CHEST Original Research

CRITICAL CARE

The Cardiopulmonary Effects of

Vasopressin Compared With
Norepinephrine in Septic Shock
Anthony C. Gordon, MD; Nan Wang, PhD; Keith R. Walley, MD; Deborah Ashby, PhD;
and James A. Russell, MD

Background: Vasopressin is known to be an effective vasopressor in the treatment of septic shock,

but uncertainty remains about its effect on other hemodynamic parameters.
Methods: We examined the cardiopulmonary effects of vasopressin compared with norepinephrine
in 779 adult patients with septic shock recruited to the Vasopressin and Septic Shock Trial. More
detailed cardiac output data were analyzed for a subset of 241 patients managed with a pulmo-
nary artery catheter, and data were collected for the first 96 h after randomization. We compared
the effects of vasopressin vs norepinephrine in all patients and according to severity of shock
(, 15 or ⱖ 15 mg/min of norepinephrine) and cardiac output at baseline.
Results: Equal BPs were maintained in both treatment groups, with a significant reduction in
norepinephrine requirements in the patients treated with vasopressin. The major hemodynamic
difference between the two groups was a significant reduction in heart rate in the patients treated
with vasopressin (P , .0001), and this was most pronounced in the less severe shock stratum
(treatment 3 shock stratum interaction, P 5 .03). There were no other major cardiopulmonary differ-
ences between treatment groups, including no difference in cardiac index or stroke volume index
between patients treated with vasopressin and those treated with norepinephrine. There was signif-
icantly greater use of inotropic drugs in the vasopressin group than in the norepinephrine group.
Conclusions: Vasopressin treatment in septic shock is associated with a significant reduction in
heart rate but no change in cardiac output or other measures of perfusion.
Trial registry: ISRCTN Register; No.: ISRCTN94845869; URL: www.isrctn.org
CHEST 2012; 142(3):593–605

Abbreviations: PA 5 pulmonary artery; VASST 5 Vasopressin and Septic Shock Trial

When cardiovascular failure develops because of

sepsis, mortality rates are high. As well as treat-
1
ing the underlying infection with antibiotics and source
control, the mainstay of the treatment of septic shock
is cardiovascular resuscitation using IV fluid and vaso-
pressor and inotropic drugs.2 In recent years, there
has been increasing interest in vasopressin treatment
as an adjunct to other catecholamine vasopressors.
The rationale behind vasopressin use is that there
is commonly a relative vasopressin deficiency in sep-
tic shock,3 and patients appear sensitive to adminis-
tration of low-dose vasopressin infusions.4 In several
small studies, often unblinded, vasopressin infusion
invariably has been shown to increase BP and spare
catecholamine use.5-8 The effect of vasopressin on
cardiac output is less clear, with reports stating that
it may reduce,8 increase,7 or have no effect on cardiac
output.5,6,9 There have also been concerns that higher
doses of vasopressin (generally . 0.05 units/min) are
associated with cardiac arrest.10 In contrast, nor-
epinephrine, the most commonly used catecholamine
vasopressor,11 has both a- and b-adrenoreceptor effects
that not only increase BP but also may increase heart
rate and cause arrhythmias, and it has been associ-
ated with mesenteric and cutaneous ischemia.12,13
The Vasopressin and Septic Shock Trial (VASST)
was a large, double-blind, randomized controlled trial
comparing low-dose vasopressin to norepinephrine
in addition to standard vasopressors in the treat-
ment of established adult septic shock.14 In the whole-
study population, there was no significant difference
in mortality rates between the treatment groups
(28-day mortality, 35.4% vs 39.3% in the vasopressin
and norepinephrine groups, respectively; P 5 .26).

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 However, in the a priori stratum of less severe
shock (defined as 5-15 mg/min of norepinephrine
at baseline), there was a significantly lower 28-day
mortality in the vasopressin group compared with the
norepinephrine group (26.5% vs 35.7%, respectively,
P 5 .05). In the more severe shock stratum (ⱖ 15 mg/min
of norepinephrine at baseline), there was no differ-
ence in mortality rates in the vasopressin and nor-
epinephrine groups (44.0% vs 42.5%, respectively,
P 5 .76).
Therefore, we planned to study the cardiopulmo-
nary effects of vasopressin compared with norepineph-
rine in VASST. Specifically, we tested the hypothesis
that there is no difference in cardiac output and other
measures of hemodynamics between vasopressin and
norepinephrine. To further explore efficacy and safety
questions about vasopressin and norepinephrine,
we compared hemodynamics of vasopressin vs nor-
epinephrine in the strata of patients who had less
and more severe septic shock (as defined originally
in VASST). Finally, because vasopressors may decrease
cardiac output, especially in patients with low car-
diac output, we compared the effects of vasopressin
vs norepinephrine in patients according to cardiac
output at baseline.
Materials and Methods
Patients and Protocol
The VASST study has been previously reported14 and was
conducted between July 2001 and April 2006. Research ethics
board approval was granted at the coordinating center (University
of British Columbia, St. Paul’s Hospital, P99-0175), and all par-
ticipants or their legal representatives gave informed consent.
In summary, this was a multicenter, double-blind, randomized
controlled trial of vasopressin vs norepinephrine in addition to
standard vasopressors for the treatment of septic shock. Patients
Manuscript received November 23, 2011; revision accepted
March 14, 2012.
Affiliations: From the Section of Anaesthetics, Pain Medicine
and Intensive Care (Dr Gordon) and Imperial Clinical Trials Unit
(Drs Wang and Ashby), School of Public Health, Faculty of
Medicine, Imperial College London, England, and Critical Care
Research Laboratories (Drs Walley and Russell), Institute for
Heart and Lung Health, St. Paul’s Hospital and University of
British Columbia, Vancouver, BC, Canada.
Funding/Support: Dr Gordon is a UK National Institute for
Health Research (NIHR) Clinician Scientists award holder and
is grateful for funding from the NIHR comprehensive Biomedical
Research Centre funding stream. The Vasopressin and Septic
Shock Trial was funded by a grant [MCT 44152] from the Canadian
Institutes of Health Research.
Correspondence to: Anthony C. Gordon, MD, Critical Care
Medicine, 11N, Imperial College/Charing Cross Hospital, Fulham
Palace Rd, London, W6 8RF, England; e-mail: anthony.gordon@
imperial.ac.uk
© 2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.11-2604
594
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were aged . 16 years and had septic shock as defined by the pres-
ence of two or more systemic inflammatory response syndrome
criteria,15 proven or suspected infection, new dysfunction of at
least one organ, and hypotension despite adequate fluid resus-
citation requiring vasopressor support of at least 5 mg/min of nor-
epinephrine (or equivalent) for 6 h. Important clinical exclusion
criteria were unstable coronary syndromes, severe chronic heart
disease (New York Heart Association class III and IV), and vaso-
spastic diathesis. Patients were randomized to receive a blinded
infusion of study drug, either vasopressin (0.01-0.03 units/min)
or norepinephrine (5-15 mg/min). The study drug and all other
vasopressors were titrated and weaned according to protocols.
The initial target mean arterial pressure was 65 to 75 mm Hg.
All other cardiovascular management, including cardiac output
monitoring, setting of cardiac output goals, and fluid and inotropic
therapy, were at the local treating physician’s discretion.
Data Analysis and Statistics
Basic cardiopulmonary variables (BP, heart rate, central venous
pressure, Pao2/Fio2, and pH) and inotrope use (dobutamine, mil-
rinone, and epinephrine) were collected for all patients in the
study and are reported for all patients in this analysis. If a pul-
monary artery (PA) catheter was in situ, details of PA pressure,
cardiac output, and mixed venous saturation were collected for
the first 96 h after randomization.
Comparison of baseline data between patients who had or did
not have a PA catheter was carried out by x2 test or t test as
appropriate. Longitudinal data were analyzed using linear mixed-
effect models (PROC MIXED in SAS Enterprise Guide 4.3; SAS
Institute Inc) comparing treatment effect over time, adjusting for
any imbalance at baseline and without imputation for missing
data variables. The analysis was done first for all patients and then
repeated for each shock stratum. The P values of fixed effects
(treatment, shock stratum, and their interaction) were provided
by the F test or two-sided t test as appropriate. The number of
patients receiving inotropes was analyzed using a generalized
linear mixed-effects model with logit link (PROC GENMOD in
SAS Enterprise Guide 4.3), and P values of fixed effects and their
interaction (baseline adjusted) were provided by the x2 test. P , .05
was considered significant.
Results
In total, 779 patients were randomized and infused
with the blinded study drugs. Cardiac output moni-
toring was used in 156 patients at baseline and was
instituted after randomization in a further 85 patients
(total, 241 patients [31%] in VASST) and was equally
balanced between the two treatment groups (vaso-
pressin, 123 patients; norepinephrine, 118 patients;
P 5 .97). The baseline characteristics of those patients
managed with and without a PA catheter are shown
in Table 1. Patients who had a PA catheter had several
markers of more severe organ dysfunction, including
more renal dysfunction, lower pH, and higher lactate
levels, and were receiving higher doses of norepineph-
rine and phenylephrine at baseline than patients who
did not have a PA catheter.
As specified in the protocol, vasopressor drugs were
titrated to maintain similar mean arterial pressure
Original Research
 Table 1—Demographics and Baseline Characteristics of Patients Who Had or Did Not Have PA Catheters

No PA Catheter PA Catheter
Characteristic (n 5 538) (n 5 241) P Value
Age, y 59.9 ⫾ 16.5 62.0 ⫾ 15.6 .10
Male sex 329 (61.2) 146 (60.6) .88
Recent surgical history 185 (34.4) 98 (40.7) .09
APACHE II score 26.6 ⫾ 7.6 28.2 ⫾ 6.4 .004
White race 453 (84.2) 203 (84.2) .99
Preexisting condition
Ischemic heart disease 85 (15.8) 48 (19.9) .16
Congestive heart failure 43 (8.0) 15 (6.2) .38
COPD 93 (17.3) 34 (14.1) .27
Chronic renal failure 60 (11.2) 28 (11.6) .85
Diabetes 110 (20.4) 55 (22.8) .45
Liver disease 66 (12.3) 22 (9.1) .20
Alcoholism 75 (13.9) 33 (13.7) .93
Injection drug abuse 29 (5.4) 5 (2.1) .04
Cancer 131 (24.3) 58 (24.1) .93
Immunocompromise 100 (18.6) 39 (16.2) .42
Solid organ transplant 25 (4.6) 6 (2.5) .15
Steroid use 109 (20.3) 59 (24.5) .19
Recent trauma 25 (4.6) 14 (5.8) .49
New organ failure
Respiratory 465 (86.4) 218 (90.5) .11
Renal 344 (63.9) 178 (73.9) .006
Hematology/coagulation 130 (24.2) 72 (29.9) .09
Neurologic 134 (24.9) 56 (23.2) .62
Cardiopulmonary variable
Systolic BP, mm Hg 109 ⫾ 16 109 ⫾ 17 .84
Mean arterial pressure, mm Hg 72.9 ⫾ 9.9 72.4 ⫾ 8.6 .52
Arterial pH 7.32 ⫾ 0.10 7.30 ⫾ 0.10 , .001
Central venous pressure, mm Hg 14.2 ⫾ 4.9 15.4 ⫾ 5.1 .002
Serum lactate, mmol/L 3.1 ⫾ 2.9 4.2 ⫾ 3.5 , .001
Pao2/Fio2, mm Hg 207 ⫾ 94 192 ⫾ 92 .05
More severe shock stratum (. 15 mg/min norepinephrine at randomization) 256 (47.6) 145 (60.2) .001
Vasoactive drug dose at randomization
Norepinephrine, mg/min 19.1 ⫾ 19.7 24.0 ⫾ 20.8 .003
Phenylephrine, mg/min 139 ⫾ 81 182 ⫾ 80 .002
Epinephrine, mg/min 14.5 ⫾ 18.0 9.0 ⫾ 7.7 .18
Dobutamine, mg/kg per min 5.4 ⫾ 4.8 6.5 ⫾ 4.1 .30
Milrinone, mg/kg per min 0.40 ⫾ 0.37 0.30 ⫾ 0.13 .36
Data are presented as mean ⫾ SD or No. (%). APACHE 5 Acute Physiology and Chronic Health Evaluation; PA 5 pulmonary artery.

in the vasopressin and norepinephrine treatment
groups (Table 2). As expected, vasopressin treatment
resulted in a significant reduction in norepinephrine
requirements. The most noticeable cardiovascular
difference in the whole population was a rapid and
significant drop in heart rate after starting the vaso-
pressin infusion (Table 2). This was most pronounced
in the less severe shock stratum (Table 3), and the
interaction statistic examining the treatment 3 shock
stratum interaction was significant (P 5 .03).
There was no difference in cardiac index, stroke
volume index, or left ventricular stroke work index
associated with vasopressin treatment in the whole
population or in either the more or the less severe
shock strata. Similarly, there was no difference in
markers of oxygen delivery, namely mixed venous oxy-
gen saturation, pH, or serum lactate levels, between
treatment groups (Tables 2-5). However, there was
significantly greater use of inotropic drugs in the
vasopressin group compared with the norepinephrine
group, particularly in the more severe shock stratum
where significantly more patients were treated with
inotropic agents, and there was a trend for a higher
mean dose of dobutamine (the most commonly used
inotrope) to be infused in the vasopressin group than
in the norepinephrine group.
Because any deterioration in cardiac function is
likely to be most clinically important in those who
have a low cardiac output, we also divided the patients
by cardiac index quartile at baseline. There was no
difference in cardiac index over time between treat-
ment groups in any of the quartiles (Fig 1), including
those who had the lowest cardiac outputs (first quar-
tile cardiac index, ⱕ 2.9 L/min per m2).

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 596
Table 2—Cardiopulmonary Variables Over Time Comparing Vasopressin vs Norepinephrine in All Patients (N 5 779)

Variable 0h 6h 12 h 24 h 36 h 48 h 60 h 72 h 84 h 96 h P Valuea
MAP, mm Hg
NE 73.2 ⫾ 9.9 75.5 ⫾ 10.1 75.0 ⫾ 10.2 75.9 ⫾ 11.8 76.7 ⫾ 11.1 76.2 ⫾ 12.8 80.3 ⫾ 12.7 79.2 ⫾ 13.7 81.1 ⫾ 14.7 82.1 ⫾ 13.7 .80
AVP 72.4 ⫾ 9.1 73.4 ⫾ 9.1 74.2 ⫾ 9.6 75.9 ⫾ 10.9 75.2 ⫾ 11.3 76.4 ⫾ 11.4 79.6 ⫾ 12.7 80.1 ⫾ 13.6 82.7 ⫾ 14.0 83.0 ⫾ 14.9 ...
Total NE infusion
rate,b mg/min
NE 15.9 (9.0-25.0) 17.0 (12.0-33.0) 15.0 (10.0-29.8) 12.5 (3.0-22.0) 15.0 (7.5-28.9) 10.0 (3.1-21.0) 7.5 (2.0-19.2) 5.0 (0.0-15.0) 2.5 (0.0-12.5) 0.0 (0.0-9.0) , .0001
AVP 14.0 (8.0- 25.0) 8.0 (3.0-17.0) 6.0 (2.0-14.4) 4.0 (0.0-10.0) 6.0 (2.0-14.0) 3.1 (0.0-9.6) 1.0 (0.0-5.9) 0.0 (0.0-2.0) 0.0 (0.0-2.0) 0.0 (0.0-1.1) ...
HR, beats/min
NE 100 ⫾ 20 99 ⫾ 19 96 ⫾ 19 95 ⫾ 20 96 ⫾ 19 95 ⫾ 20 92 ⫾ 19 92 ⫾ 19 91 ⫾ 19 92 ⫾ 18 , .0001
AVP 100 ⫾ 21 93 ⫾ 20 90 ⫾ 21 90 ⫾ 21 90 ⫾ 22 90 ⫾ 21 88 ⫾ 20 89 ⫾ 20 88 ⫾ 19 90 ⫾ 21 ...
CVP, mm Hg
NE 14.4 ⫾ 5.0 14.9 ⫾ 5.2 14.2 ⫾ 4.9 14.4 ⫾ 5.7 14.6 ⫾ 5.1 14.4 ⫾ 5.5 14.0 ⫾ 4.9 13.6 ⫾ 4.7 13.4 ⫾ 4.5 13.1 ⫾ 4.9 .14
AVP 14.8 ⫾ 5.0 15.0 ⫾ 5.0 15.1 ⫾ 5.6 15.2 ⫾ 5.3 14.9 ⫾ 4.8 15.0 ⫾ 5.0 15.0 ⫾ 4.9 14.4 ⫾ 4.9 13.8 ⫾ 4.5 13.4 ⫾ 4.9 ...
pH
NE 7.31 ⫾ 0.10 7.32 ⫾ 0.11 7.33 ⫾ 0.10 7.35 ⫾ 0.09 7.34 ⫾ 0.10 7.35 ⫾ 0.09 7.37 ⫾ 0.09 7.38 ⫾ 0.07 7.39 ⫾ 0.08 7.39 ⫾ 0.08 .66
AVP 7.32 ⫾ 0.10 7.32 ⫾ 0.11 7.34 ⫾ 0.09 7.35 ⫾ 0.08 7.34 ⫾ 0.09 7.35 ⫾ 0.09 7.36 ⫾ 0.09 7.38 ⫾ 0.07 7.39 ⫾ 0.07 7.40 ⫾ 0.08 …
Lactate, mmol/L
NE 2.3 (1.5-4.6) … 2.5 (1.5-4.5) … 2.2 (1.4-4.0) … 1.8 (1.2-2.9) … 1.7 (1.2-2.4) … .63
AVP 2.3 (1.4-4.0) … 2.4 (1.7-5.2) … 2.1 (1.4-3.8) … 1.8 (1.3-2.8) … 1.7 (1.2-2.4) … …
Pao2/Fio2, mm Hg
NE 199 ⫾ 94 207 ⫾ 97 213 ⫾ 94 217 ⫾ 91 218 ⫾ 98 218 ⫾ 89 231 ⫾ 99 229 ⫾ 103 231 ⫾ 100 227 ⫾ 88 .79
AVP 206 ⫾ 93 217 ⫾ 114 219 ⫾ 97 217 ⫾ 91 222 ⫾ 96 223 ⫾ 109 226 ⫾ 94 227 ⫾ 94 233 ⫾ 89 229 ⫾ 93 …
No. receiving
any inotropes
(existing/new)
NE 74 68 (57/11) 73 (58/11) 55 (47/8) 67 (66/1) 56 (48/8) 51 (47/4) 45 (41/4) 55 (48/7) 50 (45/5) .02
AVP 80 86 (70/16) 94 (81/13) 88 (83/5) 93 (91/2) 85 (81/4) 78 (73/5) 67 (61/6) 66 (62/4) 53 (52/1) …
Mean dose

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dobutamine,c
mg/kg per min
NE 5.1 ⫾ 3.7 6.2 ⫾ 10.3 4.4 ⫾ 3.0 4.5 ⫾ 5.2 3.7 ⫾ 2.4 5.3 ⫾ 7.5 3.7 ⫾ 1.9 3.4 ⫾ 1.5 3.4 ⫾ 1.9 3.7 ⫾ 1.8 .06
AVP 6.4 ⫾ 5.2 6.4 ⫾ 5.0 6.9 ⫾ 6.4 6.3 ⫾ 6.4 6.3 ⫾ 5.0 6.5 ⫾ 6.8 5.2 ⫾ 4.7 5.5 ⫾ 6.2 4.9 ⫾ 4.5 5.7 ⫾ 4.4 …
RPP (/100)
NE 109 ⫾ 23 112 ⫾ 24 109 ⫾ 25 109 ⫾ 27 110 ⫾ 27 109 ⫾ 27 110 ⫾ 27 110 ⫾ 28 112 ⫾ 30 115 ⫾ 28 , .0001
AVP 108 ⫾ 24 100 ⫾ 24 99 ⫾ 26 101 ⫾ 28 99 ⫾ 27 102 ⫾ 27 105 ⫾ 31 108 ⫾ 32 109 ⫾ 31 112 ⫾ 35 …
RPP . 110, %
NE 47.6 49.3 46.9 44.4 45.7 44.5 46.1 47.2 48.5 51.2 , .0001
AVP 44.9 33.0 30.9 34.5 31.3 32.0 35.2 44.1 44.0 48.8 ...
Data are presented as mean ⫾ SD or median (interquartile range), unless otherwise indicated. AVP 5 vasopressin; CVP 5 central venous pressure; HR 5 heart rate; MAP 5 mean arterial pressure;
NE 5 norepinephrine; RPP 5 rate-pressure product.
aP value comparing difference over time between treatment groups.

bNE dose calculated for all patients who were receiving NE at baseline.

cDobutamine dose calculated for patients receiving dobutamine at that time point.

Original Research

Figure 1. Cardiac index over time in patients who had pulmo-
nary artery catheters by cardiac index quartile at baseline. A, The
first quartile cardiac index was ⱕ 2.9 L/min per m2 at baseline.
B, The second quartile cardiac index was 2.91 to 3.7 L/min per m2
at baseline. C, The third quartile cardiac index was 3.71 to
4.5 L/min per m2 at baseline. D, The fourth quartile cardiac index
was . 4.5 L/min per m2 at baseline. The circles represent the patients
treated with vasopressin, and the squares represent the patients
treated with norepinephrine. The treatment (vasopressin vs nor-
epinephrine) effect on cardiac index over time was P 5 .99 in the
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strategy.29 Adhering to the lower limits of BP targets
may also help to reduce vasopressor load.30
A reduction in cardiac output associated with vaso-
pressin has previously been reported,8 although other
controlled trials have shown no effect5,6,9 and others
even an increase in cardiac output.7 The divergent
results between studies may reflect differences in
doses and methods of vasopressin administration,
concomitant IV fluid resuscitation, and inotropic infu-
sions. We administered low-dose vasopressin (max-
imum dose, 0.03 units/min) by continuous infusion
after adequate fluid resuscitation and then titrated
up the infusion while decreasing catecholamine vaso-
pressors to maintain the target BP. The fact that there
was no difference in stroke volume index between
treatment groups suggests that vasopressin treatment
does not significantly decrease cardiac contractility
and that any effect on cardiac output is due to an
effect on heart rate. Reassuringly, there was no asso-
ciated fall in cardiac output with vasopressin in those
patients who had poor cardiac function (as defined by
the lowest cardiac index quartile at baseline); how-
ever, it is important to note that there was a signif-
icantly greater proportion of patients who received
inotropic agent infusions among vasopressin-treated
patients. Although this greater use of inotropic agents
could have been due to changes in cardiac output
or markers of perfusion, the data do not show such a
difference between the vasopressin and norepineph-
rine groups. This is in agreement with another study
that reported that infusions of vasopressin or terlip-
ressin, in addition to norepinephrine in septic shock,
did not affect microcirculatory flow.31 Despite pre-
vious reports that low-dose vasopressin may reduce
PA pressures,32 we saw no effect of vasopressin on
these pressures.
There are strengths and limitations of this study.
The data come from a large, multicenter, double-blind,
randomized controlled trial in which infusion and
weaning of vasopressin and norepinephrine were
controlled by protocol and, thus, provide us with the
most extensive data set to date in which to compare
the effects of vasopressin to norepinephrine infusion
in septic shock. However, PA catheters were only
inserted in a small subgroup (31%) of patients, and
their use and the use of inotropic agents were uncon-
trolled. As can be seen from Table 1, PA catheters
were inserted in sicker patients with higher APACHE
(Acute Physiology and Chronic Health Evaluation)
II scores and more organ dysfunction and requiring
higher doses of vasopressors; therefore, they are not
representative of the whole population of patients
first quartile, P 5 .26 in the second quartile, P 5 .43 in the third quar-
tile, and P 5 .36 in the fourth quartile. IQR 5 interquartile range.
CHEST / 142 / 3 / SEPTEMBER 2012 603
 Table 3—Continued

598
P P
Variable 0h 6h 12 h 24 h 36 h 48 h 60 h 72 h 84 h 96 h Valuea Interactionb
Lactate,
mmol/L
More severe …
NE 3.0 (1.7-5.4) … 2.9 (1.8-5.8) … 2.5 (1.6-4.6) … 1.8 (1.3-3.1) … 1.7 (1.3-2.5) … .51
AVP 3.3 (2.0-6.1) … 3.5 (1.9-6.3) … 2.9 (1.8-5.6) … 2.1 (1.5-3.3) … 1.8 (1.3-2.7) … …
Less severe .69
NE 1.9 (1.3-3.7) … 1.9 (1.4-3.2) … 1.7 (1.2-2.8) … 1.7 (1.2-2.6) … 1.6 (1.2-2.2) … .95
AVP 1.6 (1.1-2.5) … 2.1 (1.3-2.5) … 1.7 (1.2-2.3) … 1.6 (1.2-2.1) … 1.7 (1.1-2.2) … …
Pao2/Fio2,
mm Hg
More severe …
NE 188 ⫾ 95 197 ⫾ 101 207 ⫾ 98 211 ⫾ 92 213 ⫾ 100 216 ⫾ 89 229 ⫾ 96 226 ⫾ 95 233 ⫾ 102 229 ⫾ 83 .74
AVP 194 ⫾ 95 206 ⫾ 118 209 ⫾ 104 212 ⫾ 91 211 ⫾ 98 224 ⫾ 129 219 ⫾ 98 230 ⫾ 92 237 ⫾ 92 233 ⫾ 93 …
Less severe .81
NE 210 ⫾ 92 218 ⫾ 92 220 ⫾ 89 223 ⫾ 90 224 ⫾ 94 221 ⫾ 90 233 ⫾ 103 231 ⫾ 111 228 ⫾ 98 225 ⫾ 94 .99
AVP 217 ⫾ 90 229 ⫾ 108 229 ⫾ 88 223 ⫾ 91 233 ⫾ 93 223 ⫾ 84 232 ⫾ 90 225 ⫾ 95 229 ⫾ 87 225 ⫾ 93 …
No. receiving any
inotropes
(existing/new)
More severe …
NE 54 53 (44/9) 53 (44/9) 40 (34/6) 50 (49/1) 41 (37/4) 39 (37/2) 30 (29/1) 34 (31/3) 34 (30/4) .03
AVP 62 67 (55/12) 72 (64/8) 65 (62/3) 72 (70/2) 64 (61/3) 56 (54/2) 46 (41/5) 45 (43/2) 37 (37/0) …
Less severe .69
NE 20 15 (13/2) 20 (14/6) 15 (13/2) 17 (17/0) 15 (11/4) 12 (10/2) 15 (12/3) 21 (17/4) 16 (15/1) .27
AVP 18 19 (15/4) 22 (17/5) 23 (21/2) 21 (21/0) 21 (20/1) 22 (19/3) 21 (20/1) 21 (19/2) 16 (15/1) …
Mean dose
dobutamine,d

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mg/kg per min
More severe …
NE 5.1 ⫾ 3.7 6.5 ⫾ 11.9 3.7 ⫾ 1.9 4.5 ⫾ 6.2 3.5 ⫾ 1.9 5.2 ⫾ 8.6 3.6 ⫾ 2.0 3.5 ⫾ 1.6 3.6 ⫾ 2.0 3.7 ⫾ 1.9 .07
AVP 7.0 ⫾ 5.7 6.9 ⫾ 5.4 7.1 ⫾ 6.9 6.8 ⫾ 7.1 6.6 ⫾ 5.4 7.1 ⫾ 7.5 5.6 ⫾ 5.1 5.6 ⫾ 4.8 5.6 ⫾ 5.0 6.4 ⫾ 4.9 …
Less severe .59
NE 5.1 ⫾ 4.0 5.3 ⫾ 4.0 5.8 ⫾ 4.4 4.5 ⫾ 1.4 4.3 ⫾ 3.4 5.4 ⫾ 2.0 5.2 ⫾ 9.0 3.1 ⫾ 1.4 3.1 ⫾ 1.6 3.6 ⫾ 1.3 .66
AVP 4.1 ⫾ 1.8 4.6 ⫾ 2.3 5.7 ⫾ 3.2 4.3 ⫾ 2.2 4.7 ⫾ 2.2 4.4 ⫾ 2.8 4.0 ⫾ 2.7 5.2 ⫾ 9.0 3.5 ⫾ 2.5 4.1 ⫾ 2.7 …
RPP (/100)
More severe …
NE 110 ⫾ 24 112 ⫾ 24 109 ⫾ 25 106 ⫾ 25 109 ⫾ 26 105 ⫾ 25 107 ⫾ 25 105 ⫾ 27 108 ⫾ 28 111 ⫾ 27 .05
AVP 112 ⫾ 26 103 ⫾ 22 103 ⫾ 26 103 ⫾ 26 103 ⫾ 26 102 ⫾ 25 102 ⫾ 26 106 ⫾ 31 109 ⫾ 30 108 ⫾ 32 …
Less severe .10
NE 108 ⫾ 23 111 ⫾ 24 109 ⫾ 25 111 ⫾ 28 112 ⫾ 27 112 ⫾ 29 114 ⫾ 29 116 ⫾ 28 116 ⫾ 31 118 ⫾ 29 , .0001
AVP 104 ⫾ 23 96 ⫾ 25 95 ⫾ 25 100 ⫾ 29 96 ⫾ 28 103 ⫾ 30 109 ⫾ 5 110 ⫾ 33 109 ⫾ 32 116 ⫾ 37 …
(Continued)

Original Research
 Details of other cardiopulmonary variables are shown

Valuea Interactionb
in Tables 2 through 5. There was no difference in

.12
…
P
mean PA pressure, PA occlusion pressure, or central
venous pressure between treatment groups other than

, .0001
a higher central venous pressure in the vasopressin-

.04
…

…
P
treated patients in the less severe shock stratum.
Although this difference was statistically significant,
the actual difference was small (generally , 1 mm Hg
96 h

48.4
44.8

53.9
52.2
between vasopressin- and norepinephrine-treated
patient groups).
In view of the complexities and interrelationship
of changes in heart rate, cardiac output, and inotrope
84 h

41.4
42.9

55.4
44.8 use between vasopressin and norepinephrine treat-
ment, we calculated the rate-pressure product (heart
rate 3 systolic BP) as an indicator of myocardial work-
load and oxygen consumption. The rate-pressure prod-
72 h

36.5
41.5

57.7
46.2
Data are presented as mean ⫾ SD or median (interquartile range), unless otherwise indicated. See Table 2 legend for expansion of abbreviations.

uct fell rapidly and was significantly lower in the

patients treated with vasopressin compared with the
patients treated with norepinephrine, and this decline
was more marked in the less severe shock stratum,
60 h

although the interaction statistic did not reach signif-

40.5
32.2

51.7
38.0

icance (P 5 .10).
48 h

Discussion
40.2
31.4

48.9
32.6
Table 3—Continued

The effect of vasopressin on cardiac output is one

of the main concerns about using vasopressin in the
treatment of septic shock, especially in patients with
36 h

43.9
36.8

47.5
25.7

poor cardiac function. In this study, we demonstrate

that vasopressin therapy is not associated with a sig-
nificant decrease in cardiac output compared with
dMean dobutamine dose calculated for patients receiving dobutamine at that time point.

norepinephrine, but there was greater use of inotropic

drugs in the vasopressin than in the norepineph-
24 h

41.2
38.0

47.7
31.0

rine treatment group, particularly in the more severe

shock stratum. The main cardiovascular effect of
cMedian NE dose calculated for all patients who received NE at baseline.

vasopressin infusion was a marked decrease in heart

rate rather than a reduction in stroke volume index,
bP value testing for a treatment group 3 shock subgroup interaction.
P value comparing difference over time between treatment groups.
12 h

47.6
36.3

46.1
25.6

and this reduction in heart rate was most striking in

the less severe shock stratum. There were no differ-
ences between vasopressin and norepinephrine in the
other cardiopulmonary variables measured, including
markers of global perfusion, cardiac filling pressures,
53.8
38.4

44.5
27.5
6h

PA pressures, and oxygenation.

In general, maintenance of a high cardiac output in
critical care,16 and specifically sepsis,17 is associated
with a better outcome and is one of the important
targets of early goal-directed therapy.18 However, the
49.0
50.7

46.2
39.0
0h

use of inotropic drugs to boost cardiac output and

oxygen delivery in established septic shock has been
shown to lead to an increased mortality rate.19 Tachy-
cardia is also believed to have adverse effects on
More severe
RPP . 110, %

Less severe

the myocardium as it both increases myocardial

oxygen demand and reduces myocardial oxygen
AVP

AVP
NE

NE
Variable

supply because of the reduction in myocardial per-

fusion in the shortened diastole. In previous studies,
a

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 600
Table 4—Detailed Cardiopulmonary Variables Over Time Comparing Vasopressin vs Norepinephrine in Patients Who Had a PA Catheter (n 5 241)

Variable 0h 6h 12 h 24 h 36 h 48 h 60 h 72 h 84 h 96 h P Valuea
Svo2, %
NE 68.6 ⫾ 14.4 69.5 ⫾ 14.3 68.4 ⫾ 13.8 69.8 ⫾ 15.6 66.9 ⫾ 14.2 66.4 ⫾ 15.9 62.9 ⫾ 17.4 63.3 ⫾ 17.7 65.3 ⫾ 17.1 62.3 ⫾ 17.4 .92
AVP 67.0 ⫾ 15.7 64.0 ⫾ 17.0 68.3 ⫾ 13.8 66.2 ⫾ 14.6 67.7 ⫾ 15.8 67.3 ⫾ 13.0 65.0 ⫾ 16.8 65.4 ⫾ 14.4 64.2 ⫾ 14.8 65.7 ⫾ 15.0 …
Cardiac index,
L/min per m2
NE 3.95 ⫾ 1.26 3.92 ⫾ 1.22 3.70 ⫾ 1.14 3.67 ⫾ 1.02 3.61 ⫾ 1.23 3.62 ⫾ 1.27 3.46 ⫾ 1.18 3.82 ⫾ 1.40 3.49 ⫾ 1.15 3.53 ⫾ 1.10 .87
AVP 3.82 ⫾ 1.31 3.51 ⫾ 1.39 3.46 ⫾ 1.29 3.70 ⫾ 1.57 3.46 ⫾ 1.45 3.65 ⫾ 1.45 3.52 ⫾ 1.46 3.59 ⫾ 1.39 3.47 ⫾ 1.48 3.65 ⫾ 1.61 …
SVI, mL/min per m2
NE 39.8 ⫾ 14.3 39.9 ⫾ 11.9 37.8 ⫾ 11.7 40.2 ⫾ 11.9 37.5 ⫾ 11.9 39.9 ⫾ 14.0 38.4 ⫾ 12.9 40.4 ⫾ 13.6 39.6 ⫾ 11.8 39.8 ⫾ 11.9 .53
AVP 37.5 ⫾ 12.5 37.2 ⫾ 14.3 36.3 ⫾ 12.7 39.0 ⫾ 14.6 37.5 ⫾ 14.9 39.1 ⫾ 14.8 38.9 ⫾ 15.1 39.5 ⫾ 13.7 38.7 ⫾ 13.0 40.0 ⫾ 13.5 …
LVSWI, g/m2
NE 28.5 ⫾ 11.7 31.2 ⫾ 11.9 29.8 ⫾ 12.5 31.7 ⫾ 12.2 29.4 ⫾ 12.4 31.3 ⫾ 12.8 32.5 ⫾ 13.4 33.2 ⫾ 13.2 32.0 ⫾ 11.5 34.8 ⫾ 12.3 .72
AVP 26.6 ⫾ 10.3 28.8 ⫾ 11.9 27.7 ⫾ 11.7 30.2 ⫾ 14.0 29.3 ⫾ 13.6 31.5 ⫾ 14.7 31.4 ⫾ 15.3 31.5 ⫾ 14.2 31.6 ⫾ 10.9 32.0 ⫾ 12.5 …
PAOP, mm Hg
NE 17.3 ⫾ 5.7 17.9 ⫾ 5.3 17.7 ⫾ 4.8 18.9 ⫾ 6.1 18.7 ⫾ 5.7 19.4 ⫾ 7.2 17.9 ⫾ 5.3 18.7 ⫾ 6.4 19.2 ⫾ 8.3 18.9 ⫾ 5.2 .32
AVP 20.6 ⫾ 5.9 19.2 ⫾ 5.0 19.6 ⫾ 6.7 20.2 ⫾ 6.0 19.0 ⫾ 5.8 19.1 ⫾ 5.9 19.5 ⫾ 6.4 19.5 ⫾ 6.8 19.4 ⫾ 5.6 19.5 ⫾ 6.3 …
MPAP, mm Hg
NE 28.0 ⫾ 6.7 29.4 ⫾ 6.3 29.0 ⫾ 5.9 29.4 ⫾ 8.7 29.4 ⫾ 6.6 29.8 ⫾ 7.1 28.6 ⫾ 6.9 30.0 ⫾ 7.7 28.9 ⫾ 7.8 30.4 ⫾ 7.3 .82

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AVP 30.3 ⫾ 6.7 30.2 ⫾ 8.2 29.9 ⫾ 8.2 29.7 ⫾ 6.3 29.8 ⫾ 8.0 30.1 ⫾ 7.1 29.8 ⫾ 7.8 29.9 ⫾ 7.3 28.7 ⫾ 6.3 29.8 ⫾ 7.4 …
Data are presented as mean ⫾ SD. LVSWI 5 left ventricular stroke work index; MPAP 5 mean pulmonary arterial pressure; PAOP 5 pulmonary artery occlusion pressure; SVI 5 stroke volume index;
Svo2 5 mixed venous oxygen saturation. See Table 1 and 2 legends for expansion of other abbreviations.
aP value comparing difference over time between treatment groups.

Original Research
 Table 5—Detailed Cardiopulmonary Variables Over Time Comparing Vasopressin vs Norepinephrine in Patients Who Had a PA Catheter in the More and
Less Severe Shock Strata

Variable 0h 6h 12 h 24 h 36 h 48 h 60 h 72 h 84 h 96 h P Valuea P Interactionb

Svo2, %
More severe …

journal.publications.chestnet.org
NE 67.4 ⫾ 16.7 68.9 ⫾ 15.6 67.4 ⫾ 14.2 70.7 ⫾ 13.1 66.9 ⫾ 12.8 67.7 ⫾ 12.6 61.4 ⫾ 16.7 62.5 ⫾ 16.4 61.8 ⫾ 17.5 63.1 ⫾ 14.7 .99
AVP 62.2 ⫾ 16.3 58.5 ⫾ 18.1 64.7 ⫾ 14.8 61.2 ⫾ 15.2 64.7 ⫾ 15.2 63.9 ⫾ 14.0 60.6 ⫾ 18.1 59.8 ⫾ 15.5 58.8 ⫾ 15.5 61.4 ⫾ 16.5 …
Less severe .97
NE 69.8 ⫾ 11.6 70.3 ⫾ 12.6 69.9 ⫾ 13.4 68.5 ⫾ 18.9 67.0 ⫾ 16.7 64.7 ⫾ 19.8 66.1 ⫾ 19.0 64.5 ⫾ 20.2 70.3 ⫾ 15.8 60.4 ⫾ 22.9 .95
AVP 74.1 ⫾ 11.8 73.4 ⫾ 9.5 72.8 ⫾ 11.0 70.8 ⫾ 12.7 71.4 ⫾ 16.1 71.7 ⫾ 10.2 70.3 ⫾ 13.7 71.9 ⫾ 10.3 73.9 ⫾ 6.4 74.2 ⫾ 5.6 …
Cardiac index, L/min per m2
More severe …
NE 3.96 ⫾ 1.14 3.67 ⫾ 0.99 3.59 ⫾ 1.26 3.55 ⫾ 1.05 3.41 ⫾ 1.22 3.47 ⫾ 1.28 3.36 ⫾ 1.16 3.54 ⫾ 1.29 3.33 ⫾ 1.16 3.22 ⫾ 0.90 .32
AVP 3.76 ⫾ 1.27 3.51 ⫾ 1.37 3.41 ⫾ 1.19 3.65 ⫾ 1.52 3.26 ⫾ 1.31 3.53 ⫾ 1.45 3.31 ⫾ 1.42 3.47 ⫾ 1.25 3.30 ⫾ 1.21 3.64 ⫾ 1.57 …
Less severe .15
NE 3.95 ⫾ 1.41 4.36 ⫾ 1.45 3.86 ⫾ 0.93 3.83 ⫾ 0.99 3.95 ⫾ 1.19 3.83 ⫾ 1.24 3.64 ⫾ 1.23 4.18 ⫾ 1.47 3.72 ⫾ 1.11 4.01 ⫾ 1.26 .30
AVP 3.93 ⫾ 1.39 3.50 ⫾ 1.44 3.55 ⫾ 1.45 3.81 ⫾ 1.69 3.80 ⫾ 1.64 3.87 ⫾ 1.45 3.85 ⫾ 1.47 3.74 ⫾ 1.56 3.73 ⫾ 1.82 3.65 ⫾ 1.74 …
SVI, mL/min per m2
More severe …
NE 39.8 ⫾ 14.3 39.9 ⫾ 11.9 37.8 ⫾ 11.7 40.2 ⫾ 11.9 37.5 ⫾ 11.9 39.9 ⫾ 14.0 38.4 ⫾ 12.9 40.4 ⫾ 13.6 39.6 ⫾ 11.8 39.8 ⫾ 11.9 .36
AVP 37.5 ⫾ 12.5 37.2 ⫾ 14.3 36.3 ⫾ 12.7 39.0 ⫾ 14.6 37.5 ⫾ 14.9 39.1 ⫾ 14.8 38.9 ⫾ 15.1 39.5 ⫾ 13.7 38.7 ⫾ 13.0 40.0 ⫾ 13.5 …
Less severe .66
NE 41.4 ⫾ 16.8 46.9 ⫾ 12.7 40.2 ⫾ 38.6 42.8 ⫾ 11.5 42.3 ⫾ 11.1 42.5 ⫾ 14.7 40.6 ⫾ 11.2 43.4 ⫾ 12.3 41.4 ⫾ 9.2 43.1 ⫾ 10.4 .86
AVP 40.8 ⫾ 14.6 38.4 ⫾ 15.7 38.6 ⫾ 14.9 42.7 ⫾ 16.2 42.6 ⫾ 17.5 42.6 ⫾ 16.0 41.9 ⫾ 15.5 41.1 ⫾ 15.3 42.2 ⫾ 16.1 41.0 ⫾ 14.9 …
LVSWI, g/m2
More severe …
NE 27.8 ⫾ 11.7 28.8 ⫾ 12.0 28.3 ⫾ 14.5 30.4 ⫾ 14.8 26.7 ⫾ 13.4 30.1 ⫾ 15.1 31.3 ⫾ 14.9 31.2 ⫾ 14.3 31.7 ⫾ 12.4 33.9 ⫾ 14.5 .62

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AVP 25.3 ⫾ 8.0 27.7 ⫾ 10.6 25.3 ⫾ 8.3 27.1 ⫾ 11.1 26.4 ⫾ 9.9 28.3 ⫾ 12.6 28.4 ⫾ 12.8 30.8 ⫾ 11.9 30.1 ⫾ 9.3 31.6 ⫾ 13.6 …
Less severe .16
NE 29.5 ⫾ 11.8 35.8 ⫾ 10.3 32.1 ⫾ 8.5 33.4 ⫾ 7.9 33.5 ⫾ 9.5 32.9 ⫾ 9.0 34.5 ⫾ 10.7 35.5 ⫾ 11.6 32.3 ⫾ 10.5 36.4 ⫾ 7.45 .16
AVP 28.4 ⫾ 12.9 30.9 ⫾ 14.2 31.6 ⫾ 15.4 34.9 ⫾ 16.7 34.2 ⫾ 17.4 37.3 ⫾ 16.7 36.9 ⫾ 18.2 32.5 ⫾ 17.2 34.2 ⫾ 13.1 32.8 ⫾ 10.6 …
PAOP, mm Hg
More severe …
NE 17.4 ⫾ 6.0 18.1 ⫾ 6.3 18.2 ⫾ 5.4 19.1 ⫾ 7.2 18.9 ⫾ 5.6 19.3 ⫾ 7.8 17.6 ⫾ 4.7 18.1 ⫾ 7.1 19.1 ⫾ 7.7 18.8 ⫾ 5.9 .20
AVP 20.6 ⫾ 4.7 19.9 ⫾ 4.2 19.5 ⫾ 4.4 20.6 ⫾ 5.2 18.9 ⫾ 4.9 19.8 ⫾ 5.1 20.6 ⫾ 6.2 19.1 ⫾ 4.2 19.9 ⫾ 6.0 19.2 ⫾ 6.8 …
Less severe .39
NE 17.2 ⫾ 5.3 17.7 ⫾ 6.2 16.9 ⫾ 3.7 18.5 ⫾ 4.4 18.3 ⫾ 5.9 19.6 ⫾ 6.3 18.3 ⫾ 6.2 19.5 ⫾ 5.5 19.4 ⫾ 9.1 19.1 ⫾ 3.5 .97
AVP 20.5 ⫾ 7.4 17.7 ⫾ 6.2 19.8 ⫾ 9.6 19.5 ⫾ 7.2 19.0 ⫾ 7.3 17.7 ⫾ 7.0 17.4 ⫾ 6.3 20.0 ⫾ 9.5 18.7 ⫾ 5.2 20.0 ⫾ 5.3 …
(Continued)

CHEST / 142 / 3 / SEPTEMBER 2012

601
 a high heart rate has been associated with higher

P Interactionb
mortality rates in septic shock.20,21 It is interesting

.02
…
that the greater decrease of heart rate was seen in
patients treated with vasopressin in the less severe
shock stratum in whom there was a significant reduc-

P Valuea
tion in mortality with vasopressin compared with nor-

.10

.12
…

…
epinephrine treatment.
We calculated the rate-pressure product in an
attempt to summarize the balance of myocardial
30.5 ⫾ 8.4
27.6 ⫾ 5.6

30.2 ⫾ 4.9
34.3 ⫾ 8.6
96 h

workload and oxygen consumption, a higher number,

particularly . 11,000,22 being associated with an
increased risk of myocardial ischemia.23 There was a
significant reduction in the rate-pressure product and
29.2 ⫾ 8.1
28.2 ⫾ 6.1

28.6 ⫾ 7.4
29.6 ⫾ 6.7
84 h

the proportion of patients who had a rate-pressure

product . 11,000 in the vasopressin-treated group
compared with those in the norepinephrine-treated
group, and this may reflect an improvement in the
29.5 ⫾ 8.6
29.7 ⫾ 7.1

30.6 ⫾ 6.4
30.2 ⫾ 7.6
72 h

balance of myocardial oxygen supply and demand.

However, there were no differences in myocardial
ischemia or infarction between treatment groups
in the primary VASST analysis or in subsequent
28.7 ⫾ 7.4
29.2 ⫾ 7.2

28.5 ⫾ 6.2
30.9 ⫾ 8.8
60 h

post hoc subgroup analyses of troponin levels or

ischemic ECG changes.24,25
These effects of vasopressin vs norepinephrine
on hemodynamics agree with many of the previously
30.4 ⫾ 8.0
29.6 ⫾ 6.1

28.9 ⫾ 5.6
31.0 ⫾ 8.6
Table 5—Continued

48 h

published smaller studies. Vasopressin has been

associated with a reduction in heart rate in several
studies.7,8 There are two possibilities for this effect.
If the normal baroreceptor response is still intact
30.1 ⫾ 7.5
29.2 ⫾ 7.4

28.2 ⫾ 4.8
30.9 ⫾ 8.8
36 h

(particularly in the less severe shock stratum) the nor-

mal physiologic response to the vasopressin-induced
Data are presented as mean ⫾ SD. See Table 1 and 3 legends for expansion of abbreviations.

vasoconstriction would be a drop in heart rate if

30.7 ⫾ 10.4

stroke volume is maintained, therefore, balancing car-

29.6 ⫾ 6.0

27.5 ⫾ 4.2
29.8 ⫾ 7.0
24 h

diac output in order to maintain the same BP. The

other explanation may be due to the well-described
catecholamine-sparing effect of vasopressin. Although
30.9 ⫾ 10.6

norepinephrine is described as an a-adrenoreceptor

29.8 ⫾ 6.5
29.2 ⫾ 6.2

27.8 ⫾ 4.6
12 h

agonist, it does have some b-adrenoreceptor activity,

bP value testing for a treatment group 3 shock subgroup interaction.
P value comparing difference over time between treatment groups.

and thus, a reduction in the rate of infusion of norepi-

nephrine may lead to a reduction in heart rate. This
may be an important characteristic of vasopressin.
29.9 ⫾ 7.4
30.1 ⫾ 7.2

28.7 ⫾ 4.3
30.3 ⫾ 9.7
6h

Work has demonstrated that increased catecholamine

vasopressor load is associated with mortality and
other adverse events once a mean arterial pressure
of 70 mm Hg is obtained.21 At the time of recruit-
27.3 ⫾ 7.2
29.6 ⫾ 6.4

28.9 ⫾ 6.0
31.2 ⫾ 7.0
0h

ment into VASST, the average mean arterial pressure

was about 72 mm Hg, and the mean norepinephrine
infusion rate was about 20 mg/min. Norepinephrine
requirements reduced significantly in the patients
treated with vasopressin. The idea of decatecholami-
nization, reducing both endogenous and exogenous
adrenergic stimulation, is now believed to be an impor-
MPAP, mm Hg
More severe

Less severe

tant treatment strategy,26 and the use of b-blockers

in septic shock is being considered.27,28 The early use
AVP

AVP
NE

NE
Variable

of vasopressin or specific V1a receptor agonists in

early septic shock may be another possible treatment
a

602 Original Research

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Figure 1. Cardiac index over time in patients who had pulmo-
nary artery catheters by cardiac index quartile at baseline. A, The
first quartile cardiac index was ⱕ 2.9 L/min per m2 at baseline.
B, The second quartile cardiac index was 2.91 to 3.7 L/min per m2
at baseline. C, The third quartile cardiac index was 3.71 to
4.5 L/min per m2 at baseline. D, The fourth quartile cardiac index
was . 4.5 L/min per m2 at baseline. The circles represent the patients
treated with vasopressin, and the squares represent the patients
treated with norepinephrine. The treatment (vasopressin vs nor-
epinephrine) effect on cardiac index over time was P 5 .99 in the
journal.publications.chestnet.org
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strategy.29 Adhering to the lower limits of BP targets
may also help to reduce vasopressor load.30
A reduction in cardiac output associated with vaso-
pressin has previously been reported,8 although other
controlled trials have shown no effect5,6,9 and others
even an increase in cardiac output.7 The divergent
results between studies may reflect differences in
doses and methods of vasopressin administration,
concomitant IV fluid resuscitation, and inotropic infu-
sions. We administered low-dose vasopressin (max-
imum dose, 0.03 units/min) by continuous infusion
after adequate fluid resuscitation and then titrated
up the infusion while decreasing catecholamine vaso-
pressors to maintain the target BP. The fact that there
was no difference in stroke volume index between
treatment groups suggests that vasopressin treatment
does not significantly decrease cardiac contractility
and that any effect on cardiac output is due to an
effect on heart rate. Reassuringly, there was no asso-
ciated fall in cardiac output with vasopressin in those
patients who had poor cardiac function (as defined by
the lowest cardiac index quartile at baseline); how-
ever, it is important to note that there was a signif-
icantly greater proportion of patients who received
inotropic agent infusions among vasopressin-treated
patients. Although this greater use of inotropic agents
could have been due to changes in cardiac output
or markers of perfusion, the data do not show such a
difference between the vasopressin and norepineph-
rine groups. This is in agreement with another study
that reported that infusions of vasopressin or terlip-
ressin, in addition to norepinephrine in septic shock,
did not affect microcirculatory flow.31 Despite pre-
vious reports that low-dose vasopressin may reduce
PA pressures,32 we saw no effect of vasopressin on
these pressures.
There are strengths and limitations of this study.
The data come from a large, multicenter, double-blind,
randomized controlled trial in which infusion and
weaning of vasopressin and norepinephrine were
controlled by protocol and, thus, provide us with the
most extensive data set to date in which to compare
the effects of vasopressin to norepinephrine infusion
in septic shock. However, PA catheters were only
inserted in a small subgroup (31%) of patients, and
their use and the use of inotropic agents were uncon-
trolled. As can be seen from Table 1, PA catheters
were inserted in sicker patients with higher APACHE
(Acute Physiology and Chronic Health Evaluation)
II scores and more organ dysfunction and requiring
higher doses of vasopressors; therefore, they are not
representative of the whole population of patients
first quartile, P 5 .26 in the second quartile, P 5 .43 in the third quar-
tile, and P 5 .36 in the fourth quartile. IQR 5 interquartile range.
CHEST / 142 / 3 / SEPTEMBER 2012 603
 with septic shock. However, if there are any adverse
hemodynamic effects of vasopressin, they are more
likely to be present in these sicker patients. This is
a post hoc subgroup analysis and, therefore, should
only be hypothesis generating in order to inform fur-
ther research studies rather than clinical practice.
It is also important to consider the inclusion and
exclusion criteria for the trial. Recruited patients had
established and treated septic shock for at least 6 h.
They had already undergone fluid resuscitation, and
the blinded study drug (vasopressin or norepineph-
rine) was substituted for existing vasopressors; thus,
it is not a direct comparison of the two vasopres-
sors on systemic hemodynamics when used as initial
therapy in septic shock. Adequate fluid resuscitation
prior to starting vasopressin or any vasopressin analog
is important, and detrimental cardiovascular effects
might occur if the patient is depleted of fluids. Addi-
tionally, patients with severe chronic heart disease
or with acute coronary syndromes were excluded
from VASST. Further evidence about the effect of
vasopressin infusion in these groups of patients is
required.
Conclusions
Vasopressin treatment in septic shock is associ-
ated with a significant reduction in heart rate but no
change in cardiac output or measures of perfusion.
Nonetheless, more patients in the vasopressin-treated
group than in the norepinephrine-treated group also
received inotropic agent infusions. Any effect of vaso-
pressin on cardiac output seems to be due to this
decrease in heart rate rather than to an effect on
stroke volume index. Finally, there were no adverse
effects on cardiac output of vasopressin vs norepi-
nephrine, even in those patients with the poorest car-
diac function (as reflected by lowest cardiac index
quartile at baseline).
Acknowledgments
Author contributions: Dr Gordon had full access to all of the
data in the study and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
Dr Gordon: contributed to the study conception and design,
acquisition of data, analysis and interpretation of data, statistical
analysis, drafting of the manuscript, and critical revision of the
manuscript for important intellectual content.
Dr Wang: contributed to the analysis and interpretation of data,
statistical analysis, and critical revision of the manuscript for impor-
tant intellectual content.
Dr Walley: contributed to the study conception and design, acqui-
sition of data, analysis and interpretation of data, statistical analysis,
drafting of the manuscript, and critical revision of the manuscript
for important intellectual content.
Dr Ashby: contributed to the analysis and interpretation of data,
statistical analysis, and critical revision of the manuscript for
important intellectual content.
604
Downloaded From: http://journal.publications.chestnet.org/ by a University of Arizona User on 06/02/2013
Dr Russell: contributed to the study conception and design,
acquisition of data, analysis and interpretation of data, statistical
analysis, drafting of the manuscript, and critical revision of the
manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Drs Russell, Walley,
and Gordon have previously served as officers for and hold stock
in Sirius Genomics Inc, which has submitted a patent, owned
by the University of British Columbia and licensed to Sirius
Genomics Inc, that is related to the genetics of vasopressin. The
University of British Columbia has also submitted a patent related
to the use of vasopressin in septic shock. Drs Russell, Walley, and
Gordon are named as inventors on this patent. Drs Russell and
Walley have received consulting fees from Ferring Pharmaceu-
ticals, Inc, which manufactures vasopressin. Drs Wang and Ashby
have reported that no potential conflicts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article.
Role of sponsors: The sponsors had no role in the design of the
study, the collection and analysis of the data, or in the preparation
of the manuscript.
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