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Effect of Venous Obstruction of Lower Extremities on Exercise Tolerance
selected reports Effect of Venous Obstruction of Lower Extremities on Exercise Tolerance* Issahar Ben-Dov, MD; Benyamina Morag, MD; and
Zvi
Farfel, MD
The effect of venous obstruction on effort tolerance appreciated. We studied a patient with severe lower body venous obstruction (with near normal heart and lung function) who had marked exercise intolerance. Peak 02 uptake for leg exercise was reduced, but peak 02 uptake for upper extrem¬ ities was normal. This difference indicates that se¬ vere venous obstruction can lead to exercise limitation. (CHEST 1997; 111:506-08) is not well
Key words: collateral veins; exercise capacity; inferior vena cava interruption; peak 02 uptake; upper extremities Abbreviations: IVC=inferior vena cava; Vo2=oxygen uptake
T71 xercise tolerance depends on adequate cardiac output and on the integrity of the peripheral arterial circula¬ tion to the exercising muscles.12 However, the effect of interruption of the venous system of an extremity on its exercise capacity is not well described. We studied an adult male with bilateral iliofemoral and inferior vena cava (IVC) thrombosis, who experienced marked exercise in¬ tolerance. The patient performed upper and lower ex¬ tremity cycle ergometry tests. This sequence was chosen to differentiate between central (cardiac or pulmonary vascular) and peripheral (arterial or venous) circulatory cause for exercise limitation. The findings suggested that venous obstruction could cause severe exercise limitation and that this diagnosis should be considered in the differential diagnosis of effort intolerance. -"
Case Report A 63-year-old man, a nonsmoker, was active and physically fit
until the appearance in 1989 of recurrent iliofemoral deep emboli. Following an embolic thrombophlebitis and pulmonary event, which occurred while the patient was receiving anticoag¬ ulant therapy, a Greenfield filter was inserted into the IVC via the *From the Institute of Respiratory Physiology and Medicine (Dr. Ben-Dov), Departments of Radiology (Dr. Morag), and Medi¬ cine E (Dr. Farfel), Tel-Aviv University, Sackler Medical School, Sheba Medical Center, Tel-Hashomer, Israel. Manuscript received May 9,1995; revision accepted February 16, 1996.
506
neck. In 1990, he underwent an elective transurethral prostatec¬ tomy for benign hypertrophy of the gland. This procedure was followed by recurrent pulmonary emboli. At that stage, contrast venography was done and was complicated by iliofemoral throm¬ bophlebitis, which led to persistent leg edema and severe effort intolerance. Walking a few steps on level ground caused tired¬ ness, dyspnea, leg discomfort, and dizziness but no chest pain. Extensive search for the cause of the effort intolerance was inconclusive. There were no physical signs of pulmonary hyper¬ tension or heart failure, and peripheral pulses and leg muscle strength were normal. An ECG and a thallium dipyridamole myocardial scan showed no ischemic zones. A Doppler echocar¬ diogram showed normal left and right ventricular function, with no signs of pulmonary hypertension. A subsequent 99mTc perfu¬ sion lung scan showed resolution of the perfusion defects. Values for FEVX, FVC, and total lung capacity were 80, 80, and 83% of those predicted, respectively, and the diffusion of CO was 71% of that predicted. The mild restriction could have resulted from the patient's being overweight (112 kg, 189 cm) but could not account for the disability. We hypothesized that the lower body venous obstruction might be causing exercise limitation. We argued that if reduced venous return (rather than central circulatory dysfunction) limits leg exer¬ cise, then arm exercise capacity should not be limited and should be to that of the lower extremities. Normally, due to the higher relative difference in muscle mass, peak 02 uptake for upper extremity exercise is approximately 70% of the lower extremity peak.1 The patient performed upper and lower extremity incremental maximal cycle ergometry, using a cardiopulmonary exercise system (CPX; MedGraphics; St. Paul, Minn). The protocol, as described,3 started with 3 min of unloaded pedaling previously the incremental period (15 W/min), which was con¬ preceding tinued to the limit of tolerance. The upper extremity test was with the patient in the sitting performed using theof same protocol position. The axis the pedals was placed at a level horizontal with the shoulders. Hemoglobin 02 saturation was measured by a pulse oximeter with an ear probe (POET; Criticare Systems Inc;
Waukesha, Wis). 02 uptake during the upper and lower extremity studies is shown in Figure 1. The lower extremity exercise capacity was severely reduced, peak 02 uptake was 1,255 mL/min (51% of predicted), while the upper extremity peak 02 uptake was normal (1,800 mL/min). Additional exercise parameters are shown in Table 1. Ventila¬ tion was not limiting (exercise breathing reserve > 15 L/min1). The ventilatory equivalents were markedly elevated, and the 02
leg exercise. pulse was reduced during the The bilateral iliofemoral vein study is shown in Figure 2. The right common iliac vein is severely obstructed, and the left common iliac vein and the IVC are completely occluded. Left paravertebral collateral veins of moderate size are demonstrated.
Discussion Exercise capacity can be maintained only if all compo¬ nents of the 02 transport chain are normal.1-2 Adequate to the heart, which depends on venous return, is preload therefore crucial. Selected
Reports
or obstruction is only rarely and vaguely described as "venous claudication."45 Our patient experi¬ enced severe distress after walking a few steps and
interruption
3
TIME
4
(min)
5
rest
02 uptake in a patient with severe lower body venous occlusion during an incremental maximal lower extremity (solid line) and upper extremity (dashed line) cycle ergometry exercise. Peak 02 uptake during the arm exercise exceeds that during the Figure 1.
leg exercise.
The marked rise in leg venous pressure during mild exercise, when the IVC was ligated or obstructed, has been appreciated in the old surgical literature.4 In fact, the chronic edema which is common following IVC obstruc¬ tion also results from chronic elevation of venous pressure. However, many textbooks on exercise physiology do not emphasize that an occluded venous system should be considered in the differential diagnosis of exercise intol¬ erance.12 Furthermore, exercise limitation following IVC Table
Parameters at the Peak of 1.Cardiorespiratory and Arm Exercise*
Leg
Legs
Parameter
02 Uptake, mL/min Anaerobic threshold
(Vo2), mL/min RER, Vco2/Vo2
02 pulse, mL/beat
Heart rate, beat/min
Ventilation, L/min
Breathing reserve, (L/min)f VeA'o2, Ve/Vco2{ PetC02, mm Hg§ % hemoglobin
1,255 (51% predicted) 1,049 1.22 10.1 124 118 59 60 64 28 97/97
saturation,
Arms
1,800 996
1.47 15.6 115 123 54 36. 36 36 97/95
rest/exercise
PetC02=partial pressure of end-tidal C02; RER respiratory exchange ratio; Vco2=carbon dioxide output; Ve minute ventilation. Breathing reserve is the difference between maximal breathing capacity at rest and peak ventilation during exercise (maximum voluntary ventilation.VEmax). *Ve/Vo2, Ve/C02=ventilatory equivalents for 02 and C02. s *
Abbreviations:
=
=
Lowest values
are
shown.
Venography. Top: right femoral injection showing defects in the iliac and femoral veins. Bottom: left multiple filling femoral injection showing homogenous filling of the external and internal iliac veins and total occlusion of the common iliac vein and of the IVC. Left paravertebral collateral veins of moderate size are seen. Figure 2.
CHEST 7111/2/ FEBRUARY, 1997
507
experienced a "pre-fainting" sensation. During the lower extremity test, cardiovascular dysfunction was the limiting abnormality (Table 1). This conclusion is based on a low-normal anaerobic threshold (42% of predicted), mark¬ edly reduced 02in pulse, and a relatively high respiratory exchange ratio the presence of a shallow oxygen uptake (Vo2) slope.1 The true, lasting, end exercise plateau of the Vo2 curve during the leg exercise (Fig 1) is consistent with inadequate 02 delivery to the leg muscles. The reduced exercise capacity may have resulted from failure of the central or the peripheral circulation. However, right and left ventricular function were normal (echocardiography). This finding does not support an important role for the central circulation, thereby directing the investigation to the peripheral circulation, arterial or venous. Further strong evidence that the extensive venous disease limited exercise was gained from the observation that peak 02 uptake was higher for the upper extremities. The advan¬ tage of the upper extremities indicates that the abnormal¬ ity which limited the lower extremities was indeed periph¬ eral, since a central abnormality should have equally limited both modes of exercise. In the absence of arterial disease or leg muscle weakness, the occluded lower body venous system must have been the limiting factor for leg exercise. We studied another lower
patient with extremity venous obstruction and IVC filter but no evidence of IVC obstruction (results not shown). In the other patient, work capacity of the lower limbs exceeded work capacity of the upper limbs.
Why does venous obstruction limit exercise? At a metabolic level achieved by the patient (02 uptake of 1.25 L/min [Fig 1]), the normal cardiac output should be 12 L/min2. Normally, about two thirds of this total blood flow should be directed to the exercising limbs.2-6 In this patient, we doubt if such a distribution could have been achieved during leg exercise. As venous pressure rose under the high leg blood flow, a fraction of the excess flow (above rest) must have been stored in the legs, causing local pain and swelling (as noticed by the patient). As venous pressure further rose, even the arterial flow to the limbs might have become compromised so that the legs remained congested and underperfused. The structural findings on the contrast venography (Fig 2) support the conclusion reached from the physiologic analysis. Only narrow left paravertebral veins, which drain to the azygos system, are demonstrable, while the iliofem¬ oral veins and the IVC are occluded. It is not surprising that under the condition of high leg flow demand (^8 L/min, see previous sentences) these poor channels limit venous return, thereby limiting the rise in cardiac output. The findings in the venogram probably overestimate the actual patency of the lower body venous system. This is because the contrast injection itself caused further severe thrombophlebitis, and only thereafter did the persistent edema and effort intolerance worsen. An invasive study could have clarified the hemodynamic sequence of events during exercise and the extent to which the leg arterial blood flow also becomes compromised during leg exercise. This study should include measure¬ ment of cardiac output and leg blood flow, as well as mixed venous and leg vein 02 saturation during exercise. We 508
thought that such a study was not feasible in our patient, repeated resting impedance plethysmography sug¬ gested persistent venous obstruction. In summary, we describe a patient with severe effort intolerance following recurrent bilateral iliofemoral thrombophlebitis and pulmonary emboli. There was no evidence that cardiac, ventilatory, or residual pulmonary vascular disease accounted for the symptoms. Exercise capacity was higher for the upper extremities, indicating that a peripheral rather than a central circulatory7 abnor¬ mality caused the limitation. Contrast venography substan¬ tiated the presence of severe venous obstruction. These findings indicate that when venous flow limitation is severe and is not compensated by an adequate collateral flow, the venous disease can lead to exercise intolerance. This diagnosis can be supported by comparing the arm and leg exercise capacity. but
References
1 Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 1st ed. Philadelphia: Lea & Febiger, 1987 2 Jones NL. Clinical exercise testing. 3rd ed. Philadelphia: WB
Saunders, 1988 3 Sietsema K, Ben-Dov I, Sullivan 4
5
C,
et
al. Lactic acid-linked
changes in 02 uptake kinetics in heart failure. Chest 1994; 105:1693-1700 Bernstein EF. Caval interruption procedures. In: Rutherford RB, ed. Vascular surgery. 3rd ed. Philadelphia: WB Saunders, 1989; 1575-83 Fishman AP. Pulmonary7 diseases and disorders. New York: McGraw-Hill, 1988; 833
6 Schaffartzik
W, Barton ED, Poole DC, et al. Effect of reduced hemoglobin concentration on leg oxygen uptake during maximal exercise in humans. J Appl Physiol 1993; 75:491-98
Pulmonary Tuberculosis
Associated With Invasive Pseudallescheriasis* Jasna Tekavec, MD; Emilija Mlinaric-Missoni, MD; and Verica
Babic-Vazic, MS
54-year-old woman with pulmonary tuberculosis developed pneumonia caused by Scedosporium apiospermum, the asexual stage of the fungus Pseudallescheria boydii. Mycobacterium tuberculosis and P boydii were cultured in BAL fluid. The patient cleaned swimming pools in a spa health resort and was highly exposed to fungal conidia. She was suc¬ cessfully treated with antituberculosis drugs, miconazole nitrate and ketoconazole, leading to remission of her pulmonary infection. Invasive pulmonary A
*From Hospital for Lung Diseases and TB Klenovnik, Klenovnik, Croatia (Dr. Tekavec); the Department of Microbiology and Parasitology, Medical School, University of Zagreb, Zagreb, Croatia (Dr. Mlinaric-Missoni); and Croatian National Institute of Public Health, Zagreb, Croatia (Dr. Babic-Vazic). Manuscript received January 17, 1996; revision accepted July 5. Selected
Reports
Zvi
Farfel, MD
The effect of venous obstruction on effort tolerance appreciated. We studied a patient with severe lower body venous obstruction (with near normal heart and lung function) who had marked exercise intolerance. Peak 02 uptake for leg exercise was reduced, but peak 02 uptake for upper extrem¬ ities was normal. This difference indicates that se¬ vere venous obstruction can lead to exercise limitation. (CHEST 1997; 111:506-08) is not well
Key words: collateral veins; exercise capacity; inferior vena cava interruption; peak 02 uptake; upper extremities Abbreviations: IVC=inferior vena cava; Vo2=oxygen uptake
T71 xercise tolerance depends on adequate cardiac output and on the integrity of the peripheral arterial circula¬ tion to the exercising muscles.12 However, the effect of interruption of the venous system of an extremity on its exercise capacity is not well described. We studied an adult male with bilateral iliofemoral and inferior vena cava (IVC) thrombosis, who experienced marked exercise in¬ tolerance. The patient performed upper and lower ex¬ tremity cycle ergometry tests. This sequence was chosen to differentiate between central (cardiac or pulmonary vascular) and peripheral (arterial or venous) circulatory cause for exercise limitation. The findings suggested that venous obstruction could cause severe exercise limitation and that this diagnosis should be considered in the differential diagnosis of effort intolerance. -"
Case Report A 63-year-old man, a nonsmoker, was active and physically fit
until the appearance in 1989 of recurrent iliofemoral deep emboli. Following an embolic thrombophlebitis and pulmonary event, which occurred while the patient was receiving anticoag¬ ulant therapy, a Greenfield filter was inserted into the IVC via the *From the Institute of Respiratory Physiology and Medicine (Dr. Ben-Dov), Departments of Radiology (Dr. Morag), and Medi¬ cine E (Dr. Farfel), Tel-Aviv University, Sackler Medical School, Sheba Medical Center, Tel-Hashomer, Israel. Manuscript received May 9,1995; revision accepted February 16, 1996.
506
neck. In 1990, he underwent an elective transurethral prostatec¬ tomy for benign hypertrophy of the gland. This procedure was followed by recurrent pulmonary emboli. At that stage, contrast venography was done and was complicated by iliofemoral throm¬ bophlebitis, which led to persistent leg edema and severe effort intolerance. Walking a few steps on level ground caused tired¬ ness, dyspnea, leg discomfort, and dizziness but no chest pain. Extensive search for the cause of the effort intolerance was inconclusive. There were no physical signs of pulmonary hyper¬ tension or heart failure, and peripheral pulses and leg muscle strength were normal. An ECG and a thallium dipyridamole myocardial scan showed no ischemic zones. A Doppler echocar¬ diogram showed normal left and right ventricular function, with no signs of pulmonary hypertension. A subsequent 99mTc perfu¬ sion lung scan showed resolution of the perfusion defects. Values for FEVX, FVC, and total lung capacity were 80, 80, and 83% of those predicted, respectively, and the diffusion of CO was 71% of that predicted. The mild restriction could have resulted from the patient's being overweight (112 kg, 189 cm) but could not account for the disability. We hypothesized that the lower body venous obstruction might be causing exercise limitation. We argued that if reduced venous return (rather than central circulatory dysfunction) limits leg exer¬ cise, then arm exercise capacity should not be limited and should be to that of the lower extremities. Normally, due to the higher relative difference in muscle mass, peak 02 uptake for upper extremity exercise is approximately 70% of the lower extremity peak.1 The patient performed upper and lower extremity incremental maximal cycle ergometry, using a cardiopulmonary exercise system (CPX; MedGraphics; St. Paul, Minn). The protocol, as described,3 started with 3 min of unloaded pedaling previously the incremental period (15 W/min), which was con¬ preceding tinued to the limit of tolerance. The upper extremity test was with the patient in the sitting performed using theof same protocol position. The axis the pedals was placed at a level horizontal with the shoulders. Hemoglobin 02 saturation was measured by a pulse oximeter with an ear probe (POET; Criticare Systems Inc;
Waukesha, Wis). 02 uptake during the upper and lower extremity studies is shown in Figure 1. The lower extremity exercise capacity was severely reduced, peak 02 uptake was 1,255 mL/min (51% of predicted), while the upper extremity peak 02 uptake was normal (1,800 mL/min). Additional exercise parameters are shown in Table 1. Ventila¬ tion was not limiting (exercise breathing reserve > 15 L/min1). The ventilatory equivalents were markedly elevated, and the 02
leg exercise. pulse was reduced during the The bilateral iliofemoral vein study is shown in Figure 2. The right common iliac vein is severely obstructed, and the left common iliac vein and the IVC are completely occluded. Left paravertebral collateral veins of moderate size are demonstrated.
Discussion Exercise capacity can be maintained only if all compo¬ nents of the 02 transport chain are normal.1-2 Adequate to the heart, which depends on venous return, is preload therefore crucial. Selected
Reports
or obstruction is only rarely and vaguely described as "venous claudication."45 Our patient experi¬ enced severe distress after walking a few steps and
interruption
3
TIME
4
(min)
5
rest
02 uptake in a patient with severe lower body venous occlusion during an incremental maximal lower extremity (solid line) and upper extremity (dashed line) cycle ergometry exercise. Peak 02 uptake during the arm exercise exceeds that during the Figure 1.
leg exercise.
The marked rise in leg venous pressure during mild exercise, when the IVC was ligated or obstructed, has been appreciated in the old surgical literature.4 In fact, the chronic edema which is common following IVC obstruc¬ tion also results from chronic elevation of venous pressure. However, many textbooks on exercise physiology do not emphasize that an occluded venous system should be considered in the differential diagnosis of exercise intol¬ erance.12 Furthermore, exercise limitation following IVC Table
Parameters at the Peak of 1.Cardiorespiratory and Arm Exercise*
Leg
Legs
Parameter
02 Uptake, mL/min Anaerobic threshold
(Vo2), mL/min RER, Vco2/Vo2
02 pulse, mL/beat
Heart rate, beat/min
Ventilation, L/min
Breathing reserve, (L/min)f VeA'o2, Ve/Vco2{ PetC02, mm Hg§ % hemoglobin
1,255 (51% predicted) 1,049 1.22 10.1 124 118 59 60 64 28 97/97
saturation,
Arms
1,800 996
1.47 15.6 115 123 54 36. 36 36 97/95
rest/exercise
PetC02=partial pressure of end-tidal C02; RER respiratory exchange ratio; Vco2=carbon dioxide output; Ve minute ventilation. Breathing reserve is the difference between maximal breathing capacity at rest and peak ventilation during exercise (maximum voluntary ventilation.VEmax). *Ve/Vo2, Ve/C02=ventilatory equivalents for 02 and C02. s *
Abbreviations:
=
=
Lowest values
are
shown.
Venography. Top: right femoral injection showing defects in the iliac and femoral veins. Bottom: left multiple filling femoral injection showing homogenous filling of the external and internal iliac veins and total occlusion of the common iliac vein and of the IVC. Left paravertebral collateral veins of moderate size are seen. Figure 2.
CHEST 7111/2/ FEBRUARY, 1997
507
experienced a "pre-fainting" sensation. During the lower extremity test, cardiovascular dysfunction was the limiting abnormality (Table 1). This conclusion is based on a low-normal anaerobic threshold (42% of predicted), mark¬ edly reduced 02in pulse, and a relatively high respiratory exchange ratio the presence of a shallow oxygen uptake (Vo2) slope.1 The true, lasting, end exercise plateau of the Vo2 curve during the leg exercise (Fig 1) is consistent with inadequate 02 delivery to the leg muscles. The reduced exercise capacity may have resulted from failure of the central or the peripheral circulation. However, right and left ventricular function were normal (echocardiography). This finding does not support an important role for the central circulation, thereby directing the investigation to the peripheral circulation, arterial or venous. Further strong evidence that the extensive venous disease limited exercise was gained from the observation that peak 02 uptake was higher for the upper extremities. The advan¬ tage of the upper extremities indicates that the abnormal¬ ity which limited the lower extremities was indeed periph¬ eral, since a central abnormality should have equally limited both modes of exercise. In the absence of arterial disease or leg muscle weakness, the occluded lower body venous system must have been the limiting factor for leg exercise. We studied another lower
patient with extremity venous obstruction and IVC filter but no evidence of IVC obstruction (results not shown). In the other patient, work capacity of the lower limbs exceeded work capacity of the upper limbs.
Why does venous obstruction limit exercise? At a metabolic level achieved by the patient (02 uptake of 1.25 L/min [Fig 1]), the normal cardiac output should be 12 L/min2. Normally, about two thirds of this total blood flow should be directed to the exercising limbs.2-6 In this patient, we doubt if such a distribution could have been achieved during leg exercise. As venous pressure rose under the high leg blood flow, a fraction of the excess flow (above rest) must have been stored in the legs, causing local pain and swelling (as noticed by the patient). As venous pressure further rose, even the arterial flow to the limbs might have become compromised so that the legs remained congested and underperfused. The structural findings on the contrast venography (Fig 2) support the conclusion reached from the physiologic analysis. Only narrow left paravertebral veins, which drain to the azygos system, are demonstrable, while the iliofem¬ oral veins and the IVC are occluded. It is not surprising that under the condition of high leg flow demand (^8 L/min, see previous sentences) these poor channels limit venous return, thereby limiting the rise in cardiac output. The findings in the venogram probably overestimate the actual patency of the lower body venous system. This is because the contrast injection itself caused further severe thrombophlebitis, and only thereafter did the persistent edema and effort intolerance worsen. An invasive study could have clarified the hemodynamic sequence of events during exercise and the extent to which the leg arterial blood flow also becomes compromised during leg exercise. This study should include measure¬ ment of cardiac output and leg blood flow, as well as mixed venous and leg vein 02 saturation during exercise. We 508
thought that such a study was not feasible in our patient, repeated resting impedance plethysmography sug¬ gested persistent venous obstruction. In summary, we describe a patient with severe effort intolerance following recurrent bilateral iliofemoral thrombophlebitis and pulmonary emboli. There was no evidence that cardiac, ventilatory, or residual pulmonary vascular disease accounted for the symptoms. Exercise capacity was higher for the upper extremities, indicating that a peripheral rather than a central circulatory7 abnor¬ mality caused the limitation. Contrast venography substan¬ tiated the presence of severe venous obstruction. These findings indicate that when venous flow limitation is severe and is not compensated by an adequate collateral flow, the venous disease can lead to exercise intolerance. This diagnosis can be supported by comparing the arm and leg exercise capacity. but
References
1 Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 1st ed. Philadelphia: Lea & Febiger, 1987 2 Jones NL. Clinical exercise testing. 3rd ed. Philadelphia: WB
Saunders, 1988 3 Sietsema K, Ben-Dov I, Sullivan 4
5
C,
et
al. Lactic acid-linked
changes in 02 uptake kinetics in heart failure. Chest 1994; 105:1693-1700 Bernstein EF. Caval interruption procedures. In: Rutherford RB, ed. Vascular surgery. 3rd ed. Philadelphia: WB Saunders, 1989; 1575-83 Fishman AP. Pulmonary7 diseases and disorders. New York: McGraw-Hill, 1988; 833
6 Schaffartzik
W, Barton ED, Poole DC, et al. Effect of reduced hemoglobin concentration on leg oxygen uptake during maximal exercise in humans. J Appl Physiol 1993; 75:491-98
Pulmonary Tuberculosis
Associated With Invasive Pseudallescheriasis* Jasna Tekavec, MD; Emilija Mlinaric-Missoni, MD; and Verica
Babic-Vazic, MS
54-year-old woman with pulmonary tuberculosis developed pneumonia caused by Scedosporium apiospermum, the asexual stage of the fungus Pseudallescheria boydii. Mycobacterium tuberculosis and P boydii were cultured in BAL fluid. The patient cleaned swimming pools in a spa health resort and was highly exposed to fungal conidia. She was suc¬ cessfully treated with antituberculosis drugs, miconazole nitrate and ketoconazole, leading to remission of her pulmonary infection. Invasive pulmonary A
*From Hospital for Lung Diseases and TB Klenovnik, Klenovnik, Croatia (Dr. Tekavec); the Department of Microbiology and Parasitology, Medical School, University of Zagreb, Zagreb, Croatia (Dr. Mlinaric-Missoni); and Croatian National Institute of Public Health, Zagreb, Croatia (Dr. Babic-Vazic). Manuscript received January 17, 1996; revision accepted July 5. Selected
Reports