Andreas Janata

Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms

AIM Mild therapeutic hypothermia (32-34°C) improves neurological recovery and reduces the risk of death in comatose survivors of cardiac arrest when the initial rhythm is ventricular fibrillation or pulseless ventricular tachycardia. The aim of the presented study was to investigate the effect of mild therapeutic hypothermia (32-34°C for 24h) on neurological outcome and mortality in patients who had been successfully resuscitated from non-ventricular fibrillation cardiac arrest. METHODS In this retrospective cohort study we included cardiac arrest survivors of 18 years of age or older suffering a witnessed out-of-hospital cardiac arrest with asystole or pulseless electric activity as the first documented rhythm. Data were collected from 1992 to 2009. Main outcome measures were neurological outcome within six month and mortality after six months. RESULTS Three hundred and seventy-four patients were analysed. Hypothermia was induced in 135 patients. Patients who were treated with mild therapeutic hypothermia were more likely to have good neurological outcomes in comparison to patients who were not treated with hypothermia with an odds ratio of 1.84 (95% confidence interval: 1.08-3.13). In addition, the rate of mortality was significantly lower in the hypothermia group (odds ratio: 0.56; 95% confidence interval: 0.34-0.93). CONCLUSION Treatment with mild therapeutic hypothermia at a temperature of 32-34°C for 24h is associated with improved neurological outcome and a reduced risk of death following out-of-hospital cardiac arrest with non-shockable rhythms.

Safety and feasibility of nasopharyngeal evaporative cooling in the emergency department setting in survivors of cardiac arrest

AIM Mild therapeutic hypothermia improves survival and neurologic recovery in primary comatose survivors of cardiac arrest. Cooling effectivity, safety and feasibility of nasopharyngeal cooling with the RhinoChill device (BeneChill Inc., San Diego, USA) were determined for induction of therapeutic hypothermia. METHODS Eleven emergency departments and intensive care units participated in this multi-centre, single-arm descriptive study. Eighty-four patients after successful resuscitation from cardiac arrest were cooled with nasopharyngeal delivery of an evaporative coolant for 1h. Subsequently, temperature was controlled with systemic cooling at 33 degrees C. Cooling rates, adverse events and neurologic outcome at hospital discharge using cerebral performance categories (CPC; CPC 1=normal to CPC 5=dead) were documented. Temperatures are presented as median and the range from the first to the third quartile. RESULTS Nasopharyngeal cooling for 1h reduced tympanic temperature by median 2.3 (1.6; 3.0) degrees C, core temperature by 1.1 (0.7; 1.5) degrees C. Nasal discoloration occurred during the procedure in 10 (12%) patients, resolved in 9, and was persistent in 1 (1%). Epistaxis was observed in 2 (2%) patients. Periorbital gas emphysema occurred in 1 (1%) patient and resolved spontaneously. Thirty-four of 84 patients (40%) patients survived, 26/34 with favorable neurological outcome (CPC of 1-2) at discharge. CONCLUSIONS Nasopharyngeal evaporative cooling used for 1h in primary cardiac arrest survivors is feasible and safe at flow rates of 40-50L/min in a hospital setting.

Hemostasis in cardiac arrest patients treated with mild hypothermia initiated by cold fluids

AIM OF THE STUDY Application of mild hypothermia (32-33 degrees C) has been shown to improve neurological outcome in patients with cardiac arrest. However, hypothermia affects hemostasis, and even mild hypothermia is associated with bleeding and increased transfusion requirements in surgery patients. On the other hand, crystalloid hemodilution has been shown to induce a hypercoagulable state. The study aim was to elucidate in which way the induction of mild therapeutic hypothermia by a bolus infusion of cold crystalloids affects the coagulation system of patients with cardiac arrest. METHODS This was a prospective pilot study in 18 patients with cardiac arrest and return of spontaneous circulation (ROSC). Mild hypothermia was initiated by a bolus infusion of cold 0.9% saline fluid (4 degrees C; 30ml/kg/30min) and maintained for 24h. At 0h (before hypothermia), 1, 6 and 24h we assessed coagulation parameters (PT, APPT), platelet count and performed thrombelastography (ROTEM) after in vitro addition of heparinase. RESULTS A total amount of 2528 (+/-528)ml of 0.9% saline fluid was given. Hematocrit (p<0.01) and platelet count (-27%; p<0.05) declined, whereas APTT increased (2.7-fold; p<0.01) during the observation period. All ROTEM parameters besides clotting time (CT) after 1h (-20%; p<0.05) did not significantly change. CONCLUSION Mild hypothermia only slightly prolonged clotting time as measured by rotation thrombelastography. Therefore, therapeutic hypothermia initiated by cold crystalloid fluids has only minor overall effects on coagulation in patients with cardiac arrest.

Hypothermia After Cardiac Arrest

Mild therapeutic hypothermia (32 degrees C-34 degrees C) is the only therapy that improved neurological outcome after cardiac arrest in a randomized, controlled trial. Induced hypothermia after successful resuscitation leads to one additional patient with intact neurological outcome for every 6 patients treated. It protects the brain after ischemia by reduction of brain metabolism, attenuation of reactive oxygen species formation, inhibition of excitatory amino acid release, attenuation of the immune response during reperfusion, and inhibition of apoptosis. Potential side effects such as infections have to be kept in mind and treated accordingly. Mild hypothermia is a safe and effective therapy after cardiac arrest, even in hemodynamically compromised patients and in patients undergoing percutaneous coronary intervention. Its use is recommended by the American Heart Association and the International Liaison Committee on Resuscitation for unconscious adult patients with spontaneous circulation after out-of-hospital ventricular fibrillation cardiac arrest. Further research is needed to maximize its potential benefits.

Factors associated with a change in functional outcome between one month and six months after cardiac arrest A retrospective cohort study

AIM OF THE STUDY The appropriate time point of evaluation of functional outcome in cardiac arrest survivors remains a matter of debate. In this cohort study we posed the hypothesis that there are no significant changes in Cerebral Performance Categories (CPC) between one month and six months after out-of hospital cardiac arrest. If changes were present we aimed to identify reasons for these changes. METHODS Based on a cardiac arrest registry, a potential change in CPC and mortality between one month and six months after cardiac arrest was analysed. Variables that were associated with these changes were identified. RESULTS Thirty percent of 681 patients showed a significant change in functional outcome and mortality between one month and six months after out-of hospital cardiac arrest, 12% improved in CPC, 1% deteriorated, 17% died. The only factor that was associated with an improvement in CPC in the multivariate analysis was time to restoration of spontaneous circulation (ROSC) (RRR 1.04, 95% CI 1.01-1.06, per minute). We could not find any significant factors associated with a deterioration of CPC. Factors that were associated with mortality were age (RRR 1.03, 95% CI 1.01-1.06) and ventricular fibrillation as initial cardiac rhythm (RRR 0.34, 95% CI 0.16-0.71). CONCLUSIONS There is a relevant change of functional outcome even one month after out-of hospital cardiac arrest. Especially when studies compare patient groups with unequal arrest times, and an unequal distribution of initial cardiac rhythms a follow-up period longer than one month should be considered for the final outcome evaluation after cardiac arrest.

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°C ± 0.2°C to 16.7°C ± 2.5°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.

Pronounced platelet hyperfunction in patients with cardiac arrest achieving restoration of spontaneous circulation

Objective:Markers of platelet activation are increased in patients undergoing cardiopulmonary resuscitation. Hyperfunctional platelets may contribute to impairment of microcirculatory function and overall poor outcome despite restoration of spontaneous circulation (ROSC). Patients with myocardial infarction have hyperfunctional platelets, which predict the degree of myocardial necrosis. Thus, we hypothesized that platelets may be even more activated in patients whose myocardial infarction leads to cardiac arrest and compared them with patients whose cardiac arrest was due to a noncardiac origin. Design:Prospective observational study. Setting:Emergency department of a tertiary care hospital. Patients:One hundred four patients with witnessed cardiac arrest who achieved ROSC. Interventions:Blood sampling. Measurements and Main Results:We assessed collagen adenosine diphosphate closure time with the platelet function analyzer-100, and measured plasma levels of von Willebrand factor: ristocetin cofactor activity levels by turbidometry. Independent physicians diagnosed the origin of cardiac arrest. The majority of cardiac arrests were caused by myocardial ischemia. Invariably, collagen adenosine diphosphate closure time values (55 seconds; 95% confidence interval: 52–58 seconds) were much shorter in these patients compared with patients with other causes of cardiac arrest (110 seconds; 95% confidence interval: 84–135 seconds, p < 0.001). von Willebrand factor: ristocetin cofactor activity plasma levels were more than three-fold above normal values in both groups. Conclusions:Patients with myocardial ischemia-triggered cardiac arrest had the highest degree of platelet hyperfunction under high shear rates, which was not solely due to increased von Willebrand factor. Future trials are necessary to clarify whether rapid, more aggressive antiplatelet therapy improves outcome after cardiac arrest.

Extracorporeal versus conventional cardiopulmonary resuscitation after ventricular fibrillation cardiac arrest in rats: a feasibility trial.

Objectives:Extracorporeal cardiopulmonary resuscitation with cardiopulmonary bypass potentially provides cerebral reperfusion, cardiovascular support, and temperature control for resuscitation from cardiac arrest. We hypothesized that extracorporeal cardiopulmonary resuscitation is feasible after ventricular fibrillation cardiac arrest in rats and improves outcome versus conventional cardiopulmonary resuscitation. Design:Prospective randomized study. Setting:University laboratory. Subjects:Adult male Sprague-Dawley rats. Interventions:Rats (intubated, instrumented with arterial and venous catheters and cardiopulmonary bypass cannulae) were randomized to conventional cardiopulmonary resuscitation, extracorporeal cardiopulmonary resuscitation with/without therapeutic hypothermia, or sham groups. After 6 minutes of ventricular fibrillation cardiac arrest, resuscitation was performed with drugs (epinephrine, sodium bicarbonate, and heparin), ventilation, either cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation, and defibrillation. Temperature was maintained at 37.0°C or 33.0°C for 12 hours after restoration of spontaneous circulation. Neurologic deficit scores, overall performance category, histological damage scores (viable neuron counts in CA1 hippocampus at 14 days; % of sham), and microglia proliferation and activation (Iba-1 immunohistochemistry) were assessed. Measurements and Main Results:Extracorporeal cardiopulmonary resuscitation induced hypothermia more rapidly than surface cooling (p < 0.05), although heart rate was lowest in the extracorporeal cardiopulmonary resuscitation hypothermia group (p < 0.05). Survival, neurologic deficit scores, overall performance category, and surviving neurons in CA1 did not differ between groups. Hypothermia significantly reduced neuronal damage in subiculum and thalamus and increased the microglial response in CA1 at 14 days (all p < 0.05). There was no benefit from extracorporeal cardiopulmonary resuscitation versus cardiopulmonary resuscitation on damage in any brain region and no synergistic benefit from extracorporeal cardiopulmonary resuscitation with hypothermia. Conclusions:In a rat model of 6-minute ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation leads to survival with intact neurologic outcomes. Twelve hours of mild hypothermia attenuated neuronal death in subiculum and thalamus but not CA1 and, surprisingly, increased the microglial response. Resuscitation from ventricular fibrillation cardiac arrest and rigorous temperature control with extracorporeal cardiopulmonary resuscitation in a rat model is feasible, regionally neuroprotective, and alters neuroinflammation versus standard resuscitation. The use of experimental extracorporeal cardiopulmonary resuscitation should be explored using longer insult durations.

Cold aortic flush and chest compressions enable good neurologic outcome after 15 mins of ventricular fibrillation in cardiac arrest in pigs.

Objective:The induction of deep cerebral hypothermia via ice-cold saline aortic flush during prolonged ventricular fibrillation cardiac arrest, followed by hypothermic stasis and delayed resuscitation (emergency preservation and resuscitation), improved neurologic outcome after cardiac arrest in pigs, as compared to conventional resuscitation. We hypothesized that emergency preservation and resuscitation with chest compressions would further improve outcome in the same model. Design:Prospective experimental study. Setting:University research laboratory. Subjects:Twenty-four female, large, white breed pigs (27–37 kg). Interventions:Fifteen minutes of ventricular fibrillation cardiac arrest were followed by 20 mins of resuscitation with chest compressions (control, n = 8), deep cerebral hypothermia via 200 mL/kg 4°C saline aortic flush and hypothermic stasis (emergency preservation and resuscitation, n = 8), and emergency preservation and resuscitation combined with chest compressions (emergency preservation and resuscitation plus chest compressions, n = 8). At 35 mins after cardiac arrest, cardiopulmonary bypass was initiated, followed by defibrillation. Mild hypothermia was continued for 20 hrs. Pigs were evaluated after 9 days using a neurologic deficit (neurologic deficit score: 100% = brain dead; 0%–10% = normal) and an overall performance category score (overall performance category score: 1 = normal; 2 = slightly handicapped; 3 = severely handicapped; 4 = comatose; 5 = dead/brain dead). Measurements and Main Results:Brain temperature decreased from 38.5°C to 15.3°C ± 3.3°C in the emergency preservation and resuscitation group, and to 11.3°C ± 1.2°C in the emergency preservation and resuscitation plus chest compressions group. In the control group, restoration of spontaneous circulation was achieved in four out of eight pigs, and one survived to 9 days. In the emergency preservation and resuscitation group, restoration of spontaneous circulation was achieved in seven out of eight pigs and five survived; in the emergency preservation and resuscitation plus chest compressions group, all had restoration of spontaneous circulation and seven survived (restoration of spontaneous circulation, p = .08). Neurologic outcome for (median and interquartile range) the control group included overall performance category score of 3, neurologic deficit score of 45%; for the emergency preservation and resuscitation group, overall performance category score was 3 (2–5) and neurologic deficit score was 45% (36; 50) and in the emergency preservation and resuscitation plus chest compressions group, overall performance category score was 2 (1–3) and neurologic deficit score was 13% (5; 21) (overall performance category score, p = .04; neurologic deficit score emergency preservation and resuscitation vs. emergency preservation and resuscitation plus chest compressions, p = .003). Conclusions:Emergency preservation and resuscitation by deep cerebral hypothermia combined with chest compressions during prolonged cardiac arrest in pigs are feasible and improve neurologic outcome.

Surface Cooling for Rapid Induction of Mild Hypothermia After Cardiac Arrest: Design Determines Efficacy

OBJECTIVES Recently, a novel cooling pad was developed for rapid induction of mild hypothermia after cardiac arrest. The aim of this study was to evaluate the cooling efficacy of three different pad designs for in-hospital cooling. METHODS Included in this prospective interventional study were patients with esophageal temperature (Tes) > 34 degrees C on admission. The cooling pad consists of multiple cooling units, filled with a combination of graphite and water, which is precooled to -18 degrees C (design A) or to -9 degrees C (designs B and C) before use. The designs of the cooling pad differed in number, shape, and thickness of the cooling units, with weights of 9.7 kg (design A), 5.3 kg (design B), and 6.2 kg (design C). All three designs were tested in sequential order and were changed according to the results found in the previous trial. Cooling was started after admission until Tes = 34 degrees C, when the cooling pad was removed. The target temperature of Tes = 32-34 degrees C was maintained for 24 hours. Data are presented as medians and interquartile ranges (IQRs = 25%-75%) or proportions. RESULTS Cooling rates were 3.4 degrees C/hour (IQR = 2.5-3.7) with design A (n = 12), 2.8 degrees C/hour (IQR = 1.6-3.3) with design B (n = 7), and 2.9 degrees C/hour (IQR = 1.9-3.6) with design C (n = 10; p = 0.5). To reach 34 degrees C, the cooling pad had to be exchanged with a new one due to melting and therefore depleting cooling capacity in three patients with design A, in five patients with design B, and in no patient with design C (p = 0.004). CONCLUSIONS With adequate design and storage temperature, the cooling pad proved to be efficient for rapid in-hospital cooling of patients resuscitated from cardiac arrest.