Cardiopulmonary cerebral resuscitation

Cardiopulmonary arrest occurs as the endpoint or consequence of many diseases. The mechanism is often unknown when treatment is initiated, and an algorithmic approach titrated to real-time monitoring is used. When the cause is known or suspected, individualized therapy can be directed at that cause. In all cases, management has two priorities: (1) rapid restoration of cardiopulmonary function and (2) minimization of ischemic damage to end organs, especially the brain. Restoration of circulation is composed largely of mechanical, pharmacologic, and electrical treatment. In contrast, treatment of brain and other organ injury primarily involves prevention of reperfusion-mediated and secondary cellular and molecular events using specific and detailed intensive care. Meaningful survival is unlikely without detailed attention to the longitudinal scope of this disease.

From the first introduction of closed-chest compressions until 2000, there was little change in long-term survival after cardiac arrest. ^, However, subsequent regional efforts to improve resuscitation practices at multiple levels, including emergency response and post–cardiac arrest care, have yielded significant improvements in meaningful survival. ^, Specific patterns of physiologic changes after cardiac arrest have been described, and there is accumulating evidence about which aspects of post–cardiac arrest management influence final outcomes. Improving outcomes further requires an integrated approach to immediate resuscitation, subsequent intensive care management, and post–intensive care recovery. This chapter reviews the epidemiology of cardiac arrest, the initial approach for reversing cardiopulmonary arrest, modifications of this approach appropriate for specific disease states, and post–cardiac arrest intensive care oriented around minimizing secondary brain injury.

Epidemiology

In industrialized countries, heart disease is the overall leading cause of death, with an incidence of cardiopulmonary arrest outside the hospital ranging from 55 to 120 events per 100,000 people per year. Median survival after out-of-hospital cardiac arrest is estimated at 10.6%, but the range varies regionally from less than 2% ^, to 16% in certain exemplary systems. The incidence of cardiac arrest in hospitals is about 0.17 events per hospital bed per year. For inpatients experiencing cardiac arrest, median survival to hospital discharge is about 20%. Almost half of in-hospital cardiac arrests occur in an intensive care unit (ICU) setting, where survival is higher than that in an unmonitored unit. Respiratory insufficiency is the most common preexisting condition for in-hospital cardiac arrest, and as many as 17% of episodes of respiratory compromise in hospitals progress to cardiac arrest.

Although out-of-hospital cardiac arrest is more common in men than in women, both outside and inside hospitals, the incidence of cardiac arrest is higher in women (6%) than in men (4.4%) who are admitted to a hospital for acute myocardial infarction (MI). Cardiac arrest outside a hospital affects blacks and Latinos more than Caucasians or Asians, ^, ^, and rates are higher in neighborhoods composed of minority and lower-socioeconomic-status populations. These groups are also more likely to have a cardiac arrest, less likely to have bystander cardiopulmonary resuscitation (CPR), and less likely to survive. ^, Although sudden death can affect patients of all ages, the mean age for sudden cardiac arrest is between 65 and 70 years in most studies. ^, ^,

Most mortality after cardiac arrest is attributable to cardiopulmonary collapse or brain injury. Only one-third to one-half of patients who collapse outside a hospital and only 44% of patients who collapse in a hospital have restoration of circulation long enough to be admitted to the ICU. Approximately two-thirds of patients who are admitted to a hospital after an out-of-hospital collapse and 60% of patients who are resuscitated from cardiac arrest in a hospital die before discharge from the hospital. Variation around this estimate differs between academic medical centers and tends to be higher in hospitals with higher case volume, higher surgical volume, and greater availability of invasive cardiac services. Postischemic brain injury is the most common reason for in-hospital death after out-of-hospital cardiac arrest, ^, whereas multiple organ failure is more common after in-hospital cardiac arrest. Failure to awaken contributes to withdrawal of life-sustaining treatment for about 61% of out-of-hospital cardiac arrest patients.

Restoring circulation

Acute treatment of cardiac arrest consists of two concurrent, goal-directed activities: (1) artificial circulation of oxygenated blood to the heart and brain and (2) electric shock to terminate ventricular fibrillation (VF) and other unstable tachydysrhythmias ( Fig. 45.1 ). Continuous, uninterrupted, high-quality chest compressions are the cornerstone of resuscitation, whereas electrical rescue shocks are used only when appropriate. The organization of an electrocardiogram (ECG) and the presence of a pulse will prompt appropriate selection of therapy. The recommended division of time and prioritization of activities to accomplish these goals is depicted in Fig. 45.2 . All other treatments, including medications and advanced airway maneuvers, are designed to supplement these two core activities, and their optimization necessitates minimal interruption. Focused bedside ultrasound evaluation can aid in the assessment of critically ill patients and identify reversible causes only if performed without interrupting resuscitation. The American Heart Association and European Resuscitation Council provide consensus scientific statements about the acute management of cardiac arrest, including a detailed review of specific drugs and procedures. The following sections provide an overview of airway management, circulation support, rescue shock for defibrillation, and drug therapy.

Fig. 45.1, Continuous reassessment of the patient during cardiac resuscitation relies on an electrocardiogram (ECG) and on the presence of cardiac mechanical activity (pulses).

Fig. 45.2, Prioritization of activities must occur during cardiac resuscitation.

Airway and gas exchange

Obstruction of the airway occurs in patients with impaired consciousness, including cardiac arrest, preventing oxygenation and ventilation. Agonal respiration occurs after acute cardiac arrest for an additional 1–2 minutes, which may confuse lay people and delay the recognition of cardiac arrest. Although associated with survival, it is unclear whether agonal respiration generates sufficient ventilation to support life. Regardless, artificial ventilation is required for patients requiring more than momentary resuscitation efforts.

Simple maneuvers to open the airway include extension of the neck (head tilt) and forward displacement of the mandible (chin lift or jaw thrust). Insertion of an oropharyngeal or nasopharyngeal airway can displace the tongue from the posterior pharynx. Positive-pressure ventilation using mouth-to-mouth or bag-valve-mask (BVM) ventilation with as little as 400 mL in adults (6–7 mL/kg) delivered over 2–3 seconds will cause the chest to rise. Minute ventilations smaller than those required for long-term support probably provide adequate gas exchange during cardiac arrest. Conversely, hyperventilation or hyperexpansion of the chest can impair venous return and decrease circulation during resuscitation.

The need for gas exchange must be balanced against the fact that even brief interruptions in chest compressions reduce coronary perfusion pressure (CPP) ( Fig. 45.3 ). In swine, comparison of different chest compressions to ventilation ratios suggests that two breaths per 50 or more chest compressions are optimal for resuscitation. One innovative practice to reduce interruptions in compressions is to provide chest compressions without any artificial ventilation or with passive insufflation of oxygen. Accounting for anatomic dead space, chest compressions alone probably do not generate significant ventilation in humans. ^, As a compromise, some systems deliver uninterrupted chest compressions and asynchronous positive-pressure breaths. A large, randomized trial comparing continuous compressions with positive-pressure ventilation to interrupted compressions at a ratio of 30 compressions per two ventilations found no meaningful difference in survival or short-term favorable neurologic recovery. Regardless of ratio, the duration of any pause to deliver breaths must be minimized.

Fig. 45.3, Chest compressions provide coronary perfusion by creating a pressure gradient between the aorta ( Ao ) and the inside of ventricles (approximated by the right atrium [ RA ]).

Waveform capnography can confirm ventilation and monitor adequacy of circulation. During cardiac arrest, end-tidal CO ₂ is related to cardiac output and pulmonary blood flow. Therefore CO ₂ levels may be very low (<10 mm Hg) at the onset of resuscitation. Adequate artificial circulation will cause CO ₂ levels to increase, and these levels may be used as a feedback to improve or modify chest compressions. An end-tidal CO ₂ level greater than 15–16 mm Hg is associated with successful cardiac resuscitation. ^, Conversely, end-tidal CO ₂ less than 10 mm Hg after 20 minutes of resuscitative efforts can confirm failure of resuscitation. Common resuscitation drugs disrupt the association between capnography readings and pulmonary blood flow: epinephrine infusion reduces CO ₂ levels, and sodium bicarbonate infusion produces a transient elevation of CO ₂ levels. An abrupt increase in end-tidal CO ₂ levels, usually to levels over 35 mm Hg, may be useful in recognizing the return of circulation, without interrupting chest compressions for pulse checks ( Fig. 45.4 ).

Fig. 45.4, End-tidal CO 2 changes during resuscitation.

Airway devices

The most common ventilation device used by rescue personnel, paramedics, and other healthcare providers is a self-inflating bag attached to a face mask (BVM), which requires adequate training and practice for ventilation success by a single provider. Two providers achieve more reliable airway management. BVM ventilation also pushes air into the stomach, which can promote emesis and abdominal distention, impair venous return, and reduce lung compliance. Normal esophageal resistance to air entry into the stomach (15–20 cm H ₂ O) declines with loss of muscle tone during cardiac arrest (5–8 cm H ₂ O).

Tracheal intubation with a cuffed tracheal tube secures the airway definitively and protects from emesis. However, laryngoscopy typically requires an interruption in chest compressions. Observational studies found extremely long interruptions in chest compressions during “uncomplicated” tracheal intubation. Conversely, supraglottic airway adjuncts such as laryngeal tubes (e.g., King LT) or laryngeal mask airways can temporarily secure the airway during resuscitation. ^, These devices have the advantage of blind insertion within seconds without laryngoscopy or associated interruptions in chest compressions.

Three randomized trials of out-of-hospital cardiac arrest subjects conducted in different emergency response systems with ranges of intubation success (52%–98%) compared various advanced airway strategies with BVM. Subjects randomized to BVM were subject to variable durations of BVM while preparing for device insertion. One trial explicitly allowed crossover between interventions at the discretion of providers. Even in settings with high tracheal intubation success rates, an advanced airway (supraglottic airway or tracheal intubation) did not improve survival or neurologic outcome compared with BVM. The rationale for transitioning from BVM to advanced airways is contingent on clinical context, patient anatomy, aspiration risk, and oxygenation and ventilation success. If an advanced airway is required, providers should select a device (supraglottic airway or tracheal intubation) based on the clinical context and their individual skill set. Ultimately, resuscitated patients with coma or continued respiratory failure will require tracheal intubation.

Artificial circulation

In patients without a pulse, compression of the heart and chest by repetitive depression and release of the sternum circulates blood. The critical parameter for restoring myocardial energy stores, and thus spontaneous circulation, is the development of adequate CPP. CPP is the pressure gradient between the aorta and the inside of the ventricles at the end of diastole or during the relaxation phase of chest compressions. Most blood flows through the ventricular walls during diastole or during the relaxation phase of chest compressions, when ventricular pressure is the lowest (see Fig. 45.3 ). CPP is highly correlated with myocardial perfusion and consequently with the likelihood of resuscitation. In humans, return of circulation requires that the developed CPP exceeds 15–20 mm Hg.

Peak arterial pressure or palpable pulses measured during chest compressions do not necessarily represent CPP because ventricular pressures are simultaneously elevated. Consequently, palpation of pulses and systolic pressures developed by chest compressions may be misleading. It is most useful to follow the “diastolic” or relaxation-phase arterial pressure. If unable to follow any of these pressures, the clinician must rely on indirect evidence of myocardial perfusion, such as improved electrical and mechanical activity or increased pulmonary CO ₂ excretion.

Even brief interruptions in chest compressions decrease CPP, and interruptions are inversely associated with restoring circulation and survival. When chest compressions are measured during actual resuscitations by paramedics or hospital providers, interruptions and pauses are frequent. ^, Some monitor-defibrillators now have features to measure and record chest compressions and to provide real-time feedback about depth and rate to providers. These features have no detectable effect on survival. The chest compression fraction is one metric of compression continuity that is emphasized as a component of high-quality resuscitation ( Fig. 45.5 ), and many clinicians feel that the real-time and automated feedback is a useful safety and quality improvement mechanism to enhance total system performance.

$Fig. 45.5, Chest compression fraction ( CCF ) describes the continuity of chest compressions during resuscitation.$

Until the 1960s, thoracotomy was the standard approach for treatment of sudden cardiac arrest, but this procedure has now been supplanted by closed-chest compressions. Direct cardiac compression is more effective than external chest compressions, producing roughly a threefold increase in CPP. This approach also allows recognition of cardiac tamponade, treatment by pericardiotomy, direct visualization of mechanical activity and fibrillation, and direct electrical defibrillation or pacing. In the setting of cardiopulmonary collapse resulting from exsanguination, thoracotomy also allows for aortic compression to shunt blood to the heart and brain and to direct control of intrathoracic bleeding. It should be considered in specific clinical circumstances, such as patients with traumatic cardiac arrest or recovering from recent cardiac surgery.

To improve delivery of uninterrupted chest compressions, a variety of mechanical devices have been developed. ^, ^, Some of these devices exploit circumferential compression or active compression/decompression of the chest. A Cochrane review of mechanical versus manual chest compressions for cardiac arrest found no evidence of benefit of mechanical compressions in the return of spontaneous circulation or survival to hospital admission, and a subsequent pragmatic randomized trial found no improvement in 30-day survival. ^, Although no current device is superior to well-conducted manual compressions, these devices may play a role in providing chest compressions in settings where manual compressions are difficult or impossible (e.g., during ambulance transport, under the fluoroscopy arm, or when multiple providers are not available) or as a bridge to recovery and/or definitive treatment of the suspected etiology (e.g., extracorporeal circulatory support, percutaneous coronary revascularization, fibrinolysis of massive pulmonary embolism).

Extracorporeal circulation

Extracorporeal perfusion for restoration of circulation (ECPR) can be used to resuscitate subjects for whom chest compressions have failed. However, this approach requires specialized technical skill, system commitment, and increased costs and risks. Logistical issues include limited availability of perfusion equipment, setup time for circuit priming, and delays in establishing adequate venous and arterial access. Portable cardiopulmonary bypass devices that can be primed quickly, along with improved techniques for rapid vascular access, have broadened the use of ECPR.

Multiple observational studies demonstrate the operational feasibility of ECPR and suggest the possibility of improved clinical outcomes, but it remains critical that ECPR be used for appropriately selected patients. The ideal candidate is young with a witnessed cardiac arrest from a shockable rhythm, with a presumed cardiac (or other reversible) etiology, who receives immediate CPR and who has a brief interval until successful cannulation and commencement of extracorporeal resuscitation. Examples of selection criteria from three centers are given in Table 45.1 .

TABLE 45.1

Sample Selection Criteria for Extracorporeal Perfusion for Restoration of Circulation (ECPR)

	Surugadai Nihon University Hospital Tokyo, Japan	Sharp Memorial Hospital San Diego, California	Alfred Hospital Melbourne, Victoria, Australia
Inclusion criteria	Age 18–74	Persistent cardiac arrest	Age 18–65
	Witnessed cardiac arrest	Shock refractory to standard therapies	Suspected cardiac etiology
	Presumed cardiac etiology		Any CPR within 10 minutes of collapse
	EMS arrival ≤15 minutes		Initial rhythm of ventricular fibrillation
	Defibrillation by AED or EMS personnel		30 minutes of persistent cardiac arrest
	Persistent cardiac arrest on arrival to ED
Exclusion criteria	Presumed noncardiac etiology	Initial rhythm of asystole	Known preexisting significant neurologic disability
	Successful ROSC ≤10 minutes of arrival to ED	Any CPR not initiated ≤10 minutes of cardiac arrest	Known significant end-stage comorbidities
	Core body temperature <30°C on arrival to ED	Estimated EMS transport time >10 minutes	Terminal illness because of malignancy
	Pregnancy	Total arrest time >60 minutes
		Suspicion of sepsis or hemorrhage
		Preexisting severe neurologic disease

Sample selection criteria for extracorporeal life support (ECLS) in out-of-hospital cardiac arrest (OHCA).

AED, Automatic external defibrillator; CPR , cardiopulmonary resuscitation; ED, emergency department; EMS , emergency medical services; ROSC, return of spontaneous circulation.

The timing of ECPR is equally important because irreversible myocardial and neurologic injury can preclude survival despite mechanically restoring circulation. Conventional resuscitation is clearly preferred when patients have early recognition, early high-quality chest compressions, and early defibrillation. However, increasing the duration of treated cardiac arrest decreases the odds of functionally favorable survival (as low as 1%–15%, depending on case features, initial cardiac rhythm, witnessed collapse, and bystander CPR). Observational data of ECPR candidates treated with traditional resuscitation suggest the therapeutic window for conversion to ECPR occurs after 10–20 minutes of professional resuscitation. Several randomized trials of ECPR are in progress.

Electrocardiogram monitoring

Continuous three-lead ECG monitoring is essential for guiding resuscitation. A practical approach is to divide rhythms into organized and nonorganized. Organized rhythms include supraventricular rhythms or ventricular tachycardia (VT). Nonorganized rhythms include VF and asystole. Nonorganized rhythms cannot support cardiac output, regardless of volume status, cardiac muscle state, or vascular integrity. Therefore restoring cardiac electrical activity to an organized rhythm is an essential step in resuscitation. Organized rhythms can support cardiac output unless they are too slow (<30–40 complexes/min) or too fast (>170–180 complexes/min). An organized rhythm in the absence of a palpable pulse is termed pulseless electrical activity (PEA).

As the incidence of PEA as the initial cardiac rhythm increases, with a relative decrease in the incidence of VF, ^, PEA is an area of increased study and focus. Point-of-care echocardiography during resuscitation allows for more nuanced assessment of PEA. PEA may be subdivided into an organized rhythm in the absence of palpable pulse with or without echocardiographic motion (“true PEA” vs. “pseudo-PEA”). In cases of pseudo-PEA, pausing compressions and administering vasopressors may aid in restoring circulation. Alternatively, cases of pseudo-PEA with insufficient cardiac output from a tachydysrhythmia and dwindling preload should be corrected by rescue shock.

The absence of perfusion with slow organized electrical activity may result from primary myocardial injury (e.g., massive MI) or from uncoupling of electrical and mechanical activity (e.g., prolonged circulatory arrest). The rate of complexes may be used to monitor resuscitation efforts. With increasing ischemia, energy depletion will occur in the electrical system and the rate of PEA will slow down. If resuscitation improves the energy state of the heart, the rate of PEA will accelerate. Narrow complexes reaching rates of 80–100 beats per minute often herald the return of a pulse. Falling rates reflect unsuccessful resuscitation efforts.

VF and asystole lie along a continuum of not-organized ECG. Arbitrary peak-to-peak amplitude of the ECG is usually used to distinguish asystole (amplitude <0.1–0.2 mV) from VF (amplitude >0.2 mV). However, VF also exhibits temporal structures that may be absent in asystole. VF is a chaotic electrical activity formed by multiple interacting waves of activation within the heart. VF emerges from broken wavefronts that result from areas of ischemia (e.g., MI), areas of prolonged refractoriness (e.g., drug-induced or inherited prolonged QT intervals), or too-rapid succession of activation potentials (e.g., tachycardia or an “R on T” premature beat). As the organization and amplitude of these waves decline because of ischemia or hypoxemia, the amplitude of the ECG also declines. Reperfusion of the heart in asystole may restore VF. Furthermore, the amplitude and organization of the VF increases with reperfusion, providing a marker of adequate artificial perfusion.

Rational use of rescue shocks for defibrillation

Delivery of immediate transthoracic electric rescue shocks to patients in VF can convert VF into an organized cardiac rhythm. Rescue shocks are highly effective when VF is for a very brief duration (<1–2 minutes). These shocks may work by depolarizing the heart, canceling the original wavefronts, or prolonging the refractory periods. Although rescue shocks can successfully restore an organized rhythm, repeated shocks may directly damage the myocardium. Optimal therapy should provide rescue shocks at the lowest effective energy while minimizing the number of unsuccessful rescue shocks.

In the out-of-hospital setting when the collapse is not witnessed by paramedics, only 9%–12% of rescue shocks restore an organized ECG, ^, and most shocks convert VF into asystole. Even after successful defibrillation, VF may recur because of incomplete depolarization by the shock, heterogeneous areas of refractoriness, or persistent foci of chaotic activity. Multiphasic shock waveforms are more effective for depolarization of individual myocytes and require less energy than monophasic waveforms. Consequently, most available defibrillators deliver biphasic waveforms. Increasing pressure of paddles from 0.5 kg to 8 kg on the chest decreases transthoracic impedance by as much as 14% and increases delivery of current to the heart. ^, This advantage of paddles must be weighed against the increased safety and convenience afforded by hands-free self-adhesive defibrillation pads, which are now used in most settings. In the past, multiple shocks would be delivered in rapid succession to decrease chest impedance. However, repetitive shocks decrease chest impedance by about 8% or less in actual patients, ^, ^, which does not justify the interruption of artificial circulation to deliver “stacked” shocks. Reducing the interruption in chest compressions before and after a rescue shock is associated with greater resuscitation success, which led to the coining of the term perishock pause . Duration of the perishock pause is inversely associated with survival to hospital discharge. Specific techniques to reduce the perishock pause include continuing chest compressions while the defibrillator is charging, only stopping at the last moment before shock, and eliminating the postshock pulse check. Alternatively, manual compressions may be continued during rescue shocks if the rescuer is using Class 1 electrical insulating gloves complying with International Electrotechnical Commission (IEC) standards and modern self-adhesive defibrillation pads. In this scenario, the risk of shock to rescuers from touching a patient during defibrillation is small.

For VF that has lasted more than 3–4 minutes, preclinical data suggest that delaying rescue shocks until after a few minutes of chest compressions will improve success. To date, two clinical studies in out-of-hospital cardiac arrest patients have found that either 90 seconds or 3 minutes of chest compressions before delivery of the initial rescue shock improved resuscitation rates for subjects with VF outside a hospital, particularly when rescuer response intervals were longer than 4 minutes. ^, However, a third study found no difference in outcome with 5 minutes of chest compressions before shock, and a fourth study found no difference in outcome with 3 minutes of chest compressions before shock. Finally, a large multicenter trial comparing immediate rescue shock to 3 minutes of chest compressions before rescue shock stopped enrollment, finding no difference between groups. Taken together, the clinical data suggest that the first rescue shock for VF should be delivered as soon as possible within 3–5 minutes as long as chest compressions are started immediately but that there is no reason to intentionally delay the rescue shock.

Quantitative analysis of the VF waveform can distinguish early VF from late VF and may be useful in estimating the likelihood of rescue shock success. Larger amplitude of VF in addition to frequency-based measures and nonlinear dynamic measures of VF organization are associated with a higher probability of rescue shock success. Future generations of defibrillators may provide real-time, semiquantitative estimates of the probability that a rescue shock will succeed in restoring an organized rhythm. It is unknown if these quantitative measures will be clinically useful for titrating resuscitation.

Beta-blockade with a short-acting agent such as esmolol represents another therapeutic option for VF. Beta-activation (e.g., systemic epinephrine) increases myocardial oxygen requirements, worsens ischemic injury, lowers the VF threshold, and worsens postresuscitation myocardial function. Blocking beta-receptors may terminate the electrical storm responsible for refractory VF. Esmolol is a favorable agent given its ultra-short half-life. Low-certainty observational evidence suggests that beta-blockade is associated with improved clinical outcomes, primarily restoration of circulation, and short-term survival.

Drug therapy

Drug therapy in cardiac arrest can be divided into three categories: pressors, antidysrhythmics, and metabolic drugs. Pressors are used during resuscitation and include epinephrine and vasopressin. Both of these drugs can increase CPP via the alpha-adrenergic (epinephrine) or vasopressin receptors ( Fig. 45.6 ). ^, Epinephrine is usually administered in 1-mg (∼0.015 mg/kg) increments. In laboratory studies, the pressor effects of epinephrine during cardiac arrest were brief (∼5 minutes). Vasopressin is administered as 40-unit boluses (∼0.5 units/kg) and produces a longer-lasting increase in CPP (∼10 minutes).

Fig. 45.6, Administration of a vasoactive drug can increase coronary perfusion pressure ( CPP ) produced by chest compressions.

Epinephrine consistently improves return of circulation and survival, but its effects on neurologic recovery are less certain. Older clinical trials testing moderate (7 mg vs. 1 mg) and higher (15 mg vs. 1 mg) initial boluses of epinephrine found higher rates of pulse restoration and admission to hospital, but overall survival was not significantly different. Accumulated beta-adrenergic toxicity likely increases myocardial oxygen consumption, ectopic ventricular arrhythmias, hypoxemia from pulmonary arteriovenous shunting, and postarrest myocardial dysfunction. However, higher doses of epinephrine may impair cerebral circulation, a detrimental effect that may offset any benefit from increasing rates of restoration of circulation. ^, A massive, population-based, matched cohort study found that prehospital epinephrine was associated with restoration of circulation but with lower probability of 1-month survival and favorable functional outcome. Taken together, these data raised the worrisome possibilities that when epinephrine is required to restore cardiac activity, severe brain injury has already occurred or that it contributes to brain injury. Two randomized trials comparing epinephrine with placebo in out-of-hospital cardiac arrest consistently demonstrated superior return of circulation, survival to hospital admission, and survival to hospital discharge. ^, One trial noted additional survivors with worse neurologic outcome at hospital discharge in the epinephrine arm, but also improved survival to 3 months without statistical difference in favorable or unfavorable neurologic outcomes. The net increase in survivors constituted those with both favorable and unfavorable neurologic outcomes. Of note, neurologic status of initially comatose cardiac arrest survivors can improve for up to 6 months.

The optimal dosing and timing of epinephrine remain an active area of investigation. Both drugs should ideally be titrated to improvement in clinical indicators (ECG waveform, mechanical activity, changes in end-tidal CO ₂ or diastolic arterial pressure as a surrogate for CPP). Rote, repeated administration is unlikely to result in meaningful outcome improvements. Titrated epinephrine infusions may balance the positive and negative physiologic effects, but this approach has not yet been explored clinically. The concept of goal-directed cardiac arrest resuscitation is an emerging paradigm within resuscitation science supported by preclinical and preliminary clinical work. ^,

Vasopressin can increase CPP without complicating beta-adrenergic effects. Resuscitation rates and survival are identical for patients resuscitated with vasopressin and standard doses of epinephrine after in-hospital or out-of-hospital cardiac arrest. Some post hoc analyses suggest vasopressin may be superior for resuscitation and survival of patients whose first ECG rhythm is asystole and for those subjects requiring multiple doses of vasopressors. Subsequent trials of the combination of epinephrine with vasopressin versus epinephrine alone found no difference in outcome with the different combinations of drugs. ^, Given its lack of clear advantage over epinephrine, vasopressin is typically excluded from treatment guidelines and algorithms in the interests of simplification.

The role of antidysrhythmic drugs during cardiac arrest is equivocal. ^, Atropine may relieve bradycardia when it is vagally mediated. However, nervous system influences on the heart are largely eliminated after more than 1–2 minutes of circulatory arrest. Therefore there is little expectation that atropine will improve resuscitation from asystole or PEA. Lidocaine, procainamide, and bretylium have a long history of use in the treatment of VF. Once VF is established, lidocaine can increase the electrical energy required to defibrillate by more than 50%. Other classes of antidysrhythmics without sodium channel blockade do not alter defibrillation energy requirements. For example, amiodarone (5 mg/kg) is superior to placebo and to lidocaine in terms of restoring the pulse in out-of-hospital patients with VF that is not terminated by three rescue shocks. A large clinical trial comparing amiodarone, lidocaine, or placebo for shock-refractory VF found no overall difference in survival. However, both lidocaine and amiodarone were superior to placebo in the subgroup of witnessed VF.

Empiric treatments of metabolic disturbances with bicarbonate or other buffers may improve acidemia resulting from ischemia, but do not necessarily translate into improved clinical outcomes. ^, Originally proposed as an antagonist of adenosine released during ischemia, two prospective studies of aminophylline in subjects with PEA or asystole found no improvement in resuscitation. ^, Use of dextrose-containing fluids versus dextrose-free fluids did not alter outcome for out-of-hospital cardiac arrest patients. Other metabolic therapies, including calcium and magnesium, also lack supporting data. ^, However, it is appropriate to consider specific use of these agents to correct known abnormalities that are contributing to cardiac arrest, such as hyperkalemia, calcium channel blocker overdose, torsades, or hypomagnesemia.

Taken together, the data support a simple pharmacologic approach to the treatment of cardiac arrest: epinephrine can augment CPP generated during chest compressions, antidysrhythmic drugs may be useful for maintaining organized rhythms in witnessed shock-refractory VF, and all other drug therapies should be based on the clinical situation and the response of the patient.

Aspects of cardiac arrest in specific situations

If the original etiology of cardiac arrest is available, treatment and prognosis can be individualized to the specific patient. Among out-of-hospital patients, as many as 66% have primary cardiac disturbances. For in-hospital patients experiencing cardiac arrest, dysrhythmia and cardiac ischemia account for 59% of events. This section reviews unique features of cardiac arrest resulting from both cardiac and noncardiac causes.

Primary cardiac events

Primary dysrhythmia or cardiogenic shock is the most common proximate cause of cardiac arrest. ^, Patients undergoing angioplasty have a 1.3% incidence of cardiac arrest, and survival in these patients resembles survival in other populations. Among patients admitted to a hospital with acute MI, cardiac arrest occurs in 4.8%. Dysrhythmias are common during the hours after reperfusion therapy, although reperfusion therapy reduces the overall risk of cardiac arrest. During acute MI, cardiac arrest is most likely to occur in patients with lower serum potassium levels, more than 20 mm of total ST elevation, and a prolonged QTc interval during the first 2 hours of their event. Some 3.3% of subjects surviving acute MI suffered sudden cardiac death. Abnormalities of the heart are present in most cases of cardiac arrest, with coronary artery disease present in at least 65% of autopsies. Taken together, these data suggest that most patients with cardiac arrest will have contributing cardiovascular disease.

When angiography was performed on consecutive patients resuscitated from cardiac arrest, acute coronary artery occlusion was identified in 48%–58% of the patients. ^, Similarly, 51% of initially resuscitated outpatients exhibited an elevation in cardiac enzymes or ECG evidence of acute MI. In one series, troponin T was elevated in 40% of out-of-hospital patients undergoing CPR. The direct myocardial injury from defibrillation and CPR may cause spurious elevations of creatine kinase that are unrelated to cardiovascular disease. However, elevation in cardiac troponin levels are believed to reflect acute MI rather than injury from electric shocks. Thus the 40% of subjects undergoing CPR with elevated troponin probably suffered myocardial injury before collapse. Unless a clearly noncardiac etiology for cardiac arrest is evident, acute coronary angiography may reveal an indication for angioplasty, thrombolysis, or other reperfusion therapy. Primary revascularization is safe in comatose patients undergoing hypothermia treatment. ^,

Primary ventricular tachydysrhythmias are rapidly reversible and are the initially recorded rhythm in 23%–41% of out-of-hospital cardiac arrest patients ^, ^, and in 25% of in-hospital cardiac arrest patients. Long-term antidysrhythmia treatment should be considered for patients who survive sudden cardiac arrest. At a minimum, treatment should be considered for patients with depressed left ventricular function or primary dysrhythmia without a reversible etiology. Importantly, subjects surviving a life-threatening ventricular dysrhythmia have a 15%–20% risk of death during a mean of 16 months of follow-up, even when a reversible cause of the dysrhythmia such as electrolyte disturbance or hypoxia is identified. Implantable defibrillators are superior to antidysrhythmic drugs for reducing the risk of subsequent death. This benefit is primarily in subjects with a left ventricular ejection fraction (LVEF) less than 35%. Implantable defibrillators were not better than antidysrhythmic drugs in a European trial that enrolled subjects resuscitated from cardiac arrest secondary to ventricular dysrhythmia without regard to LVEF. Nevertheless, these devices offer significant hope of preventing sudden cardiac death, and identification of patients that they may benefit is an active area of research. At present, implantable defibrillators should be discussed for patients who recover from coma with LVEF less than 0.35 or who survive a ventricular arrhythmia in the absence of clearly reversible causes.

Asphyxia

Asphyxia causes transient tachycardia and hypertension, followed by bradycardia and hypotension, progressing to PEA or asystole. This period of blood flow with severe hypoxemia before cardiac arrest may worsen central venous hypoxemia and subsequent oxygen debt, rendering asphyxiation a more severe injury than VF or other rapid causes of circulatory arrest. Brain edema is more common on computed tomography (CT) scans after resuscitation when cardiac arrest is caused by pulmonary rather than cardiac etiologies. During cardiac arrest, pulmonary edema develops from redistribution of blood into the pulmonary vasculature, worsening oxygenation in the asphyxiated patient. Attention to the primary cause of asphyxia, in addition to maneuvers that will increase oxygenation, may be necessary.

Pulmonary embolism

Pulmonary emboli may occur in postsurgical patients and in medical patients with impaired mobility. In two series, pulmonary emboli were present in 10% of both in-hospital deaths and out-of-hospital deaths. Pulmonary emboli can result in rapid cardiopulmonary collapse and should be considered as a possible etiology of cardiac arrest in the proper clinical setting or when collapse is preceded by sudden shortness of breath, hypoxemia, and/or pleuritic chest pain.

Pulmonary emboli cause cardiac arrest from hypoxemia or when a large thrombus obstructs right ventricular outflow into the pulmonary arteries. This situation results in a dilated, distended right ventricle and an empty left ventricle, which can be seen on a transthoracic echocardiogram. Circulation cannot be restored unless this obstruction is relieved. Because the primary disturbance is hypoxemia and decreased cardiac output, cardiac arrest from pulmonary embolism often presents with an initial rhythm of PEA or asystole.

Administration of a bolus of fibrinolytic drugs such as tenecteplase has been used with reported success in nonrandomized trials during resuscitation of undifferentiated patients, but failed to demonstrate benefit in a larger randomized trial of undifferentiated patients in cardiac arrest. Likewise, a randomized trial of tissue plasminogen activator to undifferentiated patients with out-of-hospital cardiac arrest and an initial rhythm of PEA failed to demonstrate any benefit. Observational studies and subgroup analyses from randomized data report varying degrees of association between intra-arrest systemic fibrinolysis and survival. The potential effects on longer-term outcomes are unknown. Low-certainty evidence suggests that this treatment increases overall risk of bleeding (including any intracranial hemorrhage), but not necessarily risk of major bleeding (including symptomatic or major intracranial hemorrhage). Case series report the feasibility of surgical embolectomy and percutaneous mechanical thrombectomy. When logistically feasible, ECPR is a reasonable bridge to recovery or definitive therapy in cases of cardiac arrest from known or highly suspected massive pulmonary embolism.

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