PUBLISHED 02 June 2023

DOI 10.3389/fmed.2023.1123793

Carlos Jerjes-Sanchez,
Escuela de Medicina y Ciencias de la Salud Tec
Salud, Tecnológico de Monterrey, Mexico

Antoniu Petris,
Grigore T. Popa University of Medicine and
Pharmacy, Romania Éder Iván Zamarrón-López5, Maximiliano Soto-Estrada6,
Raphaël Giraud,
Service des Soins Intensifs, Hôpitaux
Universitaires de Genève, Switzerland
*CORRESPONDENCE
1
Unidad de Cuidados Intensivos, Hospital General San Juan del Río, Querétaro, Mexico, 2Department of
hmezacomparan@gmail.com Health Science, Universidad de las Américas Puebla, San Andrés Cholula, Puebla, Mexico,
3
Coordinación Estatal de Capacitación, Mexican Red Cross, Estado de México, Mexico, 4Dirección de
RECEIVED 14 December 2022 Investigación, Instituto Nacional de Geriatría, Mexico City, Mexico, 5Unidad de Cuidados Intensivos,
Hospital MAC Tampico, Tampico, Tamaulipas, Mexico, 6Departamento de Emergencias, Hospital
PUBLISHED 02 June 2023 General de Zona 11 IMSS Delicias, Delicias, Chihuahua, Mexico, 7Unidad de Cuidados Intensivos,
Hospital Christus Muguerza, Reynosa, Tamaulipas, Mexico
CITATION

Quintero-Leyra A, Kammar-García A,
Zamarrón-López ÉI, Soto-Estrada M, Pulmonary embolism is a common and potentially fatal disease, with a significant

embolism, which can reach up to 65% in severe cases. Therefore, timely diagnosis
Front. Med. 10:1123793.
doi: 10.3389/fmed.2023.1123793

COPYRIGHT

López, Soto-Estrada, Morgado-Villaseñor and

Meza-Comparán. This is an open-access article

KEYWORDS

pulmonary embolism, respiratory therapy, oxygen inhalation therapy, fluid therapy,

oxygenation

Pulmonary embolism (PE) remains a major cause of mortality worldwide, accounting for

another 300,000 deaths annually (3).

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Pérez-Nieto et al. 10.3389/fmed.2023.1123793

Mortality in PE is determined by several factors, in particular by In one-third of patients, shunting of venous blood into the
the presence of right ventricular dysfunction (RVD) and/or systemic circulation through a patent foramen ovale may occur (11),
hemodynamic instability (2, 4). High-risk PE makes up about 5% of caused by an inverted pressure gradient between the right atrium and
the total number of PE presentations, although this may reflect that left atrium, which may lead to severe hypoxemia and give rise to
many patients die before admission, as demonstrated by postmortem paradoxical embolization and stroke.
studies (5). Altogether, in-hospital mortality due to PE ranges from On the other hand, the sudden increase in pulmonary vascular

most deaths occurring within the first hour (6), which highlights the in RV wall tension, and a prolongation of RV contraction time into
need for early recognition and treatment (7). early diastole. This increased RV wall tension increases the local
PE hinders both circulation and gas exchange (2). In this sense, demand for oxygen, causing ischemia of the RV and decreased
contractility, with a subsequent reduction in RV output (2, 10). This
a critical role in the comprehensive management of PE patients,
especially in cases of respiratory failure and RVD (8), yet this very LV distensibility as a consequence of a leftward shift of the
early management has been seldom studied (9) and given little interventricular septum (7). All in all, these mechanisms ultimately
attention in the recent literature, in favor of the novel advances lead to a reduction of cardiac output (CO), cardiogenic shock, and
concerning systemic thrombolysis, catheter-directed thrombolysis, death (2).
direct oral anticoagulants, among others. Additionally, it has been The key factors contributing to respiratory and circulatory failure
pointed out that the available evidence concerning the use of in PE are shown in Figure 1.
supportive care in PE lacks sufficient robustness (8), which further
complicates this problem.
For these reasons, in this paper, we aim to provide an up-to-date,
critical review of the hemodynamic and respiratory support in PE,
including fluid therapy, diuretics, pharmacological support with Risk stratification allows for the deliverance of optimal
treatment (5). Initially, it should be based on the identification of
and mechanical circulatory support with veno-arterial extracorporeal signs and symptoms of hemodynamic instability, which defines
high-risk PE. Hemodynamic instability encompasses one of three

circulatory failure in PE while providing a framework for risk shock –defined as systolic blood pressure (BP) < 90 mmHg or
vasopressors required to achieve a BP ≥90 mmHg despite adequate
life support in the management of cardiac arrest caused by PE. filling status, and end-organ hypoperfusion–, or (3) persistent

Respiratory and circulatory failure in PE arrhythmia, hypovolemia, or sepsis–. High-risk PE warrants

primary reperfusion treatment (in most cases, systemic
Respiratory pathophysiology and subsequent gas exchange thrombolysis) in conjunction with hemodynamic stabilization.
impairment, as well as RVD with accompanying left ventricle (LV) Nevertheless, the absence of hemodynamic instability does not
exclude the onset (and possibly progressing) of RVD, and thus a
in the high risk of death from PE and are critical determinants of high PE-related mortality risk. Therefore, further risk stratification
clinical severity and outcome (2, 10). is recommended, since it has implications for prognosis, early
Vascular occlusion is the first phenomenon in PE. When emboli discharge/hospitalization, and monitoring. In this regard, major
impact the pulmonary circulation, a local increase in the pulmonary advances have been achieved owing to the early mortality risk
arterial pressure occurs, resulting in pulmonary perfusion classification by the 2019 European Society of Cardiology (ESC)

an increase in alveolar dead space– and other areas presenting blood

heterogeneity in perfusion. This is followed by regional computed tomography pulmonary angiography), and cardiac
vasoconstriction induced by a neurologic reflex, together with biomarkers (such as cardiac troponins) (2, 4).
endothelial and platelet cytokine release (10). Both mechanical As a general rule, a PESI of class I-II or sPESI of 0 are reliable
occlusion and vasoconstriction converge, further reducing the
vascular diameter. In short, zones of reduced flow in obstructed of hemodynamic instability, signs of RVD, and elevated cardiac
pulmonary arteries, in combination with zones of overflow in the troponins. In this setting, guidelines suggest home treatment with
capillary bed served by non-obstructed pulmonary vessels, lead to anticoagulants when circumstances are adequate (12).
ventilation/perfusion (V/Q) mismatch, which contributes to As opposed, patients in the intermediate-high-risk category
hypoxemia in PE (2). In turn, hypoxemia is sensed by carotid
chemoreceptors, and this stimulates the respiratory center, causing the intermediate-low-risk category is defined by either presence of
tachypnea, often accompanied by hypocapnia (10), which occurs in RVD or increased cardiac biomarkers (or none of them). Close in-
individuals with an intact respiratory drive (e.g., patients not hospital monitoring is advised in such cases to allow for the early
under sedation). detection of hemodynamic deterioration (2).

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FIGURE 1
Pathophysiology of respiratory and circulatory failure in pulmonary embolism. Created with BioRender.com.

NIV and after exhaustion of the above-described treatment

modalities, given the detrimental effects of induction of anesthesia
In experimental PE models, oxygen therapy has been shown to and positive-pressure ventilation on BP in PE patients with RVD. In
this sense, anesthetic drugs more prone to cause hypotension, such
oxygen is indicated in patients with PE and arterial oxygen saturation as propofol, should be avoided. Therefore, etomidate, which is the
(SaO2) <90%, starting with conventional devices such as low-flow drug of choice for induction in unstable patients, or ketamine, may
nasal cannulas, standard face masks, or nonrebreather masks. be used in this setting unless contraindicated (2, 19). Indeed, when
However, if this fails, escalation of respiratory support may MV is required, care should be taken to limit its adverse
be warranted, including high-flow nasal cannula (HFNC) and hemodynamic effects. Notably, the positive intrathoracic pressure
mechanical ventilation (MV) –whether invasive or non-invasive– induced by MV may decrease venous return and worsen RVD in
when necessary (2). patients with shock. Hence, PEEP should be applied with caution
HFNC is capable of delivering 20–80 L/min (14) of a heated, and, if possible, should be aimed at 0 cmH2O (5, 7). Low tidal
volumes (roughly 6 mL/kg lean body weight) should be used to
reintubation rates and mortality in patients with acute hypoxemic
respiratory failure (15). Additionally, HFNC reduces the work of 20), although these are ultimately expert opinions. It is essential to
breathing and respiratory rate (16) and increases the end-expiratory avoid mechanical ventilation as much as is viable since it increases
lung volume and pulmonary compliance (15). A systematic review hospital stay and the cost of care, and it is related to poor outcomes.
and meta-analysis showed that, compared with conventional oxygen Additionally, it is imperative to consider advanced treatments in
patients with severe respiratory failure. In the Pulmonary Embolism
reduced dyspnea, and improved patient comfort (17). A recent
observational study found a rapid improvement (as early as 1 h) in safety of fibrinolytic therapy with a single-bolus injection of
respiratory distress in PE patients using HFNC, in terms of tenecteplase, in addition to standard anticoagulation therapy with
oxygenation and respiratory rate. Furthermore, HFNC is superiorly heparin, versus placebo plus heparin, in normotensive patients with
tolerated compared to non-invasive ventilation (NIV), since it intermediate-risk PE. In subgroup analyses, patients who had a
provides a high fraction of inspired oxygen (FiO 2) and minimal respiratory rate > 24 rpm (respirations per minute) achieved the
essential positive end-expiratory pressure (PEEP) via nasal prongs primary efficacy outcome (a clinical composite of death from any
cause or hemodynamic decompensation within 7 days after
be preferred (2). randomization) less frequently with the use of tenecteplase plus
Intubation and subsequent invasive mechanical ventilation heparin, as opposed to patients in the placebo plus heparin arm,
(IMV) should be performed only if the patient is unable to tolerate suggesting benefits for this intervention (21).

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of this study may reflect earlier RV function recovery with diuretic

therapy in intermediate-high-risk PE patients (9).
Intravenous (IV) fluids should be used with caution, since It is important to remember that in patients with PE, the clinical
aggressive volume expansion may worsen RV function by causing problem is RVD and not systemic overload. The use of diuretics
decreases preload, one of the ventricular function determinants,
that further depress its contractility, ultimately leading to a reduction which may induce further hemodynamic deterioration. Until further
in systemic CO (5, 7). Thus, judging the appropriate amount of fluid studies are conducted, the choice between diuretic therapy and
administration is particularly difficult (22). In this regard, the 2019 volume loading in PE patients must remain empirical (9).

index in patients with PE, though this recommendation is based upon

also advocate for the guidance of volume loading through monitoring

of elevated CVP are present, further volume loading should PE patients will oftentimes require vasopressor support in
be withheld. In practice, there is no reliable, well-validated standard addition to the abovementioned measures to restore RV function and
maintain coronary perfusion, in parallel with (or while waiting for)
judgment remains topmost, and every patient should be individually pharmacological, surgical, or interventional reperfusion treatments.
assessed (24). Vasopressor support should be considered early in the resuscitation
On the flip side, a recent interest in the use of diuretics in PE has of patients with hypotension due to PE. On this basis, escalation of
care to an intensive care unit (ICU) with close monitoring and
be more appropriate than volume expansion in this setting, but they multidisciplinary team care is required. Hence, transfer to a center
are commonly viewed as contraindicated because of the fear of that can provide this level of support must be considered if not
depressing right ventricular function with accompanying abrupt loss
of CO. One of the first major studies in this respect is Lim and of vasopressors appears to be safe during the first 24 h. Furthermore,
colleagues’ randomized controlled trial (RCT), which aimed to it reduces the risk of large vessel injury that can lead to bleeding
whenever thrombolytics are being used (26). Norepinephrine (NE)
against placebo in normotensive patients with intermediate-risk PE. In is an alpha-adrenergic and beta-adrenergic drug that improves
their study, a higher proportion of patients in the furosemide arm systemic pressure with a modest effect on inotropy and is also the
achieved the primary efficacy outcome (a composite of urine output
>0.5 mL/kg/h, heart rate ≤ 110 bpm, systolic BP ≥100 mmHg and clinical data are available on the effects of this drug in patients with
oxygen saturation ≥ 90%), compared with the placebo arm, with a

that furosemide increased the probability of achieving the primary be titrated to maintain a mean arterial pressure (MAP) >65 mmHg
(5, 26). NE is preferred because it maintains coronary perfusion
study, furosemide did not decrease B-type natriuretic peptide (BNP) pressure and improves systemic vascular resistance (SVR), without
or N-terminal pro B-type natriuretic peptide (NT-proBNP)
concentrations, nor it changed right ventricular/left ventricular
diameter ratio in echocardiography, as compared to placebo. but this seldom has a practical clinical impact. Vasopressin, another
Furthermore, furosemide increased creatinine levels and decreased frequently suggested option, is a non-catecholamine vasoconstrictor
systolic BP 24 h after randomization, suggesting that the chosen dose
might have been excessive (25). One recent randomized, open-label of robust data regarding its application in PE, minimal titratability,
trial explored the effects of diuretic therapy versus volume expansion and absence of inotropic properties all limit its use. Adding
in PE patients. The authors compared time to troponin normalization, vasopressin 0.04 U/min (as a second vasopressor) when NE dose
time to BNP normalization, and changes in RV function through

either an IV bolus of 40 mg furosemide on admission (diuretic therapy inotropic support may be required (28). Studies conclusively
arm), or a 500 mL 0.9% sodium chloride infusion delivered over 4 h,
followed by a 1,000 mL infusion per day (volume expansion arm). Dobutamine may increase cardiac index and decrease vascular
Notably, troponin kinetics did not differ between the groups, although resistance in PE patients (26, 29), though at the expense of systemic
the time to complete BNP normalization was shorter in the diuretic vasodilation, which can worsen hypotension if used alone (28). The
therapy group, as was the time to 50% concentration decrease. In this 2019 ESC guidelines state that dobutamine may be considered for PE
study, the number of patients with decreased BNP concentrations at
12 h after randomization was also higher in the diuretic therapy arm. kg/min (2). Nevertheless, an increased cardiac index above
physiological values may worsen V/Q mismatch through additional
pulmonary artery pressure and inferior vena cava diameter at 4 h after
randomization, as measured by echocardiography, compared to
patients in the volume expansion group. In conjunction, the findings kg/min (8, 24). Data regarding the potential use of the inotrope/

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calcium sensitizer levosimendan in PE are also scarce (8, 28), yet it

might be worth considering it in patients under beta-blockers (30).
Preclinical studies suggest that this drug may restore RV-pulmonary
In the setting of PE, both VA-ECMO and RVAD support the

available as of this day (2). No studies conclusively prove the hemodynamic stability, without any direct intervention on the clot
effectiveness of inotropes in PE patients. As observed in patients with
cardiogenic shock secondary to left ventricular dysfunction, their a bridge to RV recovery with anticoagulation alone. They may also
serve as a bridge for the decision to move along with active thrombus
A few treatments have also been proposed, but they cannot removal therapies, including surgical embolectomy or catheter-
be currently recommended due to the lack of conclusive data (5). In directed thrombolysis (37).
this sense, pulmonary vasoconstriction has long been explored as a Indeed, the physiological rationale of VA-ECMO is attractive,
specific target in PE (28), since it is widely considered a significant since it seems to be ideal for breaking the commonly named “RV
contributor to the increase of pulmonary artery pressure (PAP) and
redirecting RV venous return to the ECMO circuit, while also
oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine increasing perfusion by pumping oxygenated blood into the arterial
monophosphate (cGMP) pathway, the prostanoid pathway, and the
endothelin (ET) pathway, to mention a few (32). Within the first with subsequent decreases in RV end-diastolic volume, RV end-
diastolic pressure, and RV myocardial oxygen consumption,
as a potential therapeutic agent, given its short half-life and limited enabling RV contraction with minimal preload and afterload.
systemic absorption (24). A 2015 systematic review of mostly case Typically, the ECMO circuit provides between 4 to 6 L flow and has
reports and case series showed improvement in either systemic or the advantage of being mobile, which means that it can be readily
pulmonary pressures or oxygenation following iNO administration in transported to the patient both in and out of the hospital. Once
PE patients, with an acceptable safety profile, although the authors VA-ECMO is initiated, patients are usually rapidly stabilized,
raised concerns about possible reporting biases (33). More recently,
an RCT compared the administration of iNO versus placebo in (37, 38). According to the 2019 ESC guidelines, VA-ECMO may
patients with intermediate-risk PE. Even though the study failed to be helpful in patients with high-risk PE, and circulatory collapse or
demonstrate an improvement in the primary outcome (a composite cardiac arrest (2). Nonetheless, current ECMO literature on patients
of normal RV function on echocardiography and normal troponin T), with PE is restricted to nonrandomized, single-center case series and
observational studies. In fact, to date, there is no RCT addressing the
place of ECMO, with or without other reperfusion therapies, in the
management of high-risk PE. Further complicating this issue, the
and no serious adverse events were attributed to the study drug (34).
On the other hand, the therapeutic potential of sildenafil, a specific the presentation of patients, differences in hemodynamic parameters,
and differences in the incidence of pre-ECMO cardiopulmonary
regained some interest. A recent explorative trial compared a single resuscitation (CPR), among other factors, making the comparison
oral dose of 50 mg sildenafil versus placebo, to test if the former between studies challenging (37, 38).
improved RV function in patients with intermediate-high-risk VA-ECMO plus anticoagulation alone results in definitive therapy
PE. Notably, sildenafil did not improve cardiac index compared to in about 45% of patients, given that a substantial proportion of them
baseline. On top of that, sildenafil lowered MAP, which was not
However, in terms of mortality, several retrospective studies have
reported conflicting results concerning this approach. On the other
the pharmacological form of prostacyclin, versus placebo on hand, the VA-ECMO plus surgical embolectomy approach seems
echocardiographic and biochemical parameters in patients with PE appealing even though there is limited data to support this combined
with echocardiographic signs of RV overload. In this trial,
epoprostenol did not have a significant effect on right ventricular 29% in the group treated with ECMO and surgical embolectomy.
end-diastolic diameter (RVED), systolic PAP, tricuspid annular plane Finally, data regarding the use of catheter-directed thrombolysis in
systolic excursion (TAPSE), right ventricular fractional area change
(RVFAC), serum cardiac troponin T and NT-proBNP, as compared to
placebo (36). Lastly, the evidence concerning the use of vasodilators
derived from this procedure include cannulation site bleeding/
preclinical studies in existence, which show that ET receptor hematoma, ipsilateral leg ischemia, and acute kidney injury, to
antagonists mostly lower mean pulmonary arterial pressure (mPAP) mention a few (37, 39, 40). In general, even with a high incidence of
and PVR, as well as increase CO. Some other vasodilators such as pre-ECMO CPR (which can be as high as 70–100%), mortality is
hydralazine have not been investigated for over 20 years, neither in roughly 30%, though some studies have estimated survival rates
experimental PE models nor in patients with PE (32). At present day,
no international guideline currently recommends using vasodilators existing literature (37, 39). It has been pointed out that survival is an
during an acute PE event. imperfect metric of VA-ECMO success since it is frequently

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high-risk PE, if feasible. Rescue thrombolytic therapy should also

as CPR, failure of other treatments, and underlying medical be given in rapidly worsening patients; alternatives in this situation
conditions. In this sense, rather than survival, clinical and include surgical embolectomy or catheter-directed treatment. Within
echocardiographic parameters of RV function may be better exposure, obtaining information about past medical history,
predisposing risk factors, and medications that may support the

outcomes will depend on the experience of the center, as well as

proper patient selection (2).
RVADs, on the other hand, are peripherally inserted pumps that or hormone replacement therapy (HRT), long-distance flights,
function by bypassing the RV through pumping of RV preload into among others. Regarding cardiac arrest management, the guidelines
the pulmonary circulation. In the context of PE, two major RVADs emphasize that cardiac arrest usually presents as pulseless electrical

Danvers, Mass) is a percutaneous RVAD system that can be placed low EtCO2 readings (<1.7 kPa/13 mmHg) while performing high-
through the femoral veins with a 23F sheath. This device is
subsequently guided into the left PA over a wire under fluoroscopic echocardiography performed by a qualified sonographer should also
guidance. The pump inflow is placed in the inferior vena cava while be considered as an additional diagnostic tool in this context. These
the outflow is in the left PA, providing up to 4 L flow per minute. guidelines suggest administering thrombolytic drugs for cardiac
arrest when PE is the suspected cause and, after administration, they
to various case reports, thus impeding drawing definite conclusions recommend continuing CPR attempts for at least 60 to 90 min before
regarding its safety and efficacy in PE. The other device, the Protek termination. The use of thrombolytic drugs, surgical embolectomy,
Duo system (LivaNova, London, UK) is inserted through the right
internal jugular vein and into the right PA under fluoroscopic known cause of cardiac arrest. Finally, the guidelines recommend
considering extracorporeal CPR (ECPR) as rescue therapy for
port is in the right PA. This device is subsequently attached to an selected patients with cardiac arrest in whom conventional CPR is
extracorporeal pump, currently being the only percutaneous RVAD failing, if feasible and according to local resources (42).
capable of oxygenating. In a similar fashion to the Impella RP, the
experience with the Protek Duo is restricted to case reports, and
more research is needed to draw conclusions regarding its utility in
PE. Potential pitfalls of these devices include lack of availability in
some institutions and the need for fluoroscopy for device The hemodynamic and respiratory support in PE is particularly
implantation (37, 41). complex and heterogenous but can be summarized in what we call

cautionary approach is advised, since the harms may sometimes

outweigh the benefits if used inappropriately. Current
recommendations are fundamentally based upon studies with low
levels of evidence, most of them being expert opinions, preclinical
PE is a part of the differential diagnosis of cardiac arrest with studies, and observational studies. Although some progress has been
non-shockable rhythm. Current guidelines for advanced life support made, more high-quality research is needed to better inform clinical
should be stuck to in cardiac arrest presumably stemming from PE decisions concerning supportive therapy in PE. Hopefully, in this
(2), though there are some considerations to bear in mind in this review, we may have sparked some interest in this research area
situation, which we will carefully discuss. Concerning cardiac arrest within the ever-evolving field of PE management.
prevention, the 2021 European Resuscitation Council Guidelines
recommend following the ABCDE approach. First of all, on the
airway, these guidelines state that high-flow oxygen therapy should
be initiated in patients with life-threatening hypoxia. Within
breathing, the guidelines advocate for considering PE in all patients
with sudden onset of progressive dyspnea and absence of known draft, and writing - review and editing. AQ-L: investigation and
pulmonary diseases (though the exclusion of pneumothorax and writing - original draft. IG-O: investigation and writing - original
anaphylaxis is always necessary). On circulation, it is critical to draft. AK-G: methodology. ÉZ-L and LM-V: supervision. MS-E:
identify hemodynamic instability and high-risk PE, plus obtaining a visualization. All authors contributed to the article and approved the
12-lead ECG (making sure of excluding acute coronary syndrome, submitted version.

performing bedside echocardiography and initiating anticoagulation

therapy (heparin 80 IU/kg IV) during diagnosis, unless signs of
bleeding or absolute contraindications are present. PE diagnosis
should be confirmed with computed tomographic pulmonary The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
a multidisciplinary team for decision-making on the management of be construed as a potential conflict of interest.

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FIGURE 2
Diamond of supportive care in pulmonary embolism. Created with BioRender.com. Abbreviations: CVP, central venous pressure; HFNC, high-flow
nasal cannula; IV, intravenous; MAP, mean arterial pressure; NE, norepinephrine; PE, pulmonary embolism; PEEP, positive end-expiratory pressure;
RVAD, right ventricular assist device; VA-ECMO, veno-arterial extracorporeal membrane oxygenation.

Publisher’s note organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
and do not necessarily represent those of their affiliated endorsed by the publisher.

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