Fewer severe infections with tranexamic acid in patients with hematologic malignancies.

Background: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty. Objectives: To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies. Methods: We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901). Results: TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease. Conclusion: Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.

Comparative effectiveness of safety planning intervention with instrumental support calls (ISC) versus safety planning intervention with two-way text message caring contacts (CC) in adolescents and adults screening positive for suicide risk in emergency departments and primary care clinics: Protocol for a pragmatic randomized controlled trial.

BACKGROUND: Suicide is a leading cause of death in adolescents and adults in the US. Follow-up support delivered when patients return home after an emergency department (ED) or primary care encounter can significantly reduce suicidal ideation and attempts. Two follow-up models to augment usual care including the Safety Planning Intervention have high efficacy: Instrumental Support Calls (ISC) and Caring Contacts (CC) two-way text messages, but they have never been compared to assess which works best. This protocol for the Suicide Prevention Among Recipients of Care (SPARC) Trial aims to determine which model is most effective for adolescents and adults with suicide risk. METHODS: The SPARC Trial is a pragmatic randomized controlled trial comparing the effectiveness of ISC versus CC. The sample includes 720 adolescents (12-17 years) and 790 adults (18+ years) who screen positive for suicide risk during an ED or primary care encounter. All participants receive usual care and are randomized 1:1 to ISC or CC. The state suicide hotline delivers both follow-up interventions. The trial is single-masked, with participants unaware of the alternative treatment, and is stratified by adolescents/adults. The primary outcome is suicidal ideation and behavior, measured using the Columbia Suicide Severity Rating Scale (C-SSRS) screener at 6 months. Secondary outcomes include C-SSRS at 12 months, and loneliness, return to crisis care for suicidality, and utilization of outpatient mental health services at 6 and 12 months. DISCUSSION: Directly comparing ISC and CC will determine which follow-up intervention is most effective for suicide prevention in adolescents and adults.

Comparative effectiveness of two versions of a caring contacts intervention in healthcare providers, staff, and patients for reducing loneliness and mental distress: A randomized controlled trial.

BACKGROUND: Caring Contacts can effectively reduce suicide ideation, attempts, and death. In published clinical trials, Caring Contacts were sent by someone who knew the recipient. At scale, Caring Contacts programs rarely introduce the recipient and sender. It is not known whether receiving Caring Contacts from someone unknown is as effective as messages from someone the recipient has met. METHODS: Pragmatic randomized controlled trial comparing Caring Contacts with (CC+) versus without an introductory phone call (CC). Recruitment occurred January-July 2021, with outcomes assessed at 6 months. Participants were primary care patients or healthcare providers/staff reporting adverse mental health outcomes on a qualifying survey. Participants were sent 11 standardized caring text messages over 6 months; when participants replied, they received personalized unscripted responses. CC+ calls were semi-structured. The primary outcome was loneliness (NIH Toolkit). RESULTS: Participants included 331 patients (mean [SD] age: 45.5 [16.4], 78.9 % female) and 335 healthcare providers/staff (mean [SD] age: 40.9 [11.8], 86.6 % female). There were no significant differences in loneliness at 6 months by treatment arm in either stratum. In patients, mean (SD) loneliness was 61.9 (10.7) in CC, and 60.8 (10.3) in CC+, adjusted mean difference of -1.0 (95 % CI: -3.0, 1.0); p-value = 0.31. In providers/staff, mean (SD) loneliness was 61.2 (11) in CC, and 61.3 (11.1) in CC+, adjusted mean difference of 0.2 (95 % CI: -1.8, 2.2); p-value = 0.83. LIMITATIONS: Study population was 93 % white which may limit generalizability. CONCLUSIONS: Including an initial phone call added operational complexity without significantly improving the effectiveness of a Caring Contacts program.

Absence of hyperfibrinolysis may explain lack of efficacy of tranexamic acid in hypoproliferative thrombocytopenia.

The American Trial Using Tranexamic Acid (TXA) in Thrombocytopenia (A-TREAT, NCT02578901) demonstrated no superiority of TXA over placebo in preventing World Health Organization (WHO) grade 2 or higher bleeding in patients with severe thrombocytopenia requiring supportive platelet transfusion following myeloablative therapy for hematologic disorders. In this ancillary study, we sought to determine whether this clinical outcome could be explained on the basis of correlative assays of fibrinolysis. Plasma was collected from A-TREAT participants (n = 115) before the initiation of study drug (baseline) and when TXA was at steady-state trough concentration (follow-up). Global fibrinolysis was measured by 3 assays: euglobulin clot lysis time (ECLT), plasmin generation (PG), and tissue-type plasminogen activator (tPA)-challenged clot lysis time (tPA-CLT). TXA was quantified in follow-up samples by tandem mass spectrometry. Baseline samples did not demonstrate fibrinolytic activation by ECLT or tPA-CLT. Furthermore, neither ECLT nor levels of plasminogen activator inhibitor-1, tPA, plasminogen, alpha2-antiplasmin, or plasmin-antiplasmin complexes were associated with a greater risk of WHO grade 2+ bleeding. TXA trough concentrations were highly variable (range, 0.7-10 µg/mL) and did not correlate with bleeding severity, despite the fact that plasma TXA levels correlated strongly with pharmacodynamic assessments by PG (Spearman r, -0.78) and tPA-CLT (r, 0.74). We conclude that (1) no evidence of fibrinolytic activation was observed in these patients with thrombocytopenia, (2) trough TXA concentrations varied significantly between patients receiving the same dosing schedule, and (3) tPA-CLT and PG correlated well with TXA drug levels.

Variation in coronary angiography use in Out-of-Hospital cardiac arrest.

INTRODUCTION: Multiple studies have examined the association of early coronary angiography (CAG) among out-of-hospital cardiac arrest (OHCA) patients with conflicting results. However, patterns of use of CAG among OHCA patients in real-world settings are not well-described. METHODS: Utilizing data from the Resuscitation Outcomes Consortium's Continuous Chest Compressions trial for our analysis, we stratified patients based on initial arrest rhythm and ST-elevation on initial post-resuscitation electrocardiogram (ECG) and examined the rates of CAG in resuscitated patients. We also examined the rates of CAG across different trial clusters in the overall study population as well as in pre-specified patient subgroups RESULTS: Of 26,148 patients in the CCC trial, 5,608 survived to hospital admission and were enrolled in the study. Among them, 26 % underwent CAG. Patients with ST-elevation underwent CAG at a significantly higher rate than patients presenting without ST-elevation (70 % vs 31 %, p < 0.001). Similarly, patients presenting with shockable rhythms underwent CAG more frequently compared with patients with non-shockable rhythms (28 % vs 5 %, p < 0.001). There was marked variation in CAG frequency across different trial clusters with the proportion of patients within a trial cluster receiving CAG ranging from 4 % - 41 %. The proportion varied more among patients with ST-elevation (16 % - 82 %) or initial shockable rhythm (11 % - 75 %) compared with no ST-elevation (2 % - 28 %) or initial non-shockable rhythm (0 % - 19 %). CONCLUSION: Among a national cohort of OHCA patients, large variation in the use of CAG exists, highlighting the existing uncertainty regarding perceived benefit from early CAG in OHCA.

Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial.

Evidence of the effectiveness of prophylactic use of tranexamic acid (TXA) in thrombocytopenia is lacking. To determine whether TXA safely reduces bleeding incidence in patients undergoing treatment for hematologic malignancies, a randomized, double-blind clinical trial was conducted from June 2016 through June 2020. Of 3120 screened adults, 356 patients were eligible and enrolled, and 337 patients (mean age, 53.9; 141 [41.8%] women), randomized to 1300 mg TXA orally or 1000 mg TXA through IV (n = 168) vs placebo (n = 169) thrice daily for maximum 30 days. Three hundred thirty patients were activated when their platelet counts fell below 30 000 per µL; 279 (83%) had complete outcome ascertainment. World Health Organization (WHO) grade ≥2 bleeding was observed in the 30 days following activation in 50.3% (73/145) and 54.2% (78/144) of patients in the TXA and placebo groups, with an adjusted odds ratio of 0.83 (95% confidence interval [CI], 0.50-1.34; P = .44). There was no statistically significant difference in the mean number of platelet transfusions (mean difference, 0.1; 95% CI, -1.9 to 2.0), mean days alive without grade ≥2 bleeding (mean difference, 0.8; 95% CI, -0.4 to 2.0), thrombotic events (6/163 [3.7%] TXA, 9/163 [5.5%] placebo), or deaths due to serious bleeding. Most common adverse events were: diarrhea (116/164 [70.7%] TXA and 114/163 [69.9%] placebo); febrile neutropenia (111/164 [67.7%] TXA, 105/163 [64.4%] placebo); fatigue (106/164 [64.6%] TXA, 109/163 [66.9%] placebo); and nausea (104/164 [63.4%] TXA, 97/163 [59.5%] placebo). Among patients with hematologic malignancy undergoing chemotherapy or hematopoietic stem cell transplantation, prophylactic treatment with TXA compared with placebo did not significantly reduce the risk of WHO grade ≥2 bleeding.

Community lessons to understand resuscitation excellence (culture): Association between emergency medical services (EMS) culture and outcome after out-of-hospital cardiac arrest.

BACKGROUND: The large geographic variation in outcome after out-of-hospital cardiac arrest (OHCA) is not well explained by traditional patient and emergency medical services (EMS) characteristics. A 'culture of excellence' in resuscitation within an EMS is believed to be an important factor that influences quality of care and outcome in patients with OHCA. However, whether a culture of excellence is associated with improved survival after OHCA is not known. METHODOLOGY: We linked survey responses from EMS agency medical directors related to resuscitation culture to a retrospective analysis of prospectively collected data from the Resuscitation Outcomes Consortium (ROC) Epistry - Cardiac Arrest. We used a multivariable random effects model to assess whether EMS culture strategies were associated with OHCA survival to hospital discharge. RESULTS: Of the 46 EMS medical directors surveyed, 35 (76%) provided a complete response. Included were n = 66,597 cases of OHCA who received attempted resuscitation by one of n = 123 EMS agencies from July 1, 2010, through June 30, 2015. Overall survival to discharge was 11%. Organizational values and goals were independently associated with survival to hospital discharge in all OHCAs (adjusted odds ratio [AOR] 1.27, 95% confidence interval [CI] 1.09-1.48) and the subgroup restricted to bystander witnessed OHCAs with initial shockable rhythm (AOR 1.55, 95% CI 1.21-1.99). CONCLUSIONS: An organizational goal to improve OHCA survival was independently associated with improved survival to discharge. EMS agencies looking to improve OHCA survival should consider implementing an organizational goal to improve OHCA survival and empower quality improvement personnel to drive that goal.

Information growth for sequential monitoring of clinical trials with a stepped wedge cluster randomized design and unknown intracluster correlation.

BACKGROUND/AIMS: In a stepped wedge study design, study clusters usually start with the baseline treatment and then cross over to the intervention at randomly determined times. Such designs are useful when the intervention must be delivered at the cluster level and are becoming increasingly common in practice. In these trials, if the outcome is death or serious morbidity, one may have an ethical imperative to monitor the trial and stop before maximum enrollment if the new therapy is proven to be beneficial. In addition, because formal monitoring allows for the stoppage of trials when a significant benefit for new therapy has been ruled out, their use can make a research program more efficient. However, use of the stepped wedge cluster randomized study design complicates the implementation of standard group sequential monitoring methods. Both the correlation of observations introduced by the clustered randomization and the timing of crossover from one treatment to the other impact the rate of information growth, an important component of an interim analysis. METHODS: We simulated cross-sectional stepped wedge study data in order to evaluate the impact of sequential monitoring on the Type I error and power when the true intracluster correlation is unknown. We studied the impact of varying intracluster correlations, treatment effects, methods of estimating the information growth, and boundary shapes. RESULTS: While misspecified information growth can impact both the Type I error and power of a study in some settings, we observed little inflation of the Type I error and only moderate reductions in power across a range of misspecified information growth patterns in our simulations. CONCLUSION: Taking the study design into account and using either an estimate of the intracluster correlation from the ongoing study or other data in the same clusters should allow for easy implementation of group sequential methods in future stepped wedge designs.

Non-inferiority designs comparing placebo to a proven therapy for childhood pneumonia in low-resource settings.

BACKGROUND/AIMS: After a new treatment is recommended to be first-line treatment for a specific indication, outcome and population, it may be unethical to use placebo as a comparator in trials for that setting. Nevertheless, in specific circumstances, use of a placebo group might be warranted, for example, when it is believed that an active treatment may not be efficacious or cost-effective for a specific subpopulation. An example is antibiotic treatment for pneumonia, which may not be effective for many patients taking it due to the emergence of antibiotic-resistant strains or the high prevalence of viral and low prevalence of bacterial pneumonia. METHODS: We explore the applicability of different design options in cases where the benefit of an established treatment is questioned, with particular emphasis on issues that arise in a low-resource setting. Using the example of a clinical trial comparing the effectiveness of placebo versus amoxicillin in treating children 2-59 months of age with fast breathing pneumonia in Lilongwe, Malawi, we discuss the pros and cons of superiority versus non-inferiority designs, an intent-to-treat versus as-treated analysis and the use and interpretation of one- versus two-sided confidence intervals. RESULTS: We find that a non-inferiority design using an intent-to-treat analysis is the most appropriate design and analysis option. In addition, the presentation of one- versus two-sided confidence intervals can depend on the results but can maintain type I error. CONCLUSION: In the setting where the benefit of a previously established beneficial treatment is questioned, a non-inferiority design that includes placebo as the tested treatment option can be the most appropriate design option.

Development of a prognostic risk score to aid antibiotic decision-making for children aged 2-59 months with World Health Organization fast breathing pneumonia in Malawi: An Innovative Treatments in Pneumonia (ITIP) secondary analysis.

BACKGROUND: Due to increasing antimicrobial resistance in low-resource settings, strategies to rationalize antibiotic treatment of children unlikely to have a bacterial infection are needed. This study's objective was to utilize a database of placebo treated Malawian children with World Health Organization (WHO) fast breathing pneumonia to develop a prognostic risk score that could aid antibiotic decision making. METHODS: We conducted a secondary analysis of children randomized to the placebo group of the Innovative Treatments in Pneumonia (ITIP) fast breathing randomized, controlled, noninferiority trial. Participants were low-risk HIV-uninfected children 2-59 months old with WHO fast breathing pneumonia in Lilongwe, Malawi. Study endpoints were treatment failure, defined as either disease progression at any time on or before Day 4 of treatment or disease persistence on Day 4, or relapse, considered as the recurrence of pneumonia or severe disease among previously cured children between Days 5 and 14. We utilized multivariable linear regression and stepwise model selection to develop a model to predict the probability of treatment failure or relapse. RESULTS: Treatment failure or relapse occurred in 11.5% (61/526) of children included in this analysis. The final model incorporated the following predictors: heart rate terms, mid-upper arm circumference, malaria status, water source, family income, and whether or not a sibling or other child in the household received childcare outside the home. The model's area under the receiver operating characteristic score was 0.712 (95% confidence interval 0.66, 0.78) and it explained 6.1% of the variability in predicting treatment failure or relapse (R2, 0.061). For the model to categorize all children with treatment failure or relapse correctly, 77% of children without treatment failure or relapse would require antibiotics. CONCLUSION: The model had inadequate discrimination to be appropriate for clinical application. Different strategies will likely be required for models to perform accurately among similar pediatric populations.

International variation in survival after out-of-hospital cardiac arrest: A validation study of the Utstein template.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) survival varies greatly between communities. The Utstein template was developed and promulgated to improve the comparability of OHCA outcome reports, but it has undergone limited empiric validation. We sought to assess how much of the variation in OHCA survival between emergency medical services (EMS) across the globe is explained by differences in the Utstein factors. We also assessed how accurately the Utstein factors predict OHCA survival. METHODS: We performed a retrospective analysis of patient-level prospectively collected data from 12 OHCA registries from 12 countries for the period 1 Jan 2006 through 31 Dec 2011. We used generalized linear mixed models to examine the variation in survival between EMS agencies (n=232). RESULTS: Twelve registries contributed 86,759 cases. Patient arrest characteristics, EMS treatment and patient outcomes varied across registries. Overall survival to hospital discharge was 10% (range, 6% to 22%). Overall survival with Cerebral Performance Category of 1 or 2 (available for 8/12 registries) was 8% (range, 2% to 20%). The area-under-the-curve for the Utstein model was 0.85 (Wald CI: 0.85-0.85). The Utstein factors explained 51% of the EMS agency variation in OHCA survival. CONCLUSIONS: The Utstein factors explained 51% of the variation in survival to hospital discharge among multiple large geographically separate EMS agencies. This suggests that quality improvement and public health efforts should continue to target modifiable Utstein factors to improve OHCA survival. Further study is required to identify the reasons for the variation that is incompletely understood.

Bystander automated external defibrillator application in non-shockable out-of-hospital cardiac arrest.

BACKGROUND: An increasing proportion of patients with OHCA present with non-shockable rhythms, among whom the benefit from AED application is not known. METHODS: We performed a retrospective analysis of adults with non-traumatic, public, bystander-witnessed, non-shockable OHCA occurring between 2005-2015 at 9 locations participating in the Resuscitation Outcomes Consortium. Non-shockable arrest was defined as when no shock was administered by a bystander applied AED and confirmed by the initial rhythm on EMS arrival. Outcomes were compared between patients with non-shockable OHCA in whom a bystander AED was or was not applied. RESULTS: Among 2809 patients with non-shockable public, witnessed OHCA, 8.4% had an AED applied. CPR was more often performed in the AED-applied group (99% vs. 51% of patients, p < 0.001). Among patients in whom an AED was not applied, 39.8% had any pre-hospital ROSC, 29.6% had a pulse at ED arrival and 11.1% survived to hospital discharge compared to 44.1%, 29.6% and 9.7%, respectively with AED application. After adjustment for the Utstein variables excluding bystander CPR, the OR for survival to hospital discharge for AED application was 0.90 (95% CI:0.57-1.42); when adjusted for the higher frequency of CPR in the AED group the OR was 0.92 (95% CI:0.57-1.47). CONCLUSIONS: The application of an AED in non-shockable public witnessed OHCA was associated with a higher frequency of bystander CPR. The probabilities of pre-hospital ROSC, pulse at ED arrival, and survival to hospital discharge were not altered by the application of an AED.

Intraosseous versus intravenous access in patients with out-of-hospital cardiac arrest: Insights from the resuscitation outcomes consortium continuous chest compression trial.

AIM: To examine outcomes associated with intraosseous access route attempt for delivery of medications during out-of-hospital cardiac arrest (OHCA) resuscitation. METHODS: Using data from the Continuous Chest Compression trial, we examined rates of survival to hospital discharge, sustained return of spontaneous circulation (ROSC), and survival with favorable neurological function among patients with intraosseous and intravenous access attempts after adjusting for age, sex, initial rhythm, bystander cardiopulmonary resuscitation, public location, witnessed status, EMS response and trial randomization cluster. RESULTS: Among 19,731 patients, intraosseous access was attempted in 3068 patients and intravenous access in 16,663 patients respectively. Patients in whom intraosseous access was attempted were younger, more often female, and had marginally faster times to initial access and to initial drug administration. Unadjusted outcomes were significantly lower in patients with attempted intraosseous access compared with intravenous access: (4.6% vs. 5.7%, p = 0.01) for survival to discharge, (17.9% vs. 23.5%, p < 0.001) for sustained ROSC and (2.8% vs. 4.2%, p < 0.001) for survival with favorable neurological function. After adjustment, there were no differences in hospital survival (OR, 0.88, 95% CI 0.72-1.09, p = 0.24) or survival with favorable neurological function (OR, 0.87, 95% CI 0.67-1.12, p = 0.29) in patients with intraosseous access attempt (vs. intravenous access). However, intraosseous access continued to associate with lower rates of sustained ROSC (OR, 0.80, 95% CI 0.71 - 0.89, p < 0.001). CONCLUSIONS: Among patients with OHCA, intraosseous access attempt was associated with worse ROSC rates but no difference in survival. Further studies are necessary to elucidate the optimal access route among OHCA patients.

Impact of Bystander Automated External Defibrillator Use on Survival and Functional Outcomes in Shockable Observed Public Cardiac Arrests.

BACKGROUND: Survival following out-of-hospital cardiac arrest (OHCA) with shockable rhythms can be improved with early defibrillation. Although shockable OHCA accounts for only ≈25% of overall arrests, ≈60% of public OHCAs are shockable, offering the possibility of restoring thousands of individuals to full recovery with early defibrillation by bystanders. We sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public OHCA. METHODS: From 2011 to 2015, the Resuscitation Outcomes Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander-applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharge with normal or near-normal (favorable) functional status defined as a modified Rankin Score ≤2. Survival to hospital discharge was the secondary outcome measure. RESULTS: Among 49 555 OHCAs, 4115 (8.3%) observed public OHCAs were analyzed, of which 2500 (60.8%) were shockable. A bystander shock was applied in 18.8% of the shockable arrests. Patients shocked by a bystander were significantly more likely to survive to discharge (66.5% versus 43.0%) and be discharged with favorable functional outcome (57.1% versus 32.7%) than patients initially shocked by emergency medical services. After adjusting for known predictors of outcome, the odds ratio associated with a bystander shock was 2.62 (95% confidence interval, 2.07-3.31) for survival to hospital discharge and 2.73 (95% confidence interval, 2.17-3.44) for discharge with favorable functional outcome. The benefit of bystander shock increased progressively as emergency medical services response time became longer. CONCLUSIONS: Bystander automated external defibrillator use before emergency medical services arrival in shockable observed public OHCA was associated with better survival and functional outcomes. Continued emphasis on public automated external defibrillator utilization programs may further improve outcomes of OHCA.

What change in outcomes after cardiac arrest is necessary to change practice? Results of an international survey.

BACKGROUND: Efficient trials of interventions for patients with out-of-hospital cardiac arrest (OHCA) should have adequate but not excess power to detect a difference in outcomes. The minimum clinically important difference (MCID) is the threshold value in outcomes observed in a trial at which providers should choose to adopt a treatment. There has been limited assessment of MCID for outcomes after OHCA. Therefore, we conducted an international survey of individuals interested in cardiac resuscitation to define the MCID for a range of outcomes after OHCA. METHODS: A brief survey instrument was developed and modified by consensus. Included were open-ended responses. The survey included an illustrative example of a hypothetical randomized study with distributions of outcomes based on those in a public use datafile from a previous trial. Elicited information included the minimum significant difference required in an outcome to change clinical practice. The population of interest was emergency physicians or other practitioners of acute cardiovascular research. RESULTS: Usable responses were obtained from 160 respondents (50% of surveyed) in 46 countries (79% of surveyed). MCIDs tended to increase as baseline outcomes increased. For a population of patients with 25% survival to discharge and 20% favorable neurologic status at discharge, the MCID were median 5 (interquartile range [IQR] 3, 10) percent for survival to discharge; median 5 (IQR 2, 10) percent for favorable neurologic status at discharge, median 4 (IQR 2, 9) days of ICU-free survival and median 4 (IQR 2, 8) days of hospital-free survival. CONCLUSION: Reported MCIDs for outcomes after OHCA vary according to the outcome considered as well as the baseline rate of achieving it. MCIDs of ICU-free survival or hospital-free survival may be useful to accelerate the rate of evidence-based change in resuscitation care.

Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest.

BACKGROUND: Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit. METHODS: In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock. RESULTS: In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo. CONCLUSIONS: Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647.).

Time on the scene and interventions are associated with improved survival in pediatric out-of-hospital cardiac arrest.

BACKGROUND: Survival is less than 10% for pediatric patients following out-of-hospital cardiac arrest. It is not known if more time on the scene of the cardiac arrest and advanced life support interventions by emergency services personnel are associated with improved survival. AIM: This study was performed to determine which times on the scene and which prehospital interventions were associated with improved survival. METHODS: We studied patients aged 3 days to 19 years old with out-of-hospital cardiac arrest, using the Resuscitation Outcomes Consortium cardiac arrest database from 11 North American regions, from 2005 to 2012. We evaluated survival to hospital discharge according to on-scene times (<10, 10 to 35 and >35 min). RESULTS: Data were available for 2244 patients (1017 infants, 594 children and 633 adolescents). Infants had the lowest rate of survival (3.7%) compared to children (9.8%) and adolescents (16.3%). Survival improved over the 7 year study period especially among adolescents. Survival was highest in the 10 to 35 min on-scene time group (10.2%) compared to the >35 min. group (6.9%) and the <10 min. group (5.3%, p=0.01). Intravenous or intra-osseous access attempts and fluid administration were associated with improved survival, whereas advanced airway attempts were not associated with survival and resuscitation drugs were associated with worse survival. CONCLUSIONS: In this observational study, a scene time of 10 to 35 min was associated with the highest survival, especially among adolescents. Access for fluid resuscitation was associated with increased survival but advanced airway and resuscitation drugs were not.

A quantitative analysis of out-of-hospital pediatric and adolescent resuscitation quality--A report from the ROC epistry-cardiac arrest.

AIM: High-quality cardiopulmonary resuscitation (CPR) may improve survival. The quality of CPR performed during pediatric out-of-hospital cardiac arrest (p-OHCA) is largely unknown. The main objective of this study was to describe the quality of CPR performed during p-OHCA resuscitation attempts. METHODS: Prospective observational multi-center cohort study of p-OHCA patients ≥ 1 and < 19 years of age registered in the Resuscitation Outcomes Consortium (ROC) Epistry database. The primary outcome was an a priori composite variable of compliance with American Heart Association (AHA) guidelines for both chest compression (CC) rate and CC fraction (CCF). Event compliance was defined as a case with 60% or more of its minute epochs compliant with AHA targets (rate 100-120 min(-1); depth ≥ 38 mm; and CCF ≥ 0.80). In a secondary analysis, multivariable logistic regression was used to evaluate the association between guideline compliance and return of spontaneous circulation (ROSC). RESULTS: Between December 2005 and December 2012, 2564 pediatric events were treated by EMS providers, 390 of which were included in the final cohort. Of these events, 22% achieved AHA compliance for both rate and CCF, 36% for rate alone, 53% for CCF alone, and 58% for depth alone. Over time, there was a significant increase in CCF (p < 0.001) and depth (p = 0.03). After controlling for potential confounders, there was no significant association between AHA guideline compliance and ROSC. CONCLUSIONS: In this multi-center study, we have established that there are opportunities for professional rescuers to improve prehospital CPR quality. Encouragingly, CCF and depth both increased significantly over time.

A randomized trial of continuous versus interrupted chest compressions in out-of-hospital cardiac arrest: rationale for and design of the Resuscitation Outcomes Consortium Continuous Chest Compressions Trial.

The Resuscitation Outcomes Consortium is conducting a randomized trial comparing survival with hospital discharge after continuous chest compressions without interruption for ventilation versus currently recommended American Heart Association cardiopulmonary resuscitation with interrupted chest compressions in adult patients with out-of-hospital cardiac arrest without obvious trauma or respiratory cause. Emergency medical services perform study cardiopulmonary resuscitation for 3 intervals of manual chest compressions (each ~2 minutes) or until restoration of spontaneous circulation. Patients randomized to the continuous chest compression intervention receive 200 chest compressions with positive pressure ventilations at a rate of 10/min without interruption in compressions. Those randomized to the interrupted chest compression study arm receive chest compressions interrupted for positive pressure ventilations at a compression:ventilation ratio of 30:2. In either group, each interval of compressions is followed by rhythm analysis and defibrillation as required. Insertion of an advanced airway is deferred for the first ≥6 minutes to reduce interruptions in either study arm. The study uses a cluster randomized design with every-6-month crossovers. The primary outcome is survival to hospital discharge. Secondary outcomes are neurologically intact survival and adverse events. A maximum of 23,600 patients (11,800 per group) enrolled during the post-run-in phase of the study will provide ≥90% power to detect a relative change of 16% in the rate of survival to discharge, 8.1% to 9.4% with overall significance level of 0.05. If this trial demonstrates improved survival with either strategy, >3,000 premature deaths from cardiac arrest would be averted annually.

Chest compression rates and survival following out-of-hospital cardiac arrest.

OBJECTIVE: Guidelines for cardiopulmonary resuscitation recommend a chest compression rate of at least 100 compressions/min. A recent clinical study reported optimal return of spontaneous circulation with rates between 100 and 120/min during cardiopulmonary resuscitation for out-of-hospital cardiac arrest. However, the relationship between compression rate and survival is still undetermined. DESIGN: Prospective, observational study. SETTING: Data is from the Resuscitation Outcomes Consortium Prehospital Resuscitation IMpedance threshold device and Early versus Delayed analysis clinical trial. PARTICIPANTS: Adults with out-of-hospital cardiac arrest treated by emergency medical service providers. INTERVENTIONS: None. MEASUREMENTS MAIN RESULTS: Data were abstracted from monitor-defibrillator recordings for the first five minutes of emergency medical service cardiopulmonary resuscitation. Multiple logistic regression assessed odds ratio for survival by compression rate categories (<80, 80-99, 100-119, 120-139, ≥140), both unadjusted and adjusted for sex, age, witnessed status, attempted bystander cardiopulmonary resuscitation, location of arrest, chest compression fraction and depth, first rhythm, and study site. Compression rate data were available for 10,371 patients; 6,399 also had chest compression fraction and depth data. Age (mean±SD) was 67±16 years. Chest compression rate was 111±19 per minute, compression fraction was 0.70±0.17, and compression depth was 42±12 mm. Circulation was restored in 34%; 9% survived to hospital discharge. After adjustment for covariates without chest compression depth and fraction (n=10,371), a global test found no significant relationship between compression rate and survival (p=0.19). However, after adjustment for covariates including chest compression depth and fraction (n=6,399), the global test found a significant relationship between compression rate and survival (p=0.02), with the reference group (100-119 compressions/min) having the greatest likelihood for survival. CONCLUSIONS: After adjustment for chest compression fraction and depth, compression rates between 100 and 120 per minute were associated with greatest survival to hospital discharge.