Clinical review: Devices and drugs for cardiopulmonary resuscitation – opportunities and restraints

The science and technology of CPR is only just emerging from its infancy. However, substantial improvements are anticipated, including the ability of lay rescuers to identify cardiac arrest promptly, the availability of additional measurements, and expanded intelligence provided by expanded AEDs with which to more effectively prompt the rescuer through the resuscitation procedure. Most important in our view is the ability to maintain uninterrupted precordial compression. Better timing and better waveforms for defibrillation are emerging. The recognition of the importance of postresuscitation myocardial dysfunction and the selection of better vasopressor agents to minimize the adverse inotropic and chronotropic actions of adrenergic drugs are also likely to improve outcomes of CPR.


Introduction
Successful reversal of cardiac arrest is contingent on prompt identification of the absence of an effective heart beat and interventions that will restore effective ventilation and circulation. Typically, cardiopulmonary resuscitation (CPR) is only successful if it is instituted within 5 min after the heart stops beating. Survival rates for out-of-hospital cardiac arrest are remarkably low [1]. Especially in large cities and in rural communities, survival ranges from less than 2% to 5%, which projects the magnitude of the problem [2,3]. In communities in which there is early response by bystanders who initiate CPR or by minimally trained rescuers, including fire and police personnel, and in which there is early response by an effective professional emergency medical response system such as in Seattle, Washington [4,5] or Rochester, Minnesota [6], survival from out-of-hospital cardiac arrest may be increased as much as 10-fold.

Cardiac arrest detector
Among major changes in the guidelines from the American Heart Association [7], lay rescuers are no longer taught or expected to perform a 'pulse check'. The early diagnosis of cardiac arrest by laypersons is therefore based solely on lack of cerebral responsiveness and failure to detect breathing. Accordingly, resuscitation is initially delayed for confirmation of cardiac arrest. With the introduction of external automated defibrillators (AEDs) [8] there are even longer delays, and especially so when a pulseless rhythm prompts repetitive rhythm analyses by the AED, during which interventions must be suspended [9]. This prompted the development of a cardiac arrest detector that is based on impedance measurements [10]. The cardiac arrest detector prompts the rescuer to intervene more rapidly with chest compression, protection of the airway and ventilation -not just defibrillation. The AED therefore becomes a more comprehensive measuring device because it detects and quantifies both heart beat and breathing, and it provides an estimate of the cardiac output produced by chest compression. It therefore expands measurements to beyond those provided by the ECG, and allows more comprehensive automated decision making and therefore prompting of the rescuer.

Defibrillation
Perhaps among the greatest advances of the past decade has been the introduction of AEDs. These devices 'jump start' the heart by allowing rapid conversion of ventricular tachycardia and ventricular fibrillation when applied by minimally trained laypersons [7]. The results of the recently published Public Access Defibrillation Study in North America [11] provides additional evidence of the benefit of Review Clinical review: Devices and drugs for cardiopulmonary resuscitation -opportunities and restraints early defibrillation by lay rescuers in settings in which there is large public exposure. Unfortunately, the same study suggested little benefit in home settings. In addition, much has been learned with respect to the biology and technology, which will form the basis for improved defibrillation in the future. Repetitive electrical shocks are injurious to the arrested heart [12]. Biphasic waveforms have major advantages over monophasic waveforms and allow lower energy defibrillation, which minimizes myocardial injury and the severity of the newly identified condition 'postresuscitation myocardial dysfunction' [13,14].

Postresuscitation myocardial dysfunction
The global myocardial ischemia of cardiac arrest partially explains the large fall-off in meaningful survival of victims of cardiac arrest. As many as 40% of victims are initially resuscitated, but fewer than an average of 5% leave the hospital alive and neurologically intact. After resuscitation a progressive reduction in cardiac output and in myocardial contractility has been demonstrated, such that the heart produces lesser systemic and coronary blood flows [15][16][17][18]. This form of heart failure is similar to the 'stunning' of the myocardium in settings of acute coronary obstruction [19]. During cardiac arrest there is global myocardial ischemia during the 'no-flow' interval in which the myocardium is not perfused. Like stunning, the function of the heart is progressively impaired over an interval of 4 hours, with gradual recovery over the following days [20]. The severity of postresuscitation myocardial dysfunction is minimized by early resuscitation with restoration of an effective rhythm, cardiac output, and coronary blood flow; by reducing the numbers and the energy levels of shocks delivered by the defibrillator; and by the use of biphasic rather than monophasic waveform shocks [13,14].

Precordial compression
Precordial compression produces between 20% and 25% of the normal cardiac output. Because blood flow is preferentially delivered to the coronary and cerebral circuits, it allows these vulnerable organs to survive. The lesser importance of ventilation in contrast to the essential role of maintaining forward blood flow prompted the revision of the American Heart Association international guidelines in the year 2000 to reduce interruptions for ventilation from 5/1 to 15/2 [7]. The compression to ventilation ratios were therefore reduced in adults.
A major shortcoming of cardiac resuscitation following the introduction of AEDs has been the interruption of precordial compression, during which there is a decline in coronary perfusion and an exacerbation of myocardial injury, together with persistent ectopic ventricular arrhythmias and recurrent cardiac arrest [9,21]. Precordial compression is also interrupted following onset of cardiac arrest for endotracheal intubation. Experimental data suggest that as little as 10 s of interruption to precordial compression compromises outcomes. Efforts to improve the forward flow generated by precordial compression have prompted the use of a series of manual, pneumatic, and electrically powered mechanical devices, including the Thumper ® (Michigan Instruments Inc., Grand Rapids, MI, USA) the CardioPump ® , the Pneumatic Vest ® , and the Revivant ® Compressor (Revivant Corp., Sunnyvale, CA, USA), and re-examination of the potential benefits of open chest internal cardiac massage [22][23][24][25].
These discoveries prompted several new developments at our Institute. The first of these is the resuscitation blanket, which isolates the rescuer from electrical shocks, allowing for continuous chest compression independent of delivery of a shock [26]. Second, repetitive shocks are minimized by identifying and reacting to optimal timing of defibrillation [27] by a technique of amplitude frequency analysis. Finally, we developed a compact chest compressor so that interruption to chest compression can be avoided during transport. Such a device is likely to be essential, not only for transport through stairways, in ambulances, and through the halls of hospitals, but also because of the ability to maintain effective and uninterrupted precordial compression.

Monitoring the effectiveness of precordial compression
End-tidal carbon dioxide has emerged as a very good measure for quantifying the 'cardiac output' produced by chest compression [28,29]. Such a monitor detects operator fatigue during human resuscitation, which occurs as early as 2 min after a rescuer starts chest compression. As an additional benefit, end-tidal carbon dioxide provides almost immediate detection of return of spontaneous circulation, without interrupting chest compression to interpret the ECG or palpate for a potentially pulsatile rhythm.

Limitations and alternatives to epinephrine (adrenaline)
Epinephrine has been the vasopressor of choice because of its α-adrenergic effects, which increase systemic vascular resistance and therefore myocardial and cerebral blood flows, and consequently the success of initial resuscitation. However, epinephrine also has β-adrenergic effects by which it increases myocardial oxygen consumption and the severity of postresuscitation myocardial dysfunction. The β-adrenergic effects of epinephrine also account for increases in ventricular ectopy and the recurrence of ventricular tachycardia and ventricular fibrillation. In addition, epinephrine produces arteriovenous shunting through the lung, and therefore causes a very profound although transient reduction in the arterial oxygen content [30]. Experimentally, when the β-adrenergic effects of epinephrine are blocked by the rapid acting β-adrenergic blocker esmolol, the outcomes of advanced life support are substantially improved [31]. Optimism that vasopressin would minimize the adverse effects of epinephrine was not supported by a recently completed European Multicenter Study [32]. The prolonged vasoconstrictor action of vasopressin, we suspect, adversely effects postresuscitation myocardial dysfunction [18].
More recently, our group's attention has been focused on more selective adrenergic agents for treatment of cardiac arrest. Primary α-adrenergic drugs, including phenylephrine and methoxamine, have predominant α 1 -adrenergic actions. Unfortunately, α 1 -adrenergic receptors are desensitized during the myocardial ischemia of cardiac arrest, such that these drugs are minimally effective in increasing peripheral resistance. In addition, α 1 -adrenergic receptors also reside in the heart, although to a much lesser extent than β-adrenergic receptors [33]. Accordingly, α 1 -agonists also have inotropic effects that increase the severity of myocardial ischemia. Our attention has therefore turned to a selective α 2 -adrenergic agonist and specifically to α-methylnorepinephrine, which has yielded significantly better outcomes experimentally because of its relatively pure peripheral vasopressor action [34,35].

Therapeutic hypothermia after cardiac arrest
Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. Recent studies have shown that induced hypothermia for 12-24 hours improves outcome in patients who are resuscitated from out-of-hospital cardiac arrest [36,37]. The rapid infusion of large volume, icecold crystalloid fluid results in a significant decrease in median core temperature from 35.5°C to 33.8°C, and is associated with beneficial hemodynamic, renal, and acid-base effects. Further studies are ongoing to improve this technique [38].

Conclusion
Although laboratory research on CPR cannot directly be applied to clinical management, insights gained in the laboratory led to the extraordinary discovery of CPR itself by Kouwenhoven and coworkers [39] and, in our experience, accounted for essentially every subsequent major advance in the field, including that in adverse effects of automated defibrillation [40]. The importance thereof is even greater in light of the restraints that preclude human studies in the USA when informed consent of the patient is not possible.