Sodium Bicarbonate and Calcium Chloride for the Treatment of Hyperkalemia-Induced Cardiac Arrest: A Randomized, Blinded, Placebo-Controlled Animal Study.

OBJECTIVES: Current international guidelines recommend administrating calcium chloride and sodium bicarbonate to patients with hyperkalemia-induced cardiac arrest, despite limited evidence. The aim of this study was to evaluate the efficacy of calcium chloride and sodium bicarbonate on return of spontaneous circulation (ROSC) in a pig model of hyperkalemia-induced cardiac arrest. DESIGN: A randomized, blinded, placebo-controlled experimental pig study. Hyperkalemia was induced by continuous infusion of potassium chloride over 45 minutes followed by a bolus. After a no flow period of 7 minutes, pigs first received 2 minutes of basic cardiopulmonary resuscitation and subsequently advanced life support. The first intervention dose was administered after the fifth rhythm analysis, followed by a defibrillation attempt at the sixth rhythm analysis. A second dose of the intervention was administered after the seventh rhythm analysis if ROSC was not achieved. In case of successful resuscitation, pigs received intensive care for 1 hour before termination of the study. SETTING: University hospital laboratory. SUBJECTS: Fifty-four female Landrace/Yorkshire/Duroc pigs (38-42 kg). INTERVENTIONS: The study used a 2 × 2 factorial design, with calcium chloride (0.1 mmol/kg) and sodium bicarbonate (1 mmol/kg) as the interventions. MEASUREMENTS AND MAIN RESULTS: Fifty-two pigs were included in the study. Sodium bicarbonate significantly increased the number of animals achieving ROSC (24/26 [92%] vs. 13/26 [50%]; odds ratio [OR], 12.0; 95% CI, 2.3-61.5; p = 0.003) and reduced time to ROSC (hazard ratio [HR] 3.6; 95% CI, 1.8-7.5; p < 0.001). There was no effect of calcium chloride on the number of animals achieving ROSC (19/26 [73%] vs. 18/26 [69%]; OR, 1.2; 95% CI, 0.4-4.0; p = 0.76) or time to ROSC (HR, 1.5; 95% CI, 0.8-2.9; p = 0.23). CONCLUSIONS: Administration of sodium bicarbonate significantly increased the number of animals achieving ROSC and decreased time to ROSC. There was no effect of calcium chloride on the number of animals achieving ROSC or time to ROSC.

The effects of methylene blue during and after cardiac arrest in a porcine model; a randomized, blinded, placebo-controlled study.

PURPOSE: To evaluate the effect of methylene blue administered as a bolus on return of spontaneous circulation (ROSC), lactate levels, vasopressor requirements, and markers of neurological injury in a clinically relevant pig model of cardiac arrest. MATERIALS AND METHODS: 40 anesthetized pigs were subjected to acute myocardial infarction and 7 min of untreated cardiac arrest. Animals were randomized into three groups: one group received saline only (controls), one group received 2 mg/kg methylene blue and saline (MB + saline), and one group received two doses of 2 mg/kg methylene blue (MB + MB). The first intervention was given after the 3rd rhythm analysis, while the second dose was administered one hour after achieving ROSC. Animals underwent intensive care and observation for six hours, followed by cerebral magnetic resonance imaging (MRI). The primary outcome for this study was development in lactate levels after cardiac arrest. Categorical data were compared using Fisher's exact test and pointwise data were analyzed using one-way analysis of variance (ANOVA) or equivalent non-parametric test. Continuous data collected over time were analyzed using a linear mixed effects model. A value of p < .05 was considered statistically significant. RESULTS: Lactate levels increased in all groups after cardiac arrest and resuscitation, however lactate levels in the MB + MB group decreased significantly faster compared with the control group (p = .007) and the MB + saline group (p = .02). The proportion of animals achieving initial ROSC was similar across groups: 11/13 (85%) in the control group, 10/13 (77%) in the MB + saline group, and 12/14 (86%) in the MB + MB group (p = .81). Time to ROSC did not differ between groups (p = .67). There was no significant difference in accumulated norepinephrine dose between groups (p = .15). Cerebral glycerol levels were significantly lower in the MB + MB group after resuscitation compared with control group (p = .03). However, MRI data revealed no difference in apparent diffusion coefficient, cerebral blood flow, or dynamic contrast enhanced MR perfusion between groups. CONCLUSION: Treatment with a bolus of methylene blue during cardiac arrest and after resuscitation did not significantly improve hemodynamic function. A bolus of methylene blue did not yield the neuroprotective effects that have previously been described in animals receiving methylene blue as an infusion.

Optimizing hemodynamic function during cardiopulmonary resuscitation.

PURPOSE OF REVIEW: The purpose of this narrative review is to provide an update on hemodynamics during cardiopulmonary resuscitation (CPR) and to describe emerging therapies to optimize perfusion. RECENT FINDINGS: Cadaver studies have shown large inter-individual variations in blood distribution and anatomical placement of the heart during chest compressions. Using advanced CT techniques the studies have demonstrated atrial and slight right ventricular compression, but no direct compression of the left ventricle. A hemodynamic-directed CPR strategy may overcome this by allowing individualized hand-placement, drug dosing, and compression rate and depth. Through animal studies and one clinical before-and-after study head-up CPR has shown promising results as a potential strategy to improve cerebral perfusion. Two studies have demonstrated that placement of an endovascular balloon occlusion in the aorta (REBOA) can be performed during ongoing CPR. SUMMARY: Modern imaging techniques may help increase our understanding on the mechanism of forward flow during CPR. This could provide new information on how to optimize perfusion. Head-up CPR and the use of REBOA during CPR are novel methods that might improve cerebral perfusion during CPR; both techniques do, however, still await clinical testing.

Animal research in cardiac arrest.

The purpose of this narrative review is to provide an overview of lessons learned from experimental cardiac arrest studies, limitations, translation to clinical studies, ethical considerations and future directions. Cardiac arrest animal studies have provided valuable insights into the pathophysiology of cardiac arrest, the effects of various interventions, and the development of resuscitation techniques. However, there are limitations to animal models that should be considered when interpreting results. Systematic reviews have demonstrated that animal models rarely reflect the clinical condition seen in humans, nor the complex treatment that occurs during and after a cardiac arrest. Furthermore, animal models of cardiac arrest are at a significant risk of bias due to fundamental issues in performing and/or reporting critical methodological aspects. Conducting clinical trials targeting the management of rare cardiac arrest causes like e.g. hyperkalemia and pulmonary embolism is challenging due to the scarcity of eligible patients. For these research questions, animal models might provide the highest level of evidence and can potentially guide clinical practice. To continuously push cardiac arrest science forward, animal studies must be conducted and reported rigorously, designed to avoid bias and answer specific research questions. To ensure the continued relevance and generation of valuable new insights from animal studies, new approaches and techniques may be needed, including animal register studies, systematic reviews and multilaboratory trials.

Thiamine for the Treatment of Cardiac Arrest-Induced Neurological Injury: A Randomized, Blinded, Placebo-Controlled Experimental Study.

Background Thiamine supplementation has demonstrated protective effects in a mouse model of cardiac arrest. The aim of this study was to investigate the neuroprotective effects of thiamine in a clinically relevant large animal cardiac arrest model. The hypothesis was that thiamine reduces neurological injury evaluated by neuron-specific enolase levels. Methods and Results Pigs underwent myocardial infarction and subsequently 9 minutes of untreated cardiac arrest. Twenty minutes after successful resuscitation, the pigs were randomized to treatment with either thiamine or placebo. All pigs underwent 40 hours of intensive care and were awakened for assessment of functional neurological outcome up until 9 days after cardiac arrest. Nine pigs were included in both groups, with 8 in each group surviving the entire intensive care phase. Mean area under the curve for neuron-specific enolase was similar between groups, with 81.5 µg/L per hour (SD, 20.4) in the thiamine group and 80.5 µg/L per hour (SD, 18.3) in the placebo group, with an absolute difference of 1.0 (95% CI, -57.8 to 59.8; P=0.97). Likewise, there were no absolute difference in neurological deficit score at the end of the protocol (2 [95% CI, -38 to 42]; P=0.93). There was no absolute mean group difference in lactate during the intensive care period (1.1 mmol/L [95% CI, -0.5 to 2.7]; P=0.16). Conclusions In this randomized, blinded, placebo-controlled trial using a pig cardiac arrest model with myocardial infarction and long intensive care and observation for 9 days, thiamine showed no effect in changes to functional neurological outcome or serum levels of neuron-specific enolase. Thiamine treatment had no effect on lactate levels after successful resuscitation.

Cerebral monitoring in a pig model of cardiac arrest with 48 h of intensive care.

BACKGROUND: Neurological injury is the primary cause of death after out-of-hospital cardiac arrest. There is a lack of studies investigating cerebral injury beyond the immediate post-resuscitation phase in a controlled cardiac arrest experimental setting. METHODS: The aim of this study was to investigate temporal changes in measures of cerebral injury and metabolism in a cardiac arrest pig model with clinically relevant post-cardiac arrest intensive care. A cardiac arrest group (n = 11) underwent 7 min of no-flow and was compared with a sham group (n = 6). Pigs underwent intensive care with 24 h of hypothermia at 33 °C. Blood markers of cerebral injury, cerebral microdialysis, and intracranial pressure (ICP) were measured. After 48 h, pigs underwent a cerebral MRI scan. Data are presented as median [25th; 75th percentiles]. RESULTS: Return of spontaneous circulation was achieved in 7/11 pigs. Time to ROSC was 4.4 min [4.2; 10.9]. Both NSE and NfL increased over time (p < 0.001), and were higher in the cardiac arrest group at 48 h (NSE 4.2 µg/L [2.4; 6.1] vs 0.9 [0.7; 0.9], p < 0.001; NfL 63 ng/L [35; 232] vs 29 [21; 34], p = 0.02). There was no difference in ICP at 48 h (17 mmHg [14; 24] vs 18 [13; 20], p = 0.44). The cerebral lactate/pyruvate ratio had secondary surges in 3/7 cardiac arrest pigs after successful resuscitation. Apparent diffusion coefficient was lower in the cardiac arrest group in white matter cortex (689 × 10-6 mm2/s [524; 765] vs 800 [799; 815], p = 0.04) and hippocampus (854 [834; 910] vs 1049 [964; 1180], p = 0.03). N-Acetylaspartate was lower on MR spectroscopy in the cardiac arrest group (- 17.2 log [- 17.4; - 17.0] vs - 16.9 [- 16.9; - 16.9], p = 0.03). CONCLUSIONS: We have developed a clinically relevant cardiac arrest pig model that displays cerebral injury as marked by NSE and NfL elevations, signs of cerebral oedema, and reduced neuron viability. Overall, the burden of elevated ICP was low in the cardiac arrest group. A subset of pigs undergoing cardiac arrest had persisting metabolic disturbances after successful resuscitation.

Basic life support skills can be improved among certified basic life support instructors.

BACKGROUND: A correct visual skill demonstration is important when learning cardiopulmonary resuscitation (CPR) and the use of an automated external defibrillator (AED). Basic life support (BLS) instructors are expected to master and demonstrate CPR/AED skills correctly. The aim of this study was to evaluate certified BLS instructors' competencies in demonstrating CPR and the use of an AED. METHODS: Certified BLS instructors demonstrated CPR and the use of an AED on a resuscitation manikin. Skills were evaluated using data collected from the manikin and video recordings and compared to resuscitation guidelines. Further, instructors completed questionnaires on resuscitation guidelines and rating of their own CPR/AED skills. RESULTS: Overall, we analyzed data from 125 instructors. Of all chest compressions, only 22% were within guideline recommendations regarding depth. Instructors performed chest compressions with excessive depth (mean depth 64 mm (7.3)) and a mean rate of 115 min-1 (10.8). Only 25% of instructors placed the left AED electrode correctly (median distance 7.6 cm (5.0;10.5)), while the right AED electrode usually was placed correctly (median distance 2.9 cm (1.5;4.0), 85% placed correctly). Nearly half of the instructors failed to state correct answers regarding how to diagnose a cardiac arrest and where to place the AED electrodes. Despite their performance, instructors rated their BLS skills as good. CONCLUSION: Certified BLS instructors' have poor CPR/AED skills and several important knowledge gaps on CPR/AED guidelines in contrast to instructors' self-reported skills. This highlights a need for improving BLS instructor education, including continuous faculty development to ensure optimal learning conditions for BLS course participants.

Translation from animal studies of novel pharmacological therapies to clinical trials in cardiac arrest: A systematic review.

BACKGROUND: There is a lack of new promising therapies to improve the dismal outcomes from cardiac arrest. The objectives of this study were: (1) To identify novel pharmacological therapies investigated in experimental animal studies and (2) to identify pharmacological therapies translated from experimental animal studies to clinical trials. METHODS: PubMed was searched to first identify relevant experimental cardiac arrest animal models published within the last 20 years. Based on this, a list of interventions was created and a second search was performed to identify clinical trials testing one of these interventions. Data extraction was performed using standardised data extraction forms. RESULTS: We identified 415 animal studies testing 190 different pharmacological interventions. The most commonly tested interventions were classified as vasopressors, anaesthetics/gases, or interventions aimed at molecular targets. We found 43 clinical trials testing 26 different interventions identified in the animal studies. Of these, 13 trials reported positive findings and 30 trials reported neutral findings with regards to the primary endpoint. No study showed harm of the intervention. Some interventions tested in human clinical trials, had previously been tested in animal studies without a positive effect on outcomes. A large number of animal studies was performed after publication of a clinical trial. CONCLUSION: Numerous different pharmacological interventions have been tested in experimental animal models. Despite this only a limited number of these interventions have advanced to clinical trials, however several of the clinical trials tested interventions that were first tested in experimental animal models.

Cardiac Arrest in Pigs With 48 hours of Post-Resuscitation Care Induced by 2 Methods of Myocardial Infarction: A Methodological Description.

Background Systematic reviews have disclosed a lack of clinically relevant cardiac arrest animal models. The aim of this study was to develop a cardiac arrest model in pigs encompassing relevant cardiac arrest characteristics and clinically relevant post-resuscitation care. Methods and Results We used 2 methods of myocardial infarction in conjunction with cardiac arrest. One group (n=7) had a continuous coronary occlusion, while another group (n=11) underwent balloon-deflation during arrest and resuscitation with re-inflation after return of spontaneous circulation. A sham group was included (n=6). All groups underwent 48 hours of intensive care including 24 hours of targeted temperature management. Pigs underwent invasive hemodynamic monitoring. Left ventricular function was assessed by pressure-volume measurements. The proportion of pigs with return of spontaneous circulation was 43% in the continuous infarction group and 64% in the deflation-reinflation group. In the continuous infarction group 29% survived the entire protocol while 55% survived in the deflation-reinflation group. Both cardiac arrest groups needed vasopressor and inotropic support and pressure-volume measurements showed cardiac dysfunction. During rewarming, systemic vascular resistance decreased in both cardiac arrest groups. Median [25%;75%] troponin-I 48 hours after return of spontaneous circulation, was 88 973 ng/L [53 124;99 740] in the continuous infarction group, 19 661 ng/L [10 871;23 209] in the deflation-reinflation group, and 1973 ng/L [1117;1995] in the sham group. Conclusions This article describes a cardiac arrest pig model with myocardial infarction, targeted temperature management, and clinically relevant post-cardiac arrest care. We demonstrate 2 methods of inducing myocardial ischemia with cardiac arrest resulting in post-cardiac arrest organ injury including cardiac dysfunction and cerebral injury.

Adult post-cardiac arrest interventions: An overview of randomized clinical trials.

AIM: To provide an overview of published and registered trials related to post-cardiac arrest interventions. DATA SOURCE: We searched PubMed and the International Clinical Trials Registry Platform for randomized clinical trials in adults specifically addressing a post-cardiac arrest intervention. RESULTS: We identified 65 manuscripts reporting randomized clinical trials. The majority of the trials were published within the last 10 years and the sample sizes were generally low with a median of 90 participants (quartiles: 49, 262; range: 9, 1359). The majority of the trials were conducted in out-of-hospital cardiac arrest (79%), while only 6% were conducted specifically in in-hospital cardiac arrest and 15% included both in- and out-of-hospital cardiac arrest. We identified 48 registered trials online. The median target sample size is 100 participants (quartiles: 60, 400; range: 20, 1900). The majority of trials are enrolling patients with out-of-hospital cardiac arrest (71%) while 6% specifically focuses on in-hospital cardiac arrest. CONCLUSION: This review provides an overview of published and registered trials addressing post-cardiac arrest interventions. We believe this information will be relevant to guide future research.

Type 2 diabetes mellitus worsens neurological injury following cardiac arrest: an animal experimental study.

BACKGROUND: Cardiac arrest carries a poor prognosis. The typical cardiac arrest patient is comorbid, and studies have shown that diabetes mellitus is an independent risk factor for increased mortality after cardiac arrest. Despite this, animal studies lack to investigate cardiac arrest in the setting of diabetes mellitus. We hypothesize that type 2 diabetes mellitus in a rat model of cardiac arrest is associated with increased organ dysfunction when compared with non-diabetic rats. METHODS: Zucker diabetic fatty (ZDF) rats (n = 13), non-diabetic Zucker lean control (ZLC) rats (n = 15), and non-diabetic Sprague Dawley (SprD) rats (n = 8), underwent asphyxia-induced cardiac arrest. Animals were resuscitated and monitored for 180 min after return of spontaneous circulation (ROSC). Blood levels of neuron-specific enolase were measured to assess neurological injury. Cardiac function was evaluated by echocardiography. RESULTS: No differences in cardiac output or neuron-specific enolase existed between the groups at baseline. Median levels of neuron-specific enolase 180 min after ROSC was 10.8 µg/L (Q25;Q75-7.6;11.3) in the ZDF group, which was significantly higher compared to the ZLC group at 2.0 µg/L (Q25;Q75-1.7;2.3, p < 0.05) and the SprD group at 2.8 µg/L (Q25;Q75-2.3;3.4, p < 0.05). At 180 min after ROSC, cardiac output was 129 mL/min/kg (SD 45) in the ZDF group, which was not different from 106 mL/min/kg (SD 31) in the ZLC group or 123 mL/min/kg (SD 26, p = 0.72) in the SprD group. CONCLUSIONS: In a cardiac arrest model, neuronal injury is increased in type 2 diabetes mellitus animals compared with non-diabetic controls. Although this study lacks to uncover the specific mechanisms causing increased neuronal injury, the establishment of a cardiac arrest model of type 2 diabetes mellitus lays the important foundation for further experimental investigations within this field.