Shock Syndromes I

Low-dose AVP (up to 0.03 units/minute) can be added to norepinephrine as the second-line

adjunctive agent rather than escalating the dose of norepinephrine in patients not at goal MAP.

In patients with septic shock, a relative vasopressin deficiency may exist, and patients may be

sensitive to the vasoconstrictive effects of AVP.

ii.

Because of these effects, AVP has been used in patients with septic shock as both an endocrine

replacement therapy (with a fixed-dose infusion) and a vasopressor (titrated to MAP).

iii.

The Vasopressin and Septic Shock Trial (VASST) compared the effects of adding AVP (0.01–

0.03 units/minute) to norepinephrine with using norepinephrine monotherapy. Patients were

initiated on the study drug an average of 12 hours after meeting the trial’s inclusion criteria

and when norepinephrine was at a mean dose of 20.7 mcg/minute. Overall, the study found

no difference in 28-day mortality between treatment arms (35.4% vs. 39.3%, p=0.26), but

norepinephrine requirements were significantly lower during the first 4 study days in the patients

allocated to AVP (p<0.001). Adverse effects did not differ between groups. In an a priori–

defined subgroup analysis of patients on the basis of shock severity (less severe shock defined

as baseline norepinephrine dose 5–14 mcg/minute) with randomization stratified according to

this covariate, 28-day mortality in the less severe shock stratum (defined as norepinephrine-

equivalent doses less than 15 mcg/minute) was lower in patients randomized to AVP plus

norepinephrine (26.5% vs. 35.7%, p=0.05), with no difference between groups in the more

severe shock stratum (44.0% vs. 42.5%, p=0.76, stratum interaction p=0.10).

iv.

In the VANISH trial, which compared first-line vasopressin (up to 0.06 units/minute) with

norepinephrine, there was no difference between groups in the incidence of kidney failure in

survivors (absolute difference -2.3%; 95% CI, -13.0 to 8.5) or the number of kidney failure–free

days in nonsurvivors (absolute difference -4 days; 95% CI, -11 to 5). Patients were initiated on

the study drug within an average of 3.5 hours from shock onset and at a mean norepinephrine

dose of 0.16 mcg/kg/minute. Patients were also randomized to hydrocortisone or placebo (in

a 2 × 2 factorial design), but there was no significant interaction between vasopressin and

hydrocortisone (interaction p=0.98 for 28-day mortality). Although the study intended to

evaluate vasopressin as a first-line agent, 85% of patients were receiving open-label vasopressors

before randomization.

One consistent finding with the use of AVP in clinical trials is the reduction in norepinephrine

dose requirements after its initiation, making it an attractive norepinephrine- and catecholamine-

sparing agent.

vi.

Findings regarding the effects of AVP (and its analogs) on mortality have been conflicting

in meta-analyses. One meta-analysis found a decreased mortality risk in patients with septic

shock allocated to AVP (RR 0.87; 95% CI, 0.75–1.0; p=0.05), whereas another study found no

significant benefit with AVP (RR 0.91; 95% CI, 0.79–1.05; p=0.21). Both meta-analyses found

a significant benefit of AVP in decreasing norepinephrine doses. In an updated meta-analysis

performed for the 2016 SSC guidelines, mortality did not differ between norepinephrine and

vasopressin (RR 0.89; 95% CI, 0.79–1.00). A recent meta-analysis (which included the VANISH

study) corroborated this and found no significant effect on mortality with vasopressin use (RR

0.98; 95% CI, 0.86–1.12).

vii.

The 2021 SSC guidelines note that the threshold for adding vasopressin is unclear, but it is

reasonable to consider initiation when the dose of norepinephrine is 0.25–0.5 mcg/kg/minute.

viii.

High-dose vasopressin (doses above 0.03–0.04 units/minute) should be reserved for salvage

therapy and, if used, should be used cautiously.