Despite an intense search for methods to improve the success of cardiopulmonary. Use of Vasopressin in Cardiopulmonary Arrest: Controversy and Promise

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1 CE 448 V Vol. 25, No. 6 June 2003 Article #4 (1.5 contact hours) Refereed Peer Review Comments? Questions? compendium@medimedia.com Web: VetLearn.com Fax: KEY FACTS Cardiopulmonary arrest (CPA) is relatively common in some patient populations and is associated with significant mortality. Experimental information indicates that vasopressin may offer some benefit over epinephrine in the management of CPA, particularly in patients with prolonged arrest. The positive effects of vasopressin in cardiopulmonary resuscitation are due to extracerebral vasoconstriction and its ability to avoid the myocardial hypoxia and tachycardia that occur with the use of epinephrine. Further clinical research must be conducted to evaluate vasopressin s role in the management of veterinary patients in CPA. Use of Vasopressin in Cardiopulmonary Arrest: Controversy and Promise Dove Lewis Emergency Animal Hospital Portland, Oregon Tony Johnson, DVM ABSTRACT: Cardiopulmonary cerebral resuscitation for cardiopulmonary arrest (CPA) is often unsuccessful. Therefore, any method that could decrease the significant mortality associated with CPA would be valuable. Current pharmacologic management of CPA involves the use of epinephrine for increased cardiac output and systemic vasoconstriction; however, this agent is associated with a significant number of adverse effects, including increased myocardial oxygen consumption and tachyarrhythmia. Vasopressin has shown to be superior to epinephrine in several small animal-model experimental studies; in humans, large-scale clinical studies are underway. Despite an intense search for methods to improve the success of cardiopulmonary cerebral resuscitation (CPCR) in patients in cardiopulmonary arrest (CPA), the survival rate to discharge in humans has remained at roughly 5% to 15% for the past 2 decades. 1,2 Well-controlled veterinary survival studies are lacking, but a 1992 study of 265 cases of CPA demonstrated a 4.1% rate to discharge for dogs and 9.6% for cats. 3 The difference between the causes of CPA in veterinary and human patients makes absolute comparisons of therapeutic interventions problematic because many cases of arrest in humans occur in an out-of-hospital setting and are due to coronary artery disease, an uncommon clinical finding in companion animals. In contrast, most cases of CPA in veterinary medicine occur in the hospital setting and are the terminal stage in the process of dying. With these differences in mind, however, much of the physiology behind CPA is similar enough between human and veterinary patients that the study of CPA management in humans and experimental studies on nonhuman subjects can provide valuable information. This article highlights some of the data as well as the controversy surrounding the use of vasopressin in the management of patients in CPA. Some methods, such as interposed abdominal counterpressure, biphasic waveform defibrillation, and active compression decompression CPCR 4 and new pharmacologic agents (or new uses for old ones) have shown promise in animal models of human CPA, but not all have been shown to improve hospital discharge rates in prospective clinical studies. 5

2 Compendium June 2003 Vasopressin in Cardiopulmonary Arrest 449 Table 1. AHA Ratings for Advanced Cardiovascular Life Support Interventions 7 Rating Class I Class IIa Class IIb Class III Class indeterminate Definition Definitely recommended; supported by excellent evidence; has proven efficacy and effectiveness Acceptable and useful; good/very good evidence provides support Acceptable and useful; fair to good evidence provides support Not acceptable; not useful; may be harmful Available evidence insufficient to support a final class decision; results promising but additional confirmation is needed; evidence shows no harm but no benefit either One pharmacologic agent currently under investigation and showing some promise is vasopressin, which is also known as antidiuretic hormone. Since the publication of a 1996 human study demonstrating dramatically increased levels of vasopressin in post-cpa/cpcr patients, 6 much attention has been focused on its use as a pressor agent to improve myocardial and cerebral blood flow in CPCR while avoiding several of the negative effects of epinephrine. A large, multicenter trial is currently underway to evaluate its use in human medicine. Although early clinical trials have produced conflicting results, 5 vasopressin is listed as an alternative to epinephrine in the American Heart Association (AHA) 2000 Advanced Cardiovascular Life Support 7 guidelines for first-line pressor in defibrillation refractory ventricular fibrillation and pulseless ventricular tachycardia. Vasopressin is not approved for use in pediatric patients or those with pulseless electrical activity (formerly known as electromechanical dissociation). In the Advanced Cardiovascular Life Support ratings, which provide information regarding the evidence supporting or refuting the use of a particular drug or technique in CPCR, vasopressin was assigned an AHA intervention rating of Class IIb (acceptable; fair supporting evidence; Table 1). In contrast, epinephrine is listed as Class Indeterminate due to the paucity of clinical evidence supporting its use in CPA. 7 However, a recent prospective study 5 failed to find any advantage of using vasopressin over epinephrine for in-hospital patients in CPA. Although most studies of vasopressin in CPCR have used animal models, no veterinary clinical studies have been performed with respect to vasopressin s role in CPCR to date. EPINEPHRINE USE IN CPCR For decades, the pharmacologic mainstay of CPCR has been epinephrine, largely for its α-adrenergic effects of vasoconstriction 8 and increased cerebral and coronary perfusion. 9 However, concurrent β-adrenergic stimulation causes several undesirable effects, notably increased chronotropy, arrythmogenicity, increased myocardial oxygen demand, and decreased subendocardial perfusion. 9,10 Additionally, epinephrine is associated with post-cpcr myocardial dysfunction and lactate production. 9,11 In cases of prolonged CPCR, the adrenergic pressor response is blunted in the presence of severe acidosis, thereby limiting the usefulness of epinephrine. 12 Recent studies have either failed to show any advantage of using epinephrine over saline placebo 13 or demonstrated adverse outcomes. 11 Additionally, no benefit has been shown with the administration of a high dose (10 mg) versus a low dose (1 mg) of epinephrine. 13 PHARMACOLOGY OF VASOPRESSIN Vasopressin is a peptide hormone produced in the supraoptic nuclei adjacent to the pituitary gland and is secreted by the posterior pituitary (or neurohypophysis) in response to increased plasma osmolality or decreased intravascular volume. Osmoreceptors in the hypothalamus and baroreceptors in the carotid body and atria detect changes in plasma osmolality and blood pressure, respectively, and cause the release or sequestration of vasopressin and other regulatory hormones. Its half-life in animals with intact circulation is 10 to 20 minutes, 12 which is longer than that of epinephrine. The synthetic analogue of vasopressin, 1-deamino-8-D-arginine vasopressin, has minimal pressor effects and is not appropriate for use in CPCR. Vasopressin can be administered by IV, intratracheal, or intraosseous routes when used in CPCR. 9 Vasopressin exerts its pressor effects through stimulation of vasopressin-specific V1 receptors found in vascular smooth muscle, causing intense, nonadrenergic vasoconstriction. 8,12 V1 receptors are cell membrane bound and coupled to intracellular second messengers, such as adenylate cyclase, phospholipase A 2, and protein kinase A. 8 Vasopressin preferentially constricts arterioles in extracerebral tissues, with relatively less constriction in renal and coronary blood vessels, and may actually dilate the cerebral vasculature, thereby improving cerebral perfusion. 8 10,12 Its antidiuretic effects are due to increased permeability of the renal collecting duct cell membrane to water in the presence of vasopressin (via V2 receptor-mediated stimulation), causing water to move down its concentration gradient and be reabsorbed. V2 renal receptors

3 450 Small Animal/Exotics Compendium June 2003 are present in the medullary portion of the kidney. In the absence of vasopressin (such as in central diabetes insipidus), the collecting duct system is almost impermeable to water. 8 VASOPRESSIN USE IN CPCR Observational studies of post-cpa patients provided the background for initial investigations into the therapeutic use of vasopressin. A 1996 study by Lindner and colleagues 6 involving 60 cases of out-of-hospital CPA showed a positive association between high vasopressin levels post-cpa and return of spontaneous circulation, whereas high levels of endogenous catecholamines were associated with poorer outcomes. Animal models of CPA have largely been favorable with regards to vasopressin s role in CPCR, particularly after prolonged CPCR. Most studies on vasopressin have been conducted using swine and have reported superior coronary perfusion pressure, 14,15 cerebral blood flow, and neurologic outcomes 16 when compared with epinephrine. Doses of vasopressin used in animal models have ranged between 0.4 to 0.8 U/kg. In one swine study in which 17 subjects underwent 4 minutes of ventricular fibrillation, 3 minutes of basic life support (chest compressions), and 15 minutes of advanced life support (i.e., drugs, defibrillation), all animals in the vasopressin group (n = 6) had return of spontaneous circulation, whereas all animals in the epinephrine group (n = 6) and saline placebo group (n = 5) did not. All animals in the vasopressin group survived with only mild ataxia; however, all animals in the placebo and epinephrine groups died. Several animals in the vasopressin group needed sedation to allow weaning from mechanical ventilation after CPCR. Survivors underwent magnetic resonance imaging 4 days after resuscitation and no neuropathologic lesions were seen. 16 Coronary perfusion pressure above 15 mmhg is generally accepted as a good predictor of return of spontaneous circulation. 15 In a swine model of CPA and prolonged CPCR, animals in the vasopressin treatment group were able to maintain a coronary perfusion pressure at or above this level for the duration of the study, whereas those in the epinephrine group were only able to maintain this level transiently after drug administration. 15 One of the first human clinical studies was a case review involving the use of vasopressin in eight patients undergoing prolonged CPCR for in-hospital CPA and who were refractory to standard doses of epinephrine and defibrillation. 17 After administration of 40 U of vasopressin and defibrillation, return of spontaneous circulation was noted in all patients, three of whom (37.5%) survived to hospital discharge. A larger prospective, randomized study of 40 patients with outof-hospital CPA comparing vasopressin to epinephrine as the initial pressor demonstrated improved initial survival (70% for vasopressin versus 35% for epinephrine), 24-hour survival (60% versus 20%), and survival to discharge (40% versus 15%) with similar neurologic status on discharge to patients in the epinephrine group. 18 Different end points, such as return of spontaneous circulation, 1-hour survival, survival to hospital discharge, and level of neurologic function, have been used in many studies, thereby making comparison difficult. In addition, many studies included only small groups of patients or had methodological flaws. In addition, multiple variables, such as drug dose and route of administration, response times of rescuers, and duration of CPA, can affect an individual patient s response to pharmacologic agents during CPCR. A recent randomized, blinded, placebo-controlled study 5 comparing vasopressin to epinephrine in 200 cases of in-hospital CPA did not detect any significant increase in 1-hour survival (39% for vasopressin versus 35% for epinephrine), hospital discharge (12% versus 14%, respectively), or neurologic outcome (36% for vasopressin versus 35% for epinephrine, as assessed by the Mini-Mental State Examination Score). The authors conducting the study disagreed with the recent AHA guidelines 7 calling for vasopressin as an alternative to epinephrine in CPCR. When used during CPA, vasopressin causes vasoconstriction of peripheral arterioles and preferential shunting of blood toward the heart and central nervous system. This is a result of differential constriction of skin, skeletal muscle, intestinal blood supply, and possibly cerebral vasodilatation. 9,12 Unlike epinephrine, vasopressin does not cause increased heart rate or myocardial oxygen consumption. 9,12 Vasopressin may be of particular benefit when CPCR is prolonged as the response of V1 receptors is intact despite severe metabolic and respiratory acidosis. 12 As with epinephrine, some side effects can be seen with the administration of vasopressin for CPA, although the frequency of their occurrence is unknown. Acute pulmonary edema has been reported in a human patient after peripheral administration, and intracoronary administration has resulted in myocardial ischemia due to vasoconstriction in dogs in experimental studies. Other uncommon effects include gangrene from peripheral vasoconstriction, allergic reactions, and water retention/toxicosis. 10 CONCLUSION Although the role of vasopressin in the management of CPA is still highly controversial and under study, preliminary laboratory and clinical investigations seem to indicate that it may offer some benefit over such traditional therapies as epinephrine. Despite severe systemic

4 Compendium June 2003 Vasopressin in Cardiopulmonary Arrest 451 vasodilation, vasopressin causes intense peripheral vasoconstriction, which preferentially shunts blood flow to vital structures, such as cerebral and myocardial tissues. Vasopressin causes less chronotropy due to its absence of effect on β 1 receptors, and it does not cause increased myocardial oxygen consumption as is seen with epinephrine. Additionally, vasopressin improves several intermediate variables that correlate with increased survival, such as improved cardiac perfusion pressure, improved cerebral blood flow, and early return of spontaneous circulation. Studies on vasopressin use are currently underway in human medicine that should help shed some light on its role in CPA management, and veterinary clinical studies will be required to elucidate its place in the management of veterinary CPA cases. Until these studies show definite, statistically significant improvement in survival to hospital discharge with acceptable neurologic function in veterinary patients, the use of vasopressin in small animal CPCR must be approached with caution, if at all. REFERENCES 1. Robertson R: Sudden death from cardiac arrest Improving the odds. N Engl J Med 343: , Hallstrom A, Cobb L, Johnson E, Copass M: Cardiopulmonary resuscitation by chest compression alone or with mouth-tomouth ventilation. N Engl J Med 342: , Wingfield W, Van Pelt D: Respiratory and cardiopulmonary arrest in dogs and cats: 265 cases ( ). JAVMA 200: , Plaisance P, Lurie KG, Vicaut E, et al: A comparison of standard cardiopulmonary resuscitation and active compression decompression resuscitation for out-of-hospital cardiac arrest. N Engl J Med 341: , Stiell IG, Hebert PC, Wells GA, et al: Vasopressin versus epinephrine for inhospital cardiac arrest: A randomized controlled trial. Lancet 358: , Lindner KH, Haak T, Keller A, et al: Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart 75: , American Heart Association: 2000 Advanced cardiovascular life support guidelines. Circulation 102(Suppl I):I-86 I-89, Guyton AC, Hall JE: Textbook of Medical Physiology, ed 10. Philadelphia, WB Saunders, 2000, pp Krismer AC, Wenzel V, Voelchel WG, et al: Use of vasoactive drugs during cardiopulmonary resuscitation. Curr Opin Crit Care 5: , Hollinger CB: Vasopressin: Could it be lifesaving in patients suffering a cardiac arrest? St Francis J Med 4, Tang W, Weil MH, Sun S, et al: Epinephrine increases the severity of postresuscitation myocardial dysfunction. Circulation 92: , American Heart Association: 2000 Advanced cardiovascular life support guidelines. Circulation 102(Supp I):I-129, Woodhouse SP, Cox S, Boyd P: High dose and standard dose adrenaline do not alter survival, compared with placebo, in cardiac arrest. Resuscitation 30: , Krismer AC, Lindner KH, Kornberger R, et al: Cardiopulmonary resuscitation during severe hypothermia in pigs: Does epinephrine or vasopressin increase coronary perfusion pressure? Anesth Analg 90:69 73, Paradis NA, Martin GB, Rosenberg J, et al: The effect of standardand high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA 265: , Wenzel V, Lindner KH, Krismer AC, et al: Survival with full neurologic recovery and no cerebral pathology after prolonged cardiopulmonary resuscitation with vasopressin in pigs. J Am Coll Cardiol 35: , Lindner KH, Prengel AW, Brinkmann A, et al: Vasopressin administration in refractory cardiac arrest. Ann Intern Med 124: , Lindner KH, Dirks B, Strohmenger HU, et al: Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 349: , ARTICLE #4 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose the best answer to each of the following questions; then mark your answers on the postage-paid envelope inserted in Compendium. 1. Post-CPA survival in veterinary patients is a. up to 10%. b. 10% to 20%. c. 20% to 25%. d. 25% to 45%. 2. Epinephrine s negative side effects include a. increased lactate production. b. oliguria. c. induction of arrhythmias. d. a and c 3. Vasopressin is produced by the and released by the. a. adrenals; hypothalamus b. thyroid; carotid body c. supraoptic nuclei; posterior pituitary d. vasa recta; glomerulus 4. Vasopressin normally causes a. vasoconstriction. c. mydriasis. b. water retention. d. a and b 5. Vasopressin is less likely to induce as is seen with the use of. a. myocardial hypoxia; epinephrine b. vasoconstriction; atropine c. bradycardia; lidocaine d. hypotension; dobutamine (continues on page 454)

5 454 Small Animal/Exotics Compendium June 2003 Vasopressin in Cardiopulmonary Arrest (continued from page 451) 6. Unlike epinephrine, vasopressin still exerts its physiologic effects despite a. hyperkalemia. b. hypocalcemia. c. metabolic acidosis. d. hypothermia. 7. Vasopressin is a a. diuretic. c. peptide hormone. b. catecholamine. d. secretagogue. 8. The beneficial effects of vasopressin in cardiopulmonary arrest are thought to be of peripheral tissues and of cerebral tissues. a. vasodilation; vasodilation b. vasoconstriction; vasodilation c. vasoconstriction; vasoconstriction d. vasodilation; vasoconstriction 9. Vasopressin is also called a. von Willebrand s factor. b. antidiuretic hormone. c. serotonin. d. a and b 10. Possible negative effects of vasopressin include a. severe peripheral vasoconstriction. b. pulmonary edema. c. allergic reaction. d. all of the above