Inhaled hydroxychloroquine to improve efficacy and reduce harm in the treatment of COVID-19.

Current formulations and dose regimens of hydroxychloroquine (HCQ) put patients at risk of harm. An analysis of clinical trials registered on ClinicalTrials.gov revealed that this may continue as many studies combine HCQ with agents that prolong the QT interval. Further, almost all of the trials registered do not consider dosage adjustment in the elderly, a patient population most likely to require HCQ treatment. Here we describe an inhaled formulation of HCQ which has passed safety studies in clinical trials for the treatment of asthma and discuss how this approach may reduce side-effects and improve efficacy. As this simple formulation progressed to phase II studies, safety data can be used to immediately enable phase II trials in COVID-19.

Long-Term Prognostic Value of Gasping During Out-of-Hospital Cardiac Arrest.

BACKGROUND: Gasping is a natural reflex that enhances oxygenation and circulation during cardiopulmonary resuscitation (CPR). OBJECTIVES: This study sought to assess the relationship between gasping during out-of-hospital cardiac arrest and 1-year survival with favorable neurological outcomes. METHODS: The authors prospectively collected incidence of gasping on all evaluable subjects in a multicenter, randomized, controlled, National Institutes of Health-funded out-of-hospital cardiac arrest clinical trial from August 2007 to July 2009. The association between gasping and 1-year survival with favorable neurological function, defined as a Cerebral Performance Category (CPC) score ≤2 was estimated using multivariable logistic regression. RESULTS: The rates of 1-year survival with a CPC score of ≤2 were 5.4% (98 of 1,827) overall, and 20% (36 of 177) and 3.7% (61 of 1,643) for individuals with and without spontaneous gasping or agonal respiration during CPR, respectively. In multivariable analysis, 1-year survival with CPC ≤2 was independently associated with younger age (odds ratio [OR] for 1 SD increment 0.57; 95% confidence interval [CI]: 0.43 to 0.76), gasping during CPR (OR: 3.94; 95% CI: 2.09 to 7.44), shockable initial recorded rhythm (OR: 16.50; 95% CI: 7.40 to 36.81), shorter CPR duration (OR: 0.31; 95% CI: 0.19 to 0.51), lower epinephrine dosage (OR: 0.47; 95% CI: 0.25 to 0.87), and pulmonary edema (OR: 3.41; 95% CI: 1.53 to 7.60). Gasping combined with a shockable initial recorded rhythm had a 57-fold higher OR (95% CI: 23.49 to 136.92) of 1-year survival with CPC ≤2 versus no gasping and no shockable rhythm. CONCLUSIONS: Gasping during CPR was independently associated with increased 1-year survival with CPC ≤2, regardless of the first recorded rhythm. These findings underscore the importance of not terminating resuscitation prematurely in gasping patients and the need to routinely recognize, monitor, and record data on gasping in all future cardiac arrest trials and registries.

Pain catastrophizing moderates changes in spinal control in response to noxiously induced low back pain.

It is generally accepted that spine control and stability are relevant for the prevention and rehabilitation of low back pain (LBP). However, there are conflicting results in the literature in regards to how these variables are modified in the presence of LBP. The aims of the present work were twofold: (1) to use noxious stimulation to induce LBP in healthy individuals to assess the direct effects of pain on control (quantified by the time-dependent behavior of kinematic variance), and (2) to assess whether the relationship between pain and control is moderated by psychological features (i.e. pain catastrophizing (PC) and kinesiophobia). Participants completed three conditions (baseline, pain, recovery) during a task involving completion of 35 cycles of a repetitive unloaded spine flexion/extension movement. The neuromuscular control of spine movements was assessed during each condition using maximum finite-time Lyapunov exponents (λmax). Nociceptive stimulus involved injection of hypertonic saline into the interspinous ligament, eliciting pain that was greater than baseline and recovery (p<0.001). Although there was no overall main effect of the nociceptive stimulation (i.e. pain) on λmax when the whole group was included in the statistical model (p=0.564), when data were considered separately for those with high and low PC, two distinct and well established responses to the pain were observed. Specifically, those with high PC tightened their control (i.e. stabilized), whereas those with low PC loosened their control (i.e. destabilized). This study provides evidence that individuals' beliefs and attitudes towards pain are related to individual-specific motor behaviors, and suggests that future research studying spine control/stability and LBP should account for these variables.

Outcomes of sudden cardiac arrest in a state-wide integrated resuscitation program: Results from the Minnesota Resuscitation Consortium.

BACKGROUND: Despite many advances in resuscitation science the outcomes of sudden cardiac arrest (SCA) remain poor. The Minnesota Resuscitation Consortium (MRC) is a statewide integrated resuscitation program, established in 2011, to provide standardized, evidence-based resuscitation and post-resuscitation care. The objective of this study is to assess the outcomes of a state-wide integrated resuscitation program. METHODS: We examined the trends in resuscitation metrics and outcomes in Minnesota since 2011 and compared these to the results from the national Cardiac Arrest Registry to Enhance Survival (CARES) program. Since 2011 MRC has expanded significantly providing service to >75% of Minnesota's population. RESULTS: A total of 5192 SCA occurred in counties covered by MRC from 2011 to 2014. In this period, bystander cardiopulmonary resuscitation (CPR) and use of hypothermia, automatic CPR device and impedance threshold device increased significantly (p<0.0001 for all). Compared to CARES, SCA cases in Minnesota were more likely to be ventricular fibrillation (31% vs. 23%, p<0.0001) but less likely to receive bystander CPR (33% vs. 39%, p<0.0001). Survival to hospital discharge with good or moderate cerebral performance (12% vs. 8%, p<0.0001), survival in SCA with a shockable rhythm (Utstein survival) (38% vs. 33%, p=0.0003) and Utstein survival with bystander CPR (44% vs. 37%, p=0.003) were greater in Minnesota than CARES. CONCLUSIONS: State-wide integration of resuscitation services in Minnesota was feasible. Survival rate after cardiac arrest is greater in Minnesota compared to the mean survival rate in CARES.

Early Access to the Cardiac Catheterization Laboratory for Patients Resuscitated From Cardiac Arrest Due to a Shockable Rhythm: The Minnesota Resuscitation Consortium Twin Cities Unified Protocol.

BACKGROUND: In 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis-St. Paul. METHODS AND RESULTS: Eleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07-3.72], P=0.03). CONCLUSIONS: Early access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome.

New Non-Toxic Semi-Synthetic Derivatives from Natural Diterpenes Displaying Anti-Tuberculosis Activity.

We report herein the synthesis of six diterpene derivatives, three of which are new, generated through known organic chemistry reactions that allowed structural modification of the existing natural products kaurenoic acid (1) and copalic acid (2). The new compounds were fully characterized using high resolution mass spectrometry, infrared spectroscopy, ¹H- and (13)C-NMR experiments. We also report the evaluation of the anti-tuberculosis potential for all compounds, which showed some promising results for Micobacterium tuberculosis inhibition. Moreover, the toxicity for each of the most active compounds was also assessed.

Quality of CPR: An important effect modifier in cardiac arrest clinical outcomes and intervention effectiveness trials.

OBJECTIVES: To determine if the quality of CPR had a significant interaction with the primary study intervention in the NIH PRIMED trial. DESIGN: The public access database from the NIH PRIMED trial was accessed to determine if there was an interaction between quality of CPR performance, intervention, and outcome (survival to hospital discharge with modified Rankin Score (mRS) ≤ 3). SETTING: Multi-centered prehospital care systems across North America. PATIENTS: Of 8719 adult patients enrolled, CPR quality was electronically recorded for compression rate, depth, and fraction in 6199 (71.1%), 3750 (43.0%) and 6204 (71.2%) subjects, respectively. "Acceptable" quality CPR was defined prospectively as simultaneous provision of a compression rate of 100/min (± 20%), depth of 5 cm (± 20%) and fraction of > 50%. Significant interaction was considered as p < 0.05. INTERVENTION: Standard CPR with an activated versus sham (inactivated) ITD. MEASUREMENTS AND MAIN RESULTS: Overall, 848 and 827 patients, respectively, in the active and sham-ITD groups had "acceptable" CPR quality performed (n = 1675). There was a significant interaction between the active and sham-ITD and compression rate, depth and fraction as well as their combinations. The strongest interaction was seen with all three parameters combined (unadjusted and adjusted interaction p-value, < 0.001). For all presenting rhythms, when "acceptable" quality of CPR was performed, use of an active-ITD increased survival to hospital discharge with mRS ≤ 3 compared to sham (61/848 [7.2%] versus 34/827 [4.1%], respectively; p = 0.006). The opposite was true for patients that did not receive "acceptable" quality of CPR. In those patients, use of an active - ITD led to significantly worse survival to hospital discharge with mRS ≤ 3 compared to sham (34/1012 [3.4%] versus 62/1061 [5.8%], p = 0.007). CONCLUSIONS: There was a statistically significant interaction between the quality of CPR provided, intervention, and survival to hospital discharge with mRS ≤ 3 in the NIH PRIMED trial. Quality of CPR delivered can be an underestimated effect modifier in CPR clinical trials.

The association of health status and providing consent to continued participation in an out-of-hospital cardiac arrest trial performed under exception from informed consent.

OBJECTIVES: Emergency medical research performed under federal regulation 21 § CFR 50.24 provides a means to protect human subjects and investigate novel time-sensitive treatments. Although prospective individual consent is not required for studies conducted under this regulation, consent from a legally authorized representative (LAR) or the patient at the earliest feasible opportunity is required to obtain short- and long-term outcome data. The objective of this study was to determine which demographic, cardiac arrest, and patient outcome characteristics predicted the likelihood of obtaining informed consent following enrollment under exception from informed consent in a multicenter cardiac arrest study. METHODS: This investigation was an analysis of data collected during a multisite, randomized, controlled, out-of-hospital cardiac arrest clinical trial performed under 21 § CFR 50.24. Research personnel attempted to obtain informed consent from LARs and subjects for medical records review of primary outcome data, as well as consent for neurologic outcome assessments up to 1 year post-cardiac arrest. Hospital discharge and neurologic status were obtained from public records and/or medical records up until the time consent was formally denied, in accordance with federal regulations and guidance. Local institutional review boards also allowed medical records review for cases where consent was neither obtained nor declined despite multiple consent attempts. Patient demographic, cardiac arrest, and clinical outcome characteristics were analyzed in univariate multinomial regression models, with consent status (obtained, denied, neither obtained nor denied) as the dependent variable. A multivariate multinomial logistic regression was then performed. An exploratory secondary analysis following the same process was performed after assigning patients who neither consented nor declined to the declined consent group. RESULTS: Among a total study population of 1,655 cardiac arrest subjects, 457 were transported and had consent attempted (27.6%). The survival status and neurologic function at the time of hospital discharge were known in 440 of 457 (96%) subjects. In the multivariate analysis, initial rhythm of ventricular fibrillation/ventricular tachycardia (VF/VT) and survival with good neurologic outcome were strong predictors of obtaining consent (odds ratio [OR] = 3.15, 95% confidence interval [CI] = 1.73 to 5.75; OR = 7.64, 95% CI = 2.28 to 25.63, respectively). The exploratory secondary analysis also showed initial rhythm of VF/VT and survival with good neurologic outcome as strong predictors of obtaining consent (OR = 1.86, 95% CI = 1.17 to 2.95; OR = 4.52, 95% CI = 2.21 to 9.26, respectively). CONCLUSIONS: Initial arrest rhythm and survival with good neurologic outcome were highly predictive of obtaining consent in this cardiac arrest trial. This phenomenon could result in underrepresentation of outcome data in the study arm with the worse outcome and represents a significant potential confounder in studies performed under 21 § CFR 50.24. Future revisions to the exception from informed consent regulations should allow access to critical survival data recorded as part of standard documentation, regardless of patient consent status.

Hemodynamic improvement of a LUCAS 2 automated device by addition of an impedance threshold device in a pig model of cardiac arrest.

INTRODUCTION: The combination of the LUCAS 2 (L-CPR) automated CPR device and an impedance threshold device (ITD) has been widely implemented in the clinical field. This animal study tested the hypothesis that the addition of an ITD on L-CPR would enhance cerebral and coronary perfusion pressures. METHODS: Ten female pigs (39.0 ± 2.0 kg) were sedated, intubated, anesthetized with isofluorane, and paralyzed with succinylcholine (93.3 µg/kg/min) to inhibit the potential confounding effect of gasping. After 4 min of untreated ventricular fibrillation, 4 min of L-CPR+an active ITD or L-CPR+a sham ITD was initiated and followed by another 4 min of the alternative method of CPR. Systolic blood pressure (SBP), diastolic blood pressure (DBP), diastolic right atrial pressure (RAP), intracranial pressure (ICP), airway pressure, and end tidal CO2 (ETCO2) were recorded continuously. Data expressed as mean mmHg ± SD. RESULTS: Decompression phase airway pressure was significantly lower with L-CPR+active ITD versus L-CPR+sham ITD (-5.3 ± 2.2 vs. -0.5 ± 0.6; p<0.001). L-CPR+active ITD treatment resulted in significantly improved hemodynamics versus L-CPR+sham ITD: ETCO2, 35 ± 6 vs. 29 ± 7 (p=0.015); SBP, 99 ± 9 vs. 93 ± 15 (p=0.050); DBP, 24 ± 12 vs. 19 ± 15 (p=0.006); coronary perfusion pressure, 29 ± 8 vs. 26 ± 7 (p=0.004) and cerebral perfusion pressure, 24 ± 13 vs. 21 ± 12 (p=0.028). CONCLUSIONS: In pigs undergoing L-CPR the addition of the active ITD significantly reduced intrathoracic pressure and increased vital organ perfusion pressures.

Treatment of non-traumatic out-of-hospital cardiac arrest with active compression decompression cardiopulmonary resuscitation plus an impedance threshold device.

BACKGROUND: A recent out-of-hospital cardiac arrest (OHCA) clinical trial showed improved survival to hospital discharge (HD) with favorable neurologic function for patients with cardiac arrest of cardiac origin treated with active compression decompression cardiopulmonary resuscitation (CPR) plus an impedance threshold device (ACD+ICD) versus standard (S) CPR. The current analysis examined whether treatment with ACD+ITD is more effective than standard (S-CPR) for all cardiac arrests of non-traumatic origin, regardless of the etiology. METHODS: This is a secondary analysis of data from a randomized, prospective, multicenter, intention-to-treat, OHCA clinical trial. Adults with presumed non-traumatic cardiac arrest were enrolled and followed for one year post arrest. The primary endpoint was survival to hospital discharge (HD) with favorable neurologic function (Modified Rankin Scale score ≤ 3). RESULTS: Between October 2005 and July 2009, 2738 patients were enrolled (S-CPR=1335; ACD+ITD=1403). Survival to HD with favorable neurologic function was greater with ACD+ITD compared with S-CPR: 7.9% versus 5.7%, (OR 1.42, 95% CI 1.04, 1.95, p=0.027). One-year survival was also greater: 7.9% versus 5.7%, (OR 1.43, 95% CI 1.04, 1.96, p=0.026). Nearly all survivors in both groups had returned to their baseline neurological function by one year. Major adverse event rates were similar between groups. CONCLUSIONS: Treatment of out-of-hospital non-traumatic cardiac arrest patients with ACD+ITD resulted in a significant increase in survival to hospital discharge with favorable neurological function when compared with S-CPR. A significant increase survival rates was observed up to one year after arrest in subjects treated with ACD+ITD, regardless of the etiology of the cardiac arrest.

Synthesis, electrochemistry, and reactivity of cerium(III/IV) methylene-bis-phenolate complexes.

A series of cerium complexes containing a 2,2'-methylenebis(6-tert-butyl-4-methylphenolate) (MBP(2-)) ligand framework is described. Electrochemical studies of the compound [Li(THF)2Ce(MBP)2(THF)2] (1) reveal that the metal based oxidation wave occurs at -0.93 V vs Fc/Fc(+). This potential demonstrates significant stabilization of the cerium(IV) ion in the MBP(2-) framework with a shift of ∼2.25 V from the typically reported value for the cerium(III/IV) couple of E°' = +1.30 V vs Fc/Fc(+) for Ce(ClO4)3 in HClO4 solutions. Compound 1 undergoes oxidation to form stable cerium(IV) species in the presence of a variety of common oxidants. The coordination of the redox-active ligands 2,2'-bipyridine and benzophenone to 1 result in complexes in which no apparent metal-to-ligand charge transfer occurs and the cerium ion remains in the +3 oxidation state.

Single crystal to single crystal transformation and hydrogen-atom transfer upon oxidation of a cerium coordination compound.

Trivalent and tetravalent cerium compounds of the octamethyltetraazaannulene (H2omtaa) ligand have been synthesized. Electrochemical analysis shows a strong thermodynamic preference for the formal cerium(IV) oxidation state. Oxidation of the cerium(III) congener Ce(Homtaa)(omtaa) occurs by hydrogen-atom transfer that includes a single crystal to single crystal transformation upon exposure to an ambient atmosphere.

A comparison of the effects of symmetry and magnetoanisotropy on paramagnetic relaxation in related dysprosium single ion magnets.

Dysprosium complexes of the tmtaa(2-) ligand were synthesized and characterized by X-band EPR and magnetism studies. Both complexes demonstrate magnetoanisotropy and slow paramagnetic relaxation. Comparison of these compounds with the seminal phthalocyanine complex [Dy(Pc)(2)](-) shows the azaannulide complexes are more susceptible to relaxation through non-thermal pathways.

Impairment of carotid artery blood flow by supraglottic airway use in a swine model of cardiac arrest.

OBJECTIVE: Supraglottic airway devices (SGDs) are often used as an alternative to endotracheal tube (ETT) during cardiopulmonary resuscitation (CPR). SGDs can be inserted 'blindly' and rapidly, without stopping compressions. These devices utilize pressurized balloons to direct air to the trachea and prevent esophagus insufflation. We hypothesize that the use of a SGD will compress the carotid artery and decrease carotid blood flow (CBF) during CPR in pigs. METHODS: Ventricular fibrillation (VF) was induced in 9 female pigs (32 ± 1 kg) followed by 4 min without compressions. CPR was then performed continuously for 3-6-min intervals. During each interval, an ETT was used for the first 3 min, followed by 3 min of each SGD (King LTS-D™, LMA Flexible™, Combitube™) in a random order. The primary endpoint was mean CBF (ml/min). Statistical comparisons among the 4 airway devices were performed by Wilcoxon Rank test. Post mortem carotid arteriographies were performed with SGDs in place. RESULTS: CBF (median ml/min; 25/75 percentile) was significantly lower with each SGD [King (10; 6/41), LMA (10; 4/39), and Combitube (5; -0.4/15)] versus ETT (21; 14/46) (p<0.05 for each SGD compared with ETT). Arteriograms showed that with each SGD there was compression of the internal and external carotid vessels. CONCLUSION: The use of 3 different SGDs during CPR significantly decreased CBF in a porcine model of cardiac arrest. While the current study is limited to pigs, the findings suggest that further research on the effects of SGD use in humans and the effects on carotid artery blood flow is warranted.

Standard cardiopulmonary resuscitation versus active compression-decompression cardiopulmonary resuscitation with augmentation of negative intrathoracic pressure for out-of-hospital cardiac arrest: a randomised trial.

BACKGROUND: Active compression-decompression cardiopulmonary resuscitation (CPR) with decreased intrathoracic pressure in the decompression phase can lead to improved haemodynamics compared with standard CPR. We aimed to assess effectiveness and safety of this intervention on survival with favourable neurological function after out-of-hospital cardiac arrest. METHODS: In our randomised trial of 46 emergency medical service agencies (serving 2·3 million people) in urban, suburban, and rural areas of the USA, we assessed outcomes for patients with out-of-hospital cardiac arrest according to Utstein guidelines. We provisionally enrolled patients to receive standard CPR or active compression-decompression CPR with augmented negative intrathoracic pressure (via an impedance-threshold device) with a computer-generated block randomisation weekly schedule in a one-to-one ratio. Adults (presumed age or age ≥18 years) who had a non-traumatic arrest of presumed cardiac cause and met initial and final selection criteria received designated CPR and were included in the final analyses. The primary endpoint was survival to hospital discharge with favourable neurological function (modified Rankin scale score of ≤3). All investigators apart from initial rescuers were masked to treatment group assignment. This trial is registered with ClinicalTrials.gov, number NCT00189423. FINDINGS: 2470 provisionally enrolled patients were randomly allocated to treatment groups. 813 (68%) of 1201 patients assigned to the standard CPR group (controls) and 840 (66%) of 1269 assigned to intervention CPR received designated CPR and were included in the final analyses. 47 (6%) of 813 controls survived to hospital discharge with favourable neurological function compared with 75 (9%) of 840 patients in the intervention group (odds ratio 1·58, 95% CI 1·07-2·36; p=0·019]. 74 (9%) of 840 patients survived to 1 year in the intervention group compared with 48 (6%) of 813 controls (p=0·03), with equivalent cognitive skills, disability ratings, and emotional-psychological statuses in both groups. The overall major adverse event rate did not differ between groups, but more patients had pulmonary oedema in the intervention group (94 [11%] of 840) than did controls (62 [7%] of 813; p=0·015). INTERPRETATION: On the basis of our findings showing increased effectiveness and generalisability of the study intervention, active compression-decompression CPR with augmentation of negative intrathoracic pressure should be considered as an alternative to standard CPR to increase long-term survival after cardiac arrest. FUNDING: US National Institutes of Health grant R44-HL065851-03, Advanced Circulatory Systems.

Trimethylsilyl trifluoromethanesulfonate-accelerated addition of catalytically generated zinc acetylides to aldehydes.

In the presence of TMSOTf, a wide variety of terminal acetylenes add rapidly and efficiently to aldehydes via a catalytically generated zinc acetylide. In the absence of TMSOTf, no reaction is observed under otherwise identical conditions.

Cost-effectiveness of lay responder defibrillation for out-of-hospital cardiac arrest.

STUDY OBJECTIVE: Our objective is to evaluate the incremental cost-effectiveness of use of cardiopulmonary resuscitation (CPR) and automated external defibrillators (AEDs) by lay responders (CPR+AED) versus CPR only for cardiac arrest during a multicenter randomized trial. METHODS: This was a prospective trial from July 2000 to September 2003 that randomly assigned 993 community units (eg, office buildings, public areas) in 24 sites to an emergency response system, using lay volunteers trained in CPR only or CPR+AED. Cost and quality of life data were collected with effectiveness data. The primary analysis evaluated the incremental cost-effectiveness of defibrillator use in public locations by using Markov modeling. RESULTS: CPR only had 14 survivors to discharge and CPR+AED had 29. CPR only had a mean of 0.58 (95% confidence interval [CI] 0.28 to 0.88) quality-adjusted life-years and a mean $42,400 (95% CI $22,100 to $62,600) costs. CPR+AED had mean 1.14 (95% CI 0.44 to 1.83) quality-adjusted life-years, mean $68,400 (95% CI $28,300 to $108,400) costs, and a long-term cost of mean $46,700 (95% CI $23,100 to $68,600) per quality-adjusted life-year. Results were sensitive to the effectiveness of the intervention, time horizon, location of arrest, and other factors. CONCLUSION: Training and equipping lay volunteers to defibrillate in public places may have an incremental cost-effectiveness that is similar to that of other common health interventions.

Methodological design for economic evaluation in Public Access Defibrillation (PAD) trial.

OBJECTIVE: Our objective is to describe the rationale and methods for the economic analysis of the PAD trial. The objective of this analysis is to assess whether automated external defibrillators (AEDs) use by lay responders is good value for money. METHODS: Design. This economic evaluation is being conducted concurrently with a randomized trial of (a) control--training to recognize arrest, access 911, and administer cardiopulmonary resuscitation (CPR) while awaiting arrival of emergency medical services providers versus (b) intervention--training to recognize arrest, access 911, administer CPR, and use an AED while awaiting emergency medical services providers. Lay responders in either group were trained to deliver the study intervention. Population. Participating sites identified distinct units with a population of at least 250 people aged > or = 50 years. Outcome. The primary economic outcome is the incremental cost-effectiveness ratio of intervention versus control. RESULTS: Nine hundred ninety-three units including 1260 public and residential locations were randomized. There were 30 survivors in the intervention group and 15 in the control group (P = .03). Sampling will identify program and health care costs. A societal perspective will be adopted. Incremental cost effectiveness will be estimated by using bootstrapping and decision analytic modeling. CONCLUSION: The study will demonstrate whether defibrillation by lay responders improves outcomes at reasonable cost. If so, then the thousands of lives will be improved annually. If not, then limited resources can be invested in other interventions. Our methods also provide a framework for economic evaluations of other interventions for acute cardiovascular events.