sacrificing the benefit of these interventions.     

Pyruvate improves cardiac electromechanical and metabolic recovery from cardiopulmonary arrest and resuscitation

Severe depletion of myocardial energy and antioxidant resources during cardiac arrest culminates in electromechanical dysfunction following recovery of spontaneous circulation (ROSC). A metabolic fuel and natural antioxidant, pyruvate augments myocardial energy and antioxidant redox states in parallel with its enhancement of contractile performance of stunned and oxidant-challenged hearts. This study tested whether pyruvate improves post-arrest cardiac function and metabolism. Beagles were subjected to 5 min cardiac arrest and 5 min open-chest cardiac compression (OCCC: 80 compressions min(-1); aortic pressure 60-70 mmHg), then epicardial dc countershocks (5-10 J) were applied to restore sinus rhythm. Pyruvate was infused i.v. throughout OCCC and the first 25 min ROSC to a steady-state arterial concentration of 3.6+/-0.2 mM. Control experiments received NaCl infusions. Phosphocreatine phosphorylation potential (approximately PCr) and glutathione/glutathione disulfide ratio (GSH/GSSG), measured in snap-frozen left ventricle, indexed energy and antioxidant redox states, respectively. In control experiments, left ventricular pressure development, dP/dt and carotid flow initially recovered upon defibrillation, but then fell 40-50% by 3 h ROSC. ST segment displacement in lead II ECG persisted throughout ROSC. Approximately PCr collapsed and GSH/GSSG fell 61% during arrest. Both variables recovered partially during OCCC and completely during ROSC. Pyruvate temporarily increased approximately PCr and GSH/GSSG during OCCC and the first 25 min ROSC and enhanced pressure development, dP/dt and carotid flow at 15-25 min ROSC. Contractile function stabilized and ECG normalized at 2-3 h ROSC, despite post-infusion pyruvate clearance and waning of its metabolic benefits. In conclusion, intravenous pyruvate therapy increases energy reserves and antioxidant defenses of resuscitated myocardium. These temporary metabolic improvements support post-arrest recovery of cardiac electromechanical performance.