Congress report

A. Meier-Hellmann, S. G. Sakka,
K. Reinhart
Department of Anaesthesiology
and Intensive Care Medicine,
Friedrich-Schiller-University,
Jena (D)

Schweiz Med Wochenschr 2000;130:19427

Peer reviewed article

Catecholamines and
splanchnic perfusion1

Summary
For supportive therapy in sepsis adequate volume loading is probably the first, and possibly
the most important step in the treatment of patients with septic shock. An elevated global O2supply (DO2) may be necessary and beneficial
in most of these patients, but the increase in
DO2 should be guided by measurement of parameters assessing global and regional oxygenation. Routine strategies for elevating DO2
by the use of very high dosages of catecholamines cannot be recommended.
Vasopressors should be used to achieve adequate perfusion pressure. With noradrenaline,
no negative effects on regional perfusion have
been demonstrated when the patient is adequately volume-resuscitated and the DO2 is
normal or even slightly elevated. In contrast,
adrenaline should be avoided because it appears to redistribute blood flow away from the
splanchnic region. There is controversy as to
whether dopamine should still be used as a
first-line drug in patients with septic shock,
since some clinical and experimental data indicate unfavourable effects on mucosal perfusion of the gut.

To date there are no convincing data to support the routine use of low-dose dopamine or
dopexamine in patients with sepsis. Neither
low-dose dopamine nor dopexamine have been
proved to prevent renal failure in septic patients. Furthermore, there is evidence that lowdose dopamine may reduce mucosal perfusion
in the gut in some patients. Dopexamine has
been suggested for improvement of splanchnic
perfusion, but since these effects remain somewhat controversial there are no current
grounds for a general recommendation in
favour of dopexamine in septic patients.
These recommendations are currently limited
by the lack of sufficient outcome studies and
studies evaluating regional perfusion. Until
the various catecholamine regimes are more
fully examined, recommendations for catecholamine support in sepsis must be considered
conditional.
Keywords: sepsis; treatment; catecholamines;
dobutamine; adrenaline; noradrenaline; dopamine; dopexamine

Evidenz-basierte Vorschlge fr eine rationale

Katecholamintherapie bei kritisch kranken Patienten, insbesondere im Hinblick auf regionale Effekte, zu geben ist durch das Fehlen
grosser, prospektiver und randomisierter Studien, die sich mit den Effekten von Katechol-

aminen beschftigt haben, limitiert. Ferner

muss betont werden, dass eine adquate
Volumentherapie unbedingte Voraussetzung
einer rationalen Katecholamintherapie ist.
Das Konzept der Maximierung des DO2 mittels hochdosierter Katecholamine ist abzuleh-

Zusammenfassung

1 Main lecture at the Annual meeting of the Swiss Society

of Intensive Care, the Swiss Society of Pulmology
and the Swiss Society of Infectiology
(Lausanne, June 1516, 2000)

1942

Correspondence:
Andreas Meier-Hellmann
Department of Anaesthesiology
and Intensive Care Medicine
Friedrich-Schiller-University
Bachstrasse 18
D-07743 Jena
e-mail: meier-hellmann@med.uni-jena.de

Schweiz Med Wochenschr 2000;130: Nr 50

Congress report

nen. Zur Therapie der eingeschrnkten Pumpfunktion ist Dobutamin Katecholamin der
Wahl. Zur Entscheidung, ob ein weiterer DO2Anstieg sinnvoll ist, mssen die Marker der
peripheren Perfusion und Organfunktion (z.B.
Diurese, Laktat, rCO2) beachtet werden.
Ein inadquater Perfusionsdruck sollte nicht
wegen potentieller ungnstiger Effekte von
Vasopressoren toleriert werden. Auch der Perfusionsdruck muss unter Beachtung von Parametern der peripheren Perfusion und Organfunktion titriert werden. Noradrenalin ist Katecholamin der Wahl, da es keine Hinweise fr
ungnstige regionale Effekte gibt. Darber hinaus haben sowohl Adrenalin als auch Dopamin

in vasopressorischer Dosierung negative Effekte auf die Perfusion des Gastrointestinaltraktes.

Es gibt zurzeit keine hinreichend gesicherte
Therapieoption, die ber die Stabilisierung der
globalen Hmodynamik hinaus, eine gezielte
Beeinflussung der regionalen Zirkulation ermglicht. Dopamin (auch in sogenannter Nierendosis) scheint die Perfusion der intestinalen
Mukosa zu verschlechtern. Auch fr Dopexamin liegen zurzeit keine Daten vor, die den
klinischen Einsatz rechtfertigen.
Keywords: Sepsis; Therapie; Katecholamine;
Dobutamin; Adrenalin; Noradrenalin; Dopamin; Dopexamin

To restore and maintain the oxygen transport

and tissue oxygenation is the most important
step in the supportive treatment of patients
with sepsis. Therefore, the supportive treatment should be focused on an adequate volume
resuscitation and appropriate use of vasoactive
drugs.
Tissue hypoxia, especially in the splanchnic
area, is still considered to be an important cofactor in the pathogenesis of multiple organ
failure (MOF) [1]. Therefore, the specific effects of the various therapeutic interventions
on splanchnic perfusion and oxygenation are
of particular interest.

Since the effects of the various vasoactive drugs

on global and regional haemodynamics are
well studied, one would assume that an appropriate use of vasoactive drugs in the treatment of sepsis should easily be established. Unfortunately, there is evidence that the effects of
vasoactive drugs on global and regional perfusion in patients with sepsis or septic shock
may well differ from patients studied without
sepsis [2]. Especially important are studies
measuring the effects of various fluids and
catecholamines on splanchnic perfusion and
oxygenation under the specific conditions of
sepsis.

Under the conditions of an adequate volume

replacement, dobutamine increases cardiac
output (CO) and DO2 to a greater extent than
dopamine [3]. Hannemann et al. [4] demonstrated in septic patients that a combination of
dobutamine with noradrenaline when compared with dopamine alone, titrated to a similar mean arterial pressure, is associated with a
lower heart rate, lower filling pressures, and
lower intrapulmonary shunt. A higher DO2
with dopamine alone was not associated with
a higher oxygen consumption. Therefore, the
authors concluded that dopamine did not improve tissue oxygenation but induced a greater
myocardial stress and impaired pulmonary gas
exchange.
Hayes et al. [5] found no difference in global
oxygen consumption (VO2) between 50 patients treated with dobutamine up to 200 g/
kg/min to achieve three goals (cardiac index
above 4.5 l/min/m2, DO2 above 600 ml/min/
m2, VO2 above 170 ml/min/m2) and 50 other
patients who were only treated with an ade-

quate volume therapy. Surprisingly, survival in

the patients with the dobutamine treatment
was lower than in the control group. The authors speculated that the aggressive dobutamine treatment as an attempt to increase VO2
may have been detrimental in some patients.
That dobutamine improves splanchnic perfusion and oxygenation has been supported by
studies demonstrating an increased pHi (intramucosal pH) under dobutamine infusion [6, 7].
Nevertheless, these effects paralleled an increase in whole body blood flow. Thus, further
selective effects of dobutamine on splanchnic
circulation, beyond the global haemodynamic
effects, seem to be very unlikely [8].
In conclusion, when dobutamine is used to increase DO2, there is some evidence of improvement in tissue oxygenation. Nevertheless, there is no clear recommendation to what
extent DO2 should be increased, and it is
doubtful that there is an optimal DO2 appropriate for all septic patients. Therefore, the
increase in DO2 by dobutamine should be

Introduction

Dobutamine

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Congress report

Schweiz Med Wochenschr 2000;130: Nr 50

carefully monitored by using methods which

indicate changes in tissue oxygenation such as

lactate levels, regional CO2 production (pHi),

or changes in VO2.

In experimental models, noradrenaline increased splanchnic vascular resistance and decreased splanchnic blood flow [9]. As a consequence, noradrenaline is most commonly used
as a last resort when haemodynamic stabilisation cannot be achieved with other catecholamines [10].
It has been demonstrated that treatment with
noradrenaline in septic shock restored renal
function [11, 12]. However, it should be emphasised that these patients had markedly decreased blood pressures prior to the administration. Therefore, the potential unfavourable
effects of vasopressors must be weighed against
the known danger of inadequate perfusion
pressure.
In fact, findings on the effects of noradrenaline
on splanchnic perfusion in sepsis are inconsistent. Bersten et al. [2] compared the effects of
several catecholamines on regional blood flow
in septic and non-septic sheep. They found
a redistribution of blood flow to the heart
and away from the brain, kidneys, liver and
pancreas with noradrenaline, dobutamine,

dopamine, dopexamine or salbutamol treatment in the non-septic animals. In contrast,

such a redistribution of regional blood flow
was not observed in the septic animals.
A beneficial effect of noradrenaline on splanchnic oxygenation in septic patients was shown
by Marik and Mohedin [13] who compared
noradrenaline and dopamine as vasopressors.
Patients who were treated with noradrenaline
had an increase in pHi whereas dopamine led
to a decrease in pHi.
We measured splanchnic blood flow in 10 patients with septic shock using the indocyaninedye dilution technique [14]. After changing the
catecholamine treatment from a combination
of dobutamine with noradreanline to noradrenaline alone, we observed a parallel decrease in splanchnic perfusion and cardiac
output, while splanchnic VO2 remained unchanged.
In conclusion, as long as an adequate DO2
is maintained, treatment with noradrenaline
alone seems to be without negative effects on
tissue oxygenation.

The rationale for using adrenaline in the treatment of septic shock is its beta-receptor mediated increase in cardiac output and alpha-receptor mediated increase in systemic perfusion
pressure [1517].
We [18] measured splanchnic perfusion, DO2
and VO2 in 8 patients with septic shock who
were treated with a combination of dobutamine and noradrenaline. After a change to
adrenaline alone, titrated to achieve the same
mean arterial pressure (MAP) as before, DO2
and VO2 remained unchanged. However,
splanchnic perfusion decreased despite unchanged cardiac output. The decrease in

splanchnic DO2 was associated with a decrease

in splanchnic VO2. Furthermore, the deterioration of tissue oxygenation following the administration of adrenaline was evident by an
increase in lactate levels and a decrease in pHi.
Similar findings were reported by Levy et al.
[19] who also found an increase in lactate and
a decrease in pHi from adrenaline when compared with a combination of dobutamine and
noradrenaline. These findings point to a very
limited role for adrenaline in septic patients,
and in our opinion, noradrenaline should be
the vasopressor of first choice.

Vincent and Preiser [20] suggested dopamine

as the primary drug of choice in the management of decreased MAP in patients in septic
shock. However, other authors have suggested
that the alpha-mimetic effects of dopamine
could further compromise an already disturbed
microcirculation [3, 21]. In 437 critically ill
patients, Shoemaker et al. [10] were able to
induce an increase in DO2 and VO2 more

frequently with dobutamine than dopamine.

Lherm et al. [22] demonstrated in a group of
septic patients that low-dose dopamine increased urine output and creatinine clearance
in patients with severe sepsis, whereas no effects in patients with septic shock were found.
Nevertheless, the beneficial effects in patients
with severe sepsis were only seen for 48 hours.
Giraud and MacCannell [23] administered

Noradrenaline

Adrenaline

Dopamine

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Schweiz Med Wochenschr 2000;130: Nr 50

Congress report

dopamine in dogs and were able to measure an

increase in superior mesenteric artery blood
flow and in the muscle layer of the gut. However, they found a decreased blood flow to the
gut mucosa accompanied by a decrease in
splanchnic VO2. In the already mentioned
study from Marik and Mohedin [13], patients
who were stabilised from septic shock using
dopamine had a lower pHi than patients who
received noradrenaline. Moreover, dopamine
in a dose of 5 g/kg/min was equally effective
when compared with dobutamine but led to a
decrease in intestinal mucosa perfusion [24].
In 11 patients with septic shock treated with
noradrenaline, we added dopamine in a dosage
of 2.8 to 3.0 g/kg/min. In those patients with
a fractional splanchnic flow in the normal
range, low-dose dopamine increased splanchnic perfusion, whereas in patients with an elevated fractional splanchnic flow before treat-

ment, no further increase or even decrease in

splanchnic flow was observed [25]. This suggests that the effect of dopamine depends on
the individual baseline splanchnic flow which
in septic patients could vary from normal to
markedly increased.
Furthermore, it is well known that prolonged
dopamine infusion has important effects on the
concentrations of various circulating pituitarydependent hormones which may influence
metabolic and immunological homoeostasis in
critically ill patients [26].
In conclusion, it remains questionable whether
management of septic shock with higher doses
of dopamine alone is superior to the combination of dobutamine and noradrenaline.
Whether low-dose dopamine can prevent renal
failure has yet to be proven, and there is evidence that low-dose dopamine has deleterious
effects on splanchnic oxygenation.

Dopexamine is a relatively new catecholamine

with predominantly beta-2 and dopaminergic
receptor activity. Among animal experiments,
Cain and Curtis [27] did not note a difference
in mesenteric venous blood flow in septic dogs
treated with dopexamine when compared with
a control group without catecholamine treatment. Since the gut of the dopexamine-treated
animals released less lactate, the authors concluded that dopexamine preferentially increased perfusion of the gut mucosa.
In another animal model of sepsis, the infusion
of dopexamine was associated with less damage in hepatic cells than an infusion of dobutamine [28]. Furthermore, dopexamine increased tissue pO2 in various splanchnic organs
in animals after the induction of sepsis [29].
Also, in a dosage of 2.5 g/kg/min dopexamine prevented a hypoperfusion of the intestinal
villus after endotoxin infusion in rats [30].
In two clinical studies, dopexamine did increase a pathological low gastric mucosal pH
[31, 32]. However, it remains unclear whether
dopexamine really had a selective effect on
splanchnic perfusion or if this finding was simply the result of haemodynamic stabilisation.
Such an effect, an improved cardiac output but
no selective effect on splanchnic perfusion, has

been demonstrated in a recently published

study from Kiefer et al. [33]. Moreover, some
studies have suggested that dopexamine may
be dangerous for the splanchnic perfusion.
Uusaro et al. [34] reported an increase in whole
body DO2 and splanchnic DO2 to a similar extent after dopexamine infusion in cardiac
surgery patients. They did not find a specific
effect on splanchnic blood flow by dopexamine infusion as indicated by an unchanged
fractional splanchnic blood flow and reported
a decrease in pHi, which could be a sign of severe splanchnic hypoxia induced by the cardiac
surgery. However, this effect could also be an
indicator of a redistribution of splanchnic
blood flow and a hypoperfusion of gut mucosa
similar to the effect from low-dose dopamine.
In our own studies [35] dopexamine increased
splanchnic perfusion to the same extent as
whole body blood flow but was also associated
with a decrease in pHi.
Although some investigators recommend
dopexamine to improve splanchnic oxygenation and renal function, further studies are
needed to more clearly demonstrate the usefulness of dopexamine in the treatment of septic shock patients and to compare the effects
with those of low-dose dopamine.

An adequate fluid resuscitation is considered

essential treatment in sepsis, before or with catecholamines. Any attempt to correct low cardiac output or MAP due to hypovolaemia by

using catecholamines has to be strictly rejected.

Catecholamines may exhibit marked inter-individual variation in septic patients. Various
factors, such as the fractional flow of the car-

Dopexamine

Conclusion

1945

Congress report
diac output to the splanchnic perfusion bed or
therapy with other vasoactive substances, may
influence the effects of catecholamines. When
a supranormal value for DO2 has already been
achieved by sufficient fluid resuscitation, any
further attempt to increase global O2-supply is
questionable unless signs of inadequate tissue
perfusion are still present. The clinical decision
to further increase catecholamine dosages to elevate DO2 should be guided by parameters that
reflect organ function or tissue oxygenation,
e.g. lactate, rCO2, and urine output. Due to the
potentially harmful effects of dopamine and
adrenaline, dobutamine seems to be the catecholamine of choice to improve compromised
cardiac function. The use of dobutamine in
moderate dosages may further increase global
DO2, and thus also lead to an increase in O2supply to the splanchnic area and to an improved gastric mucosal perfusion.
Again, based on the potential negative effects
of dopamine and adrenaline, noradrenaline
may be regarded as first choice catecholamine
for increasing peripheral vascular resistance.
The well-documented negative effects of noradrenaline on kidney function in non-septic
patients do not seem to be present in sepsis
patients with adequate volume resuscitation.

Schweiz Med Wochenschr 2000;130: Nr 50

An inadequate perfusion pressure should not

be tolerated just because of concerns over the
use of noradrenaline.
There is no good evidence for a routine treatment with dopamine in the so-called renal
dosage. In septic patients with low fractional
splanchnic blood flow, dopamine increased
selective and absolute splanchnic blood flow.
However, it remains unclear whether tissue
oxygenation actually improves, since animal
studies suggest a decrease in intestinal mucosal
perfusion during dopamine infusion. In view of
the lack of evidence of benefits, and due to the
potential adverse side effects (selective impairment of mucosal perfusion, no or even negative effects on splanchnic blood flow in patients
with primarily already increased blood flow,
and its endocrinological effects) dopamine
should only be used with caution. For dopexamine a selective effect on splanchnic blood
flow has yet to be documented. Clinical studies that showed a positive effect for dopexamine on pHi could not be confirmed by others
who in fact reported a decrease in pHi with
dopexamine. Accordingly, dopexamine can
currently not be recommended in the routine
treatment of patients with sepsis.

Evidence-based assessment
It is now well documented that routine sepsis
treatment to supranormal levels of DO2 by using high doses of catecholamines is not beneficial (one multicentre, randomised, controlled
study, n = 762 [36]; one randomised, controlled study, n = 109 [5]; one meta-analysis, 7
studies with in total n = 1016 [37]). The major
role of an adequate fluid resuscitation and an
adequate arterial blood pressure has been
proved in a large number of smaller trials and
can be considered to have a high degree of evidence [38]. It has also been confirmed that
adrenaline is not considered as first choice catecholamine and that there is no indication for

the use of low-dose dopamine [38, 39]. However, due to the lack of evidence there is controversy concerning the use of high-dose
dopamine. For dopexamine only animal experiments and smaller clinical trials have been
published; thus recommendations by an expert
commission on the use of dopexamine are not
yet available.
Indeed, these strategies are quite limited due to
the lack of outcome studies and methods of
measurement of regional perfusion and oxidation. Until these limitations are addressed,
other alternative treatments should not necessarily be dismissed as inappropriate.

1 Deitch EA, Berg R, Specian R. Endotoxin promotes the

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3 Vincent JL, Van der Linden P, Domb M, Blecic S, Azimi G,
Bernard A. Dopamine compared with dobutamine in experimental septic shock: relevance to fluid administration.
Anesth Analg 1987;66:56571.

4 Hannemann L, Reinhart K, Grenzer O, Meier-Hellmann A,

Bredle DL. Comparison of dopamine to dobutamine and
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5 Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ,
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6 Silverman HJ, Tuma P. Gastric tonometry in patients with
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