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The management of pulmonary embolism
INTENSIVE CARE
The management of pulmonary embolism
Learning objectives After reading this article, you should be able to: C describe the disease entity of VTE/PE and outline risk factors for its development, recognizing the varied spectrum of presentation in PE C outline an appropriate diagnostic strategy for the evaluation of possible PE, risk stratifying according to clinical presentation and investigations C describe the various treatment options for PE and how they should be utilized in the light of the risk stratification and diagnostic findings C discuss the challenges in the management of massive and submassive PE C describe the importance of VTE prophylaxis in the prevention of PE
Tamara P Banerjee Juan Carlos Mora
Abstract Pulmonary embolism (PE) is a significant cause of hospitalization, morbidity and mortality, frequently requiring critical care services. Critically ill patients are also at increased risk of developing venous thromboembolism and acute PE. Critical care clinicians should be confident in their approach to the patient with suspected and diagnosed PE. Furthermore, the comorbid conditions in this patient group may present additional challenges both in diagnosis (e.g. safe access to radiology) and management (e.g. absolute and relative contraindications to anticoagulation/thrombolysis in critically ill patients). This brief review summarizes the contemporary evidence base regarding both diagnosis and treatment strategies and draws upon this to suggest a simple algorithm for investigation, risk stratification and management, particularly tailored to patients within a critical care setting.
Keywords Anticoagulation; computed tomographic pulmonary angiography (CTPA); embolectomy; IVC filter; massive pulmonary embolism; pulmonary embolism; submassive pulmonary embolism; thrombolysis; venous thromboembolism (VTE)
outlines the most common signs and symptoms in patients diagnosed with PE. In the setting of inconsistent patterns of presentation, risk factors are particularly useful to help determine the probability of PE. The risk factors for PE can be deduced from Virchow’s triad which governs the pathogenesis of venous thromboembolism (VTE). Virchow’s triad consists of venous stasis, endothelial injury and hypercoagulable states. Risk factors can be divided into genetic and acquired states (Table 2).
Royal College of Anaesthetists CPD Matrix: 2C00, 2C01, 2C03, 2C04, 1B00
Diagnosis The diagnostic approach depends on the patient’s haemodynamic stability. Most patients will be clinically stable enough to warrant a considered approach which starts with assessing the pre-test probability to determine what further testing is required, if any. Various decision-making tools are available to help the clinician risk stratify patients. The most widely reported and clinically validated tools are the Wells rule, the revised Geneva scoring system and the pulmonary embolism rule out criteria (PERC). Both the Wells and the revised Geneva rules have been simplified in order to increase their adoption into clinical practice (Table 3). If the patient is low risk, then PE can be safely ruled out with a negative D-dimer test, otherwise definitive imaging, such as computed tomographic pulmonary angiography (CTPA) or ventilation-perfusion scanning should be performed. The PERC rule has the advantage of excluding PE in low risk patients without the need of any additional testing such as D-dimer. The rules aim to risk stratify patients and focus resources on those most likely to benefit and avoid unnecessary tests and their downstream complications. The majority of patients who reach a critical care environment meet criteria for high-risk pretest probability. Particularly complex are pregnant patients where the risk of VTE is significantly elevated and imaging modalities are not without risk to the fetus.1 In the case of patients who are haemodynamically unstable, bedside echocardiography or limb venous Doppler ultrasound can be utilized to obtain a presumptive diagnosis of PE to justify the initiation of therapy. If a patient presents with a malignant arrhythmia or cardiac arrest, the diagnostic assessment may have to be omitted and if there is a high index of clinical suspicion
Definition Pulmonary embolism (PE) describes an obstruction of the pulmonary arterial tree with abnormal material (thrombus, tumour, air or fat), usually originating somewhere else in the body. Patients can present acutely (immediately after the event), sub-acutely (within days/weeks after the embolism) or chronically (years after the embolism). The most common cause of acute PE is the migration of thrombus from veins (or right heart) to the pulmonary arteries. Other forms of PE are beyond the scope of this article.
Clinical presentation Acute PE is a commonly considered but relatively infrequently diagnosed condition in hospitalized patients. This is unsurprising given presentation is varied and non-specific; ranging from no symptoms to dyspnoea, shock and sudden death. Table 1
Tamara P Banerjee BSc (Hons) BM BCh MRCP FRCA FFICM is a Locum Consultant in Intensive Care Medicine and Anaesthesia at The Royal Free Hospital, London, UK. Conflicts of interest: none declared. Juan Carlos Mora BSc MBChB FACEM PG Dip (Clinical US) is a Senior Intensive Care Registrar at The Alfred Hospital, Melbourne, Australia; and Locum Emergency Care Consultant at Wagga Wagga Base Hospital, NSW, Australia. Conflicts of interest: none declared.
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Clinical characteristics of patients diagnosed with PE Past history
Symptoms (sorted by a decreasing frequency)
Signs (sorted by an increasing risk of mortality)
Previous DVT/PE Family history of DVT/PE/sudden death Thrombophilia Hypercoagulability
Dyspnoea Pleuritic chest pain Cough Syncope Haemoptysis (late sign of lung infarction)
None Signs of DVT Tachycardia (most common) Fever RV dysfunction (raised JVP, loud P2, parasternal heave) Hypotension Skin mottling Cyanosis Cardiovascular collapse/arrest
Table 1
there should be a low threshold to instigate potentially life-saving therapy without diagnostic confirmation. Figure 1 Summarizes severity stratification, assessment, as well as treatment of patients with pulmonary embolism.
classically described deep S wave in lead I, with a Q-wave and inverted T-wave in lead III (S1Q3T3) is a rare sign of right heart strain and is usually only found in severe cases of acute PE. Other evidence of right ventricular (RV) strain, including T-wave
Investigations Initial investigations An arterial blood gas analysis (ABG) demonstrating hypoxia (with widened alveolar-arterial oxygen gradient) and hypocapnia with a concomitant increase in end-tidal CO2 gradient is suggestive of PE but lacks specificity. Equally, a normal blood gas does not exclude PE. The most common ECG finding is sinus tachycardia (up to 70%) but a normal ECG is found in one-third of cases. The
Clinical prediction rules for PE
Risk factors for VTE Genetic
Acquired
Factor V Leiden Prothrombin gene mutation Protein C deficiency Protein S deficiency Lupus anticoagulant Antithrombin III deficiency Dysfibrinogenaemias
Immobility Malignancy Surgery (within 3 months) Hospitalization Pregnancy Advancing age Trauma (especially pelvis, lower limb, acute spinal cord injuries) Infection Oestrogen Smoking Obesity Blood transfusion and erythropoietic agents Hyperviscosity syndromes (myeloma and other haematological disorders)
Inferior vena cava abnormalities Hyperhomocystinaemia
Score (original)
Score (simplified)
Clinical signs and symptoms of DVT Tachycardia Immobilization or surgery in previous 4 weeks Previous PE or DVT Haemoptysis Malignancy Alternative diagnosis is less likely than PE Cutoff score for PE to be UNLIKELY
3 1.5 1.5
1 1 1
1.5 1 1 3
1 1 1 1
4
1
1 3 2
1 1 1
2 3 2
1 1 1
3 5 4
1 1 1
5
2
Revised Geneva score Age >65 years old Previous DVT or PE Surgery (under general anaesthesia) or lower-limb fracture within past month Active cancer Unilateral lower-limb pain Haemoptysis Heart rate: 75e94 beats/minute 95 beats/minute Pain on lower-limb deep venous palpation and unilateral oedema Cutoff score for PE to be UNLIKELY
Table 2
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Wells rule
Table 3
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inversion, right bundle branch block and p-pulmonale may be seen, as well as atrial arrhythmias (most commonly atrial fibrillation). The ECG should be regarded as an essential test as it is useful for screening for alternate and life-threatening diagnoses (Box 1).
Differential diagnosis of PE Acute myocardial infarction Acute pulmonary oedema Exacerbation of asthma/COPD Pneumonia Pneumothorax Pericardial tamponade Pericarditis Pleural effusion/empyema Aortic dissection Fat/amniotic embolism Rib fracture Musculoskeletal pain Anxiety
Biomarkers D-dimer, a fibrin degradation product, is the most extensively investigated biomarker for PE. When a low result (usually 500 ng/ml) is used in conjunction with the Wells criteria it can play an important role in excluding VTE and PE in lowrisk individuals. However, due to the test’s low specificity and negative predictive value, it should not be used in patients with a high pre-test probability. The critical care provider should be aware of these inherent issues with D-dimers and be cautious when applying this test to critically unwell patients who will most likely be high risk for VTE. Ageadjusted cut-offs for D-dimer have been validated and provide more useful data in patients over 50 years of age.2 In patients with known acute PE, elevated levels of D-dimer at diagnosis are associated with an increased risk of death
Box 1
Severity stratification assessment and treatment of patients with pulmonary embolism Immediate or high clinical probability of PE (using clinical prediction rules)
Initial clinical assessment
Initial diagnostic test
Assessment of PE severity
Treatment
Haemodynamically stable
Haemodynamically unstable
Multi-detector CTPA (V/Q scan if CTPA unavailable/contraindicated)
Echocardiography (TTE or TOE)
using CTPA, blood tests and echocardiography
PE likely if RV dysfunction
thrombus in RV or PA
Segmental or subsegmental PE and normal troponin, BNP or NT pro-BNP
RV dysfunction present, raised troponin, BNP or NT pro-BNP
CTPA if safe
Anticoagulant therapy only
Anticoagulant therapy Consider thrombolsyis based on individual
Anticoagulant and thrombolytic therapy Embolectomy or catheter directed thrombolysis if high risk of bleeding If severe instability or cardiac arrest, consider ECMO support if available
Standard PE
Submassive PE
Massive PE
BNP, brain natriuretic peptide; CTPA, computed tomography pulmonary angiography; NT, NT-terminal; PA, pulmonary artery; PE, pulmonary embolus; RV, right ventricular; TOE, trans-oesophageal echocardiography; TTE, transthoracic echocardiography.
Figure 1
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and show a blood level-related effect. D-Dimer levels <1500 ng/ml has a negative predictive value of 99% for excluding 3-month mortality.1 Measurements of troponin, brain natriuretic peptide (BNP) or NT-terminal pro-BNP (NT-Pro-BNP) are also useful to risk stratify and determine prognosis in confirmed PE. Raised troponin is a marker of right heart strain and predicts haemodynamic instability in sub-massive PE and increased risk of death regardless of PE size. In proven PE, low levels of BNP and NTPro-BNP as well as undetectable high-sensitivity troponin correlate with good outcomes.1
Computed tomography pulmonary angiography (CTPA) CTPA has multiple advantages such as high sensitivity and high specificity, is readily available with rapid image-acquisition time and has the added ability to assess for alternative diagnoses.1 With the improved precision of CT scanners, CTPA with multi-detector scanning technique has become the imaging modality of choice for diagnosing acute PE and it is now considered a reference standard replacing pulmonary angiography (Figure 2). Highresolution images to the level of segmental and, in many cases, subsegmental pulmonary arteries can be obtained in a short timeperiod (often a single breath-hold). In addition to visualizing intraluminal filling defects, RV dilation measurements are predictive of adverse short-term events, including death in hospital, 30-day mortality and 3-month mortality.3 In contrast, measurement of clot burden is not predictive of an adverse prognosis. Patients with a negative CTPA but high pre-test probability only have a 60% negative predictive value of PE4 and hence should be managed on an individual basis. In these patients the risk of a falsely negative CTPA should encourage further testing (see options below) and/or admission for prolonged observation. In cases where diagnostic uncertainty persists, we recommend consulting a haematology specialist to discuss further options.
Imaging There are several imaging modalities that can aid the management of PE, but it is important to note that there is no ideal test to confirm the diagnosis. The choice of modality will depend on several factors, including the likelihood of PE, differential diagnosis, stability of the patient, patient allergies and availability of imaging modalities and reporting specialists. Chest X-ray In most cases of PE, the chest X-ray (CXR) will be normal but it is a useful test to exclude common differentials such as pneumothorax, pneumonia or pleural effusion. The most common abnormal findings are patchy opacification and atelectasis. Rarer findings such as Westermark sign and Hampton’s hump are not diagnostic but should make the clinician suspect the diagnosis.
Lung scintigraphy Ventilation-perfusion scans (VQ scans) utilize radioactive isotopes to evaluate lung ventilation and perfusion in a staged
Figure 2 Three images from a single CTPA study performed with a high clinical suspicion of PE. (a) demonstrates large PEs in the proximal right and inferior left pulmonary artery. (b) shows a significant concurrent pneumothorax. (c) demonstrates an RV/LV ratio >1 signifying significant RV dysfunction. Together these images show the high utility of CTPA in diagnosis/exclusion of PE, diagnosis/exclusion of differential diagnoses, and in risk stratifying a patient so as to guide therapy.
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acute PE. MRA is more complex, time-consuming, less available, cannot be performed in patients with implanted devices such as permanent pacemakers, and has limited ability to detect other causes of dyspnoea when compared to CTPA.
process. VQ scans have several disadvantages which reduce its utility in critically ill patients, these include lack of availability, long duration of scan, a normal CXR being a prerequisite in order to obtain interpretable results, and even with optimal conditions the scan can often yield indeterminate results. VQ scanning is mostly reserved for patients in whom CTPA is unavailable, inconclusive or contraindicated due to intravenous contrast allergy. Due to its lower radiation dose, a VQ scan is also an option for women in the early stages of pregnancy, when the foetus is most prone to ionizing radiation.
Disease spectrum and severity Massive PE/high risk PE This is defined as an acute PE which presents with sustained hypotension (systolic BP <90 mmHg) for at least 15 minutes despite adequate resuscitation and is not explained by another cause such as an arrhythmia, left ventricular dysfunction, or sepsis. Even when treated, this condition has a mortality exceeding 25% (65% if cardiopulmonary resuscitation is required).6 Acute RV failure is a very common feature and as a consequence, if patients survive the initial event they remain at significant risk of death for several days.
Echocardiography Transthoracic echocardiography (TTE) only has the ability to identify thrombus in the proximal pulmonary arterial tree and right ventricular and therefore will miss up to 50% of clots. It is, however, good at identifying RV strain as a result of clot burden and therefore can be useful for classifying the severity and prognosis of a PE. Findings include RV dilation, hypokinesis of RV free wall, interventricular septum flattening, inferior vena cava distension, McConnell’s sign and the 60-60 sign. Its greatest utility is in the most severe cases, where haemodynamic instability may prevent safe transport to CT. In these cases, TTE can be performed at the bedside to identify or exclude other causes of haemodynamic instability (Table 4) and assess severity of known PE (RV dysfunction on TTE is an independent predictor of an adverse outcome). In a select group of patients, where there is a high index of clinical suspicion for PE, findings on TTE may be sufficiently compelling to warrant commencement of therapy.
Sub-massive PE/intermediate risk PE In this subset of acute PEs, patients do not have hypotension but instead have evidence of RV dysfunction (best confirmed with echocardiography but also seen on CT) or myocardial necrosis (confirmed with positive troponin test). This group, if treated with anticoagulation alone, have a mortality of <3%.3 They may, however, also progress to haemodynamic decompensation in the acute phase or go on to develop chronic pulmonary hypertension. Low risk PE These are all other patients with acute PE who are haemodynamically stable with normal RV function. Most of these patients will have a small volume of clot burden and if there is no contraindication to treatment will follow an uneventful course (<2% mortality) unless further PE occurs.
Venous ultrasonography Lower extremity venous Doppler ultrasound has a high sensitivity and specificity for deep venous thrombosis (DVT) and can be done at the bedside. When DVT is detected and PE is clinically suspected, treatment can be initiated without further investigation for PE. This feature is particularly useful when the patient is unstable or definitive imaging is not available or contraindicated (contrast allergy or pregnancy). However, only up to 55% of patients with acute symptomatic PE have concomitant DVT5 and therefore a negative study does not confidently exclude PE.
Treatment The major principles of management of an acute PE are prevention of further embolization and propagation of thrombosis (anticoagulation and inferior vena cava (IVC) filters), removal of established clot (thrombolysis and embolectomy) and concurrent haemodynamic support. Choice of therapies depends on the severity of PE (See Figure 1).
Pulmonary angiography and magnetic resonance angiography (MRA) Pulmonary angiography previously has been the ‘gold standard’ for decades; however, with the advent of sophisticated and highly accurate CTPA, this is becoming significantly less utilized unless as part of a percutaneous catheter-directed treatment for
Anticoagulation Anticoagulation decreases mortality in patients with PE, hence, patients with an intermediate or high clinical probability for PE should be anticoagulated while waiting for diagnostic tests, unless there is a compelling contraindication. In patients with an absolute contraindication to anticoagulation, further investigations should be expedited so alternative therapies (including IVC filter) can be instituted if a PE is confirmed. The risk of a major bleeding event secondary to anticoagulation is lower (<3%) than the risk of death from undiagnosed PE (30%).1 Low molecular weight heparins (LMWH) and fondaparinux are as safe and effective as unfractionated heparin (UFH). In stable patients with PE, LMWHs offer several advantages over UFH including longer dosing interval, increased bioavailability, a more predictable dose response and fewer requirements for monitoring and dose adjustments. Periodic measurement of
Suggested indications for insertion of inferior vena cava filter New or recurrent PE despite anticoagulation Contraindications to anticoagulation Complications resulting from anticoagulation Other recommended indications Following thrombolytic therapy Post surgical embolectomy Extensive DVT Table 4
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Key factors contributing to haemodynamic collapse and death in acute pulmonary embolism
Increased RV afterload
RV dilation
Systemic BP
Cardiac output
Coronary perfusion
RV wall tension
LV preload
RV output
RV O2 delivery
DEATH Obstructive shock
Contractility
RV ischaemia
Neurohormonal activation
Myocardial
RV O2 demand
et al.1 Figure 3
cardiology societies.1,7 Its use may result in dramatic improvements in RV dysfunction, decrease in pulmonary artery pressures, improved haemodynamics and better oxygenation, especially in the first few days, as well as likely improved mortality. In sub-massive PE, treatment with thrombolytics remains controversial despite extensive research. To date, there have been four large randomized controlled trials investigating this topic: MAPPETT 3, PEITHO, TOPCOAT & MOPPET.1 These trials demonstrated that although thrombolytic therapy reduces the risk of haemodynamic decompensation, it does not appear to improve mortality. Furthermore, thrombolytic therapy increases risk of major bleeding and intracranial haemorrhage (ICH) by approximately ten fold. The TOPCOAT trial claimed improved functional outcomes at 3 months and the MOPPET trial showed a reduction in pulmonary hypertension at 28 months. However, neither of these benefits were confirmed in the much larger PEITHO follow up trial.1 A 2014 meta-analysis suggested that administration of thrombolytic therapy for sub-massive PE resulted in a decrease in mortality and recurrence of PE compared to standard anticoagulation but was associated with an increased risk of bleeding, including ICH.8 The most recent consensus guidelines recommend against routine thrombolysis for sub-massive PE and instead consider risk-benefit ratios in each individual case.1 If, however, haemodynamic decompensation occurs, thrombolysis should be strongly considered. Thrombolytic agents include alteplase (tPA), tenectaplase and reteplase. No study has shown a significant difference in efficacy between these different thrombolytic agents. Concerns around haemorrhagic complications are justified as major bleeding occurs in up to 10% of patients thrombolysed for PE (versus
anti-factor Xa activity (anti-Xa levels) may be considered in patients with severe renal failure, morbid obesity or during pregnancy. In contrast, UFH offers rapid therapeutic dosing, can be therapeutically monitored and reversed with protamine if required. The predominant complication of these anticoagulants is bleeding. Both bleeding complications and heparininduced thrombotic thrombocytopenia syndrome (HITTS) appear to be less common with LMWH compared with UFH. The lack of immune-mediated effect on platelets by fondaparinux has led to its safe use in patients with HITTS.1 Inferior vena cava (IVC) filters IVC filters are endovascular retrievable devices that are designed to reduce pulmonary embolisms originating in the lower limbs. Despite increasing use of these devices, their effectiveness still remains largely unproven. Three randomized controlled trials (PREPIC, PREPIC2 and FILTER-PEV1) studied the effects of combining IVC filters with systemic anticoagulation. All trials showed a reduction in the incidence of PE, but this did not translate to a mortality or morbidity benefit. There is however, a growing body of evidence showing a broad range of adverse effects of these devices including increased rates of DVT, IVC thrombosis, IVC rupture and embolism of the IVC filter or its fragments. IVC filters should therefore be reserved for patients with a clear contraindication to anticoagulation and they should be removed within 3e6 months or as soon as anticoagulation can be commenced in order to avoid unwanted complications.1 Thrombolysis In massive PE, systemic thrombolytic therapy is widely accepted practice and recommended by most of the large respiratory and
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<3% with heparin infusion alone), although ICH is less common than might be feared (1.5e2.5%). The risk of major bleeding (including ICH) increases with age, particularly in patients greater than 65 years of age.
effects which lead to improved cardiac contractility. In cases where there is severe ventricular dysfunction, ionotropic agents such as milrinone or dobutamine may have to be used for augmentation of contractility. Caution should be exercised when using these agents as they have systemic vasodilatory effects that may lead to systemic hypotension and therefore should be used in conjunction with a vasopressor such as noradrenaline. If high doses of noradrenaline are required to maintain an adequate perfusion pressure, then vasopressin should be considered as a second-line vasopressor due to its sparing effects on pulmonary vasculature, which results in a favourable PVR/SVR ratio. RV afterload can be reduced through selective pulmonary vasodilation (e.g. nitric oxide or inhaled prostacyclin) though these may also result in systemic hypotension. Extracorporeal membrane oxygenation (ECMO) is an alternative form of mechanical assistance, which may be available in specialized institutions. It should be considered for patients with PE who have had cardiopulmonary arrest or have very severe shock not responding to other less invasive therapies.
Embolectomy Although mortality from surgical embolectomy for PE ranges from 25% to 50%, there still remains a role for this intervention but this is probably limited to patients with massive PE, treated within cardiothoracic centres or where thrombolytic therapy is contraindicated or has failed. Surgery has also been advocated for removal of free-floating RV thrombus. Alternative approaches include percutaneous embolectomy, catheter-directed therapy with targeted thrombolysis or rheolysis (physical disruption of clot), or a combination of the above. These emerging techniques offer the potential of targeting therapy to the site of pathology and therefore reducing the effective dose of anticoagulant or thrombolytic agent with the hope of reducing the risk of ICH. The best clinically studied technique is ultrasound-facilitated catheter directed thrombolysis (USDCT), a form of pharmaco-mechanical thrombolysis. Two small randomized clinical trials (ULTIMA and OPTALYSE) showed that USDCT is a feasible therapy which significantly reduces thrombus burden and improves parameters of RV strain.1 However, safety and positive effects on patient orientated outcomes remain unproven. These techniques may be considered in patients who have a significant bleeding risk to systemic thrombolysis in centres with the appropriate expertise.
VTE prophylaxis For most inpatients (and a select group of patients at home), VTE prophylaxis is the most important aspect of PE management. Multiple studies have robustly demonstrated the effectiveness of prophylactic strategies in preventing DVT and PE across patient groups.8 Local protocols will vary but good evidence exists for pharmacological prophylaxis with subcutaneous heparin, LMWHs or fondaparinux. IVC filters prevent recurrent PE over the long term, but at the cost of increased DVT risk and other complications previously mentioned. Mechanical approaches with graduated compression stockings and intermittent pneumatic compression devices are other options that can be used when anticoagulation is contraindicated. Combining these therapies with prophylactic anticoagulation has been shown to have no beneficial effect in a large multinational randomized controlled trial (PREVENT trial 2019).9
Concurrent haemodynamic support Massive PE causes increased pulmonary vascular resistance (PVR), which through a chain of effects will lead to RV pressure overload and RV failure. LV function is dependent on RV output, therefore if RV failure is left untreated it can lead to systemic hypotension, reduced coronary perfusion and cardiovascular collapse. Factors contributing to haemodynamic instability are explained in detail in Figure 3. Shocked patients with massive PE need urgent supportive care in parallel to definitive and preventative treatment. Therapies should be aimed at supporting RV function, which includes optimization of preload, afterload, contractility, rate and rhythm, as well as coronary perfusion. Insertion of a PA catheter may guide therapy with vasoactive agents and monitor response to thrombolysis but should not delay definitive treatment. Also, the risk of precipitating ventricular arrhythmias maybe increased in the setting of RV strain and the risk of thrombus propagation or pulmonary artery rupture may be increased in proximal PEs. Volume loading with intravenous fluids to optimize RV preload should be carefully considered as patients with PE are often not hypovolaemic and excessive fluid administration may overload an already stressed or injured right ventricle, leading to further decline and risking left ventricular failure. Ideally, fluid administration should be guided by echocardiographic assessments. Early administration of vasoactive and ionotropic agents is recommended, especially in the setting of hypotension. Noradrenaline is the preferred first-line agent for its concomitant beneficial alpha agonism, which leads to increased diastolic pressures and therefore coronary perfusion, and beta-adrenergic
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Controversies As the accuracy of diagnostic tests continues to improve, the detection of subsegmental PE will continue to increase. The clinical significance of small subsegmental PE has been brought into question and treatment of this subgroup remains controversial. Every case should be considered on its own merits, taking into account clinical stability, comorbidities, biomarkers, evidence of DVT and risk of bleeding complications from anticoagulation. A REFERENCES 1 Konstantinides S, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J, 2019; 1e61. 2 Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism the ADJUST-PE study. J Am Med Assoc 2014; 311: 1117e24. 3 Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein
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thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the AmericanHeart Association. Circulation 2011; 123: 1788e830. 4 Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism (PIOPED II). N Engl J Med 2006; 354: 2317e27. 5 Becattini C, Cohen AT, Agnelli G, et al. Risk stratification of patients with acute symptomatic pulmonary embolism based on presence or absence of lower extremity DVT: systematic review and metaanalysis. Chest 2016; 149: 192e200. 6 Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary
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embolism: results of a multicenter registry. JACC (J Am Coll Cardiol) 1997; 30: 1165e71. 7 Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guidelines and expert panel report. Chest 2016; 149: 315e52. 8 Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. J Am Med Assoc 2014; 311: 2414e21. 9 Arabi YM, Al-Hameed F, Burns KE, et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Engl J Med 2019; 380: 1305e15.
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The management of pulmonary embolism
Learning objectives After reading this article, you should be able to: C describe the disease entity of VTE/PE and outline risk factors for its development, recognizing the varied spectrum of presentation in PE C outline an appropriate diagnostic strategy for the evaluation of possible PE, risk stratifying according to clinical presentation and investigations C describe the various treatment options for PE and how they should be utilized in the light of the risk stratification and diagnostic findings C discuss the challenges in the management of massive and submassive PE C describe the importance of VTE prophylaxis in the prevention of PE
Tamara P Banerjee Juan Carlos Mora
Abstract Pulmonary embolism (PE) is a significant cause of hospitalization, morbidity and mortality, frequently requiring critical care services. Critically ill patients are also at increased risk of developing venous thromboembolism and acute PE. Critical care clinicians should be confident in their approach to the patient with suspected and diagnosed PE. Furthermore, the comorbid conditions in this patient group may present additional challenges both in diagnosis (e.g. safe access to radiology) and management (e.g. absolute and relative contraindications to anticoagulation/thrombolysis in critically ill patients). This brief review summarizes the contemporary evidence base regarding both diagnosis and treatment strategies and draws upon this to suggest a simple algorithm for investigation, risk stratification and management, particularly tailored to patients within a critical care setting.
Keywords Anticoagulation; computed tomographic pulmonary angiography (CTPA); embolectomy; IVC filter; massive pulmonary embolism; pulmonary embolism; submassive pulmonary embolism; thrombolysis; venous thromboembolism (VTE)
outlines the most common signs and symptoms in patients diagnosed with PE. In the setting of inconsistent patterns of presentation, risk factors are particularly useful to help determine the probability of PE. The risk factors for PE can be deduced from Virchow’s triad which governs the pathogenesis of venous thromboembolism (VTE). Virchow’s triad consists of venous stasis, endothelial injury and hypercoagulable states. Risk factors can be divided into genetic and acquired states (Table 2).
Royal College of Anaesthetists CPD Matrix: 2C00, 2C01, 2C03, 2C04, 1B00
Diagnosis The diagnostic approach depends on the patient’s haemodynamic stability. Most patients will be clinically stable enough to warrant a considered approach which starts with assessing the pre-test probability to determine what further testing is required, if any. Various decision-making tools are available to help the clinician risk stratify patients. The most widely reported and clinically validated tools are the Wells rule, the revised Geneva scoring system and the pulmonary embolism rule out criteria (PERC). Both the Wells and the revised Geneva rules have been simplified in order to increase their adoption into clinical practice (Table 3). If the patient is low risk, then PE can be safely ruled out with a negative D-dimer test, otherwise definitive imaging, such as computed tomographic pulmonary angiography (CTPA) or ventilation-perfusion scanning should be performed. The PERC rule has the advantage of excluding PE in low risk patients without the need of any additional testing such as D-dimer. The rules aim to risk stratify patients and focus resources on those most likely to benefit and avoid unnecessary tests and their downstream complications. The majority of patients who reach a critical care environment meet criteria for high-risk pretest probability. Particularly complex are pregnant patients where the risk of VTE is significantly elevated and imaging modalities are not without risk to the fetus.1 In the case of patients who are haemodynamically unstable, bedside echocardiography or limb venous Doppler ultrasound can be utilized to obtain a presumptive diagnosis of PE to justify the initiation of therapy. If a patient presents with a malignant arrhythmia or cardiac arrest, the diagnostic assessment may have to be omitted and if there is a high index of clinical suspicion
Definition Pulmonary embolism (PE) describes an obstruction of the pulmonary arterial tree with abnormal material (thrombus, tumour, air or fat), usually originating somewhere else in the body. Patients can present acutely (immediately after the event), sub-acutely (within days/weeks after the embolism) or chronically (years after the embolism). The most common cause of acute PE is the migration of thrombus from veins (or right heart) to the pulmonary arteries. Other forms of PE are beyond the scope of this article.
Clinical presentation Acute PE is a commonly considered but relatively infrequently diagnosed condition in hospitalized patients. This is unsurprising given presentation is varied and non-specific; ranging from no symptoms to dyspnoea, shock and sudden death. Table 1
Tamara P Banerjee BSc (Hons) BM BCh MRCP FRCA FFICM is a Locum Consultant in Intensive Care Medicine and Anaesthesia at The Royal Free Hospital, London, UK. Conflicts of interest: none declared. Juan Carlos Mora BSc MBChB FACEM PG Dip (Clinical US) is a Senior Intensive Care Registrar at The Alfred Hospital, Melbourne, Australia; and Locum Emergency Care Consultant at Wagga Wagga Base Hospital, NSW, Australia. Conflicts of interest: none declared.
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Clinical characteristics of patients diagnosed with PE Past history
Symptoms (sorted by a decreasing frequency)
Signs (sorted by an increasing risk of mortality)
Previous DVT/PE Family history of DVT/PE/sudden death Thrombophilia Hypercoagulability
Dyspnoea Pleuritic chest pain Cough Syncope Haemoptysis (late sign of lung infarction)
None Signs of DVT Tachycardia (most common) Fever RV dysfunction (raised JVP, loud P2, parasternal heave) Hypotension Skin mottling Cyanosis Cardiovascular collapse/arrest
Table 1
there should be a low threshold to instigate potentially life-saving therapy without diagnostic confirmation. Figure 1 Summarizes severity stratification, assessment, as well as treatment of patients with pulmonary embolism.
classically described deep S wave in lead I, with a Q-wave and inverted T-wave in lead III (S1Q3T3) is a rare sign of right heart strain and is usually only found in severe cases of acute PE. Other evidence of right ventricular (RV) strain, including T-wave
Investigations Initial investigations An arterial blood gas analysis (ABG) demonstrating hypoxia (with widened alveolar-arterial oxygen gradient) and hypocapnia with a concomitant increase in end-tidal CO2 gradient is suggestive of PE but lacks specificity. Equally, a normal blood gas does not exclude PE. The most common ECG finding is sinus tachycardia (up to 70%) but a normal ECG is found in one-third of cases. The
Clinical prediction rules for PE
Risk factors for VTE Genetic
Acquired
Factor V Leiden Prothrombin gene mutation Protein C deficiency Protein S deficiency Lupus anticoagulant Antithrombin III deficiency Dysfibrinogenaemias
Immobility Malignancy Surgery (within 3 months) Hospitalization Pregnancy Advancing age Trauma (especially pelvis, lower limb, acute spinal cord injuries) Infection Oestrogen Smoking Obesity Blood transfusion and erythropoietic agents Hyperviscosity syndromes (myeloma and other haematological disorders)
Inferior vena cava abnormalities Hyperhomocystinaemia
Score (original)
Score (simplified)
Clinical signs and symptoms of DVT Tachycardia Immobilization or surgery in previous 4 weeks Previous PE or DVT Haemoptysis Malignancy Alternative diagnosis is less likely than PE Cutoff score for PE to be UNLIKELY
3 1.5 1.5
1 1 1
1.5 1 1 3
1 1 1 1
4
1
1 3 2
1 1 1
2 3 2
1 1 1
3 5 4
1 1 1
5
2
Revised Geneva score Age >65 years old Previous DVT or PE Surgery (under general anaesthesia) or lower-limb fracture within past month Active cancer Unilateral lower-limb pain Haemoptysis Heart rate: 75e94 beats/minute 95 beats/minute Pain on lower-limb deep venous palpation and unilateral oedema Cutoff score for PE to be UNLIKELY
Table 2
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Wells rule
Table 3
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inversion, right bundle branch block and p-pulmonale may be seen, as well as atrial arrhythmias (most commonly atrial fibrillation). The ECG should be regarded as an essential test as it is useful for screening for alternate and life-threatening diagnoses (Box 1).
Differential diagnosis of PE Acute myocardial infarction Acute pulmonary oedema Exacerbation of asthma/COPD Pneumonia Pneumothorax Pericardial tamponade Pericarditis Pleural effusion/empyema Aortic dissection Fat/amniotic embolism Rib fracture Musculoskeletal pain Anxiety
Biomarkers D-dimer, a fibrin degradation product, is the most extensively investigated biomarker for PE. When a low result (usually 500 ng/ml) is used in conjunction with the Wells criteria it can play an important role in excluding VTE and PE in lowrisk individuals. However, due to the test’s low specificity and negative predictive value, it should not be used in patients with a high pre-test probability. The critical care provider should be aware of these inherent issues with D-dimers and be cautious when applying this test to critically unwell patients who will most likely be high risk for VTE. Ageadjusted cut-offs for D-dimer have been validated and provide more useful data in patients over 50 years of age.2 In patients with known acute PE, elevated levels of D-dimer at diagnosis are associated with an increased risk of death
Box 1
Severity stratification assessment and treatment of patients with pulmonary embolism Immediate or high clinical probability of PE (using clinical prediction rules)
Initial clinical assessment
Initial diagnostic test
Assessment of PE severity
Treatment
Haemodynamically stable
Haemodynamically unstable
Multi-detector CTPA (V/Q scan if CTPA unavailable/contraindicated)
Echocardiography (TTE or TOE)
using CTPA, blood tests and echocardiography
PE likely if RV dysfunction
thrombus in RV or PA
Segmental or subsegmental PE and normal troponin, BNP or NT pro-BNP
RV dysfunction present, raised troponin, BNP or NT pro-BNP
CTPA if safe
Anticoagulant therapy only
Anticoagulant therapy Consider thrombolsyis based on individual
Anticoagulant and thrombolytic therapy Embolectomy or catheter directed thrombolysis if high risk of bleeding If severe instability or cardiac arrest, consider ECMO support if available
Standard PE
Submassive PE
Massive PE
BNP, brain natriuretic peptide; CTPA, computed tomography pulmonary angiography; NT, NT-terminal; PA, pulmonary artery; PE, pulmonary embolus; RV, right ventricular; TOE, trans-oesophageal echocardiography; TTE, transthoracic echocardiography.
Figure 1
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and show a blood level-related effect. D-Dimer levels <1500 ng/ml has a negative predictive value of 99% for excluding 3-month mortality.1 Measurements of troponin, brain natriuretic peptide (BNP) or NT-terminal pro-BNP (NT-Pro-BNP) are also useful to risk stratify and determine prognosis in confirmed PE. Raised troponin is a marker of right heart strain and predicts haemodynamic instability in sub-massive PE and increased risk of death regardless of PE size. In proven PE, low levels of BNP and NTPro-BNP as well as undetectable high-sensitivity troponin correlate with good outcomes.1
Computed tomography pulmonary angiography (CTPA) CTPA has multiple advantages such as high sensitivity and high specificity, is readily available with rapid image-acquisition time and has the added ability to assess for alternative diagnoses.1 With the improved precision of CT scanners, CTPA with multi-detector scanning technique has become the imaging modality of choice for diagnosing acute PE and it is now considered a reference standard replacing pulmonary angiography (Figure 2). Highresolution images to the level of segmental and, in many cases, subsegmental pulmonary arteries can be obtained in a short timeperiod (often a single breath-hold). In addition to visualizing intraluminal filling defects, RV dilation measurements are predictive of adverse short-term events, including death in hospital, 30-day mortality and 3-month mortality.3 In contrast, measurement of clot burden is not predictive of an adverse prognosis. Patients with a negative CTPA but high pre-test probability only have a 60% negative predictive value of PE4 and hence should be managed on an individual basis. In these patients the risk of a falsely negative CTPA should encourage further testing (see options below) and/or admission for prolonged observation. In cases where diagnostic uncertainty persists, we recommend consulting a haematology specialist to discuss further options.
Imaging There are several imaging modalities that can aid the management of PE, but it is important to note that there is no ideal test to confirm the diagnosis. The choice of modality will depend on several factors, including the likelihood of PE, differential diagnosis, stability of the patient, patient allergies and availability of imaging modalities and reporting specialists. Chest X-ray In most cases of PE, the chest X-ray (CXR) will be normal but it is a useful test to exclude common differentials such as pneumothorax, pneumonia or pleural effusion. The most common abnormal findings are patchy opacification and atelectasis. Rarer findings such as Westermark sign and Hampton’s hump are not diagnostic but should make the clinician suspect the diagnosis.
Lung scintigraphy Ventilation-perfusion scans (VQ scans) utilize radioactive isotopes to evaluate lung ventilation and perfusion in a staged
Figure 2 Three images from a single CTPA study performed with a high clinical suspicion of PE. (a) demonstrates large PEs in the proximal right and inferior left pulmonary artery. (b) shows a significant concurrent pneumothorax. (c) demonstrates an RV/LV ratio >1 signifying significant RV dysfunction. Together these images show the high utility of CTPA in diagnosis/exclusion of PE, diagnosis/exclusion of differential diagnoses, and in risk stratifying a patient so as to guide therapy.
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acute PE. MRA is more complex, time-consuming, less available, cannot be performed in patients with implanted devices such as permanent pacemakers, and has limited ability to detect other causes of dyspnoea when compared to CTPA.
process. VQ scans have several disadvantages which reduce its utility in critically ill patients, these include lack of availability, long duration of scan, a normal CXR being a prerequisite in order to obtain interpretable results, and even with optimal conditions the scan can often yield indeterminate results. VQ scanning is mostly reserved for patients in whom CTPA is unavailable, inconclusive or contraindicated due to intravenous contrast allergy. Due to its lower radiation dose, a VQ scan is also an option for women in the early stages of pregnancy, when the foetus is most prone to ionizing radiation.
Disease spectrum and severity Massive PE/high risk PE This is defined as an acute PE which presents with sustained hypotension (systolic BP <90 mmHg) for at least 15 minutes despite adequate resuscitation and is not explained by another cause such as an arrhythmia, left ventricular dysfunction, or sepsis. Even when treated, this condition has a mortality exceeding 25% (65% if cardiopulmonary resuscitation is required).6 Acute RV failure is a very common feature and as a consequence, if patients survive the initial event they remain at significant risk of death for several days.
Echocardiography Transthoracic echocardiography (TTE) only has the ability to identify thrombus in the proximal pulmonary arterial tree and right ventricular and therefore will miss up to 50% of clots. It is, however, good at identifying RV strain as a result of clot burden and therefore can be useful for classifying the severity and prognosis of a PE. Findings include RV dilation, hypokinesis of RV free wall, interventricular septum flattening, inferior vena cava distension, McConnell’s sign and the 60-60 sign. Its greatest utility is in the most severe cases, where haemodynamic instability may prevent safe transport to CT. In these cases, TTE can be performed at the bedside to identify or exclude other causes of haemodynamic instability (Table 4) and assess severity of known PE (RV dysfunction on TTE is an independent predictor of an adverse outcome). In a select group of patients, where there is a high index of clinical suspicion for PE, findings on TTE may be sufficiently compelling to warrant commencement of therapy.
Sub-massive PE/intermediate risk PE In this subset of acute PEs, patients do not have hypotension but instead have evidence of RV dysfunction (best confirmed with echocardiography but also seen on CT) or myocardial necrosis (confirmed with positive troponin test). This group, if treated with anticoagulation alone, have a mortality of <3%.3 They may, however, also progress to haemodynamic decompensation in the acute phase or go on to develop chronic pulmonary hypertension. Low risk PE These are all other patients with acute PE who are haemodynamically stable with normal RV function. Most of these patients will have a small volume of clot burden and if there is no contraindication to treatment will follow an uneventful course (<2% mortality) unless further PE occurs.
Venous ultrasonography Lower extremity venous Doppler ultrasound has a high sensitivity and specificity for deep venous thrombosis (DVT) and can be done at the bedside. When DVT is detected and PE is clinically suspected, treatment can be initiated without further investigation for PE. This feature is particularly useful when the patient is unstable or definitive imaging is not available or contraindicated (contrast allergy or pregnancy). However, only up to 55% of patients with acute symptomatic PE have concomitant DVT5 and therefore a negative study does not confidently exclude PE.
Treatment The major principles of management of an acute PE are prevention of further embolization and propagation of thrombosis (anticoagulation and inferior vena cava (IVC) filters), removal of established clot (thrombolysis and embolectomy) and concurrent haemodynamic support. Choice of therapies depends on the severity of PE (See Figure 1).
Pulmonary angiography and magnetic resonance angiography (MRA) Pulmonary angiography previously has been the ‘gold standard’ for decades; however, with the advent of sophisticated and highly accurate CTPA, this is becoming significantly less utilized unless as part of a percutaneous catheter-directed treatment for
Anticoagulation Anticoagulation decreases mortality in patients with PE, hence, patients with an intermediate or high clinical probability for PE should be anticoagulated while waiting for diagnostic tests, unless there is a compelling contraindication. In patients with an absolute contraindication to anticoagulation, further investigations should be expedited so alternative therapies (including IVC filter) can be instituted if a PE is confirmed. The risk of a major bleeding event secondary to anticoagulation is lower (<3%) than the risk of death from undiagnosed PE (30%).1 Low molecular weight heparins (LMWH) and fondaparinux are as safe and effective as unfractionated heparin (UFH). In stable patients with PE, LMWHs offer several advantages over UFH including longer dosing interval, increased bioavailability, a more predictable dose response and fewer requirements for monitoring and dose adjustments. Periodic measurement of
Suggested indications for insertion of inferior vena cava filter New or recurrent PE despite anticoagulation Contraindications to anticoagulation Complications resulting from anticoagulation Other recommended indications Following thrombolytic therapy Post surgical embolectomy Extensive DVT Table 4
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Key factors contributing to haemodynamic collapse and death in acute pulmonary embolism
Increased RV afterload
RV dilation
Systemic BP
Cardiac output
Coronary perfusion
RV wall tension
LV preload
RV output
RV O2 delivery
DEATH Obstructive shock
Contractility
RV ischaemia
Neurohormonal activation
Myocardial
RV O2 demand
et al.1 Figure 3
cardiology societies.1,7 Its use may result in dramatic improvements in RV dysfunction, decrease in pulmonary artery pressures, improved haemodynamics and better oxygenation, especially in the first few days, as well as likely improved mortality. In sub-massive PE, treatment with thrombolytics remains controversial despite extensive research. To date, there have been four large randomized controlled trials investigating this topic: MAPPETT 3, PEITHO, TOPCOAT & MOPPET.1 These trials demonstrated that although thrombolytic therapy reduces the risk of haemodynamic decompensation, it does not appear to improve mortality. Furthermore, thrombolytic therapy increases risk of major bleeding and intracranial haemorrhage (ICH) by approximately ten fold. The TOPCOAT trial claimed improved functional outcomes at 3 months and the MOPPET trial showed a reduction in pulmonary hypertension at 28 months. However, neither of these benefits were confirmed in the much larger PEITHO follow up trial.1 A 2014 meta-analysis suggested that administration of thrombolytic therapy for sub-massive PE resulted in a decrease in mortality and recurrence of PE compared to standard anticoagulation but was associated with an increased risk of bleeding, including ICH.8 The most recent consensus guidelines recommend against routine thrombolysis for sub-massive PE and instead consider risk-benefit ratios in each individual case.1 If, however, haemodynamic decompensation occurs, thrombolysis should be strongly considered. Thrombolytic agents include alteplase (tPA), tenectaplase and reteplase. No study has shown a significant difference in efficacy between these different thrombolytic agents. Concerns around haemorrhagic complications are justified as major bleeding occurs in up to 10% of patients thrombolysed for PE (versus
anti-factor Xa activity (anti-Xa levels) may be considered in patients with severe renal failure, morbid obesity or during pregnancy. In contrast, UFH offers rapid therapeutic dosing, can be therapeutically monitored and reversed with protamine if required. The predominant complication of these anticoagulants is bleeding. Both bleeding complications and heparininduced thrombotic thrombocytopenia syndrome (HITTS) appear to be less common with LMWH compared with UFH. The lack of immune-mediated effect on platelets by fondaparinux has led to its safe use in patients with HITTS.1 Inferior vena cava (IVC) filters IVC filters are endovascular retrievable devices that are designed to reduce pulmonary embolisms originating in the lower limbs. Despite increasing use of these devices, their effectiveness still remains largely unproven. Three randomized controlled trials (PREPIC, PREPIC2 and FILTER-PEV1) studied the effects of combining IVC filters with systemic anticoagulation. All trials showed a reduction in the incidence of PE, but this did not translate to a mortality or morbidity benefit. There is however, a growing body of evidence showing a broad range of adverse effects of these devices including increased rates of DVT, IVC thrombosis, IVC rupture and embolism of the IVC filter or its fragments. IVC filters should therefore be reserved for patients with a clear contraindication to anticoagulation and they should be removed within 3e6 months or as soon as anticoagulation can be commenced in order to avoid unwanted complications.1 Thrombolysis In massive PE, systemic thrombolytic therapy is widely accepted practice and recommended by most of the large respiratory and
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<3% with heparin infusion alone), although ICH is less common than might be feared (1.5e2.5%). The risk of major bleeding (including ICH) increases with age, particularly in patients greater than 65 years of age.
effects which lead to improved cardiac contractility. In cases where there is severe ventricular dysfunction, ionotropic agents such as milrinone or dobutamine may have to be used for augmentation of contractility. Caution should be exercised when using these agents as they have systemic vasodilatory effects that may lead to systemic hypotension and therefore should be used in conjunction with a vasopressor such as noradrenaline. If high doses of noradrenaline are required to maintain an adequate perfusion pressure, then vasopressin should be considered as a second-line vasopressor due to its sparing effects on pulmonary vasculature, which results in a favourable PVR/SVR ratio. RV afterload can be reduced through selective pulmonary vasodilation (e.g. nitric oxide or inhaled prostacyclin) though these may also result in systemic hypotension. Extracorporeal membrane oxygenation (ECMO) is an alternative form of mechanical assistance, which may be available in specialized institutions. It should be considered for patients with PE who have had cardiopulmonary arrest or have very severe shock not responding to other less invasive therapies.
Embolectomy Although mortality from surgical embolectomy for PE ranges from 25% to 50%, there still remains a role for this intervention but this is probably limited to patients with massive PE, treated within cardiothoracic centres or where thrombolytic therapy is contraindicated or has failed. Surgery has also been advocated for removal of free-floating RV thrombus. Alternative approaches include percutaneous embolectomy, catheter-directed therapy with targeted thrombolysis or rheolysis (physical disruption of clot), or a combination of the above. These emerging techniques offer the potential of targeting therapy to the site of pathology and therefore reducing the effective dose of anticoagulant or thrombolytic agent with the hope of reducing the risk of ICH. The best clinically studied technique is ultrasound-facilitated catheter directed thrombolysis (USDCT), a form of pharmaco-mechanical thrombolysis. Two small randomized clinical trials (ULTIMA and OPTALYSE) showed that USDCT is a feasible therapy which significantly reduces thrombus burden and improves parameters of RV strain.1 However, safety and positive effects on patient orientated outcomes remain unproven. These techniques may be considered in patients who have a significant bleeding risk to systemic thrombolysis in centres with the appropriate expertise.
VTE prophylaxis For most inpatients (and a select group of patients at home), VTE prophylaxis is the most important aspect of PE management. Multiple studies have robustly demonstrated the effectiveness of prophylactic strategies in preventing DVT and PE across patient groups.8 Local protocols will vary but good evidence exists for pharmacological prophylaxis with subcutaneous heparin, LMWHs or fondaparinux. IVC filters prevent recurrent PE over the long term, but at the cost of increased DVT risk and other complications previously mentioned. Mechanical approaches with graduated compression stockings and intermittent pneumatic compression devices are other options that can be used when anticoagulation is contraindicated. Combining these therapies with prophylactic anticoagulation has been shown to have no beneficial effect in a large multinational randomized controlled trial (PREVENT trial 2019).9
Concurrent haemodynamic support Massive PE causes increased pulmonary vascular resistance (PVR), which through a chain of effects will lead to RV pressure overload and RV failure. LV function is dependent on RV output, therefore if RV failure is left untreated it can lead to systemic hypotension, reduced coronary perfusion and cardiovascular collapse. Factors contributing to haemodynamic instability are explained in detail in Figure 3. Shocked patients with massive PE need urgent supportive care in parallel to definitive and preventative treatment. Therapies should be aimed at supporting RV function, which includes optimization of preload, afterload, contractility, rate and rhythm, as well as coronary perfusion. Insertion of a PA catheter may guide therapy with vasoactive agents and monitor response to thrombolysis but should not delay definitive treatment. Also, the risk of precipitating ventricular arrhythmias maybe increased in the setting of RV strain and the risk of thrombus propagation or pulmonary artery rupture may be increased in proximal PEs. Volume loading with intravenous fluids to optimize RV preload should be carefully considered as patients with PE are often not hypovolaemic and excessive fluid administration may overload an already stressed or injured right ventricle, leading to further decline and risking left ventricular failure. Ideally, fluid administration should be guided by echocardiographic assessments. Early administration of vasoactive and ionotropic agents is recommended, especially in the setting of hypotension. Noradrenaline is the preferred first-line agent for its concomitant beneficial alpha agonism, which leads to increased diastolic pressures and therefore coronary perfusion, and beta-adrenergic
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Controversies As the accuracy of diagnostic tests continues to improve, the detection of subsegmental PE will continue to increase. The clinical significance of small subsegmental PE has been brought into question and treatment of this subgroup remains controversial. Every case should be considered on its own merits, taking into account clinical stability, comorbidities, biomarkers, evidence of DVT and risk of bleeding complications from anticoagulation. A REFERENCES 1 Konstantinides S, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J, 2019; 1e61. 2 Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism the ADJUST-PE study. J Am Med Assoc 2014; 311: 1117e24. 3 Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein
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thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the AmericanHeart Association. Circulation 2011; 123: 1788e830. 4 Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism (PIOPED II). N Engl J Med 2006; 354: 2317e27. 5 Becattini C, Cohen AT, Agnelli G, et al. Risk stratification of patients with acute symptomatic pulmonary embolism based on presence or absence of lower extremity DVT: systematic review and metaanalysis. Chest 2016; 149: 192e200. 6 Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary
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embolism: results of a multicenter registry. JACC (J Am Coll Cardiol) 1997; 30: 1165e71. 7 Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guidelines and expert panel report. Chest 2016; 149: 315e52. 8 Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. J Am Med Assoc 2014; 311: 2414e21. 9 Arabi YM, Al-Hameed F, Burns KE, et al. Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Engl J Med 2019; 380: 1305e15.
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