Drug Information Center

General management of sepsis may include antimicrobial therapy, usually broad-spectrum agents, mechanical ventilation, fluid resuscitation, vasopressors, steroids, and tight glucose control.

Septic shock is characterized by vasodilatory hypotension and hemodynamic instability secondary to sepsis that is not responsive to fluid resuscitation. This results in inadequate delivery of oxygen to the tissue. Initial fluid resuscitation usually consists of giving a liter of normal saline or other crystalloid over 30 minutes; alternatively colloids such as albumin or non-protein colloids in smaller volumes can be given to patients. Goals for fluid resuscitation are to elevate and maintain central venous pressure (CVP) at 8 to 12 mmHg. For patients who are mechanically ventilated, CVP can be kept above 12 mmHg.

In 2001, the New England Journal of Medicine published a trial that evaluated the benefit of early intervention with vasoactive agents. The primary endpoint in this study was in-house mortality. Two hundred sixty three patients were randomized to receive either early goal-directed therapy or standard care. Baseline characteristics were similar in each group. Despite the fact that the standard care group spent less time in the emergency department, they had a significantly higher in-house mortality compared to the patients who received early goal-directed therapy (p=0.009). This difference remained significant at 28 days (p=0.01) and at 60 days (p=0.03). The results of the study showed that achievement of this goal CVP is important, and reaching the goal early improves mortality.

First-line vasopressors include norepinephrine and dopamine. Norepinephrine, a naturally occurring catecholamine, acts primarily on alpha receptors to cause an increase in peripheral vascular resistance and mean arterial pressure. Dopamine, also an endogenous catecholamine, has dose-dependent effects on the receptors. At doses of 5 to 10 mcg/kg/min, dopamine primarily affects the beta receptors and does so to a greater degree than norepinepherine. As a result, dopamine can cause significant tachycardia and is used less often than norepinepherine.

Vasopressin, also known as antidiuretic hormone, is an endogenous hormone that plays a role in blood pressure control. In healthy individuals, vasopressin’s primary role is in chronic maintenance of the blood pressure. It exerts its effects on the kidneys to cause the retention of free water. In patients with septic shock, the mechanism changes and its effects on the blood pressure are predominantly mediated by increased vascular tone. Vasopressin can have dramatic effects on blood pressure in patients with septic shock largely because these patients have a relative deficiency of the hormone. Low doses of vasopressin have been used to replace the endogenous source and raise blood pressure. Since there is no “catecholamine-deficiency” in patients with sepsis, it was theorized that the use of vasopressin in sepsis could have greater beneficial effects than other vasopressors even when used at low doses. In addition, the use of vasopressin in combination with catecholamines, such as dopamine and norepinephrine, is beneficial since they have different mechanisms of action.

Several trials have evaluated the use of vasopressin in patients with septic shock. A 2003 study published in Circulation revealed that the combined treatment with vasopressin and norepinephrine was superior to treatment with norepinephrine alone. Patients receiving vasopressin were able to maintain mean arterial pressure (MAP) with lower heart rates, higher wedge pressures, and higher cardiac index; additionally they required less norepinephrine. Patients receiving solely norepinephrine were at greater risk for tachyarrhythmias such as atrial fibrillation.

Despite a theoretical reason for benefits and the above improvements in hemodynamic status, there has not been any evidence of a decrease in overall mortality or improvement in patient outcome. In February of 2008, the Vasopressin and Septic Shock Trial (VASST) was published.

VASST was a multicenter, randomized, double blind trial. It included patients in septic shock who required vasopressors to maintain adequate blood pressure. It represents the first study powered to show a difference in mortality, with a primary outcome of all-cause-mortality at 28 days. Secondary outcomes evaluated 90-day mortality, length of stay in both the ICU and the hospital, and adverse events. In order to enter the trial, patients with septic shock had to fail fluid resuscitation and a low-dose infusion of norepinephrine. Patients were then randomized to receive either norepinephrine 15 mcg/min or vasopressin 0.03 U/min.

The VASST study group determined that 776 patients were needed to have an 80% power to detect an absolute difference of 10% mortality. A total of 802 patients were randomized; 382 patients who received norepinephrine and 396 who received vasopressin were evaluated. The primary endpoint of 28-day mortality was not significantly different between the groups (35.4% in the vasopressin vs. 39.3% in the norepinephrine group, p=0.26). There were also no significant differences in 90-day mortality (43.9% vs. 49.6%, p=0.11) or in organ failure (p=0.14). There was no significant difference in adverse effects between the study groups (10.3% and 10.5%, p=1.00).

A priori, patients were stratified based on the severity of sepsis. Patients were defined as having less severe sepsis if they required less than 15 mcg/hr of norepinephrine at baseline. The hypothesis was that patients with more severe sepsis would have greater benefits from vasopressin. When the subgroup analyses were completed, there was no difference for the severe sepsis group for 28-day or 90-day mortality (p= 0.76 and 0.84 respectively). Russell and colleagues concluded that low-dose vasopressin provided no mortality benefit when used in patients with septic shock.

Limitations of the study include:

• There is no evidence that patients were adequately fluid resuscitated and the trial defined resistance to fluids as no response to a bolus of 500 mL of NS, which would be under-resuscitation according to the current guidelines.
• In order to be included in the trial, the patients had to be on vasopressors for 6 hours. Early, goal-directed therapy is an important cornerstone for the current treatment of sepsis. Vasopressin may have demonstrated greater benefit if it were added earlier.
• Baseline MAP was greater than 65 in both groups, implying that patients did not require additional vasopressors at the time vasopressin was started.
• Finally, the inclusion and exclusion criteria were so rigid that over 5000 patients were evaluated but not enrolled. While they may have come up with homogenous study sample, it is unlikely that this reflects the population commonly seen in practice.

Sepsis is a severe condition that produces a vasodilatory shock that is often resistant to fluid resuscitation and can require multiple vasopressors. Patients with septic shock also have a relative vasopressin deficiency. VASST was designed to evaluate if the use of vasopressin in addition to standard vasopressor therapy would have a beneficial impact on mortality. VASST did not demonstrate a clear mortality benefit in its study population. While VASST did not promote vasopressin into a more prominent role in sepsis, the new 2008 Surviving Sepsis Guidelines still recommend the continued use of vasopressin as an add-on therapy to the first-line vasopressors, norepinephrine and dopamine.

References
O’Brien JM, Ali NA, Aberegg SK, Abraham E. Sepsis. Am J Med. 2007;120(12):1012-1022.

Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 Intensive Care Med. 2008 Jan;34(1):17-60.

Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock N Engl J Med. 2001;345(19):1368-1377.

Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004;32(9):1928-1948.

Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95(5):1122-1125.

Russell JA. Vasopressin in septic shock. Crit Care Med. 2007;35(9):S609-S615.

Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation. 2003;107(18):2313-2319.

Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358(9):877-87.