Temporal Trends in End-Tidal Capnography and Outcomes in Out-of-Hospital Cardiac Arrest: A Secondary Analysis of a Randomized Clinical Trial.

Importance: While widely measured, the time-varying association between exhaled end-tidal carbon dioxide (EtCO2) and out-of-hospital cardiac arrest (OHCA) outcomes is unclear. Objective: To evaluate temporal associations between EtCO2 and return of spontaneous circulation (ROSC) in the Pragmatic Airway Resuscitation Trial (PART). Design, Setting, and Participants: This study was a secondary analysis of a cluster randomized trial performed at multicenter emergency medical services agencies from the Resuscitation Outcomes Consortium. PART enrolled 3004 adults (aged ≥18 years) with nontraumatic OHCA from December 1, 2015, to November 4, 2017. EtCO2 was available in 1172 cases for this analysis performed in June 2023. Interventions: PART evaluated the effect of laryngeal tube vs endotracheal intubation on 72-hour survival. Emergency medical services agencies collected continuous EtCO2 recordings using standard monitors, and this secondary analysis identified maximal EtCO2 values per ventilation and determined mean EtCO2 in 1-minute epochs using previously validated automated signal processing. All advanced airway cases with greater than 50% interpretable EtCO2 signal were included, and the slope of EtCO2 change over resuscitation was calculated. Main Outcomes and Measures: The primary outcome was ROSC determined by prehospital or emergency department palpable pulses. EtCO2 values were compared at discrete time points using Mann-Whitney test, and temporal trends in EtCO2 were compared using Cochran-Armitage test of trend. Multivariable logistic regression was performed, adjusting for Utstein criteria and EtCO2 slope. Results: Among 1113 patients included in the study, 694 (62.4%) were male; 285 (25.6%) were Black or African American, 592 (53.2%) were White, and 236 (21.2%) were another race; and the median (IQR) age was 64 (52-75) years. Cardiac arrest was most commonly unwitnessed (n = 579 [52.0%]), nonshockable (n = 941 [84.6%]), and nonpublic (n = 999 [89.8%]). There were 198 patients (17.8%) with ROSC and 915 (82.2%) without ROSC. Median EtCO2 values between ROSC and non-ROSC cases were significantly different at 10 minutes (39.8 [IQR, 27.1-56.4] mm Hg vs 26.1 [IQR, 14.9-39.0] mm Hg; P < .001) and 5 minutes (43.0 [IQR, 28.1-55.8] mm Hg vs 25.0 [IQR, 13.3-37.4] mm Hg; P < .001) prior to end of resuscitation. In ROSC cases, median EtCO2 increased from 30.5 (IQR, 22.4-54.2) mm HG to 43.0 (IQR, 28.1-55.8) mm Hg (P for trend < .001). In non-ROSC cases, EtCO2 declined from 30.8 (IQR, 18.2-43.8) mm Hg to 22.5 (IQR, 12.8-35.4) mm Hg (P for trend < .001). Using adjusted multivariable logistic regression with slope of EtCO2, the temporal change in EtCO2 was associated with ROSC (odds ratio, 1.45 [95% CI, 1.31-1.61]). Conclusions and Relevance: In this secondary analysis of the PART trial, temporal increases in EtCO2 were associated with increased odds of ROSC. These results suggest value in leveraging continuous waveform capnography during OHCA resuscitation. Trial Registration: ClinicalTrials.gov Identifier: NCT02419573.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: a subgroup analysis from the prehospital TXA for TBI trial.

BACKGROUND: In the Prehospital Tranexamic Acid (TXA) for TBI Trial, TXA administered within two hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT). METHODS: This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale<13) and systolic blood pressure > =90 mmHg within two hours of injury to a 2-gram out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-gram out-of-hospital TXA bolus/1-gram in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) < = 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors. RESULTS: The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-gram TXA bolus group (17%) compared to the other two groups (1-gram bolus/1-gram infusion 26%, placebo 27%). The estimated adjusted difference between the 2-gram bolus and placebo groups was -8·5 percentage points (95% CI, -15.9 to -1.0) and between the 2-gram bolus and 1-gram bolus/1-gram infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). DRS at 6 months was lower in the 2-gram TXA bolus group than the 1-gram bolus/1-gram infusion (estimated difference -2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six-month GOSE did not differ among groups. CONCLUSIONS: A 2-gram out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level II.

Adverse Safety Events in Emergency Medical Services Care of Children With Out-of-Hospital Cardiac Arrest.

Importance: Survival for children with out-of-hospital cardiac arrest (OHCA) remains poor despite improvements in adult OHCA survival. Objective: To characterize the frequency of and factors associated with adverse safety events (ASEs) in pediatric OHCA. Design, Setting, and Participants: This population-based retrospective cohort study examined patient care reports from 51 emergency medical services (EMS) agencies in California, Georgia, Oregon, Pennsylvania, Texas, and Wisconsin for children younger than 18 years with an OHCA in which resuscitation was attempted by EMS personnel between 2013 and 2019. Medical record review was conducted from January 2019 to April 2022 and data analysis from October 2022 to February 2023. Main Outcomes and Measure: Severe ASEs during the patient encounter (eg, failure to give an indicated medication, 10-fold medication overdose). Results: A total of 1019 encounters of EMS-treated pediatric OHCA were evaluated; 465 patients (46%) were younger than 12 months. At least 1 severe ASE occurred in 610 patients (60%), and 310 patients (30%) had 2 or more. Neonates had the highest frequency of ASEs. The most common severe ASEs involved epinephrine administration (332 [30%]), vascular access (212 [19%]), and ventilation (160 [14%]). In multivariable logistic regression, the only factor associated with severe ASEs was young age. Neonates with birth-related and non-birth-related OHCA had greater odds of a severe ASE compared with adolescents (birth-related: odds ratio [OR], 7.0; 95% CI, 3.1-16.1; non-birth-related: OR, 3.4; 95% CI, 1.2-9.6). Conclusions and Relevance: In this large geographically diverse cohort of children with EMS-treated OHCA, 60% of all patients experienced at least 1 severe ASE. The odds of a severe ASE were higher for neonates than adolescents and even higher when the cardiac arrest was birth related. Given the national increase in out-of-hospital births and ongoing poor outcomes of OHCA in young children, these findings represent an urgent call to action to improve care delivery and training for this population.

Randomized controlled dose-escalation design to evaluate the safety of a novel pharmacological cardiopulmonary resuscitation strategy.

BACKGROUND/AIMS: The motivating randomized controlled phase I trial evaluates three sodium nitroprusside doses in a novel sodium nitroprusside-enhanced cardiopulmonary resuscitation strategy for improved end-organ perfusion relative to local standard of care. Sodium nitroprusside is a vasodilator with an established safety profile in other indications, whereas the local standard of care uses vasoconstrictors, typically epinephrine. The purpose of the proposed trial is to identify the highest safe dose of sodium nitroprusside in this new context as excessive doses may cause severe hypotension with compromised end-organ perfusion. METHODS: The proposed phase I trial design expands upon traditional dose-finding designs to include a randomized control arm, which is needed to assess safety through the relative increase in serum lactate on hospital admission. For guiding dose escalation, we propose and compare six Bayesian models which characterize expected serum lactate as a function of sodium nitroprusside dose and randomization group. Each model makes a different assumption about the expected change in serum lactate across control cohorts concurrently randomized with each dose. Model selection aims to minimize the expected number of times that a dose is incorrectly classified as safe or unsafe while sample size selection targets an expected number of incorrectly classified doses. Randomization is 1:1 for the initial cohort, and for subsequent cohorts is chosen to maximize the lower confidence bound. RESULTS: The spike-and-slab model minimizes the expected number of times that a dose is incorrectly classified as safe or unsafe under the most scenarios in the motivating three-dose trial, but all six models exhibit relatively similar performance. A 2:1 randomization ratio for the second and third cohorts maximizes the lower confidence bound when using the spike-and-slab model. With the optimal design, on average, 70 individuals will ensure 1 incorrectly classified dose in 6 opportunities. CONCLUSION: We recommend that the motivating trial use the spike-and-slab model with a 1:1 randomization ratio for the initial cohort and 2:1 randomization ratio for subsequent cohorts; however, the simpler fixed effects approaches performed similarly well.

Intraarrest transport, extracorporeal cardiopulmonary resuscitation, and early invasive management in refractory out-of-hospital cardiac arrest: an individual patient data pooled analysis of two randomised trials.

Background: Refractory out-of-hospital cardiac arrest (OHCA) treated with standard advanced cardiac life support (ACLS) has poor outcomes. Transport to hospital followed by in-hospital extracorporeal cardiopulmonary resuscitation (ECPR) initiation may improve outcomes. We performed a pooled individual patient data analysis of two randomised controlled trials evaluating ECPR based approach in OHCA. Methods: The individual patient data from two published randomised controlled trials (RCTs) were pooled: ARREST (enrolled Aug 2019-June 2020; NCT03880565) and PRAGUE-OHCA (enrolled March 1, 2013-Oct 25, 2020; NCT01511666). Both trials enrolled patients with refractory OHCA and compared: intra-arrest transport with in-hospital ECPR initiation (invasive approach) versus continued standard ACLS. The primary outcome was 180-day survival with favourable neurological outcome (defined as Cerebral Performance Category 1-2). Secondary outcomes included: cumulative survival at 180 days, 30-day favourable neurological survival, and 30-day cardiac recovery. Risk of bias in each trial was assessed by two independent reviewers using the Cochrane risk-of-bias tool. Heterogeneity was assessed via Forest plots. Findings: The two RCTs included 286 patients. Of those randomised to the invasive (n = 147) and standard (n = 139) groups, respectively: the median age was 57 (IQR 47-65) and 58 years (IQR 48-66), and the median duration of resuscitation was 58 (IQR 43-69) and 49 (IQR 33-71) minutes (p = 0.17). In a modified intention to treat analysis, 45 (32.4%) in the invasive and 29 (19.7%) patients in the standard arm survived to 180 days with a favourable neurological outcome [absolute difference (AD), 95% CI: 12.7%, 2.6-22.7%, p = 0.015]. Forty-seven (33.8%) and 33 (22.4%) patients survived to 180 days [HR 0.59 (0.43-0.81); log rank test p = 0.0009]. At 30 days, 44 (31.7%) and 24 (16.3%) patients had favourable neurological outcome (AD 15.4%, 5.6-25.1%, p = 0.003), 60 (43.2%), and 46 (31.3%) patients had cardiac recovery (AD: 11.9%, 0.7-23%, p = 0.05), in the invasive and standard arms, respectively. The effect was larger in patients presenting with shockable rhythms (AD 18.8%, 7.6-29.4; p = 0.01; HR 2.26 [1.23-4.15]; p = 0.009) and prolonged CPR (>45 min; HR 3.99 (1.54-10.35); p = 0.005). Interpretation: In patients with refractory OHCA, the invasive approach significantly improved 30- and 180-day neurologically favourable survival. Funding: None.

High central venous pressure amplitude predicts successful defibrillation in a porcine model of cardiac arrest.

AIM: Increasing venous return during cardiopulmonary resuscitation (CPR) has been shown to improve hemodynamics during CPR and outcomes following cardiac arrest (CA). We hypothesized that a high central venous pressure amplitude (CVP-A), the difference between the maximum and minimum central venous pressure during chest compressions, could serve as a robust predictor of return of spontaneous circulation (ROSC) in addition to traditional measurements of coronary perfusion pressure (CPP) and end-tidal CO2 (etCO2) in a porcine model of CA. METHODS: After 10 min of ventricular fibrillation, 9 anesthetized and intubated female pigs received mechanical chest compressions with active compression/decompression (ACD) and an impedance threshold device (ITD). CPP, CVP-A and etCO2 were measured continuously. All groups received biphasic defibrillation (200 J) at minute 4 of CPR and were classified into two groups (ROSC, NO ROSC). Mean values were analyzed over 3 min before defibrillation by repeated-measures Analysis of Variance and receiver operating characteristic (ROC). RESULTS: Five animals out of 9 experienced ROSC. CVP-A showed a statistically significant difference (p = 0.003) between the two groups during 3 min of CPR before defibrillation compared to CPP (p = 0.056) and etCO2 (p = 0.064). Areas-under-the-curve in ROC analysis for CVP-A, CPP and etCO2 were 0.94 (95% Confidence Interval 0.86, 1.00), 0.74 (0.54, 0.95) and 0.78 (0.50, 1.00), respectively. CONCLUSION: In our study, CVP-A was a potentially useful predictor of successful defibrillation and return of spontaneous circulation. Overall, CVP-A could serve as a marker for prediction of ROSC with increased venous return and thereby monitoring the beneficial effects of ACD and ITD.

Methods for calculating ventilation rates during resuscitation from out-of-hospital cardiac arrest.

OBJECTIVE: Ventilation control is important during resuscitation from out-of-hospital cardiac arrest (OHCA). We compared different methods for calculating ventilation rates (VR) during OHCA. METHODS: We analyzed data from the Pragmatic Airway Resuscitation Trial, identifying ventilations through capnogram recordings. We determined VR by: 1) counting the number of breaths within a time epoch ("counted" VR), and 2) calculating the mean of the inverse of measured time between breaths within a time epoch ("measured" VR). We repeated the VR estimates using different time epochs (10, 20, 30, 60 sec). We defined hypo- and hyperventilation as VR <6 and >12 breaths/min, respectively. We assessed differences in estimated hypo- and hyperventilation with each VR measurement technique. RESULTS: Of 3,004 patients, data were available for 1,010. With the counted method, total hypoventilation increased with longer time epochs ([10-s epoch: 75 sec hypoventilation] to [60-s epoch: 97 sec hypoventilation]). However, with the measured method, total hypoventilation decreased with longer time epochs ([10-s epoch: 223 sec hypoventilation] to [60-s epoch: 150 sec hypoventilation]). With the counted method, the total duration of hyperventilation decreased with longer time epochs ([10-s epochs: 35 sec hyperventilation] to [60-s epoch: 0 sec hyperventilation]). With the measured method, total hyperventilation decreased with longer time epochs ([10-s epoch: 78 sec hyperventilation] to [60-s epoch: 0 sec hyperventilation]). Differences between the measured and counted estimates were smallest with a 60-s time epoch. CONCLUSIONS: Quantifications of hypo- and hyperventilation vary with the applied measurement methods. Measurement methods are important when characterizing ventilation rates in OHCA.

Diagnostic Accuracy of a Bacterial and Viral Biomarker Point-of-Care Test in the Outpatient Setting.

Importance: Acute respiratory infections (ARIs) account for most outpatient visits. Discriminating bacterial vs viral etiology is a diagnostic challenge with therapeutic implications. Objective: To investigate whether FebriDx, a rapid, point-of-care immunoassay, can differentiate bacterial- from viral-associated host immune response in ARI through measurement of myxovirus resistance protein A (MxA) and C-reactive protein (CRP) from finger-stick blood. Design, Setting, and Participants: This diagnostic study enrolled adults and children who were symptomatic for ARI and individuals in a control group who were asymptomatic between October 2019 and April 2021. Included participants were a convenience sample of patients in outpatient settings (ie, emergency department, urgent care, and primary care) who were symptomatic, aged 1 year or older, and had suspected ARI and fever within 72 hours. Individuals with immunocompromised state and recent vaccine, antibiotics, stroke, surgery, major burn, or myocardial infarction were excluded. Of 1685 individuals assessed for eligibility, 259 individuals declined participation, 718 individuals were excluded, and 708 individuals were enrolled (520 patients with ARI, 170 patients without ARI, and 18 individuals who dropped out). Exposures: Bacterial and viral immunoassay testing was performed using finger-stick blood. Results were read at 10 minutes, and treating clinicians and adjudicators were blinded to results. Main Outcomes and Measures: Bacterial- or viral-associated systemic host response to an ARI as determined by a predefined comparator algorithm with adjudication classified infection etiology. Results: Among 520 participants with ARI (230 male patients [44.2%] and 290 female patients [55.8%]; mean [SD] age, 35.3 [17.7] years), 24 participants with missing laboratory information were classified as unknown (4.6%). Among 496 participants with a final diagnosis, 73 individuals (14.7%) were classified as having a bacterial-associated response, 296 individuals (59.7%) as having a viral-associated response, and 127 individuals (25.6%) as negative by the reference standard. The bacterial and viral test correctly classified 68 of 73 bacterial infections, demonstrating a sensitivity of 93.2% (95% CI, 84.9%-97.0%), specificity of 374 of 423 participants (88.4% [95% CI, 85.0%-91.1%]), positive predictive value (PPV) of 68 of 117 participants (58.1% [95% CI, 49.1%-66.7%), and negative predictive value (NPV) of 374 of 379 participants (98.7% [95% CI, 96.9%-99.4%]).The test correctly classified 208 of 296 viral infections, for a sensitivity of 70.3% (95% CI, 64.8%-75.2%), a specificity of 176 of 200 participants (88.0% [95% CI, 82.8%-91.8%]), a PPV of 208 of 232 participants (89.7% [95% CI, 85.1%-92.9%]), and an NPV of 176 of 264 participants (66.7% [95% CI, 60.8%-72.1%]). Conclusions and Relevance: In this study, a rapid diagnostic test demonstrated diagnostic performance that may inform clinicians when assessing for bacterial or viral etiology of ARI symptoms.

Assessment of intensive care unit-free and ventilator-free days as alternative outcomes in the pragmatic airway resuscitation trial.

OBJECTIVE: We sought to evaluate the utility and validity of ICU-free days and ventilator-free days as candidate outcomes for OHCA trials. METHODS: We conducted a secondary analysis of the Pragmatic Airway Resuscitation Trial. We determined ICU-free (days alive and out of ICU during the first 30 days) and ventilator-free days (days alive and without mechanical ventilation). We determined ICU-free and ventilator-free day distributions and correlations with Modified Rankin Scale (MRS). We tested associations with trial interventions (laryngeal tube (LT), endotracheal intubation (ETI)) using continuous (t-test), non-parametric (Wilcoxon Rank-Sum test - WRS), count (negative binomial - NB) and survival models (Cox proportional hazards (CPH) and competing risks regression (CRR)). We conducted bootstrapped simulations to estimate statistical power. MAIN RESULTS: ICU-free days was skewed; median 0 days (IQR 0, 0), survivors only 24 (18, 27). Ventilator-free days was skewed; median 0 (IQR 0, 0) days, survivors only 27 (IQR 23, 28). ICU-free and ventilator-free days correlated with MRS (Spearman's ρ = -0.95 and -0.97). LT was associated with higher ICU-free days using t-test (p = 0.001), WRS (p = 0.003), CPH (p = 0.02) and CRR (p = 0.04), but not NB (p = 0.13). LT was associated with higher ventilator-free days using t-test (p = 0.001), WRS (p = 0.001) and CRR (p = 0.03), but not NB (p = 0.13) or CPH (p = 0.13). Simulations suggested that t-test and WRS would have had the greatest power to detect the observed ICU- and ventilator-free days differences. CONCLUSION: ICU-free and ventilator-free days correlated with MRS and differentiated trial interventions. ICU-free and ventilator-free days may have utility in the design of OHCA trials.

Airway strategy and ventilation rates in the pragmatic airway resuscitation trial.

BACKGROUND: We sought to describe ventilation rates during out-of-hospital cardiac arrest (OHCA) resuscitation and their associations with airway management strategy and outcomes. METHODS: We analyzed continuous end-tidal carbon dioxide capnography data from adult OHCA enrolled in the Pragmatic Airway Resuscitation Trial (PART). Using automated signal processing techniques, we determined continuous ventilation rates for consecutive 10-second epochs after airway insertion. We defined hypoventilation as a ventilation rate < 6 breaths/min. We defined hyperventilation as a ventilation rate > 12 breaths/min. We compared differences in total and percentage post-airway hyper- and hypoventilation between airway interventions (laryngeal tube (LT) vs. endotracheal intubation (ETI)). We also determined associations between hypo-/hyperventilation and OHCA outcomes (ROSC, 72-hour survival, hospital survival, hospital survival with favorable neurologic status). RESULTS: Adequate post-airway capnography were available for 1,010 (LT n = 714, ETI n = 296) of 3,004 patients. Median ventilation rates were: LT 8.0 (IQR 6.5-9.6) breaths/min, ETI 7.9 (6.5-9.7) breaths/min. Total duration and percentage of post-airway time with hypoventilation were similar between LT and ETI: median 1.8 vs. 1.7 minutes, p = 0.94; median 10.5% vs. 11.5%, p = 0.60. Total duration and percentage of post-airway time with hyperventilation were similar between LT and ETI: median 0.4 vs. 0.4 minutes, p = 0.91; median 2.1% vs. 1.9%, p = 0.99. Hypo- and hyperventilation exhibited limited associations with OHCA outcomes. CONCLUSION: In the PART Trial, EMS personnel delivered post-airway ventilations at rates satisfying international guidelines, with only limited hypo- or hyperventilation. Hypo- and hyperventilation durations did not differ between airway management strategy and exhibited uncertain associations with OCHA outcomes.

Guidelines and standards for the study of death and recalled experiences of death--a multidisciplinary consensus statement and proposed future directions.

An inadvertent consequence of advances in stem cell research, neuroscience, and resuscitation science has been to enable scientific insights regarding what happens to the human brain in relation to death. The scientific exploration of death is in large part possible due to the recognition that brain cells are more resilient to the effects of anoxia than assumed. Hence, brain cells become irreversibly damaged and "die" over hours to days postmortem. Resuscitation science has enabled life to be restored to millions of people after their hearts had stopped. These survivors have described a unique set of recollections in relation to death that appear universal. We review the literature, with a focus on death, the recalled experiences in relation to cardiac arrest, post-intensive care syndrome, and related phenomena that provide insights into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We also identify issues and controversies related to the study of consciousness and the recalled experience of cardiac arrest and death in subjects who have been in a coma, with a view to standardize and facilitate future research.

The association of race with CPR quality following out-of-hospital cardiac arrest.

INTRODUCTION: Previous studies have shown racial disparities in outcomes after out-of-hospital cardiac arrest. Although several treatment factors may account for these differences, there is limited information regarding differences in CPR quality and its effect on survival in underrepresented racial populations. METHODS: We conducted a secondary analysis of data from patients enrolled in the Pragmatic Airway Resuscitation Trial (PART). We calculated compliance rates with AHA 2015 high quality CPR metrics as well as compliance to intended CPR strategy (30:2 or continuous chest compression) based on the protocol in place for the first responding EMS agency. The primary analysis used general estimating equations logistic regression to examine differences between black and white patients based on EMS-assessed race after adjustment for potential confounders. Sensitivity analyses examined differences using alternate race definitions. RESULTS: There were 3004 patients enrolled in PART of which 1734 had > 2 minutes of recorded CPR data and an EMS-assessed race (1003 white, 555 black, 176 other). Black patients had higher adjusted odds of compression rate compliance (OR: 1.36, 95% CI: 1.02-1.81) and lower adjusted odds of intended CPR strategy compliance (OR: 0.78, 95% CI: 0.63-0.98) compared to white patients. Of 974 transported to the hospital, there was no difference in compliance metric estimates based on ED-reported race. CONCLUSION: Compression rate compliance was higher in black patients however compliance with intended strategy was lower based on EMS-assessed race. The remaining metrics showed no difference suggesting that CPR quality differences are not important contributors to the observed outcome disparities by race.

Association of Advanced Airway Insertion Timing and Outcomes After Out-of-Hospital Cardiac Arrest.

STUDY OBJECTIVE: While often prioritized in the resuscitation of patients with out-of-hospital cardiac arrest, the optimal timing of advanced airway insertion is unknown. We evaluated the association between the timing of advanced airway (laryngeal tube and endotracheal intubation) insertion attempt and survival to hospital discharge in adult out-of-hospital cardiac arrest. METHODS: We performed a secondary analysis of the Pragmatic Airway Resuscitation Trial (PART), a clinical trial comparing the effects of laryngeal tube and endotracheal intubation on outcomes after adult out-of-hospital cardiac arrest. We stratified the cohort by randomized airway strategy (laryngeal tube or endotracheal intubation). Within each subset, we defined a time-dependent propensity score using patients, arrest, and emergency medical services systems characteristics. Using the propensity score, we matched each patient receiving an initial attempt of laryngeal tube or endotracheal intubation with a patient at risk of receiving laryngeal tube or endotracheal intubation attempt within the same minute. RESULTS: Of 2,146 eligible patients, 1,091 (50.8%) and 1,055 (49.2%) were assigned to initial laryngeal tube and endotracheal intubation strategies, respectively. In the propensity score-matched cohort, timing of laryngeal tube insertion attempt was not associated with survival to hospital discharge: 0 to lesser than 5 minutes (risk ratio [RR]=1.35, 95% confidence interval [CI] 0.53 to 3.44); 5 to lesser than10 minutes (RR=1.07, 95% CI 0.66 to 1.73); 10 to lesser than 15 minutes (RR=1.17, 95% CI 0.60 to 2.31); or 15 to lesser than 20 minutes (RR=2.09, 95% CI 0.35 to 12.47) after advanced life support arrival. Timing of endotracheal intubation attempt was also not associated with survival: 0 to lesser than 5 minutes (RR=0.50, 95% CI 0.05 to 4.87); 5 to lesser than10 minutes (RR=1.20, 95% CI 0.51 to 2.81); 10 to lesser than15 minutes (RR=1.03, 95% CI 0.49 to 2.14); 15 to lesser than 20 minutes (RR=0.85, 95% CI 0.30 to 2.42); or more than/equal to 20 minutes (RR=0.71, 95% CI 0.07 to 7.14). CONCLUSION: In the PART, timing of advanced airway insertion attempt was not associated with survival to hospital discharge.

Enhancing cardiac arrest survival with extracorporeal cardiopulmonary resuscitation: insights into the process of death.

Extracorporeal cardiopulmonary resuscitation (ECPR) is an emerging method of cardiopulmonary resuscitation to improve outcomes from cardiac arrest. This approach targets patients with out-of-hospital cardiac arrest previously unresponsive and refractory to standard treatment, combining approximately 1 h of standard CPR followed by venoarterial extracorporeal membrane oxygenation (VA-ECMO) and coronary artery revascularization. Despite its relatively new emergence for the treatment of cardiac arrest, the approach is grounded in a vast body of preclinical and clinical data that demonstrate significantly improved survival and neurological outcomes despite unprecedented, prolonged periods of CPR. In this review, we detail the principles behind VA-ECMO-facilitated resuscitation, contemporary clinical approaches with outcomes, and address the emerging new understanding of the process of death and capability for neurological recovery.

Change in out-of-hospital 12-lead ECG diagnostic classification following resuscitation from cardiac arrest.

INTRODUCTION: We evaluated the incidence of change in serial 12-lead electrocardiogram (ECG) diagnostic classifications in patients resuscitated from out-of-hospital (OH) cardiac arrest (OHCA) comparing OH to emergency department (ED) ECGs. METHODS: This retrospective case series included: 1) adults (≥ 18 years old), 2) resuscitated from OHCA, 3) ≥ 1 OH and 1 ED ECG/patient, and 4) emergency medical services (EMS) transport to the study hospital. OH and ED ECGs were classified as: 1) STEMI (ST-segment Elevation Myocardial Infarction), 2) Ischemic, and 3) Non-ischemic. Two ED physicians and one cardiologist independently classified all ECGs, then generated a consensus opinion classification for each ECG based on American Heart Association's 2018 Expert Consensus criteria. The most ischemic OH ECG classification was compared with the last ED ECG classification. RESULTS: From 7/27/12 to 7/18/19, 176 patients were entered with a mean age of 61.2 ± 16.6 years; 102/176 (58%) were male. Overall, 504 OH and ED 12-lead ECGs were acquired (2.9 ECGs/patient). ECG classification inter-rater reliability kappa score was 0.63 ± 0.02 (substantial agreement). Overall, 86/176 (49%) changed ECG classification from the OH to ED setting; 69/86 (80%) of these ECGs changed from more to less ischemic classifications. Of 49 OH STEMI ECG classifications, 33/49 (67%) changed to a less ischemic (non-STEMI) ED ECG classification. CONCLUSIONS: Change in 12-lead ECG classification from OH to ED setting in patients resuscitated from OHCA was common (49%). The OH STEMI classification changed to a less ischemic (non-STEMI) ED classification in 67% of cases.

Methodology and framework for the analysis of cardiopulmonary resuscitation quality in large and heterogeneous cardiac arrest datasets.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) data debriefing and clinical research often require the retrospective analysis of large datasets containing defibrillator files from different vendors and clinical annotations by the emergency medical services. AIM: To introduce and evaluate a methodology to automatically extract cardiopulmonary resuscitation (CPR) quality data in a uniform and systematic way from OHCA datasets from multiple heterogeneous sources. METHODS: A dataset of 2236 OHCA cases from multiple defibrillator models and manufacturers was analyzed. Chest compressions were automatically identified using the thoracic impedance and compression depth signals. Device event time-stamps and clinical annotations were used to set the start and end of the analysis interval, and to identify periods with spontaneous circulation. A manual audit of the automatic annotations was conducted and used as gold standard. Chest compression fraction (CCF), rate (CCR) and interruption ratio were computed as CPR quality variables. The unsigned error between the automated procedure and the gold standard was calculated. RESULTS: Full-episode median errors below 2% in CCF, 1 min-1 in CCR, and 1.5% in interruption ratio, were measured for all signals and devices. The proportion of cases with large errors (>10% in CCF and interruption ratio, and >10 min-1 in CCR) was below 10%. Errors were lower for shorter sub-intervals of interest, like the airway insertion interval. CONCLUSIONS: An automated methodology was validated to accurately compute CPR metrics in large and heterogeneous OHCA datasets. Automated processing of defibrillator files and the associated clinical annotations enables the aggregation and analysis of CPR data from multiple sources.

Variation in time to notification of enrollment and rates of withdrawal in resuscitation trials conducted under exception from informed consent.

IMPORTANCE: Emergency research is challenging to do well as it involves time sensitive interventions in unstable patients. There is limited time to obtain informed consent from the patient or their legally authorized representative (LAR). Such research is permitted under exception from informed consent (EFIC) if specific criteria are met, including notification after enrollment. Some question whether the risks of EFIC outweighs its benefits. To date, there is limited empiric information about time to notification (TTN) and rates of withdrawal in such trials. OBJECTIVE: To describe variation in TTN and rates of withdrawal among that patients enrolled in EFIC trials over a twelve-year period. DESIGN: We performed post hoc descriptive analyses of data from five trials conducted under EFIC. SETTING: Emergency medical services and receiving hospitals participating in the Resuscitation Outcomes Consortium in the United States and Canada. PARTICIPANTS: Patients with out-of-hospital cardiac arrest or life-threatening traumatic injury. EXPOSURES: Notification strategies were specified at each site before initiation of enrollment by a local institutional review board. We monitored TTN within each site centrally throughout each study's enrollment period. OUTCOMES: TTN was defined as time from randomization to first-reported notification of patient or LAR of enrollment. Withdrawal was defined as patient or LAR opt out of ongoing participation at the time of notification. RESULTS: Of 35,442 patients enrolled in five trials, 33,805 had cardiac arrest; and 1636 had traumatic injury. TTN varied overall and by patient outcome. Among those with cardiac arrest, TTN ranged from median (5%ile, 95%ile) of 6 (1,27) days to 28 (2, 53) days across sites. 0.3% of notified patients with cardiac arrest withdrew. Among those with traumatic injury, TTN ranged from 0 (0, 5) days to 36 (5, 68) days across sites. 7.7% of notified patients with traumatic injury withdrew. CONCLUSIONS AND RELEVANCE: There is large variation in TTN in trials conducted under EFIC for emergency research. This may be due to several factors. It may or may not be modifiable. Overall rates of withdrawal are low, which suggests current practices related to EFIC are acceptable to those who have participated in emergency research.

Compression depth measured by accelerometer vs. outcome in patients with out-of-hospital cardiac arrest.

BACKGROUND: Analyses of data recorded by monitor-defibrillators that measure CPR depth with different methods show significant relationships between the process and outcome of CPR. Our objective was to evaluate whether chest compression depth was significantly associated with outcome based on accelerometer-recordings obtained with monitor-defibrillators from a single manufacturer, and to assess whether an accelerometer-based analysis corroborated evidence-based practice guidelines on performance of CPR. METHODS AND RESULTS: We included 5434 adult patients treated from seven US and Canadian cities between January 2007 and May 2015. These had mean (SD) age of 64.2 (17.2) years, mean compression depth of 45.9 (12.7) mm, ROSC sustained to ED arrival of 26%, and survival to hospital discharge of 8%. For survival to discharge, the adjusted odds ratios were 1.15 (95% CI, 0.86, 1.55) for cases within 2005 depth range (38-51 mm), and 1.17 (95% CI, 0.91, 1.50) for cases within 2010 depth range (>50 mm) compared to those with an average depth of <38 mm. The adjusted odds ratio of survival was 1.33 (95% CI, 1.01, 1.75) for cases within 2015 depth range (50 to 60 mm) for at least 60% of minutes. CONCLUSIONS: This analysis of patients with OHCA demonstrated that increased chest compression depth measured by accelerometer is associated with better survival. It confirms that current evidence-based recommendations to compress within 50-60 mm are likely associated with greater survival than compressing to another depth.