Hemodynamic Consequences

The principal pathophysiologic effects of pulmonary thromboembolism result from the acute impaction of material into pulmonary circulation and the resulting vascular obstruction and humoral mediator release as depicted in Figure 44.1.⁵⁷ In nonthrombotic obstruction of the pulmonary vasculature, obliteration of 60% to 70% of the vascular tree is required to cause an elevation of the pulmonary artery pressure. In contrast, only 30% of the vascular tree must be obstructed in pulmonary thromboembolism for elevation of the pulmonary artery pressure to be achieved.^58,59 Therefore, factors other than simple mechanical obstruction of the pulmonary vascular system play a role in the elevation of the pressures in the pulmonary vasculature during pulmonary thromboembolism.

The production of platelet-derived vasoconstrictors may play a role in augmenting the increase in pulmonary vascular resistance (PVR) (Fig. 44.2).^57,58,60 Thromboxane A₂ (TxA₂) is a potent vasoconstrictor and is the end product of arachidonic acid metabolism. TxA₂ is produced by endothelial cells, and even in greater quantities by platelets in response to platelet aggregation. It has been demonstrated that there is increased production of TxA₂ in the early phase of PE, which contributes to the PVR elevation and may be attenuated by cyclooxygenase (COX) inhibition in animal models.⁵⁷ Serotonin (5-hydroxytryptamine) is one of the most potent pulmonary vasoconstrictors. Infusion of serotonin in an animal model can actually simulate the signs and symptoms of PE. Like TxA₂, platelets are the primary source of serotonin production in PE. Serotonin antagonism can reduce PVR.^57,60

There appears to be nearly an exponential increase in VTE events with age.²⁹ The elderly demonstrate an incidence of 300 to 500 cases/100,000 persons compared to 30 cases/100,000 of persons age 25 to 35 years.²⁹ A longitudinal study of 855 men followed from the ages of 50 to 80 years demonstrated the cumulative incidence of a VTE event was 0.5% by the age of 50 years and increased to 10.7% by the age of 80 years.³ The risk of VTE recurrences increases with age. In the elderly the PE rates are rising faster than the DVT rates; thus, a VTE event in an elderly person is more likely to be a PE, with its potential lethality.^3,30

Anderson and Spencer³¹ reviewed multiple risk factors associated with a diagnosis of VTE and found that the risk factors were not equal in their impact on VTE occurrence. The strongest risk factors were hip and leg fractures, major general surgery, hip or knee replacement, major trauma, and spinal cord injury. Moderate risk factors included arthroscopic knee surgery, central venous lines, chemotherapy, congestive heart failure, hormonal replacement or oral contraceptives, cancer, pregnancy, thrombophilia, and prior VTE.³¹ Heit and associates³² found that the hospital setting, nursing home, or other chronic facility confinement was an independent risk factor for the VTE. This is most likely reflective of the various degrees of immobility that these patients experience.

Several acquired and inherited hypercoagulable states have been shown to increase the risk of VTE and are collectively known as thrombophilia. Major acquired hypercoagulable conditions include malignancy, myeloproliferative disorders, and antiphospholipid syndrome (APS).³³ DVT, the most common manifestation of the APS, occurs in 29% to 55% of patients with the syndrome, and about half of these patients have pulmonary emboli.^34–36

The occurrence of a VTE event in a young adult alerts the clinician to the potential of an underlying inheritable thrombophilic condition. Nearly half the patients with a VTE event before the age of 45 have an associated inherited disorder.³³ Factor V Leiden mutation causing resistance to activated protein C is the most common inherited risk factor. Factor V Leiden mutation is present in up to 5% of the normal population and is the most common cause of familial thromboembolism.³³ Factor V Leiden mutation appears to be more associated with the development of DVT rather than PE.³⁷ Primary or acquired deficiencies in protein C, protein S, and antithrombin III are other risk factors and their thrombotic expression is variable.³³

Several primary disorders are associated with a high risk for fatal VTE. Patients frequently present with massive PE, and ICU admission and management is required. From the RIETE registry, risk factors of immobilization secondary to neurologic disease, cancer, and cardiopulmonary disorders had two- to threefold increased risk for fatal PE.³⁸ In hospitalized cancer patients, VTE is the second leading cause of death.³⁹ The risk of VTE in cancer patients undergoing surgery is three to five times greater than that in surgical patients without cancer. Moreover, cancer patients with symptomatic DVT exhibit a high risk of recurrent VTE.⁴⁰ Heart failure is a frequent admission diagnosis in the coronary care unit. In patients with severe heart failure (ejection fractions less than 30%) PE is a major cause of morbidity and mortality rates.^41,42 Among 198 patients with severe heart failure in the coronary care unit, 9.1% developed PE during their hospitalization, despite a majority receiving thromboprophylaxis.⁴¹ In an autopsy series of cardiac patients nearly a quarter had PE and the diagnosis was unsuspected in 82% of the patients.⁴³ Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a common reason for admission to the general hospital ward service and the ICU. Increase work of breathing leads to immobility, which is a risk factor of DVT. In a prospective cohort of 196 patients with COPD exacerbation, all patients had ultrasonography of the lower extremities performed. Among the 196 patients, 21 (10.7%) had DVT and the majority was asymptomatic.⁴⁴ Moreover, hospitalized patients with unexplained exacerbations of COPD, when routinely evaluated, show demonstrated PE in 25% to 29%.^45,46

As shown in Figure 44.1, the degree of mechanical obstruction, the interplay of neurohumoral mediators, and the patient’s underlying cardiopulmonary status will dictate the degree of RVD. A rapid rise in the pulmonary artery resistance produces a significant rise in right ventricular (RV) afterload, thereby causing RV dilatation. The dilation of the right ventricle results in shifting of the interventricular septum into the left ventricle, decreasing left ventricular (LV) preload.^61–63 Moreover, RV dilation potentially promotes an increase in constrictive forces by the pericardium, leading to reduced LV compliance. Decreasing LV preload and compliance subsequently lead to lowering of the cardiac output and systemic hypotension with resultant decrease in aortic perfusion pressure and decreasing right coronary perfusion pressure.^64,65 A compromised and burdened right ventricle is a direct result of oxygen demand outstripping oxygen supply, creating an ischemic environment for the right ventricle. The functional status of the cardiopulmonary system is very important in the initial hemodynamic presentation and is a major determinant of short- and long-term outcome.⁶⁶ In patients without cardiopulmonary disease the anatomic and humoral obstruction must be 75% or greater to cause a mean pulmonary artery pressure (MPAP) of 40 mm Hg or higher, which is not sustainable; even the previously healthy heart may proceed to cardiovascular collapse and fail.⁶⁶ Right atrial pressure (RAP) elevation occurs when the MPAP is 30 mm Hg or higher and obstruction exceeds 35% to 40%.⁶⁷ Many patients who have a pulmonary embolic event have underlying cardiopulmonary disease. In these patients cardiopulmonary deterioration (CPD) may occur with a lesser degree of vascular obstruction.⁶⁶ This is illustrated by the UKEP (Urokinase-Embolie Pulmonaire) Trial in which an initial presentation of shock with acute PE was seen in 56% of patients who had prior cardiopulmonary disease compared to 2% without cardiopulmonary disease. Obstruction of greater than 50% was uncommon.⁶⁸

Respiratory Consequences

Hypoxemia is the most common gas exchange abnormality in patients. However, the PaO₂ and alveolar-arterial (A-a) gradient have been reported to be normal in approximately 30% of patients with PE.⁶⁹ Figure 44.2 summarizes the gas exchange abnormalities as a result of the pulmonary embolic event. Ventilation-perfusion mismatch and low mixed venous oxygen levels are the prevalent causes of hypoxemia.^70,71 As pulmonary artery pressures increase, right-to-left flow across a patent foramen ovale (PFO) may occur. Endothelial damage may result from hypoxic exposure and further lead to pulmonary vasoconstriction. Hypoxemia may even promote a prothrombotic and antifibrinolytic effect.⁵⁷

In acute PE an increase in alveolar dead space impairs CO₂ elimination; however, the increase in minute ventilation results in hypocapnia. In patients with massive PE there can be a paradoxical elevation of the PaCO₂ as a result of a marked increase in dead space ventilation.⁷² In PE patients because of an increase in alveolar dead space there is a reduction in alveolar CO₂ content, which can be detected by capnography by a reduction in the capnographic waveform area. In one study, PE patients significantly demonstrated a reduction in the capnographic waveform area when compared to patients without PE.⁷³ There is widening of the PETCO₂-PaCO₂ gradient. Bedside PETCO₂ coupled with a Wells score has been shown to have a high negative predictive value.⁷⁴

Clinical Presentation on Admission to the Intensive Care Unit

In patients admitted to the ICU with PE the clinical manifestations may be more demonstrative, as shown in Table 44.2. In the Urokinase Pulmonary Embolism Trial (UPET), the clinical features of massive PE were evaluated. Sudden unexplained onset of dyspnea was the most common symptom and was present in 80% of the patients. A majority of the patients had a well-defined risk factor. Tachypnea and tachycardia were present in 88% and 63% of the patients, respectively. Accentuated second heart sound was noted in 67%, and S₃ or S₄ gallop was present in 47%. Clinical shock was noted in 12%.⁸⁰ Syncope can occur. Retrosternal nonpleuritic chest pain may mimic the pain experienced with a myocardial infarction and represent demand ischemia of the right ventricle. The differential diagnosis of pulseless electrical activity (PEA) is massive PE and should be expected when there is a known major risk factor.

The signs and symptoms of submassive PE will depend upon the degree of RVD. Dyspnea may be progressive over the last 4 to 6 days. Chest pain can be either pleuritic or nonpleuritic in nature. If pulmonary infarction occurs as result of distal embolization, then hemoptysis may occur. From the PIOPED II database, 92% of patients with main or lobar pulmonary emboli had dyspnea or tachycardia in contrast to segmental emboli dyspnea and tachycardia, where 65% had these findings.81,82

Patients with massive PE and shock manifest systemic hypotension, poor perfusion of the extremities, tachycardia, and tachypnea. In addition, patients appear weak, pale, diaphoretic, oliguric, and develop altered mental status. The patient may be hypoxemic and require high flow oxygen or urgent intubation and mechanical ventilation. Varying degrees of RVD may be observed. The presence of jugular venous distention, with and without inspiratory collapse, RV heave, summation gallop, accentuated P₂, and presence of tricuspid regurgitation represent the impact the embolus has had on pulmonary vasculature and RV function. If a central line is placed via the subclavian or jugular route, the ScvO₂ is usually less than 65%.

Recognition of Pulmonary Embolism During Intensive Care Unit Admission

When a patient is admitted to the ICU for a non-PE-related clinical diagnosis, the abrupt and unexplained occurrence of some combination of chest pain, dyspnea, tachypnea, hypotension, and hypoxemia should raise the suspicion of PE. Unexplained fever with and without mild leukocytosis could represent a possible VTE event.⁸³ Hemoptysis can occur as a result of small distal pulmonary emboli causing alveolar hemorrhage. If PE occurs while the critically ill patient or postoperative patient is on mechanical ventilation, the clinical suspicion and conformation can be difficult. An increase in minute ventilation dead space or an increase in supplemental oxygen may be clues to an embolic event. If the patient has end-tidal CO₂ (PETCO₂) monitoring an increase in the PaCO₂-PETCO₂ gradient may occur.⁷³

Arterial Blood Gas Measurement

Hypoxemia and an increased alveolar-arterial gradient are usually seen in PE but can be normal in about 14% and are most likely the result of small embolic events.84,85 The initial acid-base disturbance is a respiratory alkalosis, which may evolve to a metabolic (lactic) acidosis as hypotension and shock ensue. A linear relationship between PE severity and PaO₂ in patients without prior cardiopulmonary disease has been described. In the UPET and PIOPED trials 12% and 19% of patients, respectively, had PaO₂ 80 mm Hg or greater.⁸⁶ Hypocarbia is usually present with acute PE because of hyperventilation, but hypercapnia can occur with large PEs producing increased dead space.^87,72

Chest Radiography

The chest radiograph is abnormal in most cases of PE; however, radiographic findings possess inadequate sensitivity to rule out PE. Common radiographic abnormalities include atelectasis, pleural effusion, parenchymal opacities, and elevation of a hemidiaphragm. Radiographic findings of pulmonary infarction often show a wedge-shaped, pleural-based triangular opacity with an apex pointing toward the hilus (Hampton hump). Focal oligemia or decreased vascularity has been known as the Westermark sign. These findings are suggestive of PE but are infrequently prospectively observed.88,89 Radiographic findings of RVD may include a prominent central pulmonary artery (knuckle sign) and cardiomegaly. In one large prospective cohort of PE patients a normal chest radiograph was found in 24% of the patients.⁸⁹ A normal-appearing chest radiograph in a patient with severe dyspnea and hypoxemia, is suggestive of a pulmonary embolic event.

Electrocardiography

In 1935 McGinn and White first described the association between acute PE and specific electrocardiogram (ECG) changes when they noted the S₁Q₃T₃ pattern in seven patients with acute cor pulmonale.⁹⁰ A normal ECG can occur with PE in a frequency ranging from 9% to 30%. The most common ECG abnormalities in the setting of PE are tachycardia and nonspecific ST-T wave abnormalities. The classic findings of right-sided heart strain and acute cor pulmonale are tall, peaked P waves in lead II (P pulmonale); right-axis deviation; right bundle branch block; and an S₁Q₃T₃ pattern. Only 20% of patients with proven PE have any of these classic ECG abnormalities.^91–93 T-wave inversion in the precordial leads representing subepicardial ischemia may be seen. The presence of this ECG finding is associated with increased degree of vascular obstruction and elevation of the pulmonary artery (PA) pressure.⁹⁴ The new onset of atrial fibrillation has been thought to be associated with a pulmonary embolic event. In a recent study the occurrence of atrial fibrillation did not in general increase the probability of PE.⁹⁵ However, if chest pain were the only symptom, the presence of atrial fibrillation increases the probability of PE (odds ratio [OR] 2.42, 95% confidence interval [CI] 0.97-6.07).

D-Dimer Assay

The serum D-dimer is a degradation product produced by plasmin-mediated proteases of cross-linked fibrin. D-dimer is measured by a variety of assays. These assays are categorized as quantitative, semiquantitative, qualitative rapid enzyme-linked immunosorbent assays (ELISAs); quantitative and semiquantitative latex; and whole-blood assays. The quanitative rapid ELISAs are the best assays to use in terms of sensitivity and likelihood ratio.⁹⁶ When clinical prediction scores indicate that the patient has a low or moderate pretest probability of PE, D-dimer testing is useful to further define the likelihood of PE. Negative results on a high-sensitivity D-dimer test in a patient with a low pretest probability of PE (Wells rule) are associated with a low likelihood of VTE and reliably exclude PE.⁹⁷ In a large prospective, randomized trial in patients with a low probability of PE who had negative D-dimer results, not performing additional diagnostic testing was not associated with an increased frequency of symptomatic VTE during the subsequent 6 months.⁹⁸

D-dimer testing loses its ability to predict the likelihood of PE in older patients and in the presence of cancer, pregnancy, and various inflammatory or infectious disorders. If the pretest probability for PE is high, D-dimer testing should not be performed and objective testing should be done.⁹⁶

Combining D-dimer results with measurement of the exhaled end-tidal ratio of carbon dioxide to oxygen (PETCO₂/PO₂) can be useful for diagnosis of PE. Kline and colleagues demonstrated in moderate-risk patients a positive D-dimer (>499 ng/mL) and a PETCO₂/PO₂ less than 0.28 significantly increased the probability of finding segmental or larger PE on computed tomography (CT) multidetector-row pulmonary angiography.⁹⁹ In contrast, a PETCO₂/PO₂ greater than 0.45 predicted the absence of segmental or larger PE.

Duplex Compression Ultrasonography

Currently, DVT is largely diagnosed by duplex CUS. When using CUS, the ultrasonographic transducer pressed against veins shows they are easily compressed, but the muscular arteries are extremely resistant to compression. Where DVT is present, the veins do not collapse completely when pressure is applied using the ultrasonographic probe.100–102

Before an ultrasonographic scan can be considered negative, the entire deep venous system must be examined using centimeter-by-centimeter compression testing of every vessel. The risk of a DVT event following a single whole leg CUS in 3 months is 0.57% (95% CI 0.25-0.89).¹⁰³

CUS is associated with a sensitivity of 97% for proximal DVT, 72% for distal DVT, and a specificity of 94%.¹⁰⁴ In a meta-analysis of the role of CUS in DVT, CUS alone had a sensitivity of 93.8% (92.0-95.3%) for proximal DVT, 56.8% (49.0-66.4%) for distal DVT, and specificity of 97.8% (97.0-98.4%).¹⁰⁵

Ventilation-Perfusion Nuclear Scans

The scan has a limited role in the diagnosis of acute PE in the ICU, although its diagnostic accuracy is no different from that in non–critically ill populations.¹⁰⁶ Because of the advancing technology of CT scanning, the lung scan is used in the critical care units in special circumstances such as renal insufficiency or in the patient who is not intubated and capable of transport from the ICU to the nuclear medicine suite for a full view scan. If the institution has a portable lung scanner this can be used in the ICU but the number of images is reduced when compared to the standard scan.

A high-probability scan, as shown in Figure 44.3, is sufficient diagnostic evidence of PE to begin anticoagulation therapy, and a normal scan is considered sufficient evidence to exclude PE. However, the frequency of low- or intermediate-probability scans (indeterminate scans) can be as high as 50% to 70%, with a 10% to 50% probability of PE. Therefore, it is impossible to initiate anticoagulation therapy based on this indeterminate lung scan probability. In the first PIOPED study, only 40% of patients with PE had a high-probability scan result, whereas another 40% of patients with PE had an indeterminate result and 14% had a low-probability result. A high-probability scan had a positive predictive value of 88% in patients without prior history of PE. The combination of a high clinical probability with the high-probability lung scan resulted in a 96% positive predictive value. The negative predictive value of a low-probability scan was 88% and improved to 96% when combined with a low clinical probability. Thus, a low-probability scan with a low clinical probability score rules out PE as definitively as a normal scan. Finally, 39% of the patients had intermediate scans and 32% of these patients had angiographically proven PE.^14,107

Preexisting cardiopulmonary disease diminishes the clinical utility of scans by increasing the prevalence of nondiagnostic scans. Nondiagnostic scans are more likely to occur in patients with preexisting cardiopulmonary disease. Lung scans are not useful to either establish or rule out the diagnosis of PE in more than 80% of cases. A similar disadvantage of lung scans is noted in critically ill patients with prior cardiopulmonary disease. Nevertheless, lung scans can be performed in the critically ill, even if patients are receiving mechanical ventilation, and chest radiographic abnormalities can be used as a surrogate of ventilation defects. Despite the limited ventilation component under positive-pressure respiration, the perfusion component is not significantly affected by mechanical ventilation. scans remain a useful tool in patients with contraindications to pulmonary angiography or CT angiography.108,109

Multidetector Computed Tomography Scan of the Chest

The PIOPED II study firmly established the role of CT pulmonary angiography (CTPA) and largely replaced ventilation-perfusion () lung scintigraphy as the main imaging modality in suspected PE.¹¹⁰ The technology is continually evolving and its use is widespread. As illustrated in Figure 44.4, CTPA provides direct visualization of emboli throughout the pulmonary arterial vasculature. The advantage of CTPA over pulmonary angiography and lung scan is the discovery of an alternative diagnosis when PE is not found on CTPA. In one study, an alternative diagnosis was established in 57% of patients who did not have a PE.¹¹¹ Currently, CTPA is the “gold standard” for PE diagnosis. A meta-analysis of 23 studies with 4657 patients with a negative CTPA who did not receive anticoagulation showed a 3-month rate of subsequent VTE of 1.4% (95% CI 1.1-1.8) and a 3-month rate of fatal PE of 0.51% (0.33-0.76), which compares favorably with the results noted after a normal “gold standard” invasive contrast pulmonary angiogram.¹¹² The increased use of CTPA raises concerns about the increased incidence of cancer attributable to radiation.¹¹³ For this reason, combined use of CTPA and CT leg venography should not be performed because the latter adds little to diagnostic utility. In the PIOPED II trial, no patient with PE or DVT would have been undiagnosed if imaging of the pelvic and proximal leg veins had been omitted.^107,110

Magnetic Resonance Imaging

In the PIOPED II study, CT angiography of the chest, as many as 25% of patients had a contraindication for the test. Preexisting renal failure and pregnancy were the primary conditions that prevented this mode from being used as the primary test for the evaluation of PE.¹¹⁰ Thus, gadolinium-enhanced magnetic resonance pulmonary angiography (MRA) could potentially be used to diagnose PE because it is devoid of radiation. The accuracy of this technique combined with magnetic resonance venography (MRV) has been studied in the prospective, multicenter PIOPED III accuracy study. The proportion of technically inadequate images ranged from 11% to 52% across the seven participating centers. Technically adequate MRA had a sensitivity of 78% and a specificity of 99%, whereas technically adequate MRA and MRV had a sensitivity of 92% and a specificity of 96%. However, 194 (52%) of 370 patients had technically inadequate results, which substantially restricts its clinical use.¹¹⁴

Clinical and Hemodynamic Parameters

The initial hemodynamic presentation of PE is the most powerful predictor of outcome, as illustrated in Figure 44.5. Arterial hypotension at the time of PE presentation is an early predictor of death. In the 2392 patients from the ICOPER study, the 90-day mortality rates were 52.4% in patients with systolic arterial blood pressures below 90 mm Hg, and 14.7% in those patients who had preserved arterial blood pressures. In addition, comorbid conditions increase the risk of adverse clinical events, even in the presence of anatomically small PE. In the ICOPER findings, age over 70, congestive heart failure, cancer, and chronic lung disease were identified as independent predictors of 3-month mortality risk, with approximately twofold increase in the risk of death.² In one study, altered mental status at presentation was associated with a sevenfold increase in risk of adverse outcome. Altered mental status most likely reflected decreased cardiac perfusion or hypoxia. In the same study the initial presentation of shock was associated with a threefold increase in risk of 30-day adverse outcome (death, secondary shock, or recurrent PE).¹¹⁷

Patients can be clinically risk stratified by the use of a clinical scoring system known as the Pulmonary Embolism Severity Index (PESI), which also has a simplified version.118,119 This prognostic model was developed by Aujesky and colleagues (Table 44.3) using a large database of hospitalized PE patients from which they derived and validated a prediction rule that identified acute PE patients with low to high risk for fatal PE and adverse events. Using 11 variables of predictors, five distribution categories emerged looking at inpatient fatality, 30-day all-cause mortality rate, and the adverse outcomes of nonfatal cardiogenic shock or cardiopulmonary arrest. Class I to class III all-cause mortality rates ranged between 0% and 3.1%, although class IV to class V all-cause mortality rates were between 10% and 24%. This score has an excellent negative predictive value and readily identifies low-risk patients but suffers in the attempt to predict patients at high risk for adverse events.¹¹⁹ A more simplied PESI score has been developed and has a high negative prediction value.¹²⁰

In patients with symptomatic acute PE, the presence of DVT may have prognostic significance. In a prospective study by Jiménez and coworkers, among 707 patients diagnosed with acute PE, 51.2% had concomitant DVT and 10.9% had PE-specific fatality at a 3-month follow-up. Patients with PE with the presence of DVT at the time of diagnosis had an adjusted hazard ratio (HR) of 2.05% (95% CI 1.24 to 3.38) and PE-specific fatality-adjusted HR of 4.25 (95% CI 1.61 to 11.25). These findings were validated by a large international registry trial (RIETE) that again demonstrated a significant prediction of all-cause mortality rate and PE-specific mortality rate when the concomitant DVT was present during the acute embolic event. These results suggest that patients with symptomatic acute PE have an increase in all-cause mortality rate, PE-related death, and recurrent VTE over a 3-month period if at the time of PE a diagnosis of proximal DVT is also present.¹²¹

Electrocardiogram

Several studies have demonstrated that ECG signs of RV strain correlate with the presence of RVD.122,123 A study by Punukollu and associates showed that T-wave inversion in leads V₁ to V₃ had a specificity of 88% and diagnostic accuracy of 81% for RVD in acute PE.¹²⁴ Daniel and colleagues developed an ECG scoring system based on typical features of acute PE such as presence of right bundle branch block (RBBB), T-wave inversions, and additional features of right-sided heart strain that predicted severe pulmonary hypertension (sPAP >50 mm Hg) with a specificity of 97.7% if the patient’s “ECG score” is 10 or greater.¹²⁵ The ECG may also be a tool for risk stratification of normotensive acute PE patients. In a study by Vanni and coworkers among 306 patients with documented PE 130 (34%), patients demonstrated ECG findings of right-sided heart strain. In this study ECG findings of right-sided heart strain were defined as incomplete or complete RBBB, S₁Q₃T₃, or inverted T waves in the precordial leads V₁, V₂, and V₃. For this study only one of these ECG patterns had to be present. The investigators demonstrated that the presence of RV strain on the initial ECG was associated with clinical deterioration and death (HR 2.58) in normotensive PE patients.¹²²

Cardiac Biomarkers

 Biomarkers are relied on in the risk stratification of patients with PE. Tests for biomarkers are widely available and there is usually a quick turnaround from the clinical laboratory. Caution must be taken on the interpretation of these biomarkers. It is important for the critical care clinician to understand the clinical issues that impact the interpretation of the biomarkers and understand the negative and positive predictive values.¹¹⁵ Elevations of brain natriuretic peptide (BNP) and troponin occur in many patients with PE and correlate with magnitude of RVD.

Echocardiography

The echocardiogram has become the main imaging modality to assess RV structure and function. In addition, pulmonary artery pressures can be estimated. Most hospitals in the United States have portable echocardiographic technology allowing for serial assessment of the impact of treatment on RVD. In hemodynamically stable patients with PE, 20% to 40% will have some echocardiographic finding of RVD.116,117 Box 44.1 illustrates the echocardiographic finding of acute PE. Toosi and colleagues performed a quantitative risk assessment of various echocardiographic measurements of RVD in acute PE. For in-patient mortality rate the positive predictive values range between 11% and 20% and the negative predictive values are 97% to 100%.¹⁴⁰ The major drawback with the role of the echocardiographic definition of RVD of acute PE is that it lacks standardization. There is no clear agreement on which of the echocardiographic

findings predicts adverse outcomes and fatality in normotensive submassive PE. However, an echocardiographic finding of right ventricle/left ventricle ratio of greater than 0.9 was found to be an independent risk factor of in-hospital death (OR 2.7% CI 1.7-6.0) in a large registry trial.¹⁴¹

In the ICOPER study that included 1035 PE patients with systolic arterial pressure 90 mm Hg or higher, an echocardiogram was performed within 24 hours of PE diagnosis. The incidence of RVD was 39% (405 patients). The 30-day survival rates were lower in patients with RV hypokinesis (84%) compared with those without RV hypokinesis (91%), HR 1.94 (CI, 1.41-3.16; p ≤ 0.001). The negative predictive value of 30-day mortality rate of echocardiographic confirmation of RVD was 91%. The positive predictive value was 16%.²

In the assessment of RVD, if cardiac biomarkers are elevated, how well does this correlate with RVD on transthoracic echocardiography? A study by Logeart and coworkers found that a BNP level of less than 100 pg/mL had a negative predictive value of 100% and TnI of less than 0.10 ng/mL had a negative predictive value of 67% for the presence of RVD on echocardiography. Combining a BNP of greater than 100 pg/mL and TnI of greater than 0.10 ng/mL had a positive predictive value of 80% for the presence of RVD by echocardiography.¹⁴²

The echocardiogram can visualize free-floating right-sided heart thrombi. In the ICOPER study patients with this finding had a mortality rate of 21% compared with 11% in those without right-sided heart thrombi.¹⁴³ The detection of a patent forman ovale or atrial septal defect by echocardiography may be a warning finding for the development of paradoxical embolization, which is associated with a risk of stroke and increased mortality rate.¹⁴⁴

For the evaluation of circulatory shock transesophageal echocardiography (TEE) is a useful diagnostic modality. In patients with massive PE who cannot undergo CTPA, when TEE is performed, it has a 60% to 80% sensitivity and a 95% to 100% specificity to diagnose acute PE. TEE has a 9% to 95% sensitivity and a 100% specificity in main pulmonary artery PE.¹⁴⁵ In patients with unexplained cardiac arrest or pulseless electrical activity (PEA), TEE has been shown to identify acute massive PE. In a small study of 25 patients with PEA, TEE demonstrated eight (36%) patients with massive PE.¹⁴⁶

Echocardiography is an important diagnostic and prognostic tool in the management of patients with PE. Echocardiography also influences the therapeutic strategy based on cardiac hemodynamics and RV function. It is simple, quick, noninvasive, accurate, convenient, and safe, while providing critical information on the physiologic effects of PE on cardiac hemodynamics as well as RV size and function.

Computed Tomography Pulmonary Angiography

CT scans findings of right-sided heart dysfunction are illustrated in Figures 44.6A and B. The detection of RV enlargement by spiral chest CT has recently been evaluated in the risk stratification of patients with acute PE. Using measurements from a reconstructed CT four-chamber view, RV enlargement, defined as a ratio of RV to LV dimension of greater than 0.9, was a significant independent predictor of 30-day mortality rate.¹⁴⁶ In a recent multicenter study of 460 consecutive patients with multidetector CT confirmed PE a majority of the study cohort were hemodynamically stable and 50% had RVD at the time of diagnosis. Again, an RV/LV ratio of 0.9 or greater provided good correlation with RVD demonstrated by echocardiography. In addition, RVD found on multidetector CT was an independent risk factor for death and clinical deterioration. The investigators propose that multidetector CT scan potentially can be the single procedure, not only for diagnosis of PE but also for risk stratification. However, this assumption will require more validation studies.¹¹²

In hemodynamically stable patients with acute PE, assessing RV/LV ratio may be important in not only risk stratification but also the location of the emboli. In a recent multicenter study of 516 hemodynamically stable PE patients central localization of emboli was found to be an independent mortality risk factor, although distal localization was inversely associated with adverse events. Thus, anatomic findings by CT scan may be important in assessing risk in hemodynamically stable patients with pulmonary embolus.¹⁴⁷

Table 44.4 summarizes the various risk modalities used in risk stratification of acute PE.

Pharmacologic Management

The anticoagulation treatment for DVT and acute PE is essentially the same. Anticoagulation therapy does not dissolve the clot but prevents extension. Anticoagulation therapy indirectly decreases clot burden by allowing the natural fibrinolytic system to dissolve thrombus. When PE is suspected, if there is no contraindication, anticoagulation therapy should be started immediately while diagnostic studies are being performed.¹⁴⁸

Submassive Pulmonary Embolism with Hemodynamic Stability and Right Ventricular Dysfunction

In patients with acute PE who are normotensive but demonstrate some degree of RVD, the treatment is somewhat controversial and may depend upon the degree of RVD present to initiate aggressive steps to protect RV function. There is a spectrum of RVD and RV injury. If RVD is manifested by only RV wall dilation and not injury, then the outcome may be different when injury begins to occur. The normotensive patients with evidence of RV injury will require expedited protection of RV function.

Massive Pulmonary Embolism

Pregnancy

The incidence of PE during pregnancy ranges between 0.3 and 1 per 1000 deliveries.²⁰⁴ PE is the leading cause of pregnancy-related maternal death in developed countries. In the United States, maternal death from PE ranks third after hemorrhage and hypertensive disorders.^105,206 There is a fivefold increased risk of VTE in the pregnant woman because of venous stasis, a prothrombotic state as a result of increased levels of coagulation factors, reduced protein S, and fibrinolytic activity.²⁰⁷ The two major PE risk factors in pregnancy are a personal history of VTE and heritable thrombophilias.²⁰⁸ The risk of PE is higher in the postpartum period, particularly after a cesarean section. The clinical features of PE are no different in pregnancy compared with the nonpregnant state. There have been no prospective trials that have validated existing prediction models to exclude PE in pregnancy. It is been shown from a maternal death review that pregnant women who died from PE are over the age of 35, are obese (body mass index >30), and have chronic medical conditions.²⁰⁹

Right-Sided Heart Thrombi

Echocardiographically documented right-sided heart thrombi occur in approximately 4% of patients with PE.25,143 These patients have more hemodynamic instability and have a higher mortality rate. In the ICOPER study in patient with acute PE and a free-floating right-sided heart thrombus, the mortality rate was 15% compared to 11% without such thrombi.¹⁴³

In these patients, the treatment of choice is controversial. Thrombolytic therapy or surgical embolectomy have both been used and there have been multiple reports of successful results. In the ICOPER, thrombolytic treatment was the preferred option, but the 14-day mortality rate was above 20%.¹⁴³ In contrast, excellent results with thrombolytic therapy were reported in a series of 16 patients, in which 50%, 75%, and 100% of clots disappeared from the right side of the heart within first 2, 12, and 24 hours after administration of thrombolytics. All patients survived 30 days.²¹¹ It appears from the literature that treatment with heparin alone is not a treatment option.

For right-sided heart thrombi crossing the interatrial septum (patent foramen ovale) surgical embolectomy is warranted (Fig. 44.10). Whichever therapy is selected, it should be implemented without delay: in the presence of unequivocal echocardiographic visualization of a mobile right-sided heart thrombus, no further diagnostic tests are needed.^{25,203,212,213}

Chronic Thromboembolic Pulmonary Hypertension

 Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon but serious sequela of PE.

CTEPH is an uncommon but serious sequela of PE. Certain patients with PE develop an aberrant and incomplete resolution of the thrombotic event, resulting in endothelialized thrombi and if left unchecked will result in the development of a distal, small vessel vasculopathy. This event results in progressive increases in RV afterload and pulmonary hypertension. When small distal vessel disease develops in patients with CTEPH the patient no longer is a candidate for surgical management.²¹⁴ The reasons are unclear for this divergent pathway in thrombus resolution. Acquired and hereditary risk factors are suspected. For example, 20% of CTEPH patients have antiphospholipid syndrome and increased levels of factor VIII are found in CTEPH when compared with nonthrombotic pulmonary hypertension and control groups.^203,212,213 Characteristics of the initial acute embolic event may be associated with subsequent development of CTEPH. Persistent RVD at discharge and persistent elevation of pulmonary artery pressures may play a role.^214,215

In the past it was estimated that the incidence of CTEPH was only 0.1% to 0.5%.²¹⁴ Recent prospective studies have shown that CTEPH is much more common, with an incidence ranging from 1% to 3.8% of patients who survived their acute pulmonary embolic event. It is estimated that in the United States 6000 to 22,000 new cases potentially may occur in each year.^{214,216–218}

The lung scan plays a central role in the evaluation of patients with pulmonary hypertension. The scan in a patient suspected with CTEPH will show the “mottled” appearance of subsegmental and segmental perfusion defects. Larger defects can also be seen.²¹⁴ The lung scan is superior to CT angiography in screening patients for CTEPH. In a single center retrospective investigation comparing the lung scan with CT angiography and 227 patients with pulmonary hypertension demonstrated a sensitivity of 97.4% for scanning but only 51% for CT angiography in detecting chronic thromboembolic disease.²¹⁹

CT or MRA can be used to plan surgical intervention. Right-sided heart catheterization is required to determine the degree of hemodynamic impairment, and conventional pulmonary angiography can determine the proximal location of the thrombotic obstruction.²¹⁴

Surgical removal of the obstructing material requires a true endarterectomy as opposed to a simple embolectomy. The current approach to pulmonary endarterectomy requires median sternotomy, cardiopulmonary bypass, and periods of hypothermic circulatory arrest in order to provide adequate visibility. The main pulmonary arteries are incised and the right endarterectomy level within the wall is defined. Thereafter, the plane is followed circumferentially down to the segmental and sometimes subsegmental branches of each lobar artery, a procedure that is performed with the help of special suction dissectors.217,218

The perioperative mortality rate is related to the severity of the disease, with a mortality rate of 4% in patients with a preoperative PVR less than 900 dynes/second/cm⁻⁵ and 20% in those with PVR above 1200 dynes/second/cm⁻⁵. The functional results of a successful pulmonary thromboendarterectomy are excellent and generally are sustained over time, with a 3-year survival rate of about 80%.219–221

The major causes of postoperative fatality from pulmonary endarterectomy are RV failure related to persistent pulmonary hypertension and acute lung injury. Lifelong anticoagulation and placement of the IVC filter are recommended. In patients who are deemed inoperable because of distal chronic thromboembolic disease or in whom the surgical mortality risk of endarterectomy is high, medical therapy that is developed for idiopathic pulmonary arterial hypertension has been studied in patients with CTEPH. It is important to identify patients as early as possible so they may have the opportunity for pulmonary endarterectomy because the hemodynamic and symptomatic benefits that medical therapy provide are modest.214,222,223

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