l

1. R E S E A R C H P A P E R
Use of ephedrine and dopamine in dogs for the
management of hypotension in routine clinical cases
under isoflurane anesthesia
Hui C Chen* DVM, MVM, DVSc, Melissa D Sinclair DVM, DVSc, Diplomate ACVA & Doris H Dyson DVM, DVSc, Diplomate ACVA
Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
Correspondence: Doris Dyson, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1,
Canada. E-mail: ddyson@uoguelph.ca
Abstract
Objective To determine the cardiovascular re-
sponses of ephedrine and dopamine for the man-
agement of presurgical hypotension in anesthetized
dogs.
Study design Prospective, randomized, clinical trial.
Animals Twelve healthy client-owned dogs admit-
ted for orthopedic surgery; six per group
Methods Prior to surgery, 58 anesthetized dogs
were monitored for hypotension [mean arterial
pressure (MAP) <60 mmHg] that was not asso-
ciated with bradycardia or excessive anesthetic
depth. Ephedrine (0.2 mg kg)1
, IV) or dopamine
(5 lg kg)1
minute)1
, IV) was randomly assigned
for treatment in 12 hypotensive dogs. Ten min-
utes after the first treatment (Tx1-10), ephedrine
was repeated or the dopamine infusion rate was
doubled. Cardiovascular assessments taken at
baseline, Tx1-10, and 10 minutes following treat-
ment adjustment (Tx2-10) were compared for
differences within and between treatments
(p < 0.05).
Results Ephedrine increased cardiac index (CI),
stroke volume index (SVI), oxygen delivery index
(DO2I), and decreased total peripheral resistance
(TPR) by Tx1-10, while MAP increased transiently
(<5 minutes). The second ephedrine bolus produced
no further improvement. Dopamine failed to pro-
duce significant changes at 5 lg kg)1
minute)1
,
while 10 lg kg)1
minute)1
increased MAP, CI, SVI
significantly from baseline, and DO2I compared with
Tx1-10. The improvement in CI, SVI, and DO2I was
not significantly different between treatments at
Tx2-10.
Conclusions and clinical relevance In anesthetized
hypotensive dogs, ephedrine and dopamine
improved cardiac output and oxygen delivery.
However, the pressure-elevating effect of ephedrine
is transient, while an infusion of dopamine at
10 lg kg)1
minute)1
improved MAP significantly
by additionally maintaining TPR.
Keywords blood pressure, cardiovascular effects, ino-
tropes, lithium dilution cardiac output, sympatho-
mimetic.
Introduction
Hypotension during general anesthesia has arbi-
trarily been defined as a mean arterial pressure
(MAP) <60 mmHg, corresponding to a systolic
arterial pressure (SAP) <80–90 mmHg (Haskins
1996). Below these pressures, vital organs such as
the brain and the kidney may lose their ability to
autoregulate their own blood supply (Guyton & Hall
2000). In addition, it is speculated that organ blood
*Present address: Hui C Chen, Department of Veterinary
Clinical Studies, Faculty of Veterinary Medicine, Universiti
Putra Malaysia, 43400 UPM Serdang, Selangor DE,
Malaysia.
301
Veterinary Anaesthesia and Analgesia, 2007, 34, 301–311 doi:10.1111/j.1467-2995.2006.00327.x

2. flow declines in proportion to the decrease in blood
pressure (BP) and the extent of organ damage as-
sociated with poor oxygen delivery is assumed to be
proportional to the duration of hypotension. Hypo-
tension has been reported in some studies as one of
the most common complications observed in small
animal anesthesia (Hosgood 1998; Gaynor et al.
1999). At the Ontario Veterinary College, the small
animal anesthesia database (1998–2001) revealed
that 36% of all ASA II, dogs, during maintenance of
anesthesia were hypotensive (as defined above).
Although the consequences of low BP are difficult to
quantify in morbidity studies, early recognition and
treatment of hypotension is a logical expectation of
safe anesthetic management when actual meas-
urements of perfusion are unavailable, and may be
important in preventing adverse effects if associated
with decreased oxygen delivery.
The causes of hypotension during anesthesia are
multifactorial, with major contributing factors rela-
ted to the cardiovascular depression of the anes-
thetic agents themselves and the clinical conditions
of the patient. Management of hypotension during
anesthesia includes assessment and correction of
errors in anesthetic depth, arrhythmias (brady-
cardia, supraventricular, or ventricular premature
contractions) and obvious or potential volume
deficits. If hypotension persists despite these steps,
then administration of inotropic drugs may be
necessary to maintain BP. Ephedrine and dopamine
are two inotropic agents commonly used to manage
hypotension in small animals.
Ephedrine is commonly used to treat hypotension
associated with inhalation and spinal anesthesia in
humans (Bernards 1996; Stoelting 1999), and has
been recommended for use in small animals and
horses (Wagner & Brodbelt 1997; Wagner 2000;
Mazzaferro & Wagner 2001). It is a noncatecho-
lamine sympathomimetic that can stimulate a- and
b-adrenergic receptors directly, as well as indirectly,
by causing endogenous release of norepinephrine
(Stoelting 1999; Hoffman 2001). Ephedrine has the
advantages of being inexpensive and convenient to
use, as an intravenous (IV) bolus. Previous experi-
mental work in Beagles demonstrated an improve-
ment in MAP, cardiac output (CO), and stroke
volume (SV) without producing arrhythmias (Wag-
ner et al. 1993). However, these dogs were not
hypotensive and the effectiveness of ephedrine in
the management of clinically hypotensive patients
that have received premedicants and injectable
induction agents is not known.
Dopamine is an endogenous catecholamine that
exerts its effects through stimulation of the dop-
aminergic, a-adrenergic and b-adrenergic receptors.
Rapid metabolism of dopamine and its brief duration
of action mandate its use as a continuous IV
infusion (constant rate infusion, CRI) (Stoelting
1999; Moss & Renz 2000), which may make it less
convenient to use in the clinical setting. The
receptor and hemodynamic effects of exogenous
administration of dopamine are dose-dependent
within the typical infusion rates recommended
(2–10 lg kg)1
minute)1
) (Hosgood 1990; Wagner
& Brodbelt 1997; Stoelting 1999; Moss & Renz
2000; Muir et al. 2000). Higher infusion rates or an
accidental IV bolus injection may result in tachy-
cardia, vasoconstriction, and hypertension, with the
potential for arrhythmias.
An increase in BP achieved when either dop-
amine or ephedrine is administered clinically is
presumed to indicate an increase in CO, although
changes in vascular tone could also affect BP. This
study was undertaken to determine the cardio-
vascular responses of ephedrine at 0.2 mg kg)1
, IV
(repeated if inadequate response) and dopamine CRI
at 5 lg kg)1
minute)1
, IV (rate doubled if inad-
equate response) to manage hypotension in other-
wise healthy client-owned dogs during routine
anesthetic management prior to orthopedic surgery.
Materials and methods
Animals and selection criteria
This study was approved by the University of Gue-
lph’s Animal Care Committee. Clinical cases pre-
sented to the Veterinary Teaching Hospital of the
Ontario Veterinary College were used with client
consent. Initial selection criteria for dogs consisted
of ASA II cases, 6 months to 8 years of age and
weighing 20–35 kg, and anesthetized for orthopedic
procedures. They were judged to be healthy based
on history, physical examination and standard,
minimal, preoperative blood work (hematocrit, total
protein, and blood urea nitrogen).
Anesthesia and instrumentation
The anesthetic protocols were tailored to the
individual case: premedication with acepromazine
and hydromorphone, with or without glycopyrro-
late, given by intramuscular injection; induction
with thiopental or ketamine-diazepam (1:1)
Ephedrine & dopamine in anesthetized hypotensive dogs HC Chen et al.
302 2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311

3. administered IV via a 20 SWG catheter (BD Ins-
yte-W; Becton Dickinson, Sandy, UT, USA) placed
in a cephalic vein; and anesthetic maintenance
with isoflurane (Iso) in 100% oxygen. Following
induction the Iso concentration was adjusted
according to the requirement of the individual dog
as judged by the anesthetist, who was not
involved in the study. An epidural injection of
morphine and bupivacaine was routinely admin-
istered in cases undergoing hindlimb procedures.
Bupivacaine was used for blockade of the brachial
plexus in dogs undergoing forelimb procedures.
All dogs were allowed to breathe spontaneously
and received a balanced electrolyte solution
(Plasma-Lyte A; Baxter Corp., Toronto, ON, Can-
ada), administered IV at 10 mL kg)1
hour)1
.
A multi-channel patient monitor (Criticare Model
1100; Criticare Systems Inc., Waukesha, WI, USA)
was used to assess all physiologic parameters and
airway gas concentrations. A 20 SWG catheter (BD
Insyte-W, Becton Dickinson) was placed percutane-
ously in a dorsal pedal artery and connected to a
disposable transducer system (Model DT-36; Oh-
meda Medical Devices Division Inc., Madison, WI,
USA) to monitor the BP directly and to allow for
lithium dilution measurement of CO. The pressure
transducer and the pressure channel were calibra-
ted with a mercury manometer prior to each use
and zero was set at the level of the heart. A lead II
ECG was placed to monitor heart rate (HR) and
rhythm, and an esophageal temperature probe was
inserted to measure body temperature (Temp). An
8-French sampling line was inserted within the
endotracheal tube to the level of the carina to
perform gas sampling near its tracheal end for end-
tidal CO2 (PE¢CO2) and end-tidal Iso (ETIso). The
spectrometry component of the patient monitor was
calibrated with a commercial calibration gas
(Anesthesia Calibration Gas; Criticare Systems
Inc.) prior to each use.
Inclusion criteria and design of treatment inter-
vention
Inclusion criteria for the inotropic treatment inter-
vention were hypotension, defined as MAP
60 mmHg, not associated with bradycardia (HR
65 beats minute)1
) or excessive anesthetic depth
(as judged by the anesthetist according to typical
reflexes and appropriate Iso concentration). Only
dogs that developed hypotension prior to onset of
surgery were studied further. Once the animal was
deemed hypotensive, the Iso concentration was not
altered and baseline (T-0) measurements were ta-
ken. Random assignment of the ephedrine and
dopamine treatments was computer-generated
based on a target of six cases per treatment group.
Ephedrine (Ephedrine sulfate injection 50 mg mL)1
USP; SABEX INC., Boucherville, QC, Canada) was
diluted to 5 mg mL)1
with normal saline immedi-
ately prior to use. Dopamine (Intropin; Bristol-Myers
Squibb Canada, Montreal, Canada) was pre-diluted
in 5% dextrose to 0.4 mg mL)1
and kept in the
refrigerator at 4C for up to 30 days. It was
administered with fully primed lines using a syringe
or a fluid pump.
The target MAP was selected as 70 mmHg. The
ephedrine treatment consisted of an IV bolus of
0.2 mg kg)1
. If the MAP remained below the target
at 10 minutes after the initial dose (Tx1-10), the
ephedrine dose (0.2 mg kg)1
, IV) was repeated. The
dopamine treatment consisted of an IV infusion of
5 lg kg)1
minute)1
for 10 minutes, administered
by syringe or fluid pump through the injection port
on the IV fluid line closest to the patient (approxi-
mately 1.5 mL dead space existed before reaching
patient). This infusion rate was maintained if the
target MAP was achieved, but was doubled to
10 lg kg)1
minute)1
if MAP remained lower than
70 mmHg at Tx1-10. Dogs were monitored for an
additional 10 minutes following the second dose or
CRI adjustment, and final measurements were
repeated (Tx2-10). Transfer of the animal into the
operating room, or surgery did not commence until
all measurements were completed. Other supportive
treatments were administered, if necessary, follow-
ing complete data collection.
Data collection
Measurements consisted of HR, SAP, MAP, diastolic
arterial pressure (DAP), CO, PE¢CO2, ETIso, Temp,
arterial blood gases, sodium (Na), and hemoglobin
(Hb) concentration. Blood gases were temperature-
corrected and analyzed immediately after sampling
(ABL 700 series, Radiometer, Copenhagen,
Denmark). All parameters were measured at T-0,
Tx1-10, and Tx2-10, although BP and HR were
measured every 2.5 minutes following treatment
interventions.
A single determination of CO was carried out
following all other data collection (at T-0, Tx1-10,
and Tx2-10) and a lithium dilution technique
(LidCO plus Hemodynamic Monitor; LiDCO Ltd,
Ephedrine dopamine in anesthetized hypotensive dogs HC Chen et al.
2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311 303

4. London, UK) as described by Mason et al. (2002)
was used. Arterial blood was sampled 3 minutes
prior to the CO determination to obtain the Na and
Hb values as required by the LiDCO system. The
peripheral vein for IV fluid administration was also
used for the bolus injection of the lithium indicator
(1 mL, 0.15 mmol) through a three-way stopcock
(IV Set Stopcock, 3-Way, 10-1000; Benlan Inc.,
Oakville, Ontario, Canada) attached directly to
the catheter. Dopamine infusion was stopped (for
1–1.5 minutes) during CO determination to ensure
that the catheter dead space was free of dopamine
during the bolus lithium injection.
Cardiac index (CI), stroke volume index (SVI),
arterial oxygen content (CaO2) and oxygen delivery
index (DO2I) were calculated using standard formu-
lae (Boyd et al. 1991). Total peripheral resistance
(TPR) was calculated as 79.9 · MAP CO)1
.
Statistical analysis
A mixed model (Proc Mixed, SAS Version 8; SAS
Institute Inc., Cary, NC, USA) for the split-plot
design was used to analyze the cardiovascular
parameters for significant treatment, time, and
interactions between treatment and time effect.
Time was considered the repeated measure and
the dog, a random effect. An autoregressive
covariance structure of order 1 was included in
the analyses to account for correlations between
measurements at different time points. When
there was a significant time effect within treat-
ment, a Dunnett’s test was applied to compare for
differences from T-0. Difference of least squares
means was used to compare values at Tx1-10 and
Tx2-10 within treatment. Contrast between the
two treatments was applied to examine how the
cardiovascular responses changed over time and
whether they changed in the same way. For all
tests, residuals plots were examined for equality of
variances. Normality was tested using Shapiro–
Wilk test. Data were log-transformed when
necessary. p 0.05 was considered significant.
Results
Data are presented as mean ± SD unless otherwise
noted. A total of 58 dogs were recruited in the
study and of these, 12 developed hypotension
(MAP ¼ 56 ± 4 mmHg), while none of the animals
were excluded because of HR or rhythm abnor-
malities. The ephedrine group consisted of five fe-
males and one male, 2.7 ± 1.6 years of age and
30.1 ± 4.4 kg. Five were scheduled for repair of
ruptured anterior cruciate ligaments and one was
presented for radial osteotomy. The dopamine
group consisted of two females and four males,
2.6 ± 2.5 years and 30.7 ± 6.4 kg. One of the
following procedures was scheduled for each dog:
elbow arthrotomy, triple pelvic osteotomy, radial-
ulnar osteotomy, tibial plateau leveling osteotomy,
forelimb amputation, and bilateral shoulder joint
arthroscopy.
Anesthetic drugs and doses used are summarized
in Table 1. Time from induction to the diagnosis of
hypotension ranged from 25 to 85 (48 ± 22)
Table 1 Dose range and number of
cases that received the drug in each
treatment group prior to develop-
ment of hypotension
Drugs
Dose range
(mg kg)1
) Ephedrine Dopamine
Premedication
Glycopyrrolate* 0.005–0.01 5 5
Acepromazine 0.010–0.05 6 6
Hydromorphone 0.050–0.10 6 6
Induction
Ketamine† 3.75–5.0 2 2
Thiopental 3.3–12.5 4 4
Diazepam 0.2–0.25 2 4
Supplemental analgesia
Morphine (epidural) 0.1–0.26 (mg kg)1
) 5 3
Bupivacaine 0.5% (epidural) 0.75–1.15 (mg kg)1
) 5 2
Bupivacaine 0.5% (brachial
plexus neural blockade)
1–1.5 (mg kg)1
) 1 1
*One dog in the dopamine group received glycopyrrolate during the study period;
†ketamine was mixed with diazepam (1:1 by volume; 100 mg:5 mg, respectively)
Ephedrine dopamine in anesthetized hypotensive dogs HC Chen et al.
304 2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311

5. minutes in the ephedrine group, and 17–50
(31 ± 12) minutes in the dopamine group. The
ETIso concentration was not significantly different
(0.92 ± 0.20% and 0.87 ± 0.16%, for the dopam-
ine and ephedrine groups, respectively). Dogs in the
ephedrine group tended to have a lower Temp
(36.1 ± 1.2 C) than those in the dopamine group
(37.3 ± 0.9 C) at T-0, and Temp continued to drop
over time in all the dogs. All other variables at
baseline were not different between groups.
None of the dogs achieved the target MAP
following either treatment at Tx1-10. Blood pres-
sures (SAP, MAP, and DAP) increased immediately
following the first ephedrine bolus (Table 2;
Fig. 1a), with significant differences from baseline
at 2.5 minutes. The BP decreased rapidly, returning
to near or below baseline within 5 minutes. The
second bolus of ephedrine did not significantly
change BP. Dopamine at 5 lg kg)1
minute)1
did
not improve BP significantly by Tx1-10. By doubling
the dopamine infusion rate to 10 lg kg)1
minute)1
,
significant improvement was detected at Tx2-5, Tx2-
7.5, and Tx2-10. By the end of the study period,
the target MAP was attained in four dogs in the
dopamine group compared with one dog in the
ephedrine group, and the improvement in MAP
from baseline and Tx1-10 was significantly greater
with the dopamine treatment than with ephedrine
(p ¼ 0.0007 and 0.0076, respectively). An MAP of
less than 50 mmHg following administration of the
initial dose of the inotrope was noted in three dogs
in the ephedrine group and in one dog in the
dopamine group. Five animals in the ephedrine
group had an MAP at Tx1-10 that was lower than
baseline, and the MAP at the end of the study period
remained lower than baseline in four of them. One
dog in the dopamine group had an MAP at Tx1-10
that was lower than baseline, but by the end of the
study period, MAP was higher than baseline in all
six cases.
There was no overall treatment or time effect on
HR, but an interaction between treatment and time
was significant (p ¼ 0.0016). This significance was
related to the readings at Tx1-2.5 when HR
Table 2 Cardiovascular responses (mean ± SD) following detection of hypotension (T-0) and following each intervention:
Tx1 – ephedrine bolus (E) (0.2 mg kg)1
, IV) or dopamine infusion (D) (5 lg kg)1
minute)1
, IV); Tx2 – repeated ephedrine
bolus (0.2 mg kg)1
, IV), or dopamine at 10 lg kg)1
minute)1
, IV
Variables
Baseline
First treatment intervention (Tx1) Second treatment intervention (Tx2)
T-0 Tx1-2.5 Tx1-5 Tx1-7.5 Tx1-10 Tx2-2.5 Tx2-5 Tx2-7.5 Tx2-10
HR (beats minute)1
)
E 93 ± 14 105 ± 18* 101 ± 19 103 ± 24 102 ± 21 109 ± 22* 102 ± 23 106 ± 19 106 ± 19
D 96 ± 24 86 ± 19 92 ± 21 88 ± 19 86 ± 20 87 ± 20 90 ± 16 98 ± 23 96 ± 21
SAP (mmHg)
E 100 ± 22 125 ± 24* 107 ± 24 104 ± 38 98 ± 31 108 ± 38 106 ± 39 108 ± 29 108 ± 31bc
D 94 ± 14 86 ± 15 91 ± 15 103 ± 18 102 ± 23 106 ± 17 133 ± 37* 140 ± 40* 147 ± 39*#
DAP (mmHg)
E 43 ± 6 56 ± 15* 48 ± 9 43 ± 5 42 ± 6 44 ± 8 45 ± 12 43 ± 10 43 ± 19bc
D 44 ± 3 42 ± 7 44 ± 5 48 ± 3 48 ± 4 46 ± 4 56 ± 10* 61 ± 15* 59 ± 10*#
SVI (mL beat)1
kg)1
)
E 1.15 ± 0.22 – – – 1.4 ± 0.53* – – – 1.38 ± 0.43*
D 1.33 ± 0.32 – – – 1.49 ± 0.26 – – – 1.71 ± 0.44*
Hb (g dL)1
)
E 12.4 ± 1.0 – – – 12.0 ± 0.7* – – – 12.3 ± 1.0
D 12.7 ± 1.2 – – – 11.9 ± 1.1* – – – 11.8 ± 1.4*
CaO2 (mL L)1
)
E 190 ± 13 – – – 181 ± 16* – – – 188 ± 13
D 193 ± 15 – – – 182 ± 15* – – – 181 ± 20*
HR, heart rate; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; SVI, stroke volume index; Hb, hemoglobin
concentration; CaO2, arterial oxygen content. Tx1-y (time in minutes following first treatment); Tx2-y (time in minutes following second
treatment). Significant differences (p 0.05) are denoted as follows: within the same treatment, *value differs from baseline (T-0),
#
value at Tx2-10 differs from Tx1-10; between treatments, a
first response (T-0 to Tx1-10) differs, b
second response (Tx1-10 to Tx2-10)
differs, and c
sum of responses (T-0 to Tx2-10) differs.
Ephedrine dopamine in anesthetized hypotensive dogs HC Chen et al.
2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311 305

6. increased after the ephedrine bolus (p ¼ 0.0434),
but tended to decrease in the dopamine group
(p ¼ 0.1558). The increase in HR was significant at
Tx2-2.5 following the repeated dose of ephedrine
(p ¼ 0.0326). Sinus arrhythmia was observed fol-
lowing administration of ephedrine (n ¼ 1) and
escape beats (ventricular beat following a short
sinus arrest) with dopamine when it was increased
to 10 lg kg)1
minute)1
(n ¼ 1). Glycopyrrolate
(0.005 mg kg)1
, IV) was administered to the latter
case, resulting in a dramatic increase in HR and BP.
If the data points following treatment with glyco-
pyrrolate in this dog were excluded from the
statistical analysis, the increase in HR from T-0 to
Tx2-10 in the ephedrine group was higher than that
in the dopamine group (p ¼ 0.0436), but all other
results were not affected. Following this incident,
glycopyrrolate was included in the premedication of
subsequent cases (10/12 dogs).
The first dose of ephedrine significantly improved
CI (p ¼ 0.0040), SVI (p ¼ 0.0472), and DO2I
(p ¼ 0.0131), while the repeat dose of ephedrine
did not change these parameters further and values
at Tx2-10 remained higher than baseline (Table 2;
Figs 1b c). Dopamine at 5 lg kg)1
minute)1
did
not change the CI, SVI, or DO2I, but improvement
was seen when the infusion rate was increased to
10 lg kg)1
minute)1
, although the increase in DO2I
did not reach statistical significance (p ¼ 0.0078,
0.0006, and 0.0526, respectively). In addition, Tx2-
10 values were greater than Tx1-10 (p ¼ 0.0020,
0.0798, and 0.0045, respectively). The improve-
ment in CI and DO2I from baseline to Tx1-10 was
greater following the first ephedrine bolus compared
Figure 1 Effects (mean ± SD) of ephedrine (————) and dopamine (_ _ _ _ _) treatments on mean arterial pressure
(MAP), cardiac index (CI), oxygen delivery index (DO2I) and total peripheral resistance (TPR) following detection of
hypotension (T-0) and following each intervention: Tx1 – ephedrine bolus (0.2 mg kg)1
, IV) or dopamine infusion
(5 lg kg)1
minute)1
, IV); Tx2 – repeated ephedrine bolus (0.2 mg kg)1
, IV) or dopamine at 10 lg kg)1
minute)1
, IV
(arrows indicate commencement of treatments). Significant differences (p 0.05) are denoted as follows: within the same
treatment, *value differs from baseline (T-0), #
value at Tx1-10 differs from Tx2-10; between treatments, a
first response (T-0
to Tx1-10) differs, b
second response (Tx1-10 to Tx2-10) differs, c
sum of responses (T-0 to Tx2-10) differs.
Ephedrine dopamine in anesthetized hypotensive dogs HC Chen et al.
306 2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311

7. with dopamine at 5 lg kg)1
minute)1
(p ¼ 0.0495
and 0.0353, respectively). By the end of the study
period, there was no significant difference in the
increases in CI, SVI, or DO2I between treatments.
Following the first dose of ephedrine, TPR at Tx1-
10 was significantly lower than baseline (p ¼
0.0004) (Fig. 1d). The repeated dose of ephedrine
did not change TPR further, and TPR at Tx2-10
remained lower than baseline (p ¼ 0.0033). Dop-
amine at both infusion rates did not change the TPR
significantly at Tx1-10 and Tx2-10 when compared
with baseline.
In general, the Hb concentration decreased over
time in both groups. The repeated dose of ephedrine
tended to increase the Hb concentration toward the
baseline value, but these changes were not statisti-
cally significant. Arterial oxygen content followed a
trend similar to Hb concentration. There were no
significant treatment, time, or interaction effects in
arterial Na (148 ± 2 and 147 ± 2 mmol L)1
), pH
(7.253 ± 0.082; 7.268 ± 0.054), carbon dioxide
tension (54.4 ± 10.0 and 53.2 ± 6.1 mmHg),
oxygen tension (548.6 ± 31.6 and 532.7 ±
36.5 mmHg), bicarbonate (23.2 ± 2.2 and 23.5 ±
1.3 mmol L)1
), or base excess values ()4.3 ± 3.0
and )3.5 ± 2.2 mmol L)1
) for ephedrine and dop-
amine groups, respectively (pooled data for the three
time points).
All dogs had an uneventful recovery from
anesthesia.
Discussion
Our study showed presurgical hypotension in 21%
of these ASA II dogs. This number is lower than the
36% recorded from our whole database but the
latter represents the whole period of anesthesia
compared with just the pre-surgical period in this
study. No evidence of volume deficits was noted in
the preoperative evaluations, although subclinical
dehydration could have existed. Additional fluid
administration may have been effective in some of
these animals. The prolonged preoperative time in
our dogs was likely a contributor to the development
of this hypotension. The lack of stimulation during
radiography, clipping, and surgical preparation is
likely to result in lower BP than that associated with
surgery. Although benefits were shown with the use
of inotropes in this study, their use in clinical cases
should be reserved for those animals known to have
poor contractility or following more directed treat-
ment of the suspected problem. However, this study
confirmed that in hypotensive dogs exposed to var-
ious anesthetic agents both ephedrine and dopa-
mine improved perfusion as demonstrated by a
significant increase in CI, SVI, and DO2I. However,
ephedrine at 0.2 mg kg)1
IV increased BP transi-
ently and was not improved with a repeated dose.
The initial effect lasted less than 5 minutes and
appeared to be countered by a significant decrease in
TPR. Dopamine at 10 lg kg)1
minute)1
signifi-
cantly improved BP with a similar rise in CI, SVI,
and DO2I.
Most of the cardiovascular responses following
ephedrine administration in our study were similar
to those reported by Wagner et al. (1993). How-
ever, the increase in BP in their dogs was longer and
more intense at the higher dose. Ephedrine at
0.1 mg kg)1
IV increased MAP significantly for
5 minutes while at 0.25 mg kg)1
IV, the effect
lasted for 15 minutes. The shorter duration and
intensity in our dogs could be attributable to the
addition of other drugs as part of the anesthetic
management and the presence of baseline hypoten-
sion prior to treatment, although the overall BP
achieved was not remarkably different.
Our premedication may have been the most likely
cause for the difference in response to ephedrine.
Acepromazine is a potent a1 antagonist producing
peripheral vasodilation and resulting in a dose-
dependent decrease in BP (Coulter et al. 1980; Muir
Hubbell 1985). Previous work has demonstrated
that with prior administration of acepromazine in
dogs anesthetized with halothane, the amount of
phenylephrine required to increase MAP by 50%
increased in a dose-dependent manner (Ludders
et al. 1983). A higher dose of ephedrine may have
resulted in a better BP response. This a1 antagonist
effect may also explain the lack of increase in Hb
concentrations in response to ephedrine as noted
with both ephedrine (Wagner et al. 1993) and
higher doses of dopamine (Abdul-Rasool et al.
1987). The other drugs used for premedication and
induction (hydromorphone, thiopental, ketamine,
and diazepam) do not have direct effects on a- or
b-adrenergic receptors. Although Iso causes a dose-
dependent decrease in BP associated with a decrease
in systemic vascular resistance (SVR) and CI (Steffey
Howland 1977; Pagel et al. 1991), it is expected
that this decrease in BP will respond to a- and/or
b-adrenergic stimulation.
Spinal anesthesia and, to a lesser degree, epidural
anesthesia in humans has been shown to produce
hypotension as a result of venous and arterial
Ephedrine dopamine in anesthetized hypotensive dogs HC Chen et al.
2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311 307

8. dilation induced by the sympathetic blockade (Ber-
nards 1996). However, Torske et al. (1999) studied
the effects of epidural administration of oxymor-
phone and bupivacaine (at similar doses to the ones
used in the current study) in halothane anesthetized
dogs and reported no significant change in SVR
when the concentration was appropriately reduced
according to the MAC-sparing effect. Other studies
demonstrated reductions in BP following epidural
bupivacaine (0.36 mL kg)1
) in conscious dogs
(Franquelo et al. 1995), and epidural lidocaine
(0.1 mL kg)1
) in dogs anesthetized with 1.5%
sevoflurane (Hirabayashi et al. 1996). It is unlikely
that more sympathetic blockade was present in both
these studies as these doses are above and below
(respectively) our dose and that used by Torske
et al. (1999). Epidural bupivacaine could have
influenced the vascular response produced by eph-
edrine in our study, although the same effect was
shown in the dog that received the brachial plexus
neural blockade. Additional clinical research is
required to substantiate any confounding effect.
The variability of time from drug administration
to actual ephedrine treatment in each dog may have
contributed to some difference in the effect of
ephedrine. However, BP improvement was not
maintained even when the time for hypotension
development was delayed. This study provided no
evidence that the effect of BP from ephedrine would
last beyond 5 minutes in hypotensive dogs or be
maintained with a repeated bolus.
In our study, HR increased immediately following
both the first and second bolus doses of ephedrine,
while HR decreased significantly for up to 15 min-
utes in the study by Wagner et al. (1993). This
difference is likely due to a baroreceptor response to
the acute and prolonged increase in BP in their
dogs. The two dogs in our study, that demonstrated
the best BP response following ephedrine, also
showed a decrease in HR. The HR gradually
increased as BP decreased. Although it is possible
that glycopyrrolate may have predisposed the dogs
to an increased HR following ephedrine, this
increase in HR also fits with the underlying mech-
anism of action of ephedrine to stimulate the cardiac
b1-receptors (Lawson Meyer 1996; Stoelting
1999; Hoffman 2001).
The increase in CI and reduction in TPR with
ephedrine treatment in dogs is consistent with other
studies (Grandy et al. 1989; Wagner et al. 1993;
Lee et al. 2002). Although the increase in CO has
also been shown to be due to increased venous
return caused by selective venoconstriction (Butter-
worth et al. 1986; Lawson Meyer 1996), the
effect on cardiac b1-receptors is the primary mech-
anism (Lawson Meyer 1996; Stoelting 1999;
Hoffman 2001). We did not measure central venous
pressure in these dogs and thus have no estimation
of alterations in venous return. Moreover, the
inability to use this value in the TPR calculation
may have contributed to some error in this meas-
urement, but it is unlikely to have made a signifi-
cant impact on these results due to the narrow
range for central venous pressures.
The reduced response observed with the repeated
bolus of ephedrine may be an indication of tac-
hyphylaxis. This is explained by persistent occupa-
tion of both the adrenergic receptors by the first dose
of ephedrine or depletion of norepinephrine stores
(Stoelting 1999). It is also possible that a better
response may have been obtained if a higher dose of
ephedrine was used in the repeated bolus (Butter-
worth et al. 1986). Alternatively, an infusion of
ephedrine could be considered as has been used in
humans (Gajraj et al. 1993; Critchley et al. 1995;
Chan et al. 1997). Research to substantiate the
appropriate dose and overall cardiovascular effect
with a CRI of ephedrine in dogs requires further
investigation.
Our work indicates that ephedrine would be
useful when a very short-lived increase in BP is
sufficient, such as in the face of significant hypo-
tension immediately before surgery or when a delay
exists in starting other treatments (e.g., if prepar-
ation is required). Ephedrine should be able to
increase CO when used in hypotensive dogs at these
doses, although evidence for the degree of change in
CO is unlikely to be easily measured.
The cardiovascular responses to the dopamine
infusion in hypotensive dogs were in agreement
with the general descriptions of dose-dependent
receptor and hemodynamic effects reported by
others (Robie Goldberg 1975; Abdul-Rasool et al.
1987; Raner et al. 1995; Moss Renz 2000). The
lack of response to the 5 lg kg)1
minute)1
may be
due to the pharmacokinetics of dopamine. Although
no data have been reported in dogs, the elimination
half-life reported in humans is 12.3 minutes (Mac-
Gregor et al. 2000) which would mean that the
plasma concentration of dopamine achieved after
5 minutes would be less than 50% of the value
expected under steady-state conditions. A signifi-
cant increase in BP was noted at 5 minutes
following the start of 10 lg kg)1
minute)1
of
Ephedrine dopamine in anesthetized hypotensive dogs HC Chen et al.
308 2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311

9. dopamine. The improvement in BP appeared to
plateau at 7.5 minutes with no further change after
this time at either infusion rate. This provided
evidence that the patient should be reassessed, the
infusion rate changed, or the IV line checked for
obstructions if the desired BP is not achieved within
7.5 minutes of dopamine therapy. However, it is not
possible to define the impact from the administra-
tion of 5 lg kg)1
minute)1
for the first 10 minutes
on the response time or on the effect produced by
10 lg kg)1
minute)1
of dopamine. The reason for
using this design was to mimic the clinical situation.
In humans (MacGregor et al. 2000) and cats
(Pascoe et al. 2006) it has also been observed that
the plasma concentration of dopamine achieved
with a given infusion rate is highly variable
providing another impetus to increase the infusion
rate if the desired goal is not achieved within a
reasonable time period.
Although the improvement in CI and SVI
associated with dopamine administration at
10 lg kg)1
minute)1
was not different from that
produced by ephedrine, the lack of change in TPR
resulted in a better BP response. Although it
might be suggested that a reduction in TPR is
preferential for perfusion and reduces cardiac
workload, this must be considered in light of the
fact that both Iso and acepromazine cause some
vasodilation and thus, there may be little advant-
age to a further reduction in TPR. Unfortunately,
without the measurement of CO there may be
little evidence during anesthesia of a drug effect
on this parameter unless a change in BP is
produced. The improvement in BP with dopamine
administration is evidence of its effect and a
reflection of the increase in CO. Maintenance of
adequate systemic BP influences perfusion pres-
sure and organ blood flow (Guyton Hall 2000)
and thus, the ability of dopamine to increase MAP
above 60 mmHg in all our dogs while ephedrine
was only effective in one animal provided some
evidence for the preferred use of dopamine in
clinical cases. Only two dogs in the dopamine
group received epidural bupivacaine compared
with five in the ephedrine group. This may reduce
the comparability of the groups, but both the dogs
in the dopamine group responded well to dopam-
ine at 10 lg kg)1
minute)1
. If epidural adminis-
tration of bupivacaine contributed to the poorer
BP response of ephedrine boluses in this study,
dopamine, at 10 lg kg)1
minute)1
may be
preferable in such situations.
Variation in the actual activity of the dopamine
solution used in this study cannot be ruled out, it
was not diluted immediately before each use. The
dopamine was pre-diluted and stored in the refri-
gerator. Commercial availability of pre-diluted dop-
amine (DOPamine HCl and 5% Dextrose injection,
800 lg mL)1
, 250 mL bags; Baxter Corp.) provided
some evidence that our preparation was likely to be
effective. We have obtained good results with our
pre-diluted dopamine in clinical cases and are
confident in the efficacy of the dopamine. Despite
this shortcoming, an expected dose–response was
shown in the present study.
Individual variation was apparent in the cardio-
vascular responses to the treatment in this study.
This variability could be the result of differences in
age, sex, cardiac condition, volume status, ETIso,
PE¢CO2, residual effects of prior administered drugs,
degree of physical stimulation, differences in the
sensitivity of specific receptor types, existing endo-
genous catecholamine, and variation in the phar-
macokinetics, and thus, plasma concentrations of
the drugs used (MacGregor et al. 2000). Although
all data were collected prior to surgery, maneuvers
such as extending and hanging of the limb for
surgical preparation, and changes in position may
have produced stimulation of the dogs, as anesthe-
sia was maintained at a light plane. All the dogs in
this study hypoventilated, with PE¢CO2 values
higher than 45 mmHg. Hypercapnia augments BP
and CO through stimulation of the sympathetic
nervous system and release of catecholamines
(Cullen Eger 1974; Wagner et al. 1990). The
degree of hypercapnia was unlikely to have influ-
enced the cardiovascular values significantly. In
addition, it was similar over the assessment time,
between dogs and between groups. Ideally all
variables would have been controlled. However,
the intention of this study was to apply the
treatments in the face of the variation that occurs
in clinical cases.
In conclusion, the results of this study suggest
that ephedrine (0.2 mg kg)1
, IV), repeated at a 10-
minute interval was less effective than a dopamine
infusion to augment BP pre-surgically in hypo-
tensive dogs during routine anesthetic manage-
ment. However, the degree of improvement in CI,
SVI, and DO2I was not different between the two
treatments and hence perfusion may be increased
with either. A dopamine infusion may be more
useful clinically, as the rate can be adjusted
according to individual BP responses.
Ephedrine dopamine in anesthetized hypotensive dogs HC Chen et al.
2007 The Authors. Journal compilation 2007 Association of Veterinary Anaesthetists, 34, 301–311 309

10. Acknowledgements
This study was supported by the Pet Trust Fund,
Ontario Veterinary College. Statistical consultation
was provided by William C Sears, MS (Zoology), MSc
(Statistics), Department of Population Medicine,
University of Guelph, Guelph, Canada.
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