Vasopressin versus norepinephrine as the first-line vasopressor in septic shock: A systematic review and meta-analysis

Abstract

Background and aim:
Norepinephrine is currently the first-line vasopressor for septic shock. We conducted this meta-analysis to examine the outcomes of adult patients with septic shock who received vasopressin instead of norepinephrine.
Methods:
We selected studies in adults with septic shock that compared the outcomes of patients treated with vasopressin versus norepinephrine. Cochrane ROB 2.0 and the JBI (Joanna Briggs Institute) quality assessment tools were used to assess the risk of bias in RCTs and observational studies. Meta-analysis was conducted using RevMan 5.4.
Results:
Eight studies were included in this meta-analysis. There were no significant differences in 28-day mortality rates (OR, 1.07; CI, 0.80-1.44) and ICU mortality (OR, 0.74; CI, 0.21-2.67) between the two groups. Similarly, length of ICU stay, length of hospital stay, mean arterial pressure at 24 hours, urine output at 24 hours, and serious adverse events also did not differ significantly. However, the odds of renal replacement therapy (RRT) requirement in the vasopressin group were substantially lower than in the norepinephrine group (OR, 0.68; CI, 0.47-0.98).
Conclusion:
There were no differences in mortality, duration of hospitalization, and adverse effects in adults with septic shock across the two groups. However, the patients treated with vasopressin had lower chances of requiring RRT.
Relevance for patients:
Vasopressin use as the first-line vasopressor in septic shock showed a significant reduction in RRT though there were no significant differences in terms of mortality and other adverse events. Therefore, vasopressin can be considered as a first-line vasopressor in septic shock patients with other risk factors which may contribute to renal failure requiring RRT.

Full text

DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
Journal of Clinical and Translational Research 2022; 8(3): 185-199
REVIEW ARTICLE
Vasopressin versus norepinephrine as the rst-line vasopressor in sepc
shock: A systemac review and meta-analysis
Yub Raj Sedhai1, Dhan Bahadur Shrestha2*, Pravash Budhathoki3, Waqas Memon4, Roshan Acharya5, Suman Gaire6,
Nisheem Pokharel7, Swojay Maharjan8, Ranjit Jasaraj2, Amik Sodhi9, Dipen Kadariya10, Ankush Asija11,
Markos G. Kashiouris12
1Department of Internal Medicine, Division of Hospital Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia,
United States, 2Department of Internal Medicine, Mount Sinai Hospital, Chicago, Illinois, United States, 3Department of Internal Medicine, Bronxcare
Health System, Bronx, New York, United States, 4Department of Internal Medicine, Division of Nephrology, University of Virginia School of Medicine,
Charlottesville, Virginia, United States, 5Department of Internal Medicine, Cape Fear Valley Medical Center, Fayetteville, North Carolina, United
States, 6Department of Emergency Medicine, Palpa Hospital, Palpa, Nepal, 7Department of Emergency Medicine, KIST Medical College, Lalitpur,
Nepal, 8Nepalese Army Institute of Health Sciences, Kathmandu, Nepal, 9Department of Internal Medicine, Division of Pulmonary Disease and Critical
Care Medicine, University of Wisconsin, Madison, Wisconsin, United States, 10Attending Physician, Pulmonary Disease and Critical Care Medicine,
Independent Practitioner, 11Department of Internal Medicine, West Virginia University, Morgan Town, West Virginia, United States, 12Department of
Internal Medicine, Division of Pulmonary Disease and Critical Care Medicine, VCU School of Medicine, Richmond, Virginia, United States
Abstract
Background and Aim: Norepinephrine is currently the rst-line vasopressor for septic shock. We
conducted this meta-analysis to examine the outcomes of adult patients with septic shock who received
vasopressin instead of norepinephrine.
Methods: We selected studies in adults with septic shock that compared the outcomes of patients
treated with vasopressin versus norepinephrine. Cochrane ROB 2.0 and the Joanna Briggs Institute
quality assessment tools were used to assess the risk of bias in RCTs and observational studies. Meta-
analysis was conducted using RevMan 5.4.
Results: Eight studies were included in this meta-analysis. There were no signicant dierences in
28-day mortality rates (OR, 1.07; CI, 0.80–1.44) and intensive care unit (ICU) mortality (OR, 0.74; CI,
0.21–2.67) between the two groups. Similarly, length of ICU stay, length of hospital stay, mean arterial
pressure at 24 h, urine output at 24 h, and serious adverse events also did not dier signicantly.
However, the odds of renal replacement therapy (RRT) requirement in the vasopressin group were
substantially lower than in the norepinephrine group (OR, 0.68; CI, 0.47–0.98).
Conclusion: There were no dierences in mortality, duration of hospitalization, and adverse eects
in adults with septic shock across the two groups. However, the patients treated with vasopressin had
lower chances of requiring RRT.
Relevance for Patients: Vasopressin use as the rst-line vasopressor in septic shock showed a
signicant reduction in RRT, though there were no signicant dierences in terms of mortality and
other adverse events. Therefore, vasopressin can be considered as a rst-line vasopressor in septic
shock patients with other risk factors which may contribute to renal failure requiring RRT.
1. Introduction
Septic shock is the leading cause of mortality in intensive care units (ICUs) [1,2]. In
2015, it was estimated that there were more than 230,000 cases of septic shock in the
United States which directly caused more than 40,000 deaths per year [3]. Septic shock
management revolves around timely source control and hemodynamic resuscitation,
ARTICLE INFO
Article history:
Received: November 4, 2021
Revised: March 21, 2022
Accepted: March 30, 2022
Published online: May 25, 2022
Keywords:
norepinephrine
norepinephrine
outcomes
renal replacement
septic shock
vasopressin
*Corresponding author:
Dhan Bahadur Shrestha
Department of Internal Medicine, Mount Sinai
Hospital, Chicago, Illinois, United States.
Email: medhan75@gmail.com
© 2022 Author(s). This is an Open
Access article distributed under the terms
of the Creative Commons Attribution-
NonCommercial License, permitting all non-
commercial use, distribution, and reproduction
in any medium, provided the original work is
properly cited.
Journal of Clinical and Translational Research
Journal homepage: http://www.jctres.com/en/home

186 Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
ensuring end-organ perfusion. Crystalloids are used to expand
the intravascular volume and catecholamine infusions,
that is, norepinephrine, to provide cardiovascular support.
Catecholamines, however, may reduce blood ow to end organs
despite adequate perfusion pressure [4,5]. Vasopressin is an
endogenously released peptide hormone that has been used
as an adjunct to catecholamines for patients with septic shock
not responding to uids. Studies have shown that septic shock
patients have relative vasopressin deciency [6,7]. Vasopressin
use restores vascular tone and decreases norepinephrine
requirements [6,7]. Two small randomized and controlled
trials (RCTs) showed that vasopressin improved mean arterial
pressure (MAP) and expedited norepinephrine withdrawal [8,9].
Furthermore, vasopressin maintained glomerular ltration rate
and creatinine clearance compared with norepinephrine [8,10].
The VASST trial, the largest multicenter, double-blind RCT,
compared vasopressin, and norepinephrine in patients with septic
shock; no mortality benet was demonstrated in the trial [11].
In the subsequent VANISH trial, early use of vasopressin
compared with norepinephrine did not improve the number of
kidney failure-free days [12]. Yet, the trial mentioned that the
condence interval included a potential clinically meaningful
benet for vasopressin and the need for further large-scale trials,
highlighting a persistent knowledge gap.
In light of the knowledge gap regarding the benets of
vasopressin in septic shock, we sought to conduct this systematic
review and meta-analysis to appraise the available evidence fully
and compare the use and benets of vasopressin compared to
norepinephrine in patients with septic shock.
1.1. Objectives
The objectives of the study are as follows:
• To compare mortality and length of stay in patients with septic
shock receiving norepinephrine compared to vasopressin
• To compare MAP and urine output in patients with septic
shock receiving norepinephrine compared to vasopressin
• To compare serious adverse events and renal replacement
therapy (RRT) among patients with septic shock receiving
norepinephrine compared to vasopressin.
2. Methods
Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) guidelines were used for our systematic
review [13]. The protocol for review was published in PROSPERO
(CRD42021226012) [14].
2.1. Inclusion criteria
2.1.1. Types of studies
We included studies focusing on mortality, clinical
improvement, length of hospital stays, adverse eects, mean
dierence of clinical improvement, and recovery among patients
receiving vasopressin compared to norepinephrine for septic
shock.
2.1.2. Types of participants
We included all adult patients suering from septic shock who are
more than 18 years of age who received vasopressin or norepinephrine.
2.1.3. Types of Interventions
The treatment arm consists of patients receiving vasopressin for
septic shock, while the control arm consists of patients receiving
norepinephrine for septic shock.
2.1.4. Types of outcome measures
For our quantitative analysis, mortality, length of stay, MAP,
urine output, RRT, and serious adverse eects rates were the
outcomes of interest.
2.1.5. Outcomes
We compared mortality, length of stay, MAP, urine output, RRT,
and serious adverse eects among septic shock patients receiving
vasopressin compared to those receiving norepinephrine.
2.2. Search strategies
PubMed, PubMed Central, Embase, and Scopus were
independently searched, and the quality of the studies done in the
past decade was evaluated. Finally, we ltered the studies using
Covidence and extracted data for quantitative and qualitative
synthesis [15]. Any potential conict was solved by taking the
nal opinion of another reviewer.
2.2.1. Electronic searches
We have documented the detailed search strategy in
Supplementary File 1.
2.3. Data collection and analysis
We extracted the data for quantitative synthesis through
Covidence and did the analysis using RevMan5.4 [15,16]. We used a
random/xed eect to pool selected studies based on heterogeneity.
2.3.1. Selection of studies
We have included RCTs, prospective, observational studies, and
cohort studies for septic shock, comparing the outcomes of those
receiving vasopressin with norepinephrine. We excluded studies
in the entire study population in which vasopressin was used for
the treatment among the pediatric age group, pregnant women,
and shock other than septic shock. In addition, we excluded meta-
analyses, reviews, editorials, commentary, and the studies with no
data required for quantitative analysis.
2.3.2. Data extraction and management
We evaluated the quality of studies thoroughly and considered
only the outcomes in our interest.
2.3.3. Assessment of risk of bias in included studies
We used the Cochrane ROB 2.0 tool to analyze our RCTs
(Figure 1) and the Joanna Briggs Institute (JBI) quality assessment

Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199 187
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
tools to assess the risk of bias in our prospective and retrospective
observational studies (Table 1) [17,18]. We used RevMan 5.4 for
creating a summary of biases for RCTs using the Cochrane ROB
2.0 tool.
2.3.4. Assessment of heterogeneity
The I-squared (I2) test was used for the assessment of
heterogeneity [22]. We interpreted the I-squared (I2) test done
based on the Cochrane Handbook for Systematic Reviews of
Interventions [22].
2.3.5. Assessment of reporting biases
Reporting bias was checked by prexed reporting of the
outcome.
2.3.6. Data synthesis
Statistical analysis was performed using RevMan 5.4 software.
Odds ratio (OR) was used for outcome estimation with a 95%
condence interval (CI). The xed/random-eects model was
used according to heterogeneities. Mean and standard deviation
were formulated based on median and interquartile range. We
used mean dierences for outcomes such as the length of stay,
MAP, and urine output using the mean and standard deviation
values obtained from the study [23].
2.3.7. Subgroup analysis and investigation of heterogeneity
We used the random eect model in cases of heterogeneity.
2.3.8. Sensitivity analysis
Non-randomized studies were excluded for sensitivity analysis
to nd any alterations in the outcomes after removal.
3. Results
A total of 2442 studies were imported after a comprehensive
database search. After removing duplicates, the title and abstracts
of 2417 studies were screened, followed by the exclusion of 2382
studies. Thirty-ve full-text studies were assessed for eligibility,
and 27 studies were excluded for denite reasons. Eight studies
were included in the narrative summary (Table 2), and seven
studies were included in the quantitative analysis. The following
is represented in the PRISMA ow diagram (Figure 2).Figure 1. Cochrane ROB bias assessment.
Table 1. JBI bias assessment.
S. No JBI checklist for cohort studies Russell et al., 2018 [19]Hall et al., 2004 [20]Daley et al., 2013 [21]
1 Were the two groups similar and recruited from the same
population?
Yes Yes Yes
2 Were the exposures measured similarly to assign people to both
exposed and unexposed groups?
Yes Yes Yes
3 Was the exposure measured in a valid and reliable way? Yes Yes Yes
4 Were confounding factors identied? No Yes No
5 Were strategies to deal with confounding factors stated? No Yes No
6 Were the groups/participants free of the outcome at the start of
the study (or at the moment of exposure)?
Yes Yes Yes
7 Were the outcomes measured in a valid and reliable way? Yes Yes Yes
8 Was the follow-up time reported and sucient to be long enough
for outcomes to occur?
Yes Yes Yes
9 Was follow-up complete, and if not, were the reasons to loss to
follow-up described and explored?
Unclear Yes Yes
10 Were strategies to address incomplete follow-up utilized? No NA NA
11 Was appropriate statistical analysis used? Yes Yes Yes
Overall appraisal Include Include Include

188 Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
Table 2. Narrative summary of included studies.
Study ID Population Intervention Comparisons Outcome
Patel et al.,
2002 [8]
Prospective,
double blind,
randomized,
and controlled
trial
Patients experiencing septic
shock that required high dose
vasopressor support
N=24 (C=11, T=13)
Male: T=77% C=73%
Female T=23% C=27%
Value (Median, Q1, Q3D)
C: 68 (58,75)
T: 68 (58,70)
The starting volume of the
vasopressin infusion was
7 ml/h. This corresponded
to a vasopressin infusion
of 0.01 units/min. The
maximum rate of infusion
allowed in this study
protocol was 56 ml/h
of blinded study drug,
which corresponded to a
vasopressin infusion rate of
0.08 units/min
The starting volume
of the norepinephrine
infusion was 7 ml/h.
This corresponded to a
norepinephrine infusion of
2 μg/min. The maximum
rate of infusion allowed in
this study protocol was 56
ml/h of blinded study drug,
which corresponded to a
norepinephrine infusion rate
of 16 μg/min
Mean arterial pressure: Median (q1, q3)
T: Baseline 69 (65,72) After 4 h 69 (65,70) mm of Hg
C: Baseline 68 (65,70) After 4 h 67 (61,70) mm of Hg
Urine output: Mean
T: Baseline: 32.5 ml.h After 4 h: 65 ml/h
C: Baseline: 25 ml/h After 4 h: 15 ml/h
Cardiac index: Median (q1, q3)
T: Baseline 4.8 (3.5,5.5), After 4 h: 4.4 (3.1,5.3)
C: Baseline 5.0 (3.8, 5.6) After 4 h: 4.0 (3.2, 5.1)
Heart rate: Median (q1, q3)
T: Baseline: 102 (90, 110) bpm after 4 : 93 (91, 100) bpm
C: baseline :97 (89, 110) bpm after 4 :92 (83, 100) bpm
Systemic vascular ressitance index: Median (q1, q3)
T: Baseline: 905 (838, 1044), After 4 hours: 948 (864,1130)
C: Baseline 750 (681, 1173) After 4 hours: 781 (662, 1263)
Morelli et al.,
2009 [24]
Prospective
randomized
controlled trial
Patients with septic shock with
mean arterial pressure below
65 mm of Hg despite adequate
volume resuscitation
N=45 (T1=15/45, C=15, 45,
T2=15/45)
Male T1=67%, C=80%,
T2=73%
Female T1=33%, T2=27%,
C – 20%)
Value (median, Q1, Q3)
Age:
T1: 66 (60,74)
T2: 67 (69,71)
C: 64 (59,72)
T1: Vasopressin
(0.03 units/min)
T2: Terlipressin
(1.3 μgkg-1h-1)
All three groups received
open-label norepinephrine
and intravenous
hydrocortisone as a
continuous infusion
C: Norepinephrine
(15 μg/min-1)
ICU mortality
T1: 8/15 T2: 7/15 C: 10/15
ICU length of stay (Median, q1, q3)
T1: 17 (5,27) T2: 14 (9,25), C: 17 (7, 23)
Norepinephrine requirement at 48 h
T1: 0.8 μgkg-1 min-1
T2: 0.2 μgkg-1 min-1
C: 1.2 μgkg-1 min-1
Urine output (ml/h)
T1: Baseline: 42.3±46.9; 24 h: 42±41.6; 48 h: 43.3±58.7
T2: Baseline: 34.6±31.3; 24 h: 49.2±49.5; 48 h: 46.6±33.3
C: Baseline: 38.6±34.3; 24 h: 66±77; 48 h: 58.6±63.8
Mean arterial pressure
T1: Baseline: 53±4; 24 h: 70±3; 48 h: 71±3 mmHg
T2: Baseline: 53±4; 24 h: 71±3; 48 h: 71±4 mm Hg
C: Baseline: 54±3; 24 h: 71±2; 48 h: 71±3 mmHg
Heart rate
T1: Baseline: 100±22 At 48 h: 93±25 bpm
T2: Baseline: 95±16 At 48 h: 71±16 bpm
C: Baseline: 97±21 At 48 h: 96±21 bpm
Cardiac index
T1: Baseline: 4.0±1.1 At 48 h: 4.2±1.9 L/min/m
T2: Baseline: 4.0±1.0 At 48 h: 4.2±1.9 L/min/m
C: Baseline: 4.0±1.0 At 48 h: 3.9±1.5 L/min/m
Systemic vascular resistance index:
T1: Baseline: 41±12 At 48 h: 43±12 ml/beats/m
T2: Baseline: 46±13 At 48 h: 50±10 ml/beats/m
C: Baseline: 4.0±1.0 At 48 h: 3.9±1.5 ml/beats/m
Lauzier et al.,
2006 [10]
Multicenter
randomized
non-blinded
trial
Patients with early
hyperdynamic septic shock
N=23 (T=13/23, C=10/23)
Male T=46%, C=80%
Female T=54%, C=20%
Age, median (IQR):
T=51.2±17.2 C=58.1±17.5
Vasopressin
(0.04–0.20 Umin–1) as a
single agent for 48 hours
Norepinpehrine (0.1–2.8
μgkg–1 min–1) as a single
agent for 48 hours
Urine output
Baseline: T: 1420±656 ml C: 1146±700 ml
24h: T: 2049±562 ml C: 1895±1292 ml
48h: T: 3051±1666 ml C: 2644±1060 ml
Mean arterial pressure mean, SD
Baseline: T: 72±7 C: 68±10 mm Hg
1 h: T: 74±8 C: 72±5 mm Hg
24 h: T: 81±11 C: 77±6 mm Hg
48 h: T: 78±12 C: 81±9 mm Hg
Heart rate mean, SD
Baseline: T: 118±16 C: 109±23 bpm
1 h: T: 105±16 C: 108±22 bpm
(Contd...)

Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199 189
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Table 2. (Continued).
Study ID Population Intervention Comparisons Outcome
6 h: T: 100±15 C: 104±22 bpm
48 h: T: 93±21 C: 96±18 bpm
Cardiac index mean, SD
Baseline: T: 4.6±1.0 C: 4.4±1.4
1 h: T: 3.6±1.1 C: 4.3±1.4
6 h: T: 3.7±0.7 C: 4.3±1.7
48 h: T: 3.7±0.9 C: 3.7±1.6
Mortality ICU
T: 2/13 C: 1/10
Acute coronary syndrome T: 1/13 C: 1/10
Russell et al.,
2008 [11]
Multicenter,
randomized,
double-blind
trial
Patients older than 16 years
of age who had septic shock
that was resistant to uids (as
dened by lack of response to
500 ml of normal saline or a
requirement for vasopressors
and low-dose norepinephrine
N=778 (T=396, C=382)
Male: T=62%, C=59.9%
Female T=38%, C=40.1%
Age: T: 59.3±16.4, C=61.8±16
Blinded vasopressin
infusion was started at 0.01
U per minute and titrated
to a maximum of 0.03 U
per minute
Blinded norepinephrine
infusion was started at 5 μg
per minute and titrated to
a maximum of 15 μg per
minute
28-day mortality
Randomization:
T=144/404 C=154/395
Randomization and infusion:
T=140/396 C=150/382
90 day mortality
Randomization
T=177/400 C=194/391
Randomization and infusion
T=172/392 C=188/379
Length of ICU stay median, IQR
T (396) =15 (7-29); C (382) =16 (8-32)
Length of Hospital stay median, IQR
T (396)=27 (13-52), C (382)=26 (15-53)
Serious adverse events
T=41/396 C=40/382
Acute myocardial infarction T=8/396 C=7/382
Cardiac arrest T=3/396 C=8/382
Life-threatening arrhythmia T=8/396 C=6/382
Acute mesenteric ischemia T=9/396 C=13/382
Hyponatremia T=1/396 C=1/382
Digital ischemia T=8/396 C=2/382
Cerebrovascular accident T=1/396 C=1/382
Russell et al.,
2018 [19]
Retrospective
cohort
study using
propensity
based
matching
SPH 1 :
2001-2007
SPH 2:
2008-2012
Patients admitted to Intensive
care unit who had two of
four SIRS criteria who had
suspected or proven infection
and who were unresponsive to
uid resuscitation and received
infusion of norepinephrine or
vasopressin.
SPH 1:
Before matching
T: 165 C: 558
Age:
T: 56.1±15.7 C: 60.7±16.2
Male: T: 73.3% C: 61.8%
After matching
T: 158 C: 158
Age:
T: 56.4±15.4 C: 57.1±15.1
Male: T: 72.8% C: 67.1%
SPH 2:
Before matching
T: 525 C: 145
Vasopressin as per local
practice
Nor epinephrine as per local
practice
28 day mortality
SPH 1:
After matching
T: 96/158 C: 73/158
SPH 2:
After matching
T: 29/93 C: 25/93
(Contd...)

190 Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199
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Table 2. (Continued).
Study ID Population Intervention Comparisons Outcome
Age:
T: 60.9±13.9 C: 61.4±16.8
Male: T: 62.4% C: 66.4%
After matching
T: 93 C: 93
Age:
T: 60.9±13.9 C: 61.4±14.5
Male: T: 37.6% C: 30.1%
Gordon et al.,
2016 [12]
Double blind,
randomized
clinical trial
Adult patients (≥16 years)
who had sepsis and required
vasopressors despite adequate
intravenous uid resuscitation.
N=409
T1=101
T2=104
C1=101
C2=103
Male: T1=58%, T2=52%,
C1=62%, C2=65%
Female: T1=42%, T2=48%,
C1=38%, C2=35%
Age (median, IQR)
T1: 66 (57-76), T2: 67 (59-77),
C1: 63 (52-76), C2: 66 (54-76)
T1=Vasopressin and
hydrocortisone
T2=Vasopressin and
placebo
T=Vasopressin with
placebo or hydrocortisone
Vasopressin (titrated upto
0.06 U/min) as the initial
vasopressor infusion.
Once maximum infusion
rate of vasopressin
was reached, either 50
mg of hydrocortisone
phosphate or placebo
was administered as an
intravenous bolus every 6
h for 5 days, every 12 h for
3 days and then once daily
for 3 days
C1=Norepinephrine and
hydrocortisone
C2=Norepinephrine and
placebo
C=Norepinephrine with or
without placebo
Norepinephrine titrated
upto 12 μg/min as the
initial vasopressor infusion.
Once maximum infusion
rate of norepineprhine
was reached, either 50
mg of hydrocortisone
phosphate or placebo
was administered as an
intravenous bolus every 6
for 5 days, every 12 h for
3 days and then once daily
for 3 days
Hospital Mortality
T=68/204 C=60/204
Requirement of RRT
T=52/205 C=72/204
ICU length of stay median (IQR)
T=7 (3 to 11) C=5 ( 3 to 13)
Hospital length of stay median (IQR)
T=16 (7 – 36) days C=16 (8-38) days
Serious adverse events
T=22/205 C=17/204
Acute coronary syndrome T=7/205 C=4/204
Digital ischemia T=11/205 C=3/204
Mesenteric ischemia T=5/205 C=5/204
Life-threatening arrhythmia T=2/205 C=5/204
Urine output mean, SD
Day 1 T (205): 737±3813 ml C (204): 1010±2455
Day 2 T (189): 1521±2204 ml C (198): 1628±1733
Day 7 T (114): 2314±1150 C (99): 1906±1363
Hall et al.,
2004 [20]
Retrospective
cohort single
center study
Critically ill patients who
were receiving continuous
intravenous infusion of
vasopressin, norepinephrine
and dopamine
N=50, T1=50, T2=51 and
C=49
Male:
T1=60%, C=57% and T2=55%
Female: T1=40%, C=43% and
T2=45%
Age: T1=67.1±17.1,
T2=62.5±17.7 and C:
61.1±18.0
T1: Fixed dosage of
intravenous vasopressin
0.04 U/min
T2: Titrated intravenous
infusion of dopamine
(6.7±5.5 μg/kg/min)
C: Titrated intravenous
infusion of norepinephrine
(0.28±0. μg/kg/min)
28-day mortality
T1: 23/44 T2: 28/51 C: 30/46
Hospital stay mean, SD
T1 (50): 36±34 days
T2 (51): 29±29 days
C (49): 36±40 days
ICU length of stay mean, SD
T1 (50): 14±55 days
T2 (51): 20±26 days
C (49): 29±40 days
Serious adverse events
T1: 36/50 T2: 36/51 C: 39/49
MI T1: 2/50 T2: 2/51 C: 4/49
ARDS T1: 10/50 T2: 12/51 CL 17/49
Atrial arrhythmia T1: 6/50, T2: 6/51, C=15/49
Acute renal insuciency T1: 3/50, T2: 3/51, C: 3/49
Venous thromboembolism T1: 7/50, T2: 4/51, C=1/49
Peripheral vascular necrosis T1: 3/50, T2: 2/51, C=3/49
Urine output: mean, SD
T1 (44): Baseline: 3437±4618, 24 h: 2898±4103
T2 (44): Baseline: 3215±2958 24 h: 4210±6350
C (43): Baseline: 2495±1960 24 h: 2810±2193
Cardiac index mean, SD
T1: Baseline: 4.1±1.6; 1 h: 3.5±1.3
T2: 2.8±1.0; 1 h: 2.6±1.2
C: 3.6±1.3; 1 h: 3.3±1.0
MAP
T1: Baseline: 63.3±13.3 mm Hg 1 h: 74.4±11.3 mm Hg
T2: Baseline: 58.7±9.5 mm Hg 1 h: 70.5±11.6 mm Hg
C: Baseline: 56.8±8.5 mm Hg 1 h: 72.9±8.9 mm Hg
(Contd...)

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Table 2. (Continued).
Study ID Population Intervention Comparisons Outcome
Daley et al.,
2013 [21]
Retrospective
cohort study
Patients with septic shock with
mean arterial pressure less than
65 mm Hg.
N=130 T=65 C=65
Administration of
vasopressin 1 h after the
onset of septic shock
Administration of
norepinephrine 1 h after the
onset of septic shock
Mortality
T=29/65 C=32/65
Length of hospital stay (Median, Interquartile range)
T=15 (8-34) C=15 (7-31)
ICU length of stay: Median, Interquartile range
Male T=52.3%, C=53.8%
Female T=47.7%, C=46.2%
Age mean (SD)
T=61 (17.7) C=56 (17.7)
T=7 (4-24) C=7 (3-15)
Requirement of renal replacement therapy
T=19/65 C=21/65
MAP mean, SD (mm Hg)
T: Baseline: 57.3 (5.9), 0-6 h: 75.0 (9.6); 12-24 h: 71.7
(10.3)
C: Baseline: 56.8 (6.4) 0-6 h: 76 (8.2); 12-24 h: 73.4
(11.1)
Urine output mean, SD (ml/kg/h)
T: 0-6 h: 0.84 (1) 6-12 h: 0.72 (0.9) 12-24 h: 0.77 (0.9)
C: 0-6 h: 0.63 (1) 6-12 h: 0.66 (0.8) 12-24 h: 0.51 (0.6)
3.1. Narrative summary
Three included studies were retrospective and cohort
studies [19-21] and ve were randomized and controlled
trials [8,10-12,24].
Patel et al. randomized patients to vasopressin to norepinephrine
infusion for 4 h [8]. In the study, vasopressin decreased the
catecholamine use in septic shock and achieved signicantly
higher urine output and creatinine clearance than norepinephrine.
However, since Patel et al. were a short duration study, the
outcomes were not reported beyond 4 h, and it could not be
included in the quantitative synthesis.
Lauzier et al. randomized patients to high-dose vasopressin
or norepinephrine in early septic shock [10]. Vasopressin in the
Figure 2. Preferred Reporting Items for Systematic Reviews and Meta-analyses ow diagram.

192 Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
high dose (o.2U/min) could not attain Map in all the patients in
the study and required d additional epinephrine. However, the
patients achieved less modied sofa in the vasopressin arm than
norepinephrine arm at 48 h.
Russell et al. (VASST) were the largest RCT with 778 patients,
which randomized patients to vasopressin or norepinephrine in
septic shock [11]. The primary endpoint of the study was death at
28 days. There was no dierence in mortality at 28 days and severe
adverse eects in both arms. However, in the patients with less severe
septic shock (those who required NE <15 ug/min), vasopressin
provided a mortality benet compared to norepinephrine. Gordon
et al. (VANISH trial) were conducted to study the renal eects
of vasopressin versus norepinephrine in patients with septic
shock [12]. The primary endpoint was the number of kidney-free
days. Vasopressin did not increase the number of kidney-free days
in septic shock compared to norepinephrine.
The TERLIVAP study (Morelli et al.) was a randomized control
trial with three arms: A continuous terlipressin arm, a continuous
vasopressin arm, and a xed-dose norepinephrine arm [24]. The
primary endpoint was the additional requirement of norepinephrine.
Terlipressin required lower norepinephrine as compared to the
vasopressin arm. There was no dierence in hemodynamic dierences
achieved by vasopressin, norepinephrine, and terlipressin.
3.2. Quantitative analysis
A total of seven studies were included in the meta-analysis
(four RCTs and three cohorts).
3.2.1. Mortality outcome
Five studies reported 28-day/hospital mortality. Pooling
the data using random-eect model, there was no dierence
in odds of mortality between vasopressin and norepinephrine
group among septic shock patients (OR, 1.07; 95% CI, 0.80–
1.44; n=1929; I2=51%). Similarly, two studies reported ICU
mortality outcome which was not dierent across two groups
(OR, 0.74; 95% CI, 0.21–2.67; n=53; I2=0%) (Figure 3). Further,
no signicant dierences were seen while analyzing the 28-day
mortality outcome after excluding non-randomized studies
(Supplementary File 2, Figure 1).
3.2.2. Length of Stay
Length of ICU stays outcome was reported by ve studies.
Pooling of results using the mean dierence in length of ICU stay
in days showed some reduction in length in the vasopressin group;
however, it did not reach the level of signicance (MD, −0.24; 95%
CI, −1.35–0.86; n=1445; I2=41%). Similarly, length of hospital
stay was reported in four studies and there was no signicant
dierence across two groups (MD, −0.49; 95% CI, −3.12–2.14;
n=1415; I2=0%) (Figure 4). Further, no signicant dierences were
seen while analyzing for ICU-LOS and LOHS after excluding non-
randomized studies (Supplementary File 2, Figure 2).
3.2.3. MAP
Pooling data for MAP (mmHg) showed no signicant dierence
in mean of baseline MAP (MD, 0.08; 95% CI, −1.51–1.66; n=183;
I2=0%); MAP at 24 h (MD, −0.88; 95% CI, −2.47–0.72; n=183;
I2=3%); and MAP at 48 h (MD, −0.18; 95% CI, −2.26–1.91; n=53;
I2=0%) (Figure 5).
3.2.4. Urine output
There was no signicant dierence in urine output in terms of
mean of baseline urine output (MD, 10.91; 95% CI, −6.65–28.46;
n=140; I2=0%); urine output at 24 h (MD, −7.47; 95% CI, −25.46–
10.52; n=549; I2=0%); and urine output at 48 h (MD, −3.55; 95%
CI, −18.21–11.12; n=440; I2=0%) (Figure 6). Further, no signicant
dierences were seen while analyzing for urine output after
excluding non-randomized studies (Supplementary File 2, Figure 3).
3.2.5. Serious adverse eect
Three studies reported serious adverse events. Pooling of the
data showed no signicant dierences in its occurrence across two
Figure 3. Forest plot comparing mortality outcome across vasopressin and norepinephrine in septic shock patients.

Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199 193
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
groups (OR, 1.01; 95% CI, 0.71–1.43; n=1286; I2=0%) (Figure 7).
3.2.6. RRT
Pooling data from two studies reporting requirement of RRT,
the odds for requirement of RRT in vasopressin group were
lowered signicantly (OR, 0.68; 95% CI, 0.47–0.98; n=539;
I2=0%) (Figure 8).
4. Discussion
We analyzed eight studies in our study. When both medications
were compared, neither showed survival benet over the other.
Furthermore, no statistical dierence was found between
norepinephrine and vasopressin in terms of length of ICU stay, MAP,
severe adverse eects, and urine output. Norepinephrine was the
rst-choice vasopressor for managing hypotension in septic shock.
In contrast, vasopressin has been used as one of the rst add-on
vasopressors to norepinephrine to attain the target MAP or decrease
the norepinephrine dosage [25]. Our study found no signicant
dierence between hospital mortality and 28-day mortality among
patients treated with either medication. This nding is consistent
with other meta-analyses, which have also compared the mortality
outcome [26,27]. Similarly, there was no signicant dierence in
the length of ICU stay among the patients. A previous meta-analysis
had also reached a similar conclusion [28].
Septic shock is a state of relative vasopressin deciency
attributed to impaired baroreceptor-mediated vasopressin
secretion [29]. However, all the clinical implications of the relative
deciency state are not known. A short-term study has shown
that the microcirculation eects of vasopressin in patients are
dependent on the baseline norepinephrine dose [30]. Regarding
the hemodynamic parameters, many hemodynamic parameters
were not reported in the studies; however, they were reported with
inconsistent time duration. We compared the eect of vasopressin
versus norepinephrine on MAP, on which a signicant dierence
could not be found. The previous meta-analysis has reported
multiple hemodynamic parameters and MAP, such as heart rate,
cardiac index, systemic vascular resistance index, and oxygen
consumption, which have no signicant dierences [26]. The
study found no signicant dierence in the occurrence of major
side eects. While vasopressin may increase the incidence of
digital ischemia, prior meta-analyses have shown no increase in
the incidence of major adverse eects [28,31,32].
Figure 4. Forest plot comparing the length of intensive care unit stay and hospital stay across vasopressin and norepinephrine in septic shock patients.
Figure 5. Forest plot comparing mean arterial pressure across vasopressin and norepinephrine in septic shock patients.

194 Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
Patel et al. have shown that vasopressin increases urine output
and decreases serum creatinine compared to norepinephrine in
the early hours of administration [8]. However, there seems to
be no dierence in kidney failure-free days in patients treated
with vasopressin than norepinephrine. Although we did not nd
any signicant dierence in urine output in our study, there were
lower odds of RRT with vasopressin. Our ndings of the decreased
requirement for RRT align with the ndings of prior clinical
studies that have found improvement in glomerular ltration rate
and creatinine clearance in the vasopressin group compared to
norepinephrine [8,10]. Further studies are necessary to evaluate
the implications of possible renal benets seen with vasopressin
compared to norepinephrine.
4.1. Limitations
Our meta-analysis has several limitations, including the small
number of available studies and the heterogeneity of study
designs and demographics. Included studies have their inherent
limitations. The included studies have been conducted from 2002
to 2018 and represent a contemporary cohort of septic shock
patients. Treatment protocol, formulations, and drug dosage are
comparable and oer granularity of data in assessing individual
inuence. The presence of organ dysfunction and comorbidities
could have inuenced the clinical outcomes [33]. We could only
report adverse eects and the need for RRT based on a few studies.
We could not report various other parameters of interest as there
was wide variation in reporting among studies.
Furthermore, we have only included studies published
in English, which could have excluded studies published in
other languages. Further studies are warranted to uncover the
pathophysiology of vasopressin in septic shock and its potential
role in therapeutics.
5. Conclusion
This comprehensive meta-analysis reports no mortality benet
when comparing vasopressin to norepinephrine in septic shock
patients. Yet, the need for RRT was signicantly lower in the
vasopressin group. In addition, we found no dierence in adverse
Figure 6. Forest plot comparing urine output (ml/h) across vasopressin and norepinephrine in septic shock patients.
Figure 8. Forest plot comparing requirement of renal replacement therapy across vasopressin and norepinephrine in septic shock patients.
Figure 7. Forest plot comparing SAE across vasopressin and norepinephrine in septic shock patients.

Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199 195
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
events and duration of hospitalization in septic shock patients
receiving vasopressin compared to norepinephrine. Therefore,
further large-scale randomized clinical trials are required to
uncover the renal benet of vasopressin in septic shock.
Conict of Interest
The authors declare that they have no competing interests.
References
[1] Annane D, Aegerter P, Jars-Guincestre MC, Guidet B.
Current Epidemiology of Septic Shock: The CUB-Réa
Network. Am J Respir Crit Care Med 2003;168:165-72.
[2] Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G,
Carcillo J, Pinsky MR. Epidemiology of Severe Sepsis in
the United States: Analysis of Incidence, Outcome, and
Associated Costs of Care. Crit Care Med 2001;29:1303-10.
[3] Seymour CW, Rosengart MR. Septic Shock: Advances in
Diagnosis and Treatment. JAMA 2015;314:708-17.
[4] Bomzon L, Rosendor C. Renovascular Resistance and
Noradrenaline. Am J Physiol 1975;229:1649-53.
[5] Hayes MA, Timmins AC, Yau E, Palazzo M, Hinds CJ,
Watson D. Elevation of Systemic Oxygen Delivery in
the Treatment of Critically Ill Patients. N Engl J Med
1994;330:1717-22.
[6] Landry DW, Oliver JA. The Pathogenesis of Vasodilatory
Shock. N Engl J Med 2001;345:588-95.
[7] Holmes CL, Patel BM, Russell JA, Walley KR. Physiology
of Vasopressin Relevant to Management of Septic Shock.
Chest 2001;120:989-1002.
[8] Patel BM, Chittock DR, Russell JA, Walley KR. Benecial
Eects of Short-term Vasopressin Infusion during Severe
Septic Shock. Anesthesiology 2002;96:576-82.
[9] Malay MB, Ashton RC, Landry DW, Townsend RN. Low-
Dose Vasopressin in the Treatment of Vasodilatory Septic
Shock. J Trauma Acute Care Surg 1999;47:699-703.
[10] Lauzier F, Lévy B, Lamarre P, Lesur O. Vasopressin or
Norepinephrine in Early Hyperdynamic Septic Shock:
A Randomized Clinical Trial. Intensive Care Med
2006;32:1782-9.
[11] Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC,
Cooper DJ, et al. Vasopressin Versus Norepinephrine
Infusion in Patients with Septic Shock. N Engl J Med
2008;358:877-87.
[12] Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD,
Cecconi M, Cepkova M, et al. Eect of Early Vasopressin
vs Norepinephrine on Kidney Failure in Patients with
Septic Shock: The VANISH Randomized Clinical Trial.
JAMA 2016;316:509-18.
[13] Liberati A, Altman DG, Tetzla J, Mulrow C, Gøtzsche PC,
Ioannidis JP, et al. The PRISMA Statement for Reporting
Systematic Reviews and Meta-analyses of Studies that
Evaluate Healthcare Interventions: Explanation and
Elaboration. BMJ 2009;339:b2700.
[14] Shrestha D, Budhathoki P, Gaire S, Pokharel N, Maharjan S,
Sedhai Y, et al. Vasopressin vs Nor-adrenaline in septic
shock: A Systematic Review and Meta-analysis. PROS-
PERO; 2021. Available from: https://www.crd.york.ac.uk/
prospero/display_record.php?RecordID=226012 [Last ac-
cessede on 2021 Apr 24].
[15] How Can I Cite Covidence? Available from: https://www.
support.covidence.org/help/how-can-i-cite-covidence
[Last accessed on 2021 Jan 26].
[16] RevMan for Non-cochrane Reviews, Cochrane Training.
Available from: https://www.training.cochrane.org/online-
learning/core-software-cochrane-reviews/revman/revman-
non-cochrane-reviews [Last accessed on 2021 Jan 26].
[17] Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS,
Boutron I, et al. RoB 2: A Revised Tool for Assessing Risk
of Bias in Randomised Trials. BMJ 2019;366:4898.
[18] Critical-appraisal-tools-critical Appraisal Tools,
Joanna Briggs Institute. Available from: https://www.
joannabriggs.org/critical-appraisal-tools [Last accessed on
2020 Dec 18].
[19] Russell JA, Wellman H, Walley KR. Vasopressin Versus
Norepinephrine in Septic Shock: A Propensity Score Matched
Eciency Retrospective Cohort Study in the VASST
Coordinating Center Hospital. J Intensive Care 2018;6:73.
[20] Hall LG, Oyen LJ, Taner CB, Cullinane DC, Baird TK,
Cha SS, et al. Fixed-dose Vasopressin Compared
with Titrated Dopamine and Norepinephrine as Initial
Vasopressor Therapy for Septic Shock. Pharmacotherapy
2004;24:1002-12.
[21] Daley MJ, Lat I, Mieure KD, Jennings HR, Hall JB,
Kress JP. Una Comparación de la Monoterapia Inicial de
Norepinefrina y Vasopresina Para Resucitación De Choque
Séptico. Ann Pharmacother 2013;47:301-10.
[22] 9.5.2 Identifying and Measuring Heterogeneity.
Available from: https://www.handbook-5-1.cochrane.
org/chapter_9/9_5_2_identifying_and_measuring_
heterogeneity.htm [Last accessed on 2020 Dec 18].
[23] Mean Variance Estimation. Available from: https://www.
web.archive.org/web/20181224162602; http:/www.comp.
hkbu.edu.hk/~xwan/median2mean.html [Last accessed on
2020 Dec 19].
[24] Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A,
Cecchini V, et al. Continuous Terlipressin Versus Vasopressin
Infusion in Septic Shock (TERLIVAP): A Randomized,
Controlled Pilot Study. Crit Care 2009;13:R130.
[25] Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M,
Ferrer R, et al. Surviving Sepsis Campaign: International
Guidelines for Management of Sepsis and Septic Shock:
2016. Crit Care Med 2017;43:486-552.
[26] Zhou FH, Song Q. Clinical Trials Comparing
Norepinephrine with Vasopressin in Patients with Septic

196 Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199
DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
Shock: A Meta-analysis. Mil Med Res 2014;1:6.
[27] Nagendran M, Maruthappu M, Gordon AC, Gurusamy KS.
Comparative Safety and Ecacy of Vasopressors for
Mortality in Septic Shock: A Network Meta-analysis.
J Intens Care Soc 2016;17:136-45.
[28] Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A.
Vasopressors for the Treatment of Septic Shock: Systematic
Review and Meta-analysis. PLoS One 2015;10:e0129305.
[29] Buijk SE, Bruining HA, Oliver JA, Landry DW.
Vasopressin Deciency Contributes to the Vasodilation of
Septic Shock. Circulation 1998;98:187.
[30] Nascente AP, Freitas FG, Bakker J, Ba AT, Ladeira RT,
Azevedo LC, et al. Microcirculation Improvement after
Short-term Infusion of Vasopressin in Septic Shock is
Dependent on Noradrenaline. Clinics 2017;72:750-7.
[31] Yao R, Xia D, Wang L, Wu G, Zhu Y, Zhao H, et al. Clinical
Eciency of Vasopressin or its Analogs in Comparison
with Catecholamines Alone on Patients With Septic Shock:
A Systematic Review and Meta-analysis. Front Pharmacol
2020;11:563.
[32] Serpa Neto A, Nassar AP, Cardoso SO, Manetta JA,
Pereira VG, Espósito DC, et al. Vasopressin and Terlipressin
in adult Vasodilatory Shock: A Systematic Review and
Meta-analysis of Nine Randomized Controlled Trials. Crit
Care 2012;16:R154.
[33] Ketcham SW, Sedhai YR, Miller HC, Bolig TC, Ludwig A,
Co I, et al. Causes and Characteristics of Death in Patients
with Acute Hypoxemic Respiratory Failure and Acute
Respiratory Distress Syndrome: A Retrospective Cohort
Study. Crit Care 2020;24:391.
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REVIEW ARTICLE
Supplementary: Vasopressin versus norepinephrine as the rst-line
vasopressor in sepc shock: A systemac review and meta-analysis
Supplementary File 1. Electronic search details
Embase
Search: (“vasopressin”/exp OR vasopressin) AND (“nor adrenaline” OR “nor epinephrine”) AND (“septic shock”/exp OR “septic
shock” OR (septic AND (“shock”/exp OR shock)) OR “sepsis”/exp OR sepsis)
Link: https://www.embase.com/#advancedSearch/resultspage/history.13/page.1/25.items/orderby.date/source.
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Link: https://pubmed.ncbi.nlm.nih.gov/?term=%28%28Vasopressin%29+AND+%28Nor-adrenaline+or+Nor-epinephrine%29%29+
AND+%28Septic+shock+or+sepsis%29&sort=date
Total hits: 354
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Link: https://www.ncbi.nlm.nih.gov/pmc/?term=((Vasopressin)+AND+(Nor-adrenaline+or+Nor-epinephrine))+AND+(Septic+shock
+or+sepsis)
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198 Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199
Supplementary File 2. Additional analysis
1. Morality
Sensitivity analysis for 28-day mortality outcome conducted by excluding non-randomized studies (Hall et al., 2004, and Russell et al.,
2018) also could not show signicant dierences across two groups (OR, 0.95; 95% CI, 0.76–1.18; n=1337; I2=0%) (Figure 1).
Figure 1. Forest plot showing mortality outcome after excluding non-randomized study.
Figure 2. Forest plot showing LOS outcome after excluding non-randomized study.
2. LOS
Excluding non-randomized study (Hall et al.) also could not make signicant dierence in overall ICU (MD, −0.19; 95%
CI, −1.30–0.91; n=1346; I2=32%), and length of hospital stay (MD, −0.51; 95% CI, −3.18–2.17; n=1316; I2=0%) (Figure 2).

DOI: http://dx.doi.org/10.18053/jctres.08.202203.005
Sedhai et al. | Journal of Clinical and Translational Research 2022; 8(3): 185-199 199
3. Urine output
Excluding non-randomized study (Hall et al.) also could not make signicant dierence in baseline urine output (MD, 8.42; 95%
CI, −9.88–26.73; n=53; I2=0%), and 24-h urine output MD, −8.68; 95% CI, −27.62–10.27; n=462; I2=0%) (Figure 3).
Figure 3. Forest plot showing urine output after excluding non-randomized study.