Am J Physiol Heart Circ Physiol 287: H2545–H2554, 2004.
First published August 19, 2004; doi:10.1152/ajpheart.00450.2004.
Differing effects of epinephrine, norepinephrine, and vasopressin on survival
in a canine model of septic shock
Peter C. Minneci,1,3 Katherine J. Deans,1,3 Steven M. Banks,1 Renee Costello,2 Gyorgy Csako,2
Peter Q. Eichacker,1 Robert L. Danner,1 Charles Natanson,1 and Steven B. Solomon1
1
Critical Care Medicine Department and 2Department of Laboratory Medicine, Warren Grant
Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; and
3
Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114
Submitted 14 May 2004; accepted in final form 16 August 2004
Minneci, Peter C., Katherine J. Deans, Steven M. Banks, Renee
Costello, Gyorgy Csako, Peter Q. Eichacker, Robert L. Danner,
Charles Natanson, and Steven B. Solomon. Differing effects of
epinephrine, norepinephrine, and vasopressin on survival in a canine
model of septic shock. Am J Physiol Heart Circ Physiol 287:
H2545–H2554, 2004. First published August 19, 2004; doi:10.1152/
ajpheart.00450.2004.—During sepsis, limited data on the survival
effects of vasopressors are available to guide therapy. Therefore, we
compared the effects of three vasopressors on survival in a canine
septic shock model. Seventy-eight awake dogs infected with differing
doses of intraperitoneal Escherichia coli to produce increasing mor-
tality were randomized to receive epinephrine (0.2, 0.8, or 2.0
␮g 䡠 kg⫺1 䡠 min⫺1), norepinephrine (0.2, 1.0, or 2.0 ␮g 䡠 kg⫺1 䡠 min⫺1),
vasopressin (0.01 or 0.04 U/min), or placebo in addition to antibiotics
and fluids. Serial hemodynamic and biochemical variables were mea-
sured. Increasing doses of bacteria caused progressively greater de-
creases in survival (P ⬍ 0.06), mean arterial pressure (MAP) (P ⬍
0.05), cardiac index (CI) (P ⬍ 0.02), and ejection fraction (EF) (P ⫽
0.02). The effects of epinephrine on survival were significantly
different from those of norepinephrine and vasopressin (P ⫽ 0.03).
Epinephrine had a harmful effect on survival that was significantly
related to drug dose (P ⫽ 0.02) but not bacterial dose. Norepinephrine
and vasopressin had beneficial effects on survival that were similar at
all drug and bacteria doses. Compared with concurrent infected
controls, epinephrine caused greater decreases in CI, EF, and pH, and
greater increases in systemic vascular resistance and serum creatinine
than norepinephrine and vasopressin. These epinephrine-induced
changes were significantly related to the dose of epinephrine admin-
istered. In this study, the effects of vasopressors were independent of
severity of infection but dependent on the type and dose of vasopres-
sor used. Epinephrine adversely affected organ function, systemic
perfusion, and survival compared with norepinephrine and vasopres-
sin. In the ranges studied, norepinephrine and vasopressin have more
favorable risk-benefit profiles than epinephrine during sepsis.
vasopressors and systemic perfusion; low cardiac output septic shock;
vasopressors and acidosis; vasopressors and cardiac function
DESPITE CONTINUED IMPROVEMENTS in medical therapy, mortality
from septic shock has remained between 30% and 60% for the
past three decades (1, 2). Septic shock is a clinically descriptive
term that refers to a pathophysiological state of cardiovascular
collapse associated with overwhelming infection. After ade-
quate volume resuscitation, severe septic shock is often char-
acterized by a hyperdynamic state with increased cardiac
Address for reprint requests and other correspondence: P. C. Minneci,
Critical Care Medicine Department, National Institutes of Health, 10
Center Dr., Bldg 10, Rm 7D43, Bethesda, MD 20892 (E-mail:
pminneci@mail.cc.nih.gov).
http://www.ajpheart.org
output (CO), hypotension, and decreased systemic vascular
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resistance (SVR). However, despite adequate volume resusci-
tation, 20 –25% of adult septic patients and 50 – 60% of pedi-
atric septic patients will present with low CO (3, 33, 34). The
majority of septic patients will develop myocardial dysfunction
and many will die as a consequence of multiple organ failure
(17, 35, 44). During septic shock, tissue perfusion is compro-
mised by hypotension, by the loss of vascular integrity with
extravasation of fluid into the interstitium, and by the altered
distribution of blood flow within the microcirculation (44a).
One of the primary goals in the treatment of septic shock is
the maintenance of systemic arterial pressure with the restora-
tion of adequate tissue perfusion (43, 44a). The initiation of
vasopressor therapy during septic shock is often necessary to
maintain adequate tissue perfusion and prevent rapid death.
Whereas many studies have documented the physiological
effects of various vasopressor agents in sepsis, few have
compared their effects on survival. Furthermore, there are few
data examining the effects of a single agent over a wide range
of doses or in varying levels of severity of infection. Because
of the lack of available data, the vasopressor agent selected to
treat hypotension during septic shock is usually based on
patient-specific characteristics, physiological parameters, and
clinical experience. Over the past 20 years, epinephrine therapy
has been used to treat patients with low CO septic shock
(particularly children) with the rationale that these patients will
benefit from its ␤-agonist inotropic effects (18, 44, 44a).
Norepinephrine is commonly used to treat hypotensive patients
with hyperdynamic septic shock because of its strong ␣-agonist
vasoconstrictor properties (19), and recently, low-dose vaso-
pressin is being used more frequently to treat refractory hypo-
tension in patients with septic shock (15, 16, 20, 47). The
purpose of our study was to design a model of lethal septic
shock to prospectively evaluate and compare the effects of
epinephrine, norepinephrine, and vasopressin in conjunction
with antibiotics and intravenous fluid on 28-day survival.
METHODS
Experimental design. The experiments described below were per-
formed as part of an approved protocol by the Institutional Animal
Care and Use Committee of the Clinical Center at the National
Institutes of Health. Eighty-four purpose-bred beagles (12–28 mo of
age, 10 –12 kg body wt) were studied. Bacterial peritonitis was
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of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
H2545
H2546 VASOPRESSORS IN SEPTIC SHOCK
induced by implantation of a fibrin clot containing live Escherichia
coli 0111:B4 into the abdominal cavity. This encapsulated serum-
resistant strain of E. coli produces persistent positive blood cultures
with progressive increases in blood endotoxin levels in animals not
receiving antibiotics (12, 14, 42). Clots contained one of three con-
centration ranges of organism: 3– 4, 7.5–15, or 18 ⫻ 109 colony
forming units (CFU)/kg of body wt (Table 1). Comprehensive eval-
uations were performed at baseline (7 days before clot implantation)
and then at 6, 24, and 48 h after clot implantation. The indicated
evaluations were performed in conscious animals and consisted of
physiological measurements using arterial and pulmonary artery cath-
eters, laboratory tests, and gated radionuclide cineangiograms of the
left ventricle.
Vasopressor or saline (control) infusions were started 6 h after
bacterial clot implantation and were infused for 48 h. Three vasopres-
sors were studied at multiple doses (Table 1). Titration entailed a 50%
reduction in drug dose if mean arterial pressure (MAP) was greater
than normal for dogs (120 mmHg).
All animals received daily antibiotics for 72 h (ceftriaxone 100
mg/kg im) beginning 6 h after clot implantation. A 5% dextrose-
lactated Ringer solution was infused for a total of 42 h beginning at
6 h postclot implantation to provide fluid resuscitation to attain a
pulmonary capillary wedge pressure (PCWP) between 12 and 15
mmHg (30). The infusion rate was 8 ml 䡠 kg⫺1 䡠 h⫺1 for 30 h and was
then reduced to 4 ml 䡠 kg⫺1 䡠 h⫺1 for the last 12 h and discontinued (30,
31). The dogs were maintained in cages that provided an atmosphere
of humidified oxygen (50% H2O; FIo2 ⫽ 40%) at a temperature of
37°C.
Animals were continuously observed for the first 48 h after clot
implantation and then at least twice a day for the next 26 days or until
death. Animals were randomly assigned to a treatment arm, and the
veterinarians making euthanasia decisions were blinded. As prospec-
tively determined, any animal euthanized before completion of the
28-day study was considered a nonsurvivor and was included in the
analysis.
Bacterial clot implantation. Animals were premedicated (xylazine
0.75 mg/kg and atropine 0.04 mg/kg im). Anesthesia was induced
using propofol and maintained with inhalation of 1–3% isoflurane. An
upper abdominal midline laparotomy was performed using aseptic
technique, and bacterial peritonitis was induced by implanting a
fibrin-thrombin clot with a known number of CFUs of viable E. coli
0111:B4. The bacterial-infected clots were prepared using previously
described techniques (31). After implantation, the incision was closed,
local anesthesia (0.25% bupivicaine) was administered, and inhala-
tional anesthesia was discontinued. The animals were extubated when
awake.
Catheter placement. For baseline studies, femoral arterial (20
gauge) and external jugular venous (8-Fr) catheters (Maxxim Medi-
cal; Athens, TX) were placed percutaneously using aseptic sterile
technique. A 7-Fr pulmonary artery thermodilution catheter (Abbott
Table 1. Experimental design
Number of Escherichia coli, Epinephrine, Norepinephrine, Vasopressin,
CFUs ␮g䡠kg⫺1䡠min⫺1 ␮g䡠kg⫺1䡠min⫺1 U/min
18 ⫻ 109 0 (4) 0 (3) 0 (7)
0.8 (4) 0.2 (3) 0.01 (7)
2.0 (4) 1.0 (3) 0.04 (7)
7.5 to 15 ⫻ 109 0 (3) 0 (3)
0.2 (3) 0.2 (3)
2.0 (3) 2.0 (3)
3 to 4 ⫻ 109 0 (6)
0.2 (6)
2.0 (6)
Total no. of dogs 39 18 21
CFUs, colony forming units. Numbers in parentheses are number of dogs.
AJP-Heart Circ Physiol • VOL
Critical Care; Chicago, IL) was introduced through the catheter in the
external jugular vein. The animals were anesthetized in a similar
fashion to the clot implantation procedure using inhalational agents
for 15–20 min. The catheters were removed at the end of the 6-h
baseline study. This same procedure was used for recovery studies 28
days after clot implantation.
For the sepsis studies, the catheters were placed percutaneously
immediately before clot implantation using the methods described
above; these catheters remained in place for 55 h before removal.
Physiological measurements. CO, mean pulmonary artery pressure
(MPAP), PCWP, and central venous pressure (CVP) were determined
via pulmonary artery thermodilution catheter. MAP was measured and
heart rate (HR) was calculated via the femoral arterial pressure
recording. Left ventricular ejection fraction (LVEF) was determined
using cineangiography as previously described (31). The CO was
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standardized to the animal’s weight in kilograms [cardiac index (CI)].
These measurements were performed at baseline, 6, 24, and 48 h after
bacterial clot implantation. At 6 and 48 h, the study was performed
and then repeated after treatment was initiated and terminated, respec-
tively.
Laboratory data. Blood samples were obtained at baseline and at 8,
24, and 48 h after bacterial clot implantation. Arterial and mixed
venous blood gases were measured (ABL 500; Radiometer, Copen-
hagen, Denmark). Complete blood counts were performed using an
automatic analyzer (model STK-S; Coulter Electronics, Hialeah, FL).
Quantitative blood cultures (isolator tubes) and routine serum chem-
istries were also performed. Routine chemistries were performed with
automated chemistry analyzers.
Pain management. To relieve pain caused by peritonitis, all ani-
mals had epidural catheters placed while under general anesthesia
immediately before clot implantation. Previous experiments utilizing
sterile clots in this model have demonstrated that the epidural anes-
thesia does not significantly change LVEF, MAP, and survival (42).
The epidural also does not cause qualitative changes in the hemody-
namic alterations that occur during sepsis other than making them
more pronounced (42). To control nausea and vomiting induced by
peritonitis, all animals received intravenous ondansetron (1.0 mg/kg)
every 4 h for 48 h beginning immediately after clot implantation.
Epidural procedure. All animals were placed in the sternal recum-
bency position with the rear limbs drawn forward (24, 48). After
sterile preparation, a 19-g Touhy needle was inserted into the posterior
lumbosacral epidural space inferior to the seventh lumbar vertebrae
(L7) by loss of resistance. An epidural catheter was placed and the tip
positioned at the L2–3 vertebrae fluoroscopically. The catheter was
then secured, injected with a loading dose of morphine sulfate (0.1
mg/kg) and bupivicaine (1.25 mg/kg), and attached to a constant-
infusion pump. The morphine-bupivicaine epidural was administered
as a 50:50 mix of 0.10% morphine with 0.125% bupivicaine. A 55-h
continuous epidural infusion was initiated (0.3 mg 䡠 kg⫺1 䡠 day⫺1 mor-
phine in combination with bupivicaine) immediately after clot place-
ment (42).
Animal care. This experimental protocol was approved by the
Animal Care and Use Committee of the Clinical Center of the
National Institutes of Health. Throughout the studies, all efforts were
taken to minimize animal pain and suffering. A pain score was
performed each hour for the first 48 h following clot implantation and
then every 4 h until 72 h. The pain scoring was then continued twice
a day until 7 days. The evaluators were blinded to the treatment
groups and to the dose of bacteria. The criteria for euthanasia included
a predetermined pain score, respiratory rate of ⬍5 breaths/min,
seizure activity, or uncontrolled hemorrhage for ⬎2 min. In addition,
at any time during the study, animals were euthanized if they were
noted to be in pain or distress that could not be relieved by the facility
veterinarian or designee.
Statistical methods. Cox Proportional Hazards survival models
were used to assess significant differences in survival data (6).
Hemodynamic analyses of control animals were performed using a
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 VASOPRESSORS IN SEPTIC SHOCK
three-way analysis of variance (ANOVA), with main effects for
bacterial dose, animal variability nested within bacterial dose and
time, and a two-way interaction between dose and time (38). All
interactions including animal variability nested within bacterial dose
were pooled to form the error term. The normal range identified on the
figures represents the mean of all animals at baseline, and the 95%
confidence interval is computed using baseline variation and the
average sample size for the multiple groups included on the graph
(31).
The hemodynamic and laboratory analyses of vasopressors during
sepsis were performed by first computing the change from start of
infusion to follow-up time points for each individual animal. These
changes were then analyzed using ANOVA to estimate dose effects.
RESULTS
Effects of increasing bacterial dose on survival rates and
hemodynamics independent of vasopressor therapy. In control
animals, increasing doses of implanted E. coli resulted in
dose-dependent decreases in survival rates that approached
statistical significance [3– 4 ⫻ 109 (n ⫽ 6) ⱕ 7.5–15 ⫻ 109
(n ⫽ 6) ⱕ 18 ⫻ 109 (n ⫽ 14) CFUs of E. coli] (P ⬍ 0.06) (Fig.
1A). By 6 h after clot implantation, increasing bacterial doses
caused dose-dependent decreases in MAP, mean CI, and LVEF
(P ⬍ 0.05, P ⫽ 0.016, and P ⫽ 0.02 respectively) (Fig. 1,
B–D). In contrast, changes in CVP and PCWP were not related
to bacterial dose (all P ⫽ not significant). During the admin-
istration of fluid therapy from 6 to 48 h after clot implantation,
AJP-Heart Circ Physiol • VOL
H2547
the mean CVP and PCWP in control animals increased from 5
to 10 mmHg and from 8 to 13 mmHg, respectively (both P ⬍
0.05).
Effect of vasopressors on MAP during sepsis. During sepsis,
epinephrine and norepinephrine significantly increased
MAP compared with controls (P ⫽ 0.0002 and 0.0097),
whereas vasopressin did not (P ⫽ not significant). After clot
implantation, only the higher doses of epinephrine (0.8 and
2.0 ␮g 䡠 kg⫺1 䡠 min⫺1) and norepinephrine (1.0 and 2.0
␮g 䡠 kg⫺1 䡠 min⫺1) increased MAP into the normal or near
normal range (Fig. 2).
Effect of vasopressors on survival during sepsis. Overall, the
effect of epinephrine on survival was significantly different
from norepinephrine and vasopressin (P ⫽ 0.03). Compared
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with concurrent controls, epinephrine therapy caused a de-
crease in survival, whereas norepinephrine and vasopressin
therapy improved survival (Fig. 3). The survival effects of
these agents were consistent over all doses of E. coli studied
but not over all doses of drug studied (Fig. 4). With epineph-
rine therapy, the decreases in the odds ratio of survival were
significantly related to drug dose with the higher drug doses
being the most harmful (2.0 ⱖ 0.8 ⱖ 0.2 ␮g䡠kg⫺1 䡠min⫺1 of
epinephrine) (P ⫽ 0.02) (Fig. 4).
Effects of vasopressors on hemodynamic measurements dur-
ing sepsis (from 6 to 48 h). Upon examination of the differ-
ences between treated animals and concurrent control animals
Fig. 1. Characteristics of the canine sepsis
model. A–D: physiological responses and
mortality effect of the different bacterial
challenges in the control animals receiving
intravenous fluids and antibiotics without
vasopressor therapy [low ⫽ 3 to 4 ⫻ 109,
intermediate ⫽ 7.5 to 15 ⫻ 109, and high ⫽
18 ⫻ 109 colony-forming units (CFUs)]. A:
increasing bacterial challenges caused bac-
terial-dose dependent increases in mortality
(P ⫽ 0.06). B–D: mean and normal range for
each physiological parameter are depicted
by the horizontal gray line and bar in each
panel. The mean ⫾ SE at each time point is
demonstrated by the closed circle and verti-
cal error bars, respectively. Increasing bac-
terial challenges caused significant bacterial
dose-dependent decreases in mean arterial
pressure (MAP) (B), cardiac index (CI) (C),
and left ventricular ejection fraction (EF)
(D) (P ⬍ 0.05, P ⫽ 0.016, and P ⫽ 0.02,
respectively).
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Fig. 2. Effects of vasopressors on MAP. Mean and normal range for MAP are demonstrated by the horizontal gray line and bar.
The mean ⫾ SE of MAP at each time point is demonstrated by the closed circle and vertical error bars, respectively. Epinephrine
at 0.8 and 2.0 ␮g 䡠 kg⫺1 䡠 min⫺1 (A) and norepinephrine at 1.0 and 2.0 ␮g 䡠 kg⫺1 䡠 min⫺1 (B) elevated MAP into the normal or
near-normal range. The lowest doses of epinephrine (0.2 ␮g 䡠 kg⫺1 䡠 min⫺1) and norepinephrine (0.2 ␮g 䡠 kg⫺1 䡠 min⫺1) and both
doses of vasopressin (0.01 and 0.04 U/min) (C) caused minimal increases in MAP.

during sepsis, there was a significantly greater decrease in
mean CI and LVEF and a significantly greater increase in SVR
index (SVRI) with epinephrine therapy compared with norepi-
nephrine and vasopressin therapy (P ⫽ 0.0155, P ⫽ 0.0448,
and P ⫽ 0.003, respectively) (Fig. 5). These changes in CI,
LVEF, and SVRI caused by epinephrine treatment were dose
dependent (2.0 ⱖ 0.8 ⱖ 0.2 ␮g䡠 kg⫺1 䡠min⫺1) (P ⬍ 0.0001,
P ⬍ 0.007, and P ⬍ 0.0001, respectively) (Fig. 5).
With the examination of the differences between treated
animals and concurrent control animals, the effects of epineph-
rine, norepinephrine, and vasopressin therapy on HR, CVP,
and PCWP were similar and were not dose dependent (P ⫽ not
significant). Changes in CVP and PCWP in the vasopressor
treatment groups were similar to controls (P ⫽ not significant).
Effects of vasopressors on laboratory measurements during
sepsis (from 6 to 48 h). Upon examination of the differences
between treated animals and concurrent control animals during
sepsis, there was a greater increase in creatinine, blood urea
nitrogen (BUN), and phosphate (P ⫽ 0.0004, P ⫽ 0.0005, and
P ⫽ 0.0003, respectively) and a greater decrease in arterial pH,
bicarbonate, and base excess (P ⫽ 0.07, P ⫽ 0.02, and P ⫽
0.02, respectively) with epinephrine therapy compared with
norepinephrine and vasopressin therapy (Figs. 6 and 7). The
changes in these laboratory parameters caused by epineph-
rine treatment were dose dependent (2.0 ⱖ 0.8 ⱖ 0.2
␮g 䡠 kg⫺1 䡠 min⫺1) (parameter: P value for epinephrine dose-
dependent relationship; creatinine: P ⫽ 0.02; BUN: P ⫽
0.0004: phosphate: P ⫽ 0.0001; arterial pH: P ⫽ 0.0003;
bicarbonate: P ⫽ 0.03; base excess: P ⫽ 0.0002) (Figs. 6
and 7).

DISCUSSION

Our canine sepsis model demonstrated a bacterial dose-

Fig. 3. Effects of vasopressors on survival. The odds ratios of survival (means,
closed circles; ⫾, horizontal lines) with vasopressor therapy averaged over all
bacterial challenge and drug dose levels are shown. Overall, the effect of
epinephrine on outcome was significantly different from the effects of norepi-
nephrine and vasopressin (P ⫽ 0.03). Compared with controls, epinephrine had
a harmful effect and norepinephrine and vasopressin had beneficial effects on
survival.
AJP-Heart Circ Physiol • VOL 287 • DECEMBER 2004 •
dependent effect on survival with higher control mortality with
more severe infections. This effect was due to bacterial dose-
dependent decreases in MAP, CI, and LVEF. Epinephrine
therapy was associated with a significantly different effect on
outcome than norepinephrine and vasopressin. Compared with
concurrent controls, which received only antibiotics and intra-
venous fluids, the addition of an epinephrine infusion had a
harmful effect on survival. In contrast, the addition of vaso-
pressin or norepinephrine resulted in improved survival com-
pared with concurrent controls. Further examination of the
effect of each vasopressor on survival demonstrated that their
effects were independent of severity of infection. However, the
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Fig. 4. Left: effect of each vasopressor on survival
at the various bacterial challenge levels is shown
averaged over all drug dose levels. Right: effect of
each vasopressor on survival at the different drug
dose levels is shown averaged over all bacterial
challenge levels. The effects of each vasopressor
agent were not dependent on bacterial challenge
level; each agent demonstrated similar effects across
all bacterial doses studied. Epinephrine demon-
strated a significant drug dose-dependent harmful
effect on survival characterized by increasing harm
with increasing drug doses. Norepinephrine and va-
sopressin demonstrated similar beneficial effects
across all drug doses administered.

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Fig. 5. Effects of vasopressors on physiological parameters. Compared with changes in concurrently studied controls, the effects
(mean ⫾ SE) of all dose levels of each vasopressor on CI, left ventricular EF, and systemic vascular resistance index (SVRI) from
6 to 48 h are demonstrated. There was a significantly greater decrease in mean CI and EF and a significantly greater increase in
SVRI in the epinephrine-treated animals compared with the norepinephrine- and vasopressin-treated animals (P ⫽ 0.0155, P ⫽
0.0448, and P ⫽ 0.003, respectively). These changes caused by epinephrine treatment were dose dependent (2.0 ⱖ 0.8 ⱖ 0.2
␮g 䡠 kg⫺1 䡠 min⫺1) (P ⬍ 0.0001, P ⬍ 0.007, and P ⬍ 0.0001, respectively).

harmful effects of epinephrine on survival were demonstrated
to be drug dose dependent with increasing harm occurring at
increasing doses of epinephrine.
The contrasting survival effects of these vasopressors may
be explained by the significantly different effects of epineph-
rine, compared with vasopressin and norepinephrine, on car-
diac function, SVR, and renal and systemic perfusion. Despite
adequate intravenous fluid resuscitation, epinephrine treatment
caused dose-dependent decreases in CI and LVEF and dose-
dependent increases in SVR. Furthermore, epinephrine treat-
ment caused harmful dose-dependent changes in renal and
AJP-Heart Circ Physiol • VOL
systemic perfusion with significantly higher creatinine, BUN,
and phosphate levels and significantly lower pH, bicarbonate,
and base excess levels. There were no other measured vari-
ables, including MAP, PCWP, CVP, or HR, that demonstrated
different effects among epinephrine, norepinephrine, and va-
sopressin or that were related to the dose of epinephrine. The
increased mortality associated with epinephrine therapy may
be secondary to the metabolic, vascular, and myocardial effects
of ␣- and ␤-adrenergic stimulation. Epinephrine-mediated ad-
renergic stimulation can lead to a hypermetabolic state with
increased glycolysis, gluconeogenesis, and lipolysis with sub-
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Fig. 6. Effects of vasopressors on laboratory markers of renal function. Compared with changes in concurrently studied controls,
the effects (mean ⫾ SE) of all dose levels of each vasopressor on serum creatinine, blood urea nitrogen (BUN), and phosphate
levels from 6 to 48 h are demonstrated. There was a significantly greater increase in creatinine, BUN, and phosphate in the
epinephrine-treated animals compared with the norepinephrine- and vasopressin-treated animals (P ⫽ 0.022, P ⫽ 0.0004, and P ⫽
0.0001, respectively). These changes caused by epinephrine treatment were dose dependent (2.0 ⱖ 0.8 ⱖ 0.2 ␮g 䡠 kg⫺1 䡠 min⫺1)
(P ⫽ 0.0004, P ⫽ 0.0005, and P ⫽ 0.003 for creatinine, BUN, and phosphate. respectively).

sequent hyperglycemia, lactic acidosis, and ketoacidosis (22,
37, 50). In our study, these metabolic derangements may
account for the dose-dependent worsening of acid-base status
with epinephrine therapy. In addition, the demonstrated lactic
acidosis and renal dysfunction that occurred may be secondary
to dose-dependent, ␣-adrenergic-mediated vasoconstriction
with increases in SVR and decreases in hepatosplanchnic and
renal blood flow (7, 22, 23). Furthermore, the dose-dependent
cardiac dysfunction in our model may be due to ␣-adrenergic-
mediated increases in afterload, catecholamine-induced ␤-re-
ceptor downregulation, catecholamine-induced cardiomyopa-
thy related to prolonged exposure to high-dose epinephrine, or
a combination of these three adverse effects (4, 10, 11, 23, 36,
37, 45).
AJP-Heart Circ Physiol • VOL
Consistent with our results, increasing doses of epinephrine
have been reported to have harmful effects in sepsis. In a
previous canine endotoxic shock experiment, epinephrine and
norepinephrine increased MAP and CI and decreased gastric
mucosal pH, but only a high dose of epinephrine (1.6
␮g䡠kg 䡠 ⫺1 䡠min⫺1) significantly increased systemic lactic aci-
dosis (13). Similar findings of increased lactate levels with
epinephrine infusions have also been reported in patients with
septic shock (22). Furthermore, in a study comparing dopamine,
norepinephrine, and epinephrine titrated to maintain similar MAP
values in patients with severe septic shock, high-dose epinephrine
(mean 0.62, range 0.25–1.89 ␮g䡠kg⫺1 䡠min⫺1) increased CI but
decreased splanchnic perfusion and gastric mucosal pH compared
with norepinephrine (7). In another study comparing epinephrine
287 • DECEMBER 2004 • www.ajpheart.org
H2552 VASOPRESSORS IN SEPTIC SHOCK

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Fig. 7. Effects of vasopressors on laboratory markers of systemic perfusion. Compared with changes in controls, the effects
(mean ⫾ SE) of all dose levels of each vasopressor on pH, bicarbonate (HCO3), and base excess levels from 6 to 48 h are
demonstrated. There was a significantly greater decrease in pH, HCO3, and base excess in the epinephrine-treated animals
compared with the norepinephrine- and vasopressin-treated animals (P ⫽ 0.0003, P ⫽ 0.033, and 0.0002, respectively). These
changes caused by epinephrine treatment were dose dependent (2.0 ⱖ 0.8 ⱖ 0.2 ␮g 䡠 kg⫺1 䡠 min⫺1) (P ⫽ 0.07, P ⫽ 0.02, and P ⫽
0.02 for pH, HCO3, and base excess, respectively).

to norepinephrine plus dobutamine, epinephrine (mean 0.5, range
0.13–1.00 ␮g䡠kg⫺1 䡠min⫺1) produced decreases in splanchnic
blood flow and oxygen uptake with lower mucosal pH (29). In
contrast to high-dose epinephrine therapy, low-dose epineph-
rine (mean dose ⱕ0.3 ␮g 䡠kg⫺1 䡠min⫺1) has demonstrated ben-
eficial effects in the treatment of septic shock, including
improvements in MAP, CI, SVR, oxygen delivery, and gastric
mucosal blood flow without detrimental effects on oxygen
consumption or lactate levels (40, 50). The above studies
suggest that there are dose-dependent harmful effects of epi-
nephrine on organ perfusion in humans consistent with the
dose-dependent impairment of systemic perfusion and end-
organ injury seen in our canine study.
AJP-Heart Circ Physiol • VOL
The harmful effects of epinephrine in our model raise
concerns about its commonly accepted use in patients with low
CO septic shock. In these patients, epinephrine is used because
it is thought that its ␤-agonist properties should improve CO
and subsequently improve systemic perfusion. However, de-
spite adequate fluid resuscitation, epinephrine impaired cardiac
function in our model of low CO septic shock. In addition,
epinephrine decreased systemic perfusion, worsened acidosis,
and impaired organ function in our model. Therefore, in
contrast to the clinical rationale to use epinephrine for its
␤-agonist effects in low CO sepsis, it appears that epinephrine
may have harmful effects on the myocardium and its clinical
use should be carefully monitored.
287 • DECEMBER 2004 • www.ajpheart.org
 VASOPRESSORS IN SEPTIC SHOCK
The use of norepinephrine to treat septic shock is becoming
standard therapy. In addition to studies demonstrating in-
creases in MAP, CO, and improved renal and intestinal blood
flow (8, 26, 27, 46), norepinephrine administration has been
associated with improved outcome in septic shock patients. In
a single observational study, patients receiving norepinephrine
had significantly lower hospital mortality than patients receiv-
ing either high-dose dopamine or epinephrine (28). This im-
provement in survival is consistent with the effects of norepi-
nephrine therapy in our study. The beneficial effects of nor-
epinephrine are most likely the result of ␣-adrenergic-mediated
vasoconstriction with subsequent improvements in systemic
arterial blood pressure and organ perfusion. However, it re-
mains possible that norepinephrine therapy may have harmful
effects when administered at doses higher than those used in
our study. Similar to high-dose epinephrine therapy, higher
dose norepinephrine may lead to excessive ␣-adrenergic-me-
diated vasoconstriction with increases in SVR and decreases in
organ perfusion and may potentially cause organ failure and
acidosis.
The use of vasopressin in septic shock is becoming increas-
ingly popular secondary to the recent description of septic
shock as a state of relative vasopressin deficiency. Studies have
shown that vasopressin levels are elevated early in septic shock
and decrease as sepsis progresses, with approximately one-
third of late septic shock patients developing a vasopressin
deficiency (20, 41). Low-dose vasopressin (0.02– 0.08 U/min)
has recently been used in small trials to treat patients with
refractory septic shock. These studies have shown decreased
norepinephrine requirements, increased MAP and SVR, and
increased urine output without changes in gastric perfusion,
creatinine, lactate, and pH (9, 16, 25, 47). There have also been
reports of autonomic-mediated decreases in CI and HR with
vasopressin infusions (15, 16). Although the effects of vaso-
pressin therapy on CI in these studies were small, caution is
warranted because any decrease in CI may be detrimental
during sepsis, especially in those patients who have developed
low CO septic shock. In all of these studies, vasopressin was
administered in conjunction with another vasopressor, typi-
cally norepinephrine. Vasopressin administration may improve
hemodynamic parameters in septic patients with low circulat-
ing vasopressin levels by potentiating the effects of norepi-
nephrine and by blocking potassium-sensitive ATP channels
that may be excessively activated in septic shock (21, 32, 39,
49). Our data suggest that low-dose vasopressin has a minimal
pressor effect and does not decrease CI or HR. The absence of
these physiological changes in our study may be secondary to
sepsis-induced autonomic insufficiency or to the fact that we
did not investigate the effects of vasopressin in conjunction
with other vasopressor agents. However, despite not leading to
increases in systemic arterial pressure and SVR, vasopressin
therapy improved survival. This beneficial effect may be sec-
ondary to vasopressin causing an enhanced sensitivity to en-
dogenous catecholamines with subsequent improvement in
cardiac function. This would allow for the maintenance of
organ perfusion without the potentially detrimental effects of
excessive vasoconstriction from ␣-adrenergic stimulation with
high-dose catecholamine therapy.
The limitations of our study include the general issues
surrounding the extrapolation of results from an animal model
to the clinical setting. In addition, the effects of epinephrine,
AJP-Heart Circ Physiol • VOL
H2553
norepineprhine, and vasopressin may be different in hyperdy-
namic models of septic shock and may be different when
administered in doses outside of the studied ranges. Further-
more, our study did not have the power to demonstrate a
significant improvement in survival with either vasopressin or
norepinephrine therapy alone. Our study only showed that the
effects of these two agents are better than the effects of
epinephrine therapy. Future studies are needed to compare the
effects of vasopressin and norepinephrine alone to a combina-
tion of norepinephrine and vasopressin on survival.
In conclusion, the use of vasopressors is often necessary to
successfully treat septic shock; however, limited data are
available on the effects of the different vasopressor agents on
outcome. Each agent has a different risk-benefit profile, which
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needs to be fully characterized. Independent of the severity of
infection, epinephrine demonstrated a dose-dependent harmful
effect on cardiac function, organ perfusion, and survival in our
canine model of low CO septic shock. High doses of epineph-
rine decreased EF and CI, and increased SVR leading to
impaired organ perfusion with increased BUN and creatinine,
decreased pH and bicarbonate, and increased mortality. These
harmful effects would not have been detected without moni-
toring of cardiac function because other variables, including
HR and MAP, did not reflect these toxic effects. Within the
dose range used in our study, norepinephrine and vasopressin
did not demonstrate these effects. It is possible that with further
increases in dose, norepinephrine and vasopressin may produce
harmful physiological effects that may increase mortality.
From our study, epinephrine has a risk-benefit profile charac-
terized by harmful dose-dependent effects, whereas norepi-
nephrine and vasopressin demonstrate more favorable risk-
benefit profiles over the dose ranges administered in our study.
Norepinephrine and vasopressin should be investigated further,
both independently and in combination with each other, to
further characterize their effects over a wide range of doses in
high- and low-output models of septic shock.
ACKNOWLEDGMENTS
The authors thank Melinda Fernandez, Al Hilton, and Steve Richmond for
assistance in the performance of these experiments.
GRANTS
This project was funded by intramural sources at the Warren Grant
Magnuson Clinical Center of the National Institutes of Health.
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