Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium.

OBJECTIVE: To identify causes and timing of mortality in trauma patients to determine targets for future studies. BACKGROUND: In trials conducted by the Resuscitation Outcomes Consortium in patients with traumatic hypovolemic shock (shock) or traumatic brain injury (TBI), hypertonic saline failed to improve survival. Selecting appropriate candidates is challenging. METHODS: Retrospective review of patients enrolled in multicenter, randomized trials performed from 2006 to 2009. Inclusion criteria were as follows: injured patients, age 15 years or more with hypovolemic shock [systolic blood pressure (SBP) ≤ 70 mm Hg or SBP 71-90 mm Hg with heart rate ≥ 108) or severe TBI [Glasgow Coma Score (GCS) ≤ 8]. Initial fluid administered was 250 mL of either 7.5% saline with 6% dextran 70, 7.5% saline or 0.9% saline. RESULTS: A total of 2061 subjects were enrolled (809 shock, 1252 TBI) and 571 (27.7%) died. Survivors were younger than nonsurvivors [30 (interquartile range 23) vs 42 (34)] and had a higher GCS, though similar hemodynamics. Most deaths occurred despite ongoing resuscitation. Forty-six percent of deaths in the TBI cohort were within 24 hours, compared with 82% in the shock cohort and 72% in the cohort with both shock and TBI. Median time to death was 29 hours in the TBI cohort, 2 hours in the shock cohort, and 4 hours in patients with both. Sepsis and multiple organ dysfunction accounted for 2% of deaths. CONCLUSIONS: Most deaths from trauma with shock or TBI occur within 24 hours from hypovolemic shock or TBI. Novel resuscitation strategies should focus on early deaths, though prevention may have a greater impact.

Ventricular tachyarrhythmias after cardiac arrest in public versus at home.

BACKGROUND: The incidence of ventricular fibrillation or pulseless ventricular tachycardia as the first recorded rhythm after out-of-hospital cardiac arrest has unexpectedly declined. The success of bystander-deployed automated external defibrillators (AEDs) in public settings suggests that this may be the more common initial rhythm when out-of-hospital cardiac arrest occurs in public. We conducted a study to determine whether the location of the arrest, the type of arrhythmia, and the probability of survival are associated. METHODS: Between 2005 and 2007, we conducted a prospective cohort study of out-of-hospital cardiac arrest in adults in 10 North American communities. We assessed the frequencies of ventricular fibrillation or pulseless ventricular tachycardia and of survival to hospital discharge for arrests at home as compared with arrests in public. RESULTS: Of 12,930 evaluated out-of-hospital cardiac arrests, 2042 occurred in public and 9564 at home. For cardiac arrests at home, the incidence of ventricular fibrillation or pulseless ventricular tachycardia was 25% when the arrest was witnessed by emergency-medical-services (EMS) personnel, 35% when it was witnessed by a bystander, and 36% when a bystander applied an AED. For cardiac arrests in public, the corresponding rates were 38%, 60%, and 79%. The adjusted odds ratio for initial ventricular fibrillation or pulseless ventricular tachycardia in public versus at home was 2.28 (95% confidence interval [CI], 1.96 to 2.66; P < 0.001) for bystander-witnessed arrests and 4.48 (95% CI, 2.23 to 8.97; P<0.001) for arrests in which bystanders applied AEDs. The rate of survival to hospital discharge was 34% for arrests in public settings with AEDs applied by bystanders versus 12% for arrests at home (adjusted odds ratio, 2.49; 95% CI, 1.03 to 5.99; P = 0.04). CONCLUSIONS: Regardless of whether out-of-hospital cardiac arrests are witnessed by EMS personnel or bystanders and whether AEDs are applied by bystanders, the proportion of arrests with initial ventricular fibrillation or pulseless ventricular tachycardia is much greater in public settings than at home. The incremental value of resuscitation strategies, such as the ready availability of an AED, may be related to the place where the arrest occurs.

Early versus later rhythm analysis in patients with out-of-hospital cardiac arrest.

BACKGROUND: In a departure from the previous strategy of immediate defibrillation, the 2005 resuscitation guidelines from the American Heart Association-International Liaison Committee on Resuscitation suggested that emergency medical service (EMS) personnel could provide 2 minutes of cardiopulmonary resuscitation (CPR) before the first analysis of cardiac rhythm. We compared the strategy of a brief period of CPR with early analysis of rhythm with the strategy of a longer period of CPR with delayed analysis of rhythm. METHODS: We conducted a cluster-randomized trial involving adults with out-of-hospital cardiac arrest at 10 Resuscitation Outcomes Consortium sites in the United States and Canada. Patients in the early-analysis group were assigned to receive 30 to 60 seconds of EMS-administered CPR and those in the later-analysis group were assigned to receive 180 seconds of CPR, before the initial electrocardiographic analysis. The primary outcome was survival to hospital discharge with satisfactory functional status (a modified Rankin scale score of ≤3, on a scale of 0 to 6, with higher scores indicating greater disability). RESULTS: We included 9933 patients, of whom 5290 were assigned to early analysis of cardiac rhythm and 4643 to later analysis. A total of 273 patients (5.9%) in the later-analysis group and 310 patients (5.9%) in the early-analysis group met the criteria for the primary outcome, with a cluster-adjusted difference of -0.2 percentage points (95% confidence interval, -1.1 to 0.7; P=0.59). Analyses of the data with adjustment for confounding factors, as well as subgroup analyses, also showed no survival benefit for either study group. CONCLUSIONS: Among patients who had an out-of-hospital cardiac arrest, we found no difference in the outcomes with a brief period, as compared with a longer period, of EMS-administered CPR before the first analysis of cardiac rhythm. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.).

Resuscitation Outcomes Consortium-Amiodarone, Lidocaine or Placebo Study (ROC-ALPS): Rationale and methodology behind an out-of-hospital cardiac arrest antiarrhythmic drug trial.

BACKGROUND: Despite their wide use, whether antiarrhythmic drugs improve survival after out-of-hospital cardiac arrest (OHCA) is not known. The ROC-ALPS is evaluating the effectiveness of these drugs for OHCA due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia (VF/VT). METHODS: ALPS will randomize 3,000 adults across North America with nontraumatic OHCA, persistent or recurring VF/VT after ≥1 shock, and established vascular access to receive up to 450 mg amiodarone, 180 mg lidocaine, or placebo in the field using a double-blind protocol, along with standard resuscitation measures. The designated target population is all eligible randomized recipients of any dose of ALPS drug whose initial OHCA rhythm was VF/VT. A safety analysis includes all randomized patients regardless of their eligibility, initial arrhythmia, or actual receipt of ALPS drug. The primary outcome of ALPS is survival to hospital discharge; a secondary outcome is functional survival at discharge assessed as a modified Rankin Scale score ≤3. RESULTS: The principal aim of ALPS is to determine if survival is improved by amiodarone compared with placebo; secondary aim is to determine if survival is improved by lidocaine vs placebo and/or by amiodarone vs lidocaine. Prioritizing comparisons in this manner acknowledges where differences in outcome are most expected based on existing knowledge. Each aim also represents a clinically relevant comparison between treatments that is worth investigating. CONCLUSIONS: Results from ALPS will provide important information about the choice and value of antiarrhythmic therapies for VF/VT arrest with direct implications for resuscitation guidelines and clinical practice.

Association between survival and early versus later rhythm analysis in out-of-hospital cardiac arrest: do agency-level factors influence outcomes?

STUDY OBJECTIVE: Effectiveness of a resuscitation strategy may vary across communities. We hypothesize that a strategy that prioritizes initial emergency medical services (EMS) rhythm analysis (analyze early) will be associated with survival advantage among EMS systems with lower baseline (pretrial) ventricular fibrillation survival, whereas a strategy that prioritizes initial EMS cardiopulmonary resuscitation (analyze late) will be associated with survival advantage among systems with higher ventricular fibrillation baseline survival. METHODS: We conducted a secondary, post hoc study of a randomized trial of out-of-hospital cardiac arrest. Subjects were stratified according to randomization status (analyze early versus analyze late) and EMS agency baseline ventricular fibrillation survival. We used a mixed-effects model to determine whether the association between favorable functional survival to hospital discharge and trial intervention (analyze late versus analyze early) differed according to EMS agency baseline ventricular fibrillation survival (<20% or >20%). RESULTS: Characteristics were similar among patients randomized to analyze early (n=4,964) versus analyze late (n=4,426). For EMS agencies with baseline ventricular fibrillation survival less than 20%, analyze late compared with analyze early was associated with a lower likelihood of favorable functional survival (3.8% versus 5.5%; odds ratio [OR]=0.67 [95% CI 0.50, 0.90]). Conversely, among agencies with a ventricular fibrillation survival greater than 20%, analyze late compared with analyze early was associated with higher likelihood of favorable functional survival (7.5% versus 6.1%; OR=1.22 [95% CI 0.98, 1.52]). In the multivariable-adjusted model, for every 10% increase in baseline ventricular fibrillation survival, analyze late versus analyze early was associated with a 34% increase in odds of favorable functional survival (OR=1.34 [95% CI 1.07 to 1.66]). CONCLUSION: The findings suggest that system-level characteristics may influence resuscitation outcomes.

Association of out-of-hospital advanced airway management with outcomes after traumatic brain injury and hemorrhagic shock in the ROC hypertonic saline trial.

OBJECTIVE: Prior studies suggest adverse associations between out-of-hospital advanced airway management (AAM) and patient outcomes after major trauma. This secondary analysis of data from the Resuscitation Outcomes Consortium Hypertonic Saline Trial evaluated associations between out-of-hospital AAM and outcomes in patients suffering isolated severe traumatic brain injury (TBI) or haemorrhagic shock. METHODS: This multicentre study included adults with severe TBI (GCS ≤8) or haemorrhagic shock (SBP ≤70 mm Hg, or (SBP 71-90 mm Hg and heart rate ≥108 bpm)). We compared patients receiving out-of-hospital AAM with those receiving emergency department AAM. We evaluated the associations between airway strategy and patient outcomes (28-day mortality, and 6-month poor neurologic or functional outcome) and airway strategy, adjusting for confounders. Analysis was stratified by (1) patients with isolated severe TBI and (2) patients with haemorrhagic shock with or without severe TBI. RESULTS: Of 2135 patients, we studied 1116 TBI and 528 shock; excluding 491 who died in the field, did not receive AAM or had missing data. In the shock cohort, out-of-hospital AAM was associated with increased 28-day mortality (adjusted OR 5.14; 95% CI 2.42 to 10.90). In TBI, out-of-hospital AAM showed a tendency towards increased 28-day mortality (adjusted OR 1.57; 95% CI 0.93 to 2.64) and 6-month poor functional outcome (1.63; 1.00 to 2.68), but these differences were not statistically significant. Out-of-hospital AAM was associated with poorer 6-month TBI neurologic outcome (1.80; 1.09 to 2.96). CONCLUSIONS: Out-of-hospital AAM was associated with increased mortality after haemorrhagic shock. The adverse association between out-of-hospital AAM and injury outcome is most pronounced in patients with haemorrhagic shock.

Relationship between chest compression rates and outcomes from cardiac arrest.

BACKGROUND: Guidelines for cardiopulmonary resuscitation recommend a chest compression rate of at least 100 compressions per minute. Animal and human studies have reported that blood flow is greatest with chest compression rates near 120/min, but few have reported rates used during out-of-hospital (OOH) cardiopulmonary resuscitation or the relationship between rate and outcome. The purpose of this study was to describe chest compression rates used by emergency medical services providers to resuscitate patients with OOH cardiac arrest and to determine the relationship between chest compression rate and outcome. METHODS AND RESULTS: Included were patients aged ≥ 20 years with OOH cardiac arrest treated by emergency medical services providers participating in the Resuscitation Outcomes Consortium. Data were abstracted from monitor-defibrillator recordings during cardiopulmonary resuscitation. Multiple logistic regression analysis assessed the association between chest compression rate and outcome. From December 2005 to May 2007, 3098 patients with OOH cardiac arrest were included in this study. Mean age was 67 ± 16 years, and 8.6% survived to hospital discharge. Mean compression rate was 112 ± 19/min. A curvilinear association between chest compression rate and return of spontaneous circulation was found in cubic spline models after multivariable adjustment (P=0.012). Return of spontaneous circulation rates peaked at a compression rate of ≈ 125/min and then declined. Chest compression rate was not significantly associated with survival to hospital discharge in multivariable categorical or cubic spline models. CONCLUSIONS: Chest compression rate was associated with return of spontaneous circulation but not with survival to hospital discharge in OOH cardiac arrest.

Perishock pause: an independent predictor of survival from out-of-hospital shockable cardiac arrest.

BACKGROUND: Perishock pauses are pauses in chest compressions before and after defibrillatory shock. We examined the relationship between perishock pauses and survival to hospital discharge. METHODS AND RESULTS: We included out-of-hospital cardiac arrest patients in the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest who suffered arrest between December 2005 and June 2007, presented with a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia), and had cardiopulmonary resuscitation process data for at least 1 shock (n=815). We used multivariable logistic regression to determine the association between survival and perishock pauses. In an analysis adjusted for Utstein predictors of survival, the odds of survival were significantly lower for patients with preshock pause ≥20 seconds (odds ratio, 0.47; 95% confidence interval, 0.27 to 0.82) and perishock pause ≥40 seconds (odds ratio, 0.54; 95% confidence interval, 0.31 to 0.97) compared with patients with preshock pause <10 seconds and perishock pause <20 seconds. Postshock pause was not independently associated with a significant change in the odds of survival. Log-linear modeling depicted a decrease in survival to hospital discharge of 18% and 14% for every 5-second increase in both preshock and perishock pause interval (up to 40 and 50 seconds, respectively), with no significant association noted with changes in the postshock pause interval. CONCLUSIONS: In patients with cardiac arrest presenting in a shockable rhythm, longer perishock and preshock pauses were independently associated with a decrease in survival to hospital discharge. The impact of preshock pause on survival suggests that refinement of automatic defibrillator software and paramedic education to minimize preshock pause delays may have a significant impact on survival.

What is the role of chest compression depth during out-of-hospital cardiac arrest resuscitation?.

BACKGROUND: The 2010 international guidelines for cardiopulmonary resuscitation recently recommended an increase in the minimum compression depth from 38 to 50 mm, although there are limited human data to support this. We sought to study patterns of cardiopulmonary resuscitation compression depth and their associations with patient outcomes in out-of-hospital cardiac arrest cases treated by the 2005 guideline standards. DESIGN: Prospective cohort. SETTING: Seven U.S. and Canadian urban regions. PATIENTS: We studied emergency medical services treated out-of-hospital cardiac arrest patients from the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest for whom electronic cardiopulmonary resuscitation compression depth data were available, from May 2006 to June 2009. MEASUREMENTS: We calculated anterior chest wall depression in millimeters and the period of active cardiopulmonary resuscitation (chest compression fraction) for each minute of cardiopulmonary resuscitation. We controlled for covariates including compression rate and calculated adjusted odds ratios for any return of spontaneous circulation, 1-day survival, and hospital discharge. MAIN RESULTS: We included 1029 adult patients from seven U.S. and Canadian cities with the following characteristics: Mean age 68 yrs; male 62%; bystander witnessed 40%; bystander cardiopulmonary resuscitation 37%; initial rhythms: Ventricular fibrillation/ventricular tachycardia 24%, pulseless electrical activity 16%, asystole 48%, other nonshockable 12%; outcomes: Return of spontaneous circulation 26%, 1-day survival 18%, discharge 5%. For all patients, median compression rate was 106 per minute, median compression fraction 0.65, and median compression depth 37.3 mm with 52.8% of cases having depth <38 mm and 91.6% having depth <50 mm. We found an inverse association between depth and compression rate ( p < .001). Adjusted odds ratios for all depth measures (mean values, categories, and range) showed strong trends toward better outcomes with increased depth for all three survival measures. CONCLUSIONS: We found suboptimal compression depth in half of patients by 2005 guideline standards and almost all by 2010 standards as well as an inverse association between compression depth and rate. We found a strong association between survival outcomes and increased compression depth but no clear evidence to support or refute the 2010 recommendations of >50 mm. Although compression depth is an important component of cardiopulmonary resuscitation and should be measured routinely, the most effective depth is currently unknown.

The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo.

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.