Jeffrey F. Barletta and Jeffrey L. Wilt
KEY CONCEPTS
High-quality cardiopulmonary resuscitation (CPR) with minimal interruptions in chest compressions should be emphasized in all patients following cardiac arrest.
The AHA algorithm for basic life support following cardiac arrest now emphasizes circulation, airway, and breathing forming the pneumonic “CAB” versus the historic pneumonic “ABC.”
The purpose of using vasopressor therapy following cardiac arrest is to augment low coronary and cerebral perfusion pressures encountered during CPR.
Despite several theoretical advantages with vasopressin, clinical trials have not consistently demonstrated superior results over that achieved with epinephrine.
Amiodarone remains the preferred antiarrhythmic during cardiac arrest with lidocaine considered as an alternative.
Successful treatment of both pulseless electrical activity (PEA) and asystole depends almost entirely on diagnosis of the underlying cause.
Intraosseous administration is the preferred alternative route for administration if IV access cannot be achieved.
CARDIAC ARREST
Cardiac arrest is defined as the cessation of cardiac mechanical activity as confirmed by the absence of signs of circulation (e.g., a detectable pulse, unresponsiveness, and apnea).1 While there is wide variation in the reported incidence of cardiac arrest, it is estimated that there are 350,000 people in North America each year who suffer a cardiac arrest and receive attempted resuscitation.2 Approximately half of those are in an outpatient setting. Unfortunately, survival rates have not significantly improved over 30 years, ranging between 6.7% and 8.4%, despite enormous efforts in research and development.3Survival following in-hospital cardiac arrest is somewhat higher (approximately 18%), with higher rates being observed in victims with a shockable first documented rhythm.4
EPIDEMIOLOGY
In adult patients, cardiac arrest usually results from the development of an arrhythmia.5 Historically, ventricular fibrillation (VF) and pulseless ventricular tachycardia (PVT) have been the most common initial rhythm accounting for 40% to 60% of out-of-hospital arrests, but their incidence now is estimated to be only about 25%.2,6 In fact, one study of out-of-hospital arrests reported VF/PVT as the first recorded rhythm in only 13% of patients.7 The reason for this change has not been firmly established. Possible explanations include the influence of noncardiac causes of arrest that typically present with apnea leading to bradycardia and then pulseless electrical activity (PEA) or asystole. A second explanation is the increasing role of implantable pacemakers and defibrillators.8 Finally, it has been suggested that β-blockers and ACE inhibitors may shorten the duration of VF and the expanded use of these drug classes for ischemic heart disease and heart failure may account for the increased occurrence of non-VF/PVT rhythms.6Nonetheless, this declining incidence is particularly concerning as survival rates are substantially higher with shockable rhythms such as VF and PVT compared with those with nonshockable rhythms such as PEA and asystole. Survival rates with VF/PVT are roughly 15% to 23% versus 0% to 5% with asystole.3
A similar finding has been observed with in-hospital cardiac arrest. One study of 411 U.S. hospitals including approximately 52,000 adult patients revealed the incidence of VF and PVT to be 7.3% and 16.8%, respectively.4 In this trial, survival rates were 37% for both VF and PVT compared with 12% (PEA) and 11% (asystole). Patients with VF/PVT were more likely to have myocardial infarction (MI) as the immediate factor prearrest, while acute respiratory failure and hypotension were the immediate factors more commonly found in patients with PEA/asystole.
In pediatric patients, cardiac arrest typically results from respiratory failure and asphyxiation. As such, the initial rhythm most often encountered in out-of-hospital arrest is PEA or asystole.9 This could explain the dismal survival rates with out-of-hospital, pediatric cardiac arrest (approximately 6%), with the lowest being observed in infants compared with children and adolescents (4%, 10%, and 13%, respectively).10 Survival following in-hospital cardiac arrest appears higher with an overall rate of 27%. In fact, children are more likely to survive in-hospital arrest versus adults and infants have a higher survival rate than children.10
ETIOLOGY
The most common clinical finding in adult patients who suffer cardiac arrest is coronary artery disease accounting for roughly 80% of sudden cardiac deaths.5 Approximately 10% to 15% of sudden cardiac deaths occur in patients with cardiomyopathies (e.g., hypertrophic cardiomyopathy, dilated cardiomyopathy), and the remaining 5% to 10% are composed of either structurally abnormal congenital cardiac conditions or patients with structurally normal but electrically abnormal heart. Unfortunately, in many patients (approximately two thirds), cardiac arrest is the first clinical sign of coronary artery disease with no preceding signs or symptoms.11
In pediatric patients, cardiac arrest is often the terminal event of respiratory failure or progressive shock.12 Out-of-hospital arrests frequently are associated with trauma, sudden infant death syndrome, drowning, poisoning, choking, severe asthma, and pneumonia. In-hospital arrests, on the other hand, are associated with sepsis, respiratory failure, drug toxicity, metabolic disorders, and arrhythmias.
PATHOPHYSIOLOGY OF CARDIAC ARREST
There are two distinctly different pathophysiologic conditions associated with cardiac arrest. The first is primary cardiac arrest whereby arterial blood is typically fully oxygenated at the time of arrest. The second is cardiac arrest secondary to respiratory failure in which lack of ventilation leads to severe hypoxemia, hypotension, and secondary cardiac arrest. It is important to understand specific condition at hand as different treatment approaches are likely necessary.13
CLINICAL PRESENTATION
Cardiac arrest is characterized by the cessation of cardiac mechanical activity; therefore, signs and symptoms are consistent with those encountered when there is no circulation. In the setting of cardiac causes of arrest, anxiety, crushing chest pain, nausea, vomiting, and diaphoresis can precede the event. Following an arrest, individuals are unresponsive, apneic, and hypotensive and do not have a detectable pulse. Extremities are cold and clammy and cyanosis is common.
TREATMENT
Cardiopulmonary resuscitation (CPR) is an attempt to restore spontaneous circulation by performing chest compressions (to restore threshold blood flows, particularly to the heart and brain) with or without ventilations. There are two proposed theories describing the mechanism of blood flow during CPR.14 The original theory is known as the cardiac pump theory and is based on the active compression of the heart between the sternum and vertebrae thereby creating forward flow. Echocardiography, however, has revealed that left ventricular size does not always change with compressions and the mitral valve may, in fact, be open.14 The second theory is the thoracic pump theory. This theory is based on intrathoracic pressure alterations induced by chest compressions and the differential compressibility of the arteries and veins. In this model, the heart merely acts as a passive conduit for flow. It is likely that both models contribute to the mechanism of blood flow with CPR.
High-quality CPR continues to be emphasized in the latest guidelines published by the American Heart Association (AHA). Clinicians must focus on proper technique, including adequate rate and depth of compressions, allowance of chest recoil after each compression, avoiding excessive ventilation, and minimizing interruptions.2 One study, in patients suffering out-of-hospital VF, reported an increased chance of survival as chest compression fraction increased (e.g., the proportion of resuscitation time without spontaneous circulation where chest compressions were administered).15 Unfortunately, the provision of high-quality CPR is frequently suboptimal particularly when rescuers become fatigued.10,16 There are several devices available that provide prompts and/or feedback in “real time” however, data illustrating improvement in survival are lacking.16 Additionally, mechanical devices designed to improve hemodynamics have been studied but inconsistent results limit their applicability in routine practice.17
Desired Outcome
The global goals of resuscitation are to preserve life, restore health, relieve suffering, limit disability, and respect the individual’s decisions, rights, and privacy.18 This can be accomplished via CPR by the return of spontaneous circulation (ROSC) with effective perfusion and ventilation as quickly as possible to minimize hypoxic damage to vital organs. Survival to hospital discharge with good neurologic function should be considered the primary treatment outcome sought by clinicians. Survival to hospital discharge in a vegetative or comatose state cannot be classified as a success and can impose a tremendous economic burden on the healthcare system. Additionally, most patients would choose not to continue living in a massively disabled state.19
The presence of a healthcare advanced directive allows patients to communicate their wishes and preferences regarding medical care and may lead to a “do not attempt resuscitation (DNAR)” order. As many cardiac arrests occur following terminal illnesses and end-of-life care, “allow natural death (AND)” has become a preferred term to replace DNAR.18 These orders should explicitly state the resuscitation interventions that are to be performed and have clearly been communicated by the patient, his or her family, or a surrogate decision maker.
General Approach to Treatment
Cardiopulmonary Resuscitation
Resuscitation techniques have been studied for many years. The first landmark article was published in 1960 and described the outcome of 20 patients who were given closed chest compressions at a rate of 60/min.20 Artificial ventilation was used to augment the compressions, and three patients were given defibrillation for VF. In this landmark article, all 20 patients had ROSC, and 14 lived for an extended period of time, with reported good neurologic status. Initial descriptions after this started to integrate the approach to cardiac arrest, including three phases.21
In 1966, the AHA first published guidelines for the treatment of cardiac arrest.22 Since then, national conferences and organized committees have played a major role in encouraging widespread competency in CPR technique. There have been tremendous revisions of the guidelines over the years, and this is true of the most recent guidelines, published in 2010.2 These guidelines continue to emphasize the “chain of survival” to highlight the treatment approach and illustrate the importance of a timely response. The updated guidelines list five links in the chain of survival:
1. Immediate recognition of cardiac arrest and activation of emergency medical services (EMS)
2. Early CPR with an emphasis on chest compressions
3. Rapid defibrillation
4. Effective advanced life support
5. Integrated postcardiac arrest care
While all five links of the chain of survival are important, the most crucial would seem to be the first three, particularly early CPR with good chest compressions.2 When used together, survival rates can approach 50% following witnessed out-of-hospital VF arrest.23 CPR provides critical blood flow to the heart and brain, prolongs the time VF is present (prior to the deterioration to asystole), and increases the likelihood that a shock will terminate VF resulting in a rhythm compatible with life.2 For every minute that elapsed from collapse to successful defibrillation during witnessed VF arrests, survival rates decrease by 7% to 10% if no CPR is provided.24 If immediate CPR is added, the decrease in survival is more gradual (down to 3% to 4% per minute postcollapse).25 In effect, CPR can increase the likelihood of survival threefold from arrest to survival. Basic CPR alone, however, is not likely to terminate VF and lead to ROSC. Thus, the 2010 AHA guidelines emphasize the integration of early CPR and defibrillation, especially mentioning the use of automatic external defibrillators.25
As in the 2005 AHA guidelines for CPR and emergency cardiovascular care (ECC), the AHA continues to emphasize the provision of high-quality CPR with minimal interruptions in chest compressions. In addition, algorithms seem to be more simplified, and there is emphasis on the use of end-tidal carbon dioxide (ETCO2) to guide resuscitation.26 Furthermore, there is growing importance of postarrest care, reflecting that optimization of many organ systems may help improve outcomes.27 The use of drug therapy and airway adjuncts, on the other hand, have continued to devolve to a minimal role as survival to hospital discharge does not appear to be impacted.
Basic Life Support The 2010 AHA guidelines represent a paradigm shift in the provision of basic life support (BLS). Historically, BLS and advanced cardiac life support (ACLS) providers have been taught the pneumonic “ABC,” representing, respectively, airway, breathing, and circulation for the CPR sequence. The 2010 guidelines have changed this to “CAB,” or circulation, airway, and breathing.28
When first encountering a victim of cardiac arrest, the initial action is to determine responsiveness of the patient. If there is no response, the rescuer should immediately activate the emergency medical response team, and obtain (or call for) an automated external defibrillator (AED) (if one is available) and then immediately start CPR with chest compressions. A true cardiac arrest victim will be unresponsive, and agonal respirations can be confused with normal breathing. Thus, the “look, listen, and feel” for respirations that has been a standard protocol for initial assessment is no longer recommended.2 Similarly, pulse recognition is often inaccurate, and it is now recommended that lay rescuers not check for a pulse. Healthcare providers should assess for a pulse but take no more than 10 seconds to do so. If one is not detected within this short time frame, then chest compressions should be initiated immediately.28,29
The prompt provision of chest compressions is thus of paramount importance, and rescuers should attempt them regardless of rescuer experience or skill level. The teaching of BLS now focuses on delivering high-quality CPR with a rate of at least 100/min, adequate depth (at least 2 in [5 cm] in an adult), allowing full chest recoil, minimizing interruptions in compressions, and avoiding excessive ventilation.
While it is true that opening the airway has the potential to improve oxygenation and allow for better attempts at ventilation, this can be very challenging, especially if the rescuer is alone and is a novice. Thus, the simplified adult BLS algorithm calls for the initiation of CPR, with rhythm check every 2 minutes, shocking if indicated, with continued repetition.
Once chest compressions have been started, it is then appropriate for a trained rescuer to attempt to deliver rescue breaths, either by mouth-to-mouth or preferentially by bag-mask ventilation. The current guidelines recommend delivering a breath over 1 second, using enough volume to elicit a visible chest rise, and using a compression-to-ventilation ratio of 30:2 for one rescuer.28
The 2010 AHA guidelines for CPR and ECC continue to stress that there should be minimal interruptions in chest compressions. If there is no AED available, then cycles of compressions/breaths should continue, with pulse checks every 2 minutes until help arrives or the patient regains spontaneous circulation. If there is an AED available, then the rhythm should be checked to determine if defibrillation is advised. If so, then one shock should be delivered with the immediate resumption of chest compressions (and rescue breaths, if being provided). After 2 minutes (five cycles of 30:2 compression-to-ventilation), the rhythm should be reevaluated to determine the need for defibrillation. This algorithm should be repeated until help arrives, or the rhythm is no longer “shockable.” If the rhythm is not shockable, then chest compressions and rescue breath cycles should be continued until help arrives, or the victim recovers spontaneous circulation (Fig. 2-1).
FIGURE 2-1 Treatment algorithm for adult cardiac arrest: basic life support (BLS).
Despite widespread dissemination of cardiac arrest guidelines and the ongoing education even of healthcare providers, there is ample evidence that chest compression quality remains poor in general. Furthermore, it has been reported that only 20% to 30% of adults with out-of-hospital cardiac arrest receive bystander CPR.28 This has led to further educational interventions in an attempt to increase quality of CPR, and EMS dispatchers will often attempt to give instructions over the phone when EMS is activated.
There is now a push for hands-only CPR for lay persons, given data that show similar survival compared with the addition of rescue breaths. There has been reluctance on many bystanders to consider mouth-to-mouth, although one data set cites panic as a reason not to pursue bystander CPR rather than actual reluctance.30
Advanced Cardiac Life Support Once ACLS providers arrive, then further definitive therapy is given. An advanced airway (endotracheal tube, laryngeal mask airway, or even bag-valve mask) can be utilized to provide ventilation. When this occurs, the rescuers no longer need to provide the cycles of 30:2 compression-to-ventilation. Instead, continuous chest compressions are recommended without pauses for ventilations, and the rescuer providing the ventilations needs to deliver a breath once every 6 to 8 seconds.
Monitoring during CPR has also evolved over time. Animal and human studies have shown that monitoring of ETCO2, coronary perfusion pressure (CPP), and central venous oxygen saturation (SCVO2) can provide valuable information as to the success of resuscitation.26 Surprisingly, no study has ever shown the validity of checking a pulse during ongoing CPR. ETCO2 is the concentration of carbon dioxide in exhaled air at the end of expiration. During cardiac arrest, the level of ETCO2 decreases because there is no flow through the pulmonary circulation. Thus, a persistently low ETCO2 (i.e., <10 mm Hg [<1.3 kPa]) during CPR in intubated patients suggests that ROSC is unlikely.26 In fact, the return of ETCO2 abruptly to a normal level is likely to correlate with ROSC. In patients without ROSC and persistently decreased ETCO2, it is advised to evaluate the effectiveness of CPR, since good chest compressions can increase ETCO2 somewhat. The latest guidelines convincingly recommend ETCO2 monitoring during CPR if at all possible.26
CPP and SCVO2 require more invasive monitoring and will not be covered.
If the cardiac rhythm is not deemed to be shockable, then it is likely to be either asystole or PEA (Fig. 2-2). For PEA, the rescuer must consider reversible causes. If the person is in VF or PVT, then one shock should be delivered (appropriate to the available electrical device), with the immediate resumption of chest compressions (utilizing 30 compressions to 2 breaths for 5 cycles, or 2 minutes of continuous compressions with assisted ventilations) prior to rechecking the rhythm or pulse. If there is still a shockable rhythm, then one shock should be delivered, and at this time pharmacologic intervention can be considered. After the first unsuccessful shock, vasopressors are the initially recommended pharmacologic intervention (before or after the second shock), and after the second unsuccessful shock, antiarrhythmics can be considered (before or after the third shock). Chest compressions for 2 minutes (five cycles of chest compressions-to-breaths) should be performed in between attempts at defibrillation. This algorithm will repeat until a pulse is obtained with effective circulation, the rhythm changes, or the patient expires. For completeness, please refer to the guidelines published by the AHA.26
FIGURE 2-2 Treatment algorithm for adult cardiac arrest: advanced cardiac life support (ACLS).
Cardiocerebral Resuscitation
It was interesting that after the previous AHA publication of guidelines in 2005, there was very quick questioning of appropriateness. Authors at the time seemed to favor a concept known as cardiocerebral resuscitation (CCR).13This “clarion call for change” was made in light of the suboptimal outcomes observed with the ECC guidelines as well as several limitations with the guideline process.31 CCR has been embraced by the new 2010 AHA guidelines, and consists of three major components: (a) continuous chest compressions for bystander resuscitation, (b) simplified BLS and ACLS algorithm for providers, and (c) aggressive postresuscitation care including therapeutic hypothermia and early catheterization/intervention.
CCR initially advocated continuous chest compressions without mouth-to-mouth ventilations for witnessed cardiac arrests, and has led to updated guidelines as listed above. Chest compressions deliver a small but critical amount of oxygen to the brain and myocardium. Cerebral and CPPs, however, build up slowly once chest compressions are begun. These perfusion pressures are lost if chest compressions are stopped to deliver mouth-to-mouth ventilation. In fact, in earlier studies, approximately 16 seconds were required to deliver two breaths as recommended by earlier ECC guidelines.32 The loss of perfusion during this time period has been shown to be extremely detrimental as ROSC is closely related to perfusion pressures generated during chest compressions.33
The second component of CCR is a new simplified algorithm. This protocol is based on the three-phase time-sensitive model of cardiac arrest.34 The first phase is the electrical phase (0 to 5 minutes), where prompt defibrillation is the most important intervention. The second phase is the hemodynamic phase (5 to 15 minutes), where adequate coronary and cerebral perfusion pressures, before and after defibrillation, are crucial. In fact, defibrillation prior to CPR in this phase commonly leads to asystole or PEA. This is likely due to the presence of global tissue ischemia and the need for blood flow (via chest compressions) to “flush out” deleterious metabolic factors that have accumulated during ischemia. The third phase is the metabolic phase (beyond 15 minutes) in which survival is very low and hypothermia may be the most beneficial approach.
The third component of CCR is aggressive postresuscitation care. This consists of the use of hypothermia for all comatose patients and emergent cardiac catheterization and percutaneous coronary intervention (PCI) for patients with myocardial ischemia as a potential cause of their arrest. Since its conception in 2003, clinical studies evaluating CCR have demonstrated an improvement in survival of 250% to 300% compared with conventional CPR.13
Articles are starting to appear showing that this approach is most favorable. In one study, those who received CCR had better outcomes across age groups. For those who suffered VF arrest and were under 40 years of age, the survival increased from 3.7% (standard advanced life support) to 19% (CCR patients) (odds ratio [OR] 5.94; 95% confidence interval [CI] 1.82 to 19.26).35
Ventricular Fibrillation/Pulseless Ventricular Tachycardia
Nonpharmacologic Therapy
Electrical defibrillation is the only effective method of restoring a perfusing cardiac rhythm in either VF or PVT; therefore, it is a crucial link in the “chain of survival,” especially for a witnessed arrest.25 The probability of successful defibrillation is directly related to the time interval between the onset of VF and the delivery of the first shock.25 In one study, a 23% relative improvement in survival was observed with each 1 minute reduction in the time to defibrillation (OR 0.77 [95% CI 0.73 to 0.81]).36 If fact, survival decreases an estimated 7% to 10% for each minute after arrest to defibrillation if no CPR is given.24 When bystander CPR is delivered, this decrease in survival is cut almost in half.25
Although early defibrillation is crucial for survival following cardiac arrest, several studies have suggested that CPR prior to defibrillation (consistent with the CCR model) may lead to more successful outcomes. This was reviewed extensively in the 2010 guidelines. For in-hospital cardiac arrest, if an AED is available, CPR should begin while the AED is being placed. With out-of-hospital cardiac arrest, there is growing evidence that CPR before defibrillation is, for the most part, beneficial. In studies where EMS arrivals were delayed more than 4 to 5 minutes, CPR before defibrillation increased ROSC, survival to discharge, and 1-year survival.25,37,38 In one trial, the provision of roughly 90 seconds of CPR prior to defibrillation was associated with an increased rate of hospital survival (compared with a historical control group) when response intervals were 4 minutes or longer (27% vs. 17%; P = 0.01).37 A second trial reported higher survival rates in patients with response intervals greater than 5 minutes when 3 minutes of CPR was administered prior to defibrillation (22% vs. 4%; P = 0.006).38 In a study where each defibrillation, including the first, was preceded by 200 uninterrupted chest compressions, an increase in total survival (57% [19/33] vs. 20% [18/92], P = 0.001) and neurologically normal survival (48% [16/33] vs. 15% [14/92], P = 0.001) was reported compared with standard CPR practices.39Finally, one study noted an improvement in hospital survival (from 22% to 44%, P = 0.0024) in patients with witnessed VF using a modified resuscitation protocol that included 200 preshock chest compressions.40 In lieu of these results, the AHA guidelines continue to offer that EMS personnel may give 2 minutes of chest compressions prior to attempting defibrillation. Recommendations are similar for victims in the metabolic phase; recognizing the likelihood of achieving ROSC, however, is drastically lower.
However, as in any topic in medicine, there are data sets that can contradict standard acceptance. Koike et al. in 2011 described no better outcome with CPR before attempted defibrillation in either 1-month survival or neurologically favorable 1-month outcome.41 Thus, this is an issue of ongoing debate and study.
Clinical Controversy…
The provision of CPR prior to defibrillation has shown benefit in some studies, but there is insufficient evidence to make a strong recommendation regarding this practice.
The current guidelines continue to recommend one shock for VF or PVT (as opposed to earlier iterations, where “stacked,” multiple shocks were initially given) with the immediate resumption of chest compressions.25 This revision is largely due to the prolonged time noted (approximately 55 seconds) to deliver three stacked shocks without providing adequate chest compressions.42 The defibrillation attempt should be with 360 J (monophasic defibrillator) or 150 to 200 J (biphasic defibrillator). If an AED is available, it should be used as soon as possible. However, CPR should be started immediately (after EMS activation) while the AED is being prepared. Interestingly, AEDs, which have been shown to improve survival in out-of-hospital cardiac arrest due to VF/VT, have not been shown to improve outcome following replacement of monophasic defibrillators with biphasic AEDs for in-hospital arrest.43
After defibrillation is attempted, CPR should be immediately restarted and continued for 2 minutes without checking a pulse. The omission of the pulse check after defibrillation is also a paradigm shift in the algorithm that is related to myocardial stunning with resultant poor perfusion and diminished cardiac output immediately after electrical therapy.25 After 2 minutes of chest compressions, the rhythm and pulse should be rechecked. If there is still evidence of VF or PVT, then pharmacologic therapy with repeat attempts at single-discharge defibrillation should be attempted.
Endotracheal intubation and IV access should be obtained when feasible, but not at the expense of stopping chest compressions. The 2010 AHA guidelines for CPR and ECC continue to strongly stress the need for uninterrupted CPR.28 Once an airway is achieved, patients should be ventilated with 100% oxygen. There are several airway adjuncts that are potentially available, such as laryngeal mask airways and esophageal–tracheal combination tubes. However, the definitive airway is an endotracheal tube placed with direct laryngoscopy.
Other interventions are also being evaluated as nonpharmacologic therapy. In a porcine model of VF arrest, a percutaneously placed left ventricular assist device (LVAD) was shown to sustain vital organ perfusion.44 As well, the performance of angiography and PCI during suspected MI has been studied both in animals and anecdotally in humans refractory to traditional ACLS protocol without ROSC. A review of this topic suggests that this intervention is feasible and that further investigation is warranted.45 Extracorporeal membrane oxygenation (ECMO) has also been evaluated and has been shown to improve outcomes in some series, but the logistics of widespread implementation is daunting.46 While there are no conclusive human data regarding these issues, they do raise interesting concepts to deliberate and to research.
Pharmacologic Therapy
Sympathomimetics Sympathomimetics continue to be the first pharmacologic agents administered in the setting of cardiac arrest despite limited evidence demonstrating their ability to increase neurologically intact survival to hospital discharge. Nevertheless, sympathomimetics have been associated with an increased rate of ROSC and play a major role in the pharmacotherapy of cardiac arrest.
The primary goal of sympathomimetic therapy is to augment low coronary and cerebral perfusion pressures encountered during CPR. Chest compressions (via CPR) can provide some degree of blood flow to the heart and the brain but it is only about 25% of that encountered under basal conditions.47 In fact, even with properly performed chest compressions, CPPs are only 10 to 15 mm Hg and systolic arterial pressure is rarely above 80 mm Hg.48Clinical data have indicated that ROSC is unlikely when CPP is less than 15 mm Hg and animal studies have demonstrated higher rates of ROSC when CPP was 31 mm Hg versus 14 mm Hg.49,50 Sympathomimetics therefore work to increase these pressures through their vasoconstrictive properties.
Epinephrine continues to be a drug of first choice for the treatment of VF, PVT, asystole, and PEA. It is an α- and β-receptor agonist causing both vasoconstriction and increased inotropic/chronotropic activity on the heart. Its effectiveness however is primarily through its α effects, particularly α2-activity.51
There are few prospective data evaluating epinephrine in the setting of out-of-hospital cardiac arrest. In one study, patients were randomized to receive standard ACLS with IV drug administration or standard ACLS without IV drug administration.52 There were 851 patients analyzed and VF/PVT was the initial rhythm in 34%. IV medications administered included epinephrine (79%), atropine (46%), and amiodarone (17%). A significant increase in ROSC (40% vs. 25%, P <0.001) and hospital admission (43% vs. 29%, P <0.001) was noted in patients who received IV therapy. This difference was primarily observed in patients with initial rhythms other than VF/PVT. The role of epinephrine (vs. other IV medications) in the contribution of these outcomes was not assessed. A second randomized controlled trial compared epinephrine with placebo in 534 patients.53 VF or PVT was the initial rhythm in 44% and 48% of patients in the epinephrine and placebo groups, respectively. ROSC (23.5% vs. 8.4%, P <0.001) and survival to hospital admission (25.4% vs. 13%, P <0.001) were significantly higher with epinephrine, but there was no difference in survival to hospital discharge (4% vs. 1.9%, P = 0.15). While epinephrine was effective in achieving ROSC in both shockable (OR [95% CI] = 2.5 [1.2 to 4.5]) and nonshockable (OR [95% CI] = 6.9 [2.6 to 18.4]) rhythms, its effect was more pronounced in the latter cohort. In contrast, one large prospective registry study of over 400,000 patients failed to demonstrate a survival benefit with prehospital administration of epinephrine.54 Despite a significant improvement in ROSC with epinephrine (adjusted OR [95% CI] = 2.36 [2.22 to 2.5]), both 1-month survival (adjusted OR [95% CI] = 0.46 [0.42 to 0.51]) and survival with good neurologic function (adjusted OR [95% CI] = 0.31 [0.26 to 0.36]) were lower in patients who received epinephrine. These findings were confirmed through various sensitivity analyses accounting for in-hospital epinephrine use and CPR duration. Given the disparate results with epinephrine in clinical trials, it can be considered both a cure and a curse in cardiac arrest. One potential approach, which will require validation through clinical trials, is to administer epinephrine only in settings where aortic diastolic pressure is low (i.e., less than 30 to 40 mm Hg) recognizing that a vasoconstrictive agent will provide minimal benefit (and possible harm) when perfusion pressures are adequate.55
Clinical Controversy…
Given the disparate results with epinephrine in clinical trials, it can be considered both a cure and a curse in cardiac arrest.
One possible explanation for the negative effects of epinephrine is related to its mechanism of action. Epinephrine causes α-mediated vasoconstriction that increases coronary perfusion but can decrease perfusion to other vital organs. In fact, animal research has linked epinephrine to a decrease in cerebral microvascular blood flow and increase in brain tissue ischemia during and after CPR.56 Epinephrine also stimulates β-receptors that can increase myocardial oxygen demand, impair lactate clearance, and advance the severity of postresuscitation myocardial dysfunction.57 This has led some investigators to evaluate simultaneous adrenergic antagonist administration in conjunction with epinephrine therapy (thereby isolating the α2 effects) using an animal model.58 This approach has not been extensively studied in humans.
Several studies have compared epinephrine with other adrenergic agonists such as pure α1-agonists (phenylephrine and methoxamine) and agents with more potent α-activity (norepinephrine).59 When compared with pure α1-agonists, no advantage in long-term survival could be reported. One potential reason could be the potent α2 effects with epinephrine and the fact that these receptors lie extrajunctionally in the intima of the blood vessels making them more accessible to circulating catecholamines.60 Furthermore, during ischemia, the number of postsynaptic α1-receptors decreases, which suggests a greater role for α2-agonists during CPR.61 Epinephrine has also been compared with norepinephrine, a potent α-agonist (both α1 and α2) with some β1 effects. In the only large-scale randomized, double-blind, prospective trial in out-of-hospital cardiac arrest, there were no significant differences in ROSC, hospital admission, or discharge.62 A second, smaller study demonstrated higher resuscitation rates with norepinephrine compared with those with epinephrine (64% vs. 32%) but no significant difference in hospital discharge.63Since the use of epinephrine has been established for many decades in evidence-based guidelines, strong outcome-related data (e.g., survival to hospital discharge) would be required for an alternative to replace it. Consequently, epinephrine remains the first-line sympathomimetic for CPR.
The recommended dose for epinephrine is 1 mg administered by IV or intraosseous (IO) injection every 3 to 5 minutes26 (Table 2-1). Higher doses may be administered to treat specific disorders such as β-blocker or calcium channel blocker overdose. Additionally, higher doses can be considered if indicated through arterial diastolic pressure (or CPP) monitoring. The recommended dose for epinephrine was derived from animal studies (0.1 mg/kg in a 10-kg dog) and equates to approximately 0.015 mg/kg for a 70-kg human.64 Both animal and human studies have demonstrated a positive dose–response relationship with epinephrine suggesting that higher doses might be necessary to improve hemodynamics and achieve successful resuscitation.59 These results, however, have not been replicated in human studies. In fact, some studies have reported increased morbidity with high epinephrine doses, indicative of catecholamine toxicity, including decreased cardiac indices, left ventricular dysfunction, and decreased oxygen consumption and delivery. This discrepancy between animal and human studies could be related to most victims of cardiac arrest having coronary artery disease, which is not encountered in an animal model. Additionally, atherosclerotic plaques (in humans) can aggravate the balance between myocardial oxygen supply and demand and the interval from arrest to treatment is longer in human studies than that encountered in an animal model.
TABLE 2-1 Evidence-Based Recommendations
Vasopressin Vasopressin, also known as antidiuretic hormone, is a potent, nonadrenergic vasoconstrictor that increases blood pressure and systemic vascular resistance. Although it acts on various receptors throughout the body, its vasoconstrictive properties are due primarily to its effects on the V1 receptor. Measurement of vasopressin levels in patients undergoing CPR has shown a high correlation between the levels of endogenous vasopressin released and the potential for ROSC.65 In fact, in one study, plasma vasopressin concentrations were approximately three times as high in survivors compared with those in nonsurvivors, suggesting that vasopressin is released as an adjunct vasopressor to epinephrine in life-threatening events such as cardiac arrest.66
Vasopressin may have several advantages over epinephrine. First, the metabolic acidosis that frequently accompanies cardiac arrest can blunt the vasoconstrictive effect of adrenergic agents such as epinephrine. This effect does not occur with vasopressin. Second, the stimulation of β-receptors caused by epinephrine can increase myocardial oxygen demand and complicate the postresuscitative phase of CPR. Because vasopressin does not act on β-receptors, this effect does not occur with its use. Vasopressin also may have a beneficial effect on renal blood flow by stimulating V2 receptors in the kidney, causing vasodilation and increased water reabsorption. With regard to splanchnic blood flow, however, vasopressin has a detrimental effect when compared with epinephrine.65
Despite these theoretical advantages with vasopressin, clinical trials have not consistently demonstrated superior results over that achieved with epinephrine (Table 2-2). In one large trial of out-of-hospital arrest, no significant differences were noted in ROSC, hospital admission rate, or discharge rate.69 Although when patients were stratified according to their initial rhythm, patients with asystole had a significantly higher rate of hospital admission (29% vs. 20%; P = 0.02) and discharge (4.7% vs. 1.5%; P = 0.04) with vasopressin compared with that with epinephrine. In addition, a subgroup analysis of 732 patients who required additional epinephrine therapy despite the two doses of study drug revealed significant benefits in ROSC (37% vs. 26%; P = 0.002), hospital admission rate (26% vs. 16%; P = 0.002), and discharge rate (6.2% vs. 1.7%; P = 0.002) with vasopressin. There was a trend, however, toward a poorer neurologic state or coma among the patients who survived to discharge and received vasopressin.
TABLE 2-2 Prospective Randomized Controlled Trials with Vasopressin in Cardiac Arrest
The favorable results observed in the subgroup analysis led to a prospective study evaluating the combination of vasopressin and epinephrine versus epinephrine alone.71 In this study, patients were randomized to receive either 1 mg of epinephrine followed by 40 units of vasopressin (in less than 10 seconds) or 1 mg of epinephrine plus saline placebo. Unfortunately, there were no significant differences between the combination therapy group and epinephrine-only group in any of the outcome measures studied (ROSC, survival to hospital admission, survival to hospital discharge, 1-year survival, and good neurologic recovery at discharge). In contrast, a post hoc subgroup analysis revealed a lower rate of survival (0% vs. 5.8%, P = 0.02) with combination therapy when the initial rhythm was PEA.
One study evaluated a multidrug regimen that also included corticosteroids for patients with in-hospital cardiac arrest.72 In this study, patients were randomized to receive either epinephrine alone or 20 units of vasopressin plus 1 mg of epinephrine and 40 mg of methylprednisolone (followed by hydrocortisone in the postresuscitative phase). Vasopressin 20 units plus epinephrine 1 mg was repeated during each of four subsequent CPR cycles. This study marks the first to include corticosteroids as part of drug therapy during CPR. The rationale is based on the hemodynamic effects of steroids alone with their potential to impact the intensity of the postresuscitation systemic inflammatory response and organ dysfunction. Significant benefits were observed in ROSC (81% vs. 52%, P = 0.003) and survival to hospital discharge (19% vs. 4%, P = 0.02) with combination therapy including corticosteroids. Future studies are required to determine the role of vasopressin and corticosteroids for cardiac arrest.
In lieu of the conflicting results across numerous randomized controlled trials, a meta analysis was performed to further define the role of vasopressin.75 Six studies were chosen for analysis (4, out-of-hospital arrest; 2, in-hospital arrest) including 4,745 patients. No significant improvements were noted with vasopressin therapy in ROSC (OR [95% CI] = 1.25 [0.9 to 1.74]), long-term survival (OR [95% CI] = 1.13 [0.71 to 1.78]), or favorable neurologic outcome (OR [95% CI] = 0.87 [0.49 to 1.52]). When patients were stratified based on the presence of VF/PVT as their initial rhythm, the incidence of ROSC (OR [95% CI] = 1.18 [0.82 to 1.69]) and long-term survival (OR [95% CI] = 0.95 [0.66 to 1.37]) were similar with vasopressin. Interestingly, in patients with asystole, vasopressin was associated with superior long-term survival rates relative to control (OR [95% CI] = 1.8 [1.04 to 3.12]).
In summary, vasopressin appears to offer no benefit over epinephrine when used as an alternative to or when coadministered with epinephrine. Future prospective trials are needed to validate the role of vasopressin in certain subpopulations (e.g., asystole) or when combined with corticosteroids. The current recommendations for vasopressin are that one dose (40 units) administered IV/IO may replace either the first or second dose of epinephrine in the treatment of cardiac arrest.
Clinical Controversy…
Vasopressin could have some potential benefit in patients with initial rhythms that are nonshockable.
Antiarrhythmics The purpose of antiarrhythmic drug therapy following unsuccessful defibrillation and vasopressor administration is to prevent the development or recurrence of VF and PVT by raising the fibrillation threshold. Clinical evidence demonstrating improved survival to hospital discharge however is lacking.76
Amiodarone is the recommended antiarrhythmic in patients with VF or PVT, unresponsive to CPR, defibrillation, and vasopressor therapy. Amiodarone is classified as a Class III antiarrhythmic but possesses electrophysiologic characteristics of all four Vaughan Williams classifications. A large, randomized, double-blind trial in patients with out-of-hospital cardiac arrest secondary to VF or PVT (referred to as the ARREST trial) randomized individuals to receive either amiodarone 300 mg or placebo.77 Recipients of amiodarone were more likely to be resuscitated and survive to hospital admission (44% vs. 34%, P = 0.03), but there was no difference in survival to hospital discharge (13.4% vs. 13.2%, P = NS). This was the first trial to demonstrate the benefit of an antiarrhythmic agent over placebo in patients with out-of-hospital cardiac arrest.
A subsequent trial (known as the ALIVE trial) compared amiodarone 5 mg/kg with lidocaine 1.5 mg/kg in patients with out-of-hospital cardiac arrest due to VF.78 In this trial, amiodarone was associated with a relative improvement of 90% in survival to hospital admission compared with lidocaine (22.8% vs. 12%; OR 2.17 [95% CI 1.21 to 3.83]; P = 0.009). Similar to the ARREST trial, there was no difference in survival to hospital discharge (amiodarone, 5% vs. lidocaine, 3%; P = 0.34).
Amiodarone and lidocaine have also been compared in patients following in-hospital cardiac arrest. In a multicentered, retrospective review, 194 patients with VF or PVT who received amiodarone (n = 74), lidocaine (n = 79), or both (n = 41) were evaluated.79 The rate of survival at 24 hours was 55%, 63%, and 50% for patients receiving amiodarone, lidocaine, or both, respectively (P = 0.39). There was no difference in survival to hospital discharge (amiodarone, 39%; lidocaine, 45%; both, 42%; P = 0.72). After adjusting for multiple covariates, Cox’s regression analysis revealed higher survival to 24 hours (HR [95% CI] = 3.15 [1.68 to 5.92], P <0.001) and hospital discharge (HR [95% CI] = 3.25 [1.22 to 8.65], P = 0.02) in those patients who received lidocaine compared with that in those patients who received amiodarone. The mean initial dose of amiodarone, though, was 190 mg, and only 25% of patients received the recommended dose of 300 mg. Additionally, the time to first dose of antiarrhythmic was significantly longer in the amiodarone group than in the lidocaine group (14 minutes vs. 6 minutes, P <0.001).
Adverse effects of amiodarone encountered in cardiac arrest include hypotension and bradycardia.26 The effects however are largely due to the IV vehicle, polysorbate 80, and benzyl alcohol. A formulation of amiodarone exists that does not contain these solvents and adverse hemodynamic effects appear to be minimized. Nevertheless, administration of a vasoconstrictor prior to amiodarone can potentially prevent hypotension.
Lidocaine is currently recommended as an alternative to amiodarone, if amiodarone is not available. Minimal evidence exists supporting lidocaine use for VF/PVT. In the only published case–control trial where patients were classified according to whether they received lidocaine, no significant difference was noted in ROSC, admission to the hospital, or survival to hospital discharge between groups.80Similarly, a prospective study comparing the effectiveness of lidocaine with that of standard-dose epinephrine showed not only a lack of benefit with lidocaine but also a higher tendency to promote asystole.81In contrast, a retrospective analysis in patients with VF indicated that lidocaine was associated with a higher rate of ROSC and hospitalization (P <0.01) but not an increase in the hospital discharge rate.82
Magnesium Severe hypomagnesemia has been associated with VF/PVT, but routine administration of magnesium during a cardiac arrest has not demonstrated any benefit in clinical outcome. Two observation trials, though, have noted an improvement in ROSC in patients with arrests associated with torsade de pointes.26 Therefore, magnesium administration should only be administered to those patients.
Thrombolytics Since most cardiac arrests are related to either MI or pulmonary embolism (PE), several investigators have evaluated the role of thrombolytics during CPR. Earlier smaller studies have demonstrated some benefit with their use, but in the two largest randomized controlled trials, no difference was noted.26 In the first, 233 patients with PEA were randomized to receive either tissue plasminogen activator (tPA) or placebo.83 The proportion of patients with ROSC was 21.4% and 23.3% for tPA- and placebo-treated patients, respectively. There was no significant difference in hemorrhage rates. The second study randomized patients with out-of-hospital cardiac arrest to receive either tenecteplase or placebo.84 After a blinded review by the data and safety monitoring board, criteria for futility were met and enrollment was terminated. A total of 1,050 patients were analyzed, and both ROSC (tenecteplase, 55% vs. placebo, 55%; P = 0.96) and survival to hospital discharge (tenecteplase, 15.1% vs. placebo, 17.5%, P = 0.33) were similar between groups. Furthermore, the incidence of intracranial hemorrhage was significantly greater with tenecteplase versus placebo (2.7% vs. 0.4%, P = 0.006). Potential reasons for failure in this study include the omission of antiplatelet and antithrombin medication administration during CPR and decreased delivery of the thrombolytic to the coronary arteries (where the clots exist) due to impaired flow and perfusion. Given these results, fibrinolytic therapy should not be used routinely in cardiac arrest but when PE is presumed (or known) to be the cause, their use can be considered.
Pulseless Electrical Activity and Asystole
Nonpharmacologic Therapy
PEA is defined as the absence of a detectable pulse and the presence of some type of electrical activity other than VF or PVT. Several studies have documented that patients with PEA actually have mechanical cardiac contractions, but they are too weak to produce a palpable pulse or blood pressure. Although PEA is still classified as a “rhythm of survival,” the success rate of treatment is much lower than the rates seen with VF/PVT.85 PEA is often caused by treatable conditions, and the resuscitation team needs to identify and correct these conditions emergently if the resuscitation is to be successful (Table 2-3). Asystole is defined as the presence of a flat line on the ECG monitor and often represents confirmation of death rather than a rhythm to be treated. Therefore, withdrawal of efforts must be strongly considered if there is not a rapid ROSC.26 
Like PEA, successful treatment of asystole depends almost entirely on diagnosis of the underlying cause.
TABLE 2-3 Underlying Causes of Pulseless Electrical Activity and Asystole
The algorithm for treatment of PEA is the same as that for the treatment of asystole. Both conditions require CPR, airway control, and IV access. Asystole should be reconfirmed by checking a second lead on the cardiac monitor. Defibrillation should be avoided in patients with asystole because the parasympathetic discharge that occurs with defibrillation may reduce the chance of ROSC and worsen the chance of survival. The emphasis in resuscitation is good-quality CPR without interruption, and to try to identify a correctable cause. If available, transcutaneous pacing can be attempted.
Much like VF/PVT, there is an interest in hypothermia in these postarrest patients. Metabolic parameters (e.g., lactate and O2 extraction) have been shown to be improved when postarrest comatose adults survived their arrest and were treated with hypothermia. Further studies are warranted in this area.86
Pharmacologic Therapy
The primary pharmacologic agents used in the treatment of asystole or PEA are epinephrine and vasopressin. While there are no studies evaluating these therapies solely in patients with asystole or PEA, these rhythms represent a majority of patients included in clinical trials. For example, in the largest observational trial evaluating the role of epinephrine, 93% had either PEA or systole as the first documented rhythm.54 Epinephrine was associated with a significant improvement in ROSC, but 1-month survival and survival with good neurologic function were lower with epinephrine. In contrast, in a subgroup analysis of a randomized controlled trial comparing epinephrine with placebo, higher rates of ROSC and survival to hospital admission were observed with epinephrine in patients with nonshockable rhythms.53
Inconsistent results have also been reported with vasopressin. In a post hoc subgroup analysis of patients with out-of-hospital arrest and asystole as the first identified rhythm, survival to hospital admission (29% vs. 20%, P = 0.02) and discharge (4.7% vs. 1.5%, P = 0.04) were significantly higher with vasopressin compared with those with epinephrine.69 There was, however, a nonstatistically significant increase in coma/vegetative state with vasopressin (40% vs. 0%, P = 0.14). Similar findings were cited in a meta analysis of randomized controlled trials comparing vasopressin with control.75 Patients with asystole who had study drug administered within 20 minutes had higher rates of ROSC (OR [95% CI] = 1.7 [1.17 to 2.47]) and long-term survival (OR [95% CI] = 2.84 [1.19 to 6.79]). These results were largely influenced by the aforementioned trial that accounted for a majority of the weight in those statistics. In contrast to these findings, one randomized controlled trial that evaluated combination therapy with vasopressin and epinephrine did not report an advantage with vasopressin in patients with asystole.71 In fact, a post hoc subgroup analysis of patients with PEA as the initial rhythm revealed a lower rate of survival (0% vs. 5.8%, P = 0.02) with combination therapy compared with that with epinephrine alone.
One agent that is no longer recommended in the setting of PEA or asystole is atropine.26 Atropine is an antimuscarinic agent that blocks the depressant effect of acetylcholine on both heart rate and atrioventricular nodal conduction, thus decreasing parasympathetic tone. During asystole, parasympathetic tone may increase because of the vagal stimulation that occurs secondary to intubation, the effects of hypoxia and acidosis, or alterations in the balance of parasympathetic and sympathetic control.87 Nevertheless, there are no prospective controlled trials showing benefit from atropine for the treatment of asystole or PEA and conflicting evidence exists across retrospective and observational reports. Therefore, atropine should not be routinely administered in this setting.
Acid/Base Management
Acidosis seen during cardiac arrest is the result of decreased blood flow (leading to anaerobic metabolism) or inadequate ventilation. Chest compressions generate only approximately 20% to 30% of normal cardiac output, leading to inadequate organ perfusion, tissue hypoxia, and metabolic acidosis. In addition, the lack of ventilation causes retention of carbon dioxide, leading to respiratory acidosis. This combined acidosis produces not only reduced myocardial contractility and negative inotropic effect but also the appearance of arrhythmias because of a lower fibrillation threshold. In early cardiac arrest, adequate alveolar ventilation has been considered the mainstay of control to limit the accumulation of carbon dioxide and control the acid–base imbalance.26 With the evolution to CCR, however, there are experts arguing against ventilation because of the negative effects it can have on the effectiveness of CPR. This has led to evidence showing no negative effects if compression-only CPR is used for out-of-hospital cardiac arrest (exceptions being pediatric arrest, drowning, trauma, airway obstruction, noncardiac etiology, or due to acute respiratory disease).88 With arrests of long duration, buffer therapy is often considered; however, few data support its use during cardiac arrest.
Although sodium bicarbonate was once given routinely to reduce the detrimental effects associated with acidosis (e.g., reduced myocardial contractility), enhance the effect of epinephrine, and improve the rate of defibrillation, there are few clinical data supporting its use.89 In fact, sodium bicarbonate may have some detrimental effects.89,90 The effect of sodium bicarbonate can be described by the following reaction:
When sodium bicarbonate is added to an acidic environment, this reaction will shift to the right, thereby increasing tissue and venous hypercarbia. The carbon dioxide generated by this reaction will diffuse into the cell and decrease intracellular pH. The accumulation of intracellular carbon dioxide, specifically within the myocardium, is inversely correlated with CPP produced by CPR. Intracellular acidosis also will decrease myocardial contractility, further complicating the low-flow state associated with CPR.89 Furthermore, treatment with sodium bicarbonate often overcorrects extracellular pH because sodium bicarbonate has a greater effect when the pH is closer to normal.90The induced alkalosis causes an increase in the affinity of oxygen to hemoglobin (“left shift”), thus interfering with oxygen release into the tissues. More recently, the early administration of bicarbonate (1 mEq/kg) had no effect on survival in prehospital cardiac arrest. There was a slight trend toward improvement in prolonged arrest (>15 minutes) with a twofold improvement in survival (32.8% vs. 15.4%).91
Sodium bicarbonate can be used in special circumstances (i.e., underlying metabolic acidosis, hyperkalemia, salicylate overdose, or tricyclic antidepressant overdose); however, the dosage should be guided by laboratory analysis if possible. Tromethamine (THAM) is an alternative buffering agent that acts as a proton acceptor, but there is a dearth of clinical experience with this agent in cardiac arrest and outcome studies are not currently available.26
Postresuscitative Care
Following the ROSC from a cardiac arrest, a complex phase of resuscitation begins that has been termed postcardiac arrest syndrome.92 There are four main components of postcardiac arrest syndrome highlighting succinct pathophysiologic processes and potential areas for treatment and include postcardiac arrest brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathology. In general, many of the concepts within these four components surround the principles of basic ICU care (e.g., early hemodynamic optimization, circulatory support, sedation, etc.). Postarrest care has the significant potential to reduce early mortality from altered hemodynamics and later morbidity and mortality from multiple organ dysfunction and CNS injury.27,92,93
After ROSC, it is imperative to ensure adequate airway and oxygenation. Securing the airway to prevent inadvertent loss is an important step. If there is any question of cervical spine injury, the patient should have a cervical collar placed, with subsequent appropriate evaluation. The head of the bed should be raised to 30° (if this can be tolerated hemodynamically) to reduce the risk for aspiration, ventilator-associated pneumonia, and cerebral edema. Usually 100% oxygen is used during the initial resuscitation effort. If ROSC is obtained and the patient is placed on a mechanical ventilator, the healthcare team should titrate the oxygen fraction down as tolerated to avoid oxygen toxicity. Overventilation is common in the postresuscitation time frame; the advent of widespread ETCO2 usage can avoid this pitfall (i.e., targeting an ETCO2 of 40 to 45 mm Hg [5.3 to 6.0 kPa]).
Because the most common cause of cardiac arrest is ischemia, a rapid search for electrocardiographic changes consistent with acute MI should be undertaken as soon as possible in the postarrest time frame.94If there is an acute MI present, urgent revascularization should be enacted immediately.
Many patients do not regain consciousness immediately after a cardiac arrest. It is recommended that they be transferred to a facility with a comprehensive care plan for advanced cardiac care, advanced neurologic monitoring, and postarrest therapeutic hypothermia.27
Restoration of blood flow following cardiac arrest can lead to several chemical cascades and destructive enzymatic reactions that can result in cerebral injury. These reactions include free radical production, excitatory amino acid release, and calcium shifts, which ultimately lead to mitochondrial damage and apoptosis (programmed cell death).95 Hypothermia can protect from cerebral injury by suppressing these chemical reactions, thereby reducing the production of free radicals. Various animal models have demonstrated improved functional recovery and reduced cerebral deficits with the induction of mild therapeutic hypothermia.96 Recent data have attempted to refine this concept and even expand upon the organ systems protected. In a pig model of VF treated after 10 minutes, rapid head cooling led to more beneficial effects than surface cooling in terms of postresuscitation myocardial dysfunction.97In addition, a similar pig model of cardiac arrest showed that delayed surface cooling led to less favorable survival and neurologic outcome than early head cooling.98
Interestingly, hypothermia as a therapeutic endeavor in humans has been described since antiquity. It is reported that Hippocrates advocated for bleeding patients to be packed in snow and ice. Later, a chief battlefield surgeon for Napoleon Bonaparte noticed that survival rates were lower in wounded soldiers who were rewarmed versus survival rates in those who were left in the cold.99,100 These early human observations, as well as current animal model investigations, have been parlayed into the clinical bedside in human trials, and literature continues to accumulate.
Early human success with hypothermia was described in two pivotal trials.101,102 The first trial was conducted in nine centers in five European countries.101 In this study, patients who had been resuscitated after cardiac arrest due to VF but remained comatose were assigned randomly to undergo therapeutic hypothermia, targeting a temperature of 32°C to 34°C (89.6°F to 93.2°F), for 24 hours. The primary end point was neurologic outcome within 6 months of cardiac arrest. Secondary end points were mortality (within 6 months) and complication rate within 7 days. A favorable neurologic outcome was achieved in 55% of patients in the hypothermia group as opposed to 39% in the normothermia group (P = 0.009). Additionally, mortality rates were improved significantly in the hypothermia group (41% vs. 55%; P = 0.02). Based on this difference, seven patients would need to be treated with hypothermia to prevent one death. The rate of complications (e.g., bleeding, pneumonia, sepsis, and renal failure) did not differ between the two groups (73% for the hypothermia group and 70% for the normothermia group; P = 0.70).
The second trial was conducted in four hospitals in Melbourne, Australia.102 Entry criteria were similar to the previous trial, but the target temperature for hypothermia was 33°C (91.4°F), which was maintained for 12 hours. The primary outcome measure was survival to hospital discharge with good neurologic function. Forty-nine percent of patients in the hypothermia group had good neurologic function on discharge (to either home or a rehabilitation facility) compared with 26% of patients in the normothermia group (P = 0.046). Mortality rates were similar between the two groups (51% for the hypothermia group and 68% for the normothermia group; P = 0.145). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. It is important to note that only 8% of patients with cardiac arrest were selected for therapeutic hypothermia in these two studies.
Since that time, further data have continued to accumulate, including studies in arrests caused by rhythms other than VF. In one study, therapeutic hypothermia (combined with PCI, tight glycemic control, and seizure control) doubled the 1-year survival rate (reportedly with good brain function) from 26% to 56%.103 The implementation of therapeutic hypothermia in clinical practice (i.e., outside of the context of a clinical trial) has also been evaluated. A review of this topic showed that there is a significant variation in reported protocols, but that survival and neurologic outcomes benefit from postarrest hypothermia and “are robust when compared over a wide range of studies of actual implementation” (OR [95% CI] = 2.5 [1.8 to 3.3]).104 Nevertheless, there remains significant debate about hypothermia including when to consider limitation of care given a predicted poor outcome.105 Initially hypothermia was described with only VF without sustained circulatory shock. As part of the “cardiocerebral” concept described above, investigations have expanded to non-VF arrests since similar benefit is being found.27,106 In addition, there are case series of using therapeutic hypothermia in combination with emergent percutaneous coronary angioplasty.27,107
Methods of inducing hypothermia also continue to be in evaluation. There is debate over how quickly to achieve a therapeutic temperature, and in at least one animal model, a novel immersion device showed an average time to reach target temperature of only 9 minutes.108 As well, simple maneuvers, such as iced saline infusion, can be used even in the prehospital setting with subsequent cooling by other means.27,109 There were editorials clamoring for ongoing studies regarding methodologies and outcomes.110,111 However, there is no consensus on the optimal method to induce hypothermia. Main methods currently in use include cold water immersion, endovascular cooling catheters, and surface cooling devices.27
In light of these accumulating data, unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32°C to 34°C (89.6°F to 93.2°F) for 12 to 24 hours.27,112This is particularly true of VF arrest (Class I recommendation; Level of Evidence B).27 There is less robust evidence for other arrests, but per the guidelines, hypothermia should be considered for comatose adult patients with ROSC after in-hospital cardiac arrest with any rhythm, and/or out-of-hospital cardiac arrest with an initial rhythm of PEA (Class IIb recommendation; Level of Evidence B).27 However, given clinical experience that has been gained, most intensive care practitioners will use therapeutic hypothermia in the postarrest time frame regardless of the rhythm.
Hypothermia must be used with caution, however, as there are several complications that can develop. Coagulopathy, dysrhythmias, hyperglycemia, increased incidence of pneumonia, as well as sepsis have been described.27,102,113 In addition, hypothermia can have profound effects on drug distribution and elimination.114 Although the duration of hypothermia is typically short, careful monitoring during this time period is necessary, particularly with vasoactive agents. Further research is required in this area.
Special Populations
Asthma
Asthma is a very common disorder, and despite modern therapies, there are still in excess of 2 million emergency room visits yearly.115 Despite improvements in mechanical ventilation strategies, there are still 5,000 to 6,000 asthma-related deaths annually in the United States.115 True cardiac arrest in asthma is infrequent, as the primary pathophysiology is respiratory compromise and the inability to ventilate.116Asthma exacerbations are a combination of bronchoconstriction, airway inflammation, and mucous plugging. This leads to severe air trapping, hyperinflation, and hemodynamic compromise. While wheezing is common in an asthma exacerbation, it does not correlate with the degree of airway obstruction. In contrast, as the airflow decreases with worsening disease, wheezing can disappear. In addition, several other disease states cause wheezing, including pulmonary edema, pneumonia, anaphylaxis, foreign bodies, and tumors.115
Patients with life-threatening asthma need to be treated aggressively with bronchodilators and corticosteroids. Adjunctive therapies include anticholinergics, magnesium sulfate, ketamine, helium/oxygen mixtures, or even inhaled anesthetics.117–121 Noninvasive ventilation can be attempted if the patient is deteriorating and still awake for short-term support, and may prevent the need for mechanical ventilation.122 The decision to intubate an asthmatic is a clinical judgment; the clinician needs to remain keenly aware that the endotracheal tube will not solve the airway problem, and that ongoing aggressive asthma management needs to continue after intubation. Mechanical ventilation in the asthmatic can be very difficult, and the intubation and positive pressure can trigger further bronchoconstriction or hemodynamic compromise.
The provision of BLS in asthma is unchanged. Similarly, standard ACLS measures should be followed.115 However, since the effect of auto-positive end-expiratory pressure (PEEP), known as breath stacking, in an asthmatic with cardiac arrest is likely to be severe, a strategy of low respiratory rate and volume ventilation may be appropriate.115 Similarly, for cardiac arrest in asthma, especially when ventilation is difficult, tension pneumothorax should be strongly considered (Class I recommendation; Level of Evidence C).115
Anaphylaxis
Anaphylaxis is a severe allergic reaction involving most organs, and can lead to airway obstruction and cardiovascular collapse.115 It still accounts for between 500 and 1,000 deaths annually in the United States.123 The initial signs can be nonspecific, but with a severe reaction a “sense of impending doom” is common.115 Rhinitis often leads to laryngeal edema with stridor in the upper airway, and bronchoconstriction often mimics an acute asthma attack as described above.
Cardiovascular collapse is common in severe reactions due to vasodilation and increased capillary permeability. This can rapidly lead to myocardial hypoperfusion and ischemia and to full cardiac arrest. There are no randomized trials of algorithms for arrest due to anaphylaxis.115 Because of this lack of evidence, standard BLS and advanced life support should be provided.
Early advanced airway management is recommended due to the potential for rapid edema development. Epinephrine has been the mainstay of treatment for years, and continues to be listed first in the latest guidelines.115 The recommended dose is 0.2 to 0.5 mg and should be administered via intramuscular injection to all patients with signs of systemic allergic reaction (Class I recommendation; Level of Evidence C).115 This can be repeated every 5 to 15 minutes in the absence of clinical improvement. Vasopressin has been used successfully in patients who did not respond to standard therapy.124 Fluid resuscitation is usually required for restoration of circulation and has been evaluated in one study where hypotension did not respond immediately to vasoactive drugs.125 There are no prospective trials evaluating other agents in anaphylactic shock or arrest. Antihistamines, inhaled β-agonists, and IV corticosteroids have been used successfully in anaphylaxis and may be considered in cardiac arrest due to anaphylaxis.115
Pregnancy
Pregnancy is a unique situation in that survival of both the fetus and the mother depends on CPR. Despite the fact that pregnant patients are younger than the traditional cardiac arrest patient, the incidence of cardiac arrest in pregnancy seems to be on the rise, from 1 in 30,000 to 1 in 20,000.115 In addition, the mortality rate of cardiac arrest with pregnancy seems to be higher, with one series reporting a survival rate of just 6.9%.115,126
The best hope for survival of the fetus is maternal survival. Because of the gravid uterus, resuscitation needs to be modified. Since the vena cava and aorta can be obstructed by a uterus of approximately 20 weeks gestation or later, it is appropriate to position the patient approximately 15° to 30° back from the left lateral decubitus position, or to pull the uterus to the side.127 The optimal angle has been cited to be 27°, and has led to the development of the “Cardiff resuscitation wedge,” which has been specifically designed for performing CPR on pregnant patients.128 However, there are studies that suggest that manual left uterine displacement (with the patient supine) is as good as or better than lateral positioning.129 Thus, the current guidelines suggest that manual left uterine displacement in the supine position be attempted to optimize CPR quality, and if this is unsuccessful, transitioning to a left lateral tilt position be attempted.115
Airway control is important in the pregnant patient. The airway may be smaller because of the hormonal changes and edema that accompany pregnancy.128 Similarly, because of increased intraabdominal pressure exerted by the uterus, as well as hormonal changes that change the resting state of the gastroesophageal sphincter, clinicians need to be acutely aware of the increased risk of aspiration. Because of this, cricoid pressure needs to be maintained continuously during airway manipulation. The rescuer may need to give smaller tidal volumes than normal because of the diaphragm elevation that accompanies the later stages of pregnancy. Because of the increased ventilatory needs in pregnancy as well as the anatomic changes, some authors have suggested that it is important to perform early intubation during cardiac arrest in pregnancy and cite this rapid intubation as a difference from nonpregnant patients.128 Similarly, circulatory support also has to be adjusted. In particular, chest compressions need to be administered slightly above the center of the sternum to adjust for the anatomic changes of the pregnant uterus.115
In an arrest situation during pregnancy the ACLS provider needs to follow the standard guidelines, including the same use of defibrillation and medications. While it is true that vasoactive agents, such as epinephrine, can diminish uterine blood flow, safer alternatives do not exist.115 Available literature, though scant, suggests that the energy requirements for defibrillation do not change in pregnancy.130
While etiologies of arrest in pregnancy are often the same as in the nonpregnant patient, there are several unique situations that need to be considered in the differential diagnosis of a pregnancy arrest. These include excess magnesium sulfate administration (i.e., iatrogenic from treating eclampsia) in which case the therapeutic administration of calcium gluconate can be lifesaving; amniotic embolism, which is associated with complete cardiovascular collapse during labor and delivery (cardiopulmonary bypass has been reportedly successful in salvaging this condition); preeclampsia/eclampsia developing after the 20th week of gestation producing hypertension and multiple organ dysfunction; as well as vascular events including acute coronary syndromes and acute PE.128,131,132
It is paramount to remember that unless circulation is restored to the mother, both the mother and the fetus will succumb, especially if standard therapy is not used correctly and promptly. Because of this, the resuscitation leader should consider the need for emergent hysterotomy (i.e., Cesarean delivery) and delivery as soon as the arrest happens or if there is not immediate response after lateral uterine displacement and CPR. The best survival reported for infants >24 weeks gestation happens when delivery occurs no more than 5 minutes after the arrest of the mother.115
Hypothermia
Unintentional hypothermia (as opposed to the therapeutic hypothermia used postarrest, described above) is defined by a body temperature <30°C (86°F), and is associated with marked derangements in body function. Because it can depress virtually every body system, including pulse and respiration, the patient may appear to be dead on the initial evaluation. Hypothermia may lead to benefit on brain recovery after cardiac arrest (discussed earlier); thus, aggressive intervention is clearly indicated when there is a hypothermic arrest victim.
If the patient still has a perfusing rhythm, therapy is mainly based on rewarming techniques. For mild hypothermia (i.e., >34°C [>93.2°F]), passive rewarming is recommended. For moderate hypothermia (i.e., 30°C to 34°C [86°F to 93.2°F]), active external rewarming is recommended, and for severe hypothermia (i.e., <30°C [<86°F]), active internal rewarming is recommended. These patients need to be manipulated very gently as VF is sometimes precipitated by movement.133
If the patient is in cardiac arrest, then the standard BLS algorithm should be followed. However, there are some modifications that the rescuer needs to consider. The rescuer should evaluate for pulse for a longer time frame, since the heart rate may be slow or very difficult to palpate. If there is no pulse, then chest compressions and rescue breaths should ensue. If the patient is in VF or PVT, then electrical therapy should be given in a standard manner. However, the hypothermic heart may be less responsive to medications or defibrillation, and thus there have been worries about the optimal temperature at which to start defibrillation attempts.115 There are no published consensus guidelines regarding this, but animal data support medications during CPR in cardiac arrest associated with hypothermia.134 Immediately after defibrillation, CPR should resume as in the standard manner. During CPR, continued attempts at rewarming are of paramount importance. Included in this concept is preventing further heat loss (i.e., removal of wet clothing, protection from the environment, etc.). Patients often require significant volume challenges during the rewarming process. The use of steroids, antibiotics, and barbiturates has been proposed, but none of these agents have ever been shown to increase survival rates.115
It is debatable when to stop resuscitative efforts in the hypothermic patient. Many authors have proposed that a patient should not be pronounced dead until the core temperature has been restored to near normal.115 Once the patient is in the hospital, it is still the judgment of the treating physician when efforts should be terminated.
Trauma
Cardiac resuscitation of the trauma arrest patient is basically performed with the same guidelines as with any other arrest. There are some specific etiologies to rapidly consider, however, since the survival of an out-of-hospital cardiac arrest due to trauma is rare.115 The rescuer needs to consider airway obstruction, pneumothorax, tracheobronchial injury, cardiac or large arterial injury, cardiac tamponade, severe head injury with secondary cardiac collapse, and other injuries specific to the particular trauma.115 The best survival seems to be in young patients with treatable penetrating injuries.
Trauma patients often suffer head or cervical injuries; thus, cervical spine precautions should be used in these patients. A jaw thrust maneuver is the preferred way to open the airway, with in-line stabilization during attempts at advanced airway placement.115 The rescuer must be vigilant for the development of tension pneumothorax during ventilation. Inadequate ventilation of one side is usually due to tube malposition, tension pneumothorax, or hemothorax. These conditions are usually treated by medical personnel at the hospital after transport.
Chest compressions should be performed in a standard manner. Any visible hemorrhage should be controlled with direct pressure. Fluid resuscitation is done with a goal of adequate blood pressure and organ perfusion. The specific details of fluid resuscitation are highly controversial, however, and the optimal volume infusion for trauma resuscitation is a subject of ongoing debate.
Open thoracotomy for trauma-induced arrest has been performed in many instances. For penetrating chest trauma patients who arrest immediately before arrival or in the emergency department, open thoracotomy can allow relief of tamponade, control of major vessel hemorrhage, or direct repair of cardiac insult.115 Furthermore, some have suggested that a physician-led, out-of-hospital thoracotomy for penetrating trauma may have a higher chance of survival.135 In the case of blunt trauma, however, open thoracotomy has not been shown to definitively improve outcome.
A unique phenomenon of cardiac arrest (usually VF) caused by a blow to the anterior chest or sternum during the repolarization part of the cardiac cycle is called “commotio cordis.” 136 These events are commonly seen in young athletes, and can be caused by a myriad of mechanisms, from falling directly on the sternum to the strike of a baseball or hockey puck. Prompt recognition is of paramount importance, as rapid defibrillation is often lifesaving. Provision of BLS, the use of an automatic external defibrillator, and standard ACLS are appropriate for this type of arrest.
For definitive postarrest care, trauma patients should be rapidly transferred to a facility with expertise in the provision of trauma care, and practitioners should consult guidelines for terminating efforts of cardiac arrest published by the National Association of EMS Physicians and the American College of Surgeons Committee on Trauma.115,137
Drowning
Drowning is a process resulting in primary respiratory impairment from immersion in a liquid. It is a common, preventable cause of morbidity and mortality. The most important inciting event is the hypoxia induced by submersion. Thus, early care of the drowning patient includes immediate rescue breathing, even before he or she is removed from the water. Prompt initiation of this therapy increases chance of survival.138 Once the victim is removed from the water, immediate chest compressions should be started if he or she is pulseless. Drowning victims can present with any of the pulseless rhythms; standard guidelines need to be followed for therapy of these rhythms.
Electrocution/Lightning
There are many etiologies of electrical shock injuries, from lightning strike (mortality estimated to be 30%, with 70% of survivors sustaining significant morbidity) to high-tension current, to household current.115 The severity of injury depends on the site, type of current, duration of contact, pathway, and the magnitude of delivered electricity.
Cardiac arrest is common in electrical injury due to current passing through the heart during the “vulnerable period” of the cardiac cycle. In large-current events, such as lightning strike, the heart undergoes massive depolarization simultaneously.139 Sometimes the intrinsic pacemaker can restore an organized cardiac electrical cycle, but because of injury to other muscles, specifically the thoracic musculature, the patient cannot retain or sustain viable circulation due to the lack of ventilation and oxygenation.140
When approaching a victim of electrocution, the rescuer must first be certain of his or her own safety. Thereafter, standard BLS, prompt CPR, and ACLS when available are indicated. Electric shock is often associated with multiple trauma, including spinal injury, multiple injuries to the skeletal muscles, as well as fractures. These factors need to be evaluated by the resuscitation team.
Airway control may be difficult due to the edema that often accompanies such injuries; thus, an advanced airway early in the treatment process is recommended.115 With soft-tissue swelling, there is often a need for aggressive fluid resuscitation in these patients. The underlying tissue, or visceral organ damage, is often worse than the external appearance. It is usually recommended that these patients be transferred to centers with expertise in dealing with these types of injuries.
Drug Administration
The routes of administration that are available for drug delivery during CPR include IV (both central and peripheral access), IO, and endotracheal. The chosen route represents a compromise between the availability of access and their apparent efficacy in introducing the drug into the central circulation. When selecting a route for drug administration, it is of utmost importance to minimize any interruptions in chest compressions during CPR.
Central venous access will result in a faster and higher peak drug concentration than peripheral access, but central line access is not needed in most resuscitation attempts. If a central line is already present, however, it should be the access site of choice. An appropriately trained provider may consider placing a central line if one is not present, but CPR should not be interrupted. Central lines located above the diaphragm are preferable to those located below the diaphragm because of poor blood flow during CPR.141 If IV access (either central or peripheral) has not been established, a large peripheral venous catheter should be inserted. It has been suggested that only one attempt at peripheral IV insertion be allowed.142 If this is not successful, an IO device should be inserted. Peripheral drug administration yields a peak concentration in the major systemic arteries in roughly 1.5 to 3 minutes, but circulation time can be shortened by up to 40% if the drug is followed by a 20-mL fluid bolus with elevation of the extremity.141
IO administration is the preferred alternative route for administration if IV access cannot be achieved.26 Several studies have documented the effectiveness and safety of this administration route in both adults and children.143Pharmacokinetic data have demonstrated similar areas under the curve and times to peak concentration for sternal IO and central IV administration.144 There appears to be variability, though, based on the anatomic site for insertion as IO administration via the tibia delivered only 65% of the dose compared with that via the sternum. Potential anatomic sites for insertion for an IO needle are the distal tibia, the proximal tibia, the distal femur, the sternum, and the humerus.143,144 There are several IO access devices that are commercially available allowing for rapid insertion and are easy to use. In fact, clinical trials have documented success rates of approximately 80% with placement times of roughly 1 to 2 minutes.143 The high success rates for achieving vascular access (on first attempt) allow for more rapid drug administration (vs. IV therapy) and could offset the pharmacokinetic differences observed with this approach. Future pharmacokinetic studies are needed to identify the most optimal anatomic site for IO placement and if current dosing recommendations are appropriate.
In the event that neither IV nor IO access can be established, a few drugs can be administered through an endotracheal tube. These drugs are atropine, lidocaine, epinephrine, naloxone, and vasopressin.26There are no data with amiodarone. Medications administered through the endotracheal route, however, will have both a lower and a delayed peak concentration than when they are administered by the IV or IO routes. In fact, animal studies have suggested that the lower epinephrine concentrations achieved with endotracheal administration may lead to vasodilation through β-receptor activity. Clinical trials in humans have also failed to demonstrate any benefit with using the endotracheal route.145,146 In one clinical trial, a lower rate of ROSC (15% vs. 27%, P ≤0.01), hospital admission (9% vs. 20%, P ≤0.02), and hospital discharge (0% vs. 5%, P ≤0.02) was observed with endotracheal drug administration compared with that with IV.146 If the endotracheal route is to be used, the recommended medication dose is 2 to 2.5 times larger than the IV/IO dose. Providers should dilute the medication in 5 to 10 mL of either sterile water or normal saline, but better drug absorption may be achieved with sterile water.26
Personalized Pharmacotherapy
Several investigators have evaluated factors associated with good neurologic outcome following a cardiac arrest in an attempt to better predict prognosis, optimize resources, and decrease the percentage of patients who are left neurologically devastated. Many factors have been identified that are related to survival to hospital discharge. These include age, the occurrence of a witnessed arrest, rapid implementation of bystander CPR, presence of VF/PVT as the initial rhythm, early defibrillation therapy, achievement of ROSC in the field, and time to ROSC.3,147–149 In fact, one group developed a statistical prediction model whereby the probability for a good neurologic outcome was = exp(B)/1 + exp(B), where B = –0.02 (age in years) – 0.109 (time to ROSC in minutes) + 0.677 (ROSC prior to hospital arrival; 1 if yes, 0 if no) + 2.442 in patients with VF.147 For patients with PEA/asystole, B = –0.037 (age in years) – 0.076 (time to ROSC in minutes) + 1.735 (ROSC prior to hospital arrival; 1 if yes, 0 if no) + 1.462 (conversion to VF; 1 if yes, 0 if no) + 1.101. Areas under the receiver-operating characteristic curve were 0.867 for VF and 0.873 for PEA/asystole, indicating a high predictive ability.
Other studies have evaluated prognostic indicators to identify scenarios whereby little or no chance of survival may be evident and prehospital termination of resuscitation would be appropriate.150–152 From these data, two rules have been developed. The first rule, referred to as the BLS rule, has three criteria: (a) the event was not witnessed by EMS personnel, (b) no AED was used or manual shock applied, and (c) ROSC was not achieved in the out-of-hospital setting. The second rule, referred to as the advanced life support rule, consists of the BLS criteria plus (a) the arrest was not witnessed by a bystander and (b) no bystander CPR was administered. In one validation study of 5,505 patients, these rules accurately identified patients who were unlikely to benefit from rapid transport to a hospital with a positive predictive value of 0.998 (BLS rule) and 1 (ALS rule) when all criteria were met, respectively.153
Most patients who achieve ROSC and hospital admission ultimately do not survive to discharge; therefore, factors encountered in the ICU setting have tremendous impact on the clinical outcome obtained. In fact, postcardiac arrest care has now been added as the fifth link in the “chain of survival.” 27 In one study, the significance of hypotension following ROSC was evaluated.154 Overall, the incidence of post-ROSC hypotension was 47% with higher mortality (65% vs. 37%, P <0.001) and a decline in functional status (49% vs. 38%, P <0.001) being noted among survivors. On multivariate analysis and adjustment for confounding variables, post-ROSC hypotension had an OR (95% CI) for mortality of 2.69 (2.45 to 2.96, P <0.001). This represents an important area for bedside evaluation and potential target for therapy in the postresuscitation phase of cardiac arrest.
Prediction models have also been investigated for in-hospital cardiac arrest. One large analysis used data from more than 42,000 patients admitted over a 10-year period to develop a score card with 11 variables that were identified in a multivariate analysis155 (Table 2-4). This model was highly successful in predicting survival with favorable neurologic outcome ranging from 70% in the top decile to 2.8% in the bottom decile. While this scoring system was not designed to identify scenarios where resuscitation may be futile, it can provide useful prognostic information for the medical team, patients, and families.
TABLE 2-4 Cardiac Arrest Survival Postresuscitation In-Hospital (CASPRI) Score Card
EVALUATION OF THERAPEUTIC OUTCOMES
To measure the success of resuscitation outcomes, therapeutic outcome monitoring should occur both during the resuscitation attempt and in the postresuscitation phase. The optimal outcome following CPR is an awake, responsive, spontaneously breathing patient. Patients must remain neurologically intact with minimal morbidity following the resuscitation if it is to be truly classified as a success.
Unfortunately, there are no reliable surrogate markers that can be used at the bedside to gauge the efficacy of CPR and a positive outcome. Nonetheless, heart rate, cardiac rhythm, and blood pressure should be assessed and documented throughout the resuscitation attempt and subsequent to each intervention. Determination of the presence or absence of a pulse is paramount to deciding which interventions may be appropriate. However, clinicians must be cautious to not exceed 10 seconds when checking for a pulse. Palpating a pulse to determine the efficacy of blood flow during CPR has not been shown to be useful.
CPP (= aortic diastolic pressure – right atrial diastolic pressure) and SCVO2 correlate with cardiac output and myocardial blood flow and can provide information on the patient’s response to therapy. Moreover, thresholds have been identified that are associated with poor achievement of ROSC (<15 mm Hg for CPP, <30% [0.30] for SCVO2).26 Because CPPs are not routinely available during CPR, arterial diastolic pressure can be used as a reasonable surrogate. Arterial diastolic pressure values less than 20 mm Hg are generally considered suboptimal.26 ETCO2 monitoring is another useful method to assess cardiac output during CPR and has been associated with ROSC. The main determinant for carbon dioxide excretion is the rate of delivery from the peripheral sites (where it is produced) to the lungs. Increasing cardiac output (through effective CPR) will yield higher ETCO2 levels as delivery of carbon dioxide to the lungs increases. Persistently low ETCO2 values (<10 mm Hg [<1.3 kPa]) during CPR in intubated patients suggest ROSC is unlikely.26
ABBREVIATIONS
Interpretation
REFERENCES
1. Sandroni C, Nolan J, Cavallaro F, Antonelli M. In-hospital cardiac arrest: Incidence, prognosis and possible measures to improve survival. Intensive Care Med 2007;33:237–245.
2. Travers AH, Rea TD, Bobrow BJ, et al. Part 4: CPR overview: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S676–S684.
3. 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.
4. 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;38:101–108.
5. Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: Clinical and research implications. Prog Cardiovasc Dis 2008;51:213–228.
6. Weil MH, Tang W. Rhythms and outcomes of cardiac arrest. Crit Care Med 2010;38:310.
7. Nichol G, Thomas E, Callaway CW, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008;300:1423–1431.
8. Weil MH, Fries M. In-hospital cardiac arrest. Crit Care Med 2005;33:2825–2830.
9. Atkins DL, Everson-Stewart S, Sears GK, et al. Epidemiology and outcomes from out-of-hospital cardiac arrest in children: The Resuscitation Outcomes Consortium Epistry-Cardiac Arrest. Circulation 2009;119:1484–1491.
10. Berg MD, Schexnayder SM, Chameides L, et al. Part 13: Pediatric basic life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122: S862–S875.
11. Myerburg RJ, Castellanos A. Emerging paradigms of the epidemiology and demographics of sudden cardiac arrest. Heart Rhythm 2006;3:235–239.
12. Kleinman ME, Chameides L, Schexnayder SM, et al. Part 14: Pediatric advanced life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S876–S908.
13. Ewy GA, Kern KB. Recent advances in cardiopulmonary resuscitation: Cardiocerebral resuscitation. J Am Coll Cardiol 2009;53:149–157.
14. Cooper JA, Cooper JD, Cooper JM. Cardiopulmonary resuscitation: History, current practice, and future direction. Circulation 2006;114:2839–2849.
15. Christenson J, Andrusiek D, Everson-Stewart S, et al. Chest compression fraction determines survival in patients with out-of-hospital ventricular fibrillation. Circulation 2009;120:1241–1247.
16. Soar J, Edelson DP, Perkins GD. Delivering high-quality cardiopulmonary resuscitation in-hospital. Curr Opin Crit Care 2011;17:225–230.
17. Cave DM, Gazmuri RJ, Otto CW, et al. Part 7: CPR techniques and devices: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S720–S728.
18. Morrison LJ, Kierzek G, Diekema DS, et al. Part 3: Ethics: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S665–S675.
19. Young GB. Clinical practice. Neurologic prognosis after cardiac arrest. N Engl J Med 2009;361:605–611.
20. Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage. JAMA 1960;173:1064–1067.
21. Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc 1964;54:629–635.
22. Cardiopulmonary resuscitation. JAMA 1966;198:372–379.
23. Rea TD, Helbock M, Perry S, et al. Increasing use of cardiopulmonary resuscitation during out-of-hospital ventricular fibrillation arrest: Survival implications of guideline changes. Circulation 2006;114:2760–2765.
24. Larsen MP, Eisenberg MS, Cummins RO, Hallstrom AP. Predicting survival from out-of-hospital cardiac arrest: A graphic model. Ann Emerg Med 1993;22:1652–1658.
25. Link MS, Atkins DL, Passman RS, et al. Part 6: Electrical therapies: Automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S706–S719.
26. Neumar RW, Otto CW, Link MS, et al. Part 8: Adult advanced cardiovascular life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122: S729–S767.
27. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: Post-cardiac arrest care: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122: S768–S786.
28. Berg RA, Hemphill R, Abella BS, et al. Part 5: Adult basic life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S685–S705.
29. Eberle B, Dick WF, Schneider T, Wisser G, Doetsch S, Tzanova I. Checking the carotid pulse check: Diagnostic accuracy of first responders in patients with and without a pulse. Resuscitation 1996;33:107–116.
30. Swor R, Khan I, Domeier R, Honeycutt L, Chu K, Compton S. CPR training and CPR performance: Do CPR-trained bystanders perform CPR? Acad Emerg Med 2006;13: 596–601.
31. Ewy GA. A clarion call for change. Curr Opin Crit Care 2009;15:181–184.
32. Assar D, Chamberlain D, Colquhoun M, et al. Randomised controlled trials of staged teaching for basic life support. 1. Skill acquisition at bronze stage. Resuscitation 2000;45: 7–15.
33. Ewy GA. Cardiocerebral resuscitation: The new cardiopulmonary resuscitation. Circulation 2005;111: 2134–2142.
34. Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: A 3-phase time-sensitive model. JAMA 2002;288: 3035–3038.
35. Mosier J, Itty A, Sanders A, et al. Cardiocerebral resuscitation is associated with improved survival and neurologic outcome from out-of-hospital cardiac arrest in elders. Acad Emerg Med 2010;17:269–275.
36. De Maio VJ, Stiell IG, Wells GA, Spaite DW. Optimal defibrillation response intervals for maximum out-of-hospital cardiac arrest survival rates. Ann Emerg Med 2003;42:242–250.
37. Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA 1999;281:1182–1188.
38. Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: A randomized trial. JAMA 2003;289:1389–1395.
39. Kellum MJ, Kennedy KW, Ewy GA. Cardiocerebral resuscitation improves survival of patients with out-of-hospital cardiac arrest. Am J Med 2006;119:335–340.
40. Garza AG, Gratton MC, Salomone JA, Lindholm D, McElroy J, Archer R. Improved patient survival using a modified resuscitation protocol for out-of-hospital cardiac arrest. Circulation 2009;119:2597–2605.
41. Koike S, Tanabe S, Ogawa T, et al. Immediate defibrillation or defibrillation after cardiopulmonary resuscitation. Prehosp Emerg Care 2011;15:393–400.
42. Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 2000;343:1206–1209.
43. Forcina MS, Farhat AY, O’Neil WW, Haines DE. Cardiac arrest survival after implementation of automated external defibrillator technology in the in-hospital setting. Crit Care Med 2009;37:1229–1236.
44. Tuseth V, Salem M, Pettersen R, et al. Percutaneous left ventricular assist in ischemic cardiac arrest. Crit Care Med 2009;37:1365–1372.
45. Sunde K. Experimental and clinical use of ongoing mechanical cardiopulmonary resuscitation during angiography and percutaneous coronary intervention. Crit Care Med 2008;36:S405–S408.
46. Varon J, Acosta P. Extracorporeal membrane oxygenation in cardiopulmonary resuscitation: Are we there yet? Crit Care Med 2008;36:2685–2686.
47. Chamberlain D, Frenneaux M, Fletcher D. The primacy of basics in advanced life support. Curr Opin Crit Care 2009;15:198–202.
48. Robinson LA, Brown CG, Jenkins J, et al. The effect of norepinephrine versus epinephrine on myocardial hemodynamics during CPR. Ann Emerg Med 1989; 18: 336–340.
49. Paradis NA, Martin GB, Rivers EP, et al. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106–1113.
50. Reynolds JC, Salcido DD, Menegazzi JJ. Conceptual models of coronary perfusion pressure and their relationship to defibrillation success in a porcine model of prolonged out-of-hospital cardiac arrest. Resuscitation 2012;83:900–906.
51. Attaran RR, Ewy GA. Epinephrine in resuscitation: Curse or cure? Future Cardiol 2010;6:473–482.
52. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest: A randomized trial. JAMA 2009;302:2222–2229.
53. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation 2011;82:1138–1143.
54. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012;307:1161–1168.
55. Sutton RM, Berg RA, Helfaer MA. Epinephrine for resuscitation from cardiac arrest: A double-edged sword? Crit Care Med 2009;37:1518–1520.
56. Ristagno G, Tang W, Huang L, et al. Epinephrine reduces cerebral perfusion during cardiopulmonary resuscitation. Crit Care Med 2009;37:1408–1415.
57. Rivers EP, Wortsman J, Rady MY, Blake HC, McGeorge FT, Buderer NM. The effect of the total cumulative epinephrine dose administered during human CPR on hemodynamic, oxygen transport, and utilization variables in the postresuscitation period. Chest 1994;106:1499–1507.
58. Huang L, Sun S, Fang X, Tang W, Weil MH. Simultaneous blockade of alpha1- and beta-actions of epinephrine during cardiopulmonary resuscitation. Crit Care Med 2006;34:S483–S485.
59. Larabee TM, Liu KY, Campbell JA, Little CM. Vasopressors in cardiac arrest: A systematic review. Resuscitation 2012;83:932–939.
60. Ornato JP. Use of adrenergic agonists during CPR in adults. Ann Emerg Med 1993;22:411–416.
61. Brown C, Wiklund L, Bar-Joseph G, et al. Future directions for resuscitation research. IV. Innovative advanced life support pharmacology. Resuscitation 1996;33:163–177.
62. Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA 1992;268:2667–2672.
63. Lindner KH, Ahnefeld FW, Grunert A. Epinephrine versus norepinephrine in prehospital ventricular fibrillation. Am J Cardiol 1991;67:427–428.
64. Redding JS, Pearson JW. Evaluation of drugs for cardiac resuscitation. Anesthesiology 1963;24:203–207.
65. Wenzel V, Raab H, Dunser MW. Role of arginine vasopressin in the setting of cardiopulmonary resuscitation. Best Pract Res Clin Anaesthesiol 2008;22:287–297.
66. Lindner KH, Haak T, Keller A, Bothner U, Lurie KG. Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart 1996;75: 145–150.
67. Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 1997;349:535–537.
68. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: A randomised controlled trial. Lancet 2001;358:105–109.
69. Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350:105–113.
70. Callaway CW, Hostler D, Doshi AA, et al. Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. Am J Cardiol 2006;98: 1316–1321.
71. Gueugniaud PY, David JS, Chanzy E, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med 2008;359:21–30.
72. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009;169:15–24.
73. Mukoyama T, Kinoshita K, Nagao K, Tanjoh K. Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. Resuscitation 2009;80:755–761.
74. Ong ME, Tiah L, Leong BS, et al. A randomised, double-blind, multi-centre trial comparing vasopressin and adrenaline in patients with cardiac arrest presenting to or in the emergency department. Resuscitation 2012;83:953–960 [Epub ahead of print].
75. Mentzelopoulos SD, Zakynthinos SG, Siempos I, Malachias S, Ulmer H, Wenzel V. Vasopressin for cardiac arrest: Meta-analysis of randomized controlled trials. Resuscitation 2012;83:32–39.
76. Ong ME, Pellis T, Link MS. The use of antiarrhythmic drugs for adult cardiac arrest: A systematic review. Resuscitation 2011;82:665–670.
77. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999;341:871–878.
78. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med 2002;346:884–890.
79. Rea RS, Kane-Gill SL, Rudis MI, et al. Comparing intravenous amiodarone or lidocaine, or both, outcomes for inpatients with pulseless ventricular arrhythmias. Crit Care Med 2006;34:1617–1623.
80. Harrison EE. Lidocaine in prehospital countershock refractory ventricular fibrillation. Ann Emerg Med 1981;10:420–423.
81. Weaver WD, Fahrenbruch CE, Johnson DD, Hallstrom AP, Cobb LA, Copass MK. Effect of epinephrine and lidocaine therapy on outcome after cardiac arrest due to ventricular fibrillation. Circulation 1990;82:2027–2034.
82. Herlitz J, Ekstrom L, Wennerblom B, et al. Lidocaine in out-of-hospital ventricular fibrillation. Does it improve survival? Resuscitation 1997;33:199–205.
83. Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med 2002;346:1522–1528.
84. Bottiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med 2008;359:2651–2662.
85. Nadkarni VM, Larkin GL, Peberdy MA, et al. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA 2006;295:50–57.
86. Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: A clinical feasibility study. Resuscitation 2001;51:275–281.
87. Gonzalez ER. Pharmacologic controversies in CPR. Ann Emerg Med 1993;22:317–323.
88. Bohm K, Rosenqvist M, Herlitz J, Hollenberg J, Svensson L. Survival is similar after standard treatment and chest compression only in out-of-hospital bystander cardiopulmonary resuscitation. Circulation 2007;116: 2908–2912.
89. Levy MM. An evidence-based evaluation of the use of sodium bicarbonate during cardiopulmonary resuscitation. Crit Care Clin 1998;14:457–483.
90. Bjerneroth G. Tribonat—A comprehensive summary of its properties. Crit Care Med 1999;27:1009–1013.
91. Vukmir RB, Katz L, Sodium Bicarbonate Study Group. Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest. Am J Emerg Med 2006;24:156–1 61.
92. Neumar RW, Nolan JP, Adrie C, et al. 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;118:2452–2483.
93. Safar P. Resuscitation from clinical death: Pathophysiologic limits and therapeutic potentials. Crit Care Med 1988;16:923–941.
94. Anyfantakis ZA, Baron G, Aubry P, et al. Acute coronary angiographic findings in survivors of out-of-hospital cardiac arrest. Am Heart J 2009;157:312–318.
95. Nolan JP, Morley PT, Vanden Hoek TL, et al. Therapeutic hypothermia after cardiac arrest: An advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation 2003;108:118–121.
96. Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 1996;27:105–113.
97. Tsai M, Barbut D, Wang H, et al. Intra-arrest rapid head cooling improves postresuscitation myocardial function in comparison with delayed postresuscitation surface cooling. Crit Care Med 2008;36:S434–S439.
98. Guan J, Barbut D, Wang H, et al. A comparison between head cooling begun during cardiopulmonary resuscitation and surface cooling after resuscitation in a pig model of cardiac arrest. Crit Care Med 2008;36:S428–S433.
99. Dine CJ, Abella BS. Therapeutic hypothermia for neuroprotection. Emerg Med Clin North Am 2009;27: 137–149.
100. O’Sullivan ST, O’Shaughnessy M, O’Connor TP. Baron Larrey and cold injury during the campaigns of Napoleon. Ann Plast Surg 1995;34:446–449.
101. Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–556.
102. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563.
103. Sunde K, Pytte M, Jacobsen D, et al. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007;73:29–39.
104. Sagalyn E, Band RA, Gaieski DF, Abella BS. Therapeutic hypothermia after cardiac arrest in clinical practice: Review and compilation of recent experiences. Crit Care Med 2009;37:S223–S226.
105. Sunde K, Steen PA. Studies in hypothermia-treated cardiac arrest patients are needed to establish the accuracy of proposed outcome predictors. Crit Care Med 2009;37: 2485–2486.
106. Oddo M, Ribordy V, Feihl F, et al. Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: A prospective study. Crit Care Med 2008;36:2296–2301.
107. Hovdenes J, Laake JH, Aaberge L, Haugaa H, Bugge JF. Therapeutic hypothermia after out-of-hospital cardiac arrest: Experiences with patients treated with percutaneous coronary intervention and cardiogenic shock. Acta Anaesthesiol Scand 2007;51:137–142.
108. Janata A, Weihs W, Bayegan K, et al. Therapeutic hypothermia with a novel surface cooling device improves neurologic outcome after prolonged cardiac arrest in swine. Crit Care Med 2008;36:895–902.
109. Kim F, Olsufka M, Carlbom D, et al. Pilot study of rapid infusion of 2 L of 4 degrees C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest. Circulation 2005;112:715–719.
110. Drabek T, Kochanek PM. In quest of the optimal cooling device: Isn’t faster “too fast” ? Crit Care Med 2008;36: 1018–1020.
111. Levine RL. Cardiocerebral resuscitation: Few answers, more questions. Crit Care Med 2009;37:747–748.
112. Gaieski DF, Abella BS, Goyal M. CPR and postarrest care: Overview, documentation, and databases. Chest 2012;141: 1082–1089.
113. Bunch TJ, White RD, Gersh BJ, et al. Long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation. N Engl J Med 2003;348:2626–2633.
114. Arpino PA, Greer DM. Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. Pharmacotherapy 2008;28:102–111.
115. Vanden Hoek TL, Morrison LJ, Shuster M, et al. Part 12: Cardiac arrest in special situations: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122: S829–S861.
116. McFadden ER Jr, Warren EL. Observations on asthma mortality. Ann Intern Med 1997;127:142–147.
117. Hess DR, Acosta FL, Ritz RH, Kacmarek RM, Camargo CA Jr. The effect of heliox on nebulizer function using a beta-agonist bronchodilator. Chest 1999;115:184–189.
118. Petrillo TM, Fortenberry JD, Linzer JF, Simon HK. Emergency department use of ketamine in pediatric status asthmaticus. J Asthma 2001;38:657–664.
119. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: A systematic review with meta-analysis. Thorax 2005;60: 740–746.
120. Schultz TE. Sevoflurane administration in status asthmaticus: A case report. AANA J 2005;73:35–36.
121. Silverman RA, Osborn H, Runge J, et al. IV magnesium sulfate in the treatment of acute severe asthma: A multicenter randomized controlled trial. Chest 2002;122:489–497.
122. Soroksky A, Stav D, Shpirer I. A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest 2003;123:1018–1025.
123. Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: An investigation into its epidemiology. Arch Intern Med 2001;161:15–21.
124. Schummer C, Wirsing M, Schummer W. The pivotal role of vasopressin in refractory anaphylactic shock. Anesth Analg 2008;107:620–624.
125. Brown SG, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004;21:149–154.
126. Dijkman A, Huisman CM, Smit M, et al. Cardiac arrest in pregnancy: Increasing use of perimortem caesarean section due to emergency skills training? BJOG 2010;117:282–287.
127. Goodwin AP, Pearce AJ. The human wedge. A manoeuvre to relieve aortocaval compression during resuscitation in late pregnancy. Anaesthesia 1992;47:433–434.
128. Atta E, Gardner M. Cardiopulmonary resuscitation in pregnancy. Obstet Gynecol Clin North Am 2007;34:585–597.
129. Kundra P, Khanna S, Habeebullah S, Ravishankar M. Manual displacement of the uterus during Caesarean section. Anaesthesia 2007;62:460–465.
130. Nanson J, Elcock D, Williams M, Deakin CD. Do physiological changes in pregnancy change defibrillation energy requirements? Br J Anaesth 2001;87:237–239.
131. Munro PT. Management of eclampsia in the accident and emergency department. J Accid Emerg Med 2000;17:7–11.
132. Stanten RD, Iverson LI, Daugharty TM, Lovett SM, Terry C, Blumenstock E. Amniotic fluid embolism causing catastrophic pulmonary vasoconstriction: Diagnosis by transesophageal echocardiogram and treatment by cardiopulmonary bypass. Obstet Gynecol 2003;102:496–498.
133. Hanania NA, Zimmerman JL. Accidental hypothermia. Crit Care Clin 1999;15:235–249.
134. Wira CR, Becker JU, Martin G, Donnino MW. Anti-arrhythmic and vasopressor medications for the treatment of ventricular fibrillation in severe hypothermia: A systematic review of the literature. Resuscitation 2008;78:21–29.
135. Lockey D, Crewdson K, Davies G. Traumatic cardiac arrest: Who are the survivors? Ann Emerg Med 2006;48: 240–244.
136. Link MS, Maron BJ, Wang PJ, VanderBrink BA, Zhu W, Estes NA 3rd. Upper and lower limits of vulnerability to sudden arrhythmic death with chest-wall impact (commotio cordis). J Am Coll Cardiol 2003;41:99–104.
137. Hopson LR, Hirsh E, Delgado J, et al. Guidelines for withholding or termination of resuscitation in prehospital traumatic cardiopulmonary arrest. J Am Coll Surg 2003;196:475–481.
138. Kyriacou DN, Arcinue EL, Peek C, Kraus JF. Effect of immediate resuscitation on children with submersion injury. Pediatrics 1994;94:137–142.
139. Browne BJ, Gaasch WR. Electrical injuries and lightning. Emerg Med Clin North Am 1992;10:211–229.
140. Milzman DP, Moskowitz L, Hardel M. Lightning strikes at a mass gathering. South Med J 1999;92:708–710.
141. Vincent R. Drugs in modern resuscitation. Br J Anaesth 1997;79:188–197.
142. Kellum MJ. Improving performance of emergency medical services personnel during resuscitation of cardiac arrest patients: The McMAID approach. Curr Opin Crit Care 2009;15:216–220.
143. Weiser G, Hoffmann Y, Galbraith R, Shavit I. Current advances in intraosseous infusion—A systematic review. Resuscitation 2012;83:20–26.
144. Hoskins SL, do Nascimento P Jr, Lima RM, Espana-Tenorio JM, Kramer GC. Pharmacokinetics of intraosseous and central venous drug delivery during cardiopulmonary resuscitation. Resuscitation 2012;83:107–112.
145. Niemann JT, Stratton SJ. Endotracheal versus intravenous epinephrine and atropine in out-of-hospital “primary” and postcountershock asystole. Crit Care Med 2000;28: 1815–1819.
146. Niemann JT, Stratton SJ, Cruz B, Lewis RJ. Endotracheal drug administration during out-of-hospital resuscitation: Where are the survivors? Resuscitation 2002;53:153–157.
147. Hayakawa K, Tasaki O, Hamasaki T, et al. Prognostic indicators and outcome prediction model for patients with return of spontaneous circulation from cardiopulmonary arrest: The Utstein Osaka Project. Resuscitation 2011;82:874–880.
148. Herlitz J, Engdahl J, Svensson L, Angquist KA, Young M, Holmberg S. Factors associated with an increased chance of survival among patients suffering from an out-of-hospital cardiac arrest in a national perspective in Sweden. Am Heart J 2005;149:61–66.
149. Stiell IG, Wells GA, Field B, et al. Advanced cardiac life support in out-of-hospital cardiac arrest. N Engl J Med 2004;351:647–656.
150. Morrison LJ, Verbeek PR, Vermeulen MJ, et al. Derivation and evaluation of a termination of resuscitation clinical prediction rule for advanced life support providers. Resuscitation 2007;74:266–275.
151. Morrison LJ, Visentin LM, Kiss A, et al. Validation of a rule for termination of resuscitation in out-of-hospital cardiac arrest. N Engl J Med 2006;355:478–487.
152. Verbeek PR, Vermeulen MJ, Ali FH, Messenger DW, Summers J, Morrison LJ. Derivation of a termination-of-resuscitation guideline for emergency medical technicians using automated external defibrillators. Acad Emerg Med 2002;9:671–678.
153. Sasson C, Hegg AJ, Macy M, et al. Prehospital termination of resuscitation in cases of refractory out-of-hospital cardiac arrest. JAMA 2008;300:1432–1438.
154. Trzeciak S, Jones AE, Kilgannon JH, et al. Significance of arterial hypotension after resuscitation from cardiac arrest. Crit Care Med 2009;37:2895–2903 [quiz 904].
155. Chan PS, Spertus JA, Krumholz HM, et al. A validated prediction tool for initial survivors of in-hospital cardiac arrest. Arch Intern Med 2012;172:947–953.