Recommendations For Vasopressin In The Treatment Of Shock

David F. McAuley, Pharm D.

Introduction:

The initial interventions used to treat shock are aimed at reversing the underlying cause if possible and the administration of intravenous fluids.^1,2,3 If these interventions are not successful, catecholamines such as dopamine, epinephrine and/or norepinephrine are administered in order to help support systemic circulation.^2,3 However, loss of catecholamine pressor effects is a well-established phenomenon.² Arginine vasopressin (AVP) has been found to be a potent vasopressor even in patients with catecholamine-resistant vasodilatory shock.²

Vasopressin is synthesized in the hypothalamus and released in conditions such as hyperosmolality, hypotension and hypovolemia. Studies have shown that in acute shock states, serum vasopressin levels increase rapidly and then decrease in prolonged shock states leading to a relative deficiency of vasopressin.^4,5 Endogenous vasopressin levels are significantly lower in adult patients with severe sepsis.^1,6 This vasopressin deficiency is thought to contribute to the hypotension of shock.¹ The rationale for the use of vasopressin is its relative deficiency in circulation and the increased sensitivity to its vasopressor effects seen during septic shock.^1,5

Because vasopressin is a potent vasopressor, infusions of vasopressin in patients with several forms of shock have led to improved organ perfusion, increased mean arterial pressure, improved blood pressure and neurologic function.^2,5,6 Several studies have suggested that low-dose vasopressin (<0.04 units/min) is safe and effective for the treatment of vasodilatory shock.^1,2,5 It is also being used much more frequently in the critical care setting because it can cause arterial smooth muscle cell contraction through a non-catecholamine receptor pathway. Therefore, vasopressin represents an attractive adjunct to the management of septic shock especially when catecholamines such as norepinephrine and dopamine are ineffective.^1,2,5

Support:

Dunser et al studied 48 patients with catecholamine-resistant vasodilatory shock. Patients were prospectively randomized to receive a combined infusion of vasopressin (AVP) and norepinephrine (NE) or NE infusion alone. Patients receiving vasopressin were given a continuous infusion of 4 units/hour. Hemodynamic and systemic monitoring occurred before the initiation of the study and at 1, 12, 24, and 48 hours after study entry. Outcome: Patients given vasopressin had significantly lower heart rate, NE requirements, and incidence of new-onset tachyarrhythmias than NE patients. Also, several key indicators were significantly higher including: Mean arterial pressure (MAP), cardiac index (CI), stroke volume index, and left ventricular stroke work index. The authors concluded at the end of the study that the combined infusion of vasopressin and norepinephrine proved to be superior to infusion of norepinephrine alone in the treatment of catecholamine-resistant vasodilatory shock.²

Landry DW et al studied 19 patients (n=19) with vasodilatory septic shock. Findings: The authors stated that although vasopressin is a weak pressor in normal subjects, when infused at 0.04 units/minute to 10 patients with septic shock who were also receiving catecholamines, average arterial pressures (systolic/diastolic) increased from 92/52 to 146/66 mm Hg (P < .001/P < .05). In addition, 6 patients with septic shock who received vasopressin infused at 0.01 units/minute, without any concurrent catecholamines, increased systemic arterial pressure from 83 to 115 mm Hg (p < .01).¹

Tsuneyoshi I et al investigated the effects of exogenous vasopressin as a potential alternative to traditional high-dose catecholamine therapy for septic patients who had a suboptimal response to catecholamines. Study design: prospective, case-controlled study. (n=16) critically ill septic patients who were refractory to conventional catecholamines such as norepinephrine. These patients were given a continuous intravenous infusion of vasopressin at 0.04 units/min for 16 hours. Low-dose vasopressin was found to increase mean arterial pressure, systemic vascular resistance, and urine output in patients with vasodilatory septic shock. Study conclusion: Low-dose vasopressin infusions might be useful in treating hypotension in patients refractory to catecholamines.⁷

Müllner M et al identified only eight small randomized controlled trials reporting on the effect of vasopressors on mortality. They stated that: “The trials were underpowered and of low methodological reporting quality. “ They concluded that the current available evidence is not suitable for making clear-cut statements regarding vasopressor selection and that it is not possible to determine if a particular vasopressor is superior to other agents in states of shock.³
Malay MB et al completed a double-blinded placebo controlled clinical trial to assess the role of low-dose vasopressin as a pressor agent in septic shock. Site: trauma intensive care unit. (n=10) 5 patients received vasopressin at 0.04 units/min, while 5 other patients received placebo. After infusing vasopressin for 1 hour, attempts were made to stop any concurrent catecholamines. Agents were discontinued in the following order: norepinephrine, phenylephrine, and/or dopamine as long as the mean arterial pressure remained >/= 70 mm Hg. Study conclusion: A vasopressin infusion can improve arterial pressure and permit the withdrawal of catecholamine vasopressors and represents a useful agent in the treatment of refractory septic shock.⁸

Beale RJ et al reported that in 2003, critical care and infectious disease experts representing eleven international organizations developed guidelines for vasopressor and inotropic support in septic shock under the auspices of the Surviving Sepsis Campaign (an international effort to increase awareness and to improve outcome in severe sepsis). Key conclusions included: 1) Norepinephrine or dopamine are the vasopressors of choice in the treatment of septic shock. 2) Epinephrine, phenylephrine, and vasopressin are not recommended as first-line agents in the treatment of septic shock. 3) Vasopressin may be considered for salvage therapy (e.g. not first-line).⁹

Hall LG, Oyen LJ, Taner CB et al investigated the effects of vasopressin compared with titrated catecholamines as initial drug therapy in patients with septic shock. Design: Retrospective cohort, single-center study. Setting: Intensive care units at the Mayo Clinic, Rochester, Minnesota. Patients: (n=150): 50 treated initially with vasopressin (0.04 units/minute - fixed), 49 treated with norepinephrine (titrated), and 51 treated with dopamine (titrated) for low systemic arterial pressures. Findings: In patients receiving vasopressin, 28-day mortality was 52%, similar to those receiving norepinephrine (65%, p=0.28) and dopamine (60%, p=0.53). Further, initial, fixed-dose vasopressin infusions increased MAP to >/= 70 mm Hg at 1 hour in ICU patients with septic shock, similar to titrated norepinephrine or dopamine. Study conclusion: Fixed-dose vasopressin appears appropriate as an alternative agent for hemodynamic support in patients with septic shock.¹⁰

Conclusion:

Vasopressin may be used in patients with refractory shock despite adequate fluid resuscitation and the use of high-dose conventional catecholamines such as norepinephrine and dopamine, however, further studies are needed to determine its exact place in therapy.^3,8,9,11 Current evidence does not support the use of vasopressin as a replacement for norepinephrine or dopamine as a first-line agent.^8,9,11The recommended infusion rate for vasopressin in the treatment of shock in adults is 0.01– 0.04 units/min.^1,2,7,8,10 This dosage range is reported to be effective in about 85% of patients with norepinephrine resistant hypotension.¹¹ Doses greater than 0.04 units/min may lead to cardiac arrest.⁴ O'Brien A et al reported rapid rebound hypotension as a common problem after treatment with vasopressin is stopped.¹²
Potential side effects of vasopressin infusion range from ischemic skin lesions to possible intestinal ischemia.⁴ Vasopressin therapy may also result in decreased cardiac output and hepatosplanchnic flow.¹¹

References:

1) Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alessandro D, Oz MC, Oliver JA. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997 Mar 4;95(5):1122-5.2) Dünser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. 2003; 107: 2313–2319.

3) Müllner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock. Cochrane Database Syst Rev. 2004;(3):CD003709.

4) den Ouden DT, Meinders AE. Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review. Neth J Med. 2005 Jan;63(1):4-13.

5) Mutlu GM, Factor P. Role of vasopressin in the management of septic shock. Intensive Care Med. 2004 Jul;30(7):1276-91.

6) Holmes CL, Walley KR. Vasopressin in the ICU. Curr Opin Crit Care. 2004 Dec;10(6):442-8.

7) Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle WA 3rd. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med. 2001 Mar;29(3):487-93.

8) Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. 1999 Oct;47(4):699-703; discussion 703-5.

9) Beale RJ, Hollenberg SM, Vincent JL, Parrillo JE. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med. 2004 Nov;32(11 Suppl):S455-65.

10) Hall LG, Oyen LJ, Taner CB, Cullinane DC, Baird TK, Cha SS, Sawyer MD. Fixed-dose vasopressin compared with titrated dopamine and norepinephrine as initial vasopressor therapy for septic shock. Pharmacotherapy. 2004 Aug;24(8):1002-12.

11) Dellinger RP, Carlet JM, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73. [Available on National Guideline Clearinghouse Website (Guideline.gov): https://www.guidelines.gov/summary/summary.aspx?ss=15&doc_id=4911&nbr=3508] Accessed: June 24, 2005.

12) O'Brien A, Clapp L, Singer M. Terlipressin for norepinephrine-resistant septic shock. Lancet. 2002 Apr 6;359(9313):1209-10.