Septic shock vasopressin

Not yet a first-line agent (the recent Vasopressin in Septic Shock Trial [VASST] showed no difference in 28-d mortality when vasopressin was compared with norepinephrine)... 

Vasopressin levels are increased during hypotension to maintain blood pressure by vasoconstriction. However, there is a vasopressin deficiency in septic shock. Low doses of vasopressin increase MAP, leading to the discontinuation of vasopressors. However, routine use of vasopressin is not recommended because of lack of evidence of efficacy. Vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects and may result in decreased cardiac output and hepatosplanchnic flow. Vasopressin use may be considered in patients with refractory shock despite adequate fluid resuscitation and high-dose vasopressors.24,27-28... 

Fig. 7. Neurohumoral control of the metabolic changes during the acute phase of septic shock. AVP, vasopressin SNS, sympathetic nervous system TAG, triacylglycerol FFA, free faty acid. (Reproduced with permission from Clin. Endocrinol. K. N. Frayn, 24,577-599, 1986, by copyright permission of Blackwell Science Ltd., Oxford, UK.)...

Vasopressin is a peptide hormone produced by the hypothalamus and secreted by the posterior pituitary in response to stimulation. Normal stimuli for vasopressin release are hyperosmolarity and hypovolemia, with thresholds for secretion of greater than 280 mOsm/kg and greater than 20% plasma volume depletion. A number of other stimuli, such as pain, nausea, epinephrine, and numerous drugs, induce release of vasopressin. Vasopressin release is inhibited by volume expansion, ethanol, and norepinephrine. The physiological effect of vasopressin is to promote free water clearence by altering the permeability of the renal collecting duct to water. In addition, it has a direct vasoconstrictor effect. Consequently, vasopressin results in water retention and volume restoration. In patients with septic shock, vasopressin is appropriately secreted in response to hypovolemia and to elevated serum osmolarity (R14). 

Vasopressin causes vasoconstrictive effects that, unlike adrenergic receptor agonists, are preserved during hypoxia and severe acidosis. It also causes vasodilation in the pulmonary, coronary, and selected renal vascular beds that may reduce pulmonary artery pressure and preserve cardiac and renal function. However, based on available evidence, vasopressin is not recommended as a replacement for norepinephrine or dopamine in patients with septic shock but may be considered in patients who are refractory to catecholamine vasopressors despite adequate fluid resuscitation. If used, the dose should not exceed 0.01 to 0.04 units/min. 

The use of vasopressin and terlipressin for the management of septic shock has been reviewed a maximum dose of 0.04 U/minute is recommended (5). Vasopressin 0.23 U/minute in patients with hepatorenal syndrome did not appear to be associated with the adverse effects that occur at the lower doses that are used to treat other critically ill patients (6). 

In a retrospective analysis of 63 patients treated with arginine vasopressin for catecholamine resistant vasodila-tory shock, 30% developed ischemic skin lesions (23). Pre-existing peripheral arterial occlusive disease and septic shock were independent susceptibility factors. 

A 46-year-old woman with septic shock had a peripheral venous infusion of vasopressin 0.04 U/minute in addition to dobutamine, via the subclavian vein extravasation of vasopressin to local soft tissue resulted in ischemic skin necrosis (26). 

A review of trials has suggested that vasopressin is more likely to cause adverse effects at doses of 0.04 U/minute or more when it is used to treat septic shock mesenteric ischemia and cardiac dysfunction and ischemia were particularly associated with high doses (30). The authors suggested that limiting the dosage to 0.03 U/minute may minimize these effects. This suggestion has been supported by a retrospective audit of the effects of continuous vasopressin infusion in septic shock in 102 men and women, mean age 53 years (31). There were adverse events that may have been linked to vasopressin in 18 patients cardiac arrest (n = 9) ischemic/mottled digits (n = 8) myocardial infarction (n = 1) and hyponatremia (n = 1). Adverse events occurred with doses of vasopressin of 0.04 units/minute and over, except in one patient (dose not stated). 

Further data have come from a review of the use of high doses of vasopressin (mean dose 0.47 U/minute) to replace noradrenaline (24). There were reductions in heart rate, cardiac index, and oxygen delivery. The authors recommended that the dose of vasopressin should not exceed 0.04 U/minute and that vasopressin should not be used as a single vasopressor agent in septic shock. 

Delmas A, Leone M, Rousseau S, Albanese J, Martin C. Clinical review vasopressin and terlipressin in septic shock patients. Crit Care 2005 9 212-22. 

Kahn JM, Kress JP, Hall JB. Skin necrosis after extravasation of low-dose vasopressin administered for septic shock. Crit Care Med 2002 30(8) 1899-901. 

Obritsch MD, Bestul DJ, Jung R, Fish DN, MacLaren R. The role of vasopressin in vasodilatory septic shock. Pharmacotherapy 2004 24 1050-63. 

However, accumulating evidence supports the use of norepinephrine in patients with septic shock with a retrospective study demonstrating reduced mortality with norepinephrine over other vasopressors [106]. Furthermore, animal data demonstrates that reversal of septic hypotension with norepinephrine leads to increases in renal blood flow [107]. There are no studies that compare the renal outcomes between catecholamine therapy and vasopressin. 

Vasopressin is emerging as a potentially useful therapy in the hemodynamic support of vasodilatory septic shock. Case series and small clinical trials have reported its use in patients who remain hypotensive on vasopressors. Arginine vasopressin has little pressor activity in normal subjects but markedly increases blood pressure when sympathetic nerve function is impaired, including in septic shock. Unlike the catecholamine vasopressors, vasopressin is a direct vasoconstrictor agent and does not have inotropic or chronotropic effects. As a result, it may decrease cardiac output and hepatosplanchnic flow. In fact, studies of vasopressin in septic shock generally do not enroll patients with a cardiac index of less than 2 to 2.5 L/m per minute. 

Terlipressin, a prodrug converted into lysine vasopressin, has been used recently in septic shock patients." This drug has a half-hfe of 6 hours and acts via vascular receptors aud reual tubular V2 receptors. In one report, terlipressin 1 mg was given intravenously to 15 patients with norepinephrine-resistant septic shock."" Terhpressin was shown to increase MAP at 30 minutes, which lasted for 24 hours. Despite a decrease in cardiac output, terlipressin increased gastric mucosal perfusion, urine output, and creatinine clearance. These preliminary findings suggest that a clinical trial should be conducted that evaluates mortality, in addition to hemodynamic effects. 

Recent data with moderate doses of corticosteroids (200 to 300 mg/day) infused over 5 to 7 days may reverse septic shock and dependency on vasopressor agents, particularly in patients with relative adrenal insufficiency. Data are still needed regarding optimal dosing and the effect on outcomes such as mortality. Initial uncontrolled studies with vasopressin suggest a potential role in the management of vasopressor-refractory septic shock patients, although further data are needed. 

Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997 25 1279—1282. 

Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999 47 699-703. 

Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Chest 2001 120 989-1002. 

Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock A case series. Intensive Care Med 2001 27 1416-1421. 

Russell JA. Vasopressin in septic shock Clinical equipoise mandates a time for restraint. Crit Care Med 2003 31 2707-2708. 

Klinzing S, Simon M, Reinhart K, et al. High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med 2003 31 2646-2650. 

Adverse reactions to vasopressin generally [97 ] and in patients with septic shock [98 , 99 ] have been reviewed. Vasopressin can cause ischemia secondary to vasoconstriction and thrombosis, reduced cardiac output, and hyponatremia. 

A 45-year-old female presented with febrile neutropenia secondary of chemotherapy. The patient quickly decompensated to refractory septic shock in the critical care unit despite implementation of early goal-directed therapy as well as intravenous norepinephrine and vasopressin to stabilise her haemodynamic status. She received a 16-h infusion of 1% methylene blue 0.25 mg, titrated up... 

---