| There have been numerous studies on
cardiopulmonary resuscitation (CPR) since the last national CPR conference in 1992.
However, the survival rate for sudden cardiac arrest remains between 5% and 15%. The
American Heart Association changed its "standards" to guidelines to provide
physicians more flexibility in their recitative efforts. Most research efforts have
concentrated on new pharmacological agents, or different uses for currently available
agents. There is however, some significant research on the electrical aspect of
resuscitation, which will be lightly addressed. A more in-depth discussion requires a
separate presentation. Most of the research discussed has been on animal models. This
author is not a proponent of animal based research, but recognizes the ethics involved in
human research in life and death situations. The Pharmacologic agents will be divided by
Current guidelines designate epinephrine as the vasopressor of choice in CPR. Its alpha adrenergic effects which cause increased cerebral and coronary blood flow and prevention of anterior wall collapse from lack of pressure in the vessel, are the reasons it is a first line agent. Studies have shown that the improved cerebral blood flow occurs by vasoconstriction of extracerebral carotid arterial and peripheral vascular beds. Increased coronary perfusion pressure, identified as the major factor determining return to spontaneous circulation, occurs by increased aortic diastolic pressure due to central and peripheral vasoconstriction. There are some significant negative effects of epinephrines stimulation of beta adrenergic receptors, which cause increased myocardial oxygen consumption and reduced subendocardial vascular perfusion (Frishman, Vahdat, & Bhatta, 1998).
Studies comparing pure alpha adrenergic agents such as phenylephrine or methoxamine, have shown that they are not superior to epinephrine at restoring spontaneous circulation. However, endogenous vasopressin has been found in significantly elevated levels in cardiac arrest patients. Vasopressin is one of the major peptide hormones produced in the hypothalamo-neurohypophysial system. A few of its many functions include antidiuretic, vasopressin, and adrenocorticotropic hormone (ACTH)-releasing activity. Vasopressin is a potent vasoconstrictor that increases blood pressure and systemic vascular resistance, and decreases cardiac output, heart rate, left ventricular oxygen consumption, and myocardial contractility. With regard to cerebral blood flow, vasopressin not only increases flow to a greater degree than epinephrine, it also improves cerebral oxygenation and decreases venous hypercarbia (Prengal, Lindner, & Keller, 1996).
Possible disadvantages of vasopressin are related to its potent vasoconstrictive effects, and an increase in calcium in vascular smooth collateral muscles. This is based on canine research, with the hypothesis that collateral arteries have a greater affinity or quantity of vasopressin receptors (Rapps, Jones, Sturek, Magliola, & Parker, 1997).
In humans vasopressin was first administered to patients in cardiac arrest who had not responded to current AHA guidelines. Eight patients were given vasopressin and had restored circulation, however, only three made it to discharge (Lindner, Dirks, Strohmenger, Prengel, Lindner, & Lurie, 1996). In a more recent study of 40 patients in ventricular fibrillation who were resistant to counter shock, vasopressin was compared to epinephrine. This study was controversial, in that patients were only given one dose of vasopressin because the pharmacokinetics of repeated dose vasopressin are still unknown. Also, if spontaneous circulation was not restored within 3 minutes epinephrine was administered. The study authors stated that a significant amount of those in the study survived 24 hours (Lindner, Dirks, Strohmenger, Prengel, Lindner, & Lurie, 1997).
Future studies will have to establish the appropriate dosage, and evaluate if vasopressin should be used alone or in conjunction with epinephrine. Other lethal rhythms will have to be included in a study, and the effects of vasopressin on the other organs.
Since the beginnings of this century life-threatening ventricular arrhythmias (VT and VF) have been treated with class I antiarrhythmic agents such as Lidocaine (Lazzara, 1996). These drugs exert their action by blocking voltage-sensitive sodium ion channels, which reduces the action potential for non-nodal areas of the heart. Lidocaine has some downfalls including prolonging the refractory potential of ischemic heart tissue, and it has a narrow therapeutic to toxic range.
The Cardiac Arrhythmia Suppression Trials (CAST I and II) which evaluated primary prevention of VT and VF in high risk patients post infarction showed the ineffectiveness of Encainide, Flecainide (Tamborcor), Moricizine (Ethmozine) and Sotalol (Betapace). All four had strong proarrhythmic effects (Frishman, Vahdat, & Bhatta, 1998).
Because of the ineffectiveness of the aforementioned agents and the complexities with Lidocaine, the search for the ideal drug for VF treatment has lead to many research projects on Amiodarone. Numerous studies have shown the antiarrhythmic effectiveness of Amiodarone in long term survival of patients post infarction (Sim, McDonald, Lavori, Norbutas, & Hlatky, 1997). These studies were on the management of patients post infarct with the goal of preventing ventricular arrhythmia reoccurrence. Which begs he question, "is Amiodarone applicable for acute control of VF/VT?" Research has shown that intravenous Amiodarone can slow atrioventricular (AV) conduction, prolong AV nodal refractoriness and lengthen the conduction interval time (Chow, 1996). Other benefits show a powerful direct vasodilatory effect on systemic and coronary vessels, and negative inotropic action on the myocardium (Kosinski, Albin, Young, Lewis, & LeLand, 1984). One large study compared Amiodarone and Bretylium in patients who did not respond to Procainamide and Lidocaine, the results showed they were equal in effectiveness but that Amiodarone was better tolerated hemodynamically (Kowey, Levine, Herre, Pacifico, Lindsay, Plumb, et al., 1995).
Adverse effects of Amiodarone are presumed to be caused by its vasodilating and negative inotropic effects, which has been shown to cause hypotension in up to 20% of patients (Kosinski, Albin, Young, Lewis, & LeLand, 1984). Currently according to the United States Food and Drug Administration Amiodarone is only approved for use in arrhythmias that are refractory to Lidocaine or Procainamide. Large studies are needed to move this drug to the first line status.
Currently the treatment of bradyasystole is classified and treated the same as other non-specific algorithms (such as; electromechanical dissociation, idioventricular rhythms, post-defibrillation idioventricular rhythms, etc.) all under the category of pulseless electrical activity. With the primary therapy being treating the causation (hypovolemia, hypoxia, etc.) and supplementing with epinephrine and atropine or considering transcutaneous pacing. Stratton & Niemann (1997) discuss that bradyasystole had been the initial rhythm in 25% to 72% of out of hospital cardiac arrest cases, with the overall survival to discharge only 3% or less. They suggest that many patients are dying because of the limited treatment options for this arrhythmia.
Through studying the pathophysiology of these bradyasystole rhythms, researchers have found that there is a failure in the hearts electrical system causing inadequate blood flow to vital organs (Barenheuer & Schrader, 1986). Ornato & Peberdy (1996) discuss that when there is ischemic or infarcted cardiac tissue it is this tissue that will affect electrical activity and that endogenous adenosine is released. Somer & Frishman (1997) discuss the adenosine affects during cardiac arrest, which include negative chronotropic and dromotropic effects and as an inhibitor of negative feedback for stimulatory catecholamine action, which ultimately lead to unsuccessful resuscitations. Canine studies have shown that adenosine raises the defibrillation threshold and blocks the action of catecholamines.
Currently researchers are looking for agents that block the effects of adenosine, one agent that has proven somewhat effective is Aminophylline. The problem is that Aminophylline is a nonspecific adenosine inhibitor, and that the dosing related to the blocking action has not been established.
Other Areas of Research
Researchers are reviewing the relationship between successful cardiac arrest resuscitations and thyroid hormone levels. Canine studies have shown that during cardiac arrests there is reduced levels of circulating thyroxine and triodothyronine, and that there were better neurologic outcomes if levothyroxine was administered during the resuscitation.
Imidazolines are a new class of compounds that have been shown to act as peripheral vasoconstrictors. Another promising vasopressor agent is angiotensin. The goal of theses types of agents is to separate out the alpha and beta catecholamine effects, so that the desired effects can be more controlled (Brown, Wiklund, Bar-Joseph, Miller, Bircher, Paradis, Menegazzi, von Planta, Kramer, & Gisvold, 1996). There is question about the effectiveness of the metabolism of catecholamines (e.g., epinephrine) as they transfer through the lungs following peripheral IV administration, therefore the effectiveness of intra-arterial epinephrine is being evaluated.
There is also research related to the acidosis that occurs during cardiac arrest, and the transiently detrimental effects of sodium bicarbonate (NAHCO3). There are two new agents being studied that significantly buffer the pH and lower the CO2, THAM and Carbicarb. These agents do not induce the transient acidosis in myocardium and THAM improves myocardial contractility, it even has positive inotropic effects on ischemic myocardium (Brown, Wiklund, Bar-Joseph, Miller, Bircher, Paradis, Menegazzi, von Planta, Kramer, & Gisvold, 1996).
Lastly, there has been much research on the effectiveness of the electrical shock component of resuscitation, and the detrimental effects of high energy and the stacking of shocks. Research has shown how it creates holes in the myocardial cell and the high energy actually is permanently damaging to cells.
In summary, the research into the processes of cardiac resuscitation is continuing to grow, and many "sacred cows" are being slaughtered. But, as you can see much research is still needed. Remember, for these research findings to be put into clinical application also takes time, and the group that needs to support them is the American Heart Association. I am not supporting all of these practices; my only goal is to keep my colleagues up to date with current research.
Bardenheuer, H., & Schrader, J. (1986). Supply-to-demand
ratio for oxygen determining formation of adenosine by the heart. American Journal of
Physiology, 250, H173-H180.
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