Vasopressin Dosing for Septic Shock

The recent Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016 (SSC2016) updated previous recommendations to include vasopressin as an alternative second-line agent to epinephrine to either raise mean arterial blood pressure or decrease norepinephrine dosage. ¹ This is a welcome update that reflects contemporary practice at many institutions; however, there is debate regarding the optimal dosing strategy. The guidelines recommend adding vasopressin at a dose up to 0.03 U/min. This may be interpreted as either titrating from 0.01 to 0.03 U/min or initiating at a fixed dose of 0.03 U/min. However, early administration of vasopressin at a higher fixed dose may offer more hemodynamic benefit.

The rationale for the proposed dosing strategy by the SSC2016 comes from the VASST trial, a large randomized controlled trial where patients were randomized to either norepinephrine and placebo or norepinephrine and vasopressin (0.01 titrated up to 0.03 U/min). ² This analysis demonstrated no difference in the primary end point of mortality at 28 days, but subgroup analysis did show improved survival among patients receiving lower norepinephrine doses at randomization (<15 µg/min). The SSC2016 justification for not recommending higher doses was a result of the concern for adverse events, including cardiac, digital, and splanchnic ischemia, based on a report with doses used that ranged from 0.067 to 0.1 U/min. ³ Doses of 0.04 U/min have been shown to be effective without increasing these complications. ⁴

Vasopressin levels during septic shock are typically elevated but rapidly become depleted. A normal stress response of vasopressin is 10 to 200 pg/mL in a hypotensive state, but the optimal target vasopressin level in septic shock may be higher. ⁵ The median baseline vasopressin level in the VASST trial was 3.47 pg/mL and remained low in patients who received no vasopressin. However, plasma levels were significantly increased to a median of 73.6 pg/mL at 6 hours and 106.2 pg/mL at 24 hours in patients who received vasopressin. Vasopressin levels were higher in patients who received concomitant hydrocortisone, presumably as a result of a synergistic interaction. ⁶ Levels rapidly returned to baseline when the infusion was discontinued. ² The study investigators did not provide data on differences in vasopressin levels between patients who received higher (≥15 µg/min) and lower (<15 µg/min) doses of norepinephrine. Initiating vasopressin at a fixed rate of 0.04 U/min achieves a concentration of 289.3 pg/mL in as little as 16 hours. ⁵ Although the ideal therapeutic level of vasopressin is still unknown, either giving lower doses of vasopressin (0.01-0.03 U/min) with hydrocortisone (200 mg/d) or higher-dose vasopressin (0.04 U/min) may achieve higher levels, with potentially improved clinical outcomes. ⁶

The recent VANISH trial also assessed the impact of vasopressin on kidney failure–free days in septic shock, utilizing a titration range of 0.01 to 0.06 U/min. ⁷ However, they did not measure plasma vasopressin levels, and patients who received vasopressin in this study were titrated below 0.04 U/min after the third day of therapy. Interestingly, this analysis showed a trend toward higher rates of digital ischemia. It is unknown if allowing titration up to 0.06 U/min contributed to this phenomenon. Therefore, extrapolation from this analysis may be limited. Both the VASST and VANISH trials demonstrated that vasopressin initiation has a significant norepinephrine sparing effect.^2,7

The addition of vasopressin as a second-line agent by the SSC2016 is a major change that represents a significant step forward in reducing the overall catecholamine burden to patients in septic shock. Although the SSC2016 recommends utilizing a low vasopressin titration (up to 0.03 U/min), strategies that achieve higher concentrations, such as higher fixed doses (ie, 0.04 U/min) or adjunctive corticosteroids, may optimize hemodynamics without increasing ischemic complications. More research is needed to further explore possible benefits of early, fixed-dose vasopressin and optimal vasopressin levels in septic shock.