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Address reprint requests to Dr. J. H. Ryu, Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905
Affiliations
Division of Pulmonary and Critical Care Medicine and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota
Dyspnea, pleuritic chest pain, and tachypnea are widely appreciated as common initial features of pulmonary embolism (PE). This knowledge is derived primarily from prospective studies evaluating diagnostic tests or therapeutic interventions in which the study patients are suspected to have PE based on their initial symptoms. Autopsy studies, however, continue to show that most cases of fatal PE are unrecognized and undiagnosed. Data from studies screening for PE in patients with deep venous thrombosis and in postoperative patients suggest that many patients with PE are asymptomatic and that PE is unrecognized. We believe that the current concepts regarding the initial clinical features of PE are too narrow and biased toward symptomatic cases. High clinical suspicion may be insufficient in recognizing PE. Herein we summarize the available data and explore the implications for clinical practice.
Although the actual incidence and case fatality rates of PE are difficult to ascertain, an estimated 500,000 to 600,000 patients suffer from PE each year in the United States, and PE is the cause of death in 50,000 to 200,000 patients.
When promptly diagnosed and appropriately treated, PE rarely causes death. Despite advances in diagnostic methods, treatment, and prophylaxis, the incidence and mortality rates of acute PE seem to have changed little during the past 30 years.
The diagnosis of PE necessitates confirmation by objective testing. This diagnostic evaluation for possible PE is initiated by the clinician's suspicion based on the patient's initial symptoms and signs. Thus, diagnostic algorithms usually begin with “clinical suspicion” of PE or “suspected” PE.
Typically, the clinician expects to encounter acute onset of dyspnea, pleuritic chest pain, or tachypnea. This expectation has been reinforced by recent studies emphasizing the high sensitivity (more than 95%) of these symptoms in identifying patients with PE.
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
These diverse viewpoints likely result from the differences in the design of the studies used in supporting the respective conclusions. In this article, we summarize the available data and review the current concepts regarding the clinical features of acute PE, with an emphasis on the problem of unrecognized and asymptomatic cases.
PROSPECTIVE DIAGNOSTIC AND TREATMENT STUDIES OF PE
Most of our inferences regarding the clinical features of acute PE are based on data from large prospective studies evaluating the diagnostic accuracy of ventilation-perfusion lung scans and the therapeutic efficacy of thrombolytic agents.
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPEDI).
The frequency of the most common symptoms and signs encountered in patients in whom PE is eventually proved by pulmonary angiography is summarized in Table 1. Common initial symptoms include dyspnea, pleuritic chest pain, and cough. Apprehension, leg swelling, leg pain, diaphoresis, hemoptysis, nonpleuritic chest pain, palpitations, wheezing, and syncope occur less often.
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
Hemoptysis and pleuritic chest pain are associated with pulmonary infarctions and hemorrhage that are caused by thromboembolic obstruction of a medium-sized artery.
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
In one study, patients with pulmonary infarction syndrome accounted for about threefourths of patients with proven PE, and their initial symptoms were pleuritic chest pain and dyspnea. Those with isolated dyspnea accounted for one-fifth of patients with PE. The remaining small percentage of patients had circulatory collapse (shock or syncope). PE was thought to be mild in those with pulmonary infarction syndrome, moderate in those with isolated dyspnea, and severe in those with circulatory collapse.
The most common physical signs in patients with acute PE have been tachypnea, rales, and tachycardia, all of which are nonspecific. Other signs present in a minority of patients have included increased pulmonic component of the second heart sound, diaphoresis, fever, wheezes, Homans' sign, right ventricular lift, pleural friction rub, third or fourth heart sound, cyanosis, hepatomegaly, and hepatojugular reflux.
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
Analysis of the data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study of patients with no prior cardiac or pulmonary disease showed dyspnea, tachypnea, or chest pain to be present in 97% of patients with proven PE
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
Thus, these clinical features, although nonspecific, seem to be very sensitive in identifying patients with PE. The differential diagnoses of a patient with these symptoms commonly include pneumonia, myocardial infarction, pneumothorax, and viral pleurisy. These features are less helpful in patients with preexisting heart or lung disease.
Of importance, however, the patients enrolled in these studies had symptoms suggestive of PE. Therefore, these studies likely limit the clinical spectrum of patients to those with symptomatic embolism and exclude asymptomatic patients and those with atypical features. This dilemma is illustrated in the recent data from the French Registry of venous thromboembolic diseases that includes 387 patients with PE.
In symptomatic patients, 87% had dyspnea, a prevalence similar to that noted in previous studies (Table 1); however, 34% of patients were asymptomatic.
AUTOPSY STUDIES OF PE
In routine autopsies of adult patients, grossly recognizable emboli are found in 1.5 to 30% of cases.
Pulmonary thromboembolism: gross and microscopical findings in 508 randomized autopsies, with special reference to the relationship between central and peripheral emboli.
A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worchester DVT Study.
Thus, PE is the primary cause or a substantial contributor in more than 10% of all hospital deaths. At autopsy, PE is one of the most commonly overlooked major diagnoses.
Despite its relatively common occurrence at autopsy, PE is diagnosed before death in only a minority of patients (Table 2). In most large autopsy series; 60 to 80% of fatal PE cases are clinically unsuspected and undiagnosed.
A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worchester DVT Study.
Pulmonary thromboembolism: gross and microscopical findings in 508 randomized autopsies, with special reference to the relationship between central and peripheral emboli.
In these fatal cases, underdiagnosis of PE is partly attributable to underlying medical illnesses, such as pneumonia, congestive heart failure, and myocardial infarction, that may obscure the presence of PE.
Other contributing factors include sudden death due to initial massive embolism and impaired ability to communicate, as in patients who are intubated on mechanical ventilation and those with stroke.
Pulmonary thromboembolism: gross and microscopical findings in 508 randomized autopsies, with special reference to the relationship between central and peripheral emboli.
Despite the presence of older organizing emboli in one-half of these patients, classic symptoms of PE were often absent before death. For example, dyspnea was noted in 59% of these patients, pleuritic chest pain in 8%, cough in 3%, and hemoptysis in 3%.
reported dyspnea in only 28% and chest pain in 19.5% of patients with PE confirmed at autopsy. Other studies have reported absence of symptoms in 63 to 85% of patients with PE detected at autopsy.
In approximately one-half of patients with fatal PE, life expectancies were relatively short due to underlying diseases such as cancer, congestive heart failure, stroke, and advanced chronic lung disease.
Some long-term survivors have development of chronic thromboembolic pulmonary hypertension related to inadequate resolution of large pulmonary thromboemboli or recurrent embolism. This is estimated to occur in only 0.1 to 0.5% of patients with acute PE.
In patients who eventually have development of chronic thromboembolic pulmonary hypertension, an asymptomatic “honeymoon” period is thought to last months to years after the initial episode of PE. This is followed by gradual symptomatic decline with worsening exertional dyspnea and hypoxemia.
Despite the presence of extensive lesions in the pulmonary vascular tree, a history compatible with a prior episode of venous thromboembolism could not be elicited in about one-half of these patients, even with retrospective questioning.
Although prospective studies evaluating diagnostic tests and therapeutic agents for PE have suggested that almost all patients with PE are symptomatic, a different perspective is provided by screening studies of patients at risk for PE. Monreal and colleagues
performed ventilationperfusion lung scanning in 434 consecutive patients with venographic ally proven DVT; in 164 (38%), scans showed high probability for PE. Of those 164 patients, 54% had symptoms or signs consistent with PE, and 46% did not. Similarly, Moser and associates
described 44 patients with venographically proven DVT, in whom 52% had high probability of PE as noted on lung scans. Less than one-half of these patients with high probability of PE on lung scans had symptoms that were suggestive of PE. The data regarding the occurrence of asymptomatic PE in patients with DVT are summarized in Table 3.
These data suggest that most PE occurring in patients with DVT is asymptomatic. Distal DVT is associated with smaller pulmonary thromboemboli and is less likely to cause symptoms.
Table 3Incidence of Symptomatic and Asymptomatic Pulmonary Embolism in Patients With Deep Venous Thrombosis Confirmed by Venography
In most of these studies, ventilation-perfusion lung scanning was used to screen for PE. It is likely that some of the patients with lung scans showing high probability for PE did not have PE. Nevertheless, reversibility of the defects with anticoagulant therapy and angiographic confirmation employed in some of these studies suggest that most patients with high probability of PE on lung scans indeed did have PE.
During the past 30 years, multiple screening studies have documented the incidence of DVT and PE in high-risk patients. Pertinent studies regarding the occurrenee of asymptomatic PE are summarized in Table 4.
used ventilation-perfusion lung scanning to screen 108 patients undergoing an elective hip operation and found that 20 (19%) had high probability for PE. Of these 20 patients, only 6 had symptoms of PE—that is, 70% with high probability for PE were asymptomatic. Similarly, Williams and coworkers
used weekly ventilation-perfusion lung scanning to screen 158 patients undergoing a hip operation or major lower extremity amputation; 48 (30%) had evidence of postoperative PE, of whom 44 (92%) had no symptoms suggestive of PE. Harris and associates
studied 73 patients undergoing total hip replacement, of whom 17 had development of PE, which was confirmed by pulmonary angiography in almost all cases. Of these 17 patients 14 (82%) were asymptomatic. Although many of these asymptomatic emboli were small and peripheral, some were large and central.
The evidence summarized herein suggests that many episodes of PE are unrecognized and undiagnosed, especially in postoperative patients. Some patients with undiagnosed and untreated PE suffer unexpected death or chronic thromboembolic pulmonary hypertension (Fig. 1); however, it is likely that many of these overlooked cases have no recognizable clinical sequelae and are never identified. Although most clinicians realize that the common initial features of PE including dyspnea, pleuritic chest pain, and tachypnea are nonspecific, it is not widely appreciated that these symptoms and signs may be relatively insensitive in identifying patients with PE.
Fig. 1Schema of relationship between suspected and actual cases of pulmonary embolism (PE). Only a third of suspected PE cases are actually PE. Conversely, many cases of PE, including fatal ones, are unrecognized or undiagnosed.
During the past 30 years, we have come to realize that symptoms of myocardial infarction are absent or atypical and therefore unrecognized in 20 to 60% of all cases.
Unfortunately, no accurate screening test is available for PE. Thus, many uncertainties remain regarding the prevalence, natural history, and mortality of this disorder.
The clinical significance of pulmonary embolism: uncertainties and implications for treatment-a debate [published erratum appears in J Intern Med 1997;241:341J.
For patients who have survived an unrecognized episode of PE, the prognostic implications may not be as serious as those for silent myocardial infarction if no persistent risk factor exists for recurrence of venous thromboembolism.
If many cases of PE are indeed clinically silent, “high clinical suspicion” is inadequate in diagnosing PE. Furthermore, clinical suspicion is not only nonspecific but also insensitive in identifying patients with venous thromboembolism. This partly explains the persistently high prevalence of undiagnosed fatal PE, even with the availability of advanced imaging techniques. Possibly, some of the overlooked cases of PE represent small emboli that are not “clinically significant,” particularly if recurrence is not a risk. More studies are needed in determining whether and how often cases of clinically insignificant PE may occur.
In the meantime, more effort is needed in the area of prevention for patients at risk. Currently available methods of prophylaxis reduce the incidence of venous thromboembolism by about two-thirds.
Advances are being made in improving the efficacy of these methods in preventing venous thromboembolism; however, several studies have shown that prophylaxis for venous thromboembolism is underused, even in patients with obvious risk factors.
Clinical, laboratory, roentgenographic and electrocardiographs findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPEDI).
Pulmonary thromboembolism: gross and microscopical findings in 508 randomized autopsies, with special reference to the relationship between central and peripheral emboli.
A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worchester DVT Study.
The clinical significance of pulmonary embolism: uncertainties and implications for treatment-a debate [published erratum appears in J Intern Med 1997;241:341J.