not permitted.

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E X PE RT O P I N I O N

The role of beta-blockers in septic patients

O. HAMZAOUI 1, J.-L. TEBOUL 2, 3

1Hpitaux Universitaires Paris-Sud, Hpital Antoine Bclre, Clamart, France; 2Hpitaux Universitaires Paris-Sud,

Hpital de Bictre, Service de Ranimation Mdicale, Le Kremlin-Bictre, France; 3Universit Paris-Sud, Facult de
Mdecine Paris-Sud, Le Kremlin-Bictre, France

ABSTRACT
-blockers are widely used to treat cardiovascular diseases and in the peri-operative period in selected patients. The
main benefit in terms of morbidity and/or mortality of their use is believed to be linked to specific effects on myo-
cardial oxygen supply/demand balance, to anti-arrhythmic effects and anti-inflammatory effects. Use of -blockers
in severe sepsis is still under debate and if any, their appropriate indications remain unclear. In this article, we ana-
lyze the recent literature addressing the metabolic, immuno-modulatory and hemodynamic effects of non cardio-
selective and of cardio-selective -blockers in experimental and human sepsis in order to help clarifying the potential
place of these drugs in patients with severe sepsis. From this analysis, it appears that -adrenoceptor blocking agents
may represent a therapeutic approach in patients with severe sepsis, in whom catecholaminergic hyperactivity in-
cluding excessive tachycardia is supposed to play an aggravating role. However, many questions about effectiveness,
safety and cardio-selectivity of the drugs and about the appropriate target population remain partially unanswered.
Recently, esmolol, a short-time acting 1-adrenoceptor blocker titrated to decrease heart rate below 95 beats/min
was shown to exert beneficial effects in a monocentric randomized clinical trial including selected septic patients.
Further large multicenter randomized trials are required to confirm the potential benefit of such a therapy in patients
with severe sepsis. (Minerva Anestesiol 2015;81:312-9)
Key words: Shock, septic - Esmolol - Propranolol - Catecholamines - Tachycardia.

-blockers are widely used to treat cardiovascu-

lar diseases and have been shown to reduce re-
infarction rates and mortality following myocar-
dial infarction.1, 2 In patients with chronic heart
failure, -blockers improve cardiac function and
reduce mortality.3, 4 Because myocardial ischemia
is a frequent complication in patients undergo-
ing non-cardiac surgery, -blockers have been
proposed for their potential protective effect. The
or other proprietary information of the Publisher.
several recommendations on their use exist for
patients with inducible ischemia, coronary artery
disease, or multiple clinical risk factors who are
undergoing vascular surgery and for patients with
coronary artery disease or multiple clinical risk
factors, who are undergoing intermediate-risk
surgery.5 Nevertheless, in a recent meta-analysis 6
including nine randomized controlled trials and
10,529 patients, Bouri et al. reported a significant

main benefit of -blockers in perioperative car-
diovascular morbidity and mortality is believed to
be linked to specific effects on myocardial oxy-
gen supply and demand. -blockers may exert
also anti-inflammatory and antiarrhythmic ef-
fects. Guidelines recommend continuation of a
-blocker during the perioperative period in pa-
tients who already receive the drug.5 In addition,
27% increase in mortality when beta-blockers are
initiated during the peri-operative period of non-
cardiac surgery.6 In spite of the reduced myocar-
dial infarction rate, there was a significant increase
in stroke and in hypotension in patients treated
with beta-blockers.6 In view of their results, these
authors have claimed that guidelines should prob-
ably retract their recommendations concerning

312 MINERVA ANESTESIOLOGICA March 2015

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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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patients HAMZAOUI
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
the perioperative initiation of beta-blockers in
non-cardiac surgery patients.6
Use of -blockers in sepsis is still under debate
and their appropriate indications remain unclear.
This article reviews the recent literature address-
ing the effects of -blockers during sepsis to help
clarifying the place of these drugs in such condi-
tions.
Metabolic and immuno-modulatory
effects of -blockers in sepsis
Sepsis is often associated with large increase
in catecholamine expression leading to increased
glucose metabolism, hyperglycemia and increased
catabolism of skeletal-muscle protein. Most sep-
sis-related metabolic derangements have a specific
2-adreno-receptor origin.7 In this regard, in a
septic model in rats, propranolol (a non selec-
tive -blocker) but not atenolol (a selective 1-
blocker) attenuated the sepsis-induced increase
in basal whole body glucose turnover and the
development of peripheral insulin resistance in
this condition.8 As a consequence, non-selective
-blockers (mainly propranolol) might be pro-
posed to counterbalance not only the catecho-
lamine-induced tachycardia but also hyperglyc-
emia and net protein catabolism associated with
sepsis or with severe thermal injury. In an endo-
toxinic model in animals, propranolol attenuated
the increased plasma concentration of glucose and
the elevated glucose turnover.9 In a randomized
study including 25 severely burned children, a
two-week treatment with propranolol adjusted to
decrease heart rate by 20% from baseline value,
was associated with attenuation of the hyperme-
tabolism and improvement of the net muscle-pro-
tein balance leading to an increase in lean body
mass.10 This effect was attributed to an increase
in the intracellular recycling of free amino-acids
by incorporating them back into bound protein
or other proprietary information of the Publisher.
without leaving the myocyte.10 In 98 pediatric pa-
tients suffering from thermal injury, propranolol
was shown to reduce the delivery of fatty acids
to the liver and hepatic congestion by inhibiting
lipolysis and reducing hepatic blood flow.11 An
additional mechanism described in that study was
the down-regulation of some genes affecting lipid
metabolism.11 Consequently to the peripheral re-
Vol. 81 - No. 3 MINERVA ANESTESIOLOGICA 313
duction in lipolysis and free fatty acids oxidation,
an increase in glucose oxidation can occur.
Little is known regarding the influence of selec-
tive 1-adrenergic blockers on the metabolism in
critically ill patients. Since the metabolic effects of
catecholamines are mainly due to the activation
of 2-adrenergic receptors, no marked metabolic
effects are expected to occur with 1-adrenergic
blockers administration.8 Gore et al. investigated
the hemodynamic and metabolic effects of es-
molol, a 1-adrenergic blocker, in six moderately
septic patients.12 The dose of esmolol was titrated
to reduce heart rate by 20% from baseline. No
effect was observed on oxygen consumption, en-
ergy expenditure, ATP availability or muscle pro-
tein kinetics.12 It must be noted that in this study,
esmolol was administered during three hours
only compared to the prolonged administration
of propranolol in the above-mentioned clinical
studies.10, 11
In summary, in view of their metabolic effects,
non selective -adrenergic blockers may be ben-
eficial in severe burned patients, when adminis-
tered during a prolonged period. However, stud-
ies addressing metabolic effects of non selective
-adrenergic blockers in human sepsis are lack-
ing. No significant metabolic effect was described
when a selective 1-adrenergic blockade agent was
used.12
Catecholamines also exert immuno-modula-
tory effects, with most immunologically active
cells expressing 2-adrenoreceptors on their sur-
face.13, 14 Propranolol was reported to abolish the
catecholamine-driven increase in natural Killer
cells 15 and the marked decrease in the produc-
tion of CCL3, which is a macrophage-produced
inflammatory protein favouring the clearance of
the pathogen.16
Because -blockers have cardio-protective,
metabolic and immuno-modulating effects, they
are supposed to be beneficial in critically ill pa-
tients. In this regard, Christensen et al. found in
8087 critically ill patients that pre-admission use
of -blockers was associated with reduced mor-
tality during the 30 days following admission.17
However, this study was not randomized and can-
not answer the question about the de novo use of
-blockers after the onset of an acute critical ill-
ness.
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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Hemodynamic effects of -blockers in sepsis
Consequences of cardiac -adrenoreceptor activation
in sepsis
Severe sepsis is characterized by excessive
adrenergic stimulation, as assessed by elevated
plasma levels of circulating catecholamines.18, 19
At the cardiac level, this can theoretically pro-
duce tachycardia and increased contractility due
to activation of -adrenergic receptors. Although
cardiac 1-adrenergic receptors are predominantly
involved, cardiac 2-adrenergic receptors also con-
tribute to the chronotropic and inotropic effects
of -agonists agents, especially in end-stage con-
gestive heart failure where cardiac 1-adrenergic
receptors density and functional responsiveness
are depressed while 2-adrenergic receptor func-
tion is almost unaffected.20, 21 Activation of car-
diac 1- and 2-adrenergic receptors results in in-
creased myocardial oxygen demand with inherent
risks of myocardial hypoxia, especially in patients
with coronary artery disease. Additionally, severe
tachycardia results in restricted diastolic ventricu-
lar filling and thus in a risk of decrease in stroke
volume. When sepsis and adrenergic stimula-
tion persist, adaptive mechanisms can occur at
the cardiomyocyte level resulting in the so-called
down-regulation of -adrenergic receptors. This
phenomenon covers desensitization/decreased
density/hyporesponsivness of 1-adrenergic re-
ceptors 18, 22, 23 and depression of post-receptor
signalling pathways.18, 22, 24 Cytokines such as
TNF and Interleukin1 are involved in these
processes.25 The clinical expression of down-reg-
ulation of -adrenergic receptors is hyporespon-
siveness to dobutamine.22, 26 This phenomenon is
one of the mechanisms involved in the myocar-
dial depression frequently observed during severe
sepsis.27
The main hemodynamic reason to use
or other proprietary information of the Publisher.
-blockers during severe sepsis is to attenuate
excessive tachycardia. This can improve the di-
astolic filling of the heart and thus stroke volume
by increasing the diastolic time. Attenuation of
excessive sepsis-related tachycardia can also limit
the increased myocardial oxygen demand and its
inherent risks. Another potential interest of us-
ing -blockers is to reduce the pro-inflammatory
314 MINERVA ANESTESIOLOGICA March 2015
beta-blockers in septic patients
cytokines release 28, 29 and its potential adverse
consequences on the heart.30, 31 Finally, adminis-
tration of -blockers may reduce the down-regu-
lation of 1-adrenoreceptors and thus restore the
1-adrenoreceptors density and responsiveness as
it was shown in experimental sepsis.28 Whether
reduction of cytokines release and reduction of
down regulation of 1-adrenoreceptors may pre-
vent or correct septic myocardial depression, re-
mains unclear.
Non cardio-selective -blockers in experimental sep-
sis
The idea of using -adrenergic blockers in
septic shock is not novel. The first studies ex-
amining the effect of -adrenergic blockade on
endotoxinic shock date back to the sixties. Berk
et al.32 examined the effects of a non-selective
-adrenergic blocker (propranolol) in dogs with
endotoxinic shock. In the group of dogs treated
with -adrenergic blockers there was no second
hypotensive phase as that observed in the control
group and fewer amounts of fluid were required
to maintain the mean arterial pressure above the
target value. In addition, arterial oxygen pressure
improved at 4 to 6 hours and the survival rate was
higher in the -blocker group.32 Finally, the dogs
in endotoxin shock treated with beta blockade
did not have the pathological changes of severe
splanchnic and pulmonary congestion and atel-
ectasis consistently seen in the dogs given endo-
toxin alone. However, this study suffered from
several limitations.32 The major one was that the
-adrenergic blockers were given only one hour
after administration of endotoxin,32 a situation
that cannot obviously be extrapolated to human
septic shock. Moreover, many pathophysiologi-
cal mechanisms observed in endotoxin-induced
shock in dogs do not occur in humans. Finally,
no hemodynamic measurement was performed
in that study 32 making hypothetical the mecha-
nisms explaining the benefits of -blockade.
Cardio-selective -blockers in experimental sepsis
Some more recent studies examined the ef-
fects of esmolol, which is a selective 1-adrenergic
blocking agent. This drug has interesting proper-
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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ties since it is fast acting, rapidly reversible, eas-
ily to titrate and well tolerated.33 Esmolol selec-
tively blocks the 1-adrenoceptors involved in
the control of heart rate, contractility and atrio-
ventricular conduction. It does not block the 2-
adrenoceptors, which are present in the myocar-
dium, the bronchial muscle, the large coronary
arteries, the peripheral blood vessels, and the
neuromuscular junction. This cardio-selectivity is
relative rather than absolute, and therefore dose-
dependent.34 Esmolol has a very short distribu-
tion half-life (around 2 minutes).33 A total of
55% of esmolol binds to plasma protein.33 These
pharmacological properties made esmolol par-
ticularly suitable for a short-term administration
during unstable conditions.
Suzuki et al.28 examined the protective effects
of esmolol on myocardial function in peritonitis-
induced septic rats using an isolated working heart
preparation. The septic rats were randomized in
three groups: a control group (normal saline 2
mL/h, N.=11), low-dose esmolol group (10 mg/
kg/h, N.=10), and high dose esmolol group (20
mg/kg/h, N.=10). Surprisingly, esmolol at high
dose improved stroke volume, cardiac output and
even cardiac contractility indices, cardiac work
and myocardial oxygen consumption.28 There
were also a reduction in the TNF at 24 hours and
the restoration of the 1-adrenoreceptors density
with either dose of esmolol.28 Whether these two
events play a role in the positive effects of esmolol
on cardiac performance is suggested but not
clearly proven by the authors.28 Nevertheless, this
study suffers from several limitations. First, there
was surprisingly no reduction in the heart rate
during the first hours of sepsis in the two esmolol
groups compared to the control group. Second,
the authors used a normotensive hyperdynamic
model of sepsis and as such, there was no change
in mean arterial pressure during the first hours of
sepsis in all groups. Such conditions are obviously
or other proprietary information of the Publisher.
uncommon in human septic shock. Third, analy-
ses were performed in an isolated working heart
preparation, eliminating the circulating endog-
enous humoral mediators and inflammatory cells.
In another animal study, the authors investigat-
ed the cardiovascular tolerance of esmolol in an-
esthetized, mechanically ventilated pigs for which
intravenous lipopolysaccharide was adminis-
Vol. 81 - No. 3 MINERVA ANESTESIOLOGICA 315
tered.35 Animals were randomly assigned to con-
tinuous intravenous esmolol infusion titrated to
decrease heart rate by 20% or isotonic saline. Sys-
temic and pulmonary hemodynamics and cardiac
output were continuously monitored throughout
the 5-hour study period.35 Except for heart rate,
which decreased, and for stroke volume, which
increased compared to saline, no change in any
hemodynamic variable was observed during the
study period.35 The authors concluded that con-
tinuous infusion of esmolol in animals with en-
dotoxinic shock, titrated to decrease heart rate by
20%, was well tolerated.35
Another animal study addressed the issue of the
protective effect of 1-adrenoreceptor blockers on
cardiac and hepatic function during sepsis.29 1-
adrenoceptor blockers (metoprolol and atenolol)
given for two days before lethal endotoxemia mark-
edly improved survival.29 Metoprolol pretreatment
reduced hepatic expression of proinflammatory
cytokines and lowered plasma interleukin-6.29 It
also reduced expression of inflammatory genes
implicated in the pathogenesis of septic cardiac
dysfunction.29 However, 1-adrenoceptor blockers
commenced six hours after either endotoxemia or
fecal peritonitis did not improve survival.29 He-
modynamic studies were performed during the
48 hours following the induction of fecal perito-
nitis.29 Animals received fluids alone or fluids plus
metoprolol.29 Heart rate increased with sepsis and
was reduced with metoprolol compared to saline
at 24 hours but not at 48 hours.29 Stroke volume
measured by echocardiography increased with me-
toprolol at 48 hours but not at 24 hours compared
to saline.29 In another series of experiments, cardi-
ac function indices were measured in septic and in
sham conditions.29 Cardiac output and stroke vol-
ume, which both decreased in septic conditions,
increased with fluid infusion and with subsequent
administration of metoprolol such that their val-
ues were similar to sham values.29 Left ventricu-
lar contractility, which was assessed by the dP/
dt ratio, increased in septic conditions and then
decreased to sham values with metoprolol but not
with fluids alone.29 The authors conclude that pre-
treatment by 1-adrenergic blockers offers anti-
inflammatory and cardioprotective effects with
mortality reduction. However, in clinical practice,
the onset of acute disease (sepsis) chronologically
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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precedes its therapy. In this regard, this study did
not show beneficial effects of 1-adrenergic block-
ers in terms of survival or in hemodynamics, when
the treatment was commenced six hours after the
induction of sepsis.
When analyzing the results of the three latter
experimental studies,28, 29, 35 it is hard to have
clear ideas about the effects of 1-adrenergic
blockers on hemodynamics and cardiac func-
tion in septic conditions. Indeed, one study con-
cluded that esmolol improved cardiac output and
cardiac function indices,28 one study concluded
that metoprolol increased stroke volume but not
contractility, which was rather decreased com-
pared to saline alone,29 and one study showed an
increase in stroke volume but no change in other
hemodynamic variables.35 Differences in species,
in experimental models of sepsis, in experimental
protocols, in the pharmarcological properties or
in the doses of the studied agents might explain
so different findings. In addition, in these stud-
ies, nothing is known about the degree of the
2-adrenoreceptor activity, which is expected to
be overexpressed in case of down regulation of
1-adrenoreceptor.21 In this regard, blocking the
previously down regulated 1-adrenoreceptors
should have only little negative effects on car-
diac contractility while endogenous epinephrine
can still exert a positive inotropic effect through
2-adrenoreceptor activation. Finally, it is dif-
ficult from such animal studies to draw any de-
finitive conclusion about the efficacy and safety
of -adrenergic blocker administration in human
sepsis since experimental conditions can hardly
been extrapolated to clinical practice. For exam-
ple, it seems difficult to translate to humans the
effects of drugs aimed at reducing heart rate in ex-
perimental studies in rats, in which heart rate val-
ues ranged between 300 and 500 beats/min.28, 29
Another issue is the clinical relevance of isolated
heart models to assess hemodynamics.28 Finally,
or other proprietary information of the Publisher.
administration of 1-adrenoreceptor blockers be-
fore the onset of sepsis 29 represents an obvious
limit to clinical applicability.
-blockers in human sepsis
Studies examining the effects of -adreno
receptor blockers in septic shock patients are rare
316 MINERVA ANESTESIOLOGICA March 2015
beta-blockers in septic patients
and generally included small numbers of patients.
The first studies evaluated the cardiovascular ef-
fect of propranolol, a non-selective -adrenergic
blocker, which has been shown in patients after
severe burn injury to decrease extremity blood
flow related to both an increase in vascular re-
sistance and a decrease in cardiac performance.36
In eleven patients with persistent septic shock
despite aggressive initial treatment, propranolol
administration was associated with increases in
arterial pressure, arterial oxygen pressure, uri-
nary output, and total peripheral resistance, and
with decreases in central venous pressure, cardiac
output, and heart rate.37 Suppression of the 2-
related peripheral vasodilatation might explain
the increase in systemic vascular resistance ob-
served in these two latter studies.36, 37
Gore et al.12 examined the hemodynamic and
metabolic effects of a 3-hour infusion of esmolol
in moderately septic patients. Esmolol adminis-
tration was associated with the 20% reduction in
heart rate and a comparable decrease in cardiac
output and oxygen delivery. Esmolol adminis-
tration did no affect stroke volume, systemic or
pulmonary vascular resistance, oxygen consump-
tion, hepatic or leg blood flow, energy expendi-
ture, or ATP availability/energy charge within
muscle.12 It is noteworthy that all the included
patients had a mean arterial pressure exceeding
70 mmHg without inotropic or vasopressive sup-
port. Other than the requirement for ventilatory
support, no subject suffered from an overt organ
failure at the time of study, and no subject was
hypoxic or severely acidotic. This may explain
the well tolerated effect of 1-adrenoreceptor
blockade despite the significant decrease in car-
diac output and oxygen delivery.
In line with this previous study, Morelli et
al. in a recent monocentric randomized study
38
examined the hemodynamic effects of esmolol
titrated to maintain heart rate between 84 and
95 beats/min in septic shock patients with
persistent tachycardia (>95 beats/min) despite
fluid resuscitation. Among 336 patients eligible
to the study, only 154 patients with persistent
tachycardia were randomized. After 96 hours
of esmolol, the heart rate values ranged in the
target in all patients. Compared with the con-
trol group, stroke index and left ventricular
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
COPYRIGHT
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patients HAMZAOUI
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
stroke work index were higher whereas the doses
of norepinephrine, the need of fluids and lac-
tatemia were lower in the esmolol group.38 There
was a reduction in oxygen transport and oxygen
consumption in the esmolol group.38 The au-
thors reported also a better glomerular filtration
rate in the esmolol group but no significant dif-
ference in the requirement of renal replacement
therapy between the two groups.38 Interestingly,
the authors reported an unexpected significant
difference in 28-day mortality between the two
groups: 49.4% in the esmolol group vs. 80.5% in
the control group (P<0.001).38 The authors con-
cluded that administration of esmolol in septic
shock patients was associated with a reduction
in heart rate without any adverse effect.38 How-
ever, the improvement in survival with esmolol
needs to be confirmed.
It is noteworthy that the study by Morelli
et al.38 is the first randomized study including
a large number of patients with the key mes-
sage that the use of -blockers in septic shock
patients is safe. Nevertheless, many points need
to be discussed. Firstly, 50% of the 336 patients
had a heart rate lower than 95 beats/min after
the initial phase of resuscitation. This restricts
the number of patients, who may potentially
benefit from a -blocker treatment. Secondly, in
spite of high in-hospital mortality, patients seem
to be not severely shocked at the time of inclu-
sion since lactate was less than 2 mmol/L and
the required doses of norepinephrine were not
very high. It remains thus unknown whether ad-
ministration of esmolol in patients with a more
severe circulatory failure at inclusion would have
been so well tolerated. Thirdly, the authors stated
that the 1-blocker treatment was not associat-
ed with adverse hemodynamic effects and sug-
gest through their graphical representation that
cardiac output did not decrease with esmolol.
However, the changes in cardiac output were
or other proprietary information of the Publisher.
not reported in any table and the significant and
large decrease in oxygen delivery (-20%) sug-
gests that cardiac output decreased largely with
esmolol. This was confirmed in a pilot study (25
patients) performed by the same group of inves-
tigators reporting a significant decrease in cardiac
output (-20%) with esmolol.39 Nevertheless, the
decreased systemic blood flow with esmolol did
Vol. 81 - No. 3 MINERVA ANESTESIOLOGICA 317
not result in a decreased sublingual microcircula-
tory blood flow in this pilot study.39 Fourthly,
mean arterial pressure did not change but cal-
culated systemic vascular resistance increased
with esmolol,38 a result which is difficult to ex-
plain since esmolol is not expected to attenu-
ate the 2-adrenoreceptor-mediated peripheral
vasodilatation. Fifthly, there was no evaluation
of cardiac function using echocardiography in
the randomized study 38 but patients with pro-
nounced cardiac dysfunction identified by low
thermodilution cardiac index (<2.2 L/min/m2)
and high pulmonary artery occlusion pressure
(>18 mmHg), were excluded. Thus, this study
cannot suggest that -blockers are helpful in case
of myocardial depression by attenuating cardiac
inflammation and/or restoring -adrenoceptor
density and responsiveness. Finally, the high in-
hospital mortality rate in both groups and in
particular, in the control group (91%) remains
unexplainable with respect to the moderate se-
verity at inclusion.38 This mortality rate is far
greater than that observed in recent studies in
septic shock patients,40, 41 in which the mortality
rate, which has dropped over the last decade,40, 42
is closer to 20%.
Synthesis
The paper by Morelli et al.38 has boosted the
interest of critical care physicians for -blockers
administration in patients with severe sepsis or
septic shock. However, the analysis of the liter-
ature raises more questions than it answers, in
particular in terms of effectiveness, safety, and
cardio-selectivity of the agents and about the
appropriate target population. From the More-
lli et al. study,38 it is tempting to believe that a
1-blocker like esmolol is valuable in hyperdy-
namic septic shock patients with marked tachy-
cardia. Nevertheless, the potential of this drug to
decrease cardiac output and oxygen delivery 38
must be acknowledged so that its administra-
tion in septic patients with hypodynamic states
should be at least cautious and even avoided in
those with cardiac failure. It must be remem-
bered that in case of documented sepsis-related
cardiac failure, the Surviving Sepsis Campaign
still recommends administration of dobutamine,
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
HAMZAOUI COPYRIGHT 2015 EDIZIONI MINERVA
Role of MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
an inotropic drug having the opposite effects to
those of -blockers.43 In any case, large multi-
center randomized clinical trials investigating
the impact of selective 1-adrenoreceptors block-
ers are required to confirm the positive results
reported by Morelli et al. in selected patients.38
It must be emphasized however that in contrast
to non selective -adrenoreceptor blockers, 1-
adrenoreceptor blockers have little effect on hy-
permetabolism.8, 9 As severe sepsis is a condition,
where increased tissue oxygen demand and in-
creased inflammatory processes play a major role
in the development of tissue hypoxia and of or-
gan dysfunction, a therapy such as non selective
-adrenoreceptor blocker would be particularly
attractive in view of reducing peripheral oxygen
debt. However, little is known about the result-
ant effect of blocking the 2-adrenoreceptors in
the peripheral vessels during septic shock. On the
hand, one could expect an increase arterial pres-
sure through reduction in 2-mediated vasodila-
tation, an effect that could be highly beneficial
in severely hypotensive patients. On the other
hand, 2-adrenoreceptors blocking agents could
impair microcirculation, an effect that could be
highly deleterious in patients with an already
altered microcirculation. Surprisingly, clinical
studies using non selective -adrenoreceptors
blockers in septic shock are lacking so that the
question about their potential utility or harmful-
ness remains unanswered.
Conclusions
-adrenoceptor blocking agents may represent
an interesting therapeutic approach in patients
with severe sepsis, in whom catecholaminergic
hyperactivity including excessive tachycardia is
supposed to play an aggravating role. However,
many questions about effectiveness, safety and
cardio-selectivity of the drugs and about the
or other proprietary information of the Publisher.
appropriate target population remain partially
unanswered. Esmolol, a short-time acting 1-
adrenoceptor blocker titrated to decrease heart
rate below 95 beats/min was shown to exert ben-
eficial effects in a monocentric randomized clini-
cal trial.38 Further large multicenter randomized
trials are required to confirm the potential bene-
fit of such a therapy in patients with severe sepsis.
318 MINERVA ANESTESIOLOGICA March 2015
beta-blockers in septic patients
Key messages
Sepsis is associated with large increase
in catecholamine expression leading to in-
creased glucose metabolism, hyperglycemia,
increased catabolism of skeletal-muscle pro-
tein and tachycardia.
Due to their metabolic effects, non
selective -adrenergic blockers may repre-
sent an interesting therapy in septic patients.
However, data are still lacking in severe sep-
tic patients.
Esmolol, a short-time acting 1-
adrenoceptor blocker, has been proposed
to decrease heart rate in septic patients for
whom catecholaminergic hyperactivity in-
cluding excessive tachycardia, is supposed to
play an aggravating role.
In spite of the results of a recent mono-
centric randomized trial reporting beneficial
effects of esmolol in septic shock patients
with excessive tachycardia, multicenter ran-
domized studies are needed before drawing
any definitive conclusion about the useful-
ness of esmolol in this clinical context.
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patients HAMZAOUI
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
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in the manuscript.
Received on April 16, 2014. - Accepted for publication on June 12, 2014. - Epub ahead of print on June 19, 2014.
Corresponding author: J.-L. Teboul, Service de ranimation mdicale, Centre Hospitalier Universitaire de Bictre, 78 rue du Gnral Leclerc,
94270 Le Kremlin-Bictre, France. E-mail: jean-louis.teboul@bct.aphp.fr
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