Pulseless Electrical Activity

What is Pulseless Electrical Activity (PEA)?

Pulseless electrical activity, or PEA, is a common occurrence during arrest situations. In PEA, the monitor will show electrical activity in the heart, but the patient will have no palpable pulse. This is a very dangerous situation for the patient, and it takes a skilled ACLS practitioner to learn how to manage this condition. In other pulseless rhythms, such as ventricular fibrillation and pulseless ventricular tachycardia, shocks are advised, but defibrillation will do nothing to help the patient in PEA. The primary treatment is to find the underlying cause of the arrest.

In the early resuscitation guidelines, electrical mechanical dissociation (EMD) referred to the prescence of organized electrical activity in the absence of synchronous myocardial contraction(1–3). As such, electrical activity was detected on the surface electrocardiogram but no effective cardiac output was present owing to the absence of coupled mechanical activity. The clinical result was the absence of pulse, blood pressure, and heart tones. EMD was observed in a variety of resuscitation situations and was felt to be secondary to prolonged global cardiac ischemia. The organized rhythm varied from sinus tachycardia with a normal duration QRS complex to brady-dysrhythmias with wide aberrant or idioventricular ventricular morphologies. A poor resuscitation outcome and dismal prognosis was a common shared observation. Collectively, this ominous rhythm was found to have a resuscitation rate of only about 20% and a hospital discharge rate of 4 to 5% (4,5). Early animal studies and resuscitation attempts with inotropic and chronotropic drugs, calcium chloride, and electrical pacing proved ineffective (5–11). Recent evaluations of clinical predictors and prognosis have found that pulseless electrical activity (PEA) continues to be poor predictor of survival. Only 15% of victims of prehospital cardiac arrest (CA) are admitted alive to hospital and only 2.4% were discharged alive .

PATHOBIOLOGY 

An improved understanding of the mechanisms responsible for PEA has provided a refined pathophysiology of this disorder. As described originally, PEA was perceived as subcellular myocyte failure occurring in the presence of electrical excitation. Working myocytes have a centrally located nucleus and abundant contractile protein elements organized into myofibrils. The flux and interaction of calcium with myofibrillar elements initiates and terminates contraction by concentration characteristics at regulatory sites. This interaction is very complex and excitation–contraction coupling involves cell components called the plasma membrane, sarcoplasmic reticulum, and myofilaments. An envelope called the plasma membrane surrounds and penetrates the working myocardial cell. The surrounding plasma membrane is called the sarcolemma. Plasma membrane that penetrates into the cells interior and internally transmits the action potential is called the transverse-tubular (t-tubular) system. Physiologists have also identified an intracellular transfer system in addition to the plasma membrane separating the extracellular space from myocyte. This system is called the sarcoplasmic reticulum. After electrical excitation, calcium ions are released from storage compartments of the sarcoplasmic reticulum, called cisternae, and flood the cytosol initiating systolic contraction. Another compartment of the sarcoplasmic reticulum surrounds the contractile proteins and is called the sarcotubular network and contains adenosine triphosphate (ATP)asedependent proteins that actively pump calcium back into the cisternae, ready for the next excitatory stimulus.

Cellular Mechanisms and Contractile Dysfunction

For some time, acute coronary occlusion has been known to result in a sudden loss of contractile force. The most likely cause is abrupt loss of tissue turgor, also known as the reverse garden hose effect. The mechanism underlying the garden hose effect is uncertain but may be related to loss of optimum cross-bridge overlap (eg, Starling mechanism) when the erectile effect of the vasculature is abrogated. Because intracellular calcium (Ca²⁺) is critical for regulating myocardial contraction (see Appendix I in the online-only Data Supplement), an alternative hypothesis is that loss of vascular pressure alters vasotropic feedback, which modulates triggered Ca²⁺ entry or myofilament Ca²⁺ sensitivity. Metabolic consequences of ischemia likely contribute to further contractile dysfunction (see Appendix II in the online-only Data Supplement). This may be of particular importance for PEA following countershock after prolonged VF. It is important to recognize that many of the metabolic changes are also associated with chronic heart failure.^32.33 Thus, metabolic stress could contribute to loss of contractility, leading to PEA in patients with advanced heart failure.

Inotropic agents, particularly β-agonists, have been the mainstay of therapy for PEA on the basis of considerations of molecular factors involved in contractile function and dysfunction. β-Agonists phosphorylate L-type Ca²⁺ channels, ryanodine receptors, the sarcoplasmic reticulum calcium ATPase regulator phospholamban, and myofilaments not only to increase trigger Ca²⁺ entry into the cell but also to synchronize Ca²⁺ release from a loaded SR and improve myofilament Ca²⁺ responsiveness. There is, however, a time-dependent loss of contractile function in response to the metabolic stress of acute ischemia. Because the mechanisms for this loss are unknown, further studies to elucidate these mechanisms are needed to provide a rational basis for future therapies. In addition, whether myofilament Ca²⁺ sensitizers such as levosimendan or other agents may be of additional or greater benefit in the setting of PEA has yet to be determined.

PEA may occur when the host response to a dramatic stress on the cardiovascular system is inadequate or inappropriate. An important response that was recently recognized is overwhelming stress leading to rapid activation of the intrinsic immune system, causing direct acute depression of cardiac function or decoupling of electromechanical synchrony, resulting in PEA. Innate immune activation also produces cardiokines, which in circulation may lead to profound vasodilation and ventricular arterial decoupling, also setting the stage for arrhythmias. Recent understanding of the signaling pathways involved in innate immune activation offers potential areas of further research and therapy.

Clinical associations between the presence of inflammatory cytokines and SCA have been established. In the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial, elevation of cytokines such as osteoprotegerin was the best predictor of early sudden death after myocardial infarction.Furthermore, the proposed benefit of N-3 fatty acids on cardiac mortality after myocardial infarction and in heart failure has also been attributed at least partially to the anti-inflammatory effects of N-3 fatty acids.

The production of cytokines/cardiokines such as tumor necrosis factor and the interleukin family of cytokines may acutely depress cardiac function. This has been attributed to the effect on phosphatidylinositol 3 kinase isoforms and lipid-signaling intermediates such as sphingosine-1, which may directly interfere with Ca²⁺ signaling.More recently, there have been data to suggest that the high-mobility group box 1 or alarmin family of signals may also directly depress cardiac function and Ca²⁺ kinetics. However, this effect may be partially ameliorated through phosphatidylinositol 3 kinase-γ blockade, suggesting possible avenues for host protection.

There has been a significant interest in the role of hormones, namely relaxin, in SCA. This natural hormone increases in women during pregnancy and has been studied in acute heart failure.Its mechanisms of action are not well known. In the setting of acute ischemic arrest, relaxin was able to significantly reduce the adverse outcomes of asystole, ventricular tachyarrhythmias, or bradycardiac arrests, possibly through anti-inflammatory effects by inhibiting mast cell activation.

Further research is needed to weigh the role of immune, inflammatory, or hormonal modulation of PEA pathways, especially in the context of underlying comorbidities such as diabetes mellitus, heart failure, and other proinflammatory disease states. An intriguing hypothesis, based on the possibility that β-blockers protect against the expression of VT/VF during ischemia, is that inflammatory signals may allow PEA to emerge by default.

In contrast to VT/VF for which electric arrhythmogenesis may be associated with channelopathies, there are no specific channel dysfunction mechanisms currently known to contribute to the rapid loss of contractile function associated with PEA. However, one could hypothesize and test for the functional changes in L-type Ca²⁺ channels and ryanodine receptors described in Appendix II in the online-only Data Supplement as acquired channel defects. Even more speculative is the possibility that genetic susceptibilities to rapid reductions in L-type Ca²⁺ channel and ryanodine receptor activity, in response to metabolic stress, result in a more profound contractile failure in some individuals compared with others.