Is vasopressin only effective 50% of the time for blood pressure?

Comment by InpharmD Researcher

Most studies investigating use of vasopressin focus on clinical outcomes in the treatment of septic shock, such as mortality, duration of hospitalization, and need for renal replacement therapy (RRT). Limited data are available regarding the effects of vasopressin on blood pressure reduction, with one study reporting an average of 63% of patients treated with vasopressin achieved goal mean arterial pressure (see Table 1). Impact of vasopressin on clinical outcomes appears to be mixed across other studies, with pooled analyses finding no significant improvement in several outcomes compared to controls, while noting benefits for select endpoints, such as reduced need for RRT.

Background

Surviving sepsis campaign guidelines published in 2021 provide guidance for patients hospitalized with sepsis or septic shock. Adults who are on norepinephrine for septic shock but unable to reach mean arterial pressure levels are recommended to receive adjunct vasopressin instead of escalating norepinephrine doses. Vasopressin’s effect on blood pressure was not addressed. [1]

A 2021 systematic review and meta-analysis investigated the efficacy of vasopressin use in patients with septic shock using data compiled from 5 studies (N= 788 patients); most studies were small-scale single center cohort studies, with only one randomized controlled trial included. All studies included patients receiving vasopressin infusion within 6 hours of septic shock diagnosis compared to control group patients receiving no vasopressin or vasopressin infusion later than 6 hours after diagnosis. While study outcomes did not compare the effect of vasopressin on blood pressure outcomes, pooled data indicated that there was no significant difference between the two groups for short-term mortality, which was evaluated as the primary outcome of the analysis. Similarly results were observed for most secondary outcomes, with no difference observed between groups for incidence of new onset arrhythmias, intensive care unit length of stay, and length of hospitalization. Use of renal replacement therapy, however, was significantly less in patients treated with early vasopressin compared to those in the control group (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.44 to 0.88; p= 0.007). Overall, efficacy of early vasopressin in this clinical setting may be subpar for prevention of most assessed clinical outcomes compared to no vasopressin or later vasopressin administration. [2]

Other meta-analyses have evaluated the outcomes of patients with septic shock with vasopressin treatment versus other vasoactive comparators, including norepinephrine. Vasopressin has been reported to have no effect on 28-day mortality, serious adverse events, mesenteric ischemia, or acute coronary syndrome events compared to controls in one article, while another found no differences in mortality, duration of hospitalization, and adverse effects between vasopressin and norepinephrine. Similarly, pooled data for mean arterial pressure at 24 h was comparable across vasopressin and norepinephrine; whether these findings adequately capture the efficacy rate of vasopressin, however, is uncertain. [3], [4]

References:

[1] Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337
[2] Huang H, Wu C, Shen Q, Xu H, Fang Y, Mao W. The effect of early vasopressin use on patients with septic shock: A systematic review and meta-analysis. Am J Emerg Med. 2021;48:203-208. doi:10.1016/j.ajem.2021.05.007
[3] Nagendran M, Russell JA, Walley KR, et al. Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. Intensive Care Med. 2019;45(6):844-855. doi:10.1007/s00134-019-05620-2
[4] Sedhai YR, Shrestha DB, Budhathoki P, et al. Vasopressin versus norepinephrine as the first-line vasopressor in septic shock: A systematic review and meta-analysis. J Clin Transl Res. 2022;8(3):185-199. Published 2022 May 25.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is vasopressin only effective 50% of the time for blood pressure?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

A comparison of initial monotherapy with norepinephrine versus vasopressin for resuscitation in septic shock
Design

Retrospective noninferiority case-cohort study

N= 130 participants
Objective

To determine whether vasopressin was noninferior to norepinephrine as the initial vasopressor to achieve a mean arterial pressure (MAP) goal in the first 6 hours of shock onset
Study Groups

Norepinephrine (n= 65)

Vasopressin group (n= 65)
Inclusion Criteria Adults older than 18 years who received either vasopressin or norepinephrine monotherapy for a diagnosis of septic shock
Exclusion Criteria

Patients admitted to a cardiology or cardiothoracic surgery service, or those who did not have a 1:1 frequency match based on severity of illness ranges in the vasopressin treatment arm
Methods

Patients received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy. Vasopressin was administered at a fixed dose of 0.04 units/min per institutional protocol. Data were collected from electronic medical records, and patients were matched 1:1 to norepinephrine based on severity of illness using APACHE II scores.
Duration

Trial: May 2008 to September 2009

Intervention administered within first 6 hours of septic shock onset
Outcome Measures

Primary: Proportion of patients achieving MAP goal ≥65 mm Hg within 6 hours

Secondary: Time course of septic shock, all-cause mortality, ICU length of stay, requirement for renal replacement therapy (RRT)
Baseline Characteristics Characteristic Norepinephrine (n= 65) Vasopressin (n= 65) p-value
Age, years 56 ± 17.7 61 ± 17.7 0.11
Sex, male 35 (53.8%) 34 (52.3%) 0.86

Admission service

Medical

Surgical

 

39 (60%)

26 (40%)

 

65 (100%)

-

 

0.001

-
APACHE II score

27.8 ± 8.1

 28.1 ± 7.2 0.8
Results Variable

Norepinephrine (n= 65)

 Vasopressin (n= 65) p-value

MAP goal attainment

 44 (67.7%) 41 (63%) 0.69

Time course of septic shock

Time until goal with monotherapy (IQR), hours

Additional vasoactive agent, if goal not achieved in 6 hours

Time until additional agent added within first 6 hours (IQR), hours

 

1 (1 to 1.25); n= 44

18 (85.7%); n= 21

5 (4 to 12)

 

1 (1 to 2); n= 41

21 (87.5%); n= 24

5 (4 to 7)

 

0.23

0.86

0.23

ICU length of stay (IQR), days

 7 (3 to 15) 7 (4 to 24) 0.25

All-cause mortality

 32 of 65 (49.2%) 29 of 65 (44.6%) 0.6

Requirement for RRT

 21 of 65 (32.3%) 19 of 65 (29.2%) 0.7
Adverse Events Not specifically reported in the study.
Study Author Conclusions

Vasopressin was noninferior to norepinephrine for achieving a MAP goal in the first 6 hours from onset of septic shock. The results suggest vasopressin as a viable alternative in the setting of norepinephrine shortages.
Critique

The study's retrospective design and lack of blinding may introduce bias. The exclusion of a large portion of the cohort could lead to selection bias. The study was not powered to detect differences in mortality or adverse events. Prospective studies are needed to confirm these findings.
References:

Daley MJ, Lat I, Mieure KD, Jennings HR, Hall JB, Kress JP. A comparison of initial monotherapy with norepinephrine versus vasopressin for resuscitation in septic shock. Ann Pharmacother. 2013;47(3):301-310. doi:10.1345/aph.1R442

 

Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock
Design

Retrospective cohort study

N= 96 participants
Objective

To assess whether early initiation of vasopressin (AVP) to norepinephrine results in reduced time to target mean arterial pressure (MAP) compared to norepinephrine (NE) monotherapy in septic shock patients
Study Groups

NE and early AVP group (n= 48)

Initial NE monotherapy group (n= 48)
Inclusion Criteria

Patients aged ≥18 years, admitted to the pulmonary/critical care service, met sepsis-3 definition of septic shock, received continuous infusion of norepinephrine for at least 6 hours 
Exclusion Criteria

End-stage renal disease requiring dialysis, end-stage hepatic disease, death within 48 hours of ICU admission, receiving continuous infusion of other vasopressors prior to initiation, admitted from an outside hospital
Methods

Patient data were collected via review of electronic health records. Included patients were initiated on norepinephrine with the option to add vasopressin within 4 hours. Time to goal MAP was compared using Student t-test and Kaplan-Meier curves. SOFA scores evaluated with Wilcoxon rank sum test.
Duration

Trial: May 2014 to October 2015
Outcome Measures

Time to achieving and maintaining MAP ≥65 mm Hg for at least 4 hours
Baseline Characteristics Characteristic NE and Early AVP (n= 48) Initial NE Monotherapy (n= 48) p-value
Age, years 58.6 ± 14.6 56.9 ± 15.4 0.585
Male 23 (48%) 24 (50%) 0.999
SOFA score at 6 hours 9.9 ± 3.1 8.8 ± 2.9 0.010
Positive culture 17 (35%) 28 (58%) 0.040
Results Endpoint NE and Early AVP (n= 48) Initial NE Monotherapy (n= 48) p-value
Time to MAP target, hours 6.2 ± 4.9 9.9 ± 9.1 0.023
Adverse Events No significant difference in new-onset arrhythmias between groups (6% vs 8%).
Study Author Conclusions Early initiation of vasopressin in combination with norepinephrine within 4 hours of septic shock onset achieved MAP faster and may resolve organ dysfunction more effectively than norepinephrine monotherapy.
Critique The study's strengths include its focus on early intervention and its practical implications for clinical practice. Limitations include its retrospective design, lack of a protocol for vasopressor initiation, and potential confounding factors not controlled for in the analysis.
References:

Hammond DA, Cullen J, Painter JT, et al. Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock. J Intensive Care Med. 2019;34(11-12):910-916. doi:10.1177/0885066617725255