Unexplained Shortness of Breath in a 48 year old Man

Case History:

A 48-year-old man with no significant past medical history presents to the emergency department (ED) with a long-standing history of dyspnea (shortness of breath) that has been persistently worsening for the past two years. According to the patient, the dyspnea is worse on exertion and is associated with decreased exercise tolerance. There are no associated chest pains, palpitations, dizziness, or syncope. The patient denies any associated cough, hemoptysis, fever, or weight loss. Upon initial presentation to his primary care physician (PCP) at the time of symptom onset, a cardiac stress test and pulmonary function testing were within normal limits; however, his symptoms have persisted and have actually worsening over the prior two weeks. He has been prescribed zolpidem (sleeping medication), as needed, by his PCP, who labeled his condition secondary to anxiety. The shortness of breath has progressively gotten worse, so much so that the patient can no longer exercise, or even walk, without becoming short of breath. The patient is an active tennis player and has no family history of heart disease. He does not take any medications or herbal supplements, and he has no known drug or food allergies. There is no history of smoking, alcohol abuse, or illicit drug use.

In the emergency room, the physician has access to his medical records and notes his physician's evaluation.  He obtains the history as above.

Physical examination reveals an alert and oriented male with a regular pulse of 92 bpm, blood pressure of 135/85 mm Hg, respiratory rate of 20 breaths/min, a temperature of 98.6°F (37.0°C), and an O₂ saturation of 98% on room air. The neck is supple and without any jugular venous distention, lymphadenopathy, tracheal deviation, or thyroid nodules. Cardiac examination reveals a normal S1, fixed split S2, and a prominent P2, but no audible murmurs, rubs or gallops are noted. The chest examination shows bilateral equal air entry, without any wheezes, rhonchi, or rales. The abdomen is soft, nontender and nondistended, without any evidence of organomegaly. No lower extremity edema, cyanosis, or clubbing is seen. The peripheral arterial pulses are palpable. The neurologic examination is normal.

Laboratory investigations, including a complete blood count, comprehensive metabolic panel, B-type natriuretic peptide (BNP), and troponin are within normal limits. A stool guaiac test is negative. An ECG shows a S1Q3T3 pattern with a right bundle branch block.

The patient is discharged home with instructions to see his primary care physician in a few days.

The following day, the patient awakes and he is acutely dyspneic at rest such that he cannot speak.  His wife calls 911 and he is returned to the ER.  On route to the hospital he is given 100% high flow oxygen, but his oxygen saturation vacillates between 90% and 96%.  His blood pressure is 90/54, and he is noted to be tachypneic with a respiratory rate of 26.  On arrival to the ER, he is noted to be hemodynamically unstable.  A stat arterial blood gas on room air shows a pH of 7.48, a partial carbon dioxide pressure (pCO₂) of 31 mm Hg, and a partial oxygen pressure (pO₂) of 70 mm Hg. Stat portable chest radiography shows clear lung fields with prominent central pulmonary arteries. A 12-lead electrocardiogram (ECG) shows tall R waves in V1, inverted T waves in leads V1 to V4, II, II, and aVF. A stat computed tomography (CT) angiogram of the chest is obtained. The axial image of the chest CT angiogram demonstrated a constellation of findings suggestive of both chronic and acute pulmonary thromboemboli.

Upon completion of the study, the patient suddenly codes and undergoes cardiopulmonary resuscitation also with the administration of clot busting medication and anti-coagulants. He is successfully resuscitated and has additional work-up.

Further testing included a duplex ultrasound scan of the lower extremities, which revealed a bilateral calf deep vein thrombosis; a ventilation/perfusion scan, which showed several mismatched perfusion defects of the posterior segment of the right and anterior segments of the left upper lobes (read as high probability for pulmonary embolism); and an elevated factor VIII assay. Echocardiography showed a high pulmonary systolic pressure of 82 mm Hg, right ventricular hypertrophy, and reduced right ventricular function. A subsequent right heart catheterization confirmed the diagnosis of pulmonary hypertension, with an elevated mean pulmonary artery pressure of 52 mm Hg and pulmonary vascular resistance of 12.3 Wood units.

Unfortunately, he does not regain consciousness and neurologic testing reveals that he has minimal brain function ostensibly from an anoxic/hypoxic injury.  He stays in the ICU for several weeks and then is transferred in a vegetative state to a skilled nursing facility.  He dies from complications two months later.

Analysis and Discussion:

A patient may provide a history that is consistent with chronic or acute pulmonary emboli, but diagnostic delays can occur when the physician does not work through all the testing that is necessary to make the diagnosis. Patients who have chronic thromboembolic disease (CTEPH) usually complain of exertional dyspnea and a gradual decrease in exercise tolerance over months to years. Other symptoms that may be reported include a nonproductive cough, hemoptysis, pleuritic chest pain, and presyncope/syncope. Findings on physical examination in patients with chronic thromboembolic disease reflect the degree of pulmonary vascular disease on presentation. Physical signs attributable to this condition may be subtle or absent in the absence of right-sided heart failure. Signs of pulmonary hypertension include right parasternal heave, fixed splitting of S2 with accentuated pulmonic component (P2), right ventricular fourth heart sound gallop, tricuspid regurgitation, and/or pulmonary insufficiency murmur. As the disease progresses and if left untreated, right ventricular dysfunction and right heart failure occur; significant findings at this time include pedal edema, elevated jugular venous pressure, and hepatomegaly.

Dyspnea is a common presenting symptom with many potential causes. Most cases of dyspnea are caused by cardiac or pulmonary disease. CTEPH has been misdiagnosed as being more common causes of dyspnea, such as coronary artery disease, chronic obstructive pulmonary disease, or interstitial lung disease. Some patients have been further improperly labeled with psychogenic dyspnea or physical deconditioning when the dyspnea persists.

All clinicians evaluating patients with unexplained dyspnea must have a high index of suspicion for abnormalities of the pulmonary vascular system and should rule out pulmonary vascular etiologies such as pulmonary embolism and pulmonary hypertension. Not considering this diagnosis under these circumstances is a breach in the standard of care.

The diagnosis of CTEPH requires a high index of suspicion because the presenting symptoms and signs are nonspecific. The chest radiograph (which may be normal in early stages) can reveal dilatation of the central pulmonary arteries (suggestive of pulmonary hypertension) and oligemic lung fields or parenchymal opacities from prior infarcts. The electrocardiogram may show changes of right heart disease (right ventricular hypertrophy, right atrial enlargement, or strain with T-wave inversions in anterior, precordial and inferior limb leads), depending on the severity of CTEPH, but are not specific to this disease. Transthoracic Doppler echocardiography is a useful screening test for suspected pulmonary hypertension. Echocardiography can help estimate the level of systolic pulmonary arterial pressure (PAP) and assess the presence of associated abnormalities, such as right atrial enlargement, right ventricular dilation or hypertrophy, right or left ventricular dysfunction, valvular heart disease, interventricular septal motion abnormalities, and pericardial effusion. A diagnosis of CTEPH is supported by an echocardiographic finding of a mean PAP exceeding 40 mm Hg in a patient with a history of pulmonary emboli. Pulmonary function testing will identify coexisting parenchymal disease and exclude other causes of pulmonary hypertension, such as interstitial lung disease. Patients with CTEPH may show a mild-to-moderate restrictive ventilatory defect secondary to parenchymal scarring from prior parenchymal infarcts.

Any patient with unexplained dyspnea should have the pulmonary vascular system evaluated. Chest CT angiography can provide pertinent clues to both the presence of thromboembolic disease and pulmonary hypertension in patients with CTEPH. Direct CT signs of chronic thromboembolic disease include the presence of organized thrombus lining the pulmonary vessels in a concentric or eccentric pattern that may cause pouch defects, intimal irregularities, bands/webs, or abrupt vessel narrowing. (These signs differ from the intraluminal filling defect and complete vessel cutoff of acute thromboembolism). Indirect signs of chronic thromboembolic disease on CT include poststenotic dilatation, tortuous vessels, asymmetric dilatation of the central pulmonary arteries, enlargement of the bronchial arteries and/or presence of collaterals and parenchymal abnormalities of mosaic attenuation (from irregular perfusion), and peripheral densities (scars from prior pulmonary infarct). A CT sign of pulmonary hypertension is enlargement of the main pulmonary artery, with a ratio between the CT diameter of the main pulmonary artery to the diameter of the aorta greater than 1:1. Other CT signs of pulmonary hypertension, resulting from right heart disease secondary to the pulmonary hypertension, include right ventricular dilatation, leftward septal bowing, thickening of the free right ventricular wall, and right atrial dilatation. It should be noted that CT angiography of the chest may appear normal in the presence of CTEPH, and should not be considered the diagnostic study of choice to rule out this disorder.

Ventilation/perfusion (V/Q) scanning is another imaging technique that is important in the diagnosis of CTEPH. A normal V/Q scan rules out the diagnosis of CTEPH. In patients with chronic thromboembolic disease, the V/Q invariably shows multiple segmental or larger perfusion defects in lung regions with normal ventilation. In contrast, patients with primary pulmonary hypertension show normal or subsegmental mottled perfusion patterns. Since V/Q mismatch defects are not specific to CTEPH, further imaging studies should be done to define the vascular abnormality with a view to establishing the diagnosis. Pulmonary angiography is the gold standard test to diagnose chronic thromboembolic disease. The five angiographic patterns seen in CTEPH include pouch defects, intimal irregularities, pulmonary artery webs or band-like narrowings, abrupt and often angular narrowing of major pulmonary arteries, and proximal obstruction of the pulmonary vessels.  Right heart catheterization, which can be performed at the time of pulmonary angiography, defines the severity of pulmonary hypertension and degree of cardiac dysfunction; it measures mean pulmonary artery pressure, pulmonary vascular resistance, right atrial pressure, cardiac output, and cardiac index.

The definitive treatment of patients with CTEPH is pulmonary thromboendarterectomy (PTE). Survival without surgical treatment is based on the degree of pulmonary hypertension. With mean pulmonary artery pressures of 30-50 mm Hg, five-year survival is 30%, whereas among patients with mean pulmonary artery pressures of greater than 50 mm Hg, five-year survival is only 10%. However, survival remains approximately 90-95% (5-10% mortality rate) after pulmonary thromboendarterectomy. The decision to opt for surgery is based on the patient’s symptom severity and comorbidities. The criteria for surgical selection in patients with CTEPH include accessibility of the thrombi (more proximal thrombi are more amendable to surgery than distal ones), hemodynamic/ventilatory compromise, and the patient’s comorbid conditions and associated risks of the procedure. Moser and colleagues pointed out that there are three major areas to consider when evaluating a patient for thromboendarterectomy: hemodynamic, alveolorespiratory, and prophylactic considerations. The hemodynamic goal is to prevent or ameliorate right ventricular compromise caused by pulmonary hypertension. The respiratory objective is to improve respiratory function by the removal of a large ventilated but nonperfused physiologic dead space, regardless of the severity of pulmonary hypertension. The prophylactic goal is to prevent progressive right ventricular dysfunction or retrograde extension of the obstruction, which may result in further cardiorespiratory deterioration or death.

Surgical treatment and endarterectomy must be bilateral because this is a bilateral disease in the vast majority of patients. The procedure is conducted with the aid of cardiopulmonary bypass, and the patient is cooled to allow for hypothermic circulatory arrest. A Greenfield filter is usually inserted before surgery to minimize recurrent pulmonary embolism after pulmonary endarterectomy. However, if this is not possible, it can also be placed at the time of operation. Meticulous postoperative management is essential to the success of this surgical procedure.

All patients are mechanically ventilated for at least 24 hours, and all patients are subjected to maintained diuresis. Patients are subject to all complications associated with open-heart and major lung surgery (eg, arrhythmias, atelectasis, wound infection, pneumonia, renal failure, stroke, and mediastinal bleeding, but also may develop complications specific to this operation. These include persistent pulmonary hypertension, reperfusion injuries, and neurologic disorders related to hypothermic arrest and deep hypothermia. Reduction in pulmonary pressures, resistance to normal levels, and corresponding improvements in pulmonary blood flow and cardiac output are generally immediate and sustained. In general, these changes can be assumed to be permanent.

This case emphasizes the need for clinicians to be aware of CTEPH since its diagnosis is commonly delayed or missed because of the nonspecific nature of its presentation and, sometimes, because of a lack of prior history of acute symptomatic PE or deep vein thrombosis. All clinicians should have a high index of suspicion and consider pulmonary vascular disease (thromboembolic disease/pulmonary hypertension) in the differential diagnosis of any patient complaining of unexplained persistent dyspnea.

Outcome:

The delay in diagnosis and treatment in this patient ultimately led to his demise.  A lawsuit was filed by the family against the emergency physician, the hospital, and the primary care physician.  The case was settled out of court by all three parties for a six figure amount after all expert depositions were taken.

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