- Email: [email protected]
Etiology and diagnosis of bilateral leg edema in primary care
Etiology and Diagnosis of Bilateral Leg Edema in Primary Care Robert P. Blankfield, MD, MS, Robert S. Finkelhor, MD, J. Jeffrey Alexander, MD, Susan A. Flocke, PhD, Jan Maiocco, RN, CFNP, Meredith Goodwin, MS, Stephen J. Zyzanski, PhD PURPOSE: To identify the causes of bilateral leg edema in a primary care setting, and to determine the ability of primary care providers to arrive at the correct diagnosis using the information available at the initial clinical encounter. PATIENTS AND METHODS: Fifty-eight ambulatory adult patients with bilateral leg edema were enrolled at an inner city family practice during a 3-year period. Historical information, physical examination findings, and clinical impressions of primary care providers were compared with the results of laboratory evaluations consisting of echocardiograms, venous duplex ultrasound leg scans, serum albumin levels, and when appropriate, 24-hour urinalyses. RESULTS: Forty-five patients (78%) completed the study. The initial clinical impression was venous insufficiency in 32 (71%) patients and congestive heart failure in 8 (18%) patients. In
actuality, 15 (33%) patients had a cardiac condition as a cause of their leg edema, and 19 (42%) had pulmonary hypertension. All of the patients with heart disease, and almost all of those with pulmonary hypertension, were age 45 years or older. Only 10 (22%) of the subjects had venous insufficiency. Renal conditions, medication use, and hypoalbuminemia were less common. CONCLUSIONS: Utilizing clinical information only, many patients with cardiopulmonary pathology were incorrectly diagnosed as having more benign conditions, most commonly venous insufficiency. Echocardiographic evaluation, including an estimation of pulmonary artery pressure, may be advisable in many patients with bilateral leg edema, especially if they are at least 45 years old. Am J Med. 1998;105:192–197. q1998 by Excerpta Medica, Inc.
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common, affecting ,1% of the population (9). Although testing is usually not ordered when venous insufficiency is suspected, currently available tests include descending phlebography, photoplethysmography, and duplex ultrasound scanning. Although none of these tests is the “gold standard” for the diagnosis, duplex venous scanning is considered the most accurate laboratory test available for venous insufficiency (10 –12). Other tests, such as computerized tomography, magnetic resonance imaging, and indirect lymphography have been reported to aid in the assessment of leg swelling (13–15) but are rarely used clinically. We performed this study to identify the frequency of the causes of bilateral edema in a primary care setting, and to determine the ability of primary care providers to arrive at the correct diagnosis using the information available at the initial clinical encounter. We hypothesized that venous insufficiency would be the most common cause of bilateral leg edema, and that clinicians would be able to diagnose the cause of edema without relying upon laboratory investigations.
ilateral leg edema is a manifestation of either generalized edema—for example, due to congestive heart failure, nephrotic syndrome, acute glomerulonephritis, or cirrhosis— or to local factors, such as venous or lymphatic obstruction (1). Medications, particularly nonsteroidal anti-inflammatory drugs (NSAID) (2), corticosteroids, and nifedipine can result in bilateral leg edema. History, physical examination, and urinalysis are the first steps to determine the cause of bilateral leg edema. Echocardiography can noninvasively detect many types of cardiopulmonary disease, including valvular heart disease, systolic and diastolic ventricular dysfunction, cor pulmonale, and pulmonary hypertension (3,4). When seeing a patient with bilateral leg edema who lacks the typical signs and symptoms of congestive heart failure (5–7), and who also has an unremarkable urinalysis, clinicians may be likely to diagnose venous insufficiency as the cause of the edema. Venous insufficiency is common, affecting as many as 25% to 30% of the general population (8), whereas congestive heart failure is less
From the Departments of Family Medicine (RPB, SAF, MG, SJZ), Medicine (RSF), and Surgery (JJA), Case Western Reserve University School of Medicine, Cleveland, Ohio; Metro Health Medical Center (RFF, JJA), Cleveland, Ohio; and the Frances Payne Bolton School of Nursing (JM), Cleveland, Ohio. Requests for reprints should be addressed to R.P. Blankfield, MD, University Hospitals Primary Care Practice, Williamsport Plaza, 398 W. Bagley Road, Suite 1, Berea, Ohio 44017. Manuscript submitted February 12, 1998 and accepted May 13, 1998. 192
q1998 by Excerpta Medica, Inc. All rights reserved.
METHODS Patients were enrolled at an inner city family practice in Cleveland, Ohio, between March 1993 and February 1996. The practice is staffed by five family physicians and a family nurse practitioner. The practice population is primarily Caucasian or Hispanic, and mostly working class or indigent. 0002-9343/98/$19.00 PII S0002-9343(98)00235-6
Bilateral Leg Edema in Primary Care/Blankfield et al
Ambulatory patients 18 years of age and older who had bilateral leg edema were eligible for enrollment, regardless of the duration of the edema, any previous diagnoses, laboratory tests, or radiological evaluations. Patients who had bilateral edema known to be due to nifedipine therapy, intraabdominal malignancy, hypothyroidism, or idiopathic cyclic edema were excluded. Informed consent was obtained from each subject, and the study was approved by the Institutional Review Board at the MetroHealth Medical Center, Cleveland, Ohio. Medical information, including history of alcohol abuse, hepatitis, cirrhosis, varicose veins, deep venous thromboembolism or thrombophlebitis, congestive heart failure, coronary artery disease, hypertension, chronic obstructive pulmonary disease, and kidney disease was obtained from chart review. The primary care provider also recorded the following physical findings: bilateral pitting edema, bilateral leg swelling, varicose veins, venous stasis ulcers, brawny induration, regular heart rhythm, normal S2 splitting, rales, jugular venous distension, hepatojugular reflux, systolic murmur, shifting dullness on abdominal examination, fluid wave on abdominal examination, spider angiomas, jaundice, and proteinuria (31 or greater on urine dipstick). The primary care provider also recorded a clinical impression of the cause of the edema. Patients were asked to complete a questionnaire regarding the duration of swelling; whether they had orthopnea, paroxysmal nocturnal dyspnea, or dyspnea on exertion; whether they had ever had blood clots in their legs; whether they had ever been diagnosed with hepatitis or cirrhosis; whether they engaged in prolonged standing or walking; how much alcohol they drank; the CAGE screening questions for alcoholism (16); whether they snored and if there were pauses in the snoring greater than 10 seconds; whether they felt tired upon awakening; whether they had difficulty remaining awake during the afternoon; and if they had been previously diagnosed with sleep apnea. Women were asked how many children they had delivered. Blood was obtained from all patients for a serum albumin. A 24-hour urinalysis was ordered at the discretion of the primary care provider. A body mass index was calculated for each patient. Men were considered obese if they had a body mass index (weight in kg 4 height in m2) greater than 27.8 kg/m2, and women were considered obese if they had a body mass index greater than 27.3 kg/m2 (17). Subjects subsequently underwent laboratory evaluations consisting of an echocardiogram and a duplex venous ultrasound scan of the lower extremities. Systolic dysfunction was defined as a left ventricular ejection fraction less than 50% by visual assessment of an experienced reader (18), or a focal wall motion abnormality. Diastolic dysfunction was determined by the transmitral and pulmonary vein Doppler flow patterns (19). Aortic stenosis
was diagnosed if the peak instantaneous gradient across the valve exceeded 50 mm Hg. Mitral stenosis was diagnosed if the opening diameter was less than 1.5 cm2. Mitral regurgitation was considered to be a potential cause of pedal edema only if it was rated as being severe or moderately severe. Pulmonary artery pressure was estimated via echo Doppler by adding the Doppler systolic transtricuspid gradient to the estimated right atrial pressure using the inferior vena caval diameter and percent diameter change with respiration (3). Pulmonary hypertension was defined as an estimated pulmonary artery systolic pressure greater than 40 mm Hg, and borderline pulmonary hypertension was defined as an estimated pulmonary artery systolic pressure between 31 and 40 mm Hg. Venous insufficiency was defined as retrograde flow across the venous valves in the legs, either at the level of the femoral, popliteal, or saphenous veins. At the time of the echocardiographic evaluation, a cardiologist performed a physical examination and recorded the presence or absence of the following physical findings: pitting edema, nonpitting swelling, regular heart rhythm, normal S2 splitting, systolic murmur, S3 or S4 gallop, rales, jugular venous distension, and hepatojugular reflux. A final diagnosis of the etiology of the edema was determined for each patient using the information from the laboratory evaluations, supplemented by the clinical information obtained by the primary care provider. Statistical analysis was done with SPSS for Windows. To test the association of the historical information, physical findings, and clinical impressions of the primary care provider with the final diagnosis, chi-square tests were used. The association of the cardiologist’s physical findings by the echocardiographic diagnosis of a cardiac condition was also tested by chi-square. Fischer’s exact test was utilized when appropriate. Continuous data are presented as mean 6 SD; mean values were compared with Student’s t test.
RESULTS Fifty eight patients enrolled in the study, 13 of whom did not complete the echocardiogram and venous duplex scans. Of the remaining 45 patients, 43 had pitting edema and 2 had nonpitting edema. Patients’ ages ranged from 29 years to 83 years (Table 1). One third had edema for less than 6 months, and 30% reported edema lasting more than 6 years. Eighty-four percent of the subjects were obese. There were no significant differences between the patients who completed the study and those who did not in age, gender, marital status, education, and duration of edema. There were also no significant differences between the two groups for most of the historical variables
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Table 1. Demographic Characteristics of 45 Patients with Bilateral Leg Edema
Table 2. Initial Clinical Diagnoses for 45 Patients with Bilateral Leg Edema*
Characteristic Age (years) Body mass index (kg/m2) Female gender Race Caucasian Hispanic African American Native American Marital status Married Single Divorced/separated Widowed Level of education Did not finish high school High school graduate Some college or vocational training College graduate Duration of edema Less than 3 months 3–6 months 6–12 months 1–2 years 2–6 years .6 years
56 6 15* 38.5 6 10.5* 62% 83% 11% 4% 2% 50% 16% 16% 18% 37% 35% 23% 5% 22% 11% 13% 13% 11% 30%
* Mean 6 SD.
Diagnosis
Number (%)
Congestive heart failure Venous insufficiency Nephrotic syndrome Lymphedema Pulmonary hypertension Cor pulmonale Hypoalbuminemia Use of nonsteroidal anti-inflammatory drug Use of corticosteroids Sleep apnea Obesity Uncertain
8 (18) 33 (71) 6 (13) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 3 (7)
* Patients could have more than one diagnosis.
each diagnosis. Thirty-three percent of the subjects had a cardiac diagnosis, usually systolic or diastolic dysfunction. Two patients with systolic dysfunction also had atrial fibrillation. Forty-two percent of the patients had some degree of pulmonary hypertension: 20% had pulmonary hypertension, and 22% had borderline pulmonary hypertension. About half of these patients also had a cardiac diagnosis. Fifty-six percent of the patients had
Table 3. Final Diagnoses for 45 Patients with Bilateral Leg Edema after Laboratory Investigation Diagnosis*
and physical examination findings except that patients who dropped out were more likely to have a history of alcohol abuse (5 of 13 versus 3 of 45, P ,0.01), and a regular heart rhythm (13 of 13 versus 28 of 45, P ,0.01), and to have been diagnosed with venous insufficiency clinically (13 of 13 versus 33 of 45, P 5 0.05). Of the 45 patients who completed the study, 4 had a history of congestive heart failure and 3 patients had echocardiograms performed previously. Sixteen patients had chest radiographs in the past; only two of these chest films were consistent with a diagnosis of congestive heart failure. At the time of enrollment, 1 patient was taking digoxin, 5 patients were using angiotensin-converting enzyme inhibitors, and 15 patients were being prescribed a diuretic medication. The initial clinical impressions as to the cause of the edema are shown in Table 2. (Patients could have more than one diagnosis; hence, the total number of diagnoses is more than 45.) The most common initial impressions were venous insufficiency (71%), congestive heart failure (18%), and nephrotic syndrome (13%). The frequency of each final diagnosis is listed in Table 3. Many patients had several conditions contributing to their edema; no attempt was made to determine the relative importance of 194
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Cardiac diagnosis Left ventricular systolic dysfunction Right ventricular systolic dysfunction Diastolic dysfunction Mitral regurgitation Aortic stenosis Atrial septal defect Atrial fibrillation Pulmonary diagnosis† Pulmonary hypertension (.40 mm Hg) Borderline pulmonary hypertension (31–40 mm Hg) Venous insufficiency Nephrotic syndrome Transient renal disease Proteinuria (.1 g but ,3 g per day) Hypoalbuminemia Lymphedema Stenosis of inferior vena cava Use of nonsteroidal anti-inflammatory drug (definite) Use of corticosteroid or nonsteroidal antiinflammatory drug (probable cause) Idiopathic (none of the above) * Patients could have more than one diagnosis. † Nine of these patients also had cardiac diagnoses.
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Number (%) 8 (18) 1 (2) 4 (9) 1 (2) 1 (2) 1 (2) 2 (4) 9 (20) 10 (22) 10 (22) 1 (2) 1 (2) 6 (13) 1 (2) 1 (2) 1 (2) 1 (2) 6 (13) 12 (27)
Bilateral Leg Edema in Primary Care/Blankfield et al
either a cardiac condition, pulmonary hypertension, or both. All the patients with a cardiac diagnosis, and 89% (17 of 19) of those with pulmonary hypertension, were aged 45 or older. Twenty-two percent (n 5 10) of the patients had venous insufficiency determined by duplex ultrasound scanning. In 6 of these cases, the venous insufficiency coincided with a cardiac diagnosis or some degree of pulmonary hypertension. Four patients had venous insufficiency without a cardiac or pulmonary cause of edema. Several patients had renal diagnoses, most commonly proteinuria. One patient’s edema developed when an NSAID was begun, and resolved completely upon its cessation. For 6 other patients, the edema began close to the time that corticosteroids or NSAIDs were started, but a more definite cause-effect relationship could not be established. In 27% of the cases, no cause for the edema could be identified. These patients had entirely normal laboratory findings and no medication use to explain their edema. There was no significant difference in body mass index between these patients and those in whom a diagnosis was made. There was a significant association between the primary care provider’s clinical impression of congestive heart failure and a final diagnosis of a cardiac condition (7 of 8 versus 8 of 37, P ,0.01). There was no significant association between a clinical impression of venous insufficiency and a final laboratory diagnosis of venous insufficiency, nor was there a significant association between a clinical impression of pulmonary pathology and a final laboratory diagnosis of some degree of pulmonary hypertension. Patients with a history of hypertension were more likely to have a final diagnosis of a cardiac condition (9 of 17 with hypertension versus 5 of 27 without hypertension, P 5 0.02) as were those with a history of congestive heart failure (4 of 5 versus 11 of 39, P 5 0.04). Dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, having a history of coronary artery disease, having a clinical history or a prior chest radiograph consistent with congestive heart failure, having an echocardiogram done previously, gender, and prior treatment with digoxin, a diuretic, or an angiotensin-converting enzyme inhibitor were not significantly associated with a final diagnosis of a cardiac condition. None of the primary care provider’s physical examination findings were significantly associated with a final laboratory diagnosis of a cardiac condition. Forty of the 45 subjects had a physical examination performed by a cardiologist. There was a delay varying from 1 to several weeks between the time of enrollment in the study and the evaluation by the cardiologist. Many patients were started on medications, including diuretics, during this interval. As a result, only half of the subjects
had edema at the time of the cardiologist’s examination. For the cardiologist there was a significant association between an abnormal S2 split and a final diagnosis of a cardiac condition (3 of 3 versus 2 of 9, P 5 0.05). (The specific S2 abnormalities, such as paradoxical S2 splitting, increased wide S2 splitting, or increased P2, were not recorded.) There was no significant association between an S3 or S4 gallop, jugular venous distension, hepatojugular reflux, and rales with a final cardiac diagnosis. There was no significant association between an abnormal S2 split and a diagnosis of pulmonary hypertension. Older age was significantly associated with a final diagnosis of some degree of pulmonary hypertension: the mean age of 15 patients with pulmonary hypertension was 62 6 13 years, compared with 52 6 14 years in the other patients (P 5 0.02). A history of obstructive pulmonary disease, pauses in snoring greater than 10 seconds, feeling tired upon awakening, having difficulty remaining awake during the afternoon, being previously diagnosed with sleep apnea, and gender were not significantly associated with a diagnosis of pulmonary hypertension. Several variables were associated with a final diagnosis of venous insufficiency, including having a history of venous stasis ulcers (3 of 3 versus 7 of 42, P ,0.01), brawny induration (5 of 8 versus 5 of 36, P ,0.01), previous treatment with unna boots (2 of 2 versus 8 of 43, P 5 0.05), and older age (mean age 67 6 12 years versus 53 6 14 years, P ,0.01). There was no significant association between having varicose veins, using compression support stockings, prolonged daily walking or standing, a history of deep venous thrombosis, or gender and venous insufficiency. Among women, the number of children delivered was not significantly associated with venous insufficiency.
DISCUSSION We found a higher rate of both cardiac disease and pulmonary hypertension in patients with bilateral lower extremity edema than was initially suspected by the primary care provider. Many of the characteristic signs and symptoms of congestive heart failure were absent in many patients with echocardiographic evidence of cardiac disease. Ambulatory patients with cardiac disease may present with edema at a relatively early stage, before the other signs and symptoms of congestive heart failure become manifest. Pulmonary hypertension in the absence of right ventricular dysfunction is not generally recognized as a cause of edema (1,20 –22). There are several possible explanations for why we found that pulmonary hypertension without associated right ventricular dysfunction was a cause of edema. Half of the patients in this study no
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longer had edema at the time of echocardiographic evaluation. Intervening diuresis may have improved right ventricular function and pulmonary artery pressure. Furthermore, the standard concepts of cardiopulmonary physiology discussed in major cardiology textbooks antedate, in large part, the widespread utilization of an accurate, noninvasive estimate of pulmonary artery pressure with echocardiography. Moreover, most prior research has focused on inpatients, who might have more severe disease than the ambulatory patients evaluated in the present study. Five of the 19 patients with pulmonary hypertension had an underlying explanation: 4 had chronic obstructive pulmonary disease, and 1 had an atrial septal defect. Five additional subjects with pulmonary hypertension had left ventricular dysfunction. Of the remaining 9 patients, 8 had isolated pulmonary hypertension, and 1 had pulmonary hypertension with right ventricular dysfunction. None of these 9 patients had evidence of obstructive or interstitial lung disease, recurrent pulmonary emboli, valvular heart disease, congenital heart disease, left ventricular systolic or diastolic dysfunction, sickle cell disease, intravenous drug abuse, cocaine inhalation, or use of an appetite suppressant. Most patients were not screened for HIV infection or collagen vascular disease. Some of the patients with isolated pulmonary hypertension, and even some of those with combined left ventricular dysfunction and pulmonary hypertension, may have had obstructive sleep apnea, which affects 2% to 4% of middle-aged adults (23) and can cause pulmonary hypertension (24). Subsequent to this study, 4 patients with isolated pulmonary hypertension and 1 patient with pulmonary hypertension combined with left ventricular systolic dysfunction underwent sleep studies. Four of these 5 patients have sleep apnea. Although primary care providers were unable to accurately diagnose the cause of bilateral lower extremity edema solely on clinical grounds in most patients, our results also suggest several guidelines for clinicians. Because bilateral edema may be due to medication, most commonly a nonsteroidal anti-inflammatory drug, the first suggestion is to stop the medication. Next, clinicians should consider the age of the patient in deciding whether to order an echocardiogram. In this study, if echocardiograms had been ordered only for patients aged 45 years or older, then all 15 of the patients with cardiac conditions and 17 of the 19 patients with pulmonary hypertension would have been identified. Thus, echocardiographic evaluation, including an estimation of pulmonary artery pressure, should be considered for middle-aged and older patients with bilateral leg edema. Sleep studies may be appropriate in those who are found to have pulmonary hypertension without an apparent cause. 196
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ACKNOWLEDGMENTS The authors would like to acknowledge the support of Nicholas Davis, BM, BCh, Ann Reichsman, MD, and Heather Ways, MD; the contributions of Maureen Babjak, Linda Hall, and Lynn Steppke; and manuscript assistance from Robert Bahler, MD, Louis Rakita, MD, and Ed Ricanati, MD.
REFERENCES 1. Braunwald E. Edema. In: Wilson JD, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine. 12th ed. New York: McGraw-Hill; 1991:228 –232. 2. Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function. J Clin Pharmacol. 1991;31:588 –598. 3. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol. 1990;66:493– 496. 4. Currie PJ, Seward JB, Chan KL, et al. Continuous wave Doppler determination of right ventricular pressure: a simultaneous Doppler-catheterization study in 172 patients. J Am Coll Cardiol. 1985;6:750 –756. 5. Ducas J, Magder S, McGregor M. Validity of the hepatojugular reflux as a clinical test for congestive heart failure. Am J Cardiol. 1983;52:1299 –1303. 6. Ewy GA. The abdominojugular test: technique and hemodynamic correlates. Ann Intern Med. 1988;109:456 – 460. 7. Maisel AS, Atwood JE, Goldberger AL. Hepatojugular reflux: useful in the bedside diagnosis of tricuspid regurgitation. Ann Intern Med. 1984;101:781–782. 8. Menzoain JO, Doyle JE. Venous insufficiency of the leg. Hosp Pract. 1989;24:109 –116. 9. Kannel WB. Epidemiological aspects of heart failure. Cardiol Clin. 1989;7(1):1–9. 10. Szendro G, Nicolaides MS, Zukowski AJ, et al. Duplex scanning in the assessment of deep venous incompetence. J Vasc Surg. 1986;4: 237–242. 11. van Bemmelen PS, Bedford G, Beach K, Strandness DE. Quantitative segmental evaluation of venous valvular reflux with duplex ultrasound scanning. J Vasc Surg. 1989;10:425– 431. 12. Vasdekis SN, Clarke H, Nicolaides AN. Quantification of venous reflux by means of duplex scanning. J Vasc Surg. 1989;10:670 – 677. 13. Vaughan BF. CT of swollen legs. Clin Radiol. 1990;41:24 –30. 14. Wang J, Mezrich RS, Kostis JB. The use of magnetic resonance imaging in the study of edema. Angiology. 1991;358 –364. 15. Partsch H, Stober C, Urbanek A, Wenzel-Hora BI. Clinical use of indirect lymphography in different forms of leg edema. Lymphology. 1988;21:152–160. 16. Ewing JA. Detecting alcoholism: the CAGE questionnaire. JAMA. 1984;252:1905–1907. 17. Kuczmarski RJ, Flogal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA. 1994; 272:205–211. 18. Amico AF, Lichtenberg GS, Reisner SA, et al. Superiority of visual versus computerized echocardiographic estimation of radionuclide left ventricular ejection fraction. Am Heart J. 1989;1259 –1265. 19. Cohen GI, Pietrolungo JF, Thomas JD, Klein AL. A practical guide to assessment of ventricular diastolic function using Doppler echocardiography. J Am Coll Cardiol. 1996;27:1753–1760. 20. Braunwald E. Examination of the patient. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia: WB Saunders; 1997:9 –10. 21. Hurst JW, Morris DC. The history: symptoms and past events related to cardiovascular disease. In: Schlant RC, Alexander RW,
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Bilateral Leg Edema in Primary Care/Blankfield et al O’Rourke RA, et al, eds. The Heart. 8th ed. New York: McGrawHill; 1994:205–215. 22. Newman JH, Ross JC. Chronic cor pulmonale. In: Schlant RC, Alexander RW, O’Rourke RA, et al, eds. The Heart. 8th ed. New York: McGraw-Hill; 1994:1895–1904.
23. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. NEJM. 1993;328: 1230 –1235. 24. Strollo PJ, Rogers RM. Obstructive sleep apnea. NEJM. 1996;334: 99 –104.
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actuality, 15 (33%) patients had a cardiac condition as a cause of their leg edema, and 19 (42%) had pulmonary hypertension. All of the patients with heart disease, and almost all of those with pulmonary hypertension, were age 45 years or older. Only 10 (22%) of the subjects had venous insufficiency. Renal conditions, medication use, and hypoalbuminemia were less common. CONCLUSIONS: Utilizing clinical information only, many patients with cardiopulmonary pathology were incorrectly diagnosed as having more benign conditions, most commonly venous insufficiency. Echocardiographic evaluation, including an estimation of pulmonary artery pressure, may be advisable in many patients with bilateral leg edema, especially if they are at least 45 years old. Am J Med. 1998;105:192–197. q1998 by Excerpta Medica, Inc.
B
common, affecting ,1% of the population (9). Although testing is usually not ordered when venous insufficiency is suspected, currently available tests include descending phlebography, photoplethysmography, and duplex ultrasound scanning. Although none of these tests is the “gold standard” for the diagnosis, duplex venous scanning is considered the most accurate laboratory test available for venous insufficiency (10 –12). Other tests, such as computerized tomography, magnetic resonance imaging, and indirect lymphography have been reported to aid in the assessment of leg swelling (13–15) but are rarely used clinically. We performed this study to identify the frequency of the causes of bilateral edema in a primary care setting, and to determine the ability of primary care providers to arrive at the correct diagnosis using the information available at the initial clinical encounter. We hypothesized that venous insufficiency would be the most common cause of bilateral leg edema, and that clinicians would be able to diagnose the cause of edema without relying upon laboratory investigations.
ilateral leg edema is a manifestation of either generalized edema—for example, due to congestive heart failure, nephrotic syndrome, acute glomerulonephritis, or cirrhosis— or to local factors, such as venous or lymphatic obstruction (1). Medications, particularly nonsteroidal anti-inflammatory drugs (NSAID) (2), corticosteroids, and nifedipine can result in bilateral leg edema. History, physical examination, and urinalysis are the first steps to determine the cause of bilateral leg edema. Echocardiography can noninvasively detect many types of cardiopulmonary disease, including valvular heart disease, systolic and diastolic ventricular dysfunction, cor pulmonale, and pulmonary hypertension (3,4). When seeing a patient with bilateral leg edema who lacks the typical signs and symptoms of congestive heart failure (5–7), and who also has an unremarkable urinalysis, clinicians may be likely to diagnose venous insufficiency as the cause of the edema. Venous insufficiency is common, affecting as many as 25% to 30% of the general population (8), whereas congestive heart failure is less
From the Departments of Family Medicine (RPB, SAF, MG, SJZ), Medicine (RSF), and Surgery (JJA), Case Western Reserve University School of Medicine, Cleveland, Ohio; Metro Health Medical Center (RFF, JJA), Cleveland, Ohio; and the Frances Payne Bolton School of Nursing (JM), Cleveland, Ohio. Requests for reprints should be addressed to R.P. Blankfield, MD, University Hospitals Primary Care Practice, Williamsport Plaza, 398 W. Bagley Road, Suite 1, Berea, Ohio 44017. Manuscript submitted February 12, 1998 and accepted May 13, 1998. 192
q1998 by Excerpta Medica, Inc. All rights reserved.
METHODS Patients were enrolled at an inner city family practice in Cleveland, Ohio, between March 1993 and February 1996. The practice is staffed by five family physicians and a family nurse practitioner. The practice population is primarily Caucasian or Hispanic, and mostly working class or indigent. 0002-9343/98/$19.00 PII S0002-9343(98)00235-6
Bilateral Leg Edema in Primary Care/Blankfield et al
Ambulatory patients 18 years of age and older who had bilateral leg edema were eligible for enrollment, regardless of the duration of the edema, any previous diagnoses, laboratory tests, or radiological evaluations. Patients who had bilateral edema known to be due to nifedipine therapy, intraabdominal malignancy, hypothyroidism, or idiopathic cyclic edema were excluded. Informed consent was obtained from each subject, and the study was approved by the Institutional Review Board at the MetroHealth Medical Center, Cleveland, Ohio. Medical information, including history of alcohol abuse, hepatitis, cirrhosis, varicose veins, deep venous thromboembolism or thrombophlebitis, congestive heart failure, coronary artery disease, hypertension, chronic obstructive pulmonary disease, and kidney disease was obtained from chart review. The primary care provider also recorded the following physical findings: bilateral pitting edema, bilateral leg swelling, varicose veins, venous stasis ulcers, brawny induration, regular heart rhythm, normal S2 splitting, rales, jugular venous distension, hepatojugular reflux, systolic murmur, shifting dullness on abdominal examination, fluid wave on abdominal examination, spider angiomas, jaundice, and proteinuria (31 or greater on urine dipstick). The primary care provider also recorded a clinical impression of the cause of the edema. Patients were asked to complete a questionnaire regarding the duration of swelling; whether they had orthopnea, paroxysmal nocturnal dyspnea, or dyspnea on exertion; whether they had ever had blood clots in their legs; whether they had ever been diagnosed with hepatitis or cirrhosis; whether they engaged in prolonged standing or walking; how much alcohol they drank; the CAGE screening questions for alcoholism (16); whether they snored and if there were pauses in the snoring greater than 10 seconds; whether they felt tired upon awakening; whether they had difficulty remaining awake during the afternoon; and if they had been previously diagnosed with sleep apnea. Women were asked how many children they had delivered. Blood was obtained from all patients for a serum albumin. A 24-hour urinalysis was ordered at the discretion of the primary care provider. A body mass index was calculated for each patient. Men were considered obese if they had a body mass index (weight in kg 4 height in m2) greater than 27.8 kg/m2, and women were considered obese if they had a body mass index greater than 27.3 kg/m2 (17). Subjects subsequently underwent laboratory evaluations consisting of an echocardiogram and a duplex venous ultrasound scan of the lower extremities. Systolic dysfunction was defined as a left ventricular ejection fraction less than 50% by visual assessment of an experienced reader (18), or a focal wall motion abnormality. Diastolic dysfunction was determined by the transmitral and pulmonary vein Doppler flow patterns (19). Aortic stenosis
was diagnosed if the peak instantaneous gradient across the valve exceeded 50 mm Hg. Mitral stenosis was diagnosed if the opening diameter was less than 1.5 cm2. Mitral regurgitation was considered to be a potential cause of pedal edema only if it was rated as being severe or moderately severe. Pulmonary artery pressure was estimated via echo Doppler by adding the Doppler systolic transtricuspid gradient to the estimated right atrial pressure using the inferior vena caval diameter and percent diameter change with respiration (3). Pulmonary hypertension was defined as an estimated pulmonary artery systolic pressure greater than 40 mm Hg, and borderline pulmonary hypertension was defined as an estimated pulmonary artery systolic pressure between 31 and 40 mm Hg. Venous insufficiency was defined as retrograde flow across the venous valves in the legs, either at the level of the femoral, popliteal, or saphenous veins. At the time of the echocardiographic evaluation, a cardiologist performed a physical examination and recorded the presence or absence of the following physical findings: pitting edema, nonpitting swelling, regular heart rhythm, normal S2 splitting, systolic murmur, S3 or S4 gallop, rales, jugular venous distension, and hepatojugular reflux. A final diagnosis of the etiology of the edema was determined for each patient using the information from the laboratory evaluations, supplemented by the clinical information obtained by the primary care provider. Statistical analysis was done with SPSS for Windows. To test the association of the historical information, physical findings, and clinical impressions of the primary care provider with the final diagnosis, chi-square tests were used. The association of the cardiologist’s physical findings by the echocardiographic diagnosis of a cardiac condition was also tested by chi-square. Fischer’s exact test was utilized when appropriate. Continuous data are presented as mean 6 SD; mean values were compared with Student’s t test.
RESULTS Fifty eight patients enrolled in the study, 13 of whom did not complete the echocardiogram and venous duplex scans. Of the remaining 45 patients, 43 had pitting edema and 2 had nonpitting edema. Patients’ ages ranged from 29 years to 83 years (Table 1). One third had edema for less than 6 months, and 30% reported edema lasting more than 6 years. Eighty-four percent of the subjects were obese. There were no significant differences between the patients who completed the study and those who did not in age, gender, marital status, education, and duration of edema. There were also no significant differences between the two groups for most of the historical variables
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Table 1. Demographic Characteristics of 45 Patients with Bilateral Leg Edema
Table 2. Initial Clinical Diagnoses for 45 Patients with Bilateral Leg Edema*
Characteristic Age (years) Body mass index (kg/m2) Female gender Race Caucasian Hispanic African American Native American Marital status Married Single Divorced/separated Widowed Level of education Did not finish high school High school graduate Some college or vocational training College graduate Duration of edema Less than 3 months 3–6 months 6–12 months 1–2 years 2–6 years .6 years
56 6 15* 38.5 6 10.5* 62% 83% 11% 4% 2% 50% 16% 16% 18% 37% 35% 23% 5% 22% 11% 13% 13% 11% 30%
* Mean 6 SD.
Diagnosis
Number (%)
Congestive heart failure Venous insufficiency Nephrotic syndrome Lymphedema Pulmonary hypertension Cor pulmonale Hypoalbuminemia Use of nonsteroidal anti-inflammatory drug Use of corticosteroids Sleep apnea Obesity Uncertain
8 (18) 33 (71) 6 (13) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 3 (7)
* Patients could have more than one diagnosis.
each diagnosis. Thirty-three percent of the subjects had a cardiac diagnosis, usually systolic or diastolic dysfunction. Two patients with systolic dysfunction also had atrial fibrillation. Forty-two percent of the patients had some degree of pulmonary hypertension: 20% had pulmonary hypertension, and 22% had borderline pulmonary hypertension. About half of these patients also had a cardiac diagnosis. Fifty-six percent of the patients had
Table 3. Final Diagnoses for 45 Patients with Bilateral Leg Edema after Laboratory Investigation Diagnosis*
and physical examination findings except that patients who dropped out were more likely to have a history of alcohol abuse (5 of 13 versus 3 of 45, P ,0.01), and a regular heart rhythm (13 of 13 versus 28 of 45, P ,0.01), and to have been diagnosed with venous insufficiency clinically (13 of 13 versus 33 of 45, P 5 0.05). Of the 45 patients who completed the study, 4 had a history of congestive heart failure and 3 patients had echocardiograms performed previously. Sixteen patients had chest radiographs in the past; only two of these chest films were consistent with a diagnosis of congestive heart failure. At the time of enrollment, 1 patient was taking digoxin, 5 patients were using angiotensin-converting enzyme inhibitors, and 15 patients were being prescribed a diuretic medication. The initial clinical impressions as to the cause of the edema are shown in Table 2. (Patients could have more than one diagnosis; hence, the total number of diagnoses is more than 45.) The most common initial impressions were venous insufficiency (71%), congestive heart failure (18%), and nephrotic syndrome (13%). The frequency of each final diagnosis is listed in Table 3. Many patients had several conditions contributing to their edema; no attempt was made to determine the relative importance of 194
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Cardiac diagnosis Left ventricular systolic dysfunction Right ventricular systolic dysfunction Diastolic dysfunction Mitral regurgitation Aortic stenosis Atrial septal defect Atrial fibrillation Pulmonary diagnosis† Pulmonary hypertension (.40 mm Hg) Borderline pulmonary hypertension (31–40 mm Hg) Venous insufficiency Nephrotic syndrome Transient renal disease Proteinuria (.1 g but ,3 g per day) Hypoalbuminemia Lymphedema Stenosis of inferior vena cava Use of nonsteroidal anti-inflammatory drug (definite) Use of corticosteroid or nonsteroidal antiinflammatory drug (probable cause) Idiopathic (none of the above) * Patients could have more than one diagnosis. † Nine of these patients also had cardiac diagnoses.
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Number (%) 8 (18) 1 (2) 4 (9) 1 (2) 1 (2) 1 (2) 2 (4) 9 (20) 10 (22) 10 (22) 1 (2) 1 (2) 6 (13) 1 (2) 1 (2) 1 (2) 1 (2) 6 (13) 12 (27)
Bilateral Leg Edema in Primary Care/Blankfield et al
either a cardiac condition, pulmonary hypertension, or both. All the patients with a cardiac diagnosis, and 89% (17 of 19) of those with pulmonary hypertension, were aged 45 or older. Twenty-two percent (n 5 10) of the patients had venous insufficiency determined by duplex ultrasound scanning. In 6 of these cases, the venous insufficiency coincided with a cardiac diagnosis or some degree of pulmonary hypertension. Four patients had venous insufficiency without a cardiac or pulmonary cause of edema. Several patients had renal diagnoses, most commonly proteinuria. One patient’s edema developed when an NSAID was begun, and resolved completely upon its cessation. For 6 other patients, the edema began close to the time that corticosteroids or NSAIDs were started, but a more definite cause-effect relationship could not be established. In 27% of the cases, no cause for the edema could be identified. These patients had entirely normal laboratory findings and no medication use to explain their edema. There was no significant difference in body mass index between these patients and those in whom a diagnosis was made. There was a significant association between the primary care provider’s clinical impression of congestive heart failure and a final diagnosis of a cardiac condition (7 of 8 versus 8 of 37, P ,0.01). There was no significant association between a clinical impression of venous insufficiency and a final laboratory diagnosis of venous insufficiency, nor was there a significant association between a clinical impression of pulmonary pathology and a final laboratory diagnosis of some degree of pulmonary hypertension. Patients with a history of hypertension were more likely to have a final diagnosis of a cardiac condition (9 of 17 with hypertension versus 5 of 27 without hypertension, P 5 0.02) as were those with a history of congestive heart failure (4 of 5 versus 11 of 39, P 5 0.04). Dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, having a history of coronary artery disease, having a clinical history or a prior chest radiograph consistent with congestive heart failure, having an echocardiogram done previously, gender, and prior treatment with digoxin, a diuretic, or an angiotensin-converting enzyme inhibitor were not significantly associated with a final diagnosis of a cardiac condition. None of the primary care provider’s physical examination findings were significantly associated with a final laboratory diagnosis of a cardiac condition. Forty of the 45 subjects had a physical examination performed by a cardiologist. There was a delay varying from 1 to several weeks between the time of enrollment in the study and the evaluation by the cardiologist. Many patients were started on medications, including diuretics, during this interval. As a result, only half of the subjects
had edema at the time of the cardiologist’s examination. For the cardiologist there was a significant association between an abnormal S2 split and a final diagnosis of a cardiac condition (3 of 3 versus 2 of 9, P 5 0.05). (The specific S2 abnormalities, such as paradoxical S2 splitting, increased wide S2 splitting, or increased P2, were not recorded.) There was no significant association between an S3 or S4 gallop, jugular venous distension, hepatojugular reflux, and rales with a final cardiac diagnosis. There was no significant association between an abnormal S2 split and a diagnosis of pulmonary hypertension. Older age was significantly associated with a final diagnosis of some degree of pulmonary hypertension: the mean age of 15 patients with pulmonary hypertension was 62 6 13 years, compared with 52 6 14 years in the other patients (P 5 0.02). A history of obstructive pulmonary disease, pauses in snoring greater than 10 seconds, feeling tired upon awakening, having difficulty remaining awake during the afternoon, being previously diagnosed with sleep apnea, and gender were not significantly associated with a diagnosis of pulmonary hypertension. Several variables were associated with a final diagnosis of venous insufficiency, including having a history of venous stasis ulcers (3 of 3 versus 7 of 42, P ,0.01), brawny induration (5 of 8 versus 5 of 36, P ,0.01), previous treatment with unna boots (2 of 2 versus 8 of 43, P 5 0.05), and older age (mean age 67 6 12 years versus 53 6 14 years, P ,0.01). There was no significant association between having varicose veins, using compression support stockings, prolonged daily walking or standing, a history of deep venous thrombosis, or gender and venous insufficiency. Among women, the number of children delivered was not significantly associated with venous insufficiency.
DISCUSSION We found a higher rate of both cardiac disease and pulmonary hypertension in patients with bilateral lower extremity edema than was initially suspected by the primary care provider. Many of the characteristic signs and symptoms of congestive heart failure were absent in many patients with echocardiographic evidence of cardiac disease. Ambulatory patients with cardiac disease may present with edema at a relatively early stage, before the other signs and symptoms of congestive heart failure become manifest. Pulmonary hypertension in the absence of right ventricular dysfunction is not generally recognized as a cause of edema (1,20 –22). There are several possible explanations for why we found that pulmonary hypertension without associated right ventricular dysfunction was a cause of edema. Half of the patients in this study no
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longer had edema at the time of echocardiographic evaluation. Intervening diuresis may have improved right ventricular function and pulmonary artery pressure. Furthermore, the standard concepts of cardiopulmonary physiology discussed in major cardiology textbooks antedate, in large part, the widespread utilization of an accurate, noninvasive estimate of pulmonary artery pressure with echocardiography. Moreover, most prior research has focused on inpatients, who might have more severe disease than the ambulatory patients evaluated in the present study. Five of the 19 patients with pulmonary hypertension had an underlying explanation: 4 had chronic obstructive pulmonary disease, and 1 had an atrial septal defect. Five additional subjects with pulmonary hypertension had left ventricular dysfunction. Of the remaining 9 patients, 8 had isolated pulmonary hypertension, and 1 had pulmonary hypertension with right ventricular dysfunction. None of these 9 patients had evidence of obstructive or interstitial lung disease, recurrent pulmonary emboli, valvular heart disease, congenital heart disease, left ventricular systolic or diastolic dysfunction, sickle cell disease, intravenous drug abuse, cocaine inhalation, or use of an appetite suppressant. Most patients were not screened for HIV infection or collagen vascular disease. Some of the patients with isolated pulmonary hypertension, and even some of those with combined left ventricular dysfunction and pulmonary hypertension, may have had obstructive sleep apnea, which affects 2% to 4% of middle-aged adults (23) and can cause pulmonary hypertension (24). Subsequent to this study, 4 patients with isolated pulmonary hypertension and 1 patient with pulmonary hypertension combined with left ventricular systolic dysfunction underwent sleep studies. Four of these 5 patients have sleep apnea. Although primary care providers were unable to accurately diagnose the cause of bilateral lower extremity edema solely on clinical grounds in most patients, our results also suggest several guidelines for clinicians. Because bilateral edema may be due to medication, most commonly a nonsteroidal anti-inflammatory drug, the first suggestion is to stop the medication. Next, clinicians should consider the age of the patient in deciding whether to order an echocardiogram. In this study, if echocardiograms had been ordered only for patients aged 45 years or older, then all 15 of the patients with cardiac conditions and 17 of the 19 patients with pulmonary hypertension would have been identified. Thus, echocardiographic evaluation, including an estimation of pulmonary artery pressure, should be considered for middle-aged and older patients with bilateral leg edema. Sleep studies may be appropriate in those who are found to have pulmonary hypertension without an apparent cause. 196
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ACKNOWLEDGMENTS The authors would like to acknowledge the support of Nicholas Davis, BM, BCh, Ann Reichsman, MD, and Heather Ways, MD; the contributions of Maureen Babjak, Linda Hall, and Lynn Steppke; and manuscript assistance from Robert Bahler, MD, Louis Rakita, MD, and Ed Ricanati, MD.
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23. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. NEJM. 1993;328: 1230 –1235. 24. Strollo PJ, Rogers RM. Obstructive sleep apnea. NEJM. 1996;334: 99 –104.
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