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\begin{document}

\title{Acoustic Pulse Thrombolysis Complemented by ECMO Improved Survival in
Patients with High-Risk Pulmonary Embolism}



\author[1]{Mert Dumantepe}%
\author[2]{Cuneyd Ozturk}%
\affil[1]{Uskudar University}%
\affil[2]{Florence Nightingale Hospital}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: The optimal treatment of high-risk PE with cardiac arrest is
still controversial although various treatment approaches have been
developed and improved. Here, we present a serie of patients with
high-risk PE showing hemodynamic collapse, who were successfully treated
with extracorporeal membrane oxygenation (ECMO) as an adjunct to EKOS
acoustic pulse thrombolysis. Method: From April 2016 to June 2020, 29
patients with high-risk PE with cardiac arrest were retrospectively
included. The mean age was 55.3 \selectlanguage{ngerman}± 9.2 years. Twelve (41.3\%) patients
were female. All patients had cardiac arrest, either as an initial
presentation or in-hospital after the presentation. All patients
exhibited acute symptoms, computed tomography (CT) evidence of large
thrombus burden, and severe right ventricular dysfunction. Primary
outcome was all-cause 30-day mortality. Results: Twenty-two patients
survived to hospital discharge, with a mean ICU stay of 9.9 ± 1.6 days
(range, 7 to 22 days) and mean length of hospital stay of 23.7 ± 8.5
days (range, 11 to 44 days). Six patients died from refractory shock.
Ninety-day mortality was 24.1\% (7/29). The Mean ECMO duration was 3.5 ±
1.1 days and the mean RV/LV ratio decreased from 1.31 ± 0.17 to 0.92 ±
0.11 in patients who survived to discharge. The mean tissue plasminogen
activator (tPA) dose for survivor patients was 20.5 ± 1.6 mg.
Conclusion: Patients with high-risk pulmonary embolism who suffer a
cardiac arrest have high morbidity and mortality. APT complemented by
ECMO could be a successful treatment option for patients who have
high-risk PE with circulatory collapse.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Acute pulmonary embolism (PE) can be stratified as high-risk or massive
PE, intermediate-risk or submassive PE, and low-risk or non-massive PE,
with nearly 300,000 deaths per year attributable to
PE\textsuperscript{1}. Right ventricular dysfunction (RVD) and the
presence of hemodynamic instability are powerful predictors of poor
prognosis of patients with acute PE\textsuperscript{2}. In particular,
patients with acute high-risk PE defined as cardiogenic shock and
systemic hypotension, are at particularly increased risk of early death,
and require emergency treatment to restore circulation. Overall,
in-hospital mortality rates for massive PE range from 25\% for patients
with cardiogenic shock (CS), to 65\% for those that required
cardiopulmonary resuscitation (CPR), while in-hospital mortality rate in
stable patients with PE was 8.1\% \textsuperscript{3}.

Although systemic anticoagulation remains the cornerstone of therapy for
acute symptomatic pulmonary embolism, the morbidity and mortality
associated with high-risk PE and intermediate-high risk PE warrant
treatment beyond anticoagulation alone. More aggressive therapeutic
options include systemic intravenous thrombolysis (Class IB), surgical
embolectomy (Class IC) and catheter-directed thrombolysis needed (CDT)
(Class IIa) according to European Society of Cardiology
guidelines\textsuperscript{4}.

However, the clinical course of high-risk PE can rapidly progress before
surgical or catheter-directed treatment. Many patients are not amenable
to reperfusion therapies or fail to improve after these treatments due
to major hemodynamic instability and cardiogenic shock. Based on the
ICOPER Registry, two-thirds of patients with massive PE did not receive
any thrombolysis or surgical embolectomy\textsuperscript{5}. For those
patient group, veno- arterial extracorporeal membrane oxygenation
(VA-ECMO) is one of the most reliable and quickest way to decrease RV
overload, improve RV function and hemodynamic status, restore tissue
oxygenation and may be considered as either a bridge to reperfusion
therapy such as surgical embolectomy or CDT\textsuperscript{6}.

The general aim of catheter-directed therapy in the setting of
hemodynamically compromised patients with acute PE is to debulk and/or
redistribute the obstructive clot rendering it less hemodynamically
significant. In recent years, interest has risen in a variety of
endovascular strategies based on catheter-based technologies for
thrombus removal in patients with high-risk PE. The EKOS? EkoSonic
Endovascular System (EKOS, Boston Scientific, USA) is a catheter-based
system that uses high frequency, low-energy ultrasound waves to aid in
the delivery and uptake of thrombolytic agent within the clot.

Existing data regarding the utility of ECMO in the setting of high-risk
PE mainly come from case reports or small series\textsuperscript{(6-8)}.
The impacts of VA-ECMO in conjunction with EKOS acoustic pulse
thrombolysis (APT) on survival have not been investigated in massive PE.
Therefore, we present a serie of patients with high risk PE showing
hemodynamic collapse that required cardiopulmonary resuscitation, who
were successfully treated with VA-ECMO as an adjunct to APT.

\textbf{Methods}

Patients

A total of 154 consecutive patients with MPE, initially diagnosed by
either computed tomography or echocardiography from April 2016 to June
2020 transferred from emergency department to our catheterization
laboratory, were retrospectively evaluated, of whom 29 patients met the
criteria for high-risk PE complicated by profound cardiogenic shock or
that required CPR (n=29), were enrolled in the study to analyze clinical
outcomes. Written informed consent was obtained from each enrolled
patient or from the family after the purpose and the risk of the
treatment were fully explained. The Institutional Committee of Ethics in
Research approved this clinical research project.

\emph{Data collection}

A manual review of patient charts was then undertaken to confirm the
diagnosis and to obtain preoperative, perioperative, and postoperative
variables and outcomes. At hospital or ICU admission, we collected the
following information: demographics, presence of venous-thromboembolic
risk factors; Simplified Acute Physiology Score (SAPS)
II\textsuperscript{9} and Sequential Organ Failure Assessment (SOFA)
score\textsuperscript{10}.

During the pre-ECMO period, the inotrope score\textsuperscript{11},
defined as dobutamine dose (\selectlanguage{greek}γ/\selectlanguage{english}kg/min) + {[}norepinephrine dose
(\selectlanguage{greek}γ/\selectlanguage{english}kg/min) + epinephrine dose (\selectlanguage{greek}γ/\selectlanguage{english}kg/min){]} \selectlanguage{ngerman}× 100; cardiopulmonary
arrest with its related ``low-flow'' and ``no-flow'' situations; and
troponin level and blood gas analyses were noted. The echocardiography
variables which includes; left ventricular ejection fraction (LVEF),
RV/LV dimension ratio and visualization of a pulmonary arterial thrombus
were also recorded before ECMO insertion. RV dysfunction (none, mild,
moderate, or severe) was recorded according to a preoperative and
postoperative transthoracic echocardiogram by an independent
cardiologist, who both quantitatively and qualitatively assessed RV
function.

The pulmonary angiography was independently reviewed for quantification
of pulmonary emboli by one observer who was blinded to the clinical
course. We applied an embolic burden scoring system in our study:
observer scored main, lobar, right interlobar and segmental pulmonary
arteries for the presence of emboli and also graded whether emboli were
occlusive\textsuperscript{12}.

\emph{Indications for VA-ECMO and Management of ECMO Support}

VA-ECMO indications were: acute refractory cardiovascular failure,
defined as evidence of tissue hypoxia concomitant with adequate
intravascular volume status; severely diminished RV function or LVEF;
low cardiac index (\selectlanguage{english}[?]2.1 L/min/m2); sustained hypotension despite
high-dose catecholamine infusion (epinephrine \selectlanguage{english}[?]1 \selectlanguage{greek}γ/\selectlanguage{english}kg/min or dobutamine
[?]20 \selectlanguage{greek}γ/\selectlanguage{english}kg/min + norepinephrine [?]1 \selectlanguage{greek}γ/\selectlanguage{english}kg/min).

All patients, regardless of age or comorbid conditions, were considered
candidates for this intervention, unless their predicted survival
independent of the PE, was less than 1 year. ECMO consist of a
centrifugal pump, a hollow fiber oxygenator (Livanova, Sorin Group,
Italy) and cannulas (Xenios AG-Medos, Heilbronn Germany). Cannulation
was performed under ultrasound guidance, with a 23F to 25F venous
drainage cannula placed in a femoral vein and a 17F to 19F arterial
return cannula placed in a common femoral artery in the contralateral
groin whether in the ICU or in the operation room. A 6F distal perfusion
cannula was placed in the superficial femoral artery as a first step
previously, unless the patient was actively requiring cardiopulmonary
resuscitation (CPR), to allow for better ultrasound visualization of the
superficial femoral artery.

ECMO Flows were maintained in the range of 2 to 4 L/minute, requiring
pump speeds of approximately 3,000 to 4,000 rpm, and were adjusted with
the goals of reversing acidosis while maintaining arterial saturation
and cardiac output. Support flow was also titrated up until the right
ventricle was decompressed by TTE and maintain a systemic blood pressure
of 90 mmHg. However, some pulmonary blood pulmonary flow was maintained
to allow for APT. Systemic anticoagulation was maintained with activated
clotting time of 180-200 seconds by unfractionated heparine infusion.
Figure 1. shows one survivor patient who have high-risk PE and cardiac
arrest, stabilized hemodynamically with VA-ECMO; just before
catheter-based intervention with EKOS? APT.

\emph{Treatment Procedure}

Patients were taken to the hybrid operating room for EKOS? APT after
stabilization of hemodynamic status with the support of VA-ECMO. For the
placement of the EkoSonic Endovascular System common femoral vein access
was established by placement of a bilateral 6 French vascular sheath.
Digital subtraction angiography was performed in two bilateral anterior
oblique projections with the pigtail diagnostic catheter positioned in
the main pulmonary artery. Once the location of a pulmonary arterial
thrombus was identified angiographically, the angiographic catheters
were exchanged for an EkoSonic infusion device, which was navigated over
a 0.035-inch angled guidewire, such that the distal tip of the EKOS?
infusion catheter was positioned at the distal edge of the thrombus
under fluoroscopy (Figure 2).

Patients were transferred to the ICU for thrombolytic infusion with tPA
administered at a rate of 1 to 1.5 mg/hr (0.5 to 0.75 mg/hr through each
catheter, in case of bilateral PE). 1 mg bolus tPA per catheter was
administered to the patients before the overnight infusion. Normal
saline coolant was infused at a rate of 40 cc/hr, through the coolant
port of the EKOS? infusion catheter.

\emph{Clinical Outcomes}

The main outcome variables included ECMO weaning, survival to hospital
discharge, 90-day survival, and long-term survival. Secondary outcomes
included acute kidney injury that required renal replacement therapy,
sepsis, ischemic stroke, RV dysfunction at discharge, ECMO-related
complications and vascular complications. Furthermore, we calculated
patient's SOFA scores at cannulation and day 1, 3, and 7 and the
inotrope score; during the ECMO and mechanical ventilation.

Bleeding complications were reported using the GUSTO
classification\textsuperscript{13}. The number of packs of blood
products transfused were also collected.

\emph{Statistical analyses}

Statistical analysis was performed with Graphpad Instat software
(version 3 for Mac; version 11.5, GraphPad Software, Inc., La Jolla, CA,
USA). Results are expressed as numbers (\%) or mean \selectlanguage{ngerman}± standard deviation
(range). Continuous variables were compared with Student's t test or the
Mann--Whitney U test, as appropriate, whereas categorical variables were
compared with chi-square tests. The change from baseline to follow-up of
both the RV/LV ratio and the embolic burden score was assessed using
one-way, repeated measures analysis or variance for respiratory
parameters using ANOVA. A p-value \textless{}0.05 was considered
statistically significant.

\textbf{Results}

\emph{Study Population}

During the study period, a total of 154 patients with high-risk PE were
identified, of whom 29 patients with high risk PE, complicated by
cardiogenic shock or that required CPR were treated with ECMO in
conjunction with EKOS\selectlanguage{english}? APT. The baseline clinical characteristics of the
patients are summarized in Table 1. Twelve of 29 patients placed on ECMO
with cardiac arrest were female and mean age 55.3 +- 9.2 years. The
majority of patients had major transient risk factors for VTE, such as
surgery, immobilization, or prolonged bed rest. Nine patients (31\%) had
a prior history of VTE, 5 (17.2\%) patients have malignancy, 7 (24.1\%)
patients have positive hypercoagulable work-up after presentation. The
most frequent comorbidities were hypertension (48.2\%), smoking
(55.1\%), and cardiovascular disease (20.6\%).

Mean SAPS II and SOFA score were high, respectively, 78.3 +- 14.5 and
13.1 +- 3.8. All patients required hemodynamic support with vasoactive
drugs, resulting in a mean inotrope score of 117 +- 16.3 (20--197)
\selectlanguage{greek}μ\selectlanguage{english}g/kg/min at ECMO cannulation. The mean troponin level was 2.12 \selectlanguage{ngerman}± 0.37
ng/mL and the mean pro-B-type natriuretic peptide (pro-BNP) level was
3255 ± 1170 pg/L. Pre-ECMO mean blood pressure, pH and blood lactate
was, respectively: 55.6 ± 7.7 mmHg, 7.11 ± 0.13 and 12.5 ± 2.6 mmol/L
(Table 2). Transthoracic or transesophageal echocardiography visualized
major RV dilation in all patients (mean RV/LV dimensions ratio 1.7 ± 0.3
{[}1.1--1.9{]}). On computed tomography (CT) scan, 11 patients (38\%)
had saddle PE and an additional six patients (20.6\%) had
clot-in-transit in the right atrium. Pulmonary angiographic findings
showed that a filling defect or total occlusion was observed in all 29
the patients at the proximal lobar or lobular arteries and additionally
11 of them had massive thrombus in the main pulmonary arteries. Figure
3A showed large saddle thrombus in main pulmonary artery in CT with
contrast enhancement.

\emph{ECMO Cannulation and Management}

All patients had cardiac arrest, either as an initial presentation or
in-hospital after presentation. The patients required CPR before
cannulation for ECMO, with a range of 3 to 50 minutes of CPR. 8 of 29
patients (27.5\%) were placed on ECMO during CPR, and the remaining
patients were placed on ECMO after successful CPR at an outside or
inside of the hospital. Six patients had in-hospital onset, with
diagnosis during the hospitalization of acute myocardial infarction,
post abdominal surgery and severe pneumonia. All patients had VA- ECMO,
26 patients had femoral, three patients had central, respectively. Mean
ECMO duration was 3.5 ± 1.1 days for survivor patients, ranging from
2-11 days.

All patients underwent APT therapy using the EKOS\selectlanguage{english}? system. No other
catheter-based procedures (e.g. Percutaneous mechanical thrombectomy)
were performed. The mean tissue plasminogen activator (tPA) dose for
survivor patients was 20.5 +- 1.6 mg and the mean infusion time was 16.2
+- 3.1 hours (Table 3).

\emph{End-point Analysis, complications and 90-Day Survival}

The preoperative mean embolic burden score was 19.5 +- 4.7 and decrease
to 1.4 +- 2.1 for survivor patients (Table 3). Follow-up
contrast-enhanced CT studies were performed after 76 +- 12 hours. The
patients saddle pulmonary embolisms were clearly disappeared after
successful treatment in the CT follow-up \textbf{(} Figure 3B). For
survivor patients, the mean RV/LV ratio decreased from 1.31 +- 0.17 to
0.92 +- 0.11 at follow-up (p\textless{}0.001) and the mean right
ventricular end diastolic diameter was reduced from 54.3 +- 6.6 to 41.5 +-
5.3 mm.

Table 3 reports ECMO-related complications and short-term outcomes
according to 90-day status. Seven of 29 patients (20.6\%) experienced at
least one minor ECMO-related complication; 7 (24.1\%) patients had a
moderate hemorrhage classified as GUSTO \selectlanguage{english}[?]2 with a mean of 2.2 +- 0.3
(1-4) packed red-cell and 3.1 +- 0.8 (1--5) fresh-frozen plasma units
transfused. Four of 29 patients (13.7\%) experienced acute kidney injury
that required renal replacement therapy during the hospitalization.
However, only 2 of those patients required dialysis after discharge,
which was discontinued during follow-up.

Other complications included: ischemic stroke in three patients, with
two recovering to normal neurological function at hospital discharge and
1 patient develop hypoxic-ischemic encephalopathy, and two surgical
cannulas related, wound-infection debridement. In our patient series,
the patients did not demonstrate any signs of acute limb ischemia, the
distal perfusion cannula prevented acute limb ischemia.

Twenty-two patients survived to hospital discharge, with a mean ICU stay
of 8.9 +- 1.6 days (range 7 to 22) and mean length of hospital stay of
23.7 +- 8.5 days (range, 11 to 44 days). Six patients died from
refractory shock despite ECMO support and cardiac arrest-related
multiorgan failure. One patient died after successful ECMO weaning with
PE recurrence 55 days post- ECMO removal despite adequate
anticoagulation. Ninety-day mortality was 24.1\% (7/29) and one-year
mortality was 27.5\% (8/29). Compared with patients who died within 90
days, it is worth noting that 90-day survivors had

significantly lower inotrope scores 24 hours post ECMO cannulation and
lower SAPS II and SOFA scores on ECMO day 1 (Table 3).

\textbf{Discussion}

Pulmonary embolism is the most serious clinical presentation of venous
thromboembolism and is associated with significant morbidity and
mortality. In particular, patients with acute high-risk PE defined as
cardiogenic shock and systemic hypotension, are at particularly
increased risk of early death, and require emergency treatment to
restore circulation\textsuperscript{14}.

Current guidelines for high-risk PE treatment recommend primary
reperfusion therapy and the option of ECMO. However, these
recommendations might not be optimal for patients with poor prognoses
who are in cardiogenic shock or require CPR. Patients with collapsed
high-risk PE have an extremely high-risk mortality rate because
conventional CPR including chest compression is usually not effective
due to right ventricle outflow obstruction. The in-hospital mortality of
high-risk PE requiring CPR may reach 65\%\textsuperscript{15}.

The majority of deaths in patient presenting with circulatory collapse
occur within the first hour after the presentation, and rapid
therapeutic action is therefore essential to save
lives\textsuperscript{(4,5)}. ECMO is the most convenient circulatory
assist method widely available and is the alternative of choice for
treating patients with high-risk PE with circulatory
collapse\textsuperscript{16}. Resuscitation guidelines suggest therapy
with thrombolytics in patients with pulmonary embolism and cardiac
arrest; but, in case of refractory cardiac arrest, because of the
inherent risk of bleeding of systemic thrombolysis, no further survival
options can be offered to patients with treatment failure till
now\textsuperscript{17}.

Catheter based interventions is recommended for patients with
cardiogenic shock due to high-risk PE, and its equivalent to surgical
embolectomy\textsuperscript{18}. Furthermore, catheter interventions
during CPR has been performed successfully in a small number of
patients\textsuperscript{19}.

ECMO is recommended to provide pulmonary and circulatory support for the
emergency treatment of patients with massive pulmonary embolism and
cardiac arrest. It provides the ability to decompress the acutely
overloaded right atrium and ventricle, increase the aortic pressure and
myocardial blood flow, reverse ischemia and consequently improve the
right ventricular function. Many publications have demonstrated that
ECMO has a role as a bridge to percutaneous coronary intervention in
patients with acute coronary syndrome and cardiogenic shock, as well as
in the treatment of cardiogenic shock itself \textsuperscript{(20-21)}.
Similarly, in patients with high-risk PE, ECMO can function as an
adjunct to anticoagulation as a bridge to invasive management, such as
surgical embolectomy or CDT; or, as post-procedural support for patients
undergoing these therapies. Yusuff and colleagues, conducted a
systematic review of the literature on ECMO in patients with high-risk
PE. There were no randomized control trials, however, they reviewed over
20 years of case reports on the topic and found an overall survival of
70.1\%. They did note that those who had ECMO initiated while in cardiac
arrest had an overall higher mortality compared with those who never
experienced such an event\textsuperscript{22}.

To our knowledge, our series represents the largest review of VA-ECMO as
an adjunct to EKOS\selectlanguage{english}? APT for high-risk PE treatment reported in the
literature. Although multiple case reports and series have previously
demonstrated the use of ECMO for massive PE, published mortality rates
have been prohibitive over long study periods \textsuperscript{(23,24)}.
Hashiba et al have reported that the ECMO survival rate at discharge was
83.3\%. The outcome could be attributable to lower proportions of
patients with cardiac arrest, compared with our study
population\textsuperscript{25}. Maggio et al have found that the
survival rate of ECMO for massive PE was 13 of 21 or 62\%. However, only
8 of 21 patients experienced cardiac arrest, which was a smaller
percentage than in our study\textsuperscript{26}.

Recently, Meneveau et al published the largest multicenter series of
high-risk PE patients

with refractory cardiogenic shock or cardiac arrest undergoing
ECMO\textsuperscript{27}. The overall mortality rate was 61.5\% in
high-risk PE patients who receive ECMO, especially in those with failed
fibrinolysis and in those with no reperfusion treatment. In patients
undergoing ECMO, 30-day mortality was 76.5\% (13/17) for ECMO +
fibrinolysis and 77.8\% (14/18) for ECMO alone. They concluded that ECMO
does not appear justified as a stand-alone treatment strategy in
high-risk PE patients with cardiogenic shock, but shows promise as a
complement to another reperfusion treatment such as surgical embolectomy
or CDT. Conversely to our study, Meneveau and colleagues did not assess
the potential role of catheter directed treatments in association with
ECMO in their patient cohort. There may be unstable, severely ill
patients who are not suitable for the intervention, or center who do not
have experienced interventionalist or surgical facilities on site.
However, they also concluded that, catheter-based interventions could be
a useful alternative that would make it possible to reduce the time
delay between onset and pulmonary reperfusion, by combining the
initiation of circulatory assistance with percutaneous treatments within
the same procedure. Recent data have shown promising results regarding
the safety and efficacy of this type of procedure in patients with
intermediate and/or high-risk PE\textsuperscript{28}.

Dolmatova and colleagues described a series of 5 patients over 5 years,
with a 60\% survival. In that group's series, ECMO was used as a salvage
therapy in 4 of 5 patients after other therapies failed, with a 50\%
mortality rate in this subset\textsuperscript{29}. They also concluded
that ECMO may be reasonable to initiate in patients with a high-risk PE
who would otherwise be expected to die. However, our study contradicts
the opinion of using ECMO as a salvage therapy. Because, with early and
aggressive use of ECMO in conjunction with EKOS\selectlanguage{english}? APT, we demonstrated a
75.9\% survival rate for patients with a high-risk PE who had
cardiopulmonary arrest and required CPR. We believe that early
restoration of adequate perfusion limits ischemia, mitigates permanent
end-organ damage, and prevents initial or recurrent cardiac arrest in
this critically ill group of patients.

The clinical status of the survivor patients in our study, markedly
improved from time of cannulation to definitive intervention. Lactate,
pH, and bicarbonate levels all normalized. We also found that, in nearly
all cases, patients who survived to hospital discharge had normal RV
parameters on follow-up echocardiogram. Patients required a considerably
lower dose of inotropic/vasopressor agents, and SOFA scores notably
improved, indicating a lower predicted intensive care unit rate of
mortality after successful catheter-based intervention with the support
of VA- ECMO.

APT with EKOS\selectlanguage{english}? system enhances CDT by accelerating the fibrinolytic
process via the application of ultrasound. Improving the efficiency of
the thrombolytic process reduces the treatment time and total lytic dose
delivered. The risk of an associated bleeding complication, which is
extremely increased by the concomitant ECMO procedure, is, therefore,
reduced\textsuperscript{31}. Kuo et al reported a high pooled clinical
success rate of 86.5\% in 594 patients treated with various CDT
techniques\textsuperscript{30}. The risks of major and minor
complications were low at 2.4\% and 7.9\%, respectively.

Although ECMO may be helpful in many patients who have a low chance of
surviving high-risk PE without hemodynamic support, it does come with
complications, in particular, major bleeding. Despite the high-risk of
bleeding due to ECMO and using thrombolytics, our major bleeding rate
was lower than reported elsewhere \textsuperscript{(6,32)}. In our study
only 8 (27.5\%) patients had a moderate hemorrhage classified as GUSTO
\selectlanguage{english}[?]2 with a median of 2 packed red-cell and 3 fresh-frozen plasma units
transfused.

An important consideration in percutaneous femoral access for V-A ECMO
is lower-extremity acute limb ischemia. In a retrospective study of 43
patients with femoral arterial cannulae on ECMO, there were no cases of
limb ischemia in patients with prophylactically placed SFA distal
perfusion cannulae; 21\% of patients without such cannulae did develop
limb ischemia\textsuperscript{33}. Our practice is to routinely place a
prophylactic distal perfusion cannula in the SFA. Therefore, in our
patient series, the patients did not demonstrate any signs of acute limb
ischemia.

The results of our study require carefully interpretation. First the
study was retrospective and single center experience. Second, the
present study did not have a comparative group of patients who were not
undergoing APT with the support of V-A ECMO. Furthermore, catheter-based
interventions necessitate skilled physicians as a member of
interdisciplinary team required for successful treatment of high-risk
PE.

\textbf{Conclusion}

High-risk PE imposes a high level of morbidity and mortality. Treatment
of this entity, requires diverse, aggressive, expeditious, and
multidisciplinary approaches that are tailored to

meet patient-specific risks and needs. ECMO is a useful clinical tool,
which can be implemented to provide pulmonary and circulatory support
for the emergency treatment of patients with circulatory collapse. EKOS\selectlanguage{english}?
Acoustic pulse thrombolysis concomitantly with V-A ECMO is providing
definitive and live saving treatment in patient with high-risk PE and
cardiogenic shock.

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\textbf{Legends}

\textbf{Figure 1.} The patient with high-risk PE showing hemodynamic
collapse, who were successfully treated with ECMO as an adjunct to EKOS\selectlanguage{english}?
acoustic pulse thrombolysis. 3.52 L. ECMO flow and
1.72L/min/m\textsuperscript{2} cardiac index was achieved and the
patient stabilized hemodynamically.

\textbf{Figure 2. (} A) Selective Pulmonary angiography shows a massive
pulmonary embolism in the right main pulmonary artery (B) The EKOS\selectlanguage{english}?
infusion catheter was positioned at the distal edge of the thrombus (C)
Post treatment angiography shows complete resolution of clot burden and
normal perfusion of the right lung.

\textbf{Figure 3.} (A) Initial computed tomography image shows large
saddle thrombus in main pulmonary artery was presented in CT with
contrast enhancement. (B) Follow up CT revealed that, pulmonary thrombus
in main pulmonary artery was totally disappeared.

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/372324/articles/539735-acoustic-pulse-thrombolysis-complemented-by-ecmo-improved-survival-in-patients-with-high-risk-pulmonary-embolism}

\textbf{Hosted file}

\verb`Table 2.docx`  available at \url{https://authorea.com/users/372324/articles/539735-acoustic-pulse-thrombolysis-complemented-by-ecmo-improved-survival-in-patients-with-high-risk-pulmonary-embolism}

\textbf{Hosted file}

\verb`Table 3.doc`  available at \url{https://authorea.com/users/372324/articles/539735-acoustic-pulse-thrombolysis-complemented-by-ecmo-improved-survival-in-patients-with-high-risk-pulmonary-embolism}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

