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The Physiology of Cardiopulmonary Resuscitation

Lurie, Keith G. MD; Nemergut, Edward C. MD; Yannopoulos, Demetris MD; Sweeney, Michael MD

doi: 10.1213/ANE.0000000000000926
Critical Care, Trauma, and Resuscitation: Review Article
Continuing Medical Education

Outcomes after cardiac arrest remain poor more than a half a century after closed chest cardiopulmonary resuscitation (CPR) was first described. This review article is focused on recent insights into the physiology of blood flow to the heart and brain during CPR. Over the past 20 years, a greater understanding of heart–brain–lung interactions has resulted in novel resuscitation methods and technologies that significantly improve outcomes from cardiac arrest. This article highlights the importance of attention to CPR quality, recent approaches to regulate intrathoracic pressure to improve cerebral and systemic perfusion, and ongoing research related to the ways to mitigate reperfusion injury during CPR. Taken together, these new approaches in adult and pediatric patients provide an innovative, physiologically based road map to increase survival and quality of life after cardiac arrest.

From the *Department of Emergency and Internal Medicine, University of Minnesota, Minneapolis, Minnesota; Department of Anesthesiology and Neurological Surgery, University of Virginia, Charlottesville, Virginia; Department of Internal Medicine Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota; and Departments of §Anesthesiology and Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Accepted for publication June 8, 2015.

Funding: None.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Keith Lurie, MD, Department of Emergency Medicine, Hennepin County Medical Center, 701 Park Ave., Minneapolis, MN 55415. Address e-mail to keithlurie@icloud.com.

Sudden cardiac arrest remains a leading cause of prehospital and in-hospital death.1 Efforts to resuscitate patients after cardiac arrest have preoccupied scientists and clinicians for decades.1,2 However, the majority of patients are never successfully resuscitated.1,3–5 Based on the published reports, the overall survival rates after cardiac arrest are grim, ranging from 1% to <20% for out-of-hospital nontraumatic cardiac arrest and <40% for in-hospital cardiac arrest.1,6 Of these, 10% to 50% have poor neurological function.1,7 Surprisingly, the physiologic principles that underlie the life-saving process of cardiopulmonary resuscitation (CPR) remain only partially understood and are often controversial.1,8 Some would argue that current approaches to cardiac arrest are fatally flawed, and that is why the overall survival rates have hovered around 7% for out-of-hospital cardiac arrest and <30% for in-hospital cardiac arrest nationwide for a half a century.9

This review article is primarily focused on recent advances in the field of CPR, with primary focus on new ways to promote better perfusion to the heart and brain. There have been significant advances in our understanding of the physiology of resuscitation over the past 2 decades, with new insights into the physiologic mechanisms that regulate blood flow to the vital organs, common errors in the delivery of CPR that often reduce its effectiveness, ways to enhance circulation during CPR, and new approaches to reduce injury associated with reperfusion.3,5–8,10–48 Given the debate surrounding what is known, what we think we know, and what remains unknown about resuscitation science, this article also provides some contrarian and nihilistic points of view.

When the cause of the arrest is reversible, the primary treatment goal of sudden cardiac arrest is to fully restore cardiac and brain function. The leading causes of cardiac arrest, such as a primary or ischemia-induced arrhythmia, pulmonary emboli, hemorrhage, trauma, or medication/drug overdose, all require emergent efforts to increase cardiocerebral circulation.1,8 The critical first step to successful resuscitation is restoring blood flow with sufficient aortic pressure. Understanding the complex physiology of cardiocerebral perfusion during CPR is crucial to reducing morbidity and mortality after cardiac arrest. Vital organ flow enhancement is critical, but often by itself insufficient, to fully restore life after cardiac arrest.

There are multiple areas in resuscitation science where significant knowledge gaps and unmet needs limit our ability to consistently restore full life after cardiac arrest. First is the need for greater blood flow than the minimal amount produced by conventional closed chest cardiac massage, the most commonly used method of CPR that has not changed for over a half a century.3,49,50 Second is the need for tools that help provide better quality CPR.51–54 Third is the need to reduce the potential for brain injury associated with the simultaneous arterial and venous pressure compression waves focused toward the brain each time the chest is compressed.14 Fourth is to prevent reperfusion injury in the first seconds and minutes of reperfusion, especially after prolonged periods of no flow.37–43 The fifth large area where there are unmet clinical needs is in postresuscitation care, which is beyond the scope of this review.15–20,55–57

In what follows, we try to highlight some recent advances in resuscitation science aimed at addressing these unmet needs and to discuss why some with doubts believe that there is a lack of progress.9 We leave it to the reader to decide whether progress is being made, whether we are simply treading water, or whether the science of resuscitation is actually regressing.

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CONVENTIONAL CPR PHYSIOLOGY

The Compression Phase

Figure 1

Figure 1

Conventional or standard (S)-CPR is performed with a pair of hands.1,49 With each chest compression, intrathoracic pressure is increased, and the heart is squeezed between the sternum and the spine.49,58–62 With each compression, both the aortic and the right atrial pressures increase, with right atrial pressure similar to, or sometimes higher than, left-sided pressures.63–65 Blood is propelled forward from the nonbeating heart toward the brain, coronary arteries, and the rest of the body because of the presence of the 1-way valves within the heart and pressure differences between the thorax and the nonthoracic regions.58,61,66 Within the past decade, there has been renewed interest in the effect of increased intrathoracic pressure on intracranial pressure (ICP) during the compression phase.4,67–69 During this phase, ICP is increased, which in turn increases resistance to cerebral perfusion.14,67 It is speculated that the increase and decrease of ICP during CPR is secondary to changes in intrathoracic pressure transduced through the paravertebral venous/epidural plexus and spinal fluid to the intracranial compartment.68 ICP increases with each positive pressure ventilation.67,68 The increase in ICP and the simultaneous decrease in the calculated cerebral perfusion pressure (CerPP) are shown in Figure 1 (0° supine tracings). Right atrial, right ventricular, and pulmonary artery pressures increase in parallel with each compression.65 During CPR, the coronary artery perfusion pressure is generally calculated as the difference between the aortic and the right-sided pressures.70 Thus, high right-sided pressures during S-CPR also limit coronary perfusion pressures. The authors speculate that one of the reasons patient outcomes with some methods of CPR, including S-CPR, are so poor is that not enough attention is focused on understanding the interactions among the changes in right-side cardiac pressures, ICP, and the resultant cerebral and coronary perfusion pressures.

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Common Errors During Chest Compression

Preclinical and clinical studies support the American Heart Association (AHA) recommendation that chest compressions should be 5-cm deep.1,2 When the chest is compressed too slowly, too rapidly, too much, or too little, clinical outcomes are adversely affected.8,71–76 Similarly, interruptions in chest compressions are harmful.5,6,71,77 Obviously, without chest compressions, there is no forward blood flow. Too often, rescue personnel stop chest compressions for over a minute to intubate, feel for pulses, auscultate the chest, and/or check the underlying rhythm.78–81 In the heat of the moment, rescuers often forget to perform high-quality CPR.7,8,74 These common errors significantly and adversely affect outcomes.

Figure 2

Figure 2

A recent analysis of CPR quality during a large National Institutes of Health Resuscitation Outcomes Consortium Prehospital Resuscitation using an IMpedance valve and Early versus Delayed (ROC PRIMED) trial demonstrated that these errors were common and harmful. Nearly half of the time, compressions were performed at rates and depths outside of the recommended range of the AHA guidelines.7,8,74 At least one-third of the subjects had compression rates in excess of 120 per minute,8,74 and survival rates were poorer at these higher rates.8,30,a,74 We speculate that at higher rates of compression, diastolic filling times may be too short, and compression depth and full recoil may not be achieved. Most importantly, lack of compliance with study performance protocols and AHA guidelines in this trial was associated with worse outcomes (Fig. 2).7,8

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The Chest Decompression Phase

The physiology of the decompression, or chest recoil, phase of CPR is complex: Its importance during CPR has been only recently better understood.3,22,23,25,82,83 During the decompression phase, the heart is refilled after it has emptied from the previous chest compression.82–87 This refilling process is extremely inefficient during CPR, especially during S-CPR when passive chest wall recoil provides the only force able to draw blood back into the right side of the heart. This effect may be even more accentuated in individuals in whom chest recoil is impaired, including patients with broken ribs. In addition to enhancing venous return to the heart, ICP is reduced during the decompression phase.88 Each time the chest wall recoils, ICP decreases based on the same pressure transference mechanisms that increase ICP during the compression phase.88,89 This is shown in Figure 1 (0° supine tracings). These changes in ICP during the compression and decompression phases help to determine the level of cerebral perfusion during CPR.14,69

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Common Errors During Chest Decompression

The slight vacuum generated inside the thorax during passive chest recoil draws some blood back into the heart and some air into the lungs.24 This in turn draws blood from the extrathoracic to the intrathoracic space and partially refills the heart before the next compression. If rescue personnel inadvertently lean on the chest, preventing it from fully recoiling after each compression, then intrathoracic pressure remains greater than atmospheric pressure.5,10,87,90,91 This common error reduces the refilling of the heart and the reduction in ICP that occurs with full chest wall recoil.5 Studies in animals have shown that incomplete chest recoil, or leaning on the chest after the chest compression motion is complete, markedly reduces perfusion pressures to the brain and myocardium.5 Similarly, compressing and decompressing the chest too rapidly (>120/minute) reduces the venous return time below what is needed to refill the heart.92 These errors in technique adversely affect survival rates.8

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Positive Pressure Ventilation During CPR

During CPR, each positive pressure breath inflates the lungs, facilitates O2 delivery, and opens up the pulmonary arterial and venous vasculature, allowing for respiration and transpulmonary circulation.11,93,94 Each of these functions is critical. As well described by West,95 too little positive pressure (low rates and/or tidal volume) will not provide adequate blood oxygenation and too much (excessive rates and/or tidal volumes) may increase pulmonary vascular resistance. The interactions among the heart, lungs, and brain during positive pressure ventilation (PPV) are complex.11 A positive pressure breath increases intrathoracic pressure, which reduces venous return to the right side of the heart.6 The increase in intrathoracic pressure also momentarily increases right ventricular afterload. The end result is a decrease in right ventricular preload and an apparent increase in afterload. At the same time, the positive pressure breath increases the volume of West Zone I and decreases the volume of West Zone III, which effectively “squeezes” pulmonary venous blood into the left side of the heart.96 Thus, each positive pressure breath results in a temporary increase in left ventricular stroke volume through the Starling mechanism during normal cardiac function.97

In addition, PPV affects ICP and CerPP. Each positive pressure breath instantly increases ICP, thus generating increased resistance to forward brain flow.5,88,98 A second and less understood impact of PPV is the effect on CO2 exchange. EtCO2 values during CPR are believed to reflect circulation.99 Hypoventilation results in decreased CO2 clearance.100,101 Studies in animals suggest that high PaCO2 levels during CPR are detrimental.100 In the absence of autoregulation, less is known about the role of PCO2 in regulating cerebral perfusion during CPR.102

The net effect of these changes during CPR after cardiac arrest is less well characterized; however, the balance between circulation and respiration during CPR is obviously critical. There may not be a one-size-fits-all ventilation strategy for all patients or for the many different methods of CPR. Unfortunately, it is difficult to obtain prospective clinical data related to this issue in the setting of cardiac arrest.

Over the past 20 years, PPV, essential for providing O2 and removing CO2, has proven to be important, but not as essential as chest compression, during CPR.6,11 Some have promoted the performance of chest compressions only, with no ventilations, for the first several minutes of CPR.103,104 Compressions only, rather than compressions and mouth-to-mouth rescue breathing, are easier for a 911-dispatcher to teach and a lay rescuer to effectively perform.103 However, there are no prospective randomized studies in support of the chest compression-only approach, which was, in part, a backlash to the excessive ventilation rates observed clinically.6 As described further below, excessive ventilation rates were found to be harmful in animals.6 Based on the animal data and a consensus of experts, the AHA recommends a compression:ventilation ratio of 30:2 for basic life support and continuous chest compressions at a rate of 100 with asynchronous ventilations every 10 compressions for advanced life support.105,106 The ventilation tidal volume should be approximately 600 mL, which, for most adults, is approximately 8 mL/kg, so as to minimize CPR-induced ventilation perfusion mismatch.105

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Common Errors During Ventilation

Both excessive ventilation and hypoventilation can be harmful during CPR.6,11,12 After observing that patients in out-of-hospital cardiac arrest were ventilated on average at 37 times per minute in a clinical CPR device trial,6 animal studies were performed, which demonstrated that excessive ventilation rates were associated with a marked decrease in cerebral and myocardial perfusion pressures and markedly increased mortality.6 Similarly, after the first few minutes of CPR, the absence of periodic PPV reduces blood flow through the lungs secondary to collapse of both the bronchioles and the pulmonary vasculature.11 This can cause a profound decrease in cerebral oxygenation and perfusion.11,12 A correct balance between too little and too much ventilation is critical to neurologically favorable survival after cardiac arrest.6

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Gasping and Coughing During CPR

Figure 3

Figure 3

Gasping occurs in some patients during CPR, especially if the medullary brainstem is perfused sufficiently to trigger the gasping reflex.107 Gasping during CPR is associated with more favorable outcomes.108,109 The so-called last gasp is associated with the development of negative intrathoracic pressure that in turn causes inspiration of air, enhances venous return to the heart, and decreases ICP, facilitating increased cerebral perfusion.109–111Figure 3 demonstrates, in a pig model, the affect of gasping of cardiac arrest. In this example, a pig was being treated with active compression decompression (ACD) CPR and an impedance threshold device (ITD) when it began to gasp spontaneously during CPR. As shown, each gasp decreased intrathoracic pressure; decreased ICP; and increased carotid blood flow, aortic pressure, and the calculated CerPP.109 By contrast, PPV increased ICP.6 In these studies, right atrial pressure was measured, but flow back to the right heart was not measured. This figure helps to demonstrate how gasping increases CerPP by harnessing the thoracic pump to increase perfusion. The physiologic mechanism of benefit associated with gasping is somewhat similar to the physiology of cough CPR.112,113 Both work on a similar principle during the inspiratory portion of the cough as intrathoracic pressures are decreased.109,112 During the expiratory portion of a cough, intrathoracic pressures increase before the opening of the glottis. Cough CPR has been reported to maintain circulation and consciousness in patients in ventricular fibrillation for many minutes.112,114

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Limitations of Conventional CPR

Under the best of clinical prehospital and in-hospital settings, the rate of survival with favorable neurological function after a cardiac arrest is <20% and <40%, respectively.1,25,115–118 The average rate of survival with good brain function is only approximately 6% in those North American cities that study outcomes.3,29 As described earlier, the complex physiology of conventional S-CPR can be challenging to implement, but without the correct compression rate, compression depth, full chest recoil, lack of interruptions in CPR, and proper ventilation technique, outcomes are worse.5,6,12 Some of these challenges can be overcome with automated mechanical devices that have been shown to provide chest compressions that are at least equivalent to high-quality conventional manual CPR.119–121 By themselves, however, the use of automated CPR devices has not been shown to improve survival rates.119–121

Over the past several decades, study of the physiology of S-CPR has uncovered a number of inherent limitations, even when S-CPR is performed correctly.5,6,50,82 Recent progress has focused on ways to enhance the refilling of the heart after each compression, because S-CPR itself provides only 15% to 25% of normal cardiac output when performed perfectly.50,82,83 Understanding some of the limitations of S-CPR has resulted in several discoveries that hold promise of significantly enhancing cardiocerebral circulation during cardiac arrest.

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BEYOND CONVENTIONAL S-CPR

Studies on CPR physiology have resulted in several fundamentally new approaches to improve outcomes after cardiac arrest. These include ways to harness the thoracic pump to enhance circulation to the heart and brain by transforming the thorax into an active pump to circulate more blood.21–24 The newly appreciated concept of intrathoracic pressure regulation (IPR) has resulted in innovative technologies and approaches to enhance perfusion, decrease ICP, and improve cardiac arrest outcomes.3,4,12,25,26,30,67,69,88,115,122–141

Additional discoveries associated with cardiac arrest include ways to reduce the potential for reperfusion injury, new insight into the potential importance of the position of the head during CPR, and methods to improve postresuscitation care. Essential for all of these potential advances is the need for the delivery of high-quality CPR in accordance to AHA guidelines.1 There has also been significant progress in incorporating multiple advances in the care of cardiac patients into a bundled approach to care. This has also resulted in a significant improvement in clinical outcomes.19,106,115

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Intrathoracic Pressure Regulation Therapy

The concept of IPR is embodied in a number of noninvasive devices developed to regulate changes in intrathoracic pressure and to provide greater circulatory support than can be generated by S-CPR itself.12–14,67,82,83,115 IPR was inspired by the successful use of a household plunger, instead of a pair of hands, by someone attempting to resuscitate a family member in cardiac arrest.21 This index case resulted in a new method of CPR called ACD CPR.21 By repetitively pulling upward and pushing downward on the chest with a suction device, intrathoracic pressures increase and decrease, promoting greater ventilation and circulation than with S-CPR.21 Studies in animal showed that ACD CPR increased circulation during CPR but was insufficient by itself to maintain adequate ventilation.22,142,143

Further study of ACD CPR resulted in a discovery of the inspiratory ITD.23,24 By transiently impeding airflow into the lungs during the chest wall recoil or decompression phase of CPR, use of the ITD results in a significant reduction in intrathoracic pressure during S-CPR and ACD CPR.83,144 These mechanisms of action are shown schematically in Figure 4. By this means, the ITD significantly augments blood flow to the heart and brain during S-CPR, ACD CPR, and when used during CPR with automated devices.12,23,28,31–33,67,70,82,83,86,89,145–150 By transiently impeding gas flow into the lungs during the decompression phase of CPR, IPR therapy brings more blood back to the right heart and decreases ICP by decreasing intrathoracic pressure during the decompression phase of CPR.23,148 In this manner, use of the ITD during CPR mimics the gasping reflex as described earlier. Importantly, periodic PPV is required with the ITD, which can be attached to a facemask or advanced airway.

Figure 4

Figure 4

Over the past 2 decades, use of the ITD has been shown to significantly augment cerebral and myocardial perfusion in animals in cardiac arrest during S-CPR and ACD CPR and to improve hemodynamics in humans during S-CPR or ACD CPR.12,23,28,31,32,67,70,82,83,86,89,145–150 Further IPR research led to the development of a device able to provide a continuous negative intrathoracic pressure after each PPV.26,27 This more advanced active IPR approach has been used in animals and patients in cardiac arrest and noncardiac arrest shock states.4,26,27,69,123,128,136,138,140,141,151

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Conventional or Standard CPR and the Impedance Threshold Device

The ITD has been tested in animals and human subjects during S-CPR.28,31,83,86,106,115,147,149 The animal studies showed that the ITD increased blood flow to the heart and brain and improved survival with favorable neurological function.31,83,86,147,149 Subsequent testing in humans was also done.20,25,28,83,115,152 Most human trials showed a benefit of the ITD with S-CPR in terms of blood pressure or survival. However, the largest human trial, the National Institutes of Health Resuscitation Outcomes Consortium (ROC) Prehospital Resuscitation Impedance Valve and Early Versus Delayed Analysis (PRIMED) study compared a sham versus active ITD and early versus late analysis and defibrillation. The investigators reported no benefit of the ITD.29 In that trial, either a sham or active ITD, each with timing lights that flash 10 times/minute to guide ventilation rate, was tested in >8000 patients with out-of-hospital cardiac arrest treated with S-CPR.29 The sham device was designed to look, feel, and flash like the active ITD, but it did not impede the flow of respiratory gases into the lungs when the pressure in the thorax was subatmospheric. Only after the neutral results were published did the ROC PRIMED investigators report that there was a large variation in the compression rate and depth during the study.7,8 A third analysis by ROC investigators demonstrated that there was a statistically significant interaction between the quality of CPR delivered in the ROC PRIMED study and the effectiveness of the sham and active ITD.74 A subsequent independent reanalysis of the ROC PRIMED study similarly showed that the effectiveness of the active ITD was highly dependent on the quality of the S-CPR delivered.7,8,30,74

When chest compressions were delivered according to the recommendation of the AHA guidelines, then survival with favorable neurological function was significantly higher with the active ITD compared with the sham30 (Table 1). Taken together, these studies showed that there was a significant interaction between S-CPR quality metrics and the ITD.7,8,74

Table 1

Table 1

Figure 5

Figure 5

With excessive chest compression rates or inadequate chest compression depth, the ITD was not effective.30 Conversely, when S-CPR was delivered according to the AHA recommendations, there was a significant 50% increase in the number of survivors with favorable neurological function30 (Table 1). Figure 5 demonstrates the importance of compliance with AHA guidelines and ITD effectiveness. The highest rates of survival with favorable neurological function were observed with compressions performed at rates around 100 per minute, a depth of 5 cm, and use of the active ITD.30 From a physiologic perspective, the discovery of these critical interactions among chest compression rate, depth, and inspiratory impedance helps to emphasize the potential benefit of IPR.30,153 These findings also highlight how critically important it is to remain compliant with CPR guidelines when performing CPR.

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Active Compression Decompression CPR and the Impedance Threshold Device

Table 2

Table 2

The ITD was also assessed during ACD CPR in animals23,31,70,145,147,148 and in patients as the focus of 5 prospective randomized clinical trials.3,32–35 This device combination was shown to increase blood flow to the heart and brain and to improve survival with favorable neurological function. In the largest clinical trial, >2700 patients were randomly assigned to receive either S-CPR or the ITD + ACD CPR.3,36 Patient survival to hospital discharge with favorable neurologic outcome, the primary study end point, was approximately 50% higher with the ITD + ACD CPR combination for patients with a cardiac arrest of presumed cardiac etiology3 (Table 2). Approximately 50% survival benefit relative to S-CPR was sustained for at least a year.3,36 Based on this trial, the combination of ACD CPR and the ITD was recently approved by the US Food and Drug Administration as the first CPR adjunct to increase the likelihood of survival after nontraumatic cardiac arrest.155

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Advanced Intrathoracic Pressure Regulation

The concept of push–pull ventilation has been adopted to enhance circulation and used for the treatment of cardiac arrest and shock.4,26,27,69,123,128,136,138,140,141,151,156 A series of devices have been designed to harness the changes in intrathoracic pressure to enhance venous return to the heart and circulate more blood to the brain and heart.4,26,27,69,123,124,127,128,133,136,138,140,141,151 They work as follows: After a positive pressure breath, respiratory gases are actively withdrawn from the lungs to generate negative intrathoracic pressure during the entire expiratory phase.4,26,27,69,123,124,127,128,133,136,138,140,141,151 The airway pressure curve and associated hemodynamics with this technology in a porcine preparation with hypovolemic shock are shown in Figure 6A and in cardiac arrest are shown in Figure 6B.157 This approach has been assessed in animals in cardiac arrest26 and in patients.27 When this approach is combined with S-CPR or ACD CPR, blood flow to the heart and brain is enhanced.26,27,151,157

Figure 6

Figure 6

A device that provides this kind of IPR therapy, called the intrathoracic pressure regulator device (ITPR), has been approved for use in hypotensive patients by the Food and Drug Administration to enhance circulatory adequacy.4,27,156 In animals, brain blood flow is increased by approximately 50% with ACD + ITPR versus ACD + ITD.26 In humans, the use of S-CPR plus the ITPR significantly enhances circulation as measured by ETCO2 during CPR and significantly increases the likelihood of successful resuscitation from 46% to 73%.27 However, research with this new approach is in its infancy. Further studies are needed to determine whether the use of the ITPR and similar devices that enhance venous return during the expiratory phase of CPR will result in improved long-term survival rates after cardiac arrest.

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Head-Up CPR

By convention, CPR has been performed for over a half a century with the patient in the supine position with the entire body on the same plane horizontal to the floor. Recent studies on the position of the head and body during CPR in pigs have demonstrated that elevation of the head during CPR has a profound beneficial effect on ICP, CerPP, and brain blood flow when compared with the traditional supine horizontal position.14 With the body supine and horizontal, each compression is associated with the generation of arterial and venous pressure waves that deliver a simultaneous high-pressure compression wave to the brain. With a patient’s head up, gravity drains venous blood from the brain back to the heart, resulting in a greater refilling of the heart after each compression, a lower compression phase ICP, and a substantial decrease in ICP, thereby reducing impedance to forward brain flow.14 By contrast, CPR with the patient’s feet up and head down resulted in a marked decrease in CerPP with a simultaneous increase in ICP14 (Fig. 1). As shown in cardiac arrest studies in pigs, elevation of the head results in an immediate decrease in ICP and an increase in CerPP.14 The effect of changing from the 0° horizontal to a 30° head up on key hemodynamic parameters during ACD + ITD is shown in Figure 1.14 Head-up CPR is ultimately dependent on the ability to maintain adequate forward flow. These benefits are realized only when an ITD is present; when the ITD is removed from the airway in these studies, systolic blood pressure and coronary and CerPP decrease rapidly.14 Currently, clinical studies are lacking. However, the new insight gained by these provocative animal studies suggest that elevation of the head during CPR may provide better cerebral protection and perfusion.

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Reperfusion Injury Protection

Although nascent, the concept of postconditioning, or reperfusion injury protection, during CPR promises to provide additional benefit by reducing the potential for unintended damage in the first seconds to minutes of reperfusion after a prolonged ischemic insult.13,37,40,41,158,159

It is well established that reperfusion injury can cause microvascular and endothelial dysfunction, reduce blood flow, and lead to end-organ metabolic dysfunction, cellular necrosis, and apoptosis.37,41,158–162 In a general sense, this concept also known as “postconditioning” can be defined as brief periods of reperfusion alternating with intentional reocclusion applied during the first minutes of reperfusion.37,158–160 This strategy need not be limited to mechanical alterations in hydrodynamics and may include pharmacological measures to accomplish similar objectives.13,37–43,163 Early animal studies are supportive of the importance of preventing reperfusion injury after prolonged cardiac arrest.37,157–159,161

There are multiple ways to reduce or prevent reperfusion injury based on the putative mechanisms of action, which include ischemic postconditioning with intentional short periods of no flow after reflow, and pharmacologic agents, which activate reperfusion injury salvage kinase pathways or inhibit the opening of mitochondrial permeability transition pores.37 It is now clear that in the setting of a prolonged cardiac arrest, at least in pigs, reperfusion injury amelioration confers a significant benefit by preserving mitochondrial function.161

Figure 7

Figure 7

More recent studies suggest that with reperfusion injury protection, the brain may be able to survive for well >15 minutes in the absence of any perfusion.39 Bartos et al.43 used multiple simultaneous interventions hypothesized to improve flow, reduce reperfusion injury, and accelerate cellular and vital organ recovery. Enhanced flow was provided with ACD + ITD CPR. Postconditioning was provided by 3 short intentional 20-second pauses and administration of sevoflurane, as reported previously by the same group to preserve mitochondrial respiration after prolonged ischemia and reperfusion.161,162 In addition, a synthetic surfactant, poloxamer 188 was administered to help seal nanosized holes in and between cells.163–168 Poloxamer 188 has been assessed previously in animals and humans to treat acute myocardial infarction and, more recently, in animals in cardiac arrest.43,167,168Figure 7 demonstrates the impact of these multiple interventions on aortic pressure in a representative animal from that study.43 The authors found that more than half of the animals treated with this unique bundle were awake, alert, and functionally normal 48 hours after cardiac arrest. None of the control animals survived.43 These kinds of preclinical studies demonstrate the potential of these new approaches to markedly improve the likelihood of survival after cardiac arrest. Clinical studies are now needed to determine the potential added value of reperfusion injury protection after prolonged untreated cardiac arrest.

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The Resuscitation Bundle

One lesson from the hundreds of different CPR studies that began in the early 1960s is that multiple treatments are needed for success in the chain-of-survival approach to the treatment of cardiac arrest.19,106,115 The most effective strategies have optimized circulation during CPR and reduced postresuscitation injury.19,106,115 The most effective resuscitation bundles to date include efforts to promote widespread use of bystander CPR, public access defibrillation, high-quality CPR by first responders and advanced life support providers, use of adjuncts that lower negative intrathoracic pressure during the decompression phase of CPR, and strategies that include postresuscitation revascularization and therapeutic hypothermia, or at least the prevention of fever.19,106,115 Such system-based approaches to resuscitation are based on a multipronged biophysical approach to significantly improve the likelihood for survival with restoration of neurological function after cardiac arrest.19,106,115,122,169

Currently, the bundled approach to prehospital care has significantly improved survival with good neurological function for all patients to as high as 20% in some cities and counties.19,115,118 Care is provided by highly trained prehospital personnel and specialized resuscitation hospitals.19,106,115 The greatest improvement has been in those patients who present with ventricular tachycardia where survival with restoration of neurological function is approximately 50%.19 These data are supportive of the progress in the field to date; they also reflect the challenges that persist for the 80% of patients who never wake up despite receiving conventional CPR.1,2,15,17–20,118

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IS CPR OF BENEFIT AT ALL?

Given that survival rates after cardiac arrest have not changed much over the past half century since close chest manual CPR was first described, it is reasonable to ask whether CPR is really of benefit. This question was asked by Bardy,9 an expert in cardiac electrophysiology, who believes that early and effective defibrillation, and not CPR, is what important. There is no doubt that defibrillators are important for resuscitating some patients in cardiac arrest who present with a rhythm that can be defibrillated. However, the incidence rate of ventricular fibrillation has been declining for the past 20 years170,171 and now is reported as the presenting rhythm for only between 20% and 35% of all out-of-hospital cardiac arrest.3,29 Given that the average cardiac arrest survival rate nationwide is <10%, one could argue that efforts to resuscitate patients in cardiac arrest are largely futile and that the millions of dollars spent on education and treatment strategies should be spent elsewhere. We will not settle that debate here, but this kind of challenge from Bardy9 and others is provocative and helps to stimulate potential breakthroughs. We believe that the early work described in this review on new ways to reduce reperfusion injury, new ways to protect the brain with head-up CPR, and aggressive postresuscitation care, including acute revascularization for patients in refractory ventricular fibrillation, are steps in the right direction.14,39,40 We speculate that over the next 50 years, these new ideas will be translated to meaningful changes in care and drive survival rates to higher levels than have been reported previously. Time will tell. Meanwhile, multiple emergency medical service (EMS) systems have already reported that by combining rapid and early defibrillation with high-quality CPR, ITD use, reperfusion injury protection strategies, and therapeutic hypothermia, overall survival rates with favorable neurological function can reach approximately 20% today and those with ventricular fibrillation are upward of 50%.19,115 In-hospital survival rates with favorable neurological function have been reported upward of 35%, and this includes patients with ventricular fibrillation, pulseless electrical activity, and asystole.122

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PEDIATRIC CONSIDERATIONS

Cardiac arrest in the pediatric population presents some different challenges. Unlike in adults, common causes of pediatric cardiac arrest include respiratory arrest or drowning-induced asphyxia, prolonged shock from any cause, including trauma, and pre-existing cardiac disease that is usually congenital in nature.172

Severe bradycardia or asystole is the usual heart rhythm aberration to be dealt with. Ventricular arrhythmias are much less common (<10%) than in the adult population (>25%) and usually because of prolonged myocardial hypoxia.172 As with the adult population, survival from out-of-hospital cardiac arrest is significantly worse than in the in-hospital setting.122,172,173

To date, the experience with pediatric and adult rapid response teams on in-hospital CPR survival rates to discharge with good neurologic function has been mixed.174–176 Although the concept is appealing, a significant improvement in outcomes has not been demonstrated. Simulation experience supplemented by just-in-time and just-in-place training also hold promise to enhance outcomes even further, but to date, no definitive studies have shown a survival benefit.177–179 By consensus, the AHA child CPR guidelines apply to children from 1 year of age until puberty.180 For most pediatric patients, the age of 8 years correlates with a close approximation to the adult, from an anatomic and likely CPR physiologic perspective. In the younger patient, survival to discharge rates of in-hospital CPR are better than in those who are of school age or older.181–183

Several factors may be responsible for this, although it is postulated to be because of better CPR-induced blood flow, secondary to greater thoracic cage compliance.184 In addition, because most pediatric cardiac arrests are asphyxial/hypoxic in origin, rescue breathing with avoidance of hyperventilation and excessive positive airway pressure, in addition to prompt and uninterrupted chest compressions, is essential.44,45 As with the adult, open chest CPR provides about twice as much blood flow than S-CPR, but its use is almost always implemented when a thoracotomy of some kind is already performed, as in the operating room or pediatric intensive care unit postoperatively.185 Similar to adults, a pediatric resuscitation bundle is often used.186

As in adults, the use of post-CPR hypothermia is increasing, but its recommended duration and overall efficacy are somewhat controversial for all pediatric age groups.187,188 Studies have not unequivocally supported its use in the pediatric population. However, as with adults, most experts agree that hyperthermia, which is common in the pediatric post-CPR patient, must be avoided or managed aggressively when present.46,189

Use of venoarterial extracorporeal membrane oxygenation as a rescue therapy in the pediatric population for treatment of prolonged cardiac arrest has been demonstrated to be useful in some patients, in particular in the postoperative cardiac surgical pediatric patient, when reversible cardiac dysfunction is present.47,48 However, as with adults, rigorous studies in this area are understandably lacking.47,48

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CLINICAL IMPLICATIONS AND THE FUTURE

We remain in our infancy in understanding the complex physiology of cardiac arrest and CPR. However, similar to the treatment of other complex disease states, such as HIV infection, leukemia, or heart failure, we believe that we need to abandon the idea that there is a single “silver bullet” for the treatment of cardiac arrest, including defibrillation. In the case of HIV, 3 drugs found to be ineffective alone were shown to be highly effective when combined.190 We speculate that consistent and definitive advances in the treatment of cardiac arrest will require the synergy between multiple interventions in a bundle-of-care approach to this multifactorial disease state. Some of these potential interventions are summarized in Table 3.

Table 3

Table 3

Within the past decade, it has become clear, as we have said that there is no single magic bullet for patients in cardiac arrest. Cardiac arrest is best treated with a multipronged approach based on the physiologic and biochemical first principles. These include optimization of circulation and postresuscitation organ recovery and minimization of reperfusion injury and common errors during CPR delivery. The recognition that common errors in CPR delivery are prevalent and often lethal has results in a “back-to-basics” approach to education and delivery of basic CPR. The frequency of errors during CPR has also resulted in a better understanding of the needs for and benefits of feedback tools and automated CPR devices to assure that correct rate, depth, and full recoil are achieved.119–121,191 None of these new approaches is exceptionally difficult to implement. We anticipate that once many of them have been scientifically verified and combined with current system-based approach to care, the potential to successfully and fully resuscitate many patients who we cannot help with current management seems to be well within our reach.

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DISCLOSURES

Name: Keith G. Lurie, MD.

Contribution: This author helped prepare the manuscript.

Attestation: Keith G. Lurie approved the final manuscript.

Conflicts of Interest: Keith G. Lurie is a consultant for Zoll Medical and coinventor of the impedance threshold device and the active compression decompression CPR device.

Name: Edward C. Nemergut, MD.

Contribution: This author helped prepare the manuscript.

Conflicts of Interest: Edward C. Nemergut declares no conflicts of interest.

Attestation:Edward C. Nemergut approved the final manuscript.

Name: Demetris Yannopoulos, MD.

Contribution: This author helped prepare the manuscript.

Attestation: Demetris Yannopoulos approved the final manuscript.

Conflicts of Interest: Demetris Yannopoulos declares no conflicts of interest.

Name: Michael Sweeney, MD.

Contribution: This author helped prepare the manuscript.

Conflicts of Interest: Michael Sweeney is coinventor of the impedance threshold device.

Attestation: Michael Sweeney approved the final manuscript.

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RECUSE NOTE

Dr. Edward C. Nemergut is the Section Editor for Graduate Medical Information for Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Nemergut was not involved in any way with the editorial process or decision.

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FOOTNOTE

a Additional analyses of the ROC PRIMED study for this review (reference 30) were performed by Drs. Yannopoulos and Duval.
Cited Here...

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REFERENCES

1. Cave DM, Gazmuri RJ, Otto CW, Nadkarni VM, Cheng A, Brooks SC, Daya M, Sutton RM, Branson R, Hazinski MF. Part 7: CPR techniques and devices: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 suppl 3):S720–8
2. . 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005;112(24 suppl):IV1–203
3. Aufderheide TP, Frascone RJ, Wayne MA, Mahoney BD, Swor RA, Domeier RM, Olinger ML, Holcomb RG, Tupper DE, Yannopoulos D, Lurie KG. Standard cardiopulmonary resuscitation versus active compression-decompression cardiopulmonary resuscitation with augmentation of negative intrathoracic pressure for out-of-hospital cardiac arrest: a randomised trial. Lancet. 2011;377:301–11
4. Kiehna EN, Huffmyer JL, Thiele RH, Scalzo DC, Nemergut EC. Use of the intrathoracic pressure regulator to lower intracranial pressure in patients with altered intracranial elastance: a pilot study. J Neurosurg. 2013;119:756–9
5. Yannopoulos D, McKnite S, Aufderheide TP, Sigurdsson G, Pirrallo RG, Benditt D, Lurie KG. Effects of incomplete chest wall decompression during cardiopulmonary resuscitation on coronary and cerebral perfusion pressures in a porcine model of cardiac arrest. Resuscitation. 2005;64:363–72
6. Aufderheide TP, Lurie KG. Death by hyperventilation: a common and life-threatening problem during cardiopulmonary resuscitation. Crit Care Med. 2004;32(9 suppl):S345–51
7. Stiell IG, Brown SP, Christenson J, Cheskes S, Nichol G, Powell J, Bigham B, Morrison LJ, Larsen J, Hess E, Vaillancourt C, Davis DP, Callaway CWResuscitation Outcomes Consortium (ROC) Investigators. . What is the role of chest compression depth during out-of-hospital cardiac arrest resuscitation? Crit Care Med. 2012;40:1192–8
8. Idris AH, Guffey D, Aufderheide TP, Brown S, Morrison LJ, Nichols P, Powell J, Daya M, Bigham BL, Atkins DL, Berg R, Davis D, Stiell I, Sopko G, Nichol GResuscitation Outcomes Consortium (ROC) Investigators. . Relationship between chest compression rates and outcomes from cardiac arrest. Circulation. 2012;125:3004–12
9. Bardy GH. A critic’s assessment of our approach to cardiac arrest. N Engl J Med. 2011;364:374–5
10. Sutton RM, Niles D, Nysaether J, Stavland M, Thomas M, Ferry S, Bishnoi R, Litman R, Allen J, Srinivasan V, Berg RA, Nadkarni VM. Effect of residual leaning force on intrathoracic pressure during mechanical ventilation in children. Resuscitation. 2010;81:857–60
11. Markstaller K, Rudolph A, Karmrodt J, Gervais HW, Goetz R, Becher A, David M, Kempski OS, Kauczor HU, Dick WF, Eberle B. Effect of chest compressions only during experimental basic life support on alveolar collapse and recruitment. Resuscitation. 2008;79:125–32
12. Lurie KG, Yannopoulos D, McKnite SH, Herman ML, Idris AH, Nadkarni VM, Tang W, Gabrielli A, Barnes TA, Metzger AK. Comparison of a 10-breaths-per-minute versus a 2-breaths-per-minute strategy during cardiopulmonary resuscitation in a porcine model of cardiac arrest. Respir Care. 2008;53:862–70
13. Yannopoulos D, Segal N, McKnite S, Aufderheide TP, Lurie KG. Controlled pauses at the initiation of sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitate neurological and cardiac recovery after 15 mins of untreated ventricular fibrillation. Crit Care Med. 2012;40:1562–9
14. Debaty G, Shin SD, Metzger A, Kim T, Ryu HH, Rees J, McKnite S, Matsuura T, Lick M, Yannopoulos D, Lurie K. Tilting for perfusion: head-up position during cardiopulmonary resuscitation improves brain flow in a porcine model of cardiac arrest. Resuscitation. 2015;87:38–43
15. Bernard S. Inducing hypothermia after out of hospital cardiac arrest. BMJ. 2014;348:g2735
16. Benson DW, Williams GR Jr, Spencer FC, Yates AJ. The use of hypothermia after cardiac arrest. Anesth Analg. 1959;38:423–8
    17. Hypothermia after Cardiac Arrest Study Group. . Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–56
    18. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–63
      19. Sunde K, Pytte M, Jacobsen D, Mangschau A, Jensen LP, Smedsrud C, Draegni T, Steen PA. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation. 2007;73:29–39
      20. Camuglia AC, Randhawa VK, Lavi S, Walters DL. Cardiac catheterization is associated with superior outcomes for survivors of out of hospital cardiac arrest: review and meta-analysis. Resuscitation. 2014;85:1533–40
      21. Lurie KG, Lindo C, Chin J. CPR: the P stands for plumber’s helper. JAMA. 1990;264:1661
      22. Prengel AW, Lindner KH, Pfenninger EG, Georgieff M. Effects of ventilation on hemodynamics and myocardial blood flow during active compression-decompression resuscitation in pigs. Anesthesiology. 1996;84:135–42
      23. Lurie KG, Coffeen P, Shultz J, McKnite S, Detloff B, Mulligan K. Improving active compression-decompression cardiopulmonary resuscitation with an inspiratory impedance valve. Circulation. 1995;91:1629–32
      24. Shultz JJ, Coffeen P, Sweeney M, Detloff B, Kehler C, Pineda E, Yakshe P, Adler SW, Chang M, Lurie KG. Evaluation of standard and active compression-decompression CPR in an acute human model of ventricular fibrillation. Circulation. 1994;89:684–93
      25. Aufderheide T. A tale of seven EMS systems: an impedance threshold device and improved CPR techniques double survival rates after out-of-hospital cardiac arrest. Circulation. 2007;116:II–936
      26. Yannopoulos D, Nadkarni VM, McKnite SH, Rao A, Kruger K, Metzger A, Benditt DG, Lurie KG. Intrathoracic pressure regulator during continuous-chest-compression advanced cardiac resuscitation improves vital organ perfusion pressures in a porcine model of cardiac arrest. Circulation. 2005;112:803–11
      27. Segal N, Parquette B, Ziehr J, Yannopoulos D, Lindstrom D. Intrathoracic pressure regulation during cardiopulmonary resuscitation: a feasibility case-series. Resuscitation. 2013;84:450–3
      28. Pirrallo RG, Aufderheide TP, Provo TA, Lurie KG. Effect of an inspiratory impedance threshold device on hemodynamics during conventional manual cardiopulmonary resuscitation. Resuscitation. 2005;66:13–20
      29. Aufderheide TP, Nichol G, Rea TD, Brown SP, Leroux BG, Pepe PE, Kudenchuk PJ, Christenson J, Daya MR, Dorian P, Callaway CW, Idris AH, Andrusiek D, Stephens SW, Hostler D, Davis DP, Dunford JV, Pirrallo RG, Stiell IG, Clement CM, Craig A, Van Ottingham L, Schmidt TA, Wang HE, Weisfeldt ML, Ornato JP, Sopko GResuscitation Outcomes Consortium (ROC) Investigators. . A trial of an impedance threshold device in out-of-hospital cardiac arrest. N Engl J Med. 2011;365:798–806
      30. Yannopoulos D, Aufderheide TP, Abella BS, Duval S, Frascone RJ, Goodloe JM, Mahoney BD, Nadkarni VM, Halperin HR, O’Connor R, Idris AH, Becker LB, Pepe PE. Quality of CPR: an important effect modifier in cardiac arrest clinical outcomes and intervention effectiveness trials. Resuscitation. 2015;94:106–13
      31. Lurie K, Zielinski T, McKnite S, Sukhum P. Improving the efficiency of cardiopulmonary resuscitation with an inspiratory impedance threshold valve. Crit Care Med. 2000;28(11 suppl):N207–9
      32. Plaisance P, Lurie KG, Payen D. Inspiratory impedance during active compression-decompression cardiopulmonary resuscitation: a randomized evaluation in patients in cardiac arrest. Circulation. 2000;101:989–94
      33. Plaisance P, Soleil C, Lurie KG, Vicaut E, Ducros L, Payen D. Use of an inspiratory impedance threshold device on a facemask and endotracheal tube to reduce intrathoracic pressures during the decompression phase of active compression-decompression cardiopulmonary resuscitation. Crit Care Med. 2005;33:990–4
        34. Wolcke BB, Mauer DK, Schoefmann MF, Teichmann H, Provo TA, Lindner KH, Dick WF, Aeppli D, Lurie KG. Comparison of standard cardiopulmonary resuscitation versus the combination of active compression-decompression cardiopulmonary resuscitation and an inspiratory impedance threshold device for out-of-hospital cardiac arrest. Circulation. 2003;108:2201–5
          35. Plaisance P, Lurie KG, Vicaut E, Martin D, Gueugniaud PY, Petit JL, Payen D. Evaluation of an impedance threshold device in patients receiving active compression-decompression cardiopulmonary resuscitation for out of hospital cardiac arrest. Resuscitation. 2004;61:265–71
            36. Frascone RJ, Wayne MA, Swor RA, Mahoney BD, Domeier RM, Olinger ML, Tupper DE, Setum CM, Burkhart N, Klann L, Salzman JG, Wewerka SS, Yannopoulos D, Lurie KG, O’Neil BJ, Holcomb RG, Aufderheide TP. Treatment of non-traumatic out-of-hospital cardiac arrest with active compression decompression cardiopulmonary resuscitation plus an impedance threshold device. Resuscitation. 2013;84:1214–22
            37. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–35
            38. Bartos JA, Debaty G, Matsuura T, Yannopoulos D. Post-conditioning to improve cardiopulmonary resuscitation. Curr Opin Crit Care. 2014;20:242–9
              39. Bartos JA, Yannopoulos D. Novelties in pharmacological management of cardiopulmonary resuscitation. Curr Opin Crit Care. 2013;19:417–23
              40. Yannopoulos D, Segal N, Matsuura T, Sarraf M, Thorsgard M, Caldwell E, Rees J, McKnite S, Santacruz K, Lurie KG. Ischemic post-conditioning and vasodilator therapy during standard cardiopulmonary resuscitation to reduce cardiac and brain injury after prolonged untreated ventricular fibrillation. Resuscitation. 2013;84:1143–9
              41. Segal N, Matsuura T, Caldwell E, Sarraf M, McKnite S, Zviman M, Aufderheide TP, Halperin HR, Lurie KG, Yannopoulos D. Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation. Resuscitation. 2012;83:1397–403
              42. Schultz J, Segal N, Kolbeck J, McKnite S, Caldwell E, Yannopoulos D. Sodium nitroprusside enhanced cardiopulmonary resuscitation (SNPeCPR) improves vital organ perfusion pressures and carotid blood flow in a porcine model of cardiac arrest. Resuscitation. 2012;83:374–7
                43. Bartos JA, Matsuura TR, Sarraf M, Youngquist ST, McKnite SH, Rees JN, Sloper DT, Bates FS, Segal N, Debaty G, Lurie KG, Neumar RW, Metzger JM, Riess ML, Yannopoulos D. Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17 min of untreated cardiac arrest. Resuscitation. 2015;87:7–13
                44. Berg RA, Hilwig RW, Kern KB, Ewy GA. “Bystander” chest compressions and assisted ventilation independently improve outcome from piglet asphyxial pulseless “cardiac arrest.” Circulation. 2000;101:1743–8
                45. Berg RA, Hilwig RW, Kern KB, Babar I, Ewy GA. Simulated mouth-to-mouth ventilation and chest compressions (bystander cardiopulmonary resuscitation) improves outcome in a swine model of prehospital pediatric asphyxial cardiac arrest. Crit Care Med. 1999;27:1893–9
                46. Hickey RW, Kochanek PM, Ferimer H, Graham SH, Safar P. Hypothermia and hyperthermia in children after resuscitation from cardiac arrest. Pediatrics. 2000;106(1 pt 1):118–22
                47. Thiagarajan RR, Laussen PC, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation to aid cardiopulmonary resuscitation in infants and children. Circulation. 2007;116:1693–700
                48. Morris MC, Wernovsky G, Nadkarni VM. Survival outcomes after extracorporeal cardiopulmonary resuscitation instituted during active chest compressions following refractory in-hospital pediatric cardiac arrest. Pediatr Crit Care Med. 2004;5:440–6
                49. Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage. JAMA. 1960;173:1064–7
                50. Duggal C, Weil MH, Gazmuri RJ, Tang W, Sun S, O’Connell F, Ali M. Regional blood flow during closed-chest cardiac resuscitation in rats. J Appl Physiol. 1993;74:147–52
                51. Abella BS, Edelson DP, Kim S, Retzer E, Myklebust H, Barry AM, O’Hearn N, Hoek TL, Becker LB. CPR quality improvement during in-hospital cardiac arrest using a real-time audiovisual feedback system. Resuscitation. 2007;73:54–61
                52. Berg RA, Sanders AB, Milander M, Tellez D, Liu P, Beyda D. Efficacy of audio-prompted rate guidance in improving resuscitator performance of cardiopulmonary resuscitation on children. Acad Emerg Med. 1994;1:35–40
                  53. Bobrow BJ, Vadeboncoeur TF, Stolz U, Silver AE, Tobin JM, Crawford SA, Mason TK, Schirmer J, Smith GA, Spaite DW. The influence of scenario-based training and real-time audiovisual feedback on out-of-hospital cardiopulmonary resuscitation quality and survival from out-of-hospital cardiac arrest. Ann Emerg Med. 2013;62:47–56.e1
                    54. Bohn A, Weber TP, Wecker S, Harding U, Osada N, Van Aken H, Lukas RP. The addition of voice prompts to audiovisual feedback and debriefing does not modify CPR quality or outcomes in out of hospital cardiac arrest—a prospective, randomized trial. Resuscitation. 2011;82:257–62
                      55. Gaieski DF, Band RA, Abella BS, Neumar RW, Fuchs BD, Kolansky DM, Merchant RM, Carr BG, Becker LB, Maguire C, Klair A, Hylton J, Goyal M. Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest. Resuscitation. 2009;80:418–24
                      56. Laurent I, Monchi M, Chiche JD, Joly LM, Spaulding C, Bourgeois B, Cariou A, Rozenberg A, Carli P, Weber S, Dhainaut JF. Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol. 2002;40:2110–6
                        57. Walters EL, Morawski K, Dorotta I, Ramsingh D, Lumen K, Bland D, Clem K, Nguyen HB. Implementation of a post-cardiac arrest care bundle including therapeutic hypothermia and hemodynamic optimization in comatose patients with return of spontaneous circulation after out-of-hospital cardiac arrest: a feasibility study. Shock. 2011;35:360–6
                          58. Rudikoff MT, Maughan WL, Effron M, Freund P, Weisfeldt ML. Mechanisms of blood flow during cardiopulmonary resuscitation. Circulation. 1980;61:345–52
                          59. Fisher J, Vaghaiwalla F, Tsitlik J, Levin H, Brinker J, Weisfeldt M, Yin F. Determinants and clinical significance of jugular venous valve competence. Circulation. 1982;65:188–96
                            60. Niemann JT, Rosborough JP, Hausknecht M, Garner D, Criley JM. Pressure-synchronized cineangiography during experimental cardiopulmonary resuscitation. Circulation. 1981;64:985–91
                              61. Halperin HR, Weiss JL, Guerci AD, Chandra N, Tsitlik JE, Brower R, Beattie C, Wurmb E, Cadden J, Weisfeldt ML. Cyclic elevation of intrathoracic pressure can close the mitral valve during cardiac arrest in dogs. Circulation. 1988;78:754–60
                              62. Ma MH, Hwang JJ, Lai LP, Wang SM, Huang GT, Shyu KG, Ko YL, Lin JL, Chen WJ, Hsu KL. Transesophageal echocardiographic assessment of mitral valve position and pulmonary venous flow during cardiopulmonary resuscitation in humans. Circulation. 1995;92:854–61
                                63. Paradis NA, Martin GB, Rivers EP, Goetting MG, Appleton TJ, Feingold M, Nowak RM. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA. 1990;263:1106–13
                                64. Paradis NA, Martin GB, Rosenberg J, Rivers EP, Goetting MG, Appleton TJ, Feingold M, Cryer PE, Wortsman J, Nowak RM. The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA. 1991;265:1139–44
                                  65. Paradis NA, Martin GB, Goetting MG, Rosenberg JM, Rivers EP, Appleton TJ, Nowak RM. Simultaneous aortic, jugular bulb, and right atrial pressures during cardiopulmonary resuscitation in humans. Insights into mechanisms. Circulation. 1989;80:361–8
                                  66. Feneley MP, Maier GW, Gaynor JW, Gall SA, Kisslo JA, Davis JW, Rankin JS. Sequence of mitral valve motion and transmitral blood flow during manual cardiopulmonary resuscitation in dogs. Circulation. 1987;76:363–75
                                  67. Metzger AK, Herman M, McKnite S, Tang W, Yannopoulos D. Improved cerebral perfusion pressures and 24-hr neurological survival in a porcine model of cardiac arrest with active compression-decompression cardiopulmonary resuscitation and augmentation of negative intrathoracic pressure. Crit Care Med. 2012;40:1851–6
                                  68. Guerci AD, Shi AY, Levin H, Tsitlik J, Weisfeldt ML, Chandra N. Transmission of intrathoracic pressure to the intracranial space during cardiopulmonary resuscitation in dogs. Circ Res. 1985;56:20–30
                                  69. Yannopoulos D, McKnite SH, Metzger A, Lurie KG. Intrathoracic pressure regulation for intracranial pressure management in normovolemic and hypovolemic pigs. Crit Care Med. 2006;34(12 suppl):S495–500
                                  70. Voelckel WG, Lurie KG, Zielinski T, McKnite S, Plaisance P, Wenzel V, Lindner KH. The effects of positive end-expiratory pressure during active compression decompression cardiopulmonary resuscitation with the inspiratory threshold valve. Anesth Analg. 2001;92:967–74
                                  71. Edelson DP, Abella BS, Kramer-Johansen J, Wik L, Myklebust H, Barry AM, Merchant RM, Hoek TL, Steen PA, Becker LB. Effects of compression depth and pre-shock pauses predict defibrillation failure during cardiac arrest. Resuscitation. 2006;71:137–45
                                  72. Vadeboncoeur T, Stolz U, Panchal A, Silver A, Venuti M, Tobin J, Smith G, Nunez M, Karamooz M, Spaite D, Bobrow B. Chest compression depth and survival in out-of-hospital cardiac arrest. Resuscitation. 2014;85:182–8
                                    73. Stiell IG, Brown SP, Nichol G, Cheskes S, Vaillancourt C, Callaway CW, Morrison LJ, Christenson J, Aufderheide TP, Davis DP, Free C, Hostler D, Stouffer JA, Idris AHResuscitation Outcomes Consortium Investigators. . What is the optimal chest compression depth during out-of-hospital cardiac arrest resuscitation of adult patients? Circulation. 2014;130:1962–70
                                      74. Idris AH, Guffey D, Pepe PE, Brown SP, Brooks SC, Callaway CW, Christenson J, Davis DP, Daya MR, Gray R, Kudenchuk PJ, Larsen J, Lin S, Menegazzi JJ, Sheehan K, Sopko G, Stiell I, Nichol G, Aufderheide TPResuscitation Outcomes Consortium Investigators. . Chest compression rates and survival following out-of-hospital cardiac arrest. Crit Care Med. 2015;43:840–8
                                      75. Kern KB, Sanders AB, Raife J, Milander MM, Otto CW, Ewy GA. A study of chest compression rates during cardiopulmonary resuscitation in humans. The importance of rate-directed chest compressions. Arch Intern Med. 1992;152:145–9
                                        76. Abella BS, Sandbo N, Vassilatos P, Alvarado JP, O’Hearn N, Wigder HN, Hoffman P, Tynus K, Vanden Hoek TL, Becker LB. Chest compression rates during cardiopulmonary resuscitation are suboptimal: a prospective study during in-hospital cardiac arrest. Circulation. 2005;111:428–34
                                          77. Cheskes S, Schmicker RH, Verbeek PR, Salcido DD, Brown SP, Brooks S, Menegazzi JJ, Vaillancourt C, Powell J, May S, Berg RA, Sell R, Idris A, Kampp M, Schmidt T, Christenson JResuscitation Outcomes Consortium (ROC) Investigators. . The impact of peri-shock pause on survival from out-of-hospital shockable cardiac arrest during the Resuscitation Outcomes Consortium PRIMED trial. Resuscitation. 2014;85:336–42
                                          78. Wang HE, Simeone SJ, Weaver MD, Callaway CW. Interruptions in cardiopulmonary resuscitation from paramedic endotracheal intubation. Ann Emerg Med. 2009;54:645–52.e1
                                          79. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, Kudenchuk PJ, Ornato JP, McNally B, Silvers SM, Passman RS, White RD, Hess EP, Tang W, Davis D, Sinz E, Morrison LJ. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 suppl 3):S729–67
                                            80. Sayre MR, Koster RW, Botha M, Cave DM, Cudnik MT, Handley AJ, Hatanaka T, Hazinski MF, Jacobs I, Monsieurs K, Morley PT, Nolan JP, Travers AHAdult Basic Life Support Chapter Collaborators. . Part 5: adult basic life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010;122(16 suppl 2):S298–324
                                              81. Jost D, Degrange H, Verret C, Hersan O, Banville IL, Chapman FW, Lank P, Petit JL, Fuilla C, Migliani R, Carpentier JPDEFI 2005 Work Group. . DEFI 2005: a randomized controlled trial of the effect of automated external defibrillator cardiopulmonary resuscitation protocol on outcome from out-of-hospital cardiac arrest. Circulation. 2010;121:1614–22
                                                82. Lurie K, Voelckel W, Plaisance P, Zielinski T, McKnite S, Kor D, Sugiyama A, Sukhum P. Use of an inspiratory impedance threshold valve during cardiopulmonary resuscitation: a progress report. Resuscitation. 2000;44:219–30
                                                83. Lurie KG, Mulligan KA, McKnite S, Detloff B, Lindstrom P, Lindner KH. Optimizing standard cardiopulmonary resuscitation with an inspiratory impedance threshold valve. Chest. 1998;113:1084–90
                                                84. . Part 1: introduction to the International Guidelines 2000 for CPR and ECC: a consensus on science. Circulation. 2000;102(8 suppl):I1–11
                                                  85. Robertson C, Steen P, Adgey J, Bossaert L, Carli P, Chamberlain D, Dick W, Ekstrom L, Hapnes SA, Holmberg S, Juchems R, Kette F, Koster R, de Latorre FJ, Lindner K, Perales N. The 1998 European Resuscitation Council guidelines for adult advanced life support: a statement from the Working Group on Advanced Life Support, and approved by the executive committee. Resuscitation. 1998;37:81–90
                                                    86. Lurie KG, Zielinski T, McKnite S, Aufderheide T, Voelckel W. Use of an inspiratory impedance valve improves neurologically intact survival in a porcine model of ventricular fibrillation. Circulation. 2002;105:124–9
                                                    87. Aufderheide TP, Pirrallo RG, Yannopoulos D, Klein JP, von Briesen C, Sparks CW, Deja KA, Conrad CJ, Kitscha DJ, Provo TA, Lurie KG. Incomplete chest wall decompression: a clinical evaluation of CPR performance by EMS personnel and assessment of alternative manual chest compression-decompression techniques. Resuscitation. 2005;64:353–62
                                                    88. Metzger AK, Lurie KGIaizzo PA. Harnessing cardiopulmonary interactions to improve circulation and outcomes after cardiac arrest and other states of low blood pressure. In: Handbook of Cardiac Anatomy, Physiology, and Devices. 20092nd ed. New York, NY Humana Press:583–604
                                                    89. Aufderheide TP, Alexander C, Lick C, Myers B, Romig L, Vartanian L, Stothert J, McKnite S, Matsuura T, Yannopoulos D, Lurie K. From laboratory science to six emergency medical services systems: new understanding of the physiology of cardiopulmonary resuscitation increases survival rates after cardiac arrest. Crit Care Med. 2008;36(11 suppl):S397–404
                                                    90. Fried DA, Leary M, Smith DA, Sutton RM, Niles D, Herzberg DL, Becker LB, Abella BS. The prevalence of chest compression leaning during in-hospital cardiopulmonary resuscitation. Resuscitation. 2011;82:1019–24
                                                    91. Zuercher M, Hilwig RW, Ranger-Moore J, Nysaether J, Nadkarni VM, Berg MD, Kern KB, Sutton R, Berg RA. Leaning during chest compressions impairs cardiac output and left ventricular myocardial blood flow in piglet cardiac arrest. Crit Care Med. 2010;38:1141–6
                                                    92. Fitzgerald KR, Babbs CF, Frissora HA, Davis RW, Silver DI. Cardiac output during cardiopulmonary resuscitation at various compression rates and durations. Am J Physiol. 1981;241:H442–8
                                                    93. Markstaller K, Karmrodt J, Doebrich M, Wolcke B, Gervais H, Weiler N, Thelen M, Dick W, Kauczor HU, Eberle B. Dynamic computed tomography: a novel technique to study lung aeration and atelectasis formation during experimental CPR. Resuscitation. 2002;53:307–13
                                                    94. Aufderheide TP, Sigurdsson G, Pirrallo RG, Yannopoulos D, McKnite S, von Briesen C, Sparks CW, Conrad CJ, Provo TA, Lurie KG. Hyperventilation-induced hypotension during cardiopulmonary resuscitation. Circulation. 2004;109:1960–5
                                                    95. West JB Respiratory Physiology—The Essentials. 19955th ed Baltimore Williams & Wilkins:xii, 193 p
                                                    96. Cassidy SS, Mitchell JH. Effects of positive pressure breathing on right and left ventricular preload and afterload. Fed Proc. 1981;40:2178–81
                                                    97. Michard F. Changes in arterial pressure during mechanical ventilation. Anesthesiology. 2005;103:419–28
                                                    98. Metzger A, Herman M, McKnite S, Yannopoulos D, Lurie K. Effect of an impedance threshold device and a novel active compression decompression cardiopulmonary resuscitation device on cerebral perfusion pressures and 24-hour neurological survival in a porcine model of cardiac arrest. Circulation. 2006;114:II–554
                                                    99. Weil MH, Bisera J, Trevino RP, Rackow EC. Cardiac output and end-tidal carbon dioxide. Crit Care Med. 1985;13:907–9
                                                    100. Yannopoulos D, Tang W, Roussos C, Aufderheide TP, Idris AH, Lurie KG. Reducing ventilation frequency during cardiopulmonary resuscitation in a porcine model of cardiac arrest. Respir Care. 2005;50:628–35
                                                    101. Idris AH, Banner MJ, Wenzel V, Fuerst RS, Becker LB, Melker RJ. Ventilation caused by external chest compression is unable to sustain effective gas exchange during CPR: a comparison with mechanical ventilation. Resuscitation. 1994;28:143–50
                                                    102. Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Böttiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT Jr, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Vanden Hoek T. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 2008;118:2452–83
                                                    103. Rea TD, Fahrenbruch C, Culley L, Donohoe RT, Hambly C, Innes J, Bloomingdale M, Subido C, Romines S, Eisenberg MS. CPR with chest compression alone or with rescue breathing. N Engl J Med. 2010;363:423–33
                                                    104. Bobrow BJ, Spaite DW, Berg RA, Stolz U, Sanders AB, Kern KB, Vadeboncoeur TF, Clark LL, Gallagher JV, Stapczynski JS, LoVecchio F, Mullins TJ, Humble WO, Ewy GA. Chest compression-only CPR by lay rescuers and survival from out- of-hospital cardiac arrest. JAMA. 2010;304:1447–54
                                                    105. Berg RA, Hemphill R, Abella BS, Aufderheide TP, Cave DM, Hazinski MF, Lerner EB, Rea TD, Sayre MR, Swor RA. Part 5: adult basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122:S685–705
                                                    106. Hinchey PR, Myers JB, Lewis R, De Maio VJ, Reyer E, Licatese D, Zalkin J, Snyder GCapital County Research Consortium. . Improved out-of-hospital cardiac arrest survival after the sequential implementation of 2005 AHA guidelines for compressions, ventilations, and induced hypothermia: the Wake County experience. Ann Emerg Med. 2010;56:348–57
                                                    107. St-John WM, Paton JF. Respiratory-modulated neuronal activities of the rostral medulla which may generate gasping. Respir Physiol Neurobiol. 2003;135:97–101
                                                    108. Bobrow BJ, Zuercher M, Ewy GA, Clark L, Chikani V, Donahue D, Sanders AB, Hilwig RW, Berg RA, Kern KB. Gasping during cardiac arrest in humans is frequent and associated with improved survival. Circulation. 2008;118:2550–4
                                                    109. Srinivasan V, Nadkarni VM, Yannopoulos D, Marino BS, Sigurdsson G, McKnite SH, Zook M, Benditt DG, Lurie KG. Spontaneous gasping decreases intracranial pressure and improves cerebral perfusion in a pig model of ventricular fibrillation. Resuscitation. 2006;69:329–34
                                                    110. von Planta I, Weil MH, von Planta M, Bisera J, Bruno S, Gazmuri RJ, Rackow EC. Cardiopulmonary resuscitation in the rat. J Appl Physiol. 1988;65:2641–7
                                                      111. Zuercher M, Ewy GA, Otto CW, Hilwig RW, Bobrow BJ, Clark L, Chikani V, Sanders AB, Berg RA, Kern KB. Gasping in response to basic resuscitation efforts: observation in a Swine model of cardiac arrest. Crit Care Res Pract. 2010 2010 [epub ahead of print]
                                                        112. Girsky MJ, Criley JM. Images in cardiovascular medicine. Cough cardiopulmonary resuscitation revisited. Circulation. 2006;114:e530–1
                                                        113. Criley JM, Niemann JT, Rosborough JP, Hausknecht M. Modifications of cardiopulmonary resuscitation based on the cough. Circulation. 1986;74:IV42–50
                                                        114. Debaty G, Aufderheide TP, Swor RA, Frascone RJ, Wayne MA, Domeier RM, Olinger ML, Mahoney BD, Yannopoulos D. The paradoxical association between pulmonary edema and survival with favorable neurological function after cardiac arrest. Circulation. 2014;130:A248
                                                        115. Lick CJ, Aufderheide TP, Niskanen RA, Steinkamp JE, Davis SP, Nygaard SD, Bemenderfer KK, Gonzales L, Kalla JA, Wald SK, Gillquist DL, Sayre MR, Osaki Holm SY, Oski Holm SY, Oakes DA, Provo TA, Racht EM, Olsen JD, Yannopoulos D, Lurie KG. Take Heart America: a comprehensive, community-wide, systems-based approach to the treatment of cardiac arrest. Crit Care Med. 2011;39:26–33
                                                        116. Meaney PA, Nadkarni VM, Kern KB, Indik JH, Halperin HR, Berg RA. Rhythms and outcomes of adult in-hospital cardiac arrest. Crit Care Med. 2010;38:101–8
                                                          117. Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010;3:63–81
                                                            118. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, Rea T, Lowe R, Brown T, Dreyer J, Davis D, Idris A, Stiell IResuscitation Outcomes Consortium Investigators. . Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008;300:1423–31
                                                            119. Wik L, Olsen JA, Persse D, Sterz F, Lozano M Jr, Brouwer MA, Westfall M, Souders CM, Malzer R, van Grunsven PM, Travis DT, Whitehead A, Herken UR, Lerner EB. Manual vs. integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial. Resuscitation. 2014;85:741–8
                                                            120. Rubertsson S, Lindgren E, Smekal D, Östlund O, Silfverstolpe J, Lichtveld RA, Boomars R, Ahlstedt B, Skoog G, Kastberg R, Halliwell D, Box M, Herlitz J, Karlsten R. Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC randomized trial. JAMA. 2014;311:53–61
                                                            121. Perkins GD, Lall R, Quinn T, Deakin CD, Cooke MW, Horton J, Lamb SE, Slowther AM, Woollard M, Carson A, Smyth M, Whitfield R, Williams A, Pocock H, Black JJ, Wright J, Han K, Gates SPARAMEDIC Trial Collaborators. . Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial. Lancet. 2015;385:947–55
                                                              122. Thigpen K, Davis SP, Basol R, Lange P, Jain SS, Olsen JD, Erickson BR, Schuchard TN, Aufderheide TP. Implementing the 2005 American Heart Association guidelines, including use of the impedance threshold device, improves hospital discharge rate after in-hospital cardiac arrest. Respir Care. 2010;55:1014–9
                                                              123. Cinel I, Goldfarb RD, Metzger A, Lurie K, Jasti P, Knob CR, Parrillo JE, Phillip Dellinger R. Biphasic intra-thoracic pressure regulation augments cardiac index during porcine peritonitis: a feasibility study. J Med Eng Technol. 2014;38:49–54
                                                              124. Metzger A, Rees J, Segal N, McKnite S, Matsuura T, Convertino VA, Gerhardt RT, Lurie KG. “Fluidless” resuscitation with permissive hypotension via impedance threshold device therapy compared with normal saline resuscitation in a porcine model of severe hemorrhage. J Trauma Acute Care Surg. 2013;75(2 suppl 2):S203–9
                                                              125. Metzger A, Rees J, Puertas L, McKnite S, Lurie K. Intrathoracic pressure regulation therapy continuously improves cerebral perfusion pressure and cerebral blood flow compared to untreated controls in a porcine model of traumatic brain injury. Neurocrit Care. 2013;19:S200
                                                                126. Convertino VA, Parquette B, Zeihr J, Traynor K, Baia D, Baumblatt M, Vartanian L, Suresh M, Metzger A, Gerhardt RT, Lurie KG, Lindstrom D. Use of respiratory impedance in prehospital care of hypotensive patients associated with hemorrhage and trauma: a case series. J Trauma Acute Care Surg. 2012;73(2 suppl 1):S54–9
                                                                  127. Segal N, Rees J, Convertino VA, Metzger A, Zarama D, Voulgaropoulos L, McKnite SH, Yannopoulos D, Tang W, Vicaut E, Lurie K. Improving microcirculation with therapeutic intrathoracic pressure regulation in a porcine model of hemorrhage. Resuscitation. 2011;82(suppl 2):S16–22
                                                                  128. Metzger A, Matsuura T, McKnite S, Marino BS, Nadkarni VM, Yannopoulos D. Intrathoracic pressure regulation improves 24-hour survival in a pediatric porcine model of hemorrhagic shock. Pediatr Res. 2011;70:267–71
                                                                  129. Metzger A, Kwon Y, McKnite S, Lurie K. Decreasing intracranial pressures with the intrathoracic pressure regulator: a pilot study to evaluate the mechanism of transmission. Neurocrit Care. 2011;15(1S):S243
                                                                    130. Convertino VA, Ryan KL, Rickards CA, Glorsky SL, Idris AH, Yannopoulos D, Metzger A, Lurie KG. Optimizing the respiratory pump: harnessing inspiratory resistance to treat systemic hypotension. Respir Care. 2011;56:846–57
                                                                      131. Smith SW, Parquette B, Lindstrom D, Metzger AK, Kopitzke J, Clinton J. An impedance threshold device increases blood pressure in hypotensive patients. J Emerg Med. 2011;41:549–58
                                                                        132. Kwon Y, Metzger A, Matsuura T, McKnite S, Yannopoulos D, Lurie K. Prolonged treatment with the intrathoracic pressure regulator improves cerebral perfusion pressure and decreases intracranial pressure without compromising lung function in a porcine model of traumatic brain injury. Neurocrit Care. 2010;13(S1):S183
                                                                          133. Cinel I, Metzger A, Dellinger RVincent J. Intrathoracic pressure regulation for the treatment of hypotension. In: Yearbook of Intensive Care and Emergency Medicine. 2009 Berlin Heidelberg, Germany Springer:297–305
                                                                          134. Metzger A, Yannopoulos D, Lurie KMebazaa A, Gheorghiade M, Zannad F, Parrillo JE. Instrumental management of CPR. In: Severe Acute Heart Failure Syndromes: A Practical Approach for Physicians. 2008 London, UK Springer-Verlag:43–51
                                                                            135. Matsuura T, McKnite MS, Metzger AK, Yannopoulos D, Aufderheide TP, Lurie KG. An impedance threshold device combined with an automated active compression decompression CPR device (LUCAS) improves the chances for survival in pigs in cardiac arrest. Circulation. 2008;118:S1449–50
                                                                              136. Metzger A, Matsuura T, McKnite S, Lurie K. The intrathoracic pressure regulator improves cerebral perfusion pressures and carotid blood flow in a porcine model of traumatic brain injury. Circulation. 2008;118S:664
                                                                              137. Convertino VA, Ryan KL, Rickards CA, Cooke WH, Idris AH, Metzger A, Holcomb JB, Adams BD, Lurie KG. Inspiratory resistance maintains arterial pressure during central hypovolemia: implications for treatment of patients with severe hemorrhage. Crit Care Med. 2007;35:1145–52
                                                                                138. Yannopoulos D, McKnite S, Metzger A, Lurie KG. Intrathoracic pressure regulation improves 24-hour survival in a porcine model of hypovolemic shock. Anesth Analg. 2007;104:157–62
                                                                                139. Metzger A, Marino BS, Matsuura T, Herman M, McKnite SH, Srinivasan V, Nadkarni V, Lurie KG. An impedance threshold device improves 24-hour survival in a spontaneously breathing pediatric porcine model of hemorrhagic shock. Circulation. 2007;116:S632
                                                                                  140. Yannopoulos D, Metzger A, McKnite S, Nadkarni V, Aufderheide TP, Idris A, Dries D, Benditt DG, Lurie KG. Intrathoracic pressure regulation improves vital organ perfusion pressures in normovolemic and hypovolemic pigs. Resuscitation. 2006;70:445–53
                                                                                  141. Huffmyer JL, Groves DS, Scalzo DC, DeSouza DG, Littlewood KE, Thiele RH, Nemergut EC. The effect of the intrathoracic pressure regulator on hemodynamics and cardiac output. Shock. 2011;35:114–6
                                                                                  142. Chang MW, Coffeen P, Lurie KG, Shultz J, Bache RJ, White CW. Active compression-decompression CPR improves vital organ perfusion in a dog model of ventricular fibrillation. Chest. 1994;106:1250–9
                                                                                  143. Lurie KG. Active compression-decompression CPR: a progress report. Resuscitation. 1994;28:115–22
                                                                                  144. Sugiyama A, Lurie KG, Maeda Y, Satoh Y, Imura M, Hashimoto K. Utilization of a model lung system to assess the effects of an inspiratory impedance threshold valve on the relationship between active decompression and intra-thoracic pressure. Resuscitation. 1999;42:231–4
                                                                                  145. Voelckel WG, Lurie KG, Sweeney M, McKnite S, Zielinski T, Lindstrom P, Peterson C, Wenzel V, Lindner KH. Effects of active compression-decompression cardiopulmonary resuscitation with the inspiratory threshold valve in a young porcine model of cardiac arrest. Pediatr Res. 2002;51:523–7
                                                                                  146. Lurie KG, Zielinski T, Voelckel W, McKnite S, Plaisance P. Augmentation of ventricular preload during treatment of cardiovascular collapse and cardiac arrest. Crit Care Med. 2002;30(4 suppl):S162–5
                                                                                    147. Langhelle A, Strømme T, Sunde K, Wik L, Nicolaysen G, Steen PA. Inspiratory impedance threshold valve during CPR. Resuscitation. 2002;52:39–48
                                                                                    148. Lurie KG, Lindner KH. Recent advances in cardiopulmonary resuscitation. J Cardiovasc Electrophysiol. 1997;8:584–600
                                                                                    149. Lurie KG, Voelckel WG, Zielinski T, McKnite S, Lindstrom P, Peterson C, Wenzel V, Lindner KH, Samniah N, Benditt D. Improving standard cardiopulmonary resuscitation with an inspiratory impedance threshold valve in a porcine model of cardiac arrest. Anesth Analg. 2001;93:649–55
                                                                                    150. Debaty G, Segal N, Matsuura T, Fahey B, Wayne M, Mahoney B, Frascone R, Lick C, Yannopoulos D. Hemodynamic improvement of a LUCAS 2 automated device by addition of an impedance threshold device in a pig model of cardiac arrest. Resuscitation. 2014;85:1704–7
                                                                                      151. Yannopoulos D, Aufderheide TP, McKnite S, Kotsifas K, Charris R, Nadkarni V, Lurie KG. Hemodynamic and respiratory effects of negative tracheal pressure during CPR in pigs. Resuscitation. 2006;69:487–94
                                                                                      152. Thayne RC, Thomas DC, Neville JD, Van Dellen A. Use of an impedance threshold device improves short-term outcomes following out-of-hospital cardiac arrest. Resuscitation. 2005;67:103–8
                                                                                      153. Babbs CF. Effects of an impedance threshold valve upon hemodynamics in standard CPR: studies in a refined computational model. Resuscitation. 2005;66:335–45
                                                                                      154. Lai SM, Duncan PW. Stroke recovery profile and the modified Rankin assessment. Neuroepidemiology. 2001;20:26–30
                                                                                        155. . ResQCPR system instructions for use. 2015 FDA Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110024c.pdf. Accessed April 27, 2015
                                                                                        156. Birch M, Kwon Y, Loushin M, Puertas L, Prielipp R, Belani K, Beebe D. Intrathoracic pressure regulation to treat intra- operative hypotension: a phase 2 pilot study. Eur J Anaesthesiol. 2015;32:376–80
                                                                                        157. Debaty G, Metzger A, Rees J, McKnite S, Puertas L, Yannopoulos D, Lurie K. Enhanced perfusion during advanced life support improves survival with favorable neurologic function in a porcine model of refractory cardiac arrest. Crit Care Med. 2015;43:1087–95
                                                                                        158. Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol. 2011;8:619–29
                                                                                        159. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985;76:1713–9
                                                                                        160. Zhao ZQ, Vinten-Johansen J. Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res. 2006;70:200–11
                                                                                          161. Riess ML, Matsuura TR, Bartos JA, Bienengraeber M, Aldakkak M, McKnite SH, Rees JN, Aufderheide TP, Sarraf M, Neumar RW, Yannopoulos D. Anaesthetic postconditioning at the initiation of CPR improves myocardial and mitochondrial function in a pig model of prolonged untreated ventricular fibrillation. Resuscitation. 2014;85:1745–51
                                                                                          162. Knapp J, Bergmann G, Bruckner T, Russ N, Böttiger BW, Popp E. Pre- and postconditioning effect of sevoflurane on myocardial dysfunction after cardiopulmonary resuscitation in rats. Resuscitation. 2013;84:1450–5
                                                                                          163. Murphy AD, McCormack MC, Bichara DA, Nguyen JT, Randolph MA, Watkins MT, Lee RC, Austen WG Jr. Poloxamer 188 protects against ischemia-reperfusion injury in a murine hind-limb model. Plast Reconstr Surg. 2010;125:1651–60
                                                                                          164. Gu JH, Ge JB, Li M, Xu HD, Wu F, Qin ZH. Poloxamer 188 protects neurons against ischemia/reperfusion injury through preserving integrity of cell membranes and blood brain barrier. PLoS One. 2013;8:e61641
                                                                                            165. Walters TJ, Mase VJ Jr, Roe JL, Dubick MA, Christy RJ. Poloxamer-188 reduces muscular edema after tourniquet-induced ischemia-reperfusion injury in rats. J Trauma. 2011;70:1192–7
                                                                                              166. Bao HJ, Wang T, Zhang MY, Liu R, Dai DK, Wang YQ, Wang L, Zhang L, Gao YZ, Qin ZH, Chen XP, Tao LY. Poloxamer-188 attenuates TBI-induced blood-brain barrier damage leading to decreased brain edema and reduced cellular death. Neurochem Res. 2012;37:2856–67
                                                                                                167. Schaer GL, Spaccavento LJ, Browne KF, Krueger KA, Krichbaum D, Phelan JM, Fletcher WO, Grines CL, Edwards S, Jolly MK, Gibbons RJ. Beneficial effects of RheothRx injection in patients receiving thrombolytic therapy for acute myocardial infarction. Results of a randomized, double-blind, placebo-controlled trial. Circulation. 1996;94:298–307
                                                                                                168. Collaborative Organization for RheothRx Evaluation (CORE). . Effects of RheothRx on mortality, morbidity, left ventricular function, and infarct size in patients with acute myocardial infarction. Circulation. 1997;96:192–201
                                                                                                169. Aufderheide TP, Yannopoulos D, Lick CJ, Myers B, Romig LA, Stothert JC, Barnard J, Vartanian L, Pilgrim AJ, Benditt DG. Implementing the 2005 American Heart Association Guidelines improves outcomes after out-of-hospital cardiac arrest. Heart Rhythm. 2010;7:1357–62
                                                                                                170. Hulleman M, Berdowski J, de Groot JR, van Dessel PF, Borleffs CJ, Blom MT, Bardai A, de Cock CC, Tan HL, Tijssen JG, Koster RW. Implantable cardioverter-defibrillators have reduced the incidence of resuscitation for out-of-hospital cardiac arrest caused by lethal arrhythmias. Circulation. 2012;126:815–21
                                                                                                171. Ilkhanoff L, Goldberger JJ. Out-of-hospital cardiac arrest: getting beyond the tip of the iceberg. Circulation. 2012;126:793–6
                                                                                                172. Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, Nichol G, Lane-Truitt T, Potts J, Ornato JP, Berg RANational Registry of Cardiopulmonary Resuscitation Investigators. . First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006;295:50–7
                                                                                                173. Peberdy MA, Kaye W, Ornato JP, Larkin GL, Nadkarni V, Mancini ME, Berg RA, Nichol G, Lane-Trultt T. Cardiopulmonary resuscitation of adults in the hospital: a report of 14720 cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation. 2003;58:297–308
                                                                                                174. Bellomo R, Goldsmith D, Uchino S, Buckmaster J, Hart GK, Opdam H, Silvester W, Doolan L, Gutteridge G. A prospective before-and-after trial of a medical emergency team. Med J Aust. 2003;179:283–7
                                                                                                175. Cretikos MA, Chen J, Hillman KM, Bellomo R, Finfer SR, Flabouris AMERIT Study Investigators. . The effectiveness of implementation of the medical emergency team (MET) system and factors associated with use during the MERIT study. Crit Care Resusc. 2007;9:205–12
                                                                                                  176. Chan PS, Khalid A, Longmore LS, Berg RA, Kosiborod M, Spertus JA. Hospital-wide code rates and mortality before and after implementation of a rapid response team. JAMA. 2008;300:2506–13
                                                                                                    177. Stross JK. Maintaining competency in advanced cardiac life support skills. JAMA. 1983;249:3339–41
                                                                                                    178. Cheng A, Brown LL, Duff JP, Davidson J, Overly F, Tofil NM, Peterson DT, White ML, Bhanji F, Bank I, Gottesman R, Adler M, Zhong J, Grant V, Grant DJ, Sudikoff SN, Marohn K, Charnovich A, Hunt EA, Kessler DO, Wong H, Robertson N, Lin Y, Doan Q, Duval-Arnould JM, Nadkarni VMInternational Network for Simulation-Based Pediatric Innovation, Research, & Education (INSPIRE) CPR Investigators. . Improving cardiopulmonary resuscitation with a CPR feedback device and refresher simulations (CPR CARES Study): a randomized clinical trial. JAMA Pediatr. 2015;169:137–44
                                                                                                      179. Wayne DB, Didwania A, Feinglass J, Fudala MJ, Barsuk JH, McGaghie WC. Simulation-based education improves quality of care during cardiac arrest team responses at an academic teaching hospital: a case-control study. Chest. 2008;133:56–61
                                                                                                        180. Berg MD, Schexnayder SM, Chameides L, Terry M, Donoghue A, Hickey RW, Berg RA, Sutton RM, Hazinski MF. Part 13: pediatric basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 suppl 3):S862–75
                                                                                                        181. Kleinman ME, Chameides L, Schexnayder SM, Samson RA, Hazinski MF, Atkins DL, Berg MD, de Caen AR, Fink EL, Freid EB, Hickey RW, Marino BS, Nadkarni VM, Proctor LT, Qureshi FA, Sartorelli K, Topjian A, van der Jagt EW, Zaritsky AL. Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 suppl 3):S876–908
                                                                                                        182. Tress EE, Kochanek PM, Saladino RA, Manole MD. Cardiac arrest in children. J Emerg Trauma Shock. 2010;3:267–72
                                                                                                          183. Meaney PA, Nadkarni VM, Cook EF, Testa M, Helfaer M, Kaye W, Larkin GL, Berg RAAmerican Heart Association National Registry of Cardiopulmonary Resuscitation Investigators. . Higher survival rates among younger patients after pediatric intensive care unit cardiac arrests. Pediatrics. 2006;118:2424–33
                                                                                                            184. Dean JM, Koehler RC, Schleien CL, Michael JR, Chantarojanasiri T, Rogers MC, Traystman RJ. Age-related changes in chest geometry during cardiopulmonary resuscitation. J Appl Physiol. 1987;62:2212–9
                                                                                                            185. Anthi A, Tzelepis GE, Alivizatos P, Michalis A, Palatianos GM, Geroulanos S. Unexpected cardiac arrest after cardiac surgery: incidence, predisposing causes, and outcome of open chest cardiopulmonary resuscitation. Chest. 1998;113:15–9
                                                                                                            186. Sutton RM, Nadkarni V, Abella BS. “Putting it all together” to improve resuscitation quality. Emerg Med Clin North Am. 2012;30:105–22
                                                                                                            187. Topjian A, Hutchins L, DiLiberto MA, Abend NS, Ichord R, Helfaer M, Berg RA, Nadkarni V. Induction and maintenance of therapeutic hypothermia after pediatric cardiac arrest: efficacy of a surface cooling protocol. Pediatr Crit Care Med. 2011;12:e127–35
                                                                                                            188. Kochanek PM, Fink EL, Bell MJ, Bayir H, Clark RS. Therapeutic hypothermia: applications in pediatric cardiac arrest. J Neurotrauma. 2009;26:421–7
                                                                                                            189. Berg MD, Nadkarni VM, Zuercher M, Berg RA. In-hospital pediatric cardiac arrest. Pediatr Clin North Am. 2008;55:589–604
                                                                                                            190. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD, Valentine FT, Jonas L, Meibohm A, Emini EA, Chodakewitz JA. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337:734–9
                                                                                                            191. Meaney PA, Bobrow BJ, Mancini ME, Christenson J, de Caen AR, Bhanji F, Abella BS, Kleinman ME, Edelson DP, Berg RA, Aufderheide TP, Menon V, Leary MCPR Quality Summit Investigators, the American Heart Association Emergency Cardiovascular Care Committee, and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. . Cardiopulmonary resuscitation quality: [corrected] improving cardiac resuscitation outcomes both inside and outside the hospital: a consensus statement from the American Heart Association. Circulation. 2013;128:417–35
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