Endotracheal epinephrine at standard versus high dose for resuscitation of asystolic newborn lambs.

INTRODUCTION: Endotracheal (ET) epinephrine administration is an option during neonatal resuscitation, if the preferred intravenous (IV) route is unavailable. OBJECTIVES: We assessed whether endotracheal epinephrine achieved return of spontaneous circulation (ROSC), and maintained physiological stability after ROSC, at standard and higher dose, in severely asphyxiated newborn lambs. METHODS: Near-term fetal lambs were asphyxiated until asystole. Resuscitation was commenced with ventilation and chest compressions. Lambs were randomly allocated to: IV Saline placebo (5 ml/kg), IV Epinephrine (20 micrograms/kg), Standard-dose ET Epinephrine (100 micrograms/kg), and High-dose ET Epinephrine (1 mg/kg). After three allocated treatment doses, rescue IV Epinephrine was administered if ROSC had not occurred. Lambs achieving ROSC were monitored for 60 minutes. Brain histology was assessed for microbleeds. RESULTS: ROSC in response to allocated treatment (without rescue IV Epinephrine) occurred in 1/6 Saline, 9/9 IV Epinephrine, 0/9 Standard-dose ET Epinephrine, and 7/9 High-dose ET Epinephrine lambs respectively. Blood pressure during CPR increased after treatment with IV Epinephrine and High-dose ET Epinephrine, but not Saline or Standard-dose ET Epinephrine. After ROSC, both ET Epinephrine groups had lower pH, higher lactate, and higher blood pressure than the IV Epinephrine group. Cortex microbleeds were more frequent in High-dose ET Epinephrine lambs (8/8 lambs examined, versus 3/8 in IV Epinephrine lambs). CONCLUSIONS: The currently recommended dose of ET Epinephrine was ineffective in achieving ROSC. Without convincing clinical or preclinical evidence of efficacy, use of ET Epinephrine at this dose may not be appropriate. High-dose ET Epinephrine requires further evaluation before clinical translation.

Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Importance: It is unclear whether administration of calcium has a beneficial effect in patients with cardiac arrest. Objective: To determine whether administration of calcium during out-of-hospital cardiac arrest improves return of spontaneous circulation in adults. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial included 397 adult patients with out-of-hospital cardiac arrest and was conducted in the Central Denmark Region between January 20, 2020, and April 15, 2021. The last 90-day follow-up was on July 15, 2021. Interventions: The intervention consisted of up to 2 intravenous or intraosseous doses with 5 mmol of calcium chloride (n = 197) or saline (n = 200). The first dose was administered immediately after the first dose of epinephrine. Main Outcomes and Measures: The primary outcome was sustained return of spontaneous circulation. The secondary outcomes included survival and a favorable neurological outcome (modified Rankin Scale score of 0-3) at 30 days and 90 days. Results: Based on a planned interim analysis of 383 patients, the steering committee stopped the trial early due to concerns about harm in the calcium group. Of 397 adult patients randomized, 391 were included in the analyses (193 in the calcium group and 198 in the saline group; mean age, 68 [SD, 14] years; 114 [29%] were female). There was no loss to follow-up. There were 37 patients (19%) in the calcium group who had sustained return of spontaneous circulation compared with 53 patients (27%) in the saline group (risk ratio, 0.72 [95% CI, 0.49 to 1.03]; risk difference, -7.6% [95% CI, -16% to 0.8%]; P = .09). At 30 days, 10 patients (5.2%) in the calcium group and 18 patients (9.1%) in the saline group were alive (risk ratio, 0.57 [95% CI, 0.27 to 1.18]; risk difference, -3.9% [95% CI, -9.4% to 1.3%]; P = .17). A favorable neurological outcome at 30 days was observed in 7 patients (3.6%) in the calcium group and in 15 patients (7.6%) in the saline group (risk ratio, 0.48 [95% CI, 0.20 to 1.12]; risk difference, -4.0% [95% CI, -8.9% to 0.7%]; P = .12). Among the patients with calcium values measured who had return of spontaneous circulation, 26 (74%) in the calcium group and 1 (2%) in the saline group had hypercalcemia. Conclusions and Relevance: Among adults with out-of-hospital cardiac arrest, treatment with intravenous or intraosseous calcium compared with saline did not significantly improve sustained return of spontaneous circulation. These results do not support the administration of calcium during out-of-hospital cardiac arrest in adults. Trial Registration: ClinicalTrials.gov Identifier: NCT04153435.

Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Importance: Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes. Objective: To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021. Intervention: Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses. Main Outcomes and Measures: The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). Results: Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively. Conclusions and Relevance: Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03640949.

Inhibiting Cardiac Mitochondrial Fatty Acid Oxidation Attenuates Myocardial Injury in a Rat Model of Cardiac Arrest.

Mitochondrial fatty acid oxidation (FAO) is involved in myocardial damage after cardiopulmonary resuscitation (CPR). This study is aimed at investigating the effect of inhibiting mitochondrial FAO on myocardial injury and the underlying mechanisms of postresuscitation myocardial dysfunction. Rats were induced, subjected to 8 min of ventricular fibrillation, and underwent 6 min of CPR. Rats with return of spontaneous circulation (ROSC) were randomly divided into the Sham group, CPR group, and CPR + Trimetazidine (TMZ) group. Rats in the CPR + TMZ group were administered TMZ (10 mg/kg) at the onset of ROSC via the right external jugular vein, while rats in the CPR group were injected with equivalent volumes of vehicle. The sham rats were only administered equivalent volumes of vehicle. We found that the activities of enzymes related to cardiac mitochondrial FAO were partly improved after ROSC. TMZ, as a reversible inhibitor of 3-ketoacyl CoA thiolase, inhibited myocardial mitochondrial FAO after ROSC. In the CPR + TMZ group, the levels of mitochondrial injury in cardiac tissue were alleviated following attenuated myocardial damage and oxidative stress after ROSC. In addition, the disorder of cardiac mitochondrial metabolism was ameliorated, and specifically, the superfluous succinate related to mitochondrial reactive oxygen species (ROS) generation was decreased by inhibiting myocardial mitochondrial FAO with TMZ administration after ROSC. In conclusion, in the early period after ROSC, inhibiting cardiac mitochondrial FAO attenuated excessive cardiac ROS generation and preserved myocardial function, probably by alleviating the dysfunction of cardiac mitochondrial metabolism in a rat model of cardiac arrest.

Baicalin Improves Cardiac Outcome and Survival by Suppressing Drp1-Mediated Mitochondrial Fission after Cardiac Arrest-Induced Myocardial Damage.

Myocardial injury after cardiac arrest (CA) often results in severe myocardial dysfunction and death involving mitochondrial dysfunction. Here, we sought to investigate whether baicalin, a natural flavonoid compound, exerts cardioprotection against CA-induced injury via regulating mitochondrial dysfunction. We subjected the rats to asphyxia CA after a daily baicalin treatment for 4 weeks. After the return of spontaneous circulation, baicalin treatment significantly improved cardiac function performance, elevated survival rate from 35% to 75%, prevented necrosis and apoptosis in the myocardium, which was accompanied by reduced phosphorylation of Drp1 at serine 616, inhibited Drp1 translocation to the mitochondria and mitochondrial fission, and improved mitochondrial function. In H9c2 cells subjected to simulated ischemia/reperfusion, increased phosphorylation of Drp1 at serine 616 and subsequently enhanced mitochondrial Drp1 translocation as well as mitochondrial fission, augmented cardiomyocyte death, increased reactive oxygen species production, released cytochrome c from mitochondria and injured mitochondrial respiration were efficiently improved by baicalin and Drp1 specific inhibitor with Mdivi-1. Furthermore, overexpression of Drp1 augmented excessive mitochondrial fission and abolished baicalin-afforded cardioprotection, indicating that the protective impacts of baicalin are linked to the inhibition of Drp1. Altogether, our findings disclose for the first time that baicalin offers cardioprotection against ischemic myocardial injury after CA by inhibiting Drp1-mediated mitochondrial fission. Baicalin might be a prospective therapy for the treatment of post-CA myocardial injury.

The effect of high-dose intramuscular epinephrine on the recovery of spontaneous circulation in an asphyxia-induced cardiac arrest rat model.

BACKGROUND: Obtaining vascular access can be challenging during resuscitation following cardiac arrest, and it is particularly difficult and time-consuming in paediatric patients. We aimed to compare the efficacy of high-dose intramuscular (IM) versus intravascular (IV) epinephrine administration with regard to the return of spontaneous circulation (ROSC) in an asphyxia-induced cardiac arrest rat model. METHODS: Forty-five male Sprague-Dawley rats were used for these experiments. Cardiac arrest was induced by asphyxia, and defined as a decline in mean arterial pressure (MAP) to 20 mmHg. After asphyxia-induced cardiac arrest, the rats were randomly allocated into one of 3 groups (control saline group, IV epinephrine group, and IM epinephrine group). After 540 s of cardiac arrest, cardiopulmonary resuscitation was performed, and IV saline (0.01 cc/kg), IV (0.01 mg/kg, 1:100,000) epinephrine or IM (0.05 mg/kg, 1:100,000) epinephrine was administered. ROSC was defined as the achievement of an MAP above 40 mmHg for more than 1 minute. Rates of ROSC, haemodynamics, and arterial blood gas analysis were serially observed. RESULTS: The ROSC rate (61.5%) of the IM epinephrine group was less than that in the IV epinephrine group (100%) but was higher than that of the control saline group (15.4%) (log-rank test). There were no differences in MAP between the two groups, but HR in the IM epinephrine group (beta coefficient = 1.02) decreased to a lesser extent than that in the IV epinephrine group with time. CONCLUSIONS: IM epinephrine induced better ROSC rates compared to the control saline group in asphyxia-induced cardiac arrest, but not compared to IV epinephrine. The IM route of epinephrine administration may be a promising option in an asphyxia-induced cardiac arrest.

Synergistic Effects of Moderate Therapeutic Hypothermia and Levosimendan on Cardiac Function and Survival After Asphyxia-Induced Cardiac Arrest in Rats.

Background This study investigated whether levosimendan, an inotropic calcium sensitizer, when combined with moderate therapeutic hypothermia, may exert synergistic benefits on post-cardiac arrest myocardial dysfunction and improve outcomes. Methods and Results After 9.5-minute asphyxia-induced cardiac arrest and resuscitation, 48 rats were randomized equally into 4 groups following return of spontaneous circulation (ROSC), including normothermia, hypothermia, normothermia-levosimendan, and hypothermia-levosimendan groups. For the normothermia group, the target temperature was 37°C while for the hypothermia group, the target temperature was 32°C, both of which were to be maintained for 4 hours after ROSC. Levosimendan was administered after ROSC with a loading dose of 10 µg/kg and then infused at 0.1 µg/kg per min for 4 hours. In the hypothermia-levosimendan group, left ventricular systolic function and cardiac output increased significantly, whereas the heart rate and systemic vascular resistance decreased significantly compared with the normothermia group. Also, the concentrations of interleukin 1ß at 4 hours post-ROSC and the production of NO between 1 hour and 4 hours post-ROSC were reduced significantly in the hypothermia-levosimendan group compared with the normothermia group. The 72-hour post-ROSC survival and neurological recovery were also significantly better in the hypothermia-levosimendan group compared with the normothermia group (survival, 100% versus 50%, χ2 test, P=0.006). Conclusions Compared with normothermia, only combined moderate therapeutic hypothermia and levosimendan treatment could consistently improve post-cardiac arrest myocardial dysfunction and decrease the release of pro-inflammatory molecules, thereby improving survival and neurological outcomes. These findings suggest synergistic benefits between moderate therapeutic hypothermia and levosimendan.

Steroid use after cardiac arrest is associated with favourable outcomes: a systematic review and meta-analysis.

BACKGROUND: The effect of steroid use on outcomes in patients with cardiac arrest (CA) remains controversial. We systematically reviewed the literature to investigate whether steroid use after CA increased the return of spontaneous circulation (ROSC) rate and survival to discharge in patients with CA. METHODS: PubMed, Embase, CNKI, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) and observational studies on the effect of steroid use on outcomes in adults with CA. The outcomes were ROSC and survival to discharge. RESULTS: Seven studies (four RCTs and three observational studies) were included. Pooled analysis suggested that steroid use was associated with increased ROSC in patients with CA. Steroid use was significantly associated with survival to discharge, which was a consistent finding in RCTs and observational studies. Subgroup analysis based on the time of drug administration (during cardiopulmonary resuscitation [CPR] vs. after CA) showed that steroid use during CPR and after CA were significantly associated with an increased rate of ROSC and survival to discharge. CONCLUSION: Current evidence indicates that steroid use after CA could increase ROSC and survival to discharge in patients with CA. However, high-quality and adequately powered RCTs are warranted.

Early Administration of Adrenaline for Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-Analysis.

Background The use of adrenaline in out-of-hospital cardiac arrest (OHCA) patients is still controversial. This study aimed to determine the effects of early pre-hospital adrenaline administration in OHCA patients. Methods and Results PubMed, EMBASE, Google Scholar, and the Cochrane Library database were searched from study inception to February 2019 to identify studies that reported OHCA patients who received adrenaline. The primary outcome was survival to discharge, and the secondary outcomes were return of spontaneous circulation, favorable neurological outcome, and survival to hospital admission. A total of 574 392 patients were included from 24 studies. The use of early pre-hospital adrenaline administration in OHCA patients was associated with a significant increase in survival to discharge (risk ratio [RR], 1.62; 95% CI, 1.45-1.83; P<0.001) and return of spontaneous circulation (RR, 1.50; 95% CI, 1.36-1.67; P<0.001), as well as a favorable neurological outcome (RR, 2.09; 95% CI, 1.73-2.52; P<0.001). Patients with shockable rhythm cardiac arrest had a significantly higher rate of survival to discharge (RR, 5.86; 95% CI, 4.25-8.07; P<0.001) and more favorable neurological outcomes (RR, 5.10; 95% CI, 2.90-8.97; P<0.001) than non-shockable rhythm cardiac arrest patients. Conclusions Early pre-hospital administration of adrenaline to OHCA patients might increase the survival to discharge, return of spontaneous circulation, and favorable neurological outcomes. Registration URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42019130542.