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the incidence of the post-phlebitic syndrome. This would appear to be an incorrect conclusion. It is accepted that early streptokinase treatment for DVT will result in improved venographic appearance and improved venous valve function. The contentious issue is whether streptokinase treatment can decrease the clinical manifestations of the post-phlebitic syndrome. This has been the aim of physicians using streptokinase for DVT for the past 30 years. To date there has been no convincing evidence to support clinical improvement. Venography and other measurements are an indirect endpoint, and for reasons that are not apparent, a thrombus in the deep veins can be rapidly lysed within 24 hours, yet the post-phlebitic syndrome can still occur. One could hypothesize that this is due to abnormal microvasculature or l y m p h a t i c function, but there has been no definitive work in this area. The key reference cited by the authors supports a direct correlation between streptokinase treatment and favorable clinical outcome (Johansson E, Ericson K, Zetterquist S. Streptokinase treatment of deep venous thrombosis of the lower extremity. Acta Med Scand 1976; 199: 89-94). This article is a descriptive study of 19 patients who all received streptokinase. There was no comparative group. In this small study there did appear to be a correlation between restoration of both venous architecture and valve function and a reduction of post-phlebitic symptoms, but in a non-experimental study this finding is probably indicative of a characteristic of the patients rather than of the medication. Many thrombosis experts will use streptokinase in young patients with massive proximal thrombosis; however, this is in

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hope rather than in expectation of benefit. The authors' conclusion that streptokinase administration will result in a greater degree of lysis of DVT is acceptable, but the conclusion that streptokinase prevents the post-phlebitic syndrome is not supported by experimental clinical trials. CEDRICJ. CARTER, M.B., F.R.C.P.(U.K.), F.R.C.P.C. University Hospital--UBC Site Vancouver, British Columbia, Canada Submitted May 17, 1990, and accepted July 12, 1990

The Reply: Although Johansson et al [1] did not e v a l u a t e a c o m p a r a t i v e group, several studies have directly compared symptoms of post-phlebitic syndrome as the clinical outcomes in patients t r e a t e d with heparin versus streptokinase. In our review, we primarily reported the venographic and valve function findings at time of follow-up in nine studies directly comparing streptokinase- with heparin-treated patients [2-10]. Four of these comparative studies also assessed symptoms of post-phlebitic syndrome as experimental endpoints [2,3,8,9]. The follow-up period ranged from 7 months to 77 months. Bieger et al [2] found 100% of streptokinase-treated patients without symptoms of post-phlebitic syndrome at time of follow-up compared with 60% of heparin-treated patients. Similarly, Elliot et al [3] found 60% versus 9.5%, Arnesen et al [8] found 76% versus 33%, and Common et al [9] found 67% versus 50%. If the four comparative study results are combined, 43 of 62 (69%) streptokinase-treated patients had no clinical symptoms of post-phlebitic syndrome at time of follow-up as compared with only 17 of 56 (30%) heparintreated patients. All four comparative studies showed the same

November 1990 The American Journal of Medicine Volume 89

result, with a greater number of streptokinase-treated patients reporting no symptoms of postphlebitic syndrome at the time of follow-up when compared with heparin-treated patients. LAURA Q. ROGERS, M.D. C. LAWRENCE LUTCHER, M.D.

Medical College of Georgia Augusta, Georgia 1. Johansson E, Ericson K, Zetterquist S. Streptokinase treatment of deep venous thrombosis of the lower extremity. Acta Med Scand 1976; 199: 8994. 2. Bieger R, Boekhout-Mussert RJ, Hohmann F, Loeliger EA. Is streptokinase useful in the treatment of deep vein thrombosis? Acta Med Scand 1976; 199: 81-8. 3. Elliot MS, Immelman EJ, Jeffery P, et aL A comparative randomized trial of heparin versus streptokinase in the treatment of acute proximal venous thrombosis: an interim report of a prospective trial. Br J Surg 1979; 66: 838-43. 4. Kakkar W. Treatment of deep vein thrombosis. Proc R Soc Med 1970; 63: 133-5. 5. Kakkar W, Lawrence D. Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis, Am J Surg 1985; 150 (Suppl 4A): 5463, 8. Rosch J, Dotter CT, Seaman AJ, Porter JM, Common HH. Healing of deep venous thrombosis: venographic findings in a randomized study comparing streptokinase and heparin. AJR 1976; 127: 553-8. 7. Watz R, Savidge GF. Rapid thrombotysis and preservation of valvular venous function in high deep vein thrombosis. Acta Med Scand 1979; 205: 293-8. S. Arnesen H, Hoiseth A, Ly B. Streptokinase or heparin in the treatment of deep vein thrombosis. Acta Med Stand 1982; 211: 65-8. g. Common HH, Seaman &J, Rosch J, Porter JM, Dotter CT. Deep vein thrombosis treated with streptokinase or heparin. Angiology 1976; 27: 645-54. IO. Kakkar VV, Howe CT, Laws JW, Flanc C. Late results of treatment of deep vein thrombosis. Br Med J 1969; 1: 810-1.

EXTRAHEPATIC CHOLESTASIS AS A DISTINCT FACTOR PREDISPOSING TO GENTAMICIN NEPHROTOXICITY To the Editor: There is accumulating evidence indicating that liver disease increases the risk of nephrotoxicity during aminoglycoside therapy. Desai and Tsang (Am J Med 1988; 85: 47-50) have retrospectively observed that cholestatic liver disease does enhance the

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risk of renal damage from gentamicin in patients with high bilirubin values. Kishore (Am J Med 1989; 87: 245-6) has questioned the validity of the results reported in this study and has pointed out the role of concomitant corticosteroid therapy in the pathogenesis of gentamicin-induced renal toxicity. We are in disagreement with Dr. Kishore's contention on the basis of our experimental findings [1] demonstrating t h a t c o m p l e t e b i l i a r y obstruction increases renal sensitivity to gentamicin, an observa-

tion that is in agreement with the data reported by Vakil et al [2]. A prospective controlled clinical trial is underway to identify the significant risk factors and the incidence of gentamicin nephrotoxicity in patients with cholestasis and moderate bilirubin levels. Nevertheless, enough data are currently available to consider extrahepatic cholestasis as a distinct factor predisposing to gentamicin nephrotoxicity and to classify these patients into a high-risk group. However, when aminoglycoside administration is

considered mandatory, it should be guided by sound clinical judgment and interpretation of renal function and serum concentration data. M. •SABEL LUCENA, M.D. RAUL J. ANDRADE, M.D.

University Hospital Malaga, Spain

1. Lucena MI, Gonzalez-CorreaJA, Andrade RJ, et aL Enhancedgentamicin nephrotoxicity after exper-

imental biliary obstruction in rats. Pharmacol Toxicol 1989; 65: 352-6. 2. Vakil N, Abu-Alfa A, Mujais SK. Gentamicin nephrotoxicity in extrahepatic cholestasis: modulation by dietary calcium. Hepatology 1989; 9: 519-24. Submitted June 4, 1990, and accepted July 12, 1990

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Extrahepatic cholestasis as a distinct factor predisposing to gentamicin nephrotoxicity.

CORRESPONDENCE the incidence of the post-phlebitic syndrome. This would appear to be an incorrect conclusion. It is accepted that early streptokinase...
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