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Myocardial infarction after propranolol withdrawal
Annotations
A new bedside radioisotope test for the detection of deep-vein thrombosis
Pulmonary embolism is a tragic and not infrequently fatal occurrence in hospitalixed patients. Approximately 2,700 persons die from pulmonary embolism in Great Britain and Ireland yearly. An association between pulmonary embolism and deep-vein thrombosis @VT) has been clearly documented’ If the incidence of pulmonary embolism is to be reduced it will be necessary either to prevent DVT or to detect it at a time when effective therapy may be introduced which will prevent pulmonary embolism. A number of prophylactic methods are in use for the prevention of DVT: “low-dose” heparin2 dextran,3 hydroxychloroquine sulfate,4 mechanical aida Each of these methods has been shown to reduce the incidence of DVT and, hopefully, future larger studies will show that one or a number of these methods is effective in reducing the incidence of pulmonary embolism. Alternatively, early diagnosis and treatment of DVT would lead to a reduction in the incidence of pulmonary embolism. Unfortunately the clinical diagnosis of DVT is notoriously unreliable. On the one hand it hae been shown that in a group of patients with clinical signs of DVT 28 per cent were normal by the sensitive lzsI fibrinogen test.6 On the other hand it has been reported that in 60 per cent of cases of pulmonary embolism clinical evidence of DVT is lacking.’ Consequently if DVT is to be diagnosed prior to pulmonary embolism it will be necessary to screen large numbers of clinically “normal” hospitalized patients at frequent intervals, possibly daily. A number of techniques are presently being tried as a screening test for DVT: the “‘1 fibrinogen test,’ thermography,’ electrical impedance,” ultrasound flow detection.” None of these tests to date is ideal as a mass screening test either because of inaccuracy in diagnosis or because of the complexity of the procedure or because the procedure carries a slight risk for the patient. Therefore, until a safe and effective prophylactic method for the prevention of pulmonary embolism is available, or until a simple, safe, and accurate mass screening test for the detection of DVT is developed, this common diagnostic and management question will continue to be asked in our hospitals: “Does this patient have DVT and should anticoagulant or antithrombolitic therapy be started?” To date, x-ray phlebography is the only method that will rapidly and accurately answer this question. A new bedside radioisotope test, the 1311MAA clearance test, that my colleagues and 112 recently reported as a preliminary communication in the British Medical Journal would appear to have application in this area. This radioisotope test uses a commercially available radiopharmaceutical, ‘311-labeled macroaggregates of albumin (1311 MAA), and equipment that is portable and inexpensive. The results are available in 20 minutes. Labeled MAA has been in use as a lung-scanning agent for more than ten years. In 1969 Webber and associates’s re-
255
ported that labeled MAA had an affinity for blood clots both in vivo and in vitro. A number of reports have appeared using this radiopharmaceutical in localizing venous thrombosis.i4~ ‘s In these reports gamma cameras or rectilinear scanners have been used Such equipment is expensive and presently is available only in the larger hospitals. The procedure requires the patient to be transported to the nuclear medicine department. It resembles in complexity x-ray phlebography and so has no clear advantage. It appeared to us that less sophisticated equipment might be adequate to detect Is11 MAA labeled thrombi, since detection of the radioactive clot, without accurately localizing the site and distribution of the radioisotope, would be adequate to make a diagnosis. We have tried an inexpensive portable scintillation detector and rate meter that is in use in our department for the 126I fibrinogen test (Pitman isotope localizing monitor). Acute femoral vein thrombosis was produced in 10 dogs by electrocautery. Approximately 20 to 30 PCi of “‘1 MAA was injected intravenously distal to the clot. There was a 40 to 80 fold increase in count rate over the clot area when compared with sham control experiments, and this difference in count rate persisted for at least 20 minutes. Fifty-four patients with clinical signs suggestive of DVT have so far been investigated. Approximately 100 @Zi of 13iI MAA was injected into the deep venous system using tourniquets. Count rates were obtained at five-minute intervals for 20 minutes at seven points along the injected leg and at corresponding points on the opposite leg (control). The clearance of 1311MAA from the injected leg fell into two easily discernible patterns, a rapid clearance pattern and a delayed clearance pattern. X-ray phlebograms were performed in all 54 patients. Thrombi were identified in the leg veins in 34 patients and in 30 of these patients there was a delayed clearance of 13iI MAA from the leg (88 per cent). There were 20 patients in whom x-ray phlebography failed to demon &rate thrombi and 17 of these the 13i I MAA cleared rapidly from the limb (86 per cent). Over all there was an 87 per cent agreement between positive phlebograms and delayed clearance and negative phlebograms and rapid clearance. These results suggest that this rapid, simple bedside radioisotope test may be adequate to answer this commonly encountered diagnostic problem: “Has this patient deep-vein thrombosis?” George J LIufi, M.D., BSc., M.R.C.P.I. Medical Director, kotope Department St. Vincent h Hospital Dublin, Ireland REFERENCES
1. Sevitt S., and Gallagher, N.: Venous thrombosis pulmonary embolism, Br. J. Surg. 48~4731961.
August,
and
1974, Vol. SS, No. 2
Annotations 2. Kakkar, V. V., Spindler, J., Flute, P. T., Corrigan, T., Fossard, D. P., Crillin, R. Q., Wessler, S., and Yin, E. T.: Efficacy of low doses of heparin in prevention of deepvein thrombosis after major surgery, Lancet 2:101, 1972. 3. Lambie, J. M., Barber, D. C., Dhall, D. P., and Matheson N. N.: Dextran 70 in prophylaxis of post-operative venous thrombosis. Br. Med. J. 2:145. 1970. 4. Carter, A. E., Eban, R., and Pennett,‘R. D.: Prevention of post-operative deep venous thrombosis and pulmonary embolism, Br. Med. J. 1:312, 1971. 5. Sabri, S., Roberta, V. C., and Cotton, L. T.: Prevention of early post-operative deep-vein thrombosis by intermittent compression of the leg at surgery, Br. Med. J. 4:394,1971. 6. Lambie, J. M., Mahaffy, R. G., Barber, D. C., Karmody, A. M., Scott, M. M., and Matheson, M. A.: Diagnostic accuracy of venous thrombosis, Br. Med. J. 2:142, 1970. 7. Welch, C. F., and Faxon, H. H.: Thrombophlebitis and uulmonarv embolism. J. A. M. A. 117~1502. 1941. 8. kgus, D.: Pinto, D. J., Le Quesne, L. P., Browne, M., and Chapman, M.: ‘251-labelled fibrinogen in the diagnosis of deep-vein thrombosis and its correlation with phlebography, Br. J. Surg. 55835, 1968.
Myoccardial withdrawal
infarction
after ptoprano~ol
A number of observers have recently reported the develop ment of acute myocardial infarction in patients with angina pectoris, associated with the abrupt cessation of propranolol therapy.‘-s These observations are, to date, anecdotal and controlled studies have not been reported. However, if the discontinuation of propranolol were responsible for the induction of myocardial damage, a role for the drug in the pre vention of tissue necrosis in patients with coronary artery disease might be implied There is a body of clinical and experimental evidence to support this hypothesis. The clinical evidence for the e5cacy of propranolol in severe and intractable angina pectoris has been provided by a number of investigators. Initially, Black and Stephenson” suggested that beta-adrenergic blocking drugs might be useful in the management of patients with angina pectoris. On the basis of clinical atudles, Keelan? Fitzgerald and Grant,6 and Gianelly and colleagues’ all reported a significant reduction in the number of angina1 attacks, a decrease in the consumption of glyceryl trinltrate, and an improvement in pain-free effort tolerance of patients with angina pectoris treated with propranolol. Furthermore, Wolfson and associate@ suggested that the incidence of sudden death and acute myocardial infarction in patients with severe and intractable angina pectoris was reduced in those treated with propranolol, compared to similar patients receiving traditional therapy or treated surgically with internal mammary implants. Similarly, h&gala and associatese were impressed by the relatively low incidence of sudden death and acute myocardial infarction in their coronary artery disease patients treated with propranolol.
American Heart Journal
9. Cooke, E D., and Ritcher, M. E: Thermography in diagnosis of deep-vein thrombosis, Br. Med. J. 2~623, 1973. 10. Wheeler, H. B., Pearson, D., O’Connell, D., and Mullick, B. C.: Impedence phlebography, Arch. Surg. 100:164, 1972. 11. Standres, D. E., Jr., Scaultz, R. D., Sumner, D. S., and Rushmer, R. F.: Ultrasonic flow detector. A useful technique in the evaluation of peripheral vascular disease, Am. J. Surg. 113:311, 1967. 12. Duffy, G. J., D’Auria, D., Brien, T. G., Ormond, D., and Mehigan, J. A.: New radioisotope test for detection of deep venous thrombosis in the legs, Br. Med. J. 1:712, 1973. 13. Webber, M. M., Webb, R., Jr., and Craigin, M.: Endothelial lesions-demonstration by scintiscanning in medical isotope scintigraphy, Vienna 1 AEA 2:773, 1969. 14. Rosenthal& L., and Greyson, M.D.: Observations on the use of Tc-albumin macroaggregates for detection radiology 84:413, 1970. 15. Webber, M. M., Bennett, L. R., Craigin, M., and Webb, R., Jr.: Thrombophlebitis-demonstration by scintiscanning, Radiology 92:620, 1969.
There are experimental data, in both animals and man, to explain these observations. In the dog, Braunwald and Morok~‘~ used epicardial mapping of S-T segment elevation to deilne the extent of myocardial damage after experimental coronary occlu&n. In this oircumatance, propranolol reduced the extent of ischemic ir+y as r&c&d in a decrease in S-T sagment eIavatioti remaking from the coronary occlusion, while i@rotarenol in&&n increased both the extent and severity of iachernia. In man, Wolfson and Gorlin” have de morn&rated that, following the administration of propranolol, exercise results in a lesser increase in heart rate, ventricular work, cardiac index, and pressure time per minute both in normal au&acts and in patients with coronary disaaee. Although prepranolol admiistration increased ventricular volume, which would tend to increase myocardial oxygen conmunpt~, the over-all effect of the drug was an attenuation in the increment of MVO, associated with exercise. These observations led us to speculate on the mechanisms through which withdrawal of propranolol might result in myocardial infarction. Coronary artery diseeae is generally accepted to be a progressive disorder. Treatment with propranolol, by lowering myoeardial oxygen requirements, may permit considerable -II of the disease without induction of myocar&l damage. In some patients, the coroto the point where resting oxygen nary diamse may requirementa might not be met by the compromised coranary circulation in the abimnce of propran&& In these patients, the abrupt withdrawal of prupranolol therapy could result in myocardial infarction.
257
A new bedside radioisotope test for the detection of deep-vein thrombosis
Pulmonary embolism is a tragic and not infrequently fatal occurrence in hospitalixed patients. Approximately 2,700 persons die from pulmonary embolism in Great Britain and Ireland yearly. An association between pulmonary embolism and deep-vein thrombosis @VT) has been clearly documented’ If the incidence of pulmonary embolism is to be reduced it will be necessary either to prevent DVT or to detect it at a time when effective therapy may be introduced which will prevent pulmonary embolism. A number of prophylactic methods are in use for the prevention of DVT: “low-dose” heparin2 dextran,3 hydroxychloroquine sulfate,4 mechanical aida Each of these methods has been shown to reduce the incidence of DVT and, hopefully, future larger studies will show that one or a number of these methods is effective in reducing the incidence of pulmonary embolism. Alternatively, early diagnosis and treatment of DVT would lead to a reduction in the incidence of pulmonary embolism. Unfortunately the clinical diagnosis of DVT is notoriously unreliable. On the one hand it hae been shown that in a group of patients with clinical signs of DVT 28 per cent were normal by the sensitive lzsI fibrinogen test.6 On the other hand it has been reported that in 60 per cent of cases of pulmonary embolism clinical evidence of DVT is lacking.’ Consequently if DVT is to be diagnosed prior to pulmonary embolism it will be necessary to screen large numbers of clinically “normal” hospitalized patients at frequent intervals, possibly daily. A number of techniques are presently being tried as a screening test for DVT: the “‘1 fibrinogen test,’ thermography,’ electrical impedance,” ultrasound flow detection.” None of these tests to date is ideal as a mass screening test either because of inaccuracy in diagnosis or because of the complexity of the procedure or because the procedure carries a slight risk for the patient. Therefore, until a safe and effective prophylactic method for the prevention of pulmonary embolism is available, or until a simple, safe, and accurate mass screening test for the detection of DVT is developed, this common diagnostic and management question will continue to be asked in our hospitals: “Does this patient have DVT and should anticoagulant or antithrombolitic therapy be started?” To date, x-ray phlebography is the only method that will rapidly and accurately answer this question. A new bedside radioisotope test, the 1311MAA clearance test, that my colleagues and 112 recently reported as a preliminary communication in the British Medical Journal would appear to have application in this area. This radioisotope test uses a commercially available radiopharmaceutical, ‘311-labeled macroaggregates of albumin (1311 MAA), and equipment that is portable and inexpensive. The results are available in 20 minutes. Labeled MAA has been in use as a lung-scanning agent for more than ten years. In 1969 Webber and associates’s re-
255
ported that labeled MAA had an affinity for blood clots both in vivo and in vitro. A number of reports have appeared using this radiopharmaceutical in localizing venous thrombosis.i4~ ‘s In these reports gamma cameras or rectilinear scanners have been used Such equipment is expensive and presently is available only in the larger hospitals. The procedure requires the patient to be transported to the nuclear medicine department. It resembles in complexity x-ray phlebography and so has no clear advantage. It appeared to us that less sophisticated equipment might be adequate to detect Is11 MAA labeled thrombi, since detection of the radioactive clot, without accurately localizing the site and distribution of the radioisotope, would be adequate to make a diagnosis. We have tried an inexpensive portable scintillation detector and rate meter that is in use in our department for the 126I fibrinogen test (Pitman isotope localizing monitor). Acute femoral vein thrombosis was produced in 10 dogs by electrocautery. Approximately 20 to 30 PCi of “‘1 MAA was injected intravenously distal to the clot. There was a 40 to 80 fold increase in count rate over the clot area when compared with sham control experiments, and this difference in count rate persisted for at least 20 minutes. Fifty-four patients with clinical signs suggestive of DVT have so far been investigated. Approximately 100 @Zi of 13iI MAA was injected into the deep venous system using tourniquets. Count rates were obtained at five-minute intervals for 20 minutes at seven points along the injected leg and at corresponding points on the opposite leg (control). The clearance of 1311MAA from the injected leg fell into two easily discernible patterns, a rapid clearance pattern and a delayed clearance pattern. X-ray phlebograms were performed in all 54 patients. Thrombi were identified in the leg veins in 34 patients and in 30 of these patients there was a delayed clearance of 13iI MAA from the leg (88 per cent). There were 20 patients in whom x-ray phlebography failed to demon &rate thrombi and 17 of these the 13i I MAA cleared rapidly from the limb (86 per cent). Over all there was an 87 per cent agreement between positive phlebograms and delayed clearance and negative phlebograms and rapid clearance. These results suggest that this rapid, simple bedside radioisotope test may be adequate to answer this commonly encountered diagnostic problem: “Has this patient deep-vein thrombosis?” George J LIufi, M.D., BSc., M.R.C.P.I. Medical Director, kotope Department St. Vincent h Hospital Dublin, Ireland REFERENCES
1. Sevitt S., and Gallagher, N.: Venous thrombosis pulmonary embolism, Br. J. Surg. 48~4731961.
August,
and
1974, Vol. SS, No. 2
Annotations 2. Kakkar, V. V., Spindler, J., Flute, P. T., Corrigan, T., Fossard, D. P., Crillin, R. Q., Wessler, S., and Yin, E. T.: Efficacy of low doses of heparin in prevention of deepvein thrombosis after major surgery, Lancet 2:101, 1972. 3. Lambie, J. M., Barber, D. C., Dhall, D. P., and Matheson N. N.: Dextran 70 in prophylaxis of post-operative venous thrombosis. Br. Med. J. 2:145. 1970. 4. Carter, A. E., Eban, R., and Pennett,‘R. D.: Prevention of post-operative deep venous thrombosis and pulmonary embolism, Br. Med. J. 1:312, 1971. 5. Sabri, S., Roberta, V. C., and Cotton, L. T.: Prevention of early post-operative deep-vein thrombosis by intermittent compression of the leg at surgery, Br. Med. J. 4:394,1971. 6. Lambie, J. M., Mahaffy, R. G., Barber, D. C., Karmody, A. M., Scott, M. M., and Matheson, M. A.: Diagnostic accuracy of venous thrombosis, Br. Med. J. 2:142, 1970. 7. Welch, C. F., and Faxon, H. H.: Thrombophlebitis and uulmonarv embolism. J. A. M. A. 117~1502. 1941. 8. kgus, D.: Pinto, D. J., Le Quesne, L. P., Browne, M., and Chapman, M.: ‘251-labelled fibrinogen in the diagnosis of deep-vein thrombosis and its correlation with phlebography, Br. J. Surg. 55835, 1968.
Myoccardial withdrawal
infarction
after ptoprano~ol
A number of observers have recently reported the develop ment of acute myocardial infarction in patients with angina pectoris, associated with the abrupt cessation of propranolol therapy.‘-s These observations are, to date, anecdotal and controlled studies have not been reported. However, if the discontinuation of propranolol were responsible for the induction of myocardial damage, a role for the drug in the pre vention of tissue necrosis in patients with coronary artery disease might be implied There is a body of clinical and experimental evidence to support this hypothesis. The clinical evidence for the e5cacy of propranolol in severe and intractable angina pectoris has been provided by a number of investigators. Initially, Black and Stephenson” suggested that beta-adrenergic blocking drugs might be useful in the management of patients with angina pectoris. On the basis of clinical atudles, Keelan? Fitzgerald and Grant,6 and Gianelly and colleagues’ all reported a significant reduction in the number of angina1 attacks, a decrease in the consumption of glyceryl trinltrate, and an improvement in pain-free effort tolerance of patients with angina pectoris treated with propranolol. Furthermore, Wolfson and associate@ suggested that the incidence of sudden death and acute myocardial infarction in patients with severe and intractable angina pectoris was reduced in those treated with propranolol, compared to similar patients receiving traditional therapy or treated surgically with internal mammary implants. Similarly, h&gala and associatese were impressed by the relatively low incidence of sudden death and acute myocardial infarction in their coronary artery disease patients treated with propranolol.
American Heart Journal
9. Cooke, E D., and Ritcher, M. E: Thermography in diagnosis of deep-vein thrombosis, Br. Med. J. 2~623, 1973. 10. Wheeler, H. B., Pearson, D., O’Connell, D., and Mullick, B. C.: Impedence phlebography, Arch. Surg. 100:164, 1972. 11. Standres, D. E., Jr., Scaultz, R. D., Sumner, D. S., and Rushmer, R. F.: Ultrasonic flow detector. A useful technique in the evaluation of peripheral vascular disease, Am. J. Surg. 113:311, 1967. 12. Duffy, G. J., D’Auria, D., Brien, T. G., Ormond, D., and Mehigan, J. A.: New radioisotope test for detection of deep venous thrombosis in the legs, Br. Med. J. 1:712, 1973. 13. Webber, M. M., Webb, R., Jr., and Craigin, M.: Endothelial lesions-demonstration by scintiscanning in medical isotope scintigraphy, Vienna 1 AEA 2:773, 1969. 14. Rosenthal& L., and Greyson, M.D.: Observations on the use of Tc-albumin macroaggregates for detection radiology 84:413, 1970. 15. Webber, M. M., Bennett, L. R., Craigin, M., and Webb, R., Jr.: Thrombophlebitis-demonstration by scintiscanning, Radiology 92:620, 1969.
There are experimental data, in both animals and man, to explain these observations. In the dog, Braunwald and Morok~‘~ used epicardial mapping of S-T segment elevation to deilne the extent of myocardial damage after experimental coronary occlu&n. In this oircumatance, propranolol reduced the extent of ischemic ir+y as r&c&d in a decrease in S-T sagment eIavatioti remaking from the coronary occlusion, while i@rotarenol in&&n increased both the extent and severity of iachernia. In man, Wolfson and Gorlin” have de morn&rated that, following the administration of propranolol, exercise results in a lesser increase in heart rate, ventricular work, cardiac index, and pressure time per minute both in normal au&acts and in patients with coronary disaaee. Although prepranolol admiistration increased ventricular volume, which would tend to increase myocardial oxygen conmunpt~, the over-all effect of the drug was an attenuation in the increment of MVO, associated with exercise. These observations led us to speculate on the mechanisms through which withdrawal of propranolol might result in myocardial infarction. Coronary artery diseeae is generally accepted to be a progressive disorder. Treatment with propranolol, by lowering myoeardial oxygen requirements, may permit considerable -II of the disease without induction of myocar&l damage. In some patients, the coroto the point where resting oxygen nary diamse may requirementa might not be met by the compromised coranary circulation in the abimnce of propran&& In these patients, the abrupt withdrawal of prupranolol therapy could result in myocardial infarction.
257