Background The mechanism by which bystander cardiopulmonary resuscitation (CPR) improves survival following out-of-hospital cardiac arrest is unclear. We hypothesized that ventricular fibrillation (VF) waveform measures, as surrogates of myocardial physiology, mediate the relationship between bystander CPR and survival. Methods and Results We performed a retrospective cohort study of adult, bystander-witnessed patients with out-of-hospital cardiac arrest with an initial rhythm of VF who were treated by a metropolitan emergency medical services system from 2005 to 2018. Patient, resuscitation, and outcome variables were extracted from emergency medical services and hospital records. A total of 3 VF waveform measures (amplitude spectrum area, peak frequency, and median peak amplitude) were computed from a 3-second ECG segment before the initial shock. Multivariable logistic regression estimated the association between bystander CPR and survival to hospital discharge adjusted for Utstein elements. Causal mediation analysis quantified the proportion of survival benefit that was mediated by each VF waveform measure. Of 1069 patients, survival to hospital discharge was significantly higher among the 814 patients who received bystander CPR than those who did not (0.52 versus 0.43, respectively; <0.01). The multivariable-adjusted odds ratio for bystander CPR and survival was 1.6 (95% CI, 1.2, 2.1), and each VF waveform measure attenuated this association. Depending on the specific waveform measure, the proportion of mediation varied: 53% for amplitude spectrum area, 31% for peak frequency, and 29% for median peak amplitude. Conclusions Bystander CPR correlated with more robust initial VF waveform measures, which in turn mediated up to one-half of the survival benefit associated with bystander CPR. These results provide insight into the biological mechanism of bystander CPR in VF out-of-hospital cardiac arrest.

Background Hypertension is a known risk factor for heart failure ( HF ), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy ( LVH ). We studied the extent to which blood pressure ( BP ) change and evolving LVH contribute to the effect that lisinopril, doxazosin, and amlodipine have on HF compared with chlorthalidone. Methods and Results We conducted causal mediation analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) data (1994-2002; in-trial follow-up). ALLHAT participants with available serial ECG s and BP measurements were included (n=29 892; mean age 67±4 years; 32% black; 56% men): 11 008 were randomized to chlorthalidone, 5967 to doxazosin, 6593 to amlodipine, and 6324 to lisinopril. Evolving ECG LVH and BP lowering served as mediators. Incident symptomatic HF was the primary outcome. Linear regression (for mediator) and logistic regression (for outcome) models were adjusted for mediator-outcome confounders (demographic and clinical characteristics known to be associated both with both LVH /hypertension and HF ). A large majority of participants (96%) had ECG LVH status unchanged, but 4% developed evolving ECG LVH . On average, BP decreased by 11/7 mm Hg. In adjusted Cox regression analyses, progressing ECG LVH (hazard ratio [ HR ] 1.78 [95% CI 1.43-2.22]), resolving ECG LVH ( HR 1.33 [95% CI 1.03-1.70]), and baseline ECG LVH (1.17 [95% CI 1.04-1.31]) carried risk of incident HF . After full adjustment, evolving ECG LVH mediated 4% of the effect of doxazosin on HF . Systolic BP lowering mediated 12% of the effect of doxazosin, and diastolic BP lowering mediated 10% of the effect of doxazosin, 7% of the effect of amlodipine, and borderline 9% of the effect of lisinopril on HF . Conclusions Evolving ECG LVH and BP change account for 4% to 13% of the mechanism by which antihypertensive medications prevent HF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00000542.

BACKGROUND:Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS:This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS:Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS:A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.