Basic science

The importance of arterial vascular tone in resuscitation from cardiac arrest has been described in detail in the previous chapters of this book.

Efficacy of non-adrenergic pressors

There is a longstanding concern that administration of adrenaline during resuscitation may result in detrimental effects during the postresuscitation period. Forexample, laboratory studies with adrenaline during cardiopulmonary resuscitation (CPR) showed increased myocardial oxygen consumption, ventricular arrhythmias, ventilation–perfusion defects, and postresuscitation myocardial dysfunction. Therefore, non-adrenergic vasoactive peptides such as vasopressin hold considerable promise, since theymayraise perfusion pressure without the β-receptor-mediated side effects of adrenergic vasopressors. Another intriguing possibility is that they may act synergistically when administered together with catecholamines, and that concomitant use of adrenergic drugs and nonadrenergic vasoactive peptides may allow lowering of the dose of each agent.

Vasopressin, an endogenous stress hormone

A number of fundamental endocrine responses of the human body to cardiac arrest and CPR have been investigated in past years, and are summarized in another chapter of this book. Circulating endogenous vasopressin concentrations were high in patients undergoing CPR, and levels in successfully resuscitated patients have been shown to be significantly higher than those in patients who died. This may indicate that the human body discharges vasopressin as an adjunct endogenous vasopressor to epinephrine in life-threatening situations such as cardiac arrest in order to preserve homeostasis. In a clinical study of 60 out-of-hospital cardiac arrest patients, parallel increases in plasma vasopressin and endothelin during CPR were found only in surviving patients. Thus, plasma concentrations of vasopressin may have a more important effect on CPR outcome than was previously thought. These observations prompted several investigations to assess the role of arginine vasopressin in the management of CPR in order to improve patient outcome.

This chapter is designed to provide a comprehensive, systematic account of the methods of conducting clinical research in resuscitation, in particular, how to set up and carry out a comprehensive and meaningful clinical trial. We will follow the natural conduct of a study, from designing the protocol through data collection to evaluation and interpretation. As an example of some of the difficulties and also the satisfactions of a job well done, in the Appendix we present Professor Wenzel's personal description of the trials and tribulations of determining the role of vasopressin in treatment for cardiac arrest.

Study design

Study objectives

Clinical research in cardiac arrest has developed slowly during the last few decades as compared with other disciplines. The objectives of completed, scheduled, or planned studies can roughly be divided into three categories: (1) epidemiology, i.e., collection of information on prevalence, chance and risks of clinical conditions that require resuscitation attempts; for example, anecdote in the Appendix, elevated endogenous vasopressin levels in survivors of cardiac arrest were found in previous epidemiological studies; (2) evaluation of established treatments and algorithms for resuscitation that are practiced with or without proof of efficacy; for example, in the anecdote, historical data on CPR with vasopressin were available; (3) randomized clinical trials performed to collect evidence on the efficacy and safety of established or new interventions or therapeutic strategies following cardiac arrest; for example, the anecdote describes a randomized clinical trial performed to gain evidence on the efficacy of vasopressin as compared to the established epinephrine injections during out-of-hospital CPR.

The neuroendocrine system

Early during evolution, the neuroendocrinium developed as its own organ system. With its numerous intercellularand inter-organ mediators, the hormones, it fulfills important functions to synchronize and connect organs and tissues. Likewise, during stress, the neuroendocrine system, as a complex orchestra with not yet fully understood interactive mechanisms, plays one of the most important roles in the body's adaptation to harmful events, such as injury or disease.

Operational definitions (by Jacobo Wortsman, M.D.)

In general terms the endocrine system comprises hormone-producing organs (glands) that regulate the function of other organs. On functional activation, endocrine organs release their secretory products into the blood. Thus, activation can be assumed to occur when there is evidence of increased hormone concentrations in plasma.

Stress may be defined as any changes in the external or internal environment that elicit a highly organized and synchronized neuroendocrine response. Whereas changes in the internal environment can be quantified according to the degree of interference with homeostasis, changes in the external environment (psychologic stress) cannot be quantified in this manner. Thus, the description of stress must include both the nature of the stressful stimulus and the subsequent functional changes. Nevertheless, because of the universal and severe organ involvement during cardiac arrest, it can be safely assumed that this condition per se represents a stress of maximal degree, without consideration of hormone levels.

The term neuroendocrine response, as used in the description of endocrine reactions to stress, emphasizes the regulatory control placed by the hypothalamus over the entire endocrine system.

There is a no more frightening experience for a clinician than a patient's sudden and complete loss of vital signs. The need to initiate multiple complex therapies, all the while knowing that each minute that passes dramatically decreases the chances for a good outcome, makes sudden death the penultimate medical emergency.

Premature death is the adversary of physicians. For millennia, the loss of life signs was considered the victory of death. Students were taught that once patients had succumbed they were beyond the healing arts. Only relatively recently have physicians regularly attempted to wrest such patients back from death.

Accurate numbers are difficult to obtain. It is said that more than 300,000 persons die each year from sudden cardiac death in the United States alone. Worldwide the figure is in the millions. Sudden death is not, however,caused by coronary artery disease alone. Hemorrhage and asphyxiation, among others, can kill physiologically competent patients without warning. Sudden death is not defined by etiology; it is the circumstance of cardiopulmonary arrest in a person with functional vital organ systems. It is death in the midst of life, and it is always tragic.

We are just beginning to appreciate the magnitude of this problem and the potential for therapy. Just a 5% improvement in outcome – something that could be achieved in many communities by better application of standard care – would save more lives than therapies that have received far more attention. The potential for good is astounding; the relationship of cost to benefit compelling.