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RussellAnthony C. Gordon, Nan Wang, Keith R. Walley, Deborah Ashby and James A. NOREPINEPHRINE IN SEPTIC SHOCKVASOPRESSIN COMPARED TO THE CARDIO-PULMONARY EFFECTS OF

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1

Word count: 2706

Abstract word count: 249

THE CARDIO-PULMONARY EFFECTS OF VASOPRESSIN COMPARED

TO NOREPINEPHRINE IN SEPTIC SHOCK.

Running head: Cardio-pulmonary effects of vasopressin

Authors: Anthony C Gordon1 MD, Nan Wang

2 PhD, Keith R Walley

3 MD, Deborah

Ashby2 PhD, James A Russell

3 MD

Emails: [email protected]

[email protected]

[email protected]

[email protected]

[email protected]

Institutions:

1. Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of

Medicine, Imperial College London, UK.

2. Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine,

Imperial College London, UK.

3. Critical Care Research Laboratories, Institute for Heart + Lung Health, St.

Paul’s Hospital and University of British Columbia, Vancouver, British

Columbia, Canada V6Z 1Y6.

Corresponding author:

Dr Anthony Gordon

Clinical Senior Lecturer & Consultant, Critical Care Medicine

11N, Imperial College / Charing Cross Hospital

Fulham Palace Road

Page 1 of 32



2

London W6 8RF,

UK

Tel: +44 20 3313 0657

Fax: +44 20 3311 1975

Email: [email protected]

KEY WORDS: Vasopressin, norepinephrine, septic shock, hemodynamics, cardiac

output

Conflicts of interest:

Drs. Russell, Walley, and Gordon have previously served as officers for and hold

stock in Sirius Genomics, which has submitted a patent, owned by the University of

British Columbia and licensed to Sirius Genomics, 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, which manufactures vasopressin.

Drs Wang and Ashby have no conflicts of interest.

Page 2 of 32



3

Abstract

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 cardio-pulmonary effects of vasopressin compared to

norepinephrine in 779 adult patients who had septic shock recruited to the

Vasopressin and Septic Shock Trial (VASST). More detailed cardiac output data was

analyzed for the subset of 241 patients managed with a pulmonary artery catheter and

data was collected for the first 96 hours after randomization. We compared the effects

of vasopressin versus norepinephrine in all patients and also according to severity of

shock (< or ≥ 15µg/min of norepinephrine) and cardiac output at baseline.

Results: Equal blood pressures were maintained in both treatment groups with a

significant reduction in norepinephrine requirements in the vasopressin treated

patients. The major haemodynamic difference between the two groups was a

significant reduction in heart rate in the vasopressin treated patients (p < 0.0001) and

this was most pronounced in the less severe shock stratum (treatment x shock stratum

interaction, p = 0.03). There were no other major cardio-pulmonary differences

between treatment groups, including no difference in cardiac index or stroke volume

index between vasopressin and norepinephrine treated patients. There was

significantly greater use of inotropic drugs in the vasopressin group compared to 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.

(Controlled Trials number, ISRCTN94845869.)

Page 3 of 32



4

Abbreviation list

APACHE – Acute Physiology and Chronic Health Evaluation

AVP – Arginine vasopressin

CI – Cardiac Index

COPD - chronic obstructive pulmonary disease

CVP - central venous pressure

ECG – Electrocardiogram

FiO2 – Fraction of inspired oxygen

HR – Heart rate

LVSWI – left ventricular stroke work index

MAP – mean arterial pressure

MPAP - mean pulmonary artery pressure

NE- norepinephrine

NYHA - New York Heart Association

PA – Pulmonary Artery

PaO2 – Arterial partial pressure of oxygen

PAOP - pulmonary artery occlusion pressure

RPP – Rate pressure product

SBP - Systolic blood pressure

SIRS - Systemic inflammatory response syndrome

SVI – stroke volume index

SvO2 – Mixed venous oxygen saturation

VASST - Vasopressin and Septic Shock Trial

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5

Introduction:

When cardiovascular failure develops due to sepsis, mortality rates are high1.

As well as treating the underlying infection with antibiotics and source control, the

mainstay of treatment of septic shock is cardiovascular resuscitation using

intravenous fluid, and vasopressor and/or inotropic drugs2. In recent years there has

been increasing interest in vasopressin treatment as an adjunct to other catecholamine

vasopressors.

The rationale behind its use is that there is commonly a relative vasopressin

deficiency in septic shock3 and patients appear sensitive to administration of low-dose

vasopressin infusions4. In several small studies, often unblinded, vasopressin infusion

has invariably been shown to increase blood pressure and spare catecholamine use5-8

.

The effect of vasopressin on cardiac output is less clear with reports that it may

reduce8, 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 U/min) are associated

with cardiac arrest10

. In contrast norepinephrine, the most commonly used

catecholamine vasopressor11

, has both α and β-adrenoreceptor effects and so

increases blood pressure but also may increase heart rate, cause arrhythmias and has

been associated with mesenteric and cutaneous ischemia12,13

.

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 treatment of established adult septic shock14

.

In the whole study population there was no significant difference in mortality rates

between the treatment groups (28-day mortality, 35.4% in the vasopressin group vs.

39.3% in the norepinephrine group, p=0.26). However, in the a priori stratum of less

severe shock (defined as 5-15µg/min of norepinephrine at baseline) there was a

significantly lower 28-day mortality in vasopressin group compared to the

Page 5 of 32



6

norepinephrine group (26.5% vs. 35.7%, respectively, p=0.05). In the more severe

shock stratum (≥15µg/min of norepinephrine at baseline) there was no difference in

mortality rates (44.0% vs. 42.5%, p=0.76 in the vasopressin and norepinephrine

groups respectively).

We, therefore, planned to study the cardio-pulmonary effects of vasopressin

compared to norepinephrine 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 also compared hemodynamics of

vasopressin versus norepinephrine 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 who have a low cardiac output, we

compared the effects of vasopressin versus norepinephrine in patients according to

cardiac output at baseline.

Page 6 of 32



7

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 Hospital, P99-0175) and

all participants or their legal representatives gave informed consent. In summary, this

was a multi-center randomized double-blind controlled trial of vasopressin versus

norepinephrine in addition to standard vasopressors for the treatment of septic shock.

Patients were greater than 16 years of age and had septic shock, defined by the

presence of two or more of the systemic inflammatory response syndrome (SIRS)

criteria15

, proven or suspected infection, new dysfunction of at least one organ, and

hypotension despite adequate fluid resuscitation requiring vasopressor support of at

least 5 µg/min of norepinephrine (or equivalent) for six hours. Important clinical

exclusion criteria were unstable coronary syndromes, severe chronic heart disease

(New York Heart Association class III and IV) and vasospastic diathesis. Patients

were randomized to receive a blinded infusion of study drug, either vasopressin (0.01

- 0.03 U/min) or norepinephrine (5 – 15 µg/min). The study drug and all other

vasopressors were titrated and weaned according to protocols. The initial target mean

arterial pressure was 65 – 75 mmHg. All other cardiovascular management including

cardiac output monitoring, setting of cardiac output goals, fluid and inotropic therapy

were at the local treating physician’s discretion.

Data analysis & statistics

Basic cardio-pulmonary variables (blood pressure, heart rate, central venous

pressure, PaO2/FiO2 and pH) and inotrope use (dobutamine, milrinone and

epinephrine) were collected in all patients in the study and are reported for all patients

in this analysis. If a pulmonary artery (PA) catheter was in situ details of pulmonary

Page 7 of 32



8

artery pressures, cardiac output and mixed venous saturations were collected for the

first 96 after randomization.

Comparison of baseline data between patients who had or did not have a PA catheter

was carried out by chi-squared test or t-test as appropriate. Longitudinal data were

analyzed using linear mixed effect models (PROC MIXED in SAS Enterprise Guide

4.3) 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 numbers of patients receiving inotropes was analyzed

using a generalized linear mixed effect 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 Chi-square test. A p-value less than 0.05 was

considered significant.

Page 8 of 32



9

Results:

In total 779 patients were randomized and infused with the blinded study

drugs. Cardiac output monitoring was used in 156 patients at baseline and was

instituted after randomization in a further 85 patients (total = 241, or 31% of patients

in VASST) and was equally balanced between the two treatment groups (vasopressin

n=123 and norepinephrine n=118, p = 0.97). 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, higher lactate and were receiving higher doses of

norepinephrine and phenylephrine at baseline compared to patients who did not have

a PA catheter.

As specified in the protocol vasopressor drugs were titrated to maintain similar

mean arterial pressure 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

vasopressin infusion (table 2). This was most pronounced in the less severe shock

stratum (table 4) and the interaction statistic examining the treatment x shock stratum

interaction was significant (p=0.03).

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 less severe shock strata. Similarly there was no

difference in markers of oxygen delivery, namely SvO2, 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 to the norepinephrine group,

particularly in the more severe shock stratum where significantly more patients were

Page 9 of 32



10

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 compared to the norepinephrine group.

As 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 treatment groups in any of the quartiles (Figure 1A-D) including those who

had the lowest cardiac outputs (1st quartile CI ≤2.9l/min/m

2).

Details of other cardio-pulmonary variables are shown in tables 2-5. There

was no difference in mean pulmonary artery pressure (MPAP), pulmonary artery

occlusion pressure (PAOP) or central venous pressure (CVP) between treatment

groups other than a higher CVP in the vasopressin treated patients in the less severe

shock stratum. Although this difference was statistically significant the actual

difference was small (generally < 1mmHg between vasopressin and norepinephrine

patients).

In view of the complexities and inter-relationship of changes in heart rate,

cardiac output, and inotrope use between vasopressin and norepinephrine treatment

we calculated the rate-pressure product (HR x SBP) as an indicator of myocardial

workload and oxygen consumption. This fell rapidly and was significantly lower in

the vasopressin treated patients compared to the norepinephrine-treated patients and

this decline in rate-pressure product was more marked in the less severe shock

stratum, although the interaction statistic did not reach significance (p = 0.10).

Page 10 of 32



11

Discussion:

The effect of vasopressin on cardiac output is one of the main concerns about

using vasopressin in the treatment of septic shock, especially in those patients with

poor cardiac function. In this study we have demonstrated that vasopressin therapy

was not associated with a significant decrease in cardiac output compared to

norepinephrine but there was greater use of inotropic drugs in the vasopressin

compared to the norepinephrine treatment group, particularly in the more severe

shock subgroup. The main cardiovascular effect of vasopressin infusion was a

marked decrease in heart rate rather than a reduction in stroke volume index, and this

reduction in heart rate was most striking in the less severe shock stratum. There were

no differences between vasopressin and norepinephrine in the other cardio-pulmonary

variables measured including markers of global perfusion, cardiac filling pressures,

pulmonary artery pressures and oxygenation.

In general, maintenance of a high cardiac output in critical care16

and

specifically sepsis17

is associated with a better outcome and is one of the important

targets of early goal directed therapy18

. However, the use of inotropic drugs to boost

cardiac output and oxygen delivery in established septic shock has been shown to lead

to an increased mortality rate19

. Tachycardia is also thought to have adverse effects on

the myocardium as it both increases myocardial oxygen demand as well as reducing

myocardial oxygen supply due to the reduction in myocardial perfusion in the

shortened diastole. In previous studies a high heart rate has been associated with

higher mortality rates in septic shock20,21

. It is interesting that the greater decrease of

heart rate was seen in vasopressin patients in the less severe shock stratum in whom

there was a significant reduction in mortality with vasopressin compared to

norepinephrine treatment.

Page 11 of 32



12

We calculated the rate-pressure product in an attempt to summarize the

balance of myocardial workload and oxygen consumption, a higher number

particularly >11,00022

, being associated with an increased risk of myocardial

ischemia23

. There was a significant reduction in the rate-pressure product and the

proportion of patients who had a rate-pressure product >11,000 in the vasopressin-

treated patients (compared to norepinephrine-treated patients) and this may reflect an

improvement in the 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 post-hoc subgroup analyses

of troponin levels or ischemic ECG changes24,25

.

These effects of vasopressin vs. norepinephrine on hemodynamics agree with

many of the previously published smaller studies. Vasopressin has been associated

with a reduction in heart rate in several studies7,8

. There are two possibilities for this

effect. If the normal baroreceptor response is still intact (particularly in the less severe

shock stratum) the normal physiological response to the vasopressin-induced

vasoconstriction would be a drop in heart rate if stroke volume is maintained,

therefore balancing cardiac output in order to maintain the same blood pressure. The

other explanation may be due to the well-described catecholamine-sparing effect of

vasopressin. Although norepinephrine is described as an α-adrenoreceptor agonist it

does have some β-adrenoreceptor activity and thus a reduction in the rate of infusion

of norepinephrine may lead to a reduction in heart rate. This may be an important

characteristic of vasopressin. Recent work has demonstrated that increased

catecholamine vasopressor load is associated with mortality and other adverse events

once a mean arterial pressure of 70mmHg is obtained21

. At the time of recruitment

into VASST the average mean arterial pressure was ~72mmHg and the mean

norepinephrine infusion rate was ~20µg/min. Norepinephrine requirements reduced

Page 12 of 32



13

significantly in the vasopressin treated patients. The idea of decatecholaminization,

reducing both endogenous and exogenous adrenergic stimulation, is now thought to

be an important treatment strategy26

and the use of beta-blockers in septic shock is

being considered27,28

. The early use of vasopressin or specific V1a receptor agonists

in early septic shock may be another possible treatment strategy29

. Adhering to the

lower limits of a blood pressure targets may also help reduce vasopressor load30

.

A reduction in cardiac output associated with vasopressin has previously been

reported8 although other controlled trials have shown no effect

5,6,9 and others even an

increase in cardiac output7. The divergent results between studies may reflect

differences in doses and methods of vasopressin administration, concomitant

intravenous fluid resuscitation and inotropic infusions. We administered low-dose

vasopressin (maximum dose 0.03U/min) by continuous infusion after adequate fluid

resuscitation, and then titrated up the infusion while decreasing catecholamine

vasopressors to maintain the target blood pressure. The fact that there was no

difference in stroke volume index between treatment groups suggests that vasopressin

treatment is not significantly decreasing cardiac contractility and that any effect on

cardiac output is due to an effect on heart rate. Reassuringly there was no associated

fall in cardiac output with vasopressin in those patients who had poor cardiac function

(as defined by the lowest cardiac index quartile at baseline); however, it is important

to note that there was a significantly greater proportion of patients who received

inotropic agent infusions amongst vasopressin treated patients. While this greater use

of inotropic agents could have been due to changes in cardiac output or markers of

perfusion, our data do not show such a difference between the vasopressin and

norepinephrine groups. This is in agreement with another recent study that reported

that infusions of vasopressin or terlipressin, in addition to norepinephrine in septic

shock, did not affect microcirculatory flow31

. Despite previous reports that low-dose

Page 13 of 32



14

vasopressin may reduce pulmonary artery pressures32

, we saw no effect of

vasopressin on these pressures.

There are of course strengths and limitations of this study. The data come

from a large multi-center double-blind randomized controlled trial in which infusion

and weaning of vasopressin and norepinephrine was 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 was uncontrolled. As can be seen clearly from table 1, PA catheters

were inserted in sicker patients with higher APACHE II scores, more organ

dysfunction and requiring higher doses of vasopressors. Therefore they are not

representative of the whole population of patients 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, informing further research studies, rather than

used to inform clinical practice. It is also important to consider the inclusion and

exclusion criteria for the trial. Patients were recruited who had established and treated

septic shock for at least 6 hours. Patients had already been fluid resuscitated and the

blinded study drug (vasopressin or norepinephrine) was substituted for existing

vasopressors and thus it is not a direct comparison of the two vasopressors on

systemic hemodynamics when used as initial therapy in septic shock. Adequate fluid

resuscitation prior to starting vasopressin or any vasopressin analogue is important

and detrimental cardiovascular effects might occur if the patient is fluid deplete. Also

patients with severe chronic heart disease and patients with acute coronary syndromes

were excluded from VASST. Further evidence about the effect of vasopressin

infusion in these groups of patients is required.

Page 14 of 32



15

Conclusions:

Vasopressin treatment in septic shock is associated with a significant reduction in

heart rate but no change in cardiac output or measures of perfusion. Nonetheless,

more patients in the vasopressin-treated than the norepinephrine-treated group also

received inotropic agent infusions. Any effect of vasopressin on cardiac output seems

due to this decrease in heart rate rather than an effect on stroke volume index. Finally,

there were no adverse effects on cardiac output of vasopressin versus norepinephrine

even in those patients with the poorest cardiac function (as reflected by lowest cardiac

index quartile at baseline).

Page 15 of 32



16

Acknowledgments:

Funding: 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 VASST trial was funded by a grant

(MCT 44152) from the Canadian Institutes of Health Research.

Author contributions: All authors provided intellectual input to the research and

manuscript. Dr Gordon acts as a guarantor of the paper, taking responsibility for the

integrity of the work as a whole.

Drs Gordon, Walley and 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.

Drs Wang and Ashby contributed to the analysis and interpretation of data, statistical

analysis, and critical revision of the manuscript for important intellectual content.

Page 16 of 32



17

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Legend

Figure 1 Cardiac index over time in patients who had PA catheters by cardiac index

quartile at baseline. A - 1st quartile CI ≤2.9 l/min/m

2 at baseline. B- 2

nd quartile CI

2.91-3.7 l/min/m2 at baseline. C - 3

rd quartile CI 3.71-4.5 l/min/m

2 at baseline. D - 4

th

quartile CI >4.5 l/min/m2 at baseline. The grey circles represent the vasopressin-

treated patients and the black squares norepinephrine-treated patients. The treatment

(vasopressin vs. norepinephrine) effect on CI over time was p=0.99 in the first

quartile, p=0.26 in the second quartile, p=0.43 in the third quartile, p=0.36 in the

fourth quartile.

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21

TABLE 1. DEMOGRAPHICS AND BASELINE CHARACTERISTICS OF PATIENTS WHO HAD OR DID NOT

HAVE PA CATHETERS

CHARACTERISTIC

NO PA

CATHETER N (%)

(N = 538)

PA

CATHETER N (%)

(N = 241)

P-VALUE

Age (years) 59.9 ± 16.5 62.0 ± 15.6 0.10

Sex – Male 329 (61.2) 146 (60.6) 0.88

Recent surgical history 185 (34.4) 98 (40.7) 0.09

APACHE II score 26.6 ± 7.6 28.2 ± 6.4 0.004

Ethnicity – Caucasian 453 (84.2) 203 (84.2) 0.99

Pre-existing conditions

Ischemic Heart Disease 85 (15.8) 48 (19.9) 0.16

Congestive Heart Failure 43 (8.0) 15 (6.2) 0.38

COPD 93 (17.3) 34 (14.1) 0.27

Chronic Renal Failure 60 (11.2) 28 (11.6) 0.85

Diabetes 110 (20.4) 55 (22.8) 0.45

Liver Disease 66 (12.3) 22 (9.1) 0.20

Alcoholism 75 (13.9) 33 (13.7) 0.93

Injection Drug Abuse 29 (5.4) 5 (2.1) 0.04

Cancer 131 (24.3) 58 (24.1) 0.93

Immunocompromised 100 (18.6) 39 (16.2) 0.42

Solid Organ Transplant 25 (4.6) 6 (2.5) 0.15

Steroid use 109 (20.3) 59 (24.5) 0.19

Recent Trauma 25 (4.6) 14 (5.8) 0.49

New Organ Failure

Respiratory 465 (86.4) 218 (90.5) 0.11

Renal 344 (63.9) 178 (73.9) 0.006

Hematology/Coagulation 130 (24.2) 72 (29.9) 0.09

Neurologic 134 (24.9) 56 (23.2) 0.62

Cardio-pulmonary variables

Systolic Blood Pressure (mmHg) 109 ± 16 109 ± 17 0.84

Mean Arterial Pressure (mmHg) 72.9 ± 9.9 72.4 ± 8.6 0.52

Arterial pH 7.32 ± 0.10 7.30 ± 0.10 <0.001

Central venous pressure (mmHg) 14.2 ± 4.9 15.4 ± 5.1 0.002

Serum lactate (mmol/L) 3.1 ± 2.9 4.2 ± 3.5 <0.001

PaO2/FiO2 (mmHg) 207 ± 94 192 ± 92 0.05

More severe shock subgroup (>15µg/min

norepinephrine at randomization)

256 (47.6) 145 (60.2) 0.001

Vasoactive Drug Dosage at randomization

Norepinephrine (µg/min) 19.1 ± 19.7 24.0 ± 20.8 0.003

Phenylephrine (µg/min) 139 ± 81 182 ± 80 0.002

Epinephrine (µg/min) 14.5 ± 18.0 9.0 ± 7.7 0.18

Dobutamine (µg/kg/min) 5.4 ± 4.8 6.5 ± 4.1 0.30

Milrinone (µg/kg/min) 0.40 ± 0.37 0.30 ± 0.13 0.36

Plus-minus values are means ± SD. PA denotes pulmonary artery catheter, COPD - chronic

obstructive pulmonary disease, and APACHE II - Acute Physiology and Chronic Health

Evaluation II

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Table 2: Cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in all patients (n=779). 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs p

#

MAP (mmHg) NE AVP

73.2 ± 9.9 72.4 ± 9.1

75.5 ± 10.1 73.4 ± 9.1

75.0 ± 10.2 74.2 ± 9.6

75.9 ± 11.8 75.9 ± 10.9

76.7 ± 11.1 75.2 ± 11.3

76.2 ± 12.8 76.4 ± 11.4

80.3 ± 12.7 79.6 ± 12.7

79.2 ± 13.7 80.1 ± 13.6

81.1 ± 14.7 82.7 ± 14.0

82.1 ± 13.7 83.0 ± 14.9

0.80

Total NE infusion rate^ (µ g/min) NE AVP

15.9 (9.0-25.0) 14.0 (8.0- 25.0)

17.0 (12.0-33.0) 8.0 (3.0-17.0)

15.0 (10.0-29.8) 6.0 (2.0-14.4)

12.5 (3.0-22.0) 4.0 (0.0-10.0)

15.0 (7.5-28.9) 6.0 (2.0-14.0)

10.0 (3.1-21.0) 3.1 (0.0-9.6)

7.5 (2.0-19.2) 1.0 (0.0-5.9)

5.0 (0.0-15.0) 0.0 (0.0-2.0)

2.5 (0.0-12.5) 0.0 (0.0-2.0)

0.0 (0.0-9.0) 0.0 (0.0-1.1)

<0.0001

HR (bpm) NE AVP

100 ± 20 100 ± 21

99 ± 19 93 ± 20

96 ± 19 90 ± 21

95 ± 20 90 ± 21

96 ± 19 90 ± 22

95 ± 20 90 ± 21

92 ± 19 88 ± 20

92 ± 19 89 ± 20

91 ± 19 88 ± 19

92 ± 18 90 ± 21

<0.0001

CVP (mmHg) NE AVP

14.4 ± 5.0 14.8 ± 5.0

14.9 ± 5.2 15.0 ± 5.0

14.2 ± 4.9 15.1 ± 5.6

14.4 ± 5.7 15.2 ± 5.3

14.6 ± 5.1 14.9 ± 4.8

14.4 ± 5.5 15.0 ± 5.0

14.0 ± 4.9 15.0 ± 4.9

13.6 ± 4.7 14.4 ± 4.9

13.4 ± 4.5 13.8 ± 4.5

13.1 ± 4.9 13.4 ± 4.9

0.14

pH NE AVP

7.31 ± .10 7.32 ± .10

7.32 ± .11 7.32 ± .11

7.33 ± .10 7.34 ± .09

7.35 ± .09 7.35 ± .08

7.34 ± .10 7.34 ± .09

7.35 ± .09 7.35 ± .09

7.37 ± .09 7.36 ± .09

7.38 ± .07 7.38 ± .07

7.39 ± .08 7.39 ± .07

7.39 ± .08 7.40 ± .08

0.66

Lactate (mmol/l) NE AVP

2.3 (1.5-4.6) 2.3 (1.4-4.0)

2.5 (1.5-4.5) 2.4 (1.7-5.2)

2.2 (1.4-4.0) 2.1 (1.4-3.8)

1.8 (1.2-2.9) 1.8 (1.3-2.8)

1.7 (1.2-2.4) 1.7 (1.2-2.4)

0.63

PaO2/FiO2 (mmHg) NE AVP

199 ± 94 206 ± 93

207 ± 97 217 ± 114

213 ± 94 219 ± 97

217 ± 91 217 ± 91

218 ± 98 222 ± 96

218 ± 89 223 ± 109

231 ± 99 226 ± 94

229 ± 103 227 ± 94

231 ± 100 233 ± 89

227 ± 88 229 ± 93

0.79

N receiving any inotropes (existing / new) NE AVP

74 80

68 (57 / 11) 86 (70 / 16)

73 (58 / 11) 94 (81 / 13)

55 (47 / 8) 88 (83 / 5)

67 (66 / 1) 93 (91 / 2)

56 (48 / 8) 85 (81 / 4)

51 (47 / 4) 78 (73 / 5)

45 (41 / 4) 67 (61 / 6)

55 (48 / 7) 66 (62 / 4)

50 (45 / 5) 53 (52 / 1)

0.02

Mean dose dobutamine§ (µ g/kg/min) NE AVP

5.1 ± 3.7 6.4 ± 5.2

6.2 ± 10.3 6.4 ± 5.0

4.4 ± 3.0 6.9 ± 6.4

4.5 ± 5.2 6.3 ± 6.4

3.7 ± 2.4 6.3 ± 5.0

5.3 ± 7.5 6.5 ± 6.8

3.7 ± 1.9 5.2 ± 4.7

3.4 ± 1.5 5.5 ± 6.2

3.4 ± 1.9 4.9 ± 4.5

3.7 ± 1.8 5.7 ± 4.4

0.06

RPP (/100) NE AVP

109 ± 23 108 ± 24

112 ± 24 100 ± 24

109 ± 25 99 ± 26

109 ± 27 101 ± 28

110 ± 27 99 ± 27

109 ± 27 102 ± 27

110 ± 27 105 ± 31

110 ± 28 108 ± 32

112 ± 30 109 ± 31

115 ± 28 112 ± 35

<0.0001

RPP >110 (%) NE AVP

47.6 44.9

49.3 33.0

46.9 30.9

44.4 34.5

45.7 31.3

44.5 32.0

46.1 35.2

47.2 44.1

48.5 44.0

51.2 48.8

<0.0001

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Values are means ± SD and median (interquartile range) for NE dose and serum lactate levels. # p-value is comparing difference over time between

treatment groups. The abbreviations are NE – norepinephrine, AVP – vasopressin, MAP – mean arterial pressure, HR – heart rate, CVP – central venous

pressure, RPP – rate pressure product (divided by 100). ^NE dose is calculated for all patients who were receiving NE at baseline.

§Dobutamine dose is

calculated for patients receiving dobutamine at that time point.

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Table 3 Detailed cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in patients who had a PA catheter (n=241) 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs p

#

SvO2 (%) NE AVP

68.6 ± 14.4 67.0 ± 15.7

69.5 ± 14.3 64.0 ± 17.0

68.4 ± 13.8 68.3 ± 13.8

69.8 ± 15.6 66.2 ± 14.6

66.9 ± 14.2 67.7 ± 15.8

66.4 ± 15.9 67.3 ± 13.0

62.9 ± 17.4 65.0 ± 16.8

63.3 ± 17.7 65.4 ± 14.4

65.3 ± 17.1 64.2 ± 14.8

62.3 ± 17.4 65.7 ± 15.0

0.92

CI (l/min/m2) NE AVP

3.95 ± 1.26 3.82 ± 1.31

3.92 ± 1.22 3.51 ± 1.39

3.70 ± 1.14 3.46 ± 1.29

3.67 ± 1.02 3.70 ± 1.57

3.61 ± 1.23 3.46 ± 1.45

3.62 ± 1.27 3.65 ± 1.45

3.46 ± 1.18 3.52 ± 1.46

3.82 ± 1.40 3.59 ± 1.39

3.49 ± 1.15 3.47 ± 1.48

3.53 ± 1.10 3.65 ± 1.61

0.87

SVI (ml/min/m2) NE AVP

39.8 ± 14.3 37.5 ± 12.5

39.9 ± 11.9 37.2 ± 14.3

37.8 ± 11.7 36.3 ± 12.7

40.2 ± 11.9 39.0 ± 14.6

37.5 ± 11.9 37.5 ± 14.9

39.9 ± 14.0 39.1 ± 14.8

38.4 ± 12.9 38.9 ± 15.1

40.4 ± 13.6 39.5 ± 13.7

39.6 ± 11.8 38.7 ± 13.0

39.8 ± 11.9 40.0 ± 13.5

0.53

LVSWI (g/m2) NE AVP

28.5 ± 11.7 26.6 ± 10.3

31.2 ± 11.9 28.8 ± 11.9

29.8 ± 12.5 27.7 ± 11.7

31.7 ± 12.2 30.2 ± 14.0

29.4 ± 12.4 29.3 ± 13.6

31.3 ± 12.8 31.5 ± 14.7

32.5 ± 13.4 31.4 ± 15.3

33.2 ± 13.2 31.5 ± 14.2

32.0 ± 11.5 31.6 ± 10.9

34.8 ± 12.3 32.0 ± 12.5

0.72

PAOP (mmHg) NE AVP

17.3 ± 5.7 20.6 ± 5.9

17.9 ± 5.3 19.2 ± 5.0

17.7 ± 4.8 19.6 ± 6.7

18.9 ± 6.1 20.2 ± 6.0

18.7 ± 5.7 19.0 ± 5.8

19.4 ± 7.2 19.1 ± 5.9

17.9 ± 5.3 19.5 ± 6.4

18.7 ± 6.4 19.5 ± 6.8

19.2 ± 8.3 19.4 ± 5.6

18.9 ± 5.2 19.5 ± 6.3

0.32

MPAP (mmHg) NE AVP

28.0 ± 6.7 30.3 ± 6.7

29.4 ± 6.3 30.2 ± 8.2

29.0 ± 5.9 29.9 ± 8.2

29.4 ± 8.7 29.7 ± 6.3

29.4 ± 6.6 29.8 ± 8.0

29.8 ± 7.1 30.1 ± 7.1

28.6 ± 6.9 29.8 ± 7.8

30.0 ± 7.7 29.9 ± 7.3

28.9 ± 7.8 28.7 ± 6.3

30.4 ± 7.3 29.8 ± 7.4

0.82

Values are means ± SD. # p-value is comparing difference over time between treatment groups. The abbreviations are NE – norepinephrine, AVP –

vasopressin, SvO2 mixed venous saturation, CI – cardiac index, SVI – stroke volume index, LVSWI – left ventricular stroke work index, PAOP –

pulmonary artery occlusion pressure, MPAP – mean pulmonary arterial pressure.

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Table 4: Cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in all patients in the more and less severe shock strata. 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs #

p value *p value

interaction

MAP (mmHg) More severe NE AVP Less severe NE AVP

71.7 ± 10.5 71.4 ± 8.8 74.7 ± 9.1 73.3 ± 9.3

74.5 ± 10.4 72.4 ± 9.5 76.6 ± 9.7 74.4 ± 8.6

74.8 ± 10.3 73.6 ± 10.2 75.2 ± 10.0 74.9 ± 9.0

74.6 ± 11.3 74.8 ± 11.3 77.2 ± 12.2 77.0 ± 10.4

76.0 ± 11.9 73.9 ± 11.9 77.5 ± 10.2 76.5 ± 10.5

74.8 ± 12.6 75.1 ± 11.7 77.6 ± 12.9 77.6 ± 10.9

79.7 ± 11.4 76.9 ± 12.3 80.9 ± 13.8 82.1 ± 12.6

77.8 ± 11.8 78.5 ± 13.6 80.7 ± 15.2 81.3 ± 13.5

79.7 ± 14.0 82.8 ± 14.0 82.4 ± 15.2 82.7 ± 14.0

81.7 ± 12.6 81.7 ± 14.8 82.4 ± 14.8 84.0 ± 14.9

0.73 0.55

0.51

Total NE infusion rate^ (µ g/min) More severe NE AVP Less severe NE AVP

22.7 (16.0-37.8) 24.0 (17.0-35.0) 10.0 (7.0-12.0) 9.0 (6.0-11.0)

27.0 (15.5-45.0) 15.0 (8.0-28.0) 12.5 (7.5-16.6) 5.0 (1.0-8.0)

23.0 (15.0-40.0) 12.7 (4.0-26.2) 10.0 (5.0-15.0) 4.0 (0.0-6.0)

17.6 (7.5-27.0) 6.0 (0.0-18.0) 5.0 (1.5-15.0) 2.0 (0.0-6.0)

21.2 (15.0-37.0) 12.0 (4.0-24.0) 10.0 (5.0-15.0) 3.7 (0.0-7.0)

17.0 (28.6-7.5) 5.7 (0.0-16.0) 5.0 (2.0-15.0) 1.5 (0.0-6.0)

15.0 (4.0-23.0) 2.5 (0.0-10.6) 5.0 (0.0-15.0) 0.0 (0.0-3.9)

6.5 (0.0-17.0) 0.0 (0.0-5.3) 2.5 (0.0-10.0) 0.0 (0.0-2.0)

2.5 (0.0-13.0) 0.0 (0.0-3.7) 1.1 (0.0-11.0) 0.0 (0.0-2.0)

0.0 (0.0-10.0) 0.0 (0.0-2.0) 0.0 (0.0-7.5) 0.0 (0.0-0.5)

<0.0001 <0.0001

0.16

HR (bpm) More severe NE AVP Less severe NE AVP

100 ± 20 100 ± 21 97 ± 19 95 ± 18

99 ± 19 93 ± 20 97 ± 18 88 ± 19

96 ± 19 90 ± 21 96 ± 20 85 ± 19

95 ± 20 90 ± 21 95 ± 21 86 ± 20

96 ± 19 90 ± 22 95 ± 19 84 ± 20

95 ± 20 90 ± 21 95 ± 20 88 ± 21

92 ± 19 88 ± 20 93 ± 19 87 ± 21

92 ± 19 89 ± 20 95 ± 20 89 ± 20

91 ± 19 88 ± 19 94 ± 20 87 ± 19

92 ± 18 90 ± 21 95 ± 20 92 ± 22

0.02 <0.0001

0.03

CVP (mmHg) More severe NE AVP Less severe NE AVP

14.7 ± 5.1 15.6 ± 5.1 14.2 ± 4.8 14.0 ± 4.8

15.5 ± 5.4 15.7 ± 4.8 14.2 ± 4.8 14.3 ± 5.2

14.7 ± 5.0 15.9 ± 6.0 13.7 ± 4.8 14.3 ± 5.0

14.9 ± 5.8 15.9 ± 5.4 13.8 ± 4.8 14.5 ± 5.1

15.1 ± 5.5 15.5 ± 4.9 14.0 ± 4.5 14.2 ± 4.6

15.1 ± 6.0 15.7 ± 5.3 13.6 ± 4.8 14.4 ± 4.7

14.6 ± 5.5 15.1 ± 4.9 13.3 ± 4.1 14.9 ± 4.9

14.1 ± 5.2 14.7 ± 4.7 13.1 ± 4.2 14.1 ± 5.1

14.2 ± 5.0 13.9 ± 4.5 12.6 ± 3.9 13.6 ± 4.7

13.6 ± 5.2 13.6 ± 5.1 12.7 ± 4.4 13.2 ± 4.8

0.57 0.007

0.02

pH More severe NE AVP Less severe NE AVP

7.29 ± 0.11 7.29 ± 0.10 7.35 ± 0.08 7.35 ± 0.08

7.29 ± 0.12 7.29 ± 0.12 7.35 ± 0.09 7.35 ± 0.09

7.31 ± 0.11 7.32 ± 0.10 7.35 ± 0.10 7.36 ± 0.08

7.33 ± 0.10 7.33 ± 0.09 7.36 ± 0.08 7.37 ± 0.07

7.32 ± 0.10 7.32 ± 0.10 7.36 ± 0.09 7.36 ± 0.08

7.34 ± 0.10 7.34 ± 0.10 7.37 ± 0.08 7.37 ± 0.08

7.36 ± 0.09 7.35 ± 0.10 7.38 ± 0.08 7.38 ± 0.08

7.37 ± 0.07 7.37 ± 0.07 7.39 ± 0.08 7.39 ± 0.07

7.38 ± 0.08 7.39 ± 0.07 7.40 ± 0.07 7.40 ± 0.07

7.39 ± 0.08 7.39 ± 0.08 7.40 ± 0.09 7.40 ± 0.08

0.91 0.59

0.76

Lactate (mmol/l) More severe

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NE AVP Less severe NE AVP

3.0 (1.7-5.4) 3.3 (2.0-6.1) 1.9 (1.3-3.7) 1.6 (1.1-2.5)

2.9 (1.8-5.8) 3.5 (1.9-6.3) 1.9 (1.4-3.2) 2.1 (1.3-2.5)

2.5 (1.6-4.6) 2.9 (1.8-5.6) 1.7 (1.2-2.8) 1.7 (1.2-2.3)

1.8 (1.3-3.1) 2.1 (1.5-3.3) 1.7 (1.2-2.6) 1.6 (1.2-2.1)

1.7 (1.3-2.5) 1.8 (1.3-2.7) 1.6 (1.2-2.2) 1.7 (1.1-2.2)

0.51 0.95

0.69

PaO2/FiO2 (mmHg) More severe NE AVP Less severe NE AVP

188 ± 95 194 ± 95 210 ± 92 217 ± 90

197 ± 101 206 ± 118 218 ± 92 229 ± 108

207 ± 98 209 ± 104 220 ± 89 229 ± 88

211 ± 92 212 ± 91 223 ± 90 223 ± 91

213 ± 100 211 ± 98 224 ± 94 233 ± 93

216 ± 89 224 ± 129 221 ± 90 223 ± 84

229 ± 96 219 ± 98 233 ± 103 232 ± 90

226 ± 95 230 ± 92 231 ± 111 225 ± 95

233 ± 102 237 ± 92 228 ± 98 229 ± 87

229 ± 83 233 ± 93 225 ± 94 225 ± 93

0.74 0.99

0.81

N receiving any inotropes (existing/new) More severe NE AVP Less severe NE AVP

54 62 20 18

53 (44 / 9) 67 (55 / 12) 15 (13 / 2) 19 (15 / 4)

53 (44 / 9) 72 (64 / 8) 20 (14 / 6) 22 (17 / 5)

40 (34 / 6) 65 (62 / 3) 15 (13 / 2) 23 (21 / 2)

50 (49 / 1) 72 (70 / 2) 17 (17 / 0) 21 (21 / 0)

41 (37 / 4) 64 (61 / 3) 15 (11 / 4) 21 (20 / 1)

39 (37 / 2) 56 (54 / 2) 12 (10 / 2) 22 (19 / 3)

30 (29 / 1) 46 (41 / 5) 15 (12 / 3) 21 (20 / 1)

34 (31 / 3) 45 (43 / 2) 21 (17 / 4) 21 (19 / 2)

34 (30 / 4) 37 (37 / 0) 16 (15 / 1) 16 (15 / 1)

0.03 0.27

0.69

Mean dose dobutamine§ (µ g/kg/min) More severe NE AVP Less severe NE AVP

5.1 ± 3.7 7.0 ± 5.7 5.1 ± 4.0 4.1 ± 1.8

6.5 ± 11.9 6.9 ± 5.4 5.3 ± 4.0 4.6 ± 2.3

3.7 ± 1.9 7.1 ± 6.9 5.8 ± 4.4 5.7 ± 3.2

4.5 ± 6.2 6.8 ± 7.1 4.5 ± 1.4 4.3 ± 2.2

3.5 ± 1.9 6.6 ± 5.4 4.3 ± 3.4 4.7 ± 2.2

5.2 ± 8.6 7.1 ± 7.5 5.4 ± 2.0 4.4 ± 2.8

3.6 ± 2.0 5.6 ± 5.1 5.2 ± 9.0 4.0 ± 2.7

3.5 ± 1.6 5.6 ± 4.8 3.1 ± 1.4 5.2 ± 9.0

3.6 ± 2.0 5.6 ± 5.0 3.1 ± 1.6 3.5 ± 2.5

3.7 ± 1.9 6.4 ± 4.9 3.6 ± 1.3 4.1 ± 2.7

0.07 0.66

0.59

RPP (/100) More severe NE AVP Less severe NE AVP

110 ± 24 112 ± 26 108 ± 23 104 ± 23

112 ± 24 103 ± 22 111 ± 24 96 ± 25

109 ± 25 103 ± 26 109 ± 25 95 ± 25

106 ± 25 103 ± 26 111 ± 28 100 ± 29

109 ± 26 103 ± 26 112 ± 27 96 ± 28

105 ± 25 102 ± 25 112 ± 29 103 ± 30

107 ± 25 102 ± 26 114 ± 29 109 ± 5

105 ± 27 106 ± 31 116 ± 28 110 ± 33

108 ± 28 109 ± 30 116 ± 31 109 ± 32

111 ± 27 108 ± 32 118 ± 29 116 ± 37

0.05 <0.0001

0.10

RPP >110 (%) More severe NE AVP Less severe

49.0 50.7

53.8 38.4

47.6 36.3

41.2 38.0

43.9 36.8

40.2 31.4

40.5 32.2

36.5 41.5

41.4 42.9

48.4 44.8

0.04

0.12

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NE AVP

46.2 39.0

44.5 27.5

46.1 25.6

47.7 31.0

47.5 25.7

48.9 32.6

51.7 38.0

57.7 46.2

55.4 44.8

53.9 52.2

<0.0001

Values are means ± SD and median (interquartile range) for NE dose and serum lactate levels. # p-value is comparing difference over time between

treatment groups; *p-value is testing for a treatment group x shock subgroup interaction. The abbreviations are NE – norepinephrine, AVP –

vasopressin, MAP – mean arterial pressure, HR – heart rate, CVP – central venous pressure, RPP – rate pressure product (divided by 100). ^Median NE

dose is calculated for all patients who were receiving NE at baseline. §Mean dobutamine dose is calculated for patients receiving dobutamine at that time

point

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Table 5: Detailed cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in patients who had a PA catheter in the more and

less severe shock strata. 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs #

p value ##

p

value interaction

SvO2 (%) More severe NE AVP Less severe NE AVP

67.4 ± 16.7 62.2 ± 16.3 69.8 ± 11.6 74.1 ± 11.8

68.9 ± 15.6 58.5 ± 18.1 70.3 ± 12.6 73.4 ± 9.5

67.4 ± 14.2 64.7 ± 14.8 69.9 ± 13.4 72.8 ± 11.0

70.7 ± 13.1 61.2 ± 15.2 68.5 ± 18.9 70.8 ± 12.7

66.9 ± 12.8 64.7 ± 15.2 67.0 ± 16.7 71.4 ± 16.1

67.7 ± 12.6 63.9 ± 14.0 64.7 ± 19.8 71.7 ± 10.2

61.4 ± 16.7 60.6 ± 18.1 66.1 ± 19.0 70.3 ± 13.7

62.5 ± 16.4 59.8 ± 15.5 64.5 ± 20.2 71.9 ± 10.3

61.8 ± 17.5 58.8 ± 15.5 70.3 ± 15.8 73.9 ± 6.4

63.1 ± 14.7 61.4 ± 16.5 60.4 ± 22.9 74.2 ± 5.6

0.99 0.95

0.97

CI (l/min/m2) More severe NE AVP Less severe NE AVP

3.96 ± 1.14 3.76 ± 1.27 3.95 ± 1.41 3.93 ± 1.39

3.67 ± 0.99 3.51 ± 1.37 4.36 ± 1.45 3.50 ± 1.44

3.59 ± 1.26 3.41 ± 1.19 3.86 ± 0.93 3.55 ± 1.45

3.55 ± 1.05 3.65 ± 1.52 3.83 ± 0.99 3.81 ± 1.69

3.41 ± 1.22 3.26 ± 1.31 3.95 ± 1.19 3.80 ± 1.64

3.47 ± 1.28 3.53 ± 1.45 3.83 ± 1.24 3.87 ± 1.45

3.36 ± 1.16 3.31 ± 1.42 3.64 ± 1.23 3.85 ± 1.47

3.54 ± 1.29 3.47 ± 1.25 4.18 ± 1.47 3.74 ± 1.56

3.33 ± 1.16 3.30 ± 1.21 3.72 ± 1.11 3.73 ± 1.82

3.22 ± 0.90 3.64 ± 1.57 4.01 ± 1.26 3.65 ± 1.74

0.32 0.30

0.15

SVI (ml/min/m2) More severe NE AVP Less severe NE AVP

39.8 ± 14.3 37.5 ± 12.5 41.4 ± 16.8 40.8 ± 14.6

39.9 ± 11.9 37.2 ± 14.3 46.9 ± 12.7 38.4 ± 15.7

37.8 ± 11.7 36.3 ± 12.7 40.2 ± 38.6 38.6 ± 14.9

40.2 ± 11.9 39.0 ± 14.6 42.8 ± 11.5 42.7 ± 16.2

37.5 ± 11.9 37.5 ± 14.9 42.3 ± 11.1 42.6 ± 17.5

39.9 ± 14.0 39.1 ± 14.8 42.5 ± 14.7 42.6 ± 16.0

38.4 ± 12.9 38.9 ± 15.1 40.6 ± 11.2 41.9 ± 15.5

40.4 ± 13.6 39.5 ± 13.7 43.4 ± 12.3 41.1 ± 15.3

39.6 ± 11.8 38.7 ± 13.0 41.4 ± 9.2 42.2 ± 16.1

39.8 ± 11.9 40.0 ± 13.5 43.1 ± 10.4 41.0 ± 14.9

0.36 0.86

0.66

LVSWI (g/m2) More severe NE AVP Less severe NE AVP

27.8 ± 11.7 25.3 ± 8.0 29.5 ± 11.8 28.4 ± 12.9

28.8 ± 12.0 27.7 ± 10.6 35.8 ± 10.3 30.9 ± 14.2

28.3 ± 14.5 25.3 ± 8.3 32.1 ± 8.5 31.6 ± 15.4

30.4 ± 14.8 27.1 ± 11.1 33.4 ± 7.9 34.9 ± 16.7

26.7 ± 13.4 26.4 ± 9.9 33.5 ± 9.5 34.2 ± 17.4

30.1 ± 15.1 28.3 ± 12.6 32.9 ± 9.0 37.3 ± 16.7

31.3 ± 14.9 28.4 ± 12.8 34.5 ± 10.7 36.9 ± 18.2

31.2 ± 14.3 30.8 ± 11.9 35.5 ± 11.6 32.5 ± 17.2

31.7 ± 12.4 30.1 ± 9.3 32.3 ± 10.5 34.2 ± 13.1

33.9 ± 14.5 31.6 ± 13.6 36.4 ± 7.45 32.8 ± 10.6

0.62 0.16

0.16

PAOP (mmHg) More severe NE AVP Less severe NE AVP

17.4 ± 6.0 20.6 ± 4.7 17.2 ± 5.3 20.5 ± 7.4

18.1 ± 6.3 19.9 ± 4.2 17.7 ± 6.2 17.7 ± 6.2

18.2 ± 5.4 19.5 ± 4.4 16.9 ± 3.7 19.8 ± 9.6

19.1 ± 7.2 20.6 ± 5.2 18.5 ± 4.4 19.5 ± 7.2

18.9 ± 5.6 18.9 ± 4.9 18.3 ± 5.9 19.0 ± 7.3

19.3 ± 7.8 19.8 ± 5.1 19.6 ± 6.3 17.7 ± 7.0

17.6 ± 4.7 20.6 ± 6.2 18.3 ± 6.2 17.4 ± 6.3

18.1 ± 7.1 19.1 ± 4.2 19.5 ± 5.5 20.0 ± 9.5

19.1 ± 7.7 19.9 ± 6.0 19.4 ± 9.1 18.7 ± 5.2

18.8 ± 5.9 19.2 ± 6.8 19.1 ± 3.5 20.0 ± 5.3

0.20 0.97

0.39

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MPAP (mmHg) More severe NE AVP Less severe NE AVP

27.3 ± 7.2 29.6 ± 6.4 28.9 ± 6.0 31.2 ± 7.0

29.9 ± 7.4 30.1 ± 7.2 28.7 ± 4.3 30.3 ± 9.7

29.8 ± 6.5 29.2 ± 6.2 27.8 ± 4.6 30.9 ± 10.6

30.7 ± 10.4 29.6 ± 6.0 27.5 ± 4.2 29.8 ± 7.0

30.1 ± 7.5 29.2 ± 7.4 28.2 ± 4.8 30.9 ± 8.8

30.4 ± 8.0 29.6 ± 6.1 28.9 ± 5.6 31.0 ± 8.6

28.7 ± 7.4 29.2 ± 7.2 28.5 ± 6.2 30.9 ± 8.8

29.5 ± 8.6 29.7 ± 7.1 30.6 ± 6.4 30.2 ± 7.6

29.2 ± 8.1 28.2 ± 6.1 28.6 ± 7.4 29.6 ± 6.7

30.5 ± 8.4 27.6 ± 5.6 30.2 ± 4.9 34.3 ± 8.6

0.10 0.12

0.02

Values are means ± SD. # p-value is comparing difference over time between treatment groups; *p-value is testing for a treatment group x shock

subgroup interaction. The abbreviations are NE – norepinephrine, AVP – vasopressin, SvO2 mixed venous saturation, CI – cardiac index, SVI – stroke

volume index, LVSWI – left ventricular stroke work index, PAOP – pulmonary artery occlusion pressure, MPAP – mean pulmonary arterial pressure,

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DOI 10.1378/chest.11-2604; Prepublished online April 19, 2012;Chest

RussellAnthony C. Gordon, Nan Wang, Keith R. Walley, Deborah Ashby and James A.

NOREPINEPHRINE IN SEPTIC SHOCKTHE CARDIO-PULMONARY EFFECTS OF VASOPRESSIN COMPARED TO

June 15, 2012This information is current as of

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