Objective The purpose of this study is to: 1) describe a newly discovered mechanism of blood flow to the brain during CPR using the impedance threshold device (ITD) in a piglet model of cardiac arrest, and 2) describe the survival benefits in humans of applying all of the highly recommended changes in the 2005 Guidelines related to increasing circulation during CPR, including use of the ITD, from 6 EMS systems in the United States Design Animal studies prospective trial with each piglet serving as its own control. Historical controls were used for the human studies. Subjects Piglet and patients with out-of-hospital cardiac arrest Interventions Piglets (10-12 kg) were treated with an active (n=9) or sham (n=9) ITD after 6 minutes of ventricular fibrillation. Humans were treated with CPR per the AHA 2005 Guidelines and the ITD. Measurements and Main Results Animals The primary endpoint in the piglet study was carotid blood flow which increased from 59 ml/min without an ITD to 91 ml/min (p=0.017) with ITD use. Airway pressures during the chest recoil phase decreased from -0.46 mmHg to -2.59 mmHg (p=0.0006) with the active ITD. Intracranial pressure (ICP) decreased more rapidly and to a greater degree during the decompression phase of CPR with the active ITD Humans Conglomerate quality assurance data were analyzed from 6 EMS systems in the United States serving a population of ~3 million people. There were 920 patients treated for cardiac arrest following implementation of the 2005 AHA Guidelines, including ITD use, and 1750 patients in the control group during the year prior to implementation. Demographics were similar between the two groups. Survival to hospital discharge was 9.3 % in the control group versus 13.6 % in the intervention group. The odds ratio, 95% confidence interval, and p values were, 1.54 (1.19, 1.99), and P = 0.0008, respectively. This survival advantage was conferred to patients with a presenting cardiac arrest rhythm of ventricular fibrillation (28.5% vs. 18.0%, P = 0.0008). Conclusions Use of the ITD in piglets increased carotid blood flow and coronary and cerebral perfusion pressures and reduced intracranial pressure during the decompression phase of CPR at a faster rate than controls, resulting in a greater duration of time when intracranial pressures are at their nadir. Patients in 6 EMS systems treated with the ITD together with the renewed emphasis on more compressions, fewer ventilations, and complete chest wall recoil had a nearly 50% increase in survival rates after out-of-hospital cardiac arrest compared with historical controls.