Excerpt from Pulmonary Embolism

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Background

Pulmonary embolism (PE) is an extremely common and highly lethal condition that is a leading cause of death in all age groups. A good clinician actively seeks the diagnosis as soon as any suspicion of PE whatsoever is warranted, because prompt diagnosis and treatment can dramatically reduce the mortality rate and morbidity of the disease. Unfortunately, the diagnosis is missed more often than it is made, because PE often causes only vague and nonspecific symptoms.

The most sobering lessons about PE are those obtained from a careful study of the autopsy literature. Deep vein thrombosis (DVT) and PE are much more common than usually realized. Most patients with DVT develop PE and the majority of cases are unrecognized clinically. Untreated, approximately one third of patients who survive an initial PE die of a future embolic episode. This is true whether the initial embolism is small or large.

Most cases of PE are diagnosed at autopsy, and most who die of PE have not had any diagnostic workup or treatment of the disease. In most cases, the diagnosis has not even been considered, even when classic signs and symptoms are documented in the medical chart. Sadly, appropriate diagnostic and therapeutic management often is withheld even when the potential diagnosis of PE has been considered explicitly and documented in the chart.

Under Investigation

Prompt diagnosis and stratification in patients with suspected PE and a high risk of adverse events may help to improve outcomes. Serum troponin, although seemingly marginal for purposes of diagnosis of PE, may contribute significantly to the ability to stratify patients by risk for short-term death or adverse outcome events when they reach the ED. In patients with PE and normal blood pressure specifically, elevated serum troponin level has been associated with right ventricular overload.^{1, 2}

Elevated levels of brain-type natriuretic peptides (BNP) may also provide prognostic information. A recent meta-analysis demonstrated a significant association between elevated N-terminal–pro-BNP (NT-pro-BNP) and right ventricular function in patients with PE (p<0.001), leading to an increased risk for complicated in-hospital course (odds ratio [OR] 6.8; 95% confidence interval [CI], 9.0-13) and 30-day mortality (OR 7.6; 95% CI, 3.4-17).³ Importantly, increased NT-pro-BNP alone does not justify more invasive treatment.

Pathophysiology

The pathophysiology of pulmonary embolism. Although pulmonary embolism can arise from anywhere in the body, most commonly it arises from the calf veins. The venous thrombi predominately originate in venous valve pockets (inset) and at other sites of presumed venous stasis. To reach the lungs, thromboemboli travel through the right side of the heart. RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.

Pulmonary thromboembolism is not a disease in and of itself. Rather, it is an often fatal complication of underlying venous thrombosis. Under normal conditions, microthrombi (tiny aggregates of red cells, platelets, and fibrin) are formed and lysed continually within the venous circulatory system. This dynamic equilibrium ensures local hemostasis in response to injury without permitting uncontrolled propagation of clot. Under pathological conditions, microthrombi may escape the normal fibrinolytic system to grow and propagate. PE occurs when these propagating clots break loose and embolize to block pulmonary blood vessels.

Thrombosis in the veins is triggered by venostasis, hypercoagulability, and vessel wall inflammation. These 3 underlying causes are known as the Virchow triad. All known clinical risk factors for DVT and PE have their basis in one or more elements of the triad.

Patients who have undergone gynecologic surgery, those with major trauma, and those with indwelling venous catheters may have DVTs that start at any location. For other patients, venous thrombosis most often involves the lower extremities and nearly always starts in the calf veins, which are involved in virtually 100% of all cases of symptomatic spontaneous lower extremity DVT. Although DVT starts in the calf veins, it already has propagated above the knee in 87% of symptomatic patients before the diagnosis is made.

Studies suggest that nearly every patient with thrombus in the upper leg or thigh will have a PE if a sensitive enough test is done to look for it. Current techniques allow us to demonstrate PE in 60-80% of these patients, even though about half have no clinical symptoms to suggest PE. Thrombus in the popliteal segment of the femoral vein (the segment behind the knee) is the cause of PE in more than 60% of cases.

PE can arise from DVT anywhere in the body. Fatal PE often results from thrombus that originates in the axillary or subclavian veins (deep veins of the arm or shoulder) or in veins of the pelvis. Thrombus that forms around indwelling central venous catheters is a common cause of fatal PE.

The belief that calf vein DVT is only a minor threat is outdated and inaccurate. DVT of the calf is a significant source of PE and often causes serious morbidity or death. In fact, one third of the cases of massive PE have their only identified source in the veins of the calf. One important autopsy study showed that more than 35% of patients who died from PE had isolated calf vein thrombosis. Other studies have shown that the overall frequency of PE from DVT isolated to the small deep veins of the calf is 33-46%. Most of the time, emboli from calf veins are of smaller caliber than those from more proximal venous segments, but not all emboli from calf veins are small. Even a very narrow vein can produce a long, sinuous clot that can cause hemodynamic collapse, and approximately 40% of PEs from calf veins produce perfusion scan defects that are large or massive.

Calf emboli that are very small carry their own special risks. In a 1993 study of patients with identifiable thrombi causing paradoxical embolization through a patent foramen ovale, the source was isolated to the calf veins in 15 of 24 cases.

Frequency

United States

PE is the third most common cause of death in the US, with at least 650,000 cases occurring annually. It is the first or second most common cause of unexpected death in most age groups. The highest incidence of recognized PE occurs in hospitalized patients. Autopsy results show that as many as 60% of patients dying in the hospital have had a PE, but the diagnosis has been missed in about 70% of the cases. Surgical patients have long been recognized to be at special risk for DVT and PE, but the problem is not confined to surgical patients. Prospective studies show that in the absence of prophylaxis acute DVT may be demonstrated in any of the following:

• General medical patients placed at bed rest for a week (10-13%)
• Patients in medical intensive care units (29-33%)
• Patients with pulmonary disease kept in bed for 3 or more days (20-26%)
• Patients admitted to a coronary care unit after myocardial infarction (27-33%)
• Patients who are asymptomatic after coronary artery bypass graft (48%)

Not only are these patient groups at high risk for clinically unrecognized DVT, but half or more of the patients with DVT also can be shown to have suffered a PE, even though the majority have had none of the classic symptoms of PE.

International

Several papers suggest that the incidence of PE may differ substantially from country to country, but no prospective controlled studies lend support to this notion. The observed variance may be due more to differences in the rate of diagnosis than to differences in the frequency of the disease. If the differences are real, whether they are due to genetic variation or to population differences in diet and activity is not known.

Mortality/Morbidity

• Massive PE is one of the most common causes of unexpected death, being second only to coronary artery disease as a cause of sudden unexpected natural death at any age. Most clinicians do not appreciate the extent of the problem, because the diagnosis is unsuspected until autopsy in approximately 80% of cases.
• Although PE often is fatal, prompt diagnosis and treatment can reduce the mortality rate dramatically.
• • Approximately 10% of patients in whom acute PE is diagnosed die within the first 60 minutes. Of the remainder, the condition eventually is diagnosed and treated in one third and remains undiagnosed in two thirds.
  • Among the group with PE that is correctly diagnosed and treated, only about one twelfth die from massive PE or its complications. Among the group with PE that is undiagnosed and therefore untreated, roughly one third die. The diagnosis of PE is missed more than 400,000 times in the US each year, and approximately 100,000 patients die who would have survived with the proper diagnosis and treatment.
• Patients who survive an acute PE are at high risk for recurrent PE and for the development of pulmonary hypertension and chronic cor pulmonale, which occurs in up to 70% of patients and carries its own attendant mortality and morbidity.

Race

Subtle population differences may exist in the incidence of DVT and PE, but the incidence is high in all racial groups.

Sex

PE is common in all trimesters of pregnancy and the puerperium, and the incidence of PE is increased in women receiving oral contraceptive or hormone replacement therapy; however, sex alone is not an independent risk factor.

Age

• Although the frequency of PE increases with age, age is not an independent risk factor. Rather, the accumulation of other risk factors, such as underlying illness and decreased mobility, causes the increased frequency of PE in older patients.
• Unfortunately, the diagnosis of PE is especially likely to be missed in older patients. The correct diagnosis of PE is made in 30% of all patients who die with massive PE but in only 10% of those who are 70 years of age or older. It is the most commonly missed diagnosis responsible for death in the elderly institutionalized patient.

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