Full text of DOI:10.1007/BF03019752

2
38
GEN ERAL AN ESTH ESIA
Dopexamine hydrochlo-
ride does not modify
hemodynamic response
or tissue oxygenation or
gut permeability during
J. McGinley FFARCSI,*
L. Lynch FRCA,†
K. H ubbard SRN,*
D. McCoy FFARCSI,†
abdominal aortic surgery A.J. Cunningham MD FRCPC*
Purpose: To assess the effects of intraoperative infusion of dopexamine (a DA-1 and B2 adrenoreceptor agonist)
on hemodynamic function, tissue oxygen delivery and consumption, splanchnic perfusion and gut permeability fol-
lowing aortic cross- clamp and release.
Methods: In a randomised double blind controlled trial 24 patients scheduled for elective infrarenal abdominal
aortic aneurysm repair were studied in two centres and were assigned to one of two treatment groups. Group I
–1
–1
–1
–1
received a dopexamine infusion starting at 0.5 µg·kg ·min increased to 2 µg·kg ·min maintaining a stable heart
rate; Group II received a placebo infusion titrated in the same volumes following induction of anesthesia. Measured
and derived hemodynamic data, tissue oxygen delivery and extraction and gut permeability were recorded at set
time points throughout the procedure.
–1
–1
Results: Dopexamine infusion (0.5 -2 µg·kg ·min ) was associated with enhanced hemodynamic function (MAP
5 ± 5.5 vs 92 ± 5.7 mm Hg, P = < 0.05) only during the period of aortic cross clamping. However, during the
6
most part of infrarenal abdominal aortic surgery, dopexamine did not reduce systemic vascular resistance index,
mean arterial pressure nor oxygen extraction compared with the control group. The lactulose/ rhamnose per-
meation ratio was elevated above normal in both groups (0.22 and 0.29 in groups I and II respectively).
–
1
–1
Conclusions: Dopexamine infusion (0.5 -2 µg·kg ·min ) did not enhance hemodynamic function and tissue
oxygenation values during elective infrarenal abdominal aortic aneurysm repair.
Objectif : Évaluer les effets d’une perfusion peropératoire de dopexamine, un agoniste des adrénorécepteurs
DA-1 et B2, sur l’hémodynamie, l’apport et la consommation d’oxygène tissulaire, la perfusion splanchnique et la
perméabilité intestinale à la suite d’un clampage total de l’aorte et de son retrait.
Méthode : Il s’agit d’un essai randomisé, contrôlé et à double insu auprès de 24 patients, provenant de deux
centres et répartis en deux groupes, qui ont subi la réparation d’un anévrysme aortique abdominal sous-rénal. Le
–1
–1
–1
–1
groupe I a reçu une perfusion de dopexamine amorcée à 0,5 µg·kg ·min , augmentée à 2 µg·kg ·min , main-
tenant une fréquence cardiaque stable; le groupe II a reçu une perfusion placebo de même volume après l’in-
duction de l’anesthésie. Les données hémodynamiques mesurées et dérivées, l’apport et la consommation
d’oxygène tissulaire et la perméabilité intestinale ont été notés à des moments de mesure déterminés au cours
de l’intervention.
–1
–1
Résultats : La perfusion de dopexamine (0,5 -2µg·kg ·min ) a stimulé la fonction hémodynamique (TAM 65 ±
,5 vs 92 ± 5,7 mm Hg, P = < 0,05) pendant le clampage aortique seulement. Cependant, pendant la majeure
5
partie de l’intervention aortique abdominale sous-rénale, la dopexamine n’a pas réduit l’indice de résistance vas-
culaire générale, la tension artérielle moyenne ou la consommation d’oxygène, ces données étant comparées
avec celles du groupe témoin. Le ratio de dissémination de lactulose / rhamnose s’est élevé au-dessus de la nor-
male dans les deux groupes (0,22 et 0,29 dans les groupes I et II respectivement).
–1
–1
Conclusion : La perfusion de dopexamine (0,5 -2µg·kg ·min ) n’a pas amélioré l’hémodynamie ni haussé les
valeurs d’oxygénation tissulaire pendant la réparation d’un anévrysme aortique abdominal sous-rénal.
From the Departments of Anaesthesia, Professorial Unit, Beaumont Hospital,* Dublin, Ireland and St. James’s Hospital,† Leeds, UK.
Address correspondence to: Professor A.J. Cunningham, Department of Anaesthesia, Professorial Unit, Beaumont Hospital, Dublin 9,
Ireland. Phone: 353-1-8376843; Fax: 353-1-837 0091; E-mail: anthonyc@rcsi.ie
Accepted for publication November 11, 2000.

McGinley et al.: D O PEXAMIN E A N D ABD O M I N AL AO RTIC SU RGERY
239
O RTIC cross clamping reduces or abolish-
es blood flow to the pelvis and lower
extremities distal to the clamp. The cardio-
anaerobic glycolysis and acidosis. Dopexamine, a
dopaminergic (DA-1) and beta-2 adrenoreceptor ago-
nist has been reported to increase splanchnic blood
1
A
flow in patients with chronic congestive heart fail-
vascular changes occurring during aortic
2
–4
1 7
cross clamping have been well described. In gener-
al, the hemodynamic responses to aortic cross clamp-
ing consist of an increase in arterial pressure and
systemic vascular resistance with no change in heart
ure.
This effect is achieved primarily through
splanchnic vasodilatation, although a mild positive
inotropic effect may be exerted indirectly at beta-1
1
8
adrenoreceptors. Inhibition of neuronal re-uptake of
5
1 9
rate. Enhanced impedance to aortic flow and
endogenous noradrenaline has also been suggested.
increased left ventricular end- systolic wall stress have
been implicated in post aortic cross clamp hyperten-
The objectives of this study were to assess the
effects of dopexamine infusion on hemodynamic func-
tion, tissue oxygen delivery and consumption and gut
permeability following aortic cross- clamp and release.
6
– 7
sion.
Various investigators have reported
8
9
unchanged or increased cardiac filling pressures.
Increases in right and left sided filling pressures during
aortic cross clamping may result from blood volume
distribution from the central vasculature in the lower
part of the body to the upper body or may represent
an increase in afterload, with subsequent increase in
the volume of blood remaining in the left ventricle at
the end of systole.1 0
Methods and materials
Following institutional Ethics Committee approval
and informed patient consent, 24 patients scheduled
for elective infrarenal abdominal aortic aneurysm
repair (ASA physical status II-IV) were studied in two
centres - Beaumont H ospital, Dublin and St. James’s
H ospital, Leeds. The study was carried out according
to the instructions of the Ethics Committee. Twelve
patients were recruited in each centre. The study
design was prospective, randomized and double-
blinded. An assistant randomly selected the agent to
be used (dopexamine hydrochloride or placebo) by
drawing a piece of paper from an envelope. Exclusion
criteria included a history of gastrointestinal patholo-
gy and pre-operative hemodynamic instability (mean
arterial pressure < 70 mmH g).
The substantial differences in hemodynamic
responses observed after supra- celiac vs infra-renal
aortic cross clamp may result, in part, from different
1
1
degrees and patterns of blood volume redistribution.
If the aorta is occluded below the splanchnic system,
blood may shift into the splanchnic system or into
other tissues proximal to the clamp. The distribution
of this blood between the splanchnic and nonsplanch-
nic vasculature may determine changes in cardiac pre-
load. Variations in blood volume status or splanchnic
vascular tone resulting from differences in fluid load,
depth of anesthesia, pharmacokinetics of the anesthet-
ic agents and other factors may effect the degree and
pattern of blood volume redistribution.1 0
Preoperative cardiac status was assessed by physical
examination,
resting
12-lead
ECG,
chest
roentgenogram, and echocardiographic determination
of left ventricular ejection fraction. Patients were ran-
domly assigned to two treatment groups. Based on pre-
Increasing duration of cross clamp may be associat-
ed with the release and accumulation of vasoactive
substances and may play a role in the time-dependent
reductions in cardiac output and increases in systemic
1
3,17
vious work,
we elected to use an infusion of
dopexamine hydrochloride commencing at 0.5
–1
–1
–1
–1
µg·kg ·min that was increased up to 2 µg·kg ·min
while a stable heart rate was maintained.
1
2
vascular resistance during aortic cross clamping.
Attention has recently focused on the adequacy of
splanchnic bed perfusion during acute changes in car-
Patients in Group I received a dopexamine infusion
following induction of anesthesia commencing at 0.5
1
3
– 1
–1
–1
–1
diac output. Gut ischemia increases the permeability
of the gastrointestinal mucosa and thereby allows bac-
teria and endotoxin within the gut lumen to enter the
systemic circulation, resulting in sepsis syndrome and
ultimately multiorgan failure.1 4 Relative hypoperfu-
sion of the liver, gut and related organs is the putative
mechanism of multiple organ dysfunction following
abdominal aortic surgery.1
µg·kg ·min
and increased by 0.5 µg·kg ·min
–
1
– 1
every 15 min up to 2 µg·kg ·min until the end of
surgery. Those in Group II received a saline infusion
titrated in the same volumes and at the same time
intervals. Measured and derived hemodynamic data,
tissue oxygen delivery and extraction and gut perme-
ability were recorded at set time points throughout
the procedure.
5–16
Infrarenal aortic cross clamping may be associated
with decreases in splanchnic blood flow if cardiac out-
put is reduced. Decreases in splanchnic and gastroin-
testinal blood flow may result in tissue hypoxia,
None of the 24 patients received H antagonists pre-
2
operatively. A standardised general anesthetic technique
–
1
was used for all patients. Fentanyl, 5-10 µg·kg , fol-
–
1
lowed by 3-4 mg·kg thiopental, was administered to

2
40
C AN AD I AN JO U RN AL O F AN ESTH ESIA
–
1
induce anesthesia. Vecuronium, 0.1 mg·kg , was given
to facilitate tracheal intubation. Controlled normocap-
nic ventilation was commenced with N O / O and
All patients received a 5 g bolus of lactulose and a
1 g bolus of L-rhamnose via the naso-gastric tube at
the end of surgery. The urine bag was emptied and the
collection begun. The total urine volume for five
hours was noted and a 20 ml sample preserved with
methiorlate was collected for further sugar concentra-
tion analysis. The percentage recovery of each sugar
was calculated. The percentage recovery lactulose to
L-rhamnose ratio was also calculated. Percentage
recovery = sugar concentration × urine volume ×100
times the amount of sugar given enterally. The normal
range of the percentage recovery of lactulose to L-
rhamnose ratio is 0-0.05.
2
2
isoflurane 0.5-1.0% with incremental doses of fentanyl.
Pulmonary artery occlusion pressure was maintained
between 10 and 15 mmH g with crystalloid or colloid
infusions. H ypertension >25% of baseline was con-
trolled by nitroglycerin infusion. Blood loss >15% of the
estimated blood volume or documented hematocrit
<
26% were treated with red cell concentrate infusions.
A radial arterial catheter was inserted under local
anesthesia before induction of general anesthesia. A
pulmonary artery catheter was inserted through the
right internal jugular vein following induction of anes-
thesia. The pulmonary and radial arterial catheters
were measured with reference to the mid-axillary line.
H eart rate was measured by the electrocardiogram
Results are expressed as mean ± standard deviation
or as group percentages. Comparisons of differences
between groups were made using the two-tailed
Student t test for unpaired data. A P value < 0.05) was
considered significant.
(
Merlin, H ewlett Packard, Blacknell UK). Central
venous pressure (CVP), pulmonary capillary wedge
pressure (PCWP) and mean arterial pressure (MAP)
were measured using standard pressure transducers
and monitors (H ewlett-Packard M1166A, Andover,
Mass) and were recorded at end-expiration.
Results
The mean age of patients in Groups I and II was 75 ±
5 yr and 73 ± 4 yr respectively. Mean body surface area
was similar in both groups. The male/ female ratio was
10/ 2 in Group I and 11/ 1 in Group II. Preoperative
cardiac evaluation indicated that three patients in each
group had a previous history of myocardial infarction
and, similarly, three patients had a history of conges-
tive cardiac failure. Ten patients in Group I and nine
patients in Group II had resting left ventricular frac-
tions greater than or equal to 40 % (Table I).
Baseline cardiac index (CI), oxygen delivery index
(
D O ) and oxygen consumption (VO ) were calculated
2
2
under stable non operating conditions after induction
of anesthesia and at specific time points throughout the
procedure using the following formula;
D O = CI x CaO x 10: VO = CI x CvO x 10:
2
2
2
2
OER = CaO - CvO / CaO
2
2
2
The mean duration of surgery for patients in
Groups I and II was 224 (± 88) and 241 (± 109) min
respectively (Table II). There were no differences
between the two groups in terms of duration of cross
clamp, volumes of intravenous fluid administered and
blood volume transfused. One patient died in each
group within 48 hr of surgery - one in the control
group, with a history of previous myocardial infarct,
sustained a myocardial infarction with severe left ven-
tricular failure two days after surgery and a patient in
the dopexamine group, with severe pre-existing lung
disease, died as a consequence of postoperative respi-
ratory and multisystem organ failure.
CaO2
/ CvO = ([H emoglobin] × 1.34 × % O
2 2
Saturation) + (PO × 0.003)
2
–
1
– 2
Cardiac Index (L·min ·m ) was measured by ther-
modilution in triplicate (ice cold 10 ml bolus of dex-
trose 5%) after withdrawal of arterial and mixed
venous blood samples. Arterial and mixed venous
blood samples were withdrawn anaerobically and used
for the measurement of oxygen and carbon dioxide
tensions (Instrumentation Laboratory 1312 blood gas
analyser, Warrington, England), and oxygen satura-
tion and hemoglobin concentration (Instrumentation
Laboratory 282 cooximeter).
H emodynamic and oxygen transport variables were
obtained from measurements after arterial and pul-
monary artery catheterization at the following times:
T1- following induction of anesthesia; T2- five min-
utes before aortic cross clamp; T3- 30 min following
aortic cross clamp; T4- 60 min following aortic cross
clamp; T5- five minutes after aortic cross clamp
release; T6- 30 min after aortic cross clamp release; T7
and T8, one, and two hours after aortic cross clamp
release respectively.
Changes in heart rate (H R) and mean arterial pres-
sure (MAP) following induction of anesthesia, aortic
cross clamp and release are included in Figures 1 and 2.
The horizontal arrow in each of the figures provided
indicates the duration of dopexamine/ saline drug infu-
sion. The rectangular areas represent periods of aortic
cross clamping. The mean arterial pressure was lower in
the dopexamine group (Group I) than in the control
(Group II). This MAP reduction was statistically signif-
icant during the cross clamp period (65 ± 5.5 vs 92 ±

McGinley et al.: D O PEXAMIN E A N D ABD O M I N AL AO RTIC SU RGERY
241
TABLE I Patient demographic data and past cardiac medical his-
tory (mean (SD or range) or number). No significant difference in
patient and demographic data.
Group I
n=12)
Group II
(n=12)
(
Age; yr
BSA; m
Sex; M/ F
75 (68-84)
1.8 (1.5-2.1)
10:2
73 (66-79)
1.8 (1.5-2.4)
11:1
2
Echocardiographic left
ventricular fraction
>
<
40%
40%
10
2
3
9
3
3
3
Previous Myocardial Infarction
Congestive Cardiac Failure
3
BSA = Body Surface Area.
FIGU RE 1 Changes in heart rate in Groups I and II throughout
the study period. Dopexamine/ saline drug infusion is given by the
horizontal arrow. The rectangule represents the period of cross
clamping. ◆= Group I and ■= Group II. * P < 0.05. Data are
mean (sem).
TABLE II Perioperative surgical details, fluid administration and
patient outcome. Results are expressed as mean ± SD [range].
Group I
n=12)
Group II
(n=12)
(
Duration of cross clamp (min)
61 ±29
30-125]
4 ±0.86
2.5-5]
Colloid administered (500 ml units) 1.6 ±0.4
1-2]
5.6 ±1.5
2-7]
224 ±88
120-450]
86 ±58
[
[40-225]
4.25 ±0.78
[3-5]
1.3 ±0.8
[0-3]
5 ±2.8
[0-12]
Crystalloids administered (Litres)
[
[
Units of blood transfused
Duration of surgery (mins)
Morbidity/ mortality within
[
241 ±109
[120-495]
[
4
8 hr of surgery
Deaths
1
1
TABLE III Sugar studies. Saccharide recovery (in urine) from
groups I and II, expressed as a percentage of the enterally adminis-
tered dose. Results expressed as means (SD). No significant differ-
ences between the two groups. The lactulose/ rhamnose ratios
were markedly elevated above normal mean values.
FIGU RE 2 Changes in mean arterial pressure in Groups I and II
throughout the study period. Dopexamine/ saline drug infusion is
given by the horizontal arrow. The rectangle represents the period
of cross clamping. ◆ = Group I and ■= Group II. * P < 0.05.
Data are mean (sem).
Sugar
Group I
0.3 ± 0.33 0.32 ± 0.27 0.315
3.3 ± 3.6 1.36 ± 0.8 11.88
Group II
Normal mean
Lactulose %
Rhamnose %
Lactulose/ rhamnose ratio 0.22 ± 0.21 0.29 ± 0.18 0 - 0.05
afterload,1 2 was reduced in the dopexamine group
during cross clamp (1183 ± 174 vs 2954 ± 403, P <
0
.05). There was no difference in VO values between
2
5
.7 mm H g, P <0.05). Mean heart rates tended to be
the two groups. The oxygen extraction ratio (Figure
4) was lower in group I during the cross clamp period
(17.2 ± 2.4 vs 25.1 ± 2.6, P < 0.05).
Gastrointestinal sugar absorption/ permeability data
are included in Table III. The laboratory reference val-
ues for percentage recovery of lactulose and L-rham-
nose are 0.315% and 11.88% respectively. Renal
rhamnose levels were markedly reduced compared with
higher in the dopexamine treated group throughout
the study period. This increased heart rate response was
only statistically significant compared with controls
prior to cross clamping (87 ± 5 vs 69 ± 4, P <0.05).
Calculated systemic vascular resistance index
(
SVRI) values at the various time points are represent-
ed in Figure 3. SVRI, an indicator of left ventricular

2
42
C AN AD I AN JO U RN AL O F AN ESTH ESIA
enhanced hemodynamic function only during the
period of aortic cross clamping. During the most part
of infrarenal abdominal aortic surgery, dopexamine
did not reduce systemic vascular resistance index,
mean arterial pressure or oxygen extraction compared
with the control group. On a regional level, dopex-
amine hydrochloride did not improve splanchnic
blood flow. Gastrointestinal sugar absorption/ perme-
ability assessment confirmed that renal L-rhamnose
levels were reduced compared with reference values in
both the dopexamine and control group.
Both groups received similar volumes of intra-
venous fluids and blood products intraoperatively. An
increased heart rate was observed associated with
–1
–1
dopexamine infused in the range 0.5-2 µg·kg ·min .
There was no ECG evidence of ST segment depres-
sion in either group. Nonetheless, tachycardia associ-
ated with dopexamine infusion is a concern in a
patient population with a high incidence of overt and
FIGU RE 3 Changes in systemic vascular resistance in Groups I
and II throughout the study period. Dopexamine/ saline drug
infusion is given by the horizontal arrow. The rectangle represents
the period of cross clamping. ◆ = Group I and ■= Group II. * P
<
0.05. Data are mean (sem).
6
covert ischaemic heart disease.
Dopexamine hydrochloride is a synthetic dopamin-
ergic (DA-1) and beta-2 adrenoreceptor agonist. As
such, it has been reported to be one third as potent as
dopamine in stimulating DA-1 receptors but 60 times
1
8
more potent as a beta-2 adrenoceptor agonist.
Unlike dopamine, it has weak beta-1 adrenoreceptor
agonist properties and does not stimulate vascular
alpha-1 adrenoceptors in higher doses. H uman stud-
ies, in both healthy volunteers and patients with
hypertension, suggest that dopexamine hydrochloride
–1
–1
in doses >0.25 µg·kg ·min increases cardiac output
2
0
as a result of increased stroke volume and heart rate.
Boyd and colleagues reported a dopexamine
induced increased cardiac output and oxygen delivery
2
1
in a series of sixteen high-risk surgical patients. The
enhanced hemodynamic function and tissue oxygena-
tion observed in their study was attributed to vasodila-
tory and mild inotropic properties. In a more
extensive study involving 107 high-risk surgical
patients, the same investigators reported a 75% reduc-
tion in mortality and halving of the mean number of
complications per patient treated with dopexamine
FIGU RE 4 Changes in oxygen extraction ratios in Groups I and
II throughout the study period. Dopexamine/ saline drug infusion
is given by the horizontal arrow. The rectangle represents the peri-
od of cross clamping. ◆ = Group I and ■= Group II. * P < 0.05.
Data are mean (sem).
2
2
hydrochloride.
reference values in the dopexamine treated and control
group. H owever, there were no differences between
the groups. The lactulose/ rhamnose permeation ratio
is normally 0 - 0.05. This ratio was elevated to 0.22
and 0.29 in groups I and II respectively, indicating
poor gastrointestinal permeability following surgery.
Global tissue oxygen delivery within normal or
enhanced physiological ranges does not address the
issue of regional variations in oxygen delivery and con-
sumption, particularly splanchnic circulation.
Permeability refers to the ease with which the intesti-
nal mucosal surface can be penetrated by diffusion of
specific constituents. Permeability remains unchanged
in healthy bowel. Estimates of permeability can be
made through measurements of permeation of these
two markers, lactulose and L-rhamnose. Lactulose is a
Discussion
A dopexamine infusion, administered during elective
abdominal aortic aneurysm repair, was associated with

McGinley et al.: D O PEXAMIN E A N D ABD O M I N AL AO RTIC SU RGERY
243
nonhydrolyzable disaccharide that permeates the
intercellar tight junctions, while L-rhamnose, a small-
er molecule, is absorbed mainly via the transcellular
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