- Email: [email protected]
Aspergilloma: An Unusual Cause of Late Failure of Aortocoronary Bypass Graft
WHITING ET AL
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in the lung, and sometimes even result in a slow but definite resolution. The level of chorionic gonadotropins permits a more precise control of the disease. In our patient, after an initial response to methotrexate, resistance developed after the fourth series. At this stage the lung shadow appeared slightly reduced. During the treatment with actinomycin-D, the chorionic gonadotropins tended to increase again. Lobectomy finally solved the situation, and follow-up controls remained normal one year following operation.
REFERENCES
FIGURE 3. Chest x-ray picture eight months after right upper lobectomy. orally in one ingestion for five consecutive days. Daily blood counts remained normal. Five series of methotrexate at interval of two to three and one-half weeks were given. Frequent clinical, radiologic and hormonal controls were performed. After an initial fall of urinary human chorionic gonadotropins (Fig 2) and a slight reduction of the lung shadow, an increase of gonadotropins indicated resistance to methotrexate. Chemotherapy with actinomycin-D was then started: 0.5 mg per day intravenously for five consecutive days. Three series at intervals of three and four weeks were given. We could not detect any influence upon the gonadotropins nor on the lung shadow. After consultation with the thoracic surgeon, a right upper lobectomy was performed on October, 1971. Histologic examination showed metastatic choriocarcinoma. In the follow-up, the clinical and radiologic studies (Fig 3) were normal, and no more chorionic activity could be detected one year after operation.
1 Li MC: Choriocarcinoma-Medical aspects. In Gynecological Oncology. Barber HRK, Graber EA (eds). Amsterdam, Excerpta Medica Foundation, 1970, p 291 2 Ross GT, Goldstein DP, Hertz R, et al: Sequential use of methotrexate and actinomycin-D in the treatment of metastatic choriocarcinoma and related trophoblastic disease in women. Am J Obstet Gynec 93:223-229, 1965 3 Gallmeier WM, Bertrams J, Kuwert E, et a1: Regression of choriocarcinoma. German Med Monthly 15:697-703, 1970 4 Ober WB: Gestational choriocarcinoma-Immunologic aspects, diagnosis and treatment. In Gynecological Oncology. Barber HKR, Graber EA, eds. Amsterdam, Excerpta Medica Foundation, 1970, p 304 5 Lewis Jr JL: Choriocarcinome: Surgery-Is there a place for it? In Gynecological Oncology. Barher HRK, Graber EA, eds, Amsterdam, Excerpta Medica Foundation, 1970, p300 6 Bagshawe KD: The treatment of trophoblastic tumours. In Gynecological Cancer. Deeley TJ, ed. London, Butterworths, 1971, p 228
Aspergilloma: An Unusual Cause of Late Failure of Aortocoronary Bypass Graft* Richard B. Whiting, M.D.;·· Hendrick B. Bamer, M.D.;t Phillip Leone, M.D.;:!: and Edwin E. Westura,M.D.,F.C.C.P.1I
DISCUSSION
Many problems are to be faced by a clinician when metastatic trophoblastic disease is present. He must consider the possibility of an occult primary in the uterus, the presence of solitary or multiple metastases, biologic activity, and finally the most adequate method of treatment, which today may include chemotherapy, surgery or both methods." At present radiotherapy is only used in brain metastasis in conjunction with chemotherapy." Experimental immunotherapy" is being tried and constitutes a challenge for the future.' TIle results, however, so far have been poor. I t is difficult to give a schematic program for the treatment of all cases with lung metastatic choriocarcinoma, because of the great individual variations in the clinical course and responsiveness to treatment. Chemotherapy is-in any case-the best initial treatment of choice. It may sterilize all occult foci, including an occult primary in the uterus, reduce the size of the tumor
A young woman abruptly developed the return of angiDa pectoris after a successful coronary bypass graft. Angiography and repeated surgery revealed a proximal occlusion of the vein graft, not related to poor distal run-oft. Pathologic examination of the removed vein graft revealed thrombotic occlusion associated with an intimal mycotic alJscess. here is currently great interest in various myocardial T revasoularization techniques. Aortocoronary bypass grafting is being widely used, and preliminary data suggest very gratifying results in relieving angina pectoris and increasing exercise tolerance. 1 - 2 A relatively ·From St. Louis University School of Medicine. Assistant Professor of Medicine. tAssociate Professor of Surgery. +Resident in Pathology. IIAssociate Professor of Medicine. Reprint requests: Dr. Whiting, 1325 South Grand, St. Louis 63104 • 0
CHEST, VOL. 63, NO.6, JUNE, 1973
ASPERGILLOMA
1031
low incidence of vein graft occlusion has been documented,".• but nonetheless, factors favoring such occlusion remain to be elucidated. The present case is described because it represents vein graft occlusion secondary to infection with Aspergillus. CASE REPORT
A 37-year-old housewife entered Saint Louis University Hospital for the first time on Aug. 19, 1970, for evaluation of recurrent substernal pain over the previous three years. There was no history of hypertension, lipid disorders, use of contraceptives or diabetes mellitus, although her father had adult onset diabetes. The patient smoked approximately one package of cigarettes per day for some 15 years. She was married, but had never been pregnant, in spite of regular menstrual cycles. Physical examination was that of a healthy woman: height 5'3," weight 112 pounds, blood pressure, 110/70 mm Hg, pulse rate, 60 per minute. The heart rhythm was regular, and there was no evidence of cardiomegaly or murmur. On admission, the complete blood count, urinalysis, blood urea nitrogen, fasting blood sugar (90 mg!100 ml), cholesterol (210 mg/loo ml) and chest radiograph were all within normal limits. Electrocardiogram revealed sinus bradycardia and an incomplete right bundle branch block pattern. A treadmill maximum exercise test result was positive with 2 mm depression of the ST segment. At cardiac catheterization, a normal left ventricular end diastolic pressure (0-5 mm Hg) was demonstrated, with no aortic valve gradient and a normal ventriculogram. Selective coronary arteriography revealed an BO percent stenosis of the main left coronary artery, with 5 mm poststenotic dilation. The rest of the coronary arterial tree was free of major vessel disease., On Sept. 23, 1970, grafting with a saphenous vein was undertaken to the left anterior descending (LAD) coronary artery, with good blood flow through the graft by electromagnetic flow meter. Beginning one day before surgery and continuing for eight days, the patient received prophylactic antibiotics in the form of lincomycin, 600 mg, intramuscularly (1M) every eight hours, and kanamycin, 500 mg 1M every 12 hours. There was no fever. Routine sputum culture grew alpha-hemolytic streptococci and a few colonies of Candida albicans. She was discharged and did remarkably well, without further angina
'.,
FIGURE 1. Cross section of wall from excised vein graft, showing intimal thickening by granulomatous inflammation. Internal elastic membrane can be seen immediately external to tissue reaction. (Elastic tissue stain, BOX.) encountered, indicating that the point of obstruction had occurred in the first few centimeters of the vein graft, and that distally it was patent to the left anterior descending coronary artery. A new aortotomy was used to form a second bypass graft using the saphenous vein from the other leg, and the original vein graft was removed. Gross pathologic examination of the removed vein graft revealed an irregular tubular fragment of a vessel, with a thickened wall. The lumen of the vessel was occluded, filled with a granular brown material. Microscopic sections showed marked thickening of the vessel wall and thrombotic occlusion of the lumen. A mycotic abscess was located in the thickened intima internal to the elastic lamina and surrounded by a granulomatous infiltrate of giant cells, lymphocytes, histiocytes and fibroblasts (Fig 1 and 2). With the Gomori methenamine silver stain, organisms were clearly identified with septated, branched hyphae consistent with the Aspergillus species. Multiple cultures taken at the time of surgery including acid-fast bacillus and fungal cultures failed to grow pathogens. Similarly, multiple cultures of the sputum did not grow Aspergillus. The patient did well, and angina did not recur. The graft was shown to be patent six months later by repeated angiography with filling of the LAD and circumflex coronary arteries.
pectoris.
In January, a repeated exercise test was without ST segment deviation, although the test was similar in duration and cardioacceleration to the original one. Angiography revealed the bypass graft to be patent, with excellent filling of the LAD and also retrograde filling of the circumflex coronary artery. On August 22, she was awakened by her first episode of nocturnal angina and over the next several days experienced bouts of anginal pain at rest. She, therefore, was readmitted to the hospital, and cardiac catheterization demonstrated total block of the aortocoronary bypass graft near its proximal end. On Sept. 14, 1971, the patient was returned to the operating room where the original vein graft was identiHed, and the first three centimeters of the graft were seen to be encased in dense scar tissue, surrounded by softer areas appearing caseous, but without definite purulence. When the vein graft was transected at the junction of the proximal and middle third, a 3 mm lumen with excellent back-bleeding was
CHEST, VOL. 63, NO.6, JUNE, 1973
FIGURE 2. Fungal elements revealing septated hyphae with dichotomous branching taken from center of granuloma. (Hematoxylin and eosin, 500 X.)
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WHITI NG ET AL
During her multiple admissions, no immunoelectrophoretic study was performed. However, several determinations of albumin/globulin ratios were all within normal limits (total protein ranged from 6.4 to 7.5 gm percent and albumin 3.5 to 4.2 gm percent) . DISCUSSION
Symptomatic coronary artery disease in young menstruating women, while unusual, has now been described often enough to no longer be considered rare, even in the absence of diabetes mellitus, vasculitis or lipid disorders.>" The abrupt return of angina after successful revascularization suggests vein graft occlusion. The factors which favor such a loss of patency of grafted saphenous veins are not fully elucidated, but technical problems, such as turbulence at the anastomotic site or vessel kinking, intimal fibrous proliferation and poor How through the graft secondary to poor distal run-off, have all been implicated.v -" In oases where the graft occlusion occurs due to poor distal run-off and very low How , . there would seem to be little value in reconstructing the graft. Indeed, if a reliable means of assessing distal arterial How preoperatively could be devised, such pa tients probably should not be treated with vein grafting at all . The patient herein described was known to have very good How after the initial grafting procedure, and subsequent graft occlusion was proximal. Therefore, she was operated on again, and a new graft placed. The pathologic demonstration of fungal structures with septate hyphae and surrounding tissue reaction suggested an unusual cause of vein graft occlusion. Although the mycotic abscess per se did not occlude the vessel, it probably played an important role in the pathogenesis of the thrombotic occlusion of the vessel lumen. The abscess and surrounding inflammatory response were located in the intima just beneath the attachment of the thrombus to the vessel wall. It is therefore quite possible that this inflammatory focus altered the integrity of the intimal surface, creating favorable conditions for the formation of mural thrombus. Aspergillus species are ubiquitous fungi and are occasional contaminants in culture material. They are unusual and opportunistic causes of human disease and more likely found in patients with deficient immune responses due to disease or drug therapy or possibly associated with heavy broad spectrum antibiotic treatment.t' This patient had normal serum globulin levels and did not receive steroid medications, although she did receive a course of antibiotics prophylactically. She had no other site of Aspergillus infection, nor have we seen other instances of aspergillosis, postoperatively. Cardiac Aspergillus infection, including endocarditis and myocardial abscesses, have been described.P?" Aspergillus endocarditis has been described following cardiac surgery'8-'9 and recently as a complication of cardiac transplantation. 2 0 - 2 1 In a recent review of 98 cases of aspergillosis, Young et al 2 2 described seven patients with heart or pericardial involvement, all of
whom had pulmonary aspergillosis with dissemination. Three of these patients had extensive myocarditis, with myocardial abscesses containing Aspergillus. Vascular involvement was a prominent feature and coronary vessels were occluded by fungal masses producing thrombosis and infarction. Thus, Aspergillus has the ability to invade blood vessels and produce occlusion supporting the concept that the patient presented here represents the first instance of saphenous vein bypass graft occlusion by this organism. Therapy of aspergillosis has largely been unrewarding; however, in the absence of another focus of infection or debilitating disease, removal of the aspergilloma is probably curative. REFERENCES
1 Favaloro RG: Surgical treatment of coronary arteriosclerosis by the saph enous vein graft technique. Am J Cardio128 :493-495, 1971 2 Sabiston DC: Editorial : Direct revascularization procedure in the management of myocardial ischemia. Circulation 43:175-177,1971 3 Morris GC, Reul GJ, Howell JF , et al: Follow-up results of distal coronary artery bypass for ischemic heart disease. Am J CardioI29:180-185, 1972 4 Kaiser GC, Barner HB, Willman VL, et al: Aortocoronary bypass grafting. Arch Surg 105:319-323, 1972 5 Waxler EB, Kimbiris D, Van Den Broeck H, et al : Myocardial infarction and oral contraceptive agents. Am J Cardiol 28:96-101, 1971 6 Underdahl L, Smith H: Coronary artery disease in women und er the age of forty. Proc Staff Meet Mayo Clin 22:479-482, 1947 7 Manchest er JH, Herman MV, Gorlin R: Premenopausal castration and docum ented coronary atheroscl erosis. Am J Cardiol 28:33-37, 1971 8 Glancy DL, Marcus ML, Epstein SE: Myocardial infarc tion in young women with normal coronary arteriograms. Circulation 44:495-502, 1971 9 Johnson W, Auer J, Tector A: Late changes in coronary vein grafts (abstract) . Am J Cardiel 26:640, 1970 10 Favaloro RG, Effier DB, Groves LK, et al : Severe segmental obstruction of the left main coronary artery and its division. Surgical treatment by the saphenous vein graft .technique. J Thorac Cardiovasc Surg 60:469-477,1970 11 Grondin CM, Meere C, Castonguay Y, et al : Progressive and late obstruction of an aorto-coronary venous bypass graft. Circulation 43:698-702, 1971 12 Vlodaver Z, Edwards JE : Pathologic changes in aorticcoronary arterial saphenous vein grafts . Circulation 44:719-728,1971 13 Marti MC, Bouchardy B, Cox IN: Aorto-coronary bypass with autog enous saphenous vein grafts: histopathological aspects. Virchows Arch [Pathol Anat] 352 :255-266, 1971 14 Finegold SM, Will D, Murray JF : Aspergillosis a review and report of twelve cases. Am J Med 27 :463-482, 1959 15 Fraumeni JF, Fear RE : Purulent pericarditis in aspergillosis. Ann Intern Med 57:823-828,1962 16 Caplan H, Frisch E, Houghton J, et al : Aspergillus fumigatus endocarditis. Ann Intern Med 68:378-385, 1968 17 Cawley EP: Aspergillosis and the aspergilli. Report of a unique case of the disease . Arch Intern Med 80:423-434, 1947
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HEPARIN ABSORPTION DURING LUNG LAVAGE 18 Newman W, Cordell A: Aspergillus Endocarditis after open heart surgery. J Thorac Cardiovasc Surg 48:652675, 1964 19 Gage AA, Dean DC, Schimert G, et al: Aspergillus infection after cardiac surgery. Arch Surg 101:384-387,
uno
20 Saunders AM, Bieber C: Pathologic findings in a case of cardiac transplantation. JAMA 206:815-820, 1968 21 Stinson EB, Bieber CP, Griepp RB, et al: Infectious complications after cardiac transplantation in man. Ann Intern Med 74:22-36,1971 22 Young RC, Bennett JE, Vogel CL, et al: Aspergillosis. The spectrum of the disease in 98 patients. Medicine 49:147-173,1970
Heparin Absorption during HeparinSaline Lung Lavage in a Patient with Pulmonary Alveolar Proteinosis* Walter A. Sunderland, M.D.,OO and Roger L. Klein, M.D.t
Lung lavage with beparin-saline solution in the treatment of a patient with pulmonary alveolar proteinosis was no better than lavage with saline alone. Sufticient heparin was absorbed from the lung so that the patient's clotting time was prolonged and be sustained a retroperitoneal bleed. We believe clinicians should be alert to the p0ssibility of heparin absorption from the lung, especially .\Vben large doses are used during lung lavage. Heparin has been added to the fluid used for long lavage of patients with pulmonary alveolar proteinosis (PAP) since 1963;1 however, in amounts used, there has been increasing doubt about the value of the heparin for the treatment of PAP.2-5 Clinicians who use heparin by aerosol or lavage have not reported absorption of the drug from the lung nor problems due to bleeding that one might ascribe to heparin effect. We wish to report our experience with the use of a high concentration of heparin while a pa·tient with PAP was being Iavaged. CASE REpORT
The patient, 17 years of age, developed PAP at 14 years of age and had two massive bilateral lung lavages during the next 2" years.f The later lavage was done in October 1970 with good results and he continued well until March 1971 when he noted increasing exertional dyspnea, cough and sputum production, headaches and early fatigue. His hematocrit rose from 53 percent to 61 percent and lung vital capacity fell from 2400 to 2000 milliliters. On April 12, 1971 lavage of the left lung was performed with the use of 12 liters of sterile 0.9 percent saline solution °From the University of Oregon Medical School, Portland. ° °Assistant Professor of Pediatrics. t Assistant Professor of Anesthesiology. Reprint requests: Dr. Sunderland, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201
CHEST, VOL. 63, NO.6, JUNE, 1973
(N/S) in one liter cycles. To each liter of solution were added 200,000 units of sodium heparin. ° Lee-White blood clotting time before the procedure was nine minutes, during the lavage it was prolonged to 35 minutes, and at the end of the washing it was one hour with poor clot formation. Therefore he was treated with 200 mg of protamine sulfate by intravenous drip over two hours. Clotting time returned to normal and a slightly bloody discharge from his nares stopped. He had ecchymoses about the venipuncture sites on his arms but none from a femoral artery puncture area. The next morning he had bowel cramps, moderate lower abdominal rebound tenderness with associated decreased bowel sounds. We felt that he had endured abdominal bleeding; his hematocrit had dropped to 49 percent and his stools were guaiac positive without visible blood. Symptoms were alleviated with simple analgesics whereafter the patient became ambulatory, developed a good appetite and felt better during the day. Flat plate radiographs of the abdomen were interpreted as normal and of the chest showed the left lung more radiolucent than before the lavage. His hematocrit stabilized at 44.8 percent. Two days later he developed fever, increased cough and sputum production, shortness of breath and lower abdominal pains. He felt most comfortable with his legs flexed onto his abdomen. An intravenous pyelogram demonstrated prompt renal function, but there was elevation and retrodisplacement of the bladder, presumably due to a blood clot about the inferior border. An ecchymosis appeared on the lower left abdominal wall. Although the left inguinal area remained nontender and normal in appearance, we believed the patient had bled from the posterior wall of the femoral artery. His white blood count was normal. However, penicillin and ampicillin antibiotics were selected for therapy because sputum cultures before and after lavage had yielded Hemophilus influenza and once previously had yielded Actinomyces. His symptoms abated except for mild suprapubic tenderness elicited with walking or during micturition; no complications developed and he was sent home. Three weeks later his right lung was lavaged with 8 liters of plain N/S with the majority of the sediment being removed in the first 4 liters of lavage fluid. Even though there were no problems, he was treated prophylactically with penicillin and sulfonamide after the procedure. Since then his vital capacity has risen to 2600 ml and chest radiographs show further clearing. DISCUSSION
Heparin has been used or evaluated for use in such lung diseases as asthma, cystic fibrosis and PAP.l.7.B Previous concentrations have varied from 5 to 250 units per millimeter of N/S. For a short time prior to the first massive lavage of this patient in 1968, he was treated with a solution of 250 units of heparin per millimeter sterile N/S via transtracheal catheter drip and the PAP effluent was noted to be much more emulsified than with N/S alone. Since the higher concentration of heparin acted as a better solvent that saline alone and since none of the previous lavages in this patient appeared to remove all the PAP sediment, we believed more material might be removed with a high concentration of heparin during a massive lavage. Ramirez and colleagues I also °Frequently in the past, potency was expressed in milligrams and units with 1 mg varying from 100 to 120 units. Current potency is standardized in units.
1030
in the lung, and sometimes even result in a slow but definite resolution. The level of chorionic gonadotropins permits a more precise control of the disease. In our patient, after an initial response to methotrexate, resistance developed after the fourth series. At this stage the lung shadow appeared slightly reduced. During the treatment with actinomycin-D, the chorionic gonadotropins tended to increase again. Lobectomy finally solved the situation, and follow-up controls remained normal one year following operation.
REFERENCES
FIGURE 3. Chest x-ray picture eight months after right upper lobectomy. orally in one ingestion for five consecutive days. Daily blood counts remained normal. Five series of methotrexate at interval of two to three and one-half weeks were given. Frequent clinical, radiologic and hormonal controls were performed. After an initial fall of urinary human chorionic gonadotropins (Fig 2) and a slight reduction of the lung shadow, an increase of gonadotropins indicated resistance to methotrexate. Chemotherapy with actinomycin-D was then started: 0.5 mg per day intravenously for five consecutive days. Three series at intervals of three and four weeks were given. We could not detect any influence upon the gonadotropins nor on the lung shadow. After consultation with the thoracic surgeon, a right upper lobectomy was performed on October, 1971. Histologic examination showed metastatic choriocarcinoma. In the follow-up, the clinical and radiologic studies (Fig 3) were normal, and no more chorionic activity could be detected one year after operation.
1 Li MC: Choriocarcinoma-Medical aspects. In Gynecological Oncology. Barber HRK, Graber EA (eds). Amsterdam, Excerpta Medica Foundation, 1970, p 291 2 Ross GT, Goldstein DP, Hertz R, et al: Sequential use of methotrexate and actinomycin-D in the treatment of metastatic choriocarcinoma and related trophoblastic disease in women. Am J Obstet Gynec 93:223-229, 1965 3 Gallmeier WM, Bertrams J, Kuwert E, et a1: Regression of choriocarcinoma. German Med Monthly 15:697-703, 1970 4 Ober WB: Gestational choriocarcinoma-Immunologic aspects, diagnosis and treatment. In Gynecological Oncology. Barber HKR, Graber EA, eds. Amsterdam, Excerpta Medica Foundation, 1970, p 304 5 Lewis Jr JL: Choriocarcinome: Surgery-Is there a place for it? In Gynecological Oncology. Barher HRK, Graber EA, eds, Amsterdam, Excerpta Medica Foundation, 1970, p300 6 Bagshawe KD: The treatment of trophoblastic tumours. In Gynecological Cancer. Deeley TJ, ed. London, Butterworths, 1971, p 228
Aspergilloma: An Unusual Cause of Late Failure of Aortocoronary Bypass Graft* Richard B. Whiting, M.D.;·· Hendrick B. Bamer, M.D.;t Phillip Leone, M.D.;:!: and Edwin E. Westura,M.D.,F.C.C.P.1I
DISCUSSION
Many problems are to be faced by a clinician when metastatic trophoblastic disease is present. He must consider the possibility of an occult primary in the uterus, the presence of solitary or multiple metastases, biologic activity, and finally the most adequate method of treatment, which today may include chemotherapy, surgery or both methods." At present radiotherapy is only used in brain metastasis in conjunction with chemotherapy." Experimental immunotherapy" is being tried and constitutes a challenge for the future.' TIle results, however, so far have been poor. I t is difficult to give a schematic program for the treatment of all cases with lung metastatic choriocarcinoma, because of the great individual variations in the clinical course and responsiveness to treatment. Chemotherapy is-in any case-the best initial treatment of choice. It may sterilize all occult foci, including an occult primary in the uterus, reduce the size of the tumor
A young woman abruptly developed the return of angiDa pectoris after a successful coronary bypass graft. Angiography and repeated surgery revealed a proximal occlusion of the vein graft, not related to poor distal run-oft. Pathologic examination of the removed vein graft revealed thrombotic occlusion associated with an intimal mycotic alJscess. here is currently great interest in various myocardial T revasoularization techniques. Aortocoronary bypass grafting is being widely used, and preliminary data suggest very gratifying results in relieving angina pectoris and increasing exercise tolerance. 1 - 2 A relatively ·From St. Louis University School of Medicine. Assistant Professor of Medicine. tAssociate Professor of Surgery. +Resident in Pathology. IIAssociate Professor of Medicine. Reprint requests: Dr. Whiting, 1325 South Grand, St. Louis 63104 • 0
CHEST, VOL. 63, NO.6, JUNE, 1973
ASPERGILLOMA
1031
low incidence of vein graft occlusion has been documented,".• but nonetheless, factors favoring such occlusion remain to be elucidated. The present case is described because it represents vein graft occlusion secondary to infection with Aspergillus. CASE REPORT
A 37-year-old housewife entered Saint Louis University Hospital for the first time on Aug. 19, 1970, for evaluation of recurrent substernal pain over the previous three years. There was no history of hypertension, lipid disorders, use of contraceptives or diabetes mellitus, although her father had adult onset diabetes. The patient smoked approximately one package of cigarettes per day for some 15 years. She was married, but had never been pregnant, in spite of regular menstrual cycles. Physical examination was that of a healthy woman: height 5'3," weight 112 pounds, blood pressure, 110/70 mm Hg, pulse rate, 60 per minute. The heart rhythm was regular, and there was no evidence of cardiomegaly or murmur. On admission, the complete blood count, urinalysis, blood urea nitrogen, fasting blood sugar (90 mg!100 ml), cholesterol (210 mg/loo ml) and chest radiograph were all within normal limits. Electrocardiogram revealed sinus bradycardia and an incomplete right bundle branch block pattern. A treadmill maximum exercise test result was positive with 2 mm depression of the ST segment. At cardiac catheterization, a normal left ventricular end diastolic pressure (0-5 mm Hg) was demonstrated, with no aortic valve gradient and a normal ventriculogram. Selective coronary arteriography revealed an BO percent stenosis of the main left coronary artery, with 5 mm poststenotic dilation. The rest of the coronary arterial tree was free of major vessel disease., On Sept. 23, 1970, grafting with a saphenous vein was undertaken to the left anterior descending (LAD) coronary artery, with good blood flow through the graft by electromagnetic flow meter. Beginning one day before surgery and continuing for eight days, the patient received prophylactic antibiotics in the form of lincomycin, 600 mg, intramuscularly (1M) every eight hours, and kanamycin, 500 mg 1M every 12 hours. There was no fever. Routine sputum culture grew alpha-hemolytic streptococci and a few colonies of Candida albicans. She was discharged and did remarkably well, without further angina
'.,
FIGURE 1. Cross section of wall from excised vein graft, showing intimal thickening by granulomatous inflammation. Internal elastic membrane can be seen immediately external to tissue reaction. (Elastic tissue stain, BOX.) encountered, indicating that the point of obstruction had occurred in the first few centimeters of the vein graft, and that distally it was patent to the left anterior descending coronary artery. A new aortotomy was used to form a second bypass graft using the saphenous vein from the other leg, and the original vein graft was removed. Gross pathologic examination of the removed vein graft revealed an irregular tubular fragment of a vessel, with a thickened wall. The lumen of the vessel was occluded, filled with a granular brown material. Microscopic sections showed marked thickening of the vessel wall and thrombotic occlusion of the lumen. A mycotic abscess was located in the thickened intima internal to the elastic lamina and surrounded by a granulomatous infiltrate of giant cells, lymphocytes, histiocytes and fibroblasts (Fig 1 and 2). With the Gomori methenamine silver stain, organisms were clearly identified with septated, branched hyphae consistent with the Aspergillus species. Multiple cultures taken at the time of surgery including acid-fast bacillus and fungal cultures failed to grow pathogens. Similarly, multiple cultures of the sputum did not grow Aspergillus. The patient did well, and angina did not recur. The graft was shown to be patent six months later by repeated angiography with filling of the LAD and circumflex coronary arteries.
pectoris.
In January, a repeated exercise test was without ST segment deviation, although the test was similar in duration and cardioacceleration to the original one. Angiography revealed the bypass graft to be patent, with excellent filling of the LAD and also retrograde filling of the circumflex coronary artery. On August 22, she was awakened by her first episode of nocturnal angina and over the next several days experienced bouts of anginal pain at rest. She, therefore, was readmitted to the hospital, and cardiac catheterization demonstrated total block of the aortocoronary bypass graft near its proximal end. On Sept. 14, 1971, the patient was returned to the operating room where the original vein graft was identiHed, and the first three centimeters of the graft were seen to be encased in dense scar tissue, surrounded by softer areas appearing caseous, but without definite purulence. When the vein graft was transected at the junction of the proximal and middle third, a 3 mm lumen with excellent back-bleeding was
CHEST, VOL. 63, NO.6, JUNE, 1973
FIGURE 2. Fungal elements revealing septated hyphae with dichotomous branching taken from center of granuloma. (Hematoxylin and eosin, 500 X.)
1032
WHITI NG ET AL
During her multiple admissions, no immunoelectrophoretic study was performed. However, several determinations of albumin/globulin ratios were all within normal limits (total protein ranged from 6.4 to 7.5 gm percent and albumin 3.5 to 4.2 gm percent) . DISCUSSION
Symptomatic coronary artery disease in young menstruating women, while unusual, has now been described often enough to no longer be considered rare, even in the absence of diabetes mellitus, vasculitis or lipid disorders.>" The abrupt return of angina after successful revascularization suggests vein graft occlusion. The factors which favor such a loss of patency of grafted saphenous veins are not fully elucidated, but technical problems, such as turbulence at the anastomotic site or vessel kinking, intimal fibrous proliferation and poor How through the graft secondary to poor distal run-off, have all been implicated.v -" In oases where the graft occlusion occurs due to poor distal run-off and very low How , . there would seem to be little value in reconstructing the graft. Indeed, if a reliable means of assessing distal arterial How preoperatively could be devised, such pa tients probably should not be treated with vein grafting at all . The patient herein described was known to have very good How after the initial grafting procedure, and subsequent graft occlusion was proximal. Therefore, she was operated on again, and a new graft placed. The pathologic demonstration of fungal structures with septate hyphae and surrounding tissue reaction suggested an unusual cause of vein graft occlusion. Although the mycotic abscess per se did not occlude the vessel, it probably played an important role in the pathogenesis of the thrombotic occlusion of the vessel lumen. The abscess and surrounding inflammatory response were located in the intima just beneath the attachment of the thrombus to the vessel wall. It is therefore quite possible that this inflammatory focus altered the integrity of the intimal surface, creating favorable conditions for the formation of mural thrombus. Aspergillus species are ubiquitous fungi and are occasional contaminants in culture material. They are unusual and opportunistic causes of human disease and more likely found in patients with deficient immune responses due to disease or drug therapy or possibly associated with heavy broad spectrum antibiotic treatment.t' This patient had normal serum globulin levels and did not receive steroid medications, although she did receive a course of antibiotics prophylactically. She had no other site of Aspergillus infection, nor have we seen other instances of aspergillosis, postoperatively. Cardiac Aspergillus infection, including endocarditis and myocardial abscesses, have been described.P?" Aspergillus endocarditis has been described following cardiac surgery'8-'9 and recently as a complication of cardiac transplantation. 2 0 - 2 1 In a recent review of 98 cases of aspergillosis, Young et al 2 2 described seven patients with heart or pericardial involvement, all of
whom had pulmonary aspergillosis with dissemination. Three of these patients had extensive myocarditis, with myocardial abscesses containing Aspergillus. Vascular involvement was a prominent feature and coronary vessels were occluded by fungal masses producing thrombosis and infarction. Thus, Aspergillus has the ability to invade blood vessels and produce occlusion supporting the concept that the patient presented here represents the first instance of saphenous vein bypass graft occlusion by this organism. Therapy of aspergillosis has largely been unrewarding; however, in the absence of another focus of infection or debilitating disease, removal of the aspergilloma is probably curative. REFERENCES
1 Favaloro RG: Surgical treatment of coronary arteriosclerosis by the saph enous vein graft technique. Am J Cardio128 :493-495, 1971 2 Sabiston DC: Editorial : Direct revascularization procedure in the management of myocardial ischemia. Circulation 43:175-177,1971 3 Morris GC, Reul GJ, Howell JF , et al: Follow-up results of distal coronary artery bypass for ischemic heart disease. Am J CardioI29:180-185, 1972 4 Kaiser GC, Barner HB, Willman VL, et al: Aortocoronary bypass grafting. Arch Surg 105:319-323, 1972 5 Waxler EB, Kimbiris D, Van Den Broeck H, et al : Myocardial infarction and oral contraceptive agents. Am J Cardiol 28:96-101, 1971 6 Underdahl L, Smith H: Coronary artery disease in women und er the age of forty. Proc Staff Meet Mayo Clin 22:479-482, 1947 7 Manchest er JH, Herman MV, Gorlin R: Premenopausal castration and docum ented coronary atheroscl erosis. Am J Cardiol 28:33-37, 1971 8 Glancy DL, Marcus ML, Epstein SE: Myocardial infarc tion in young women with normal coronary arteriograms. Circulation 44:495-502, 1971 9 Johnson W, Auer J, Tector A: Late changes in coronary vein grafts (abstract) . Am J Cardiel 26:640, 1970 10 Favaloro RG, Effier DB, Groves LK, et al : Severe segmental obstruction of the left main coronary artery and its division. Surgical treatment by the saphenous vein graft .technique. J Thorac Cardiovasc Surg 60:469-477,1970 11 Grondin CM, Meere C, Castonguay Y, et al : Progressive and late obstruction of an aorto-coronary venous bypass graft. Circulation 43:698-702, 1971 12 Vlodaver Z, Edwards JE : Pathologic changes in aorticcoronary arterial saphenous vein grafts . Circulation 44:719-728,1971 13 Marti MC, Bouchardy B, Cox IN: Aorto-coronary bypass with autog enous saphenous vein grafts: histopathological aspects. Virchows Arch [Pathol Anat] 352 :255-266, 1971 14 Finegold SM, Will D, Murray JF : Aspergillosis a review and report of twelve cases. Am J Med 27 :463-482, 1959 15 Fraumeni JF, Fear RE : Purulent pericarditis in aspergillosis. Ann Intern Med 57:823-828,1962 16 Caplan H, Frisch E, Houghton J, et al : Aspergillus fumigatus endocarditis. Ann Intern Med 68:378-385, 1968 17 Cawley EP: Aspergillosis and the aspergilli. Report of a unique case of the disease . Arch Intern Med 80:423-434, 1947
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HEPARIN ABSORPTION DURING LUNG LAVAGE 18 Newman W, Cordell A: Aspergillus Endocarditis after open heart surgery. J Thorac Cardiovasc Surg 48:652675, 1964 19 Gage AA, Dean DC, Schimert G, et al: Aspergillus infection after cardiac surgery. Arch Surg 101:384-387,
uno
20 Saunders AM, Bieber C: Pathologic findings in a case of cardiac transplantation. JAMA 206:815-820, 1968 21 Stinson EB, Bieber CP, Griepp RB, et al: Infectious complications after cardiac transplantation in man. Ann Intern Med 74:22-36,1971 22 Young RC, Bennett JE, Vogel CL, et al: Aspergillosis. The spectrum of the disease in 98 patients. Medicine 49:147-173,1970
Heparin Absorption during HeparinSaline Lung Lavage in a Patient with Pulmonary Alveolar Proteinosis* Walter A. Sunderland, M.D.,OO and Roger L. Klein, M.D.t
Lung lavage with beparin-saline solution in the treatment of a patient with pulmonary alveolar proteinosis was no better than lavage with saline alone. Sufticient heparin was absorbed from the lung so that the patient's clotting time was prolonged and be sustained a retroperitoneal bleed. We believe clinicians should be alert to the p0ssibility of heparin absorption from the lung, especially .\Vben large doses are used during lung lavage. Heparin has been added to the fluid used for long lavage of patients with pulmonary alveolar proteinosis (PAP) since 1963;1 however, in amounts used, there has been increasing doubt about the value of the heparin for the treatment of PAP.2-5 Clinicians who use heparin by aerosol or lavage have not reported absorption of the drug from the lung nor problems due to bleeding that one might ascribe to heparin effect. We wish to report our experience with the use of a high concentration of heparin while a pa·tient with PAP was being Iavaged. CASE REpORT
The patient, 17 years of age, developed PAP at 14 years of age and had two massive bilateral lung lavages during the next 2" years.f The later lavage was done in October 1970 with good results and he continued well until March 1971 when he noted increasing exertional dyspnea, cough and sputum production, headaches and early fatigue. His hematocrit rose from 53 percent to 61 percent and lung vital capacity fell from 2400 to 2000 milliliters. On April 12, 1971 lavage of the left lung was performed with the use of 12 liters of sterile 0.9 percent saline solution °From the University of Oregon Medical School, Portland. ° °Assistant Professor of Pediatrics. t Assistant Professor of Anesthesiology. Reprint requests: Dr. Sunderland, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201
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(N/S) in one liter cycles. To each liter of solution were added 200,000 units of sodium heparin. ° Lee-White blood clotting time before the procedure was nine minutes, during the lavage it was prolonged to 35 minutes, and at the end of the washing it was one hour with poor clot formation. Therefore he was treated with 200 mg of protamine sulfate by intravenous drip over two hours. Clotting time returned to normal and a slightly bloody discharge from his nares stopped. He had ecchymoses about the venipuncture sites on his arms but none from a femoral artery puncture area. The next morning he had bowel cramps, moderate lower abdominal rebound tenderness with associated decreased bowel sounds. We felt that he had endured abdominal bleeding; his hematocrit had dropped to 49 percent and his stools were guaiac positive without visible blood. Symptoms were alleviated with simple analgesics whereafter the patient became ambulatory, developed a good appetite and felt better during the day. Flat plate radiographs of the abdomen were interpreted as normal and of the chest showed the left lung more radiolucent than before the lavage. His hematocrit stabilized at 44.8 percent. Two days later he developed fever, increased cough and sputum production, shortness of breath and lower abdominal pains. He felt most comfortable with his legs flexed onto his abdomen. An intravenous pyelogram demonstrated prompt renal function, but there was elevation and retrodisplacement of the bladder, presumably due to a blood clot about the inferior border. An ecchymosis appeared on the lower left abdominal wall. Although the left inguinal area remained nontender and normal in appearance, we believed the patient had bled from the posterior wall of the femoral artery. His white blood count was normal. However, penicillin and ampicillin antibiotics were selected for therapy because sputum cultures before and after lavage had yielded Hemophilus influenza and once previously had yielded Actinomyces. His symptoms abated except for mild suprapubic tenderness elicited with walking or during micturition; no complications developed and he was sent home. Three weeks later his right lung was lavaged with 8 liters of plain N/S with the majority of the sediment being removed in the first 4 liters of lavage fluid. Even though there were no problems, he was treated prophylactically with penicillin and sulfonamide after the procedure. Since then his vital capacity has risen to 2600 ml and chest radiographs show further clearing. DISCUSSION
Heparin has been used or evaluated for use in such lung diseases as asthma, cystic fibrosis and PAP.l.7.B Previous concentrations have varied from 5 to 250 units per millimeter of N/S. For a short time prior to the first massive lavage of this patient in 1968, he was treated with a solution of 250 units of heparin per millimeter sterile N/S via transtracheal catheter drip and the PAP effluent was noted to be much more emulsified than with N/S alone. Since the higher concentration of heparin acted as a better solvent that saline alone and since none of the previous lavages in this patient appeared to remove all the PAP sediment, we believed more material might be removed with a high concentration of heparin during a massive lavage. Ramirez and colleagues I also °Frequently in the past, potency was expressed in milligrams and units with 1 mg varying from 100 to 120 units. Current potency is standardized in units.