Opinion
EDITORIAL
β-Blockers in Patients With Sepsis
Putting the Puzzle Together, Piece by Piece
Steven M. Hollenberg, MD
Challenging conventional wisdom is important and fre-
quently useful. Septic shock is a form of distributive shock in
which hypotension results from vasodilation.1 Although myo-
cardial performance may not always be entirely normal,
a phenomenon termed septic
Related article page 1641
cardiomyopathy,2 cardiac out-
put is usually preserved, in
part by increased heart rate. Therapy of septic shock refrac-
tory to fluid administration entails administration of vaso-
pressor agents; norepinephrine is generally preferred as an
initial agent.3 In those cases in which cardiac output is felt to
be low enough to compromise perfusion, inotropic agents
may be used.3 In this context, use of β-blockers may well be
regarded as counterintuitive inasmuch as their hemody-
namic effects would tend to decrease arterial pressure and
cardiac output. Despite this, investigators have challenged
conventional wisdom and evaluated the effects of β-blockade
for treating sepsis.
β-Blockers have been shown to improve survival in some
small animal models of septic shock.4 Despite decreased heart
rate, cardiac output is often preserved in these models, and some
studies have suggested that a decrease in myocardial work-
load may be associated with improved myocardial energy
efficiency.5 Not all animal studies have shown benefits with
β-blockade, however. In a sheep model, esmolol was associ-
ated with deterioration of kidney and microvascular perfusion.6
Among patients with sepsis, a retrospective study re-
ported that chronic use of β-blockers prior to hospital admis-
sion was associated with improved outcomes.7 Clinical stud-
ies of administration of β-blockers for sepsis have used the
short-acting intravenous agents, esmolol and landiolol. Early
studies showed that these agents could usually be given with-
out marked deterioration of hemodynamics. The largest ran-
domized trial of β-blockade in sepsis was a single-center, open-
label study that examined the safety of reducing heart rate to
a target range of 80/min to 94/min among 154 patients with
sepsis receiving norepinephrine infusion randomized to re-
ceive esmolol or placebo.8 The heart rate end point was met,
stroke volume was increased, and cardiac output was un-
changed with esmolol. The adjusted hazard ratio for mortal-
ity was 0.61, with a decrease from 80.5% to 49.4% with esmo-
lol, but this was a nonprimary outcome. Another challenge with
this trial was that mortality in the control group was much
higher than most other trials involving patients with septic
shock.8 This trial, although not regarded as definitive, spurred
interest in this strategy.
Landiolol is an ultrashort-acting β-blocker that is 8 times
more selective for the β1-receptor than esmolol and as such
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was hypothesized to provide more myocardial protection
and immunomodulation while providing a margin of safety
due to its very short half-life. Whitehouse and the STRESS-L
investigators9 report the results of a pragmatic randomized
trial that compared landiolol with placebo. Patients were eli-
gible for randomization if they met Sepsis-3 criteria,10 had
been adequately fluid resuscitated, were receiving norepi-
nephrine at a dose of 0.1 μg/kg/min for more than 24 hours
and less than 72 hours, and had a heart rate greater than
95/min. Open-label landiolol was given to achieve a heart
rate of 80/min to 94/min via a specified protocol with titra-
tion every 15 minutes. The primary end point was mean
SOFA score averaged over the first 14 days of the trial and
while patients remained in the ICU, an end point previously
used in the Levosimendan for the Prevention of Acute Organ
Dysfunction in Sepsis (LeoPARDs)11 trial. Secondary out-
comes included mortality at 28 and 90 days, length of stay,
mean arterial pressure, and norepinephrine doses over the
first 5 days, lactate concentrations, and fluid balance. Safety
outcomes included bradycardia and heart block, with and
without hypotension.
There were no formal stopping rules, but the trial was
stopped early by the data monitoring committee after enroll-
ment of 126 of a planned 340 patients on the basis that lan-
diolol was unlikely to demonstrate benefit even if recruit-
ment had continued to the study’s full sample size and also
because there was a signal of possible harm in relation to mor-
tality in the intervention group. The mean (SD) SOFA score over
the 14 days was 8.8 (3.9) for the landiolol group compared with
8.1 (3.2) for the standard care group (P = .24). Mortality at day
28 was 37.1% in the landiolol group and 25.4% in the standard
care group (P = .16) and at 90 days was 43.5% for the landio-
lol group compared with 28.6% for the standard care group
(P = .08). The landiolol group had lower mean arterial pres-
sure, greater norepinephrine doses, and numerically higher lac-
tate levels. A higher proportion of patients receiving landio-
lol experienced serious adverse events. The subgroup analyses,
although underpowered due to the entirely appropriate deci-
sion of the data monitoring committee to terminate the trial
given the early signal of potential harm, showed consistent re-
sults across subgroups of norepinephrine dose, presence of
acute respiratory distress syndrome, and use of β-blockers prior
to randomization.
Why did landiolol fail to show benefit in this trial? One
possibility is a hemodynamic effect. The current study started
β-blockade after 24 hours in the face of data from a pilot trial
showing instances of hypotension and decreased cardiac out-
put with early β-blockade12; such patients may have septic
(Reprinted) JAMA November 7, 2023 Volume 330, Number 17 1627
 Opinion Editorial

cardiomyopathy and may not tolerate β-blockade. Cardiac
output monitoring was left to the discretion of the investiga-
tors for pragmatic reasons, and this is an important limitation
of the trial. It is hard to exclude the possibility that at least
some of the patients in the landiolol group may have had
decreased cardiac output, with or without a vasodilatory
effect, a possibility that is supported by decreased blood
pressure, elevated lactate levels, and increased norepineph-
rine requirements in this group. It is conceivable that closer
hemodynamic monitoring, at least in selected patients,
would have allowed more careful titration of β-blockers so as
to minimize decreases in cardiac output. In this respect, dif-
ferences between the STRESS-L trial and the trial by Morelli
et al8 included the use of hemodynamic monitoring, a re-
quirement of a mixed-venous oxygen saturation of more than
65%, and use of levosimendan in the trial by Morelli et al,
all of which may have helped ensure that cardiac output
was maintained.
One of the postulated mechanisms of benefit from
β-blockade is decreased myocardial oxygen requirement at a
lower heart rate. There is little evidence for myocardial ische-
mia as a cause of septic cardiomyopathy, however.2 In addi-
tion, to the extent that energetic failure in sepsis may result from
dysfunction in mitochondrial oxygen use rather than perfu-
sion failure, this is likely to be independent of hemodynamic
status and also not especially responsive to β-blockers.
Another possibility is that potential benefits of β-blockade
in sepsis are independent of systemic hemodynamic effects.
Although it is hard to imagine titrating β-blockade to any-
thing other than heart rate, if only for purposes of safety, those
effects might require dosages different from those needed to
control heart rate.
It is also possible if not likely that β-blockers have the po-
tential for both beneficial and deleterious effects, both within
and among patients. Sepsis is nothing if not complex.
β-Blockade may have beneficial effects in some areas, such as
inflammation and metabolism, but potentially deleterious ef-
fects in others. The balances between various effects may well
diverge in different patients and at different times. In this con-
text, further exploration of mechanisms of action in patients
with sepsis could help guide future trials, in terms of patient
selection, or dosing, or timing, or all of the above.
The authors should be commended for conducting a rig-
orous randomized trial with a clinical end point, something that
had been previously lacking despite promising findings from
other investigations with surrogates as primary end points.
Does this signal the end for investigation of β-blockade for sep-
sis? One would hope not. Further elucidation of mechanisms
by which β-blockers may be beneficial or harmful might lend
insight into the pathophysiology of septic shock and poten-
tially allow for identification of patient subsets that might be
selected for β-blockade. There is still much more to be learned.

ARTICLE INFORMATION
Author Affiliation: Emory University School of
Medicine, Atlanta, Georgia.
Corresponding Author: Steven M. Hollenberg, MD,
Department of Cardiology, Emory University School
of Medicine, 1365 Clifton Rd NE, A2243, Atlanta, GA
30322 (steven.hollenberg@emory.edu).
Published Online: October 25, 2023.
doi:10.1001/jama.2023.20455
Conflict of Interest Disclosures: None reported.
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