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Microvascular Effects of Heart Rate Control With
Esmolol in Patients With Septic Shock: A Pilot
Study*
Andrea Morelli, MD1; Abele Donati, MD2; Christian Ertmer, MD3; Sebastian Rehberg, MD3; Tim
Kampmeier, MD3; Alessandra Orecchioni, MD1; Annalia D’Egidio, MD1; Valeria Cecchini, MD1;
Giovanni Landoni, MD4; Paolo Pietropaoli, MD1; Martin Westphal, MD3; Mario Venditti, MD5;
Alexandre Mebazaa, MD6; Mervyn Singer, MD, FRCP7

Objective: β-blocker therapy may control heart rate and attenuate
the deleterious effects of β-stimulating catecholamines in septic
shock. However, their negative chronotropy and inotropy may
potentially lead to an inappropriately low cardiac output, with a
subsequent compromise of microvascular blood flow. The purpose
of the present pilot study was to investigate the effects of reducing
heart rate to less than 95 beats per minute in patients with septic
shock using the β-1 adrenoceptor blocker, esmolol, with specific
focus on systemic hemodynamics and the microcirculation.
Design: Prospective, observational clinical study.
Setting: Multidisciplinary ICU at a university hospital.
Measurements and Main Results: After 24 hours of initial hemodynamic optimization, 25 septic shock patients with a heart

*See also p. 2237.
1
Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, University of Rome, “La Sapienza”, Italy.
2
Department of Neuroscience-Anesthesia and Intensive Care Unit, Università Politecnica delle Marche, Italy.
3
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Germany.
4
Department of Anesthesia and Intensive Care, Università Vita-Salute San
Raffaele, Milano, Italy.
5
Department of Public Health and Infectious Diseases, University of Rome,
“La Sapienza”, Italy.
6
Department of Anesthesiology and Critical Care Medicine, Lariboisière
Hospital, University Paris Diderot, Paris, France.
7
Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom.
Supported, in part, by an independent research grant from the Department of
Anesthesiology and Intensive Care of the University of Rome “La Sapienza”.
Dr. Morelli received honorarium from Baxter for speaking at one symposium. Dr. Singer has received honoraria from Baxter for chairing or speaking at satellite symposia. The remaining authors have not disclosed any
potential conflicts of interest.
For information regarding this article, E-mail: andrea.morelli@uniroma1
Copyright © 2013 by the Society of Critical Care Medicine and Lippincott
Williams & Wilkins
DOI: 10.1097/CCM.0b013e31828a678d

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rate greater than or equal to 95 beats per minute and requiring
­norepinephrine to maintain mean arterial pressure greater than or
equal to 65 mm Hg received a titrated esmolol infusion to maintain
heart rate less than 95 beats per minute. Sublingual microcirculatory blood flow was assessed by sidestream dark-field imaging. All
measurements, including data from right heart catheterization and
norepinephrine requirements, were obtained at baseline and 24
hours after esmolol administration. Heart rates targeted between
80 and 94 beats per minute were achieved in all patients. Whereas
cardiac index decreased (4.0 [3.5; 5.3] vs 3.1 [2.6; 3.9] L/min/m2;
p < 0.001), stroke volume remained unchanged (34 [37; 47] vs
40 [31; 46] mL/beat/m2; p = 0.32). Microcirculatory blood flow in
small vessels increased (2.8 [2.6; 3.0] vs 3.0 [3.0; 3.0]; p = 0.002),
while the heterogeneity index decreased (median 0.06 [interquartile
range 0; 0.21] vs 0 [0; 0]; p = 0.002). Pao2 and pH increased while
Paco2 decreased (all p < 0.05). Of note, norepinephrine requirements were significantly reduced by selective β-1 blocker therapy
(0.53 [0.29; 0.96] vs 0.41 [0.22; 0.79] µg/kg/min; p = 0.03).
Conclusions: This pilot study demonstrated that heart rate control
by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular
blood flow, and a reduction in norepinephrine requirements. (Crit
Care Med 2013; 41:2162–2168)
Key Words: β-blockers; esmolol; septic shock; tachycardia

I

n the early phase of septic shock, overwhelming inflammation, arterial hypotension, and severe hypovolemia trigger
massive sympathetic activation in a physiologic attempt
to maintain vital organ perfusion. This activation is typically
associated with tachycardia and vasoconstriction to compensate for systemic vasodilatation (1). Yet, despite this increase
in endogenous sympathetic outflow, patients with septic shock
often require high doses of exogenously administered catecholamines to stabilize hemodynamics (2). Because 75% to
80% of myocardial adrenergic receptors are β1 and adrenergic
September 2013 • Volume 41 • Number 9

Clinical Investigations

stress is predominantly mediated by β receptors, the heart is
the main target of sympathetic overstimulation (3, 4). As a
consequence, septic patients often have an elevated heart rate
(HR), even after excluding common causes of tachycardia such
as hypovolemia, anemia, pain, and agitation (3–5). An elevated
HR is associated with adverse outcomes in septic shock (4–9)
and thus represents an expression of disease severity. There are
suggestions that a high HR in itself is pathologic, rather than
simply being a biomarker of sympathetic activation (4–9).
Tachycardia persisting after fluid resuscitation and control
of pain and agitation may indicate an inappropriate degree of
sympathetic activation (3–11). As suggested by Leibovici et al
(4), β-blockers may be effective in controlling HR by modulating the intrinsic response to β-adrenergic overstimulation
(12–14). In this context, previous experimental and clinical
studies reported that a reduction in HR with β-blockers was
well tolerated and cardiovascular performance was preserved
(15–18). Nevertheless, reducing HR with β-blockers in the
early phase of septic shock may potentially lead to an inappropriately low cardiac output with a consequent decrease in
microvascular blood flow and compromise of tissue perfusion.
The purpose of the present prospective observational study
was to investigate the effects of reducing HR in septic shock
patients below a predefined threshold, by using the β-1 adrenoceptor blocker, esmolol, with specific focus on the macrocirculation (using pulmonary artery catheterization) and the
microcirculation, as judged by modifications of sublingual
microvascular blood flow using sidestream dark-field (SDF)
imaging (19). We hypothesized that esmolol infusion would
have no significant impact on the sublingual microcirculation.

METHODS
Patients
After approval by the local institutional ethics committee, the
present study was performed in an 18-bed multidisciplinary
ICU at the Department of Anesthesiology and Intensive Care
of the University of Rome “La Sapienza.” Informed consent
was obtained from the patients’ next of kin. Twenty-five septic
shock patients requiring norepinephrine to maintain a mean
arterial pressure (MAP) of at least 65 mm Hg despite appropriate fluid resuscitation (2), and presenting with an HR greater
than 95 beats per minute (bpm), were treated with a continuous
infusion of esmolol to achieve HRs between 80 and 94 bpm.
Exclusion criteria were the following: age less than 18 years,
need for an inotropic agent, pronounced cardiac dysfunction
(i.e., cardiac index [CI] ≤ 2.2 L/min/m2 in the presence of a
pulmonary artery occlusion pressure [PAOP] > 18 mm Hg),
significant valvular heart disease, and pregnancy. All patients
were sedated with sufentanil and midazolam and were receiving mechanical ventilation using a volume-controlled mode.
Hemodynamics, Global Oxygen Transport, and
Acid-Base Balance
Systemic hemodynamic monitoring included pulmonary
artery (7.5F; Edwards Lifesciences, Irvine, CA) and radial
Critical Care Medicine

artery catheterization. MAP, right atrial pressure, mean pulmonary arterial pressure, and PAOP were measured at end expiration. HR was analyzed from continuous electrocardiographic
recording. CI was measured using the continuous thermodilution technique (Vigilance II; Edwards Lifesciences). Arterial and mixed venous blood samples were taken to determine
oxygen tensions and saturations, carbon dioxide tensions, pH,
arterial lactate, standard bicarbonate, and base excess. Mixed
venous oxygen saturation (Svo2) was measured discontinuously by intermittent blood gas analyses. Stroke volume index,
left and right ventricular stroke work indices, oxygen delivery
index, oxygen consumption index, and oxygen extraction rate
were calculated using standard formulae.
Microvascular Circulation
Microvascular blood flow was visualized by SDF imaging
(MicroScan; MicroVision Medical, Amsterdam, The Netherlands) with a five-fold magnification lens (19). The optical probe was applied to the sublingual mucosa after gently
removing the saliva with a gauze swab. Three discrete fields
were captured with care being taken to minimize motion artifacts. Individual sequences of approximately 15 seconds were
analyzed off-line using dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, Amsterdam, The
Netherlands) in a randomized fashion by a single investigator
unaware of the study protocol.
Vessel density was calculated automatically by the software as the total vessel length of the small, medium, and large
vessels divided by the total area of the image (19). This “De
Backer Score” is based on the principle that vessel density is
proportional to the number of vessels crossing arbitrary catheters. In this scoring system, three equidistant horizontal and
three equidistant vertical lines are drawn on the screen, with
the score calculated as the number of small, medium, and
large vessels crossing the lines divided by the total length of
the lines (19). The microvascular flow index (MFI) scores flow
as normal 3, sluggish 2, intermittent 1, and absent 0 (19). This
is categorized visually as normal continuous flow for at least
15 seconds (“normal”), decreased but continuous flow for 15
seconds (“sluggish”), no flow for less than 50% of the time
(“intermittent”), or no flow for at least greater than or equal to
50% of the time (“absent”) (19). The proportion of perfused
vessels (PPVs) was calculated as 100 × (total number of vessels
– [no flow + intermittent flow])/total number of vessels.
Finally, perfused vessel density was calculated by multiplying
vessel density by the PPVs (19). Vessel size was determined with
the aid of a micrometer scale. Medium vessels were defined as
vessels with a diameter of 20 to 50 µm and small as vessels less
than 20 µm diameter. Because our investigation was focused
upon small vessels, MFI calculations were separately performed
for vessels with diameters less than 20 µm (MFIs). For each
patient, values obtained from three fields were averaged (19).
To assess the flow heterogeneity between these different areas,
we used the heterogeneity index, calculated as the highest site
flow velocity minus the lowest site flow velocity, and divided by
the mean flow velocity of all sublingual sites (18).
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Morelli et al

Study Design
After 24 hours of hemodynamic stabilization targeted at
achieving values of PAOP greater than or equal to 12 mm Hg,
CVP greater than or equal to 8 mm Hg, Svo2 greater than 65%,
and MAP greater than or equal to 65 mm Hg (2), those patients
who remained with an HR greater than 95 bpm were included
in the present study and treated with a continuous esmolol infusion to maintain an HR between 80 and 94 bpm. The
protocol required a titrated esmolol infusion commenced at
25 mg/hr, with an upper dose limit of 2,000 mg/hr, to maintain
this predefined HR range for 24 hours. During this intervention period, conventional treatment was continued as per usual
practice. Fluid challenges were performed, and repeated as
necessary, to maintain CVP greater than or equal to 8 mm Hg
and PAOP greater than or equal to 12 mm Hg (2). Packed red
blood cells were transfused when hemoglobin concentrations
fell less than 7 g/dL (2) or if the patient exhibited clinical signs
of inadequate systemic oxygen supply. Norepinephrine was
titrated to maintain MAP greater than or equal to 65 mm Hg.
If Svo2 fell less than 65% despite appropriate arterial oxygenation (≥ 95%) and hemoglobin concentrations were greater
than or equal to 8 g/dL, and/or arterial lactate concentrations
increased, the esmolol infusion was discontinued. Systemic
and pulmonary hemodynamic variables, microcirculatory
flow variables, blood gases, and norepinephrine requirements
were determined at baseline and after 24 hours of esmolol
administration.
Statistical Analysis
The primary endpoint was a change in MFI in response to
esmolol administration. We used the “sampsi” command
(STATA Statistical Software: Release 11, College Station,
TX) to estimate the sample size for one sample specifying
one measurement at baseline and another at 24 hours. We
specified a correlation (between baseline and follow-up) of
0.99, reaching 90% power, considering an expected standard
deviation for MFI of 0.6 and a minimum detectable difference of 0.4 units before and after esmolol infusion. The estimated sample size was 24, and we included 25 patients to
account for possible protocol deviations. Data are expressed
as median (25th; 75th percentile), if not otherwise specified.
Values before and after esmolol administration were compared using the Wilcoxon signed-rank test for all continuous variables. Sigma Stat 3.10 software (SPSS, Chicago, IL)
was used for statistical analysis. A p value less than 0.05 was
regarded as statistically significant.

RESULTS
Patient demographics, sepsis etiology, baseline physiologic and
biochemical characteristics, and the duration of norepinephrine administration prior to study commencement are summarized in Table 1. Four patients in the present study were
also included in an ongoing open, randomized, prospective,
controlled trial assessing the impact of esmolol on systemic
hemodynamics and organ function in septic shock (http://
clinicaltrials.gov identifier: NCT01231698). In this controlled
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study, HR control by esmolol was continued until ICU discharge or death.
Concomitant Therapies
All patients received intravenous hydrocortisone (200 mg/d)
as a continuous infusion. During the 24-hour study period,
the median amount of fluids infused was 4,800 (4,100; 5,200)
mL. However, six patients required additional administration of 500 mL 6% hydroxyethyl starch 130/0.4 to maintain
PAOP within predefined threshold values. None of the patients
received inotropic support during the study period, while two
required continuous renal replacement therapy.
Hemodynamic Variables and Norepinephrine
Requirements
Compared with baseline, HR and CI were significantly decreased
after 24 hours’ esmolol therapy (p < 0.001). Other systemic and
pulmonary hemodynamic variables remained unchanged; however, norepinephrine requirements were significantly reduced
(p = 0.03; Table 2). At the end of the 24-hour infusion, the
median dose of esmolol administered to achieve targeted HRs
between 80 and 94 bpm was 250 (100; 1,050) mg/hr.
Acid-Base Homeostasis and Oxygenation
After the 24-hour infusion of esmolol, arterial pH and Pao2
were higher and Paco2 lower. Both oxygen delivery and consumption index decreased (all p < 0.05; Table 3). No significant
changes were seen in other variables of acid-base homeostasis
or gas exchange.
Microcirculatory Variables
The MFI significantly increased after 24 hours’ esmolol infusion from median 2.8 (interquartile range, 2.6; 3.0) to 3.0
(3.0; 3.0) (p = 0.002). The heterogeneity index significantly
decreased from 0.06 (0; 0.21) to 0 (0; 0) (p = 0.002). No significant differences were seen for other microcirculatory variables
(Fig. 1 and Table 4).

DISCUSSION
We demonstrate that titrating an esmolol infusion to reduce
HR less than 95 bpm in a cohort of septic shock patients was
associated with maintenance of stroke volume and preservation (or even improvement) of microvascular blood flow.
Although cardiac output fell because of the lower HR, stroke
volume, MAP, and lactate levels were unchanged while norepinephrine requirements were reduced.
Tachycardia increases myocardial oxygen consumption and
the shortened diastolic relaxation time may impair coronary
perfusion. Both these factors may contribute to the development of ischemia (8), worsen myocardial dysfunction, and
potentially increase mortality (6, 7). In a prospective study of
23 patients with prolonged, severe septic shock, HR at both
presentation and after hemodynamic stabilization was higher
in nonsurvivors (7). In another study of 48 septic shock
patients, statistically significant predictors of survival included
HR less than 106 bpm on ICU admission or less than 95 bpm
September 2013 • Volume 41 • Number 9

Clinical Investigations

TABLE 1.

Baseline Characteristics of Study Patients
Cause of Septic
Shock

Norepinephrine
Infusion
Prior to Esmolol
Infusion (Hr)

Norepinephrine
Dose at Baseline
(µg/kg/min)

Sex

Age (Yr)

Simplified
Acute Physiology
Score II

1

M

83

62

Peritonitis

26

0.95

2

F

70

57

Pyelonephritis

27

0.60

3

M

80

50

Pneumonia

30

0.24

4

M

58

49

Pneumonia

24

0.50

5

M

38

40

Pneumonia

32

0.20

6

M

47

63

Pneumonia

26

0.76

7

F

75

47

Pneumonia

25

0.16

8

M

75

66

Peritonitis

28

2.67

9

F

62

55

Pneumonia

30

1.71

10

M

18

38

Pneumonia

24

0.71

11

F

77

50

Pneumonia

28

0.47

12

M

43

52

Pneumonia

30

0.06

13

M

35

46

Pneumonia

32

0.30

14

M

81

54

Pneumonia

26

0.30

15

M

83

70

Pneumonia

24

0.85

16

M

33

56

Pneumonia

24

0.44

17

M

73

74

Pancreatitis

28

0.67

18

M

62

66

Pneumonia

24

1.80

19

M

31

50

Pneumonia

29

0.41

20

M

47

61

Peritonitis

30

0.16

21

F

43

58

Endocarditis

24

0.50

22

M

50

46

Peritonitis

24

2.80

23

M

76

52

Pneumonia

28

1.30

24

F

78

42

Pneumonia

26

0.53

25

F

61

71

Peritonitis

24

1.0

All

M, 72%

62 (43; 76)

55 (48; 62)

Not available

26 (24; 29)

0.53 (0.29; 0.96)

Patient

a

M = male, F = female.
a
Data are expressed as median (25th; 75th percentile).

at 24 hours, or an incremental fall in HR greater than 18 bpm
within this 24-hour period (6).
Although tachycardia is associated with a higher mortality
in septic shock (4, 5, 7, 8), this does not necessarily imply that
lowering HR improves survival; an elevated HR may simply be
a biomarker rather than a cause of a poor outcome. In addition,
the correct timeframe for intervention and the optimal HR range
are currently undefined. In the very early phase of septic shock
(prior to fluid resuscitation), tachycardia constitutes the main
mechanism that compensates for the decrease in stroke volume
(1, 8, 20). At this stage, reducing HR may blunt this adaptive
physiologic response, leading to a fall in cardiac output which, in
turn, may further compromise microvascular blood flow (1, 19).
Critical Care Medicine

Nevertheless, in some patients, HR remains elevated after excluding other causes of tachycardia, such as hypovolemia (1, 4, 5, 7, 8).
Here, tachycardia may indicate sympathetic overstimulation and/
or an adverse effect of catecholamine therapy (3–5).
Although reducing HR decreases myocardial oxygen consumption and improves diastolic function and coronary
perfusion (10), in some septic patients an inadequate chronotropic response may considerably decrease cardiac output
and thus worsen systemic hemodynamics and tissue perfusion.
Therefore, predefining a threshold value for HR is difficult as it
needs to be individualized in context with the patient’s overall
hemodynamic condition and any pre-existing comorbidities
(10). In a retrospective analysis of critically ill patients with a
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Morelli et al

TABLE 2.

Hemodynamic Data of the Study Patients (n = 25)

Variable

Baseline

Cardiac index (L/min/m2)

24 Hr

p

4.0 (3.5; 5.3)

3.1 (2.6; 3.8)

< 0.001

34 (27; 46)

40 (31; 46)

0.31

117 (112; 126)

86 (80; 89)

< 0.001

Mean arterial pressure (mm Hg)

71 (68; 75)

72 (70; 74)

0.67

Mean pulmonary arterial pressure (mm Hg)

31 (28; 34)

31 (28; 34)

0.73

Pulmonary arterial occlusion pressure (mm Hg)

17 (15; 20)

18 (16; 20)

0.50

Central venous pressure (mm Hg)

13 (11; 16)

14 (12; 17)

0.09

Left ventricular stroke work index [g m/beat/m2]

25 (22; 31)

29 (21; 34)

0.56

Right ventricular stroke work index [g m/beat/m ]

8.0 (6; 12)

9.0 (6; 12)

0.89

Stroke volume index (mL/beat /m )
2

2

Heart rate (/min)

2

0.53 (0.29; 0.96)

Norepinephrine dosage (µg/kg/min)

0.41 (0.22; 0.78)

0.03

Data are given as median (25th; 75th percentile).

high risk of cardiac complications (6), an HR greater than 95
bpm was associated with a greater occurrence of major cardiac events, including nonfatal myocardial infarction, nonfatal
cardiac arrest, and cardiac death (48.7% vs 13.3%), and a newonset atrial fibrillation (41.0% vs 6.7%). In the light of these
findings, patients in the present study were treated to achieve
an HR threshold less than 95 bpm.
The long-term prescription of β-blockers may confer a
survival advantage to patients who subsequently develop
severe sepsis (21). This may act by protecting the septic myocardium and/or modulating the inflammatory response and
adds further weight to the notion of treating tachycardia with
β-blockade if caused by sympathetic overstimulation (4, 12, 13).
Esmolol, because of its half-life of approximately 2 min (22), allows
titration against a predefined HR target and, crucially, a rapid resolution of any potential adverse effect on drug discontinuation.
In all patients investigated within the present study, targeted
HRs between 80 and 94 bpm were achieved within the 24-hour
period. This intervention was accompanied by a decrease in
TABLE 3.

cardiac output, yet maintained stroke volume. In agreement
with previous experimental studies of septic shock (15–17),
titrating esmolol against a predefined HR threshold did not
cause significant cardiovascular derangement in any of our
patients. Indeed, a reduction was recorded in norepinephrine
requirements suggest that, in the presence of an preload, lowering HR allows better ventricular filling during diastole, hence
maintaining stroke volume (8).
Another important finding from the present study is that
microvascular blood flow was not adversely affected by esmolol,
despite the HR-related reduction in cardiac output. This is supported by the maintenance of lactate and Svo2. Similar results were
observed by Schmittinger et al (18), who administered enteral
metoprolol to achieve HR targets between 65 and 95 bpm from 48
hours after the onset of shock. Although not specifically studied,
nonhemodynamic effects of esmolol could conceivably play a role
in microcirculatory protection. As β1-blockade normalized the
depressed fibrinolytic status induced by β1-adrenergic stimulation
(23, 24), esmolol could potentially improve fibrinolytic activity in

Acid-Base Homeostasis and Oxygenation Profile (n = 25)

Variable

Baseline

24 Hr

p

Arterial pH

7.33 (7.27; 7.40)

7.38 (7.35; 7.44)

0.002

Arterial oxygen saturation (%)

100 (99; 100)

100 (99; 100)

0.73

70 (67; 79)

70 (68; 74)

0.12

Mixed venous oxygen saturation (%)
Oxygen delivery index (mL/min/m )
2

Oxygen consumption index (mL/min/m )
2

Oxygen extraction rate (%)

539 (442; 720)

407 (313; 495)

< 0.001

148 (125; 205)

121 (104; 147)

0.002

32 (23; 33)

31 (28; 35)

0.052

Pao2 (mm Hg)

128 (96; 167)

Paco2 (mm Hg)

43 (36; 50)

Base excess (mmol/L)

2.0 (−5.3; 0.2)

Arterial lactate (mmol/L)

2.4 (1.3; 4.9)

158 (123; 206)

0.02

39 (35; 42)

0.01

−1.3 (−2.7; 1.0)

0.10

2.0 (1.3; 3.9)

0.41

Data are given as median (25th; 75th percentile).

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September 2013 • Volume 41 • Number 9

Clinical Investigations
Microvascular Flow Index of small vessels

3,0

MFIs

2,5

2,0

P = 0.002

1,5

1,0
0

24
Time [h]

Figure 1. Change in microcirculatory flow index of small vessels (MFIs)
after 24 hr of esmolol administration. Small vessels were defined as those
with a diameter less than 20 µm. Data are expressed as median (25th;
75th percentile).

the procoagulant state represented by sepsis (24). β-blockers may
also modulate cytokine profile production. Whereas β2-blockers
induce a proinflammatory state, β1-blockade appears to exert
antiinflammatory activity (15, 16, 25, 26).
Finally, an intriguing question is the mechanism by which
esmolol reduces norepinephrine requirements. Studies in normal
volunteers demonstrated increased vascular reactivity to norepinephrine following nonselective β-blockade (27, 28); this has also
been shown in anesthetized rats (29) and in isolated canine arteries (30). The authors postulated various mechanisms including
blockade of a peripheral β2-mediated vasodilatory effect of norepinephrine (29, 30), decreased clearance of infused norepinephrine (31), or a centrally mediated effect on reflex activity (32).
Another study suggested the inhibition of vascular endothelial
nitric oxide synthase activity as a potential mechanism (33).
Clearly, these postulates need to be explored specifically in the
setting of sepsis, and the relevance of these studies to esmolol, a
relatively selective β1-adrenergic antagonist, clarified.
During septic shock, excessive and protracted adrenergic stimulation may cause increased resting energy expenditure, extensive
protein and fat catabolism, and hyperglycemia, contributing to
organ dysfunction (25). Interestingly, propranolol, a nonselective β-receptor antagonist, has been shown to decrease muscle
catabolism and reduce elevations in resting energy expenditure
TABLE 4.

in children with burns (34). Similarly, it has been postulated that
β-blockers may counteract the sepsis-related hypermetabolic state.
In the present study, we found a significant decrease in oxygen
consumption with an unchanged oxygen extraction and lactate,
suggesting an esmolol action on metabolism. Our findings vary
from the study of Gore and Wolfe (35), in which a 20% HR reduction with esmolol did not affect oxygen consumption nor energy
expenditure in six patients with sepsis. Nevertheless, differences
in the study designs (sample size, esmolol dosages, observational
period) and, more importantly, severity of the disease (high norepinephrine requirements) may explain the discrepancy between
our results and this previous observation (35). However, because
we measured oxygen consumption using a pulmonary artery
catheter instead of indirect calorimetry, our study does not allow
us to draw any definitive conclusions about the possible effects of
esmolol in modulating sepsis-associated metabolic dysfunction.
Such effects should be further investigated in future studies.
There are several limitations to this present pilot study. Being
the first clinical study to investigate the macro- and microcirculatory effects of an esmolol-titrated reduction in HR in septic
shock patients, in whom tachycardia persisted after conventional
hemodynamic stabilization, we sought, for safety reasons, to
use a case-crossover design in which the patient served as his/
her own control. We thus lack a control group so we cannot be
certain that our findings are the consequence of the esmololinduced reduction in HR rather than an independent evolution
in the patients’ condition. However, the lack of any significant
deterioration in hemodynamics, microcirculation, blood gas
analyses, or organ function seen in any patient, nor any large
increase in norepinephrine requirement, do all imply a positive contribution from esmolol. This will need to be formally
tested in a prospective, controlled study. Our findings do provide further encouragement and reassurance that this study can
be performed safely and with potential outcome benefit. The
sample size was relatively small, similar to previous studies (36–
38); however, the consistency of the macro- and microvascular
response to esmolol was notable. The predefined HR threshold
was chosen arbitrarily rather than being individualized according to the specific myocardial characteristics of each patient.
Nevertheless, we adopted this threshold as previous data demonstrated that HR values greater than 95 bpm are associated with
adverse cardiac events (5). Pragmatically, it also offers a readily
achievable target without a round-the-clock reliance on skilled
echocardiography. We also have to acknowledge that while SDF
imaging allows visualization of the intact microcirculation in

Microcirculatory Variables (n = 25)

Variable

Baseline

Total vessel density (mm/mm2)

p

24 Hr

22 (19; 25)

22 (20; 25)

0.53

2

Perfused vessel density (mm/mm )

20 (18; 22)

21 (18; 23)

0.73

Proportion of perfused vessels (%)

96 (93; 99)

95 (93; 99)

0.99

De Backer score (vessels/mm)

14 (12; 15)

14 (12; 15)

0.51

0 (0; 0)

0.002

Heterogeneity index

0.06 (0; 0.21)

Data are given as median (25th; 75th percentile).

Critical Care Medicine

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Morelli et al

the clinical setting, the assessment currently remains semiquantitative and data reliability may be affected by technical expertise, pressure artifact, and interobserver bias. Finally, we chose a
change in MFI in the sublingual microcirculation as our primary
endpoint. It is still unclear whether this is the optimal variable to
target (39) and whether the effects of esmolol on the sublingual
circulation are representative of other organ beds.

CONCLUSIONS
This is the first prospective study investigating the macro- and
microcirculatory effects of esmolol-titrated reduction in HR
below a predefined threshold of 95 bpm in septic shock patients in
whom tachycardia persisted after conventional hemodynamic stabilization. After 24 hours’ therapy, stroke volume and microvascular blood flow were maintained while norepinephrine dosage was
reduced with no detriment to lactate or Svo2. This pilot study supports the hypothesis that HR reduction with esmolol may safely
preserve myocardial function in septic shock by decreasing cardiac workload but without compromising the microcirculation.
Appropriately powered, randomized, controlled trials are needed
to determine the effects of β-blockade on outcomes.

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September 2013 • Volume 41 • Number 9


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