Vasopressin: Improving Resuscitation?

The history of resuscitation contains the stories of many medications that initially appeared to increase the success rate, but widespread usage and the light of research failed to demonstrate an increase in the rate of hospital discharge.1

Epinephrine has been used for decades as a primary pharmacological agent in the treatment of cardiac arrest. The use of epinephrine is supported by animal studies and case reports.2 The primary aim in using epinephrine as the frontline drug treatment of cardiac arrest is to produce selective vasoconstriction in an attempt to maintain vital organ perfusion during CPR. However, its use is less than ideal, as epinephrine creates its own set of potential problems, including increased myocardial oxygen demand.

Researchers are working to identify a pharmacological agent that produces the main beneficial effect of epinephrine without the potentially damaging or harmful side effects.

Vasopressin has been presented as one alternative to epinephrine, although its value remains controversial. A recent study on the use of vasopressin in out-of-hospital cardiac arrests was widely reported in the lay press.3 This study, although debated, may show an improvement in the rate of return of spontaneous circulation (ROSC) when a combination of epinephrine and vasopressin is used in prehospital cardiac arrests. The key to a treatment's success remains in demonstrating an improvement in the clinically relevant end-point of the hospital discharge rate of a neurologically intact patient. Despite years of scrutiny and research, survival rates for patients undergoing prehospital cardiopulmonary resuscitation remain at 5%¡V10%.4

Pharmacology of Vasopressin

Vasopressin is a promising alternative to epinephrine. Some of the most recent pharmacological interventions under investigation include the use of vasopressin as a vasopressor. Normal endogenous release of vasopressin occurs in response to increased serum osmolality or reduced plasma volume. Its major physiologic role is to regulate water balance. It does not play a major role in vascular regulation of blood pressure.

As an IV medication however, vasopressin plays a role as an antidiuretic, as well as adrenocorticotropic-hormone (ACTH)-releasing activity.5 It 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.6

In low-perfusion states, endogenous vasopressin is an important vasoconstrictor mechanism. It is released via activation of aortic and carotid baroreceptors. Vasopressin is also an important endogenous hormone, released from the posterior pituitary gland, which increases in levels during cardiac arrest and CPR. These levels also rise in response to hemorrhagic shock, septic shock, myocardial infarction (MI), cardiopulmonary bypass, anesthesia, surgery and exercise.

Prolonged shock states may lead to inappropriately low levels of vasopressin and can lead to the development of pathologic vasodilation. Possible explanations can be the depleted stores of vasopressin. In addition, autonomic dysfunction occurring with septic shock may reduce the baroreflex-mediated stimulation of vasopressin release.

The pressor action of vasopressin in shock results from an overall increase in systemic vascular resistance (SVR), but can vary markedly in different circulating regions of the body. Blood flow is reduced to the skin, skeletal muscle, small bowel and fat tissue, and is increased to the heart and brain. Vasopressin acts via specific receptors located in the vasculature to cause vasoconstriction. This effect can reverse the pathologic vasodilatory processes that may occur with advanced shock states and are refractory to catecholamine vasopressors.

Epinephrine in Cardiac Arrest

Epinephrine's role in cardiac arrest is primarily for its alpha properties-vasoconstriction and enhancing internal carotid and coronary perfusion. Its beta-agonist properties are controversial in the peri-arrest state, increasing oxygen consump-tive-demands and reducing subendocardial vascular perfusion.7 Studies comparing selective alpha-adrenergic agents have demonstrated that-they are at least equal to epinephrine at restoring spontaneous circulation.8

Epinephrine is an adrenergic agonist, which is employed in cardiac arrest for the effect it has on the alpha-1 receptor of selective vasoconstriction. However, like many pharmacological agents, epinephrine also targets other receptor sites, including alpha-2, beta-1 and beta-2. Stimulation of some of these other receptor sites may have a detrimental effect on the outcome of cardiac arrest, in particular the beta-1 effects.

Epinephrine is used in EMS protocols for the treatment of cardiac arrest. Potential side effects include increased myocardial oxygen demand, ventricular dysrhythmias, ventilation/perfusion mismatch, post-resuscitation myocardial depression and poor neurological recovery following cardiac arrest. Another potential side effect of epinephrine is that it induces a platelet aggregation, a potential problem in patients with coronary artery disease (CAD).

Vasopressin in Cardiac Arrest

In recent years, vasopressin has received considerable interest as an alternative to epinephrine, as it generates a similar pattern of vasoconstriction following intravenous administration. Several studies have identified a link between the level of endogenous vasopressin and outcome of cardiac arrest. One study demonstrated that in 60 victims of out-of-hospital cardiac arrest, the endogenous plasma levels of vasopressin were significantly higher during CPR in patients with a return of spontaneous circulation, although the clinically relevant end-point remained hospital discharge.9 Alternatively, plasma epinephrine concentrations were significantly higher in patients who died. Laboratory studies have suggested that vasopressin is a moderately selective stimulator of muscle receptors, resulting in intense peripheral vasoconstriction of skin, skeletal muscle, fat and intestine, and relatively less constriction of coronary, renal and cerebral blood supply. Some animal studies have confirmed that vasopressin increased vital organ perfusion under CPR, in comparison with epinephrine. Vasopressin produces little increase in myocardial oxygen demand during ventricular fibrillation or after resuscitation. Vasopressin has been shown to improve the ability to terminate ventricular fibrillation.10

In 1996, investigators reported on the successful use of vasopressin in the treatment of eight patients in cardiac arrest refractory to epinephrine and defibrillation. Patients were given 40 U of intravenous vasopressin followed by defibrillation. Defibrillation was successful in all eight patients, three of whom were discharged from the hospital with intact neurological function.11-This study remains anecdotal in nature.

Studies have suggested that intravenous vasopressin is associated with better vital-organ perfusion and resuscitation rates than is epinephrine in the treatment of refractory cardiac arrest.12 Forty patients in ventricular fibrillation resistant to electrical defibrillation were prospectively and randomly assigned epinephrine (1 mg intravenously; n=20) or vasopressin (40 U intravenously; n=20) as primary drug therapy for cardiac arrest. The end-points of this double blind study were successful resuscitation (hospital admission), survival for 24 hours, survival to hospital discharge and neurological outcome (Glasgow Coma Scale).

Seven (35%) patients in the epinephrine group and 14 (70%) in the vasopressin group survived to hospital admission (p=0.06). At 24 hours, four (20%) epinephrine-treated patients and 12 (60%) vasopressin-treated patients were alive (p=0.02). Fifteen percent of the patients in the epinephrine group and 40% in the vasopressin group survived to hospital discharge (p=0.16). Neurological outcomes were similar (mean Glasgow score at hospital discharge 10.7% versus 11.7%). A significantly larger proportion of patients treated with both vasopressin and epinephrine than those treated with epinephrine alone were resuscitated successfully from out-of-hospital ventricular fibrillation and survived for 24 hours. The use of both medications in some of the study patients creates issues related to identifying the benefits of vasopressin as an individual medication.

In the CPR laboratory, simulating adult pigs with ventricular fibrillation or postcountershock pulseless electrical activity, vasopressin improved vital organ blood flow, cerebral oxygen delivery, resuscitability and neurological recovery better than did epinephrine. In pediatric porcine preparations with asphyxia, epinephrine was superior to vasopressin, whereas in both pediatric pigs with ventricular fibrillation and adult porcine models with asphyxia, combinations of vasopressin and epinephrine proved to be highly effective. This may suggest a different efficiency of vasopressors in pediatric vs. adult preparations. Different effects of dysrhythmic vs. asphyxial cardiac arrest on vasopressor efficiency may be of significant importance.

Whether these theories can be extrapolated to humans is unknown at this time. In patients with out-of-hospital ventricular fibrillation, a larger proportion of patients treated with vasopressin survived 24 hours compared with patients treated only with epinephrine. During in-hospital CPR, comparable short-term survival was found in groups treated with either vasopressin or epinephrine.

The American Heart Association (AHA) and European Resuscitation Council (ERC) recommend 40 U vasopressin intravenously or 1 mg epinephrine intravenously as equally effective for the treatment of adult patients in ventricular fibrillation; however, to date, no recommendation has been made for vasopressin for adult patients with asystole and pulseless electrical activity and pediatrics, due to lack of clinical data at the time the guidelines were developed.

Innsbruck Study of Vasopressin in Out-of-Hospital Cardiac Arrests

Although vasopressin is an alternative to epinephrine for vasopressor therapy during CPR, clinical experience with this treatment has been limited in prehospital care. European researchers recently published a study that indicates vasopressin use may improve hospital discharge rates following out-of-hospital cardiac arrest.13

A total of 1,219 adult patients with out-of-hospital cardiac arrest were randomized to receive two injections of either 40 IU of vasopressin or 1 mg of epinephrine, followed by additional treatment with epinephrine, if needed. This portion of the study protocol mixes the use of vasopressin and epinephrine, producing some information that demonstrates an improvement with both medications. The primary end-point was survival to hospital admission; the secondary end-point was survival to hospital discharge. Thirty-three patients were excluded from the study due to missing information. Of the remaining 1,186 patients, 589 were assigned to receive vasopressin and 597 to receive epinephrine. The two treatment groups had similar clinical profiles. There were no significant differences in the rates of hospital admission between the vasopressin group and the epinephrine group, either among patients with ventricular fibrillation or those with pulseless electrical activity (PEA). Among patients with asystole, however, vasopressin use was associated with significantly higher rates of hospital admission (29.0% in the vasopressin group vs. 20.3% in the epinephrine group) and hospital discharge (4.7% in the vasopressin group vs.

1.5% in the epinephrine group). In the group of 732 patients in whom spontaneous circulation was not restored with two injections of the initial study drug, additional treatment with epinephrine resulted in significant improvement in the rates of survival in the vasopressin group, but not in the epinephrine group (hospital admission rate 25.7% in the vasopressin group vs. 16.4% in the initial epinephrine group). Hospital discharge was also higher in the vasopressin group, (6.2% vs. 1.7%), but does not address the issue of mixed use of vasopressin and epinephrine. Neurologic outcome was similar in the two groups. The effects of vasopressin were similar to those of epinephrine in management of ventricular fibrillation and pulseless electrical activity, but vasopressin was superior to epinephrine in patients with asystole. This study remains controversial in comparing successful resuscitation with epinephrine vs. vasopressin.

Vasopressin in Ventricular Fibrillation

High-dose epinephrine for treating ventricular fibrillation has not led to better short-term survival in cardiac arrest patients. Additionally, myocardial injury after resuscitation may be worsened by furthering the imbalance between myocardial oxygen supply and demand. Vasopressin has been looked at as an alternative, with possible improvement in survival rates. This may be due to the improvement in myocardial and cerebral blood flow seen during CPR with vasopressin use. In the latest ACLS guidelines, a single 40-unit bolus of vasopressin may replace epinephrine in treating ventricular fibrillation.

Vasopressin in Hypovolemic Shock

Hypovolemia from blood loss that leads to cardiac arrest has had a dismal outcome. Even after restoration of circulating volume, a refractory hypotension resistant to catecholamines and further fluids can ensue.14 Vasopressin may be beneficial in improving survival in this situation.15

Vasopressin in Septic Shock

The hemodynamic disturbances caused by septic shock are generalized vasodilation and myocardial depression. Blood pressure is frequently restored through the use of catecholamine vasopressors, but reductions in regional blood flow, such as splanchnic circulation, can reach critical levels. In some patients with vasodilated septic shock, the pressor response to catecholamines may be markedly reduced. Vasopressin administered as a continuous drip at 0.04 units/min can result in an increased systolic blood pressure, allowing the catecholamine pressors to be titrated down or entirely off.

Summary

Historically, epinephrine has been used in the treatment of cardiac arrest for its alpha effects of peripheral vasoconstriction to promote vital organ perfusion. Unfortunately, epinephrine, like many other pharmacological agents, targets other receptor sites that can have a detrimental effect on the patient in cardiac arrest.

Vasopressin is an endogenous hormone that may be an ideal alternative or adjunctive to epinephrine in the setting of cardiac arrest.16,17 Vasopressin, like epinephrine, promotes selective but potent vasoconstriction of smooth muscle, but unlike epinephrine, without the potentially harmful side effects of increasing myocardial workload, therefore increasing oxygen demand and subsequent worsening of cardiac function. The newest data on the impact of vasopressin in cardiac arrest is promising. Further studies are required to determine if vasopressin has a significantly positive impact in outcome as measured by discharge of the neurologically intact patient in the North American EMS model.

References

1. Gueugniaud PY, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group. N Engl J Med 339(22):1595–1601, Nov 26, 1998.
2. Chugh SS, Lurie KG, Lindner KH. Pressor with promise: Using vasopressin in cardiopulmonary arrest. Circulation 96(7):2453–2454, Oct 7, 1997.
3. Grady D. Study finds a drug that works better than adrenaline for some types of cardiac arrest. New York Times, Jan 8, 2004.
4. Nichol G, Detsky AS, Stiell IG, et al. Effectiveness of emergency medical services for victims of out-of-hospital cardiac arrest: A metaanalysis. Ann Emerg Med 27(6):700–710, Jun 27, 1996.
5. Holmes CL, Landry DW, Granton JT. Science Review: Vasopressin and the cardiovascular system, Part 2: Clinical physiology. Crit Care 8(1):15–23. Epub, Jun 26, 2003.
6. Prengel AW, Lindner KH, Keller A, Lurie KG. Cardiovascular function during the postresuscitation phase after cardiac arrest in pigs: A comparison of epinephrine versus vasopressin. Crit Care Med 24(12):2014–2019, Dec 1996.
7. Frishman W, Vahdat S, Bhatta S. Innovative pharmacologic approaches to cardiopulmonary resuscitation. J Clin Pharmacol 38(9):765–772, Sep 1998.
8. Wenzel V, Krismer A, Arntz H, et al. Comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 350(2):105–113, Jan 8, 2004.
9. Lindner K, Dirks B, Strohmenger H, et al. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet 349(9051):535–537, Feb 22, 1997.
10. Babbs C, Berg R, Kette F, et al. Use of pressors in the treatment of cardiac arrest. Ann Emerg Med 37(4 Suppl):S152–162, Apr 2001.
11. Lindner KH, Prengel AW, Brinkmann A, et al. Vasopressin administration in refractory cardiac arrest. Ann Intern Med 124:1061–1064, 1996.
12. Wenzel V, Krismer A, Arntz H, et al. Comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 350(2):105–113, Jan 8, 2004.
13. Wayne MA, Racht EM, Aghababian RV, et al. Prehospital management of cardiac arrest: How useful are vasopressor and antiarrhythmic drugs? Prehosp Emerg Care 6(1):72–80, Jan–Mar 2002.
14. Voelckel WG, Raedler C, Wenzel V, et al. Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med 31(4):1160–1165, Apr 2003.
15. Stadlbauer KH, Wagner-Berger HG, Raedler C, et al. Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs. Anesthesiology 98(3):699–704, Mar 2003.
16. Hogg K, Mahu R. Vasopressin or adrenaline in cardiac resuscitation. Emerg Med J 20(5):467, Sep 2003.
17. Klouche K, Weil MH, Tang W, et al. A selective alpha(2)-adrenergic agonist for cardiac resuscitation. J Lab Clin Med 140(1):27–34, Jul 2002.