JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 9, NO.

1, 2023

ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

INNOVATIONS IN CLINICAL ELECTROPHYSIOLOGY

Isoproterenol-Assisted Differentiation
Between Sludge and Organized
Thrombus to Guide Left Atrial
Appendage Occlusion
Sandeep K. Goyal, MD,a Syed Hyder, BS,a Shizhen Liu, MD, PHD,b Mani A. Vannan, MBBSb

ABSTRACT

Percutaneous left atrial appendage occlusion (LAAO) is contraindicated in presence of left atrial appendage (LAA)
thrombus. It is often difficult to separate LAA sludge from an organized thrombus on transesophageal echocardiography.
The inability to differentiate sludge from thrombus leads to patients not receiving LAAO despite contraindication to long-
term anticoagulation. Retrospective 6-month follow-up outcomes are reported on patients undergoing LAAO in presence
of LAA sludge cleared by isoproterenol. This study showed no increased risk of transient ischemic attack/stroke in the
6 months following LAAO in the presence of LAA sludge, which was cleared with isoproterenol. This study suggests a role
for isoproterenol in differentiating sludge from thrombus. (J Am Coll Cardiol EP 2023;9:111–116) © 2023 by the American
College of Cardiology Foundation.

P ercutaneous left atrial appendage occlusion

(LAAO) is indicated for patients with atrial
fibrillation, who are unable to tolerate long-
term anticoagulation. 1 A left atrial appendage (LAA)
thrombus is a discrete, organized mass that is an ab-
solute contraindication to percutaneous LAAO,1 LAA
sludge is a dynamic viscid, layered echo-dense
finding without a discrete mass. It appears more
dense than spontaneous echo contrast (SEC) and
less dense than a thrombus, and is therefore consid-
ered to be a stage between SEC and thrombus.2 It is
often difficult to separate sludge from a true orga-
nized thrombus on transesophageal echocardiogra-
phy (TEE). 3 Sludge is independently associated with
subsequent thromboembolic events and all-cause
mortality. 2 The inability to differentiate sludge from
thrombus often leads to patients not receiving LAAO
closure, and those patients continue to remain at
high risk of adverse events, especially given that
continuous oral anticoagulation is not clinically toler-
ated in the LAAO-indicated patient population.2
Reversal of atrial stunning postcardioversion for
atrial fibrillation using isoproterenol infusion has
been previously described. 4 There are published
case reports of using isoproterenol to differentiate
sludge from thrombus prior to LAAO. 5,6 However,
there are no midterm to long-term data on events
during follow-up. We aimed to assess thromboem-
bolic outcomes in patients with LAA sludge undergo-
ing LAAO after confirmation of clear LAA with
isoproterenol infusion.
METHODS
The study was approved by the Institutional Review
Board. Retrospective chart review of patients

From the aDivision of Cardiac Electrophysiology, Piedmont Heart Institute, Atlanta, Georgia, USA; and the bDivision of Cardio-
vascular Imaging, Piedmont Heart Institute, Atlanta, Georgia, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received September 9, 2022; revised manuscript received September 27, 2022, accepted October 3, 2022.

ISSN 2405-500X/$36.00 https://doi.org/10.1016/j.jacep.2022.10.026

112 Goyal et al
Left Atrial Appendage Sludge vs Thrombus
ABBREVIATIONS undergoing LAAO at Piedmont Atlanta Hos-
AND ACRONYMS pital from July 2019 to December 2021 was
performed. The study cohort included pa-
DAPT = dual antiplatelet
therapy
tients with LAA sludge on TEE, who received
isoproterenol to differentiate sludge from
LAA = left atrial appendage
thrombus. Patients with LAA sludge who did
LAAO = left atrial appendage
occlusion not receive isoproterenol due to patient or
SEC = spontaneous echo
operator preference were excluded from
contrast analysis. Figure 1 shows a process diagram for
TEE = transesophageal assessment and decision making when eval-
echocardiography uating patients for LAAO in presence of
TIA = transient ischemic attack known LAA sludge.
PREPROCEDURE PROTOCOL. Study patients had
contraindications to long-term anticoagulation but
were suitable for short term anticoagulation. All pa-
tients had a known diagnosis of LAA sludge based on
prior imaging via TEE or computed tomography scan.
Four weeks of standard-dose anticoagulation was
used in all patients between the initial diagnosis of
LAA sludge and the index LAAO procedure. Higher-
dose anticoagulation was only attempted in 1 pa-
tient, as other patients were unwilling to take higher-
dose anticoagulation due to adverse events on
standard-dose anticoagulation. Preprocedure
informed consent included discussion of presence of
LAA sludge, need for uninterrupted anticoagulation
prior to the procedure, and a potential for an un-
known increase in risk of stroke if isoproterenol
infusion was used to clear the LAA. Our group had
used cerebral embolic protection devices in the first 4
patients, in which isoproterenol infusion was used to
clear the LAA. Postprocedure evaluation of embolic
protection devices showed no retained thrombus.
Those patients are not included in this analysis.
INTRAPROCEDURE PROTOCOL. After general anes-
thesia was induced, TEE was performed to evaluate
the LAA for sludge or thrombus. If a definite orga-
nized LAA thrombus was seen, isoproterenol infusion
was not attempted and LAAO was not performed. If
LAA sludge was present, isoproterenol was adminis-
tered as a 3-m g bolus followed by 1-m g/min infusion.
Heart rate and left ventricular contractility were used
as surrogates to decide on adequate response. Infu-
sion was uptitrated to a maximum of 3 m g/min. The
infusion was continued for up to 10 minutes after the
maximal infusion dose was achieved. If a clear LAA
was seen, the infusion was stopped, and we pro-
ceeded with venous access for LAAO (Central
Illustration). LAA sludge reappeared in all cases once
isoproterenol was stopped. Heart rate and left ven-
tricular contractility were allowed to return to base-
line prior to transseptal puncture. Intravenous
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 9, NO. 1, 2023
JANUARY 2023:111–116
heparin was administered immediately after venous
access, and an activated clotting time of >350 seconds
was achieved prior to transseptal puncture.
LAA angiography was performed in select cases in
which it was deemed necessary to further define LAA
anatomy to achieve a successful LAAO. No LAA filling
defects were seen on LAA angiography. Six patients
underwent first-generation WATCHMAN device
(Boston Scientific) implantation and rest were
implanted with a WATCHMAN FLX (Boston Scientific)
device. Protamine was used to reverse the effect of
heparin at the end of the procedure, as all patients
were on uninterrupted therapeutic oral
anticoagulation.
POSTPROCEDURE PROTOCOL. First, 10 patients
were admitted for overnight observation and other
patients were discharged home the same day if clin-
ical condition allowed. All patients underwent a
focused neurological examination by the attending
electrophysiologist prior to discharge. A comprehen-
sive neurological exam or routine brain imaging was
not performed.
Patients were maintained on uninterrupted oral
anticoagulation, and aspirin 81 mg was added on
discharge. If oral anticoagulation was not tolerated
and had to be stopped, we switched to a dual an-
tiplatelet therapy (DAPT). All patients underwent
TEE between 30 and 60 days postprocedure and
were switched to DAPT if no thrombus or peri-
device leaks (>5 mm) were seen. A follow-up office
visit was conducted at w6 months from
implantation.
Data were collected on medical history, procedural
details, and composite 6-month outcome defined as
transient ischemic attack (TIA), stroke, or device-
related thrombus. Descriptive statistics were used to
analyze the data. Median (IQR) are reported for
continuous variables.
RESULTS
Thirty-four patients were identified to have LAA
sludge vs early thrombus. Four of these patients had
persistent LAA echogenicity despite isoproterenol
infusion and thus were classified as likely thrombus
and were excluded from analysis (Video 1). Thirty
patients with sludge at baseline and clear LAA after
isoproterenol infusion were included in analysis
(Figure 2). Median age was 76.5 (IQR: 73.7-82.0) years,
21 (70%) were men, median left ventricular ejection
fraction was 55.0% (IQR: 55.0%-59.5%), and median
CHA 2DS2-VASc score was 4 (IQR: 3-5). All patients
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 9, NO. 1, 2023 Goyal et al 113
JANUARY 2023:111–116 Left Atrial Appendage Sludge vs Thrombus

F I G U R E 1 Process Diagram for Treatment Decision

Process used to assess and make treatment decisions when evaluating patients for left atrial appendage occlusion (LAAO) in the presence of known left atrial appendage
(LAA) sludge. CT ¼ computed tomography; DRT ¼ device-related thrombus; PDL ¼ peridevice leak; TEE ¼ transesophageal echocardiography.

underwent successful LAAO without acute proce-
dural complications, and TEE imaging between 30
and 60 days postprocedure showed no evidence of
significant peridevice leaks (>5 mm) or device
embolization. Device-related thrombus was present
in 1 patient; oral anticoagulation was continued for
additional 45 days, and repeat imaging showed
complete resolution. Six-month follow-up data were
available in all study patients. There were no deaths,
TIA, or stroke at 6-month follow-up. Two patients had
gastrointestinal bleeding on oral anticoagulation
prior to initial imaging and were switched to DAPT
before 45-day TEE; they completed 6 months of DAPT
therapy.
114 Goyal et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 9, NO. 1, 2023

Left Atrial Appendage Sludge vs Thrombus JANUARY 2023:111–116

C E N T R A L IL L U ST R A T I O N Role of Isoproterenol in Management of Patients With LAA Stasis

A B

Atrial fibrillation and stasis in LAA leading to sludge

Reduced LAA emptying velocity

(Isoproterenol infusion after excluding

organized thrombus)

C D

Increased contractility with “clear” LAA

Increased LAA emptying velocity

LAA closure after resolution

of sludge on isoproterenol

LAA occlusion providing durable elimination of LAA stasis

Goyal SK, et al. J Am Coll Cardiol EP. 2023;9(1):111–116.

(A) Stasis of blood in the left atrial appendage (LAA) during atrial fibrillation. (B) Reduced LAA emptying velocity during atrial fibrillation.
(C, D) LAA after isoproterenol infusion. (C) Movement of stagnant blood out of the LAA with isoproterenol infusion and (D) increase in LAA
velocity on echo Doppler signal. (E) An implanted LAA occlusion device (WATCHMAN FLX) after clear LAA was confirmed.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 9, NO. 1, 2023
JANUARY 2023:111–116
F I G U R E 2 LAA Imaging Pre- and Post-Isoproterenol
Left atrial appendage (LAA) on transesophageal echocardiography with (A) echogenic material and (B) reduced LAA emptying velocity, (C) clear LAA after isoproterenol,
and (D) increase in LAA emptying velocity after isoproterenol.
DISCUSSION
Our series of patients showed no increased risk of
TIA/stroke in the 6 months following LAAO in pres-
ence of LAA sludge, which cleared with isoproterenol
infusion. This series adds to the published evidence
on the role of isoproterenol in differentiating sludge
from thrombus. We also provide new data suggesting
midterm safety and efficacy of LAAO in patients with
LAA sludge.
Cardiologists consider sludge a relative contrain-
dication to cardioversion or LAAO due to concern for
increased risk of thromboembolism. A small study of
21 patients showed that outcomes after cardioversion
of patients presenting with LAA sludge are not
Goyal et al 115
Left Atrial Appendage Sludge vs Thrombus
significantly different than ones with a clear LAA, if
postcardioversion anticoagulation is maintained for
at least 1 month. 3 We studied a unique population of
patients who have LAA sludge but are not suitable
candidates for long-term oral anticoagulation. These
patients remain at higher risk of TIA and stroke,
especially in the absence of continuous oral anti-
coagulation.2 Sanders et al4 showed that after abla-
tion of atrial flutter, isoproterenol resulted in a
significant increase in LAA emptying velocity,
returning stunned atrial mechanical function to
magnitudes more than preablation values with the
disappearance of SEC. The increase in LAA emptying
velocity is the likely mechanism for clearance of LAA
with isoproterenol when sludge or SEC is present due
116 Goyal et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 9, NO. 1, 2023

Left Atrial Appendage Sludge vs Thrombus JANUARY 2023:111–116

to slow flow. By the same token, there would be a FUNDING SUPPORT AND AUTHOR DISCLOSURES
theoretical risk that if isoproterenol is administered
in the setting of organized thrombus; it could increase The authors have reported that they have no relationships relevant to
the contents of this paper to disclose.
the risk of thrombus dislodgement and consequent
thromboembolic events.
ADDRESS FOR CORRESPONDENCE: Dr Sandeep K.
To mitigate this risk, we did not administer
Goyal, Piedmont Heart Institute, 275 Collier Road, Suite
isoproterenol in patients with definite organized
500, Atlanta, Georgia 30306, USA. E-mail: sandeep.
thrombus and used cerebral protection in an initial 4
goyal@piedmont.org. Twitter: @DrSGoyal_EP.
patients in which isoproterenol was used in setting of
LAA sludge. A robust informed consent discussion
was performed with the patients regarding risks, PERSPECTIVES
benefits, and alternatives prior to proceeding with
LAAO in this unique situation.
COMPETENCY IN MEDICAL KNOWLEDGE: Pa-
To our knowledge, this study is first published
tients with LAA sludge and inability to tolerate long-
report of clinical outcomes on a cohort of patients
term anticoagulation should be made aware of po-
with LAA sludge undergoing LAAO. Our data provide
tential management options with LAAO and its asso-
further information to help guide management of
ciated risks and benefits.
these patients. However, the relatively small number
of patients and single-center retrospective design of
TRANSLATIONAL OUTLOOK: Larger, multicenter
our series limits its ability to generalize the results to
studies evaluating the role of isoproterenol-assisted
broader population. We view our results as additive
LAAO in patients with LAA sludge should be under-
but not conclusive. There is need for a larger, pro-
taken to further understand the safety profile and
spective, multicenter registry to further validate
develop best practices.
these findings before this could be considered general
standard of care.

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KEY WORDS isoproterenol, LAAO, sludge,
stroke, thrombus
AP PE NDIX For a supplemental
video, please see the online version of this
paper.