Original Research

Journal of Intensive Care Medicine

2017, Vol. 32(7) 451-459
Comparative Effectiveness of Second ª The Author(s) 2016
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Vasoactive Agents in Septic Shock DOI: 10.1177/0885066616647941
journals.sagepub.com/home/jic
Refractory to Norepinephrine

H. Bryant Nguyen, MD, MS1,2,3, Samantha Lu, MD4,

Isabella Possagnoli, MD2, and Phillip Stokes, MD4

Abstract
Objective: We aim to identify the appropriate vasoactive agent in patients with septic shock who are refractory to optimal doses
of norepinephrine. Methods: In this retrospective observational cohort study over a 4-year period, patients who received
norepinephrine within 24 hours of ICU admission and a second agent within 48 hours were enrolled. Results: Among 2640
patients screened, 234 patients were enrolled, aged 60.8 + 17.8 years, Acute Physiology and Chronic Health Evaluation IV 98.3 +
27.5, 81.6% mechanically ventilated, and 65.8% in-hospital mortality. Within 96 hours, 2.8 + 1.0 vasoactive agents were admi-
nistered. Fifty, 50, 66, and 68 patients received dobutamine, dopamine, phenylephrine, and vasopressin as the second agent, with
crude in-hospital mortality 40.0%, 66.0%, 74.2%, and 76.5%, respectively, P < .001. Survival analysis showed a statistically significant
difference in survival time by second vasoactive agent, P < .001. After adjusting for confounding variables, dobutamine showed
significant decreased odds ratio (OR) for mortality compared to vasopressin: OR 0.34 (95% confidence interval 0.14-0.84, P ¼ .04).
The relative risk of dying was 55.8% lower in patients receiving dobutamine versus vasopressin, P < .01. Conclusion: Dobutamine is
associated with decreased mortality compared to other second vasoactive agents in septic shock when norepinephrine is
not sufficient. A prospective randomized trial examining the outcome impact of the second vasoactive agent is needed.

Keywords
septic shock, vasoactive agent, norepinephrine, vasopressin, dobutamine, dopamine, phenylephrine

Introduction Materials and Methods

Vasoactive agents are integral to the treatment of septic shock.
Norepinephrine has traditionally been the drug of choice to
achieve and maintain mean arterial pressure greater than
65 mm Hg after adequate fluid resuscitation.1 For a subset of
patients, norepinephrine is not sufficient and a second vasoac-
tive agent is required. Currently, no conclusive studies exist
pointing to which agent is best in this situation. The choice of
agent in shock refractory to norepinephrine is thus determined
based on patient presentation, ongoing hemodynamic profile,
comorbid conditions, and clinician preference. Potential
second-line agents include dobutamine, dopamine, epinephr-
ine, phenylephrine, and vasopressin.1
The purpose of this study was to evaluate the outcomes of
patients with refractory septic shock who received norepinephr-
ine and a second vasoactive agent, dobutamine, dopamine,
epinephrine, phenylephrine, or vasopressin, in order to maintain
adequate blood pressure. To reflect common practice, we
include agents that have a range from inotropic (dobutamine)
to vasoconstrictive (phenylephrine) properties. The aim of this
study was to identify the appropriate agent for use in patients
who have not responded to optimal doses of norepinephrine.
This study is a retrospective observational cohort of patients
admitted to a tertiary care academic medical center from July 1,
2008, to June 30, 2012. During this study period, there were no
institution guidelines for vasoactive agent(s) in patients with
refractory septic shock after failure of norepinephrine to
achieve hemodynamic stability. The choice of second vasoac-
tive agent was based on clinician discretion. The study was
1
Division of Pulmonary and Critical Care Medicine, Loma Linda University,
Loma Linda, CA, USA
2
Department of Medicine, Loma Linda University, Loma Linda, CA, USA
3
Department of Emergency Medicine, Loma Linda University, Loma Linda,
CA, USA
4
School of Medicine, Loma Linda University, Loma Linda, CA, USA
Received December 22, 2015. Received revised April 12, 2016. Accepted
April 13, 2016.
Corresponding Author:
H. Bryant Nguyen, Loma Linda University, 11234 Anderson St, Loma Linda, CA
92354, USA.
Email: hbnguyen@llu.edu
452
approved by the Office of Human Research Protection at our
institution.
Patient Selection
Adult patients of 18 years or older who were admitted to
any intensive care unit (ICU: medical, surgical, cardiac, or
cardiothoracic surgery) and required vasoactive substance(s)
(norepinephrine, dobutamine, dopamine, epinephrine, phe-
nylephrine, or vasopressin) were considered for enrollment.
Thus, we reviewed our pharmacy database and screened all
patients during the study period who (1) were 18 years or
older; (2) had admission to ICU; and (3) were on at least 1
vasoactive agent.
We then reviewed the medical records of all patients
screened from the pharmacy database above. Study inclusion
criteria to detect refractory septic shock were (1) documented
suspicion or known diagnosis of sepsis, suspected or proven
infectious source, or administration of antibiotics within
24 hours of admission; (2) admission to ICU (medical, surgical,
cardiac, or cardiothoracic surgery); (3) norepinephrine received
in the emergency department or within 24 hours of admission;
and (4) a second vasoactive agent received in the emergency
department or within 48 hours of admission. We defined a
vasoactive agent as one that may include a range from inotropic
(dobutamine) to vasoconstrictive (phenylephrine) properties.
Patients had to meet all 4 inclusion criteria in order to be
considered for enrollment.
Patients solely diagnosed with other forms of shock (car-
diogenic, hypovolemic, or obstructive) without meeting sep-
sis criteria were excluded. Given that our enrolled patients
were receiving vasoactive agent(s), the type of shock was
determined by reviewing the clinician documentation, for
example, ‘‘cardiogenic shock’’ or ‘‘hypovolemic shock’’
was determined by a clinical diagnosis. Patients who were
administered an initial vasoactive agent other than norepi-
nephrine or if norepinephrine was discontinued prior to the
administration of the second agent were also excluded from
this study.
Data Collection
Electronic medical records were reviewed for patient demo-
graphics, comorbidities, hemodynamic variables at presenta-
tion, culture results, infection source, initial laboratory
findings, vasoactive agents during the first 96 hours, norepi-
nephrine rate prior to administration of the second vasoactive
agent, total number of antibiotics, volume of fluids during the
first 96 hours, units of packed red blood cells within the first
96 hours, use of corticosteroids, use of mechanical ventila-
tion, and hospital length of stay. Acute Physiology and
Chronic Health Evaluation (APACHE) IV and Sequential
Organ Failure Assessment (SOFA) scores were calculated
based on the worst required variables within the first 24 hours
of admission to the hospital.2,3
Journal of Intensive Care Medicine 32(7)
Measurable Outcomes
The primary outcome was in-hospital death from any cause.
Statistical Analysis
Descriptive statistics are presented as mean +standard devia-
tion. Categorical variables are presented as count (percentage).
Ten multiple imputation procedures were performed using the
Markov Chain Monte Carlo method in order to handle arbitrary
missing data. Improbable values were excluded or set to the
minimum or maximum value for a given variable. Student t test
and w2 test were used to determine statistically significant dif-
ferences between survivors and nonsurvivors. One-way analy-
sis of variance and w2 test were used to determine statistically
significant differences between patients receiving different sec-
ond vasoactive agents after refractory to norepinephrine.
Survival analysis was used to determine differences in total
hospital days, which concluded in death or censoring. The
survival estimates were stratified by second vasoactive agent,
and a log-rank test was used to compare survival curves
between patients on each of the second vasoactive agent.
The effect of variables on mortality was assessed using
multivariable logistic regression. We a priori selected demo-
graphic, comorbidity, laboratory, and treatment variables that
may be clinically significant in affecting outcome in refractory
septic shock. Age, gender, congestive heart failure, lactate,
fluid volume within 96 hours, packed red blood cells within
96 hours, norepinephrine rate, second vasoactive agent, and
mechanical ventilation were used as variables in the model.
When comparing the effect of second vasoactive agents on
mortality, vasopressin was used as the reference agent. To
avoid collinearity in the model, we did not include the physio-
logic scores, APACHE IV, and SOFA in the model.
A P value of <.05 was considered statistically significant.
The statistical analysis was performed using the SPSS 16.0
package (SPSS, Chicago, Illinois) and SAS 9.3 (SAS Institute,
Cary, North Carolina).
Results
We screened 2640 patients from July 1, 2008, to June 30, 2012,
admitted to the ICU requiring a vasoactive agent. Two hundred
thirty-five patients met the enrollment criteria. Only 1 patient
had epinephrine as the second vasoactive agent and was
excluded from the analysis. Two hundred thirty-four patients
had dobutamine (50 patients), dopamine (50), phenylephrine
(66), or vasopressin (68) as the second vasoactive agent (Figure
1). Their mean age was 60.8 + 17.8 years, 122 (52.1%) were
male, 81.6% mechanically ventilated, with mean hospital
length of stay of 5.4 + 3.5 days (Table 1). The maximum dose
of norepinephrine was 29.8 + 31.7 mg/min. Within 96 hours,
2.8 + 1.0 vasoactive agents were administered. Mean
APACHE IV and SOFA scores were 98.3 + 27.5 and 12.8
+ 3.7, respectively. Predicted mortality was 47.2% + 25.4%
Nguyen et al
Figure 1. Enrollment flowchart. *Only 1 patient required epinephrine as the second vasoactive agent and thus was excluded from analysis.
by APACHE IV scores; however, actual in-hospital mortality
was 65.8% (154 deaths).
Univariate analysis based on mortality showed statistically
significant difference between survivors and nonsurvivors for
second vasoactive agent, liver disease, malignancy, central
venous pressure, total bilirubin, lactate, mechanical ventilation,
norepinephrine rate, maximum number of vasoactive agents,
96-hour fluid volume, hospital length of stay, APACHE IV,
and SOFA (Table 1). In examining patients receiving different
second vasoactive agents, statistically significant difference
was observed for liver disease, malignancy, central venous
pressure, creatinine, total bilirubin, lactate, mechanical ventila-
tion, norepinephrine rate, maximum number of vasoactive
agents, 96-hour packed red blood cells, hospital length of stay,
and SOFA (Table 2). There were no differences in source of
infection between survivors and nonsurvivors or among
patients receiving different second vasoactive agents (Tables
1 and 2; Figure 2).
Predicted mortality by APACHE IV and actual mortality
were significantly different among patients receiving
453
different second vasoactive agents. The crude in-hospital
mortality for patients receiving dobutamine, dopamine, phe-
nylephrine, and vasopressin as the second agent was 40.0%,
66.0%, 74.2%, and 76.5%, respectively, P < .001 (Table 2).
Survival analysis with log-rank test demonstrated significant
difference in survival time by second vasoactive agent,
P ¼ .0002 (Figure 3).
In the multivariable logistic regression model adjusted
for variables determined a priori as being clinically signif-
icant in determining outcome in septic shock, age, lactate,
96-hour fluid volume, norepinephrine rate, and mechanical
ventilation were significantly associated with odds ratios
(ORs) for mortality, P values <.05 (Table 3). With vaso-
pressin as the reference second vasoactive agent, dobuta-
mine was associated with decreased OR for mortality, OR
¼ 0.34 (95% confidence interval: 0.14-0.84), P ¼ .04.
Dopamine and phenylephrine were not associated with
decreased OR for mortality compared to vasopressin. The
relative risk of dying was 55.8% lower in patients receiving
dobutamine versus vasopressin, P < .01.
454 Journal of Intensive Care Medicine 32(7)

Table 1. Patient Characteristics.a

All Patients (N ¼ 234) Survivors (N ¼ 80) Nonsurvivors (N ¼ 154) P Value

Age, years (N ¼ 234) 60.8 + 17.8 58.7 + 20.2 61.8 + 16.4 .24
Weight, kg (N ¼ 234) 79.6 + 25.5 77.7 + 23.2 80.6 + 26.7 .42
Gender, no. (%) (N ¼ 234) .78
Female 112 (47.9) 37 (46.3) 75 (48.7)
Male 122 (52.1) 43 (53.8) 79 (51.3)
Race, no. (%) (N ¼ 234) .59
White 109 (46.6) 40 (50.0) 69 (44.8)
Hispanic 57 (24.4) 17 (21.3) 40 (26.0)
Other 43 (18.4) 14 (18.8) 29 (18.8)
Black 18 (7.7) 5 (6.3) 13 (8.4)
Asian 7 (3.0) 4 (5.0) 3 (2.0)
Second vasoactive agent, no. (%) (N ¼ 234) .0001b
Dobutamine 50 (21.4) 30 (37.5) 20 (13.0)
Dopamine 50 (21.4) 17 (21.3) 33 (21.4)
Phenylephrine 66 (28.2) 17 (21.3) 49 (31.8)
Vasopressin 68 (29.1) 16 (20.0) 52 (33.8)
Comorbidities, no. (%) (N ¼ 233)
Diabetes 82 (35.0) 30 (37.5) 52 (33.8) .57
Hypertension 116 (49.6) 41 (51.3) 75 (48.7) .71
CHF 61 (26.1) 26 (32.5) 35 (22.7) .11
Valvular heart disease 65 (27.8) 28 (35.0) 37 (24.0) .07
COPD 31 (13.3) 11 (13.8) 20 (13.1) .88
Asthmac 7 (3.0) 4 (5.0) 3 (2.0) .24
ESRD 36 (15.4) 9 (11.3) 27 (27.5) .21
CKD 24 (10.3) 8 (10.0) 16 (10.4) .93
Liver disease 49 (20.9) 8 (10.0) 41 (26.6) .003b
Malignancy 48 (20.5) 7 (8.8) 41 (26.6) .001b
Vital signs and laboratory test values
Temperature,  F (N ¼ 232) 98.5 + 2.8 98.8 + 2.6 98.3 + 3.0 .19
Heart rate, per min (N ¼ 234) 103.5 + 26.1 103.0 + 27.7 103.7 + 25.2 .84
Respiratory rate, per min (N ¼ 234) 21.9 + 7.4 20.8 + 6.0 22.5 + 7.9 .06
SBP, mm Hg (N ¼ 234) 101.1 + 26.7 105.0 + 30.5 99.1 + 24.3 .14
DBP, mm Hg (N ¼ 234) 58.3 + 22.7 60.0 + 24.4 57.4 + 21.9 .41
CVP, mm Hg (N ¼ 90) 14.1 + 12.6 10.6 + 11.7 16.0 + 12.7 .002b
MAP, mm Hg (N ¼ 234) 72.6 + 22.8 75.3 + 25.5 71.2 + 21.2 .22
ScvO2, % (N ¼ 67) 68.2 + 11.1 69.4 + 6.3 67.7 + 12.9 .18
WBC, 109/L (N ¼ 233) 15.6 + 13.3 14.3 + 7.3 16.3 + 15.5 .19
BUN, mg/dL (N ¼ 234) 46.0 + 30.3 43.2 + 31.4 47.5 + 29.7 .30
Creatinine, mg/dL (N ¼ 234) 2.6 + 2.1 2.3 + 2.0 2.7 + 2.1 .10
Glucose, mg/dL (N ¼ 234) 163.0 + 119.7 174.1 + 141.2 157.3 + 106.8 .35
TBili, mg/dL (N ¼ 232) 2.7 + 5.1 1.0 + 1.0 3.5 + 6.0 <.0001b
Lactate, mmol/L (N ¼ 233) 5.8 + 5.4 3.8 + 3.7 6.9 + 5.8 <.0001b
Source of infection, no. (%) (N ¼ 234)
Pneumonia 121 (51.7) 45 (56.3) 76 (49.4) .32
UTI 85 (36.3) 36 (45.0) 49 (31.8) .05
Soft tissue 20 (8.6) 8 (10.0) 12 (7.8) .57
Intra-abdominal 32 (13.7) 6 (7.5) 26 (16.9) .05
Catheter related 8 (3.4) 5 (6.3) 3 (2.0) .13
Other 38 (16.2) 10 (12.5) 28 (18.2) .26
Treatment characteristics
Mechanical ventilation, no. (%) (N ¼ 234) 191 (81.6) 56 (70.0) 135 (87.7) .0009b
Norepinephrine rate, mg/min (N ¼ 234) 29.8 + 31.7 20.1 + 23.5 34.9 + 34.3 <.0001b
Time to antibiotics, hours (N ¼ 230) 5.3 + 5.0 5.7 + 5.4 5.1 + 4.7 .35
Total antibiotics, no. (N ¼ 234) 3.3 + 1.10 3.4 + 1.0 3.2 + 1.1 .10
Maximum number of vasoactive agents, no. (N ¼ 234) 2.8 + 1.0 2.4 + 0.8 3.0 + 1.0 <.0001b
96-hour fluid volume, mL (N ¼ 234) 13 261.0 + 7875.7 14 866.9 + 6854.6 12 426.8 + 8255.3 .02b
96-hour PRBC, U (N ¼ 234) 1.4 + 2.5 1.0 + 1.9 1.6 + 2.8 .07
Corticosteroid, no. (%) (N ¼ 234) 136 (58.1) 44 (55.0) 92 (59.7) .49
(continued)
Nguyen et al 455

Table 1. (continued)

All Patients (N ¼ 234) Survivors (N ¼ 80) Nonsurvivors (N ¼ 154) P Value

Hospital length of stay, daysd (N ¼ 234) 5.4 + 3.5 14.9 + 2.3 3.2 + 2.9 <.0001b
Physiologic scores
SOFA (N ¼ 228) 12.8 + 3.7 10.8 + 3.1 13.8 + 3.5 <.0001b
APACHE IV (N ¼ 226) 98.3 + 27.5 82.3 + 25.1 107.1 + 24.7 <.0001b
Predict mortality, % (N ¼ 226) 47.2 + 25.4 31.9 + 21.7 55.6 + 23.3 <.0001b
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; BUN, blood urea nitrogen; CHF, congestive heart failure; CKD, chronic kidney disease;
COPD, chronic obstructive lung disease; CVP, central venous pressure; DBP, diastolic blood pressure; ESRD, end-stage renal disease; MAP, mean arterial
pressure; PRBC, packed red blood cells; SBP, systolic blood pressure; ScvO2, central venous oxygen saturation; SOFA, Sequential Organ Failure Assessment; TBili,
total bilirubin; UTI, urinary tract infection; WBC, white blood count.
a
Data are presented as mean + standard deviation or count (percentage).
b
A P value of <.05 was considered statistically significant.
c
Fisher exact test.
d
Hospital length of stay was log transformed for the analysis. The geometric mean is reported.

Table 2. Patient Characteristics by Second Vasoactive Agent.a

Dobutamine Dopamine Phenylephrine Vasopressin

(N ¼ 50) (N ¼ 50) (N ¼ 66) (N ¼ 68) P Value

Age, years 62.6 + 19.5 60.8 + 18.5 59.8 + 17.4 60.4 + 16.7 .85
Weight, kg 76.9 + 25.0 88.0 + 30.2 76.0 + 23.5 78.9 + 23.1 .06
Gender, no. (%) .88
Female 22 (44.0) 24 (48.0) 34 (51.5) 32 (47.1)
Male 28 (56.0) 26 (52.0) 32 (48.5) 36 (52.9)
Race, no. (%) .15
White 30 (60.0) 21 (42.0) 32 (48.5) 26 (38.2)
Hispanic 10 (20.0) 10 (20.0) 13 (19.7) 24 (35.3)
Other 8 (16.0) 9 (18.0) 12 (18.2) 14 (20.6)
Black 2 (4.0) 7 (14.0) 6 (9.1) 3 (4.4)
Asian 0 (0.0) 3 (6.0) 3 (4.6) 1 (1.5)
Comorbidities, no. (%)
Diabetes 17 (34.0) 18 (36.0) 27 (40.9) 20 (29.4) .57
Hypertension 24 (48.0) 27 (54.0) 31 (47.0) 34 (50.0) .89
CHF 16 (32.0) 19 (38.0) 12 (18.2) 14 (20.6) .05
Valvular heart disease 17 (34.0) 16 (32.0) 11 (16.7) 21 (30.9) .12
COPD 9 (18.0) 6 (12.0) 3 (4.6) 13 (19.1) .06
Asthma 2 (4.0) 2 (4.0) 1 (1.5) 2 (2.9) .84
ESRD 6 (12.0) 7 (14.0) 13 (19.7) 10 (14.7) .69
CKD 4 (8.0) 8 (16.0) 7 (10.6) 5 (7.4) .44
Liver disease 2 (4.0) 6 (12.0) 22 (33.3) 19 (27.9) .0002b
Malignancy 1 (2.0) 13 (26.0) 19 (28.8) 15 (22.1) .0025b
Vital signs and lab values
Temperature,  F 98.6 + 2.9 98.2 + 2.7 98.3 + 3.0 98.8 + 2.7 .57
Heart rate, per min 102.6 + 23.5 99.0 + 26.0 110.6 + 29.4 100.6 + 23.4 .06
Respiratory rate, per min 20.5 + 6.4 22.5 + 6.8 21.7 + 8.3 22.7 + 7.4 .39
SBP, mm Hg 107.0 + 28.2 100.4 + 28.6 100.9 + 24.6 97.6 + 25.8 .30
DBP, mm Hg 63.6 + 24.6 57.3 + 22.2 59.5 + 21.6 54.0 + 22.4 .14
CVP, mm Hg 10.9 + 10.2 17.2 + 16.4 16.6 + 12.3 11.9 + 10.2 .01b
MAP, mm Hg 77.2 + 24.6 72.0 + 23.0 73.8 + 21.4 68.5 + 22.4 .21
ScvO2, % 67.0 + 10.7 68.5 + 8.8 68.3 + 9.7 68.9 + 13.9 .82
WBC, 109/L 14.2 + 11.9 14.8 + 11.0 15.2 + 14.2 17.8 + 14.8 .44
BUN, mg/dL 41.0 + 30.2 49.8 + 35.3 42.2 + 25.4 50.6 + 30.3 .19
Creatinine, mg/dL 2.1 + 1.6 3.2 + 2.9 2.3 + 1.9 2.7 + 1.8 .03b
Glucose, mg/dL 183.3 + 147.5 179.6 + 145.8 156.2 + 89.0 142.5 + 98.3 .20
TBili, mg/dL 1.6 + 4.6 1.5 + 2.0 3.1 + 4.7 3.9 + 6.8 .02b
Lactate, mmol/L 4.0 + 3.5 6.2 + 5.6 6.9 + 5.3 5.8 + 6.1 .03b
(continued)
456 Journal of Intensive Care Medicine 32(7)

Table 2. (continued)

Dobutamine Dopamine Phenylephrine Vasopressin

(N ¼ 50) (N ¼ 50) (N ¼ 66) (N ¼ 68) P Value

Source of infection, no. (%)

Pneumonia 27 (54.0) 25 (50.0) 26 (39.4) 43 (63.2) .05
UTI 18 (36.0) 15 (30.0) 23 (34.9) 29 (42.7) .55
Soft tissue 5 (10.0) 4 (8.0) 6 (9.1) 5 (7.4) .96
Intra-abdominal 1 (2.0) 9 (18.0) 12 (18.2) 10 (14.7) .05
Catheter related 3 (6.0) 2 (4.0) 1 (1.5) 2 (2.9) .61
Other 8 (16.0) 5 (10.0) 16 (24.2) 9 (13.2) .17
Treatment characteristics
Mechanical ventilation, no. (%) 31 (62.0) 40 (80.0) 60 (90.9) 60 (88.2) .0003b
Norepinephrine rate, mg/min 15.8 + 21.1 40.6 + 46.4 28.9 + 28.5 33.1 + 23.9 .0008b
Time to antibiotics, hours 5.2 + 5.2 5.3 + 4.8 5.8 + 5.5 5.0 + 4.4 .83
Total antibiotics, number 3.4 + 1.1 3.0 + 1.2 3.1 + 1.1 3.4 + 1.0 .16
Maximum number of vasoactive agents, no. 2.5 + 0.9 3.1 + 1.1 2.8 + 1.0 2.7 + 0.9 .0093b
96-hour fluid volume, mL 13 881.1 + 6668.8 11 490.7 + 7929.4 14 307.1 + 9441.1 13 091.5 + 6855.1 .26
96-hour PRBC, units 0.7 + 1.4 0.9 + 1.8 1.6 + 2.8 2.0 + 3.1 .01b
Corticosteroid, no. (%) 25 (50.0) 27 (54.0) 44 (66.7) 40 (58.8) .30
Hospital length of stay, daysc 10.3 + 2.5 4.5 + 3.9 4.5 + 3.5 4.5 + 3.3 .0004b
Physiology scores
SOFA 10.7 + 3.3 12.3 + 2.9 13.0 + 3.9 14.3 + 3.5 <.0001b
APACHE IV 74.6 + 23.3 100.0 + 27.7 105.9 + 23.1 107.0 + 24.4 .52
Predict mortality, % 28.2 + 21.4 46.8 + 24.9 55.2 + 22.3 53.4 + 24.4 <.0001b
Mortality, no. (%) .0001b
Lived 30 (60.0) 17 (34.0) 17 (25.8) 16 (23.5)
Died 20 (40.0) 33 (66.0) 49 (74.2) 52 (76.5)
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; BUN, blood urea nitrogen; CHF, congestive heart failure; CKD, chronic kidney disease;
COPD, chronic obstructive lung disease; CVP, central venous pressure; DBP, diastolic blood pressure; ESRD, end-stage renal disease; MAP, mean arterial
pressure; PRBC, packed red blood cells; SBP, systolic blood pressure; ScvO2, central venous oxygen saturation; SOFA, Sequential Organ Failure Assessment; TBili,
total bilirubin; UTI, urinary tract infection; WBC, white blood count.
a
Data are presented as mean +standard deviation, or count (%).
b
A P value of <.05 was considered statistically significant.
c
Hospital length of stay was log transformed for the analysis. The geometric mean is reported.

Figure 2. Sources of infection stratified by the second vasoactive Figure 3. Survival analysis using log-rank test to compare total hos-
agent. pital days among patients stratified by the second vasoactive agent.
Hospital days were concluded by death or discharge from the hospital.

Discussion norepinephrine dose or increasing the mean arterial pressure.1

In the setting of septic shock that is refractory to norepinephr- However, in our study population, patients receiving vasopres-
ine, vasopressin is recommended for either decreasing sin as the second agent were associated with the worst mortality
Nguyen et al
Table 3. Multivariable Logistic Regression Model for Mortality,
Including Variables That Were Determined a Priori to Be Clinically
Significant in Affecting Outcome in Septic Shock.a
Variable OR (95% CI)
Age 1.02 (1.00-1.04)
Gender 1.21 (1.64-2.28)
Congestive heart failure 0.91 (0.45-1.85)
Lactate 1.14 (1.05-1.25)
96-hour fluid volume 1.00 (1.00-1.00)
96-hour PRBC units 1.06 (0.92-1.23)
Norepinephrine rate 1.01 (1.00-1.03)
Second vasoactive agent
Dobutamine versus vasopressin 0.34 (0.14-0.84)
Dopamine versus vasopressin 0.54 (0.22-1.35)
Phenylephrine versus vasopressin 0.83 (0.35-1.94)
Mechanical ventilation 2.75 (1.21-6.24)
Abbreviations: CI, confidence interval; PRBC, packed red blood cells; OR, odds
ratio.
a
For the variable second vasoactive agent, vasopressin is the reference variable.
compared to other available agents. Several trials have inves-
tigated vasopressin. A randomized, double-blinded study found
that vasopressin improved urine output and creatinine clear-
ance compared to norepinephrine; however, the study was not
sufficiently powered to elucidate larger outcomes, such as mor-
tality.4 The multicenter Vasopressin And Septic Shock Trial
(VASST) trial showed that vasopressin added to low-dose nor-
epinephrine resulted in no outcome benefit compared to high-
dose norepinephrine alone.5 Despite these results, vasopressin
is often used as an adjuvant agent to norepinephrine. Such use
may be associated with significant risk of adverse cardiac and
splanchnic function, even though cytokines may be decreased
more than with norepinephrine.6,7 A recent study in a sheep
peritonitis model showed that a cousin of vasopressin, the
selective V1A receptor agonist, selepressin, may be superior
to vasopressin and norepinephrine in preserving cardiac func-
tion.8 In the meantime, our pragmatic study suggests that vaso-
pressin may not be the best agent in norepinephrine refractory
septic shock.
A number of patients received dopamine as a second vasoac-
tive agent during our study period. Although dopamine is no
longer used for the purpose of renal protection, guidelines sug-
gest that it can be an alternative to norepinephrine in patients
with low risk for tachyarrhythmia.1,9,10 However, dopamine use
in patients with septic shock may be associated with increased
mortality compared to patients who never received dopamine.11
As a second agent, one study showed that low-dose dopamine
was similar to dopexamine with respect to influencing organ
failures in norepinephrine-treated septic shock.12 Our study
showed that dopamine was also similar to vasopressin as a sec-
ond vasoactive agent with respect to mortality outcome.
Phenylephrine is known to increase systemic vascular resis-
tance by selective action on a1 adrenergic receptors; however,
there are no differences in cardiac performance and hepatos-
planchnic hemostasis when compared to norepinephrine.13
457
Although guidelines recommend that phenylephrine be used
as salvage therapy when combined vasopressor/inotrope agents
and low-dose vasopressin have failed to achieve blood pressure
P Value target,1 we did not observe phenylephrine preferentially used
for this purpose compared to other agents in our study. To our
.03 knowledge, we could not find previous studies regarding the
.56 outcome effects of phenylephrine when used in addition to
.79
norepinephrine. Our data showed that it is associated with high
.003
.01 mortality as a second agent, similar to vasopressin.
.41 Dobutamine is recommended as an adjuvant inotrope to
.03 norepinephrine for patients who display myocardial dysfunc-
tion in the face of appropriate left ventricular filling pressure or
.04 clinically adequate volume resuscitation.1 However, the com-
.62 bination of dobutamine and norepinephrine is not better than
.30
epinephrine alone.14,15 To the best of our knowledge, there is
.02
no previous data comparing dobutamine against other second
vasoactive agents in patients refractory to norepinephrine. As
such, the standard approach to the management of septic shock
in our ICU includes central venous oxygen saturation (ScvO2)
monitoring, as a surrogate for cardiac function (or cardiac out-
put), in the decision tree to initiate dobutamine.16 After optimal
volume resuscitation and norepinephrine, dobutamine would
be added as the second vasoactive agent only if ScvO2 <
70%, even though the target goal of mean arterial pressure
>65 mm Hg is already achieved. It may be possible that
patients with optimal mean arterial pressure would have better
outcome compared to patients with hypotension refractory to
norepinephrine. However, persistently low ScvO2 is indepen-
dently associated with mortality.17 Thus, it would be rational to
optimize ScvO2 with vasoactive agents such as dobutamine in
addition to norepinephrine.
Previous studies showed that the ability of dobutamine to
elicit a positive response in oxygen transport variables, for
example, increased ScvO2, was associated with good out-
come.16,18-20 We hypothesize that these responders may be
patients with evidence of myocardial depression and would
benefit from additional inotropic support. 21 Contrary to
patients with refractory vasodilatory shock requiring multiple
vasoconstricting agents, perhaps patients with myocardial
depression may have better outcome if treated with dobuta-
mine. In our study, we observed 21.4% of patients who
required dobutamine had significantly lower mortality than
those requiring vasopressin or phenylephrine. Our cohort
was similar to previous studies showing that 20% to 24% of
patients with septic shock have evidence of reversible ventri-
cular dysfunction.22,23 Although we did not obtain formal
echocardiogram for these patients to assess their cardiac func-
tion, there was no difference in congestive heart failure
between survivors and nonsurvivors and between patients
receiving different second vasoactive agents. We further
included congestive heart failure in our multivariable logistic
regression analysis and showed that this variable in itself was
not associated with outcome.
Our study was naturally limited by its retrospective design.
However, the sample size for the observed mortality rates in
patients with dobutamine compared to vasopressin was
458
appropriate to achieve a power of 0.986 (b ¼ .014) or only
1.4% probability that dobutamine is similar to vasopressin in
mortality outcome, with a ¼ .05 (2 sided). Given a weak rec-
ommendation (grade 2B) for epinephrine, we did not com-
monly use epinephrine as the second vasoactive agent during
the study period at our institution.24 As such, we observed only
1 patient receiving epinephrine, which precluded any conclu-
sion from our study regarding the benefit of this agent. We also
observed a moderate number of patients with dopamine as a
second agent, which was not surprising given the guidelines
strong recommendation (grade 1C) during the study period that
dopamine be used as ‘‘the first-choice vasopressor agent to
correct hypotension in septic shock.’’24 We did not collect data
on the total dosage of the second vasoactive agent or informa-
tion on additional agent(s) beyond the second agent. However,
our aim was to determine which second vasoactive agent, in
and of itself, was associated with outcome, rather than its
dosage. Finally, the common practice at our institution was
to add a second vasoactive agent when the patient appears
refractory to escalating dose of norepinephrine. Thus, we did
not have a comparison group in which norepinephrine was
continued as the only agent for septic shock.
In summary, our study showed that patients requiring a
second vasoactive agent within 48 hours after receiving nore-
pinephrine have high mortality. Patients with vasopressin
added to norepinephrine had the highest mortality, whereas
patients requiring dobutamine had the lowest mortality in the
study. These results may be related to the use of dobutamine at
our institution in patients with perhaps a phenotype of lower
sepsis severity. However, our study was not designed to con-
clude any cause and effect relationship but rather provides
rationale for future randomized trials comparing dobutamine
with other vasoactive agents in the treatment of septic shock
refractory to norepinephrine.
Acknowledgments
We appreciate Azmina Ghelani, Brad Hardesty, Anna Lee, Michelle
Ngo, Emily Nguyen, Bryan Solis, Vu Truong, and Keda Xu for their
contributions in the data collection and analysis of the study.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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