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tabolites. A pulmonary vascular permeability defect would have to be transient and easily repaired to explain the 16-hour time course of resolution. This pulmonary edema was apparently not cardiogenic. While emesis is usually effective in removing undigested pills in patients who have overdosed, the use of ipecac in a patient with hypotension is dangerous. The yield is frequently poor, and vagally induced decreases in heart rate in hemodynamically unstable patients should discourage its use. The increased vagal tone witnessed in our patient probably exacerbated the hypotension and led to her generalized seizure. Gastric lavage is as effective and safer in these patients. The search for an antidote for verapamil overdose is, to date, incomplete. A drug that reverses nondepolarizing neuromuscular blockade, 4-aminopyridine, has been used effectively in cats.29 In an extensive study, Korstanje and colleagues examined the calcium-entry promoters Bay k 8644 and CGP 28932, as well as 4-aminopyridine, and found them all to be effective in rabbits.30 Bay k 8644 was substantially better at improving the hypotension and electrocardiographic and heart rate abnormalities. No human trials of any of these agents have been reported. REFERENCES 1. Goenen M, Col J, Compere A, Bonte J: Treatment of severe verapamil poisoning with combined amrinone-isoproterenol therapy. Am J Cardiol 1986; 58:1142-1143 2. Coaldrake LA: Verapamil overdose (Letter). Anaesth Intensive Care 1984; 12:174-175 3. Van der Meer J, van der Wall E: Fatal acute intoxication with verapamil. Neth J Med 1983; 26:130-132 4. Passal DE, Crespin FH Jr: Verapamil poisoning in an infant. Pediatrics 1984; 73:543-545 5. Chimienti M, Previtali M, Medici A, Piccinini M: Acute verapamil poisoning: Successful treatment with epinephrine. Clin Cardiol 1982; 5:219-222 6. Orr GM, Bodansky HJ, Dymond DS, Taylor M: Fatal verapamil overdose (Letter). Lancet 1982; 2:1218-1219 7. Crump BJ, Holt DW, Vale JA: Lack of response to intravenous calcium in severe verapamil poisoning (Letter). Lancet 1982; 2:939-940 8. Jain SC, Bharadwaj RPS, Shukla RK, Ahmad M, Mathur SP: Severe hypotension and bradycardia after suicidal consumption of 100 tablets of verapamil: A case report. Indian Heart J 1982; 34:175-176 9. Immonen P, Linkola A, Waris E: Three cases of severe verapamil poisoning. Int J Cardiol 198 1; 1:101 - 105 10. Woie L, Storstein L: Successful treatment of suicidal verapamil poisoning with calcium gluconate. Eur Heart J 1981; 2:239-242 11. Moroni F, Mannaioni PF, Dolara A, Ciaccheri M: Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning. Clin Toxicol 1980; 17:395400 12. Candell J, Valle V, Soler M, Rius J: Acute intoxication with verapamil. Chest 1979; 75:200-201 13. Enyeart JJ, Price WA, Hoffman DA, Woods L: Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coll Cardiol 1983; 2:1228-1231 14. Da Silva OA, de Melo RA, Jorge Filho JP: Verapamil acute self-poisoning. Clin Toxicol 1979; 14:361-367 15. Perkins CM: Serious verapamil poisoning: Treatment with intravenous calcium gluconate. Br Med J 1978; 2:1127 16. De Faire U, Lundman T: Attempted suicide with verapamil. Eur J Cardiol 1977; 6:195-198 17. Kozlowski JH, Kozlowski JA, Schuller D: Poisoning with sustained-release verapamil. Am J Med 1988; 85:127 18. McMillan R: Management of acute severe verapamil intoxication. J Emerg Med 1988; 6:193-196 19. Roth A, Miller HI, Belhassen B, Laniado S: Slow-release verapamil and hyperglycemic metabolic acidosis (Letter). Ann Intern Med 1989; 110:171-172 20. Samniah N, Schlaeffer F: Cerebral infarction associated with oral verapamil overdose. J Toxicol Clin Toxicol 1988; 26:365-369 21. Anderson P: Pharmacokinetics of calcium channel blocking agents. Acta Pharmacol Toxicol (Copenh) 1986; 58 (Suppl 2):43-57 22. Strubelt 0: Antidotal treatment of the acute cardiovascular toxicity of verapamil. Acta Pharmacol Toxicol (Copenh) 1984; 55:231-237 23. Govoni S, Battaini F, Magnoni MS, Trabucchi M: Non-vascular central nervous system effects of calcium entry blockers. Cephalalgia 1985; Suppl 2:115-118 24. De Marinis L, Barbarino A: Calcium antagonists and hormone release-I. Effects of verapamil on insulin release in normal subjects and patients with islet-cell tumor. Metabolism 1980; 29:599-604 25. Midtbo K, Hals 0: Can blood pressure reduction induced by slow calcium

2

211 channel blockade (verapamil) be reversed by calcium infusion? Pharmacol Toxicol 1987; 60:330-332 26. Dembo DH: Calcium in advanced life support. Crit Care Med 1981; 9:358-359 27. Carlon GC, Howland WS, Kahn RC, Schweizer 0: Calcium chloride administration in normocalcemic critically ill patients. Crit Care Med 1980; 8:209-212 28. Colice GL, Matthay MA, Bass E, Matthay RA: Neurogenic pulmonary edema. Am Rev Respir Dis 1984; 130:941-948 29. Agoston S, Maestrone E, van Hezik EJ, Ket JM, Houwertjes MC, Uges DRA: Effective treatment of verapamil intoxication with 4-aminopyridine in the cat. J Clin Invest 1984; 5:1291-1296 30. Korstanje C, Jonkman FAM, Van Kemenade JE, van Zwieten PA: Bay k 8644, a calcium entry promoter, as an antidote in verapamil intoxication in rabbits. Arch Int Pharmacodyn Ther 1987; 287:109-119

Phlegmasia Cerulea Dolens Associated With the Lupus Anticoagulant BRUCE A. BAETHGE, MD D. KEITH PAYNE, MD Shreveport, Louisiana PHLEGMASIA CERULEA DOLENS (PCD) is a severe form of

peripheral venous thrombosis characterized by massive edema, severe pain, and cyanosis. It is the result of the complete obstruction of the venous drainage of a limb and may result in shock, distal gangrene, pulmonary embolus, or death.' Phlegmasia cerulea dolens often occurs in association with hypercoagulable states including clotting disorders,2 malignancy,3 oral contraceptive use,4 trauma,5 and the postsurgical and postpartum periods.' In the following report, we describe the occurrence of PCD in a woman who was found to have the lupus anticoagulant. A computerized literature search elicited no previous reports of this association.

Report of a Case The patient, a 50-year-old woman, was admitted to the hospital because of sudden pain and swelling of the right calf and thigh. She had suffered an episode of deep vein thrombosis in the same leg three years previously. Long-term warfarin sodium (Coumadin) therapy had been discontinued two

weeks before her symptoms started. She said she had not had recent trauma or prolonged periods of immobility. There was no history of a clotting disorder or systemic rheumatic disease. On physical examination the patient was morbidly obese and had marked edema of the right leg, which had a dusky, erythematous appearance. There was a difference in circumference of 8 cm at midthigh and 6 cm at midcalf of the right leg compared with the left. Dorsalis pedis and posterior tibial pulses were palpable in the right foot on initial examination. Admission laboratory tests revealed a.serum creatinine level of 194.5 itmol per liter (2.2 mg per dl) and a blood urea nitrogen concentration of 8.6 mmol per liter of urea (24 mg per dl). A urinalysis revealed no proteinuria. The prothrombin time was 14 seconds with a normal control range of 10 to

(Baethge BA, Payne DK: Phlegmasia cerulea dolens associated with the lupus anticoagulant. West J Med 1991 Feb; 154:211-213) From the Sections of Rheumatology (Dr Baethge) and Pulmonary Disease (Dr Payne), Department of Medicine, Louisiana State University Medical Center, Shreveport. Reprint requests to Bruce A. Baethge, MD, LSU Medical Center, PO Box 33932, Shreveport, LA 71130-3932.

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ALERTS, NOTICES, AND CASE REPORTS

2l

ABBREVIATIONS USED IN TEXT APTT = activated partial thromboplastin time PCD = phlegmasia cerulea dolens

13 seconds. The activated partial thromboplastin time (APTT) was 57 seconds with a normal control range of 22 to 31 seconds using activated cephaloplastin as the thromboplastin reagent (Baxter/Dade, Rutherford, New Jersey). The APTT corrected to only 41 seconds after a 1:1 mix with normal serum, confirming the presence of an inhibitor. A thromboplastin dilution assay was consistent with the presence of the lupus anticoagulant (Table 1). She also had a positive rapid plasma reagin test with a nonreactive microhemagglutination assay for Treponemapallidum. Antithrombin III levels were within the normal range. The diagnosis of phlegmasia cerulea dolens was made on clinical grounds, and intravenous heparin therapy was started. There was no evidence to support the diagnosis of systemic lupus erythematosus. Impedance plethysmography was attempted but was technically impossible because of the size of the right leg (Figure 1). Venography was not done because of the concern that her azotemia would be exacerbated. Ultrasonography and computed tomography of the pelvis and right leg revealed massive edema with enlarged subcutaneous veins consistent with occlusion of the deep venous system. No evidence of a mass lesion or extrinsic compression of the venous system was seen. Despite leg elevation and continuous heparin therapy (500 units per hour) for 36 hours, swelling and cyanosis continued and the patient suffered intense pain. The distal pulses could no longer be palpated in the right foot and were detectable only by Doppler. Streptokinase therapy was initiated with an intravenous bolus of 250,000 units and maintained at a continuous infusion of 100,000 units per hour for three days. The patient had a notable reduction in pain and swelling. Following the discontinuation of streptokinase, heparin therapy was resumed. Over the next 14 days, there was a gradual improvement in the appearance of the leg with less swelling and the return of palpable pedal pulsations. A year after discharge, the patient remains on continuous warfarin therapy with venous stasis dermatopathy and persistent edema of the right lower extremity.

Discussion The lupus anticoagulant is an acquired inhibitor of blood coagulation initially described more than 30 years ago in patients with systemic lupus erythematosus.6 The term "lupus anticoagulant" is a misnomer because bleeding rarely occurs without the presence of additional clotting abnormalities, and clinically the lupus anticoagulant is associated with thrombotic events.7`9 The lupus anticoagulant occurs in as many as 16% of patients with systemic lupus but can also be found in association with other autoimmune disorders, with the use of certain drugs, and in patients with no underlying problems.7-9 Lupus anticoagulant activity has been shown to be the result of immunoglobulin G and immunoglobulin M antibodies directed against phospholipids including cardiolipins. '0 It is not known how the lupus anticoagulant leads to thrombosis. Suggested hypotheses include its interacting with endothelial or platelet cell surfaces (or both) that directly results in

increased platelet aggregation, or modulation of the protein C pathway by the lupus anticoagulant that leads to inhibition of the fibrinolytic system and thus indirectly results in clot formation. I Anticoagulation therapy is usually successful in the treatment of venous thrombosis associated with the lupus anticoagulant. 7,8 The lupus anticoagulant is recognized by a prolongation of the APTT that occurs in all patients and by prolongation of the prothrombin and thrombin times that is found in some patients.8 Mixing studies will confirm the presence of a circulating inhibitor that does not correct with the addition of normal plasma. The dilute tissue thromboplastin assay or a platelet neutralization procedure can be used to confirm the presence of the lupus anticoagulant.'12, Additional laboratory features found in some patients include the presence of a biologically false-positive test for syphilis and thrombocytopenia. The association of the lupus anticoagulant with arterial and venous thrombosis, spontaneous abortion, and other clinical abnormalities has recently been the subject of extenTABLE 1.-Thromboplastin Dilution Assay' Dilution

1:1 .... 1:100 ....

1:1,000 ....

Prothrombin Time Patient, s Normol Control, s 14 14

82.4 170.7

Ratiot

45.9 91.6

1.8 1.9

Thromboplastin C, Baxter/Dade, Becton Dickinson & Company, Rutherford, NJ 07070. tRatio is of the patient/control prothrombin times using diluted Thromboplastin C In our laboratory the lupus anticoagulant is considered present when the ratio at the 1:100 dilution is greater than 1:1.5 and when the ratio at the 1:1,000 dilution is greater than 1:1.7.

11

i.

f.'t

44kk,

.1 .,

00W

'N'

li.

.1:

,i'w.;

-.0.

Figure 1.-The photograph shows the pronounced edema and dusky appearof the right leg in a patient with phlegmasia cerulea dolens.

ance

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sive investigation and has been called the anticardiolipin syndrome. II Phlegmasia cerulea dolens is a life-threatening disorder that requires aggressive intervention to combat the high frequency of morbidity and mortality."'4',5 The treatment of PCD includes anticoagulation, thrombolytic therapy, and surgical thrombectomy used alone or in combination. 41,5 A recent review of the therapeutic options for PCD suggests that surgical intervention is needed when patients fail to respond to heparin therapy within 6 to 12 hours.15 The discovery of the lupus anticoagulant in our patient led to the institution of thrombolytic therapy that proved to be successful. It has been suggested that all patients with hypercoagulable clotting abnormalities are at high risk for the development of PCD.2 This case supports that suggestion. Cohen and colleagues have recently described six cases of PCD in patients who had associated hypercoagulable states, including heparin-induced thrombocytopenia, congenital protein C deficiency, and antithrombin III deficiency.2 The authors commented that recognition of an underlying coagulopathy is essential for the proper management of PCD. We agree and think the lupus anticoagulant should be included as another coagulopathy associated with PCD. Our patient had no evidence of an underlying collagen vascular disease or occult malignant neoplasm. The lupus anticoagulant contributed to the development of PCD, although she had morbid obesity and a previous deep vein

Rhabdomyolysis Associated With Lovastatin and Erythromycin Use DAVID H. SPACH, MD J. ERIC BAUWENS, MD CHRISTINE D. CLARK, MD WYLIE G. BURKE, MD, PhD

Seattle, Washington

LOVASTATIN,

a

hydroxymethylglutaryl-coenzyme A reduc-

tase inhibitor used to treat patients with hypercholesterole-

mia, has become a commonly administered drug. Its use has been associated with a low incidence of side effects that include elevated aminotransferase levels, skin rash, gastrointestinal symptoms, and skeletal muscle abnormalities.12 Clinically, the most important of these side effects is the skeletal muscle abnormalities that can manifest as asymptomatic creatine kinase elevations; muscle aches, tenderness, and weakness; and rhabdomyolysis.2 Patients at greatest risk of muscle abnormalities developing include those with an underlying illness or concurrently taking medication such as cyclosporine, gemfibrozil, or niacin. I We present a case of rhabdomyolysis associated with lovastatin use that occurred shortly after a course of erythromycin. In addition, we re(Spach DH, Bauwens JE, Clark CD, Burke WG: Rhabdomyolysis associated with lovastatin and erythromycin use. West J Med 1991 Feb; 154:213215) From the Departments of Internal Medicine (Drs Spach, Bauwens, and Burke) and Pathology (Dr Clark), University of Washington School of Medicine, Seattle. Reprint requests to David H. Spach, MD, Harborview Medical Center, ZA-89, 325 9th Ave, Seattle, WA 98104.

213

thrombosis as additional risk factors. She will require anticoagulation therapy indefinitely. REFERENCES 1. Brockman SK, Vasko JS: Phlegmasia cerulea dolens. Surg Gynecol Obstet 1965; 121:1347-1356 2. Cohen DJ, Briggs R, Heard HD, Acher CW: Phlegmasia cerulea dolens and its association with hypercoagulable states: Case reports. Angiology 1989; 40:498-508 3. Chalmers N, Campbell 1: Phlegmasia coerulia dolens revisited. Practitioner 1987; 231:1520-1521 4. Coddington CC, Drake TS: Phlegmasia cerulea dolens as a complication of short-course oral contraceptives for dysfunctional bleeding. South Med J 1982; 75:377-378 5. Wilson B, Hawkins ML, Mansberger AR: Posttraumatic phlegmasia cerulea dolens: An indication for the Greenfield filter. South Med J 1989; 82:780-782 6. Conley CL, Hartman RC: A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 1952; 31: 62 1-622 7. Mueh JR, Herbst KD, Rapaport SI: Thrombosis in patients with the lupus anticoagulant. Ann Intem Med 1980; 92:150-159 8. Elias M, Eldor A: Thromboembolism in patients with the 'lupus'-type circulating anticoagulant. Arch Intern Med 1984; 144:510-515 9. Gastineau DA, Kazmler FJ, Nichols WL, Bowie EJW: Lupus anticoagulant: An analysis of the clinical and laboratory features of 219 cases. Am J Hematol 1985; 19:265-275 10. Triplett DA, Brandt JT, Mass RL: The laboratory heterogeneity of lupus anticoagulants. Arch Pathol Lab Med 1985; 109:446-451 11. Freyssinet JM, Cazenave JP: Lupus-like anticoagulants, modulation of the protein C pathway and thrombosis. Thromb Haemost 1987; 58:679-681 12. Schleider MA, Nachman RL, Jaffe EA, Coleman MA: A clinical study of the lupus anticoagulant. Blood 1976; 48:499-509 13. Hughes GRV, Harris NN, Gharavi AE: The anticardiolipin syndrome (Editorial). J Rheumatol 1986; 13:486-489 14. Elliot MS, Immelman EJ, Jeffery P, et al: The role of thrombolytic therapy in the management of phlegmasia caerulea dolens. Br J Surg 1979; 66:422-424 15. Weaver FA, Meacham PW, Adkins RB, Dean RH: Phlegmasia cerulea dolens: Therapeutic considerations. South Med J 1988; 81:306-312

view two previously reported cases of rhabdomyolysis that occurred after the concomitant use of lovastatin and erythromycin and conclude that erythromycin should be added to the known list of drugs associated with lovastatin-induced rhabdomyolysis.

Report of a Case The patient, a 68-year-old woman with diabetes mellitus, coronary artery disease, congestive heart failure, and chronic renal insufficiency, was admitted to the hospital for the evaluation of dyspnea and pulmonary infiltrates. Seven months before admission, a regimen of lovastatin, 20 mg twice a day, was started for hypercholesterolemia. The patient's baseline-total cholesterol level of 7.34 mmol per liter (282 mg per dl) decreased to 4.45 mmol per liter (171 mg per dl) after six months oflovastatin therapy. Nine days before the current admission, the patient had been admitted to the hospital with dyspnea, fever, and pulmonary infiltrates. During this previous hospital admission, she received a combination drug containing ampicillin sodium and sulbactam sodium intravenously for three days, followed by a combination of amoxicillin and clavulanate potassium orally for three days. She responded well and was discharged on the oral antibiotic regimen but was readmitted to the hospital four days later with a recurrence of her symptoms. Her medications on admission included lovastatin, 20 mg twice a day; amoxicillinclavulanate; furosemide; sucralfate; ranitidine; allopurinol; insulin; isosorbide dinitrate; enalapril; and digoxin. Pertinent physical examination findings included rales at the bases of both lung fields, a holosystolic murmur heard best at the mitral region, and an absence of hepatosplenomegaly. Laboratory studies on admission elicited the follow-