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CLINICAL PROBLEM-SOLVING
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows. STUDYING THE CLASSICS GEORGE E. THIBAULT, M.D. A 25-year-old Hispanic woman in the 27th week of pregnancy came to the emergency room complaining of cough and shortness of breath. She reported that she had been well until two days earlier. In the past day she had also been nauseated, and she had vomited once. In the emergency room she was found to have a temperature of 38 C (100.5F) and was thought to be dehydrated. Intravenous uids, ampicillin, and gentamicin were administered. She was given a prescription for erythromycin and sent home. She returned the next day because she was more dyspneic and explained that she had coughed up a half-cup of blood. She also reported that she had been treated with antibiotics one month earlier for a presumed upper respiratory infection. Since then she had been tired and short of breath. Four previous pregnancies and deliveries had been unremarkable. Four years earlier she had been treated for tuberculosis. On examination her temperature was 38.6 C (101.4F), her pulse was 120 to 130 beats per minute, her blood pressure was 94/50 mm Hg, and the respiratory rate was 30 per minute. The cardiac examination was considered to be unremarkable, but the chest examination revealed bibasilar rhonchi and wheezes. Her arterial oxygen saturation was 94 percent while she was breathing oxygen at a rate of 2 liters per minute. At the time of her rst visit to the emergency room, the patients fever and symptoms were most suggestive of a respiratory infection, but there also seemed to be a gastrointestinal component. A community-acquired febrile illness with respiratory and gastrointestinal symptoms would be consistent with legionella infection; erythromycin may have been an appropriate drug. I do not know how sick she looked at the time of the rst visit, so I cannot say whether further investigation should have been undertaken then. Because hemoptysis is not a common feature of community-acquired pneumonias, I would want to consider either a more aggressive, necrotizing bacterial pneumonia or another process responsible for the hemoptysis. Hemoptysis could
From Brigham and Womens Hospital, 75 Francis St., Boston, MA 02115, where reprint requests should be addressed to Dr. Thibault.

also be caused by reactivation of the old tuberculosis infection. She could also be having pulmonary emboli, since there is an increased incidence of pulmonary emboli in pregnancy. I would also worry that hemoptysis and breathlessness could be due to left heart failure. In heart failure hemoptysis is caused by the rupture of fragile anastomoses between the pulmonary and bronchial veins when they are subjected to high pressure. The patient is Hispanic; we have not been told where she spent her childhood. Acute rheumatic fever and rheumatic heart disease are still endemic in many developing countries. This could be the clinical presentation of mitral stenosis in a previously asymptomatic woman who became symptomatic only in the third trimester of pregnancy, when the cardiac output is at its maximum. The failure to hear a murmur on cardiac examination does not exclude mitral stenosis, particularly in the presence of tachycardia and a lot of respiratory noise. She could also have heart failure due to other causes, such as cardiomyopathy. It is a bit early in the pregnancy for peripartum cardiomyopathy. The serum sodium and potassium, blood urea nitrogen, and serum creatinine concentrations were normal. The hematocrit was 35 percent; the white-cell count was 9900 per cubic millimeter with 82 percent neutrophils and 4 percent band forms; the platelet count was 230,000 per cubic millimeter. The urinalysis was unremarkable. Arterial-blood gas values measured while the patient was breathing 2 liters of supplemental oxygen per minute were as follows: partial pressure of oxygen, 61 mm Hg; partial pressure of carbon dioxide, 26 mm Hg; pH 7.44; and calculated bicarbonate concentration, 17 mmol per liter. Her chest lm is shown in Figure 1. The patient is mildly anemic and has no leukocytosis, but there is a slight leftward shift. She has a substantial arterialalveolar pressure gradient. The blood gas values are consistent with chronic respiratory alkalosis but she could also have a mild degree of metabolic acidosis. The chest lm is quite interesting. The hilar vessels are plump, the upper-lobe vessels also appear to be enlarged, and there are increased interstitial markings. This could be interstitial inammation or interstitial pneumonia, but it looks more like heart failure to me. There is also straightening of the left heart border, which is suggestive of left atrial enlargement, and some enlargement of her central pulmonary arteries. The x-ray lm makes me suspect heart failure more strongly; the ndings would be quite consistent with mitral stenosis. I still cannot exclude the diagnosis of interstitial pneumonitis. The chest lm does not show evi-

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Figure 1. Chest Film Obtained in the Emergency Room.

dence of lobar pneumonia, active tuberculosis, or ndings suggestive of pulmonary emboli, though chest lms are both insensitive and nonspecic with respect to the last diagnosis. On the basis of the chest lm, I believe tuberculosis, necrotizing bacterial pneumonia, and pulmonary emboli are unlikely. The probability of heart failure has gone up, and I am particularly concerned about the possibility that she has rheumatic heart disease. I would want to repeat the cardiac examination in a quiet room and obtain an echocardiogram. I also would want to obtain expectorated sputum for examination, because I have not entirely excluded the possibility that she has an atypical pulmonary infection. The patient was treated with uids and intravenous erythromycin (500 mg every six hours), but she became increasingly dyspneic and was airlifted to a tertiary care center. On arrival she had an arterial oxygen saturation of 40 percent, and she was immediately intubated. The uid suctioned from the endotracheal tube was pink and frothy. The physical examination revealed jugular venous distention to the angle of the jaw. The cardiac examination disclosed tachycardia (120 beats per minute and regular); S1 and S2 were audible; no gallops or murmurs were heard. Examination of the chest revealed diffuse rhonchi. She had no cyanosis, clubbing, or edema of the arms and legs. The patient did not get better on erythromycin and got worse when she received a large volume load. If she did have rapidly progressive pneumonia, the failure to improve in the rst 24 hours does not necessarily mean that the wrong antibiotic was chosen. But I am even more suspicious that she has something other than infection. Pink frothy uid coming from the endotracheal tube is characteristic of pulmonary edema and points strongly to severe heart failure. I would still want to

perform Grams staining of the uid to look for bacteria and white cells. The fact that her jugular venous pressure is elevated means that she has right atrial hypertension and, by denition, right heart failure. That does not prove that she has left heart failure, although that is the most common cause of right heart failure. However, patients with severe pneumonia or recurrent pulmonary emboli can present with acute cor pulmonale and isolated right heart failure. Given her earlier x-ray lm, these ndings are most consistent with left heart failure leading to or coincident with right heart failure. We are told no gallops were heard. If this were a case of severe, dilated cardiomyopathy caused by acute myocarditis or of peripartum cardiomyopathy, I would expect to hear a loud third heart sound. In a patient who has a rapid heartbeat with a lot of respiratory noise, murmurs of mitral stenosis and the opening snap may not be recognized. There was only slight cardiomegaly on the chest lm. That would still be consistent with early acute myocarditis or mitral stenosis. I would do an echocardiogram to evaluate the valves and myocardial function. The electrocardiogram is shown in Figure 2 and the chest lm obtained after the patient was intubated in Figure 3. The electrocardiogram shows sinus tachycardia and a vertical axis. This axis could be normal, but it could also be indicative of right heart strain. There is also evidence of left atrial enlargement. The vertical axis and left atrial enlargement are consistent with mitral stenosis, though neither of these abnormalities is specic. She now has progressive opacication of both lung elds. What was previously an interstitial process is now an alveolar process. With this degree of radiographic abnormality, one cannot be specic about the cause. It is consistent with cardiogenic pulmonary edema, but it is also consistent with noncardiogenic pulmonary edema or any progressive lung injury leading to the adult respiratory distress syndrome.

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

II

Figure 2. Electrocardiogram and Lead II Rhythm Strip Obtained at the Time of Transfer to a Tertiary Care Center.

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Neelsen stains of three sputum samples were negative for acid-fast bacilli. Sputum cultures were negative. The results of thyroid-function tests were normal. Viral studies were negative. The patient was treated with digoxin and furosemide. She delivered a healthy child and later underwent balloon mitral valvuloplasty, with an excellent result. Mitral stenosis masquerading as pneumonia! I think the main problem was that no one thought of the diagnosis. In any event, it was a happy ending. COMMENTARY This is, in fact, a classic case of a previously common, and now relatively uncommon, disease. The doctors caring for this patient probably never thought of the diagnosis of mitral stenosis. It may be that none of them had ever actually seen a patient with mitral stenosis; certainly pulmonary infection is far more common. On the other hand, even without consideration of mitral stenosis, the evidence for heart failure should have led them to the differential diagnosis of heart failure in a young pregnant woman. It shows once again that when parts of the patients clinical course and some of the ndings are incongruent with the assigned diagnosis, we must broaden the differential diagnosis and reexamine the primary data. The natural history of mitral stenosis in the era before mechanical intervention has been well described, and because the disease has become so uncommon in the United States, the description is worth reiterating.1-3 Mitral stenosis is virtually always a sequela of acute rheumatic fever, although there are rare congenital cases that usually present in infancy or childhood, and even rarer cases of obstruction of the mitral valve due to other inammatory or inltrative processes.4 Mitral stenosis primarily affects women, and as many as 40 percent of the patients have no history of acute rheumatic fever. After an episode of rheumatic fever, the physical ndings of mitral stenosis evolve over the next 5 to 15 years.5 This natural history may be condensed into a much shorter period in certain geographic regions, such as Asia, Africa, and Central America.6 This acceleration may be due to climatic conditions, socioeconomic factors, or repeated streptococcal infections. The clinical presentation of mitral stenosis may take one of several forms.7,8 Patients may be entirely asymptomatic until an acute stress causes tachycardia and increased cardiac output, leading to an abrupt elevation of left atrial pressure and acute pulmonary edema. The precipitating factor may be a febrile illness, the onset of rapid atrial brillation, intense physical activity, or pregnancy. In fact, the onset of symptoms at the beginning of the third trimester of pregnancy is common because it is a time of maximal hemodynamic stress caused by the increased blood volume, cardiac output,

Figure 3. Chest Film Obtained at the Time of Transfer.

The patient was treated with ampicillin, gentamicin, erythromycin, and isoniazid. A SwanGanz catheter was inserted and the following initial ndings were obtained: pulmonary-artery pressure, 58/39 mm Hg; pulmonary-capillary wedge pressure, 35 mm Hg; central venous pressure, 20 mm Hg; cardiac output, 4.75 liters per minute; and systemic vascular resistance, 779 dyn sec cm 5. The patient was treated with furosemide; her systolic pressure fell to 60 mm Hg and metabolic acidosis developed. Dopamine was given, but the fetus was apparently still viable. This patient was treated with four antibiotics for possible bacterial pneumonia, atypical pneumonia, and tuberculosis. She is clearly very sick, and it is hard to fault this decision, but I fear that the preoccupation with nding an infectious cause for her illness may have distracted her physicians from making the logical diagnosis of heart failure. The hemodynamic measurements conrm my impression that she is in severe heart failure, and I suspect that she has been in heart failure all along. In addition to severe myocardial disease and mitral stenosis, aortic stenosis can cause pulmonary edema that is refractory to therapy. At this point, we need to focus our attention on the cause of the severe heart failure, and I am even more eager to see her echocardiogram. I still think she may have severe mitral stenosis. An echocardiogram showed severe rheumatic mitral stenosis with a mean mitral-valve gradient of 17 mm Hg and a mean valve area of 0.8 cm2. Mild mitral regurgitation was present. The left atrium was enlarged, but there were no thrombi. The pulmonary-artery systolic pressure was estimated to be 75 to 85 mm Hg. The right atrium was enlarged. The left ventricle and aortic valve were normal. Blood cultures were negative. Ziehl

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and heart rate.9 The increased heart rate is poorly tolerated because the diastolic time is shortened and the left atrium cannot empty adequately. Similarly, increased ow across the valve in any high-output state leads to increased pressures, because the valve orice is xed. One large study of pregnancy and rheumatic heart disease showed that in 75 percent of the patients who had heart failure it developed after the 26th week of pregnancy.10 The clinical presentation in this case was classic. The patient was at the beginning of her third trimester and had tachycardia when she rst presented. She may have had an upper respiratory infection that initially contributed to her increased hemodynamic load, but her fever may also have been due to pulmonary edema. A vicious circle was thus established: increased left atrial pressure led to tachycardia, hypoxemia, and fever, which led to further increases in left atrial pressure. As the mitral valve narrows, exercise intolerance and dyspnea on exertion due to gradually rising left atrial pressure slowly develop in many patients. Once the valve is damaged, further narrowing does not require new episodes of rheumatic fever or other acute insults. In some patients cardiac output decreases in response to the valve stenosis, and thus the left atrial pressure remains nearly normal. These patients have fewer symptoms of pulmonary congestion and complain of fatigue and exercise intolerance caused by the limitation of cardiac output. A small number of patients present with symptoms and signs of pulmonary hypertension leading to right heart failure. Such patients appear to have disproportionate reactivity of the pulmonary vasculature for any given degree of left atrial hypertension. They rapidly go through the phase of left atrial hypertension and rst come to medical attention with pulmonary hypertension and right ventricular failure. Accordingly, mitral stenosis should always be part of the differential diagnosis of idiopathic pulmonary hypertension and unexplained right heart failure. Before interventions were available to relieve mitral stenosis, approximately 40 percent of patients were dead 10 years after the onset of symptoms, and at 20 years only 20 percent were still alive. Sixty percent of the deaths were attributable to heart failure, but 30 percent were caused by systemic or pulmonary emboli.11 Atrial brillation is an almost inevitable consequence of the long-standing left atrial hypertension, and systemic embolization, which affects 30 to 40 percent of patients over the course of the disease if they do not receive anticoagulant therapy, is often a devastating complication. It should be possible to make the diagnosis of mitral stenosis on physical examination, but it can be difcult to do so. This patients story is a familiar one in that the murmur of mitral stenosis was not recognized by several observers. As the discussant noted, when a patient with mitral stenosis has tachycardia and heart failure, it is particularly difcult to hear the murmur

and the opening snap. The optimal situation for hearing the low-frequency rumble is a quiet room, with the patient lying in a left lateral decubitus position and the bell of the stethoscope lightly applied at the cardiac apex. In truth, silent mitral stenosis is usually the result of inadequate auscultation.12 There are patients, however, in whom the cardiac output is so low that the murmur may become inaudible. In addition to the murmur, there are other helpful ndings on auscultation. A loud rst heart sound may rst suggest the diagnosis, but this sound may diminish as the valve becomes more xed and immobile. The opening snap of the stenotic valve may be mistaken for a third heart sound, but it occurs earlier in diastole and has a higher frequency. The length of time between the opening snap and the second heart sound correlates inversely with the left atrial pressure.13 The higher the left atrial pressure, the closer the opening snap will be to the second heart sound; this nding may be helpful in serial physical examinations of a patient with known mitral stenosis. An accentuated pulmonary component of the second sound, indicative of pulmonary hypertension, may rst suggest mitral stenosis by leading to an exploration of the causes of pulmonary hypertension. None of these ndings were recognized in this patient, partly because of her tachycardia and loud lung sounds, but the fact that they were not detected is also a reminder that physical-examination skills have atrophied in our era of sophisticated imaging studies. Ultrasonography was rst used in cardiology in the diagnosis of mitral stenosis,14 and one of the rst uses of two-dimensional echocardiography was the estimation of mitral-valve area in mitral stenosis.15 Doppler ow studies are helpful for assessing coexisting mitral regurgitation and for estimating the degree of pulmonary hypertension, an important prognostic factor in the natural history of the disease. Cardiac catheterization has been the gold standard for quantifying the severity of mitral stenosis. A calculated mitral-valve area of 1.0 cm2 or less per square meter of body-surface area, according to the formula of Gorlin and Gorlin,16 is evidence of critical mitral stenosis and constitutes an indication for mechanical intervention in a symptomatic patient. Though cardiac catheterization is still required in patients who are suspected of having coronary artery disease, other valvular lesions, or myocardial disease, young patients with pure mitral stenosis (such as this patient) can be treated with mechanical interventions on the basis of noninvasive studies alone. The medical treatment of severe mitral stenosis is difcult, as this case illustrates. Most of the interventions that are used to treat other causes of heart failure either are ineffective or may have adverse consequences. Digoxin is helpful in controlling the ventricular response in a patient with atrial brillation, but it has no role in lowering the left atrial pressure in patients in normal sinus rhythm, because depressed left ventricu-

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lar function is not the cause of the left atrial hypertension. Vasodilators, which are effective in treating heart failure due to decreased left ventricular systolic function or regurgitant valvular lesions, may exacerbate symptoms in patients with mitral stenosis. Such patients are unable to increase cardiac output in response to vasodilation, and the decrease in systemic blood pressure leads to reex tachycardia. Diuretics lower left atrial pressure and relieve symptoms of congestion, but at the risk of markedly depressing cardiac output. Hence, mechanical intervention is the only effective means to improve hemodynamic function in a patient with severe symptoms. Patients in whom pulmonary hypertension has developed as a result of mitral stenosis are almost always symptomatic, and they are candidates for mechanical intervention to lower the left atrial pressure and improve ow across the mitral valve. Pulmonary hypertension increases the risks associated with all interventions, but it is not a contraindication to intervention to alter the natural history of the disease. Unlike pulmonary hypertension due to increased arterial ow from left-to-right cardiac shunts (Eisenmengers syndrome), the pulmonary hypertension due to mitral stenosis is reversible. If the left atrial pressure is normalized, the pulmonary-artery pressures will fall.17 Closed mitral-valve commissurotomy was one of the rst successful surgical interventions for cardiac disease.18 Open surgical valvotomy or repair and mitralvalve replacement are now common for severe mitral stenosis. In properly selected patients, however, percutaneous balloon valvotomy successfully relieves mitral stenosis.19-21 Balloon valvotomy is likely to be successful when the valve is not severely thickened, when the valve is not heavily calcied, when the mobility of the leaets is preserved, and when there is little subvalvular fusion.22 These factors are most likely to be present in younger patients who are still in normal sinus rhythm. In this case the patient appeared to be an ideal candidate for this less invasive intervention. Balloon valvotomy has been successfully used during pregnancy to stabilize a patient until delivery at term.23 Despite a classic clinical presentation, the diagnosis in the case of this patient was missed by many of those who were caring for her. In medicine, as in art and literature, the study of the classics may provide guidance and knowledge that are still relevant today.

REFERENCES
1. Bland EF, Jones TD. Rheumatic fever and rheumatic heart disease: a twenty year report on 1000 patients followed since childhood. Circulation 1951;4: 836-43. 2. Wilson JK, Greenwood WF. The natural history of mitral stenosis. Can Med Assoc J 1954;71:323-31. 3. Olesen KH. The natural history of 271 patients with mitral stenosis under medical treatment. Br Heart J 1962;24:349-57. 4. Braunwald E. Mitral stenosis. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 4th ed. Philadelphia: W.B. Saunders, 1992: 1007-18. 5. Walsh BJ, Bland EF, Jones TD. Pure mitral stenosis in young persons. Arch Intern Med 1940;65:321-7. 6. Joswig BC, Glover MU, Handler JB, et al. Contrasting progression of mitral stenosis in Malayans versus American-born caucasians. Am Heart J 1982; 104:1400-3. 7. Wood P. An appreciation of mitral stenosis. I. Clinical features. BMJ 1954; 1:1051-63. 8. Hugenholtz PG, Ryan TJ, Stein SW, Abelmann WH. The spectrum of pure mitral stenosis: hemodynamic studies in relation to clinical disability. Am J Cardiol 1962;10:773-84. 9. Elkayam U, Gleicher N. Hemodynamics and cardiac function during normal pregnancy and the puerperium. In: Elkayam U, Gleicher N, eds. Cardiac problems in pregnancy: diagnosis and management of maternal and fetal disease. 2nd ed. New York: Alan R. Liss, 1990:5-24. 10. Szekely P, Turner R, Snaith L. Pregnancy and the changing pattern of rheumatic heart disease. Br Heart J 1973;35:1293-303. 11. Rowe JC, Bland EF, Sprague HB, White PD. The course of mitral stenosis without surgery: ten- and twenty-year perspectives. Ann Intern Med 1960; 52:741-9. 12. Harvey WP. Silent valvular heart disease. In: Likoff W, ed. Valvular heart disease. Vol. 5. No. 2 of Cardiovascular clinics. Philadelphia: F.A. Davis, 1973:77-95. 13. Ebringer R, Pitt A, Anderson ST. Haemodynamic factors inuencing opening snap interval in mitral stenosis. Br Heart J 1970;32:350-4. 14. Zaky A, Nasser WK, Feigenbaum H. A study of mitral valve action recorded by reected ultrasound and its application in the diagnosis of mitral stenosis. Circulation 1968;37:789-99. 15. Henry WL, Grifth JM, Michaelis LL, McIntosh CL, Morrow AG, Epstein SE. Measurement of mitral valve orice area in patients with mitral valve disease by real-time, two-dimensional echocardiography. Circulation 1975; 51:827-31. 16. Gorlin R, Gorlin SG. Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves, and central circulatory shunts. Am Heart J 1951;41:1-29. 17. Braunwald E, Braunwald NS, Ross J Jr, Morrow AG. Effects of mitral-valve replacement on the pulmonary vascular dynamics of patients with pulmonary hypertension. N Engl J Med 1965;273:509-14. 18. Ellis LB, Abelman WH, Harken DE. Selection of patients for mitral and aortic valvuloplasty. Circulation 1957;15:924-35. 19. Palacios I, Block PC, Brandi S, et al. Percutaneous balloon valvotomy for patients with severe mitral stenosis. Circulation 1987;75:778-84. 20. Reyes VP, Soma Rajn B, Wynn J, et al. Percutaneous balloon valvuloplasty compared with open surgical commissurotomy for mitral stenosis. N Engl J Med 1994;331:961-7. 21. Carabello BA, Crawford FA. Therapy for mitral stenosis comes full circle. N Engl J Med 1994;331:1014-5. 22. Abascal VM, Wilkins GT, OShea JP, et al. Prediction of successful outcome in 130 patients undergoing percutaneous balloon mitral valvotomy. Circulation 1990;82:448-56. 23. Palacios IF, Block PC, Wilkins GT, Rediker DE, Daggett WM. Percutaneous mitral balloon valvotomy during pregnancy in a patient with severe mitral stenosis. Cathet Cardiovasc Diagn 1988;15:109-11.

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