LETTERS
Letters that report new clinical or laboratory observations; cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style.
with duplication of the Ph 1 chromosome entered an acute phase of their disease, but it must be pointed out that there are a few who did not ( 3 ) . From a cytogenetic standpoint, acute transition of chronic granulocytic leukaemia is frequently characterized by an increased number of chromosomes due to preferential gain of additional chromosomes ( 4 ) . This is also true in the present observation. Thus, this chromosomal marker would give strong evidence for extramedullary acute transition in chronic granulocytic leukaemia. Cytologic evidence for this hypothesis has previously been presented by others (2) *. F. OBERLING, M.D. C. STOLL J. M. LANG G. MAYER
Duplication of Philadelphia Chromosome in Acute Transition of Chronic Granulocytic Leukaemia DUPLICATION of the Philadelphia (Ph 1 ) chromosome is known to occur in the course of chronic granulocytic leukaemia ( 1 ) . Usually, if not always, this acquired cytogenetic development precedes or occurs with an acute transition of chronic granulocytic leukaemia. The acute phase of chronic granulocytic leukaemia with duplication of the Ph 1 chromosome is frequently associated with the development of enlarged myeloid lymph nodes, resembling reticulum cell malignancies on histologic examination ( 2 ) . We present here a pertinent case report of a 39-year-old woman with typical chronic granulocytic leukaemia whom we have followed for 7 years. She was treated with successive courses of busulfan and hydroxyurea. In 1973, she was readmitted to our clinic because of fever and increasing pain in bones, joints, and muscles. We noted on physical examination a moderate splenomegaly and enlarged lymph nodes in the cervical and inguinal areas. The hemoglobin level was 8.7 g/100 ml; leukocyte count, 23 000/ mm3 with metamyelocytes, myelocytes, and 3% myeloblasts; platelets, 420 000/mm3. A bone marrow aspirate showed hypercellularity with 3% promyelocytes and 8% myeloblasts. Histopathology of a lymph node biopsy specimen was classified as reticulum cell sarcoma. Cytologic examination, however, showed a mixed myeloid cell population infiltrating the lymph node. Chromosome analysis on bone marrow and lymph node cells showed a similar pattern, that is, presence of a Ph1 chromosome and lack of a group of G chromosome. Subsequently, an increasing number of blast cells in peripheral blood and bone marrow signalled the acute transition of the disease. A splenectomy was done, and the spleen weight was 1.4 kg. Histologic and cytologic examination of the spleen showed a diffuse infiltration with myeloid cells. On chromosome analysis, two Ph1 chromosomes were detected in all dividing cells in the spleen (screening of 100 mitotic figures). After splenectomy and without any chemotherapy, the absolute number of myeloblasts in the peripheral blood dropped 6800/mm3 to 0/mm3 within 12 days. This observation shows that an extramedullary clonal development with duplication of the Ph 1 chromosome has occurred in the spleen simultaneously with an acute transition of chronic granulocytic leukaemia. Myeloid cells in bone marrow and the lymph node did not show this chromosomal development. In most cases reported, the patients
Service des Maladies du Sang, et Laboratoire de Cytogenetique Clinique Infantile CHU 67000 Strasbourg, France Received 2 April 1975. REFERENCES
1. HAMMOUDA F, QUAGLINO D, HAYHOE FGJ: Blastic crisis in chron-
ic granulocytic leukaemia. Cytochemical, cytogenetic, and autoradiographic studies in four cases. Br Med J 5393:1275-1281, 1964 2. GARFINKEL LS, BENNETT DE: Extramedullary myeloblasts transformation in chronic myelocytic leukemia simulating a coexistent malignant lymphoma. Am J Clin Pathol 51:638-645, 1969 3. DUVALL CP, CARBONE PP, BELL WR: Chronic myelocytic leuke-
mia with two Philadelphia chromosomes and prominent peripheral lymphadenopathy. Blood 29:652-666, 1967 4. GROUCHY J DE, NAVA C DE, FEINGOLD J: Onze observations d'un
modele precis devolution caryotypique au cours de la leucemie myeloide chronique. Eur J Cancer 4:481-492, 1968 * Since this letter was sent out, L. Brandt and D. K. Hossfeld have presented evidence for extramedullary acute transition in some chronic granulocytic leukaemias. [Personal communication from Dr. Oberling, 16 June 1975.]
Acute Dystonic Reaction Due to Benzquinamide ACUTE DYSTONIC REACTION due to short-term,
low-dose
prochlorperazine (Compazine®) therapy is a well-known adverse drug reaction (1) that occurs in approximately 0.5% of the general medical patient-population ( 2 ) . We report here a case in which a patient developed a dystonic reaction when given a single dose of benzquinamide (Emete-con®), an antiemetic agent chemically unrelated to the phenothiazines. A 30-year-old man was admitted to receive chemotherapy for his Hodgkin's disease (stage IV, nodular). This diagnosis was originally made in 1972, and he has been treated with six cycles of COPP combination chemotherapy (Cytoxan®, Oncovin®, procarbazine, prednisone). He is currently receiving the ABVD regimen of therapy (adriamycin, bleomycin, vincristine, DTIC) and was admitted for the third cycle of treatment. The patient's history included recurrent nausea and vomiting associated with his chemotherapy, which were relieved somewhat by premedication with prochlorperazine. Present physical findings and laboratory reports were essentially normal
231
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and consistent for a person with this disease. The patient was given prophylactic antiemetic therapy corresponding with his course of chemotherapy as follows. Day 1 Prochlorperazine, rectal 25 mg 1 dose Prochlorperazine, intramuscularly (i.m.) 10 mg 3 doses 10 mg 1 dose Day 2 Prochlorperazine, i.m. Day 3 Benzquinamide, i.m. 50 mg 1 dose Approximately 10 minutes after receiving the prochlorperazine on Day 2 (total dose received for 2 days, 40 mg i.m., and 25 mg rectally), the patient experienced sudden difficulty talking, with a tightening of tongue musculature. He developed a wide palpebral angle and had some difficulty with upward gaze. These symptoms were immediately diagnosed as oculogyric crisis secondary to prochlorperazine. Intramuscular diphenhydramine (Benadryl®), 25 mg, was administered, and all manifestations returned to normal within 15 minutes. Because of the previous day's events, antiemetic prophylaxis before chemotherapy was attempted with 50 mg of benzquinamide, i.m., on Day 3. Again, the patient developed difficulty in speaking and swallowing, with tightening of the tongue musculature. Torticollis, spasm of the occipitalis frontalis muscles, and wide stare were also observed. All symptoms were relieved within 10 minutes after 50 mg of diphenhydramine, i.m. B e n z q u i n a m i d e is a benzoquinolizine derivative effective parenterally in t h e t r e a t m e n t a n d prevention of druginduced emesis, with a low incidence of associated adverse reactions ( 3 ) . This is t h e first case report of a n acute dystonic reaction d u e to low-dose b e n z q u i n a m i d e therapy. Severe behavioral toxicity h a s been reported in some p a tients receiving m o r e than 800 m g of b e n z q u i n a m i d e ( 4 ) . A l t h o u g h several m e c h a n i s m s o r contributing factors of phenothiazine-induced dystonic dyskinesia have been suggested ( 1 , 2, 5 ) this adverse reaction seems to b e idiosyncratic, based on individual hyperreactivity. W e n o w present t h e possibility that this same predisposition m a y exist for a chemically unrelated therapeutic agent a n d that an individual might display dystonic cross-sensitivity b e tween the phenothiazine a n d benzoquinolizine antiemetics. W i t h this possibility in mind, w e m a y expect t o see additional reports of b e n z q u i n a m i d e adverse reactions in t h e future.
developed a n e r y t h e m a t o u s lesion at t h e extravasation site, which ultimately necrosed, ulcerated, a n d slowly began to heal at about \Vi m o n t h s after t h e accident. After this incident t h e patient received multiple courses of nitrogen m u s t a r d a n d vinblastine w i t h o u t a p p a r e n t difficulty. T w o m o n t h s after t h e extravasation of a d r i a m y c i n ( a t a time w h e n t h e w o u n d seemed well o n its w a y t o h e a l i n g ) , a n other course of a d r i a m y c i n w a s given in a n o t h e r extremity without difficulty. W i t h i n 2 days t h e lesion manifested a significant increase in e r y t h e m a , pain, drainage, a n d i m paired healing, which h a s n o w c o n t i n u e d with m i n i m a l i m p r o v e m e n t b y 8 weeks. N o other event seemed r e sponsible for this exacerbation in clinical findings. T h e w o u n d h a s never seemed infected, a n d cultures have s h o w n the presence of skin flora. T h e r e h a s been n o evidence of peripheral vascular disease. R e c e n t experience suggests that a d r i a m y c i n m a y b e r a d i o m i m e t i c , causing skin d a m a g e in areas of previously irradiated skin ( 1 ) . W e feel that this is a similar c i r c u m stance, w h e r e tissue d a m a g e d by exposure t o a d r i a m y c i n manifested further d a m a g e a n d necrosis after re-exposure to this agent. P r i o r tissue d a m a g e b y extravasation of a d r i a m y c i n m a y b e a relative contraindication t o further a d r i a m y c i n therapy. W e a r e n o t p l a n n i n g further a d r i a m y c i n t h e r a p y unless complete healing occurs o r t h e present clinical situation changes such that adriamycin, previously efficacious, seems warranted. W e would b e interested if others have had a similar experience. S T E P H E N C. C O H E N , M . D . N I C H O L A S J. D I B E L L A , M . D . J O H N C. M I C H A L A K , M . D .
Department of Medicine Fitzsimons Army Medical Center Denver, CO 80240 Received 28 April 1975. REFERENCE 1. DONALDSON SS, GLICK JM, WILBUR JR: Adriamycin activating
a recall phenomenon after radiation therapy. Ann Intern Med 81:407-408, 1974
T H O M A S E. R O S E , M . D . S T E V E N D . A V E R B U C H , B.S., R . P H .
University of Chicago Hospitals and Clinics Chicago, Illinois 60637
Reversible Acute Renal Failure After Cephalothin
Received 7 April 1975. REFERENCES
1. AYD F : A survey of drug-induced extrapyramidal reactions. JAMA 175:1054-1060, 1961 2. BOSTON COLLABORATIVE DRUG SURVEILLANCE PROGRAM:
Drug-
induced extrapyramidal symptoms. JAMA 224:889-891, 1973 3. KLEIN R, GRAVES C, K I M Y, et al: Inhibition of apomorphine-
induced vomiting by benzquinamide. Clin Pharmacol Ther 11: 99-106, 1970 4. BISHOP M, GALLANT D : Behavioral toxicity associated with benzquinamide (Quantril) therapy in schizophrenic patients. Am J Psychiatry 120:180-181, 1963 5. SCHAAF M, PAYNE C: Dystonic reactions to prochlorperazine in hypoparathyroidism. N Engl J Med 275:991-995, 1966
Recall Injury from Adriamycin WE
HAVE R E C E N T L Y S E E N a 6 3 - y e a r - o l d m a n w i t h
mixed
cell H o d g k i n ' s disease w h o h a s been receiving multiple agent c h e m o t h e r a p y for difficult-to-control retroperitoneal disease. O n e of t h e agents t h e patient h a s received is adriamycin. After extravasation of a d r i a m y c i n , t h e patient 232
W E R E C E N T L Y TREATED a patient with oliguric acute renal failure after cephalothin (Keflin®) t h e r a p y . This 48-year-old man was referred to the M. S. Hershey Medical Center because of azotemia and oliguria. Twelve days before admission he was admitted to another hospital for right renal colic. His blood urea nitrogen ( B U N ) was 15 mg/dl; an intravenous pyelogram showed a normal left kidney and nonvisualization of the right kidney, with several calcific densities in the area of the right kidney. Because of fever, he was given cephalothin intravenously, 16 g/day for 8 days. On the eighth day of therapy, oliguria was noted, his B U N was 79 mg/dl, and serum creatinine was 9.5 mg/dl. He was transferred to our institution. His blood pressure was 150/90 m m Hg, his temperature was 37.5 °C, and he had moderate edema and a diffuse maculopapular rash. His hematocrit was 3 3 % ; leukocyte count, 31 000/mm 3 with no eosinophilia; BUN, 89 mg/dl; and serum creatinine, 11.3 mg/dl. His urine contained 100 mg/dl albumin, 30 to 40 leukocytes/high power field, and 8 to 10 erythrocytes/high power field, with no erythrocyte casts. He stated that a rash had occurred after penicillin administration several years previously. An infusion intra-
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venous pyelogram showed poor visualization, and a cystoscopy and left retrograde pyelogram showed normal results. Intermittent hemodialysis was begun because of marked oliguria and fluid overload. This was continued until 3 weeks after admission because of a urine volume less than 300 ml/day and a serum creatinine above 9 mg/dl. His renal function slowly improved, and 6 weeks after admission his BUN was 44 mg/dl, and his serum creatinine was 2.8 mg/dl. He developed an eosinophilia of 30% during the third week in the hospital. During his hospitalization he required a right nephrolithotomy and nephrostomy for pyonephrosis; this has subsequently closed spontaneously. Five months after admission his BUN was 13 mg/dl, and his serum creatinine was 1.4 mg/dl. Acute renal failure o c c u r r e d in this patient after h e r e ceived only cephalothin. A recent report described five p a tients with similar courses of acute renal failure temporally related to cephalothin therapy, b u t three of these patients had also been given other potentially n e p h r o t o x i c antibiotics ( 1 ) . Also, n o previously reported case of renal failure after cephalothin t h e r a p y has been severe e n o u g h to require dialysis. Others have reported renal failure during therapy with both cephalothin a n d gentamicin ( 2 ) , a n d cephalothin, in high doses, h a s caused reversible impairm e n t of renal function in patients with preexisting renal disease ( 3 ) . T h e previous history of penicillin allergy a n d subsequent renal failure after cephalothin in o u r patient is similar to that reported in a n o t h e r patient ( 4 ) a n d suggests some type of hypersensitivity reaction. T h e p a t h o genesis m a y be similar to that which occurs in acute renal failure with interstitial nephritis after penicillin, methicillin, and other penicillin analogues ( 5 ) . Cephalothin should be administered with great caution to patients with a history of penicillin allergy, and, if it is given, t h e patient should be carefully m o n i t o r e d for d e creased renal function a n d manifestations of hypersensitivity, such as fever, eosinophilia, o r a rash. In addition, high doses of cephalothin should be avoided in patients with preexisting renal disease. J O H N E. E N G L E , M . D . JOSEPH DRAGO, M.D. BRUCE CARLIN, M.D. A N T O N C. S C H O O L W E R T H , M . D .
Renal Division Department of Medicine Milton S. Hershey Medical Center Hershey, Pennsylvania 17033 Received 31 March 1975. REFERENCES 1. BURTON JR, LICHTENSTEIN NS, COLVIN RB, et al: Acute renal
failure during cephalothin therapy. JAMA 229:679-682, 1974 2. BOBROW SN, JAFFE E, YOUNG RC: Anuria and acute tubular
necrosis associated with gentamicin and cephalothin. JAMA 222: 1546-1547, 1972 3. PICKERING MJ, SPOONER GR, DEQUESADA A, et al:
Declining
renal function associated with administration of cephalothin. South Med J 63:426-428, 1970 4. SIMPSON IJ: Nephrotoxicity and acute renal failure associated with cephalothin and cephaloridine. NZ Med J 74:312-315, 1971 5. BALDWIN DS, LEVINE BB, MCCLUSKEY RT, et al: Renal failure
and interstitial nephritis due to penicillin and methicillin. N Engl J Med 279:1245-1252, 1968
Coumadin®-lnduced Necrosis of Breast, Disseminated Intravascular Coagulation, and Hemolytic Anemia T H E D E V E L O P M E N T of infarction a n d necrosis of t h e skin and s u b c u t a n e o u s tissue is an u n c o m m o n complication of
anticoagulant t h e r a p y with c o u m a r i n derivatives. W e have recently cared for a patient with bilateral breast necrosis due to sodium warfarin ( C o u m a d i n ® ) whose illness w a s complicated by disseminated intravascular coagulation a n d m i c r o a n g i o p a t h i c hemolytic anemia. A l t h o u g h intravenous heparin h a s been r e p o r t e d to b e of value in t h e t r e a t m e n t of c o u m a r i n necrosis ( 1 , 2 ) , w e a r e u n a w a r e of a n y previous case in which disseminated intravascular coagulation has been d o c u m e n t e d . W e present here a case in which bilateral breast necrosis o c c u r r e d after the u s e of sodium warfarin ( C o u m a d i n ) . A 59-year-old woman was admitted to a local hospital because of right ileofemoral thrombophlebitis. The patient was treated with intravenous heparin for 8 days, and the signs of thrombophlebitis disappeared. She was then begun on sodium warfarin (Coumadin), 2.5 mg/day. On the fourth day of Coumadin therapy, the patient suddenly developed bruises over both breasts. She had had no history of trauma. The skin developed blisters filled with serosanguineous fluid. The following day the breasts became very painful and turned black, and the patient was transferred to the Massachusetts General Hospital. On examination the patient was markedly obese and seemed toxic. Her temperature was 39.2 °C. There were petechiae and ecchymoses on the lower extremities. Her breasts were swollen with a central purple-black area surrounded by an erythematous rim that was exquisitely tender. There were no residual findings of the right leg thrombophlebitis. Initial laboratory data showed a hematocrit of 2 5 % , a leukocyte count of 12 400/mm 3 , a platelet count of 47 000/mm 3 , and a reticulocyte count of 1 2 % . The differential included 77 neutrophils, 5 bands, 16 lymphocytes, and 1 eosinophil. There were various helmet cells, triangular-shaped cells and schistocytes, occasional spherocytes, and decreased platelets on the blood smear. Additional laboratory data included prothrombin time, 13.6 seconds (normal, 11.2 seconds); partial thromboplastin time, 44.9 seconds (normal, 25 to 37 seconds); fibrinogen, 0.29 g/100 ml (normal, 0.15 to 0.29 g/100 m l ) ; and fibrin-split products by the staphylococcal clumping test, 153.6 fig/m\ (normal, less than 9.6 yug/ml). The direct and indirect Coombs' tests showed negative results. Tests of liver and kidney function, urinalysis, lumbar puncture, electrocardiogram, and chest roentgenogram were unremarkable. A bone marrow aspirate showed increased megakaryocytes and erythroid hyperplasia. A skin biopsy from the edge of the area of skin necrosis showed hemorrhage, mostly in the reticular dermis, and marked fibrin thrombi in small venules without any vasculitis. The patient's course is summarized in Figure \A. She was started on penicillin G, 10 000 000 units intravenously per day and sodium heparin, 5000 units intravenously every 4 hours. On the fourth day the patient developed a recurrence of the right ileofemoral thrombophlebitis, despite what was considered adequate anticoagulation by partial thromboplastin time determinations. The treatment was changed to continuous heparin infusion with resolution of the phlebitis during the next week. Despite general improvement in the patient's condition, dry gangrene of the breast developed (Figure \B), and the patient underwent bilateral simple mastectomy. Her recovery was uneventful. The surgical specimen showed necrotic skin and subcutaneous tissue with multiple small venous thrombi. There was no evidence of vasculitis. C o u m a r i n necrosis h a s a m a r k e d predilection for areas with a b u n d a n t s u b c u t a n e o u s fat, such as t h e thighs a n d buttocks a n d , less c o m m o n l y , t h e a b d o m e n a n d breasts. It occurs between the third a n d tenth days of t h e r a p y a n d develops almost exclusively in w o m e n w h o a r e usually obese. T h e lesions a p p e a r suddenly a n d are characterized by the d e v e l o p m e n t of pain, e r y t h e m a , edema, a n d h e m o r rhagic bullae, followed by necrosis, sloughing of the eschar, Letters
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233
coagulation data to determine whether or not disseminated intravascular coagulation was present. T h e histologic resemblance of c o u m a r i n necrosis to the localized S h w a r t z m a n reaction, the reported beneficial effect of heparin therapy in some cases of c o u m a r i n necrosis, and the discovery of disseminated intravascular coagulation a n d microangiopathic hemolytic a n e m i a in t h e present case suggest that disseminated intravascular coagulation m a y play a significant role in the pathogenesis of c o u m a r i n necrosis. Clarification of the role of disseminated intravascular coagulation in c o u m a r i n necrosis will require systematic coagulation studies being done early in the course of this s y n d r o m e in additional patients. MARIO-ANTOINE DICATO, M.D. LEONARD E L L M A N , M . D .
Hematology Unit Massachusetts General Hospital Boston, Massachusetts 02114 Received
24 March
1975.
REFERKNCES
1. BF.LLER F K : Therapie der sogenannten Med Bilddienst 4:116-118, 1961
"Cumarin
Nekrosen."
2. NALBANDIAN R M , BELLER FK, K A M P AL, et al: C o u m a r i n necro-
sis of skin treated successfully with heparin. Obstet Gynecol 38: 395-399, 1971 3. I.IEB F : Uber die Kumarinnekrose und ihre Beziehung zum Schwartzman-Sanarelli-Phanomen. Zbl Chir 89:81-90, 1964 4. H J O R T
PR,
RAPPAPORT SI, JORC.ENSON L:
Purpura
fulminans.
Report of a case successfully treated with heparin and hydrocortisone. Review of 50 cases from the literature. Scatid J Haematol 1:169-192, 1964 5. GOOD RA, THOMAS L: Studies on the generalized Shwartzman reaction. IV. Prevention of the local and generalized Shwartzman reactions with heparin. J Exp Med 97:871-888, 1953
Figure l a (top). Course of our patient. Fibrin-split products (FSP) measured by the staphylococcal clumping test. 5000 units of heparin were administered every 4 hours for the first 3 days (hatched bar), followed by 24 000 units per day by continuous infusion for 5 days (so//'d bar). The patient then received 4000 units of heparin every 4 hours from Day 8 until Day 21 (hatched bar), l b (bottom). Massive gangrene of both breasts on the day before surgical amputation.
and healing with various degrees of scarring. Lesions have occasionally required a m p u t a t i o n , as was true in o u r case. T h e pathogenesis of this rare complication of the c o u m a rins is u n k n o w n . T h e evidence for disseminated intravascular coagulation in otir patient included t h r o m b o c y t o p e n i a , large a m o u n t s of fibrin-split products, histologic demonstration of fibrin occlusion of small blood vessels, a n d a microangiopathic hemolytic anemia. We are u n a w a r e of any previous report of disseminated intravascular coagulation in association with c o u m a r i n necrosis. T h e r e is a morphologic similarity between c o u m a r i n necrosis and the localized S h w a r t z m a n reaction a n d the cutaneotis lesion of p u r p u r a fulminans ( 3 ) . Disseminated intravascular coagulation is the hallmark of both the S h w a r t z m a n reaction and p u r p u r a fulminans, and the beneficial effect of heparin in blocking intravascular coagulation and ameliorating the skin lesions in these conditions has been shown ( 4 , 5 ) . Citing the ability of heparin to inhibit thrombosis of small vessels, Beller ( 1 ) and N a l bandian and colleagues ( 2 ) have reported successful treatment of c o u m a r i n necrosis with intravenous heparin. U n fortunately, their published cases d o not present sufficient 234
Propranolol Effect on Tremor in Alcoholic Withdrawal ALCOHOLIC
TREMOR
frequently
appears
in
Four chronic alcoholics admitted to the Clinical Investigation Unit of the Addiction Research Foundation were selected for a single-blind study of intravenous propranolol by the following criteria: (a) they were in severe withdrawal, characterised by elevated heart rates (exceeding 90 beats per minute), profuse sweating, and extreme tremulousness, and (b) they had no history of cardiovascular disease or asthma. Prior to withdrawal, all subjects had been consuming at least 150 g of ethanol per day for more than 2 weeks. Informed consent for the sttidy was obtained in all cases. Subjects were seated comfortably and an indwelling venous cannula was inserted with a three-way stopcock attached to allow for injection of the drug and blood sampling. A-33 g piezoelectric accelerometer (Brtiel and Kjaer type 4332*) was firmly affixed to the first phalanx of the right index
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WITHDRAWAL
chronic alcoholics 6 to 48 hours after the cessation of longterm heavy alcohol c o n s u m p t i o n ( 1 ) . T h e t r e m o r is often sufficiently large to cause an i m p a i r m e n t of coordinated m o t o r activity a n d can be a major source of anxiety for the subject. Oral propranolol has been shown to be effective in d e creasing essential, familial, a n d senile tremors ( 2 ) , while intravenous injections (5 m g ) significantly reduce the t r e m o r of anxious and thyrotoxic subjects ( 3 ) . Because of the success of p r o p r a n o l o l in other pathological states w h e r e t r e m o r is a principle part of the s y n d r o m e , it was felt that the drug might also be successful in alcoholic withdrawal.
* Briiel and Kjaer, Copenhagen, Denmark.
finger and the forearm was supported on a flat surface up to the wrist. For each tremor measurement, which lasted 40 to 50 seconds, the subject held the hand outstretched with the fingers together. The small voltages generated by the accelerometer in response to the tremor were amplified, low-pass filtered at 30 Hz, and recorded on a Hewlett-Packard 3960 FM tape recorder*. After a rest period of 15 to 20 minutes, a placebo injection of normal saline (1 ml) was administered during 5 seconds. Ten minutes later propranolol (0.1 or 0.5 mg) was injected in an identical manner. Blood samples were drawn at 10-minute intervals after the injection, and tremor was recorded 1 minute after each sample was taken. Repeat injections of propranolol were given 20 and 40 minutes after the initial dose if the preceding one was not sufficient to decrease the tremor by 2 0 % below the baseline value. The tape-recorded tremor signals were digitized at 156 Hz, stored on digital magnetic tape, and analyzed on an IBM 360/44 computer!. Segments of 26.25 seconds were selected from the raw tremor data with an IBM 2250 graphics termi nalt connected to the computer, and band filtered between * Hewlett-Packard Co., Palo Alto, California. t International Business Machines Corp., White Plains, New York.
3 to 30 Hz with a zero-phase nonrecursive, Fast Fourier transform digital filter. The mean square ( M S ) value, which gives a number proportional to the "intensity" of the hand tremor, was calculated for all tremor records using the appropriate numerical algorithms. Serum propranolol concentrations were measured in all blood samples ( 4 ) . T h e effect of intravenous p r o p r a n o l o l on t h e t r e m o r size and frequency in o n e subject is shown in Figure 1. T h e t r e m o r size fell by 9 5 % within 30 minutes, a n d the t r e m o r frequency increased t o w a r d s the value seen in n o r m a l subjects. H e a r t rate was initially unaffected but did fall slightly at 70 minutes after t h e placebo injection. T h e h a n d t r e m o r of t h e other subjects was similarly r e duced by p r o p r a n o l o l , but changes in t r e m o r frequency were m u c h less a p p a r e n t . F o r all subjects, t h e initial small dose of intravenous p r o p r a n o l o l p r o d u c e d the largest decrease in t r e m o r , while subsequent injections w h e n administered were found to be correspondingly less effective. Anxiety a n d thyrotoxicosis a r e both associated with an increase in t r e m o r a m p l i t u d e . T h e r e is evidence ( 5 ) to suggest that increased c a t e c h o l a m i n e production in anxiety or a u g m e n t e d sensitivity to adrenaline in thyrotoxicosis causes increased t r e m o r by m e c h a n i s m s that a r e related to an increase in the speed of skeletal muscle contraction a n d changes in n e u r o m u s c u l a r transmission or muscle spindle activity, all of which a r e mediated by the peripheral /?receptors. Both anxiety a n d thyrotoxic t r e m o r s a r e significantly reduced by intravenous p r o p r a n o l o l ( 3 ) . Alcoholic w i t h d r a w a l is associated with raised plasma and u r i n a r y catecholamines a n d clinical signs indicating increased sympathetic activity. It follows, therefore, that increases in circulating catecholamines m a y account for the increased t r e m o r in withdrawal. It has been shown that the /^-blocking drug, p r o p r a n o l o l , dramatically redu es w i t h d r a w a l t r e m o r . Because of the rapid onset of t h e effect and the d e m o n s t r a t e d peripheral site of action of p r o p r a n o lol in other h y p e r a d r e n e r g i c states, t h e action of p r o p r a n o lol in reducing alcoholic w i t h d r a w a l t r e m o r m a y be by blockade of the peripheral /^-receptors. D U A N E H . Z l L M , B.A.SC, M.PHIL., D.I.C. EDWARD M. SELLERS, M.D., PH.D., F . R . C P . ( C ) STUART M . M A C L E O D , M.D., PH.D., F . R . C P . ( C ) N A E E M A DEGANI, M.B.B.S.
Clinical Institute Alcohol and Drug Addiction Research Foundation 33 Russell Street Toronto, Ontario, M5S 2S1, Canada Toronto Western Hospital 399 Bathurst Street Toronto, Ontario, M5T 2S8, Canada Departments of Pharmacology and Medicine, and The Institute of Biomedical Engineering University of Toronto Toronto, Ontario, Canada Received 27 December 1974. REFERENCES 1. GROSS MM, LEWIS E, HASTEY J: Acute alcohol withdrawal syn-
drome, in The Biology of Alcoholism, vol. 3 of Clinical Pathology, edited by KISSIN B, BEGLEITER H. New York, Plenum Press, 1974, p. 191 2. WINKLER GF, YOUNG RR: Efficacy of chronic propranolol therapy in action tremors of the familial, senile or essential varieties. N Engl J Med 290:984-988, 1974 Figure 1. Influence of intravenous propranolol on withdrawal tremor and heart rate.
3. MARSDEN CD, GIMLETTE TM, MCALLISTER RG, et al:
Letters
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Effects
of /^-adrenergic blockade on finger tremor and achilles reflex
235
time in anxious and thyrotoxic patients. Acta Endocrinol 57: 353-362, 1968 4. SHAND DG,
NUCKOLLS EM, OATES JA:
Plasma
5. MARSDEN CD, MEADOWS JC, LANGE GW: Effect of speed of
propranolol
levels in adults with observations in four children. Clin Pharmacol Ther 11:112-120, 1970
muscle contraction on physiological tremor in normal subjects and in patients with thyrotoxicosis and myxoedema. J Neurol Neurosurg Psychiatry 33:776-782, 1970
The Teaching of Medical History . . . the physician-professional-historian is undoubtedly the best qualified person to teach medical history (11). However, present limitations associated with admission to medical schools, the length and cost of education, an uncertain job market for historians, and the temptations of a decidedly more prosperous practice of medicine will continue to deter qualified applicants from pursuing such a dual career. Thus, professional historians should be encouraged to work and teach in fields related to medicine, especially those areas related to the social history of medicine which do not require any professional medical training. The advantage inherent in a teacher with both a medical and historical background is the capacity to better perceive the relevance of certain contemporary issues with the subsequent employment of historical antecedents to explain or clarify these questions. Therefore, it is preferable to have a physician-historian at least as the coordinator or adviser for the previously outlined teaching program. Ideally the competent teacher should be committed to the subject on a full-time basis in order to research and prepare an issue-oriented teaching program in medical history. Whether the historian heads an independent department in the medical school, is a member in a clinical department, or shares membership in a history or history of science department will depend on the particular institutional conditions and traditions. However, failure to belong in any capacity to the health sciences unit on campus would seriously hamper the teaching of health professionals. GUENTER B. RlSSE, M.D., PH.D. The Role of Medical History in the Education of the "Humanist" Physician: A Reevaluation Journal of Medical Education 50:458-465, 1975
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Letters that report new clinical or laboratory observations; cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style.
with duplication of the Ph 1 chromosome entered an acute phase of their disease, but it must be pointed out that there are a few who did not ( 3 ) . From a cytogenetic standpoint, acute transition of chronic granulocytic leukaemia is frequently characterized by an increased number of chromosomes due to preferential gain of additional chromosomes ( 4 ) . This is also true in the present observation. Thus, this chromosomal marker would give strong evidence for extramedullary acute transition in chronic granulocytic leukaemia. Cytologic evidence for this hypothesis has previously been presented by others (2) *. F. OBERLING, M.D. C. STOLL J. M. LANG G. MAYER
Duplication of Philadelphia Chromosome in Acute Transition of Chronic Granulocytic Leukaemia DUPLICATION of the Philadelphia (Ph 1 ) chromosome is known to occur in the course of chronic granulocytic leukaemia ( 1 ) . Usually, if not always, this acquired cytogenetic development precedes or occurs with an acute transition of chronic granulocytic leukaemia. The acute phase of chronic granulocytic leukaemia with duplication of the Ph 1 chromosome is frequently associated with the development of enlarged myeloid lymph nodes, resembling reticulum cell malignancies on histologic examination ( 2 ) . We present here a pertinent case report of a 39-year-old woman with typical chronic granulocytic leukaemia whom we have followed for 7 years. She was treated with successive courses of busulfan and hydroxyurea. In 1973, she was readmitted to our clinic because of fever and increasing pain in bones, joints, and muscles. We noted on physical examination a moderate splenomegaly and enlarged lymph nodes in the cervical and inguinal areas. The hemoglobin level was 8.7 g/100 ml; leukocyte count, 23 000/ mm3 with metamyelocytes, myelocytes, and 3% myeloblasts; platelets, 420 000/mm3. A bone marrow aspirate showed hypercellularity with 3% promyelocytes and 8% myeloblasts. Histopathology of a lymph node biopsy specimen was classified as reticulum cell sarcoma. Cytologic examination, however, showed a mixed myeloid cell population infiltrating the lymph node. Chromosome analysis on bone marrow and lymph node cells showed a similar pattern, that is, presence of a Ph1 chromosome and lack of a group of G chromosome. Subsequently, an increasing number of blast cells in peripheral blood and bone marrow signalled the acute transition of the disease. A splenectomy was done, and the spleen weight was 1.4 kg. Histologic and cytologic examination of the spleen showed a diffuse infiltration with myeloid cells. On chromosome analysis, two Ph1 chromosomes were detected in all dividing cells in the spleen (screening of 100 mitotic figures). After splenectomy and without any chemotherapy, the absolute number of myeloblasts in the peripheral blood dropped 6800/mm3 to 0/mm3 within 12 days. This observation shows that an extramedullary clonal development with duplication of the Ph 1 chromosome has occurred in the spleen simultaneously with an acute transition of chronic granulocytic leukaemia. Myeloid cells in bone marrow and the lymph node did not show this chromosomal development. In most cases reported, the patients
Service des Maladies du Sang, et Laboratoire de Cytogenetique Clinique Infantile CHU 67000 Strasbourg, France Received 2 April 1975. REFERENCES
1. HAMMOUDA F, QUAGLINO D, HAYHOE FGJ: Blastic crisis in chron-
ic granulocytic leukaemia. Cytochemical, cytogenetic, and autoradiographic studies in four cases. Br Med J 5393:1275-1281, 1964 2. GARFINKEL LS, BENNETT DE: Extramedullary myeloblasts transformation in chronic myelocytic leukemia simulating a coexistent malignant lymphoma. Am J Clin Pathol 51:638-645, 1969 3. DUVALL CP, CARBONE PP, BELL WR: Chronic myelocytic leuke-
mia with two Philadelphia chromosomes and prominent peripheral lymphadenopathy. Blood 29:652-666, 1967 4. GROUCHY J DE, NAVA C DE, FEINGOLD J: Onze observations d'un
modele precis devolution caryotypique au cours de la leucemie myeloide chronique. Eur J Cancer 4:481-492, 1968 * Since this letter was sent out, L. Brandt and D. K. Hossfeld have presented evidence for extramedullary acute transition in some chronic granulocytic leukaemias. [Personal communication from Dr. Oberling, 16 June 1975.]
Acute Dystonic Reaction Due to Benzquinamide ACUTE DYSTONIC REACTION due to short-term,
low-dose
prochlorperazine (Compazine®) therapy is a well-known adverse drug reaction (1) that occurs in approximately 0.5% of the general medical patient-population ( 2 ) . We report here a case in which a patient developed a dystonic reaction when given a single dose of benzquinamide (Emete-con®), an antiemetic agent chemically unrelated to the phenothiazines. A 30-year-old man was admitted to receive chemotherapy for his Hodgkin's disease (stage IV, nodular). This diagnosis was originally made in 1972, and he has been treated with six cycles of COPP combination chemotherapy (Cytoxan®, Oncovin®, procarbazine, prednisone). He is currently receiving the ABVD regimen of therapy (adriamycin, bleomycin, vincristine, DTIC) and was admitted for the third cycle of treatment. The patient's history included recurrent nausea and vomiting associated with his chemotherapy, which were relieved somewhat by premedication with prochlorperazine. Present physical findings and laboratory reports were essentially normal
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and consistent for a person with this disease. The patient was given prophylactic antiemetic therapy corresponding with his course of chemotherapy as follows. Day 1 Prochlorperazine, rectal 25 mg 1 dose Prochlorperazine, intramuscularly (i.m.) 10 mg 3 doses 10 mg 1 dose Day 2 Prochlorperazine, i.m. Day 3 Benzquinamide, i.m. 50 mg 1 dose Approximately 10 minutes after receiving the prochlorperazine on Day 2 (total dose received for 2 days, 40 mg i.m., and 25 mg rectally), the patient experienced sudden difficulty talking, with a tightening of tongue musculature. He developed a wide palpebral angle and had some difficulty with upward gaze. These symptoms were immediately diagnosed as oculogyric crisis secondary to prochlorperazine. Intramuscular diphenhydramine (Benadryl®), 25 mg, was administered, and all manifestations returned to normal within 15 minutes. Because of the previous day's events, antiemetic prophylaxis before chemotherapy was attempted with 50 mg of benzquinamide, i.m., on Day 3. Again, the patient developed difficulty in speaking and swallowing, with tightening of the tongue musculature. Torticollis, spasm of the occipitalis frontalis muscles, and wide stare were also observed. All symptoms were relieved within 10 minutes after 50 mg of diphenhydramine, i.m. B e n z q u i n a m i d e is a benzoquinolizine derivative effective parenterally in t h e t r e a t m e n t a n d prevention of druginduced emesis, with a low incidence of associated adverse reactions ( 3 ) . This is t h e first case report of a n acute dystonic reaction d u e to low-dose b e n z q u i n a m i d e therapy. Severe behavioral toxicity h a s been reported in some p a tients receiving m o r e than 800 m g of b e n z q u i n a m i d e ( 4 ) . A l t h o u g h several m e c h a n i s m s o r contributing factors of phenothiazine-induced dystonic dyskinesia have been suggested ( 1 , 2, 5 ) this adverse reaction seems to b e idiosyncratic, based on individual hyperreactivity. W e n o w present t h e possibility that this same predisposition m a y exist for a chemically unrelated therapeutic agent a n d that an individual might display dystonic cross-sensitivity b e tween the phenothiazine a n d benzoquinolizine antiemetics. W i t h this possibility in mind, w e m a y expect t o see additional reports of b e n z q u i n a m i d e adverse reactions in t h e future.
developed a n e r y t h e m a t o u s lesion at t h e extravasation site, which ultimately necrosed, ulcerated, a n d slowly began to heal at about \Vi m o n t h s after t h e accident. After this incident t h e patient received multiple courses of nitrogen m u s t a r d a n d vinblastine w i t h o u t a p p a r e n t difficulty. T w o m o n t h s after t h e extravasation of a d r i a m y c i n ( a t a time w h e n t h e w o u n d seemed well o n its w a y t o h e a l i n g ) , a n other course of a d r i a m y c i n w a s given in a n o t h e r extremity without difficulty. W i t h i n 2 days t h e lesion manifested a significant increase in e r y t h e m a , pain, drainage, a n d i m paired healing, which h a s n o w c o n t i n u e d with m i n i m a l i m p r o v e m e n t b y 8 weeks. N o other event seemed r e sponsible for this exacerbation in clinical findings. T h e w o u n d h a s never seemed infected, a n d cultures have s h o w n the presence of skin flora. T h e r e h a s been n o evidence of peripheral vascular disease. R e c e n t experience suggests that a d r i a m y c i n m a y b e r a d i o m i m e t i c , causing skin d a m a g e in areas of previously irradiated skin ( 1 ) . W e feel that this is a similar c i r c u m stance, w h e r e tissue d a m a g e d by exposure t o a d r i a m y c i n manifested further d a m a g e a n d necrosis after re-exposure to this agent. P r i o r tissue d a m a g e b y extravasation of a d r i a m y c i n m a y b e a relative contraindication t o further a d r i a m y c i n therapy. W e a r e n o t p l a n n i n g further a d r i a m y c i n t h e r a p y unless complete healing occurs o r t h e present clinical situation changes such that adriamycin, previously efficacious, seems warranted. W e would b e interested if others have had a similar experience. S T E P H E N C. C O H E N , M . D . N I C H O L A S J. D I B E L L A , M . D . J O H N C. M I C H A L A K , M . D .
Department of Medicine Fitzsimons Army Medical Center Denver, CO 80240 Received 28 April 1975. REFERENCE 1. DONALDSON SS, GLICK JM, WILBUR JR: Adriamycin activating
a recall phenomenon after radiation therapy. Ann Intern Med 81:407-408, 1974
T H O M A S E. R O S E , M . D . S T E V E N D . A V E R B U C H , B.S., R . P H .
University of Chicago Hospitals and Clinics Chicago, Illinois 60637
Reversible Acute Renal Failure After Cephalothin
Received 7 April 1975. REFERENCES
1. AYD F : A survey of drug-induced extrapyramidal reactions. JAMA 175:1054-1060, 1961 2. BOSTON COLLABORATIVE DRUG SURVEILLANCE PROGRAM:
Drug-
induced extrapyramidal symptoms. JAMA 224:889-891, 1973 3. KLEIN R, GRAVES C, K I M Y, et al: Inhibition of apomorphine-
induced vomiting by benzquinamide. Clin Pharmacol Ther 11: 99-106, 1970 4. BISHOP M, GALLANT D : Behavioral toxicity associated with benzquinamide (Quantril) therapy in schizophrenic patients. Am J Psychiatry 120:180-181, 1963 5. SCHAAF M, PAYNE C: Dystonic reactions to prochlorperazine in hypoparathyroidism. N Engl J Med 275:991-995, 1966
Recall Injury from Adriamycin WE
HAVE R E C E N T L Y S E E N a 6 3 - y e a r - o l d m a n w i t h
mixed
cell H o d g k i n ' s disease w h o h a s been receiving multiple agent c h e m o t h e r a p y for difficult-to-control retroperitoneal disease. O n e of t h e agents t h e patient h a s received is adriamycin. After extravasation of a d r i a m y c i n , t h e patient 232
W E R E C E N T L Y TREATED a patient with oliguric acute renal failure after cephalothin (Keflin®) t h e r a p y . This 48-year-old man was referred to the M. S. Hershey Medical Center because of azotemia and oliguria. Twelve days before admission he was admitted to another hospital for right renal colic. His blood urea nitrogen ( B U N ) was 15 mg/dl; an intravenous pyelogram showed a normal left kidney and nonvisualization of the right kidney, with several calcific densities in the area of the right kidney. Because of fever, he was given cephalothin intravenously, 16 g/day for 8 days. On the eighth day of therapy, oliguria was noted, his B U N was 79 mg/dl, and serum creatinine was 9.5 mg/dl. He was transferred to our institution. His blood pressure was 150/90 m m Hg, his temperature was 37.5 °C, and he had moderate edema and a diffuse maculopapular rash. His hematocrit was 3 3 % ; leukocyte count, 31 000/mm 3 with no eosinophilia; BUN, 89 mg/dl; and serum creatinine, 11.3 mg/dl. His urine contained 100 mg/dl albumin, 30 to 40 leukocytes/high power field, and 8 to 10 erythrocytes/high power field, with no erythrocyte casts. He stated that a rash had occurred after penicillin administration several years previously. An infusion intra-
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venous pyelogram showed poor visualization, and a cystoscopy and left retrograde pyelogram showed normal results. Intermittent hemodialysis was begun because of marked oliguria and fluid overload. This was continued until 3 weeks after admission because of a urine volume less than 300 ml/day and a serum creatinine above 9 mg/dl. His renal function slowly improved, and 6 weeks after admission his BUN was 44 mg/dl, and his serum creatinine was 2.8 mg/dl. He developed an eosinophilia of 30% during the third week in the hospital. During his hospitalization he required a right nephrolithotomy and nephrostomy for pyonephrosis; this has subsequently closed spontaneously. Five months after admission his BUN was 13 mg/dl, and his serum creatinine was 1.4 mg/dl. Acute renal failure o c c u r r e d in this patient after h e r e ceived only cephalothin. A recent report described five p a tients with similar courses of acute renal failure temporally related to cephalothin therapy, b u t three of these patients had also been given other potentially n e p h r o t o x i c antibiotics ( 1 ) . Also, n o previously reported case of renal failure after cephalothin t h e r a p y has been severe e n o u g h to require dialysis. Others have reported renal failure during therapy with both cephalothin a n d gentamicin ( 2 ) , a n d cephalothin, in high doses, h a s caused reversible impairm e n t of renal function in patients with preexisting renal disease ( 3 ) . T h e previous history of penicillin allergy a n d subsequent renal failure after cephalothin in o u r patient is similar to that reported in a n o t h e r patient ( 4 ) a n d suggests some type of hypersensitivity reaction. T h e p a t h o genesis m a y be similar to that which occurs in acute renal failure with interstitial nephritis after penicillin, methicillin, and other penicillin analogues ( 5 ) . Cephalothin should be administered with great caution to patients with a history of penicillin allergy, and, if it is given, t h e patient should be carefully m o n i t o r e d for d e creased renal function a n d manifestations of hypersensitivity, such as fever, eosinophilia, o r a rash. In addition, high doses of cephalothin should be avoided in patients with preexisting renal disease. J O H N E. E N G L E , M . D . JOSEPH DRAGO, M.D. BRUCE CARLIN, M.D. A N T O N C. S C H O O L W E R T H , M . D .
Renal Division Department of Medicine Milton S. Hershey Medical Center Hershey, Pennsylvania 17033 Received 31 March 1975. REFERENCES 1. BURTON JR, LICHTENSTEIN NS, COLVIN RB, et al: Acute renal
failure during cephalothin therapy. JAMA 229:679-682, 1974 2. BOBROW SN, JAFFE E, YOUNG RC: Anuria and acute tubular
necrosis associated with gentamicin and cephalothin. JAMA 222: 1546-1547, 1972 3. PICKERING MJ, SPOONER GR, DEQUESADA A, et al:
Declining
renal function associated with administration of cephalothin. South Med J 63:426-428, 1970 4. SIMPSON IJ: Nephrotoxicity and acute renal failure associated with cephalothin and cephaloridine. NZ Med J 74:312-315, 1971 5. BALDWIN DS, LEVINE BB, MCCLUSKEY RT, et al: Renal failure
and interstitial nephritis due to penicillin and methicillin. N Engl J Med 279:1245-1252, 1968
Coumadin®-lnduced Necrosis of Breast, Disseminated Intravascular Coagulation, and Hemolytic Anemia T H E D E V E L O P M E N T of infarction a n d necrosis of t h e skin and s u b c u t a n e o u s tissue is an u n c o m m o n complication of
anticoagulant t h e r a p y with c o u m a r i n derivatives. W e have recently cared for a patient with bilateral breast necrosis due to sodium warfarin ( C o u m a d i n ® ) whose illness w a s complicated by disseminated intravascular coagulation a n d m i c r o a n g i o p a t h i c hemolytic anemia. A l t h o u g h intravenous heparin h a s been r e p o r t e d to b e of value in t h e t r e a t m e n t of c o u m a r i n necrosis ( 1 , 2 ) , w e a r e u n a w a r e of a n y previous case in which disseminated intravascular coagulation has been d o c u m e n t e d . W e present here a case in which bilateral breast necrosis o c c u r r e d after the u s e of sodium warfarin ( C o u m a d i n ) . A 59-year-old woman was admitted to a local hospital because of right ileofemoral thrombophlebitis. The patient was treated with intravenous heparin for 8 days, and the signs of thrombophlebitis disappeared. She was then begun on sodium warfarin (Coumadin), 2.5 mg/day. On the fourth day of Coumadin therapy, the patient suddenly developed bruises over both breasts. She had had no history of trauma. The skin developed blisters filled with serosanguineous fluid. The following day the breasts became very painful and turned black, and the patient was transferred to the Massachusetts General Hospital. On examination the patient was markedly obese and seemed toxic. Her temperature was 39.2 °C. There were petechiae and ecchymoses on the lower extremities. Her breasts were swollen with a central purple-black area surrounded by an erythematous rim that was exquisitely tender. There were no residual findings of the right leg thrombophlebitis. Initial laboratory data showed a hematocrit of 2 5 % , a leukocyte count of 12 400/mm 3 , a platelet count of 47 000/mm 3 , and a reticulocyte count of 1 2 % . The differential included 77 neutrophils, 5 bands, 16 lymphocytes, and 1 eosinophil. There were various helmet cells, triangular-shaped cells and schistocytes, occasional spherocytes, and decreased platelets on the blood smear. Additional laboratory data included prothrombin time, 13.6 seconds (normal, 11.2 seconds); partial thromboplastin time, 44.9 seconds (normal, 25 to 37 seconds); fibrinogen, 0.29 g/100 ml (normal, 0.15 to 0.29 g/100 m l ) ; and fibrin-split products by the staphylococcal clumping test, 153.6 fig/m\ (normal, less than 9.6 yug/ml). The direct and indirect Coombs' tests showed negative results. Tests of liver and kidney function, urinalysis, lumbar puncture, electrocardiogram, and chest roentgenogram were unremarkable. A bone marrow aspirate showed increased megakaryocytes and erythroid hyperplasia. A skin biopsy from the edge of the area of skin necrosis showed hemorrhage, mostly in the reticular dermis, and marked fibrin thrombi in small venules without any vasculitis. The patient's course is summarized in Figure \A. She was started on penicillin G, 10 000 000 units intravenously per day and sodium heparin, 5000 units intravenously every 4 hours. On the fourth day the patient developed a recurrence of the right ileofemoral thrombophlebitis, despite what was considered adequate anticoagulation by partial thromboplastin time determinations. The treatment was changed to continuous heparin infusion with resolution of the phlebitis during the next week. Despite general improvement in the patient's condition, dry gangrene of the breast developed (Figure \B), and the patient underwent bilateral simple mastectomy. Her recovery was uneventful. The surgical specimen showed necrotic skin and subcutaneous tissue with multiple small venous thrombi. There was no evidence of vasculitis. C o u m a r i n necrosis h a s a m a r k e d predilection for areas with a b u n d a n t s u b c u t a n e o u s fat, such as t h e thighs a n d buttocks a n d , less c o m m o n l y , t h e a b d o m e n a n d breasts. It occurs between the third a n d tenth days of t h e r a p y a n d develops almost exclusively in w o m e n w h o a r e usually obese. T h e lesions a p p e a r suddenly a n d are characterized by the d e v e l o p m e n t of pain, e r y t h e m a , edema, a n d h e m o r rhagic bullae, followed by necrosis, sloughing of the eschar, Letters
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233
coagulation data to determine whether or not disseminated intravascular coagulation was present. T h e histologic resemblance of c o u m a r i n necrosis to the localized S h w a r t z m a n reaction, the reported beneficial effect of heparin therapy in some cases of c o u m a r i n necrosis, and the discovery of disseminated intravascular coagulation a n d microangiopathic hemolytic a n e m i a in t h e present case suggest that disseminated intravascular coagulation m a y play a significant role in the pathogenesis of c o u m a r i n necrosis. Clarification of the role of disseminated intravascular coagulation in c o u m a r i n necrosis will require systematic coagulation studies being done early in the course of this s y n d r o m e in additional patients. MARIO-ANTOINE DICATO, M.D. LEONARD E L L M A N , M . D .
Hematology Unit Massachusetts General Hospital Boston, Massachusetts 02114 Received
24 March
1975.
REFERKNCES
1. BF.LLER F K : Therapie der sogenannten Med Bilddienst 4:116-118, 1961
"Cumarin
Nekrosen."
2. NALBANDIAN R M , BELLER FK, K A M P AL, et al: C o u m a r i n necro-
sis of skin treated successfully with heparin. Obstet Gynecol 38: 395-399, 1971 3. I.IEB F : Uber die Kumarinnekrose und ihre Beziehung zum Schwartzman-Sanarelli-Phanomen. Zbl Chir 89:81-90, 1964 4. H J O R T
PR,
RAPPAPORT SI, JORC.ENSON L:
Purpura
fulminans.
Report of a case successfully treated with heparin and hydrocortisone. Review of 50 cases from the literature. Scatid J Haematol 1:169-192, 1964 5. GOOD RA, THOMAS L: Studies on the generalized Shwartzman reaction. IV. Prevention of the local and generalized Shwartzman reactions with heparin. J Exp Med 97:871-888, 1953
Figure l a (top). Course of our patient. Fibrin-split products (FSP) measured by the staphylococcal clumping test. 5000 units of heparin were administered every 4 hours for the first 3 days (hatched bar), followed by 24 000 units per day by continuous infusion for 5 days (so//'d bar). The patient then received 4000 units of heparin every 4 hours from Day 8 until Day 21 (hatched bar), l b (bottom). Massive gangrene of both breasts on the day before surgical amputation.
and healing with various degrees of scarring. Lesions have occasionally required a m p u t a t i o n , as was true in o u r case. T h e pathogenesis of this rare complication of the c o u m a rins is u n k n o w n . T h e evidence for disseminated intravascular coagulation in otir patient included t h r o m b o c y t o p e n i a , large a m o u n t s of fibrin-split products, histologic demonstration of fibrin occlusion of small blood vessels, a n d a microangiopathic hemolytic anemia. We are u n a w a r e of any previous report of disseminated intravascular coagulation in association with c o u m a r i n necrosis. T h e r e is a morphologic similarity between c o u m a r i n necrosis and the localized S h w a r t z m a n reaction a n d the cutaneotis lesion of p u r p u r a fulminans ( 3 ) . Disseminated intravascular coagulation is the hallmark of both the S h w a r t z m a n reaction and p u r p u r a fulminans, and the beneficial effect of heparin in blocking intravascular coagulation and ameliorating the skin lesions in these conditions has been shown ( 4 , 5 ) . Citing the ability of heparin to inhibit thrombosis of small vessels, Beller ( 1 ) and N a l bandian and colleagues ( 2 ) have reported successful treatment of c o u m a r i n necrosis with intravenous heparin. U n fortunately, their published cases d o not present sufficient 234
Propranolol Effect on Tremor in Alcoholic Withdrawal ALCOHOLIC
TREMOR
frequently
appears
in
Four chronic alcoholics admitted to the Clinical Investigation Unit of the Addiction Research Foundation were selected for a single-blind study of intravenous propranolol by the following criteria: (a) they were in severe withdrawal, characterised by elevated heart rates (exceeding 90 beats per minute), profuse sweating, and extreme tremulousness, and (b) they had no history of cardiovascular disease or asthma. Prior to withdrawal, all subjects had been consuming at least 150 g of ethanol per day for more than 2 weeks. Informed consent for the sttidy was obtained in all cases. Subjects were seated comfortably and an indwelling venous cannula was inserted with a three-way stopcock attached to allow for injection of the drug and blood sampling. A-33 g piezoelectric accelerometer (Brtiel and Kjaer type 4332*) was firmly affixed to the first phalanx of the right index
August 1975 • Annals of Internal Medicine • Volume 83 • Number 2
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WITHDRAWAL
chronic alcoholics 6 to 48 hours after the cessation of longterm heavy alcohol c o n s u m p t i o n ( 1 ) . T h e t r e m o r is often sufficiently large to cause an i m p a i r m e n t of coordinated m o t o r activity a n d can be a major source of anxiety for the subject. Oral propranolol has been shown to be effective in d e creasing essential, familial, a n d senile tremors ( 2 ) , while intravenous injections (5 m g ) significantly reduce the t r e m o r of anxious and thyrotoxic subjects ( 3 ) . Because of the success of p r o p r a n o l o l in other pathological states w h e r e t r e m o r is a principle part of the s y n d r o m e , it was felt that the drug might also be successful in alcoholic withdrawal.
* Briiel and Kjaer, Copenhagen, Denmark.
finger and the forearm was supported on a flat surface up to the wrist. For each tremor measurement, which lasted 40 to 50 seconds, the subject held the hand outstretched with the fingers together. The small voltages generated by the accelerometer in response to the tremor were amplified, low-pass filtered at 30 Hz, and recorded on a Hewlett-Packard 3960 FM tape recorder*. After a rest period of 15 to 20 minutes, a placebo injection of normal saline (1 ml) was administered during 5 seconds. Ten minutes later propranolol (0.1 or 0.5 mg) was injected in an identical manner. Blood samples were drawn at 10-minute intervals after the injection, and tremor was recorded 1 minute after each sample was taken. Repeat injections of propranolol were given 20 and 40 minutes after the initial dose if the preceding one was not sufficient to decrease the tremor by 2 0 % below the baseline value. The tape-recorded tremor signals were digitized at 156 Hz, stored on digital magnetic tape, and analyzed on an IBM 360/44 computer!. Segments of 26.25 seconds were selected from the raw tremor data with an IBM 2250 graphics termi nalt connected to the computer, and band filtered between * Hewlett-Packard Co., Palo Alto, California. t International Business Machines Corp., White Plains, New York.
3 to 30 Hz with a zero-phase nonrecursive, Fast Fourier transform digital filter. The mean square ( M S ) value, which gives a number proportional to the "intensity" of the hand tremor, was calculated for all tremor records using the appropriate numerical algorithms. Serum propranolol concentrations were measured in all blood samples ( 4 ) . T h e effect of intravenous p r o p r a n o l o l on t h e t r e m o r size and frequency in o n e subject is shown in Figure 1. T h e t r e m o r size fell by 9 5 % within 30 minutes, a n d the t r e m o r frequency increased t o w a r d s the value seen in n o r m a l subjects. H e a r t rate was initially unaffected but did fall slightly at 70 minutes after t h e placebo injection. T h e h a n d t r e m o r of t h e other subjects was similarly r e duced by p r o p r a n o l o l , but changes in t r e m o r frequency were m u c h less a p p a r e n t . F o r all subjects, t h e initial small dose of intravenous p r o p r a n o l o l p r o d u c e d the largest decrease in t r e m o r , while subsequent injections w h e n administered were found to be correspondingly less effective. Anxiety a n d thyrotoxicosis a r e both associated with an increase in t r e m o r a m p l i t u d e . T h e r e is evidence ( 5 ) to suggest that increased c a t e c h o l a m i n e production in anxiety or a u g m e n t e d sensitivity to adrenaline in thyrotoxicosis causes increased t r e m o r by m e c h a n i s m s that a r e related to an increase in the speed of skeletal muscle contraction a n d changes in n e u r o m u s c u l a r transmission or muscle spindle activity, all of which a r e mediated by the peripheral /?receptors. Both anxiety a n d thyrotoxic t r e m o r s a r e significantly reduced by intravenous p r o p r a n o l o l ( 3 ) . Alcoholic w i t h d r a w a l is associated with raised plasma and u r i n a r y catecholamines a n d clinical signs indicating increased sympathetic activity. It follows, therefore, that increases in circulating catecholamines m a y account for the increased t r e m o r in withdrawal. It has been shown that the /^-blocking drug, p r o p r a n o l o l , dramatically redu es w i t h d r a w a l t r e m o r . Because of the rapid onset of t h e effect and the d e m o n s t r a t e d peripheral site of action of p r o p r a n o lol in other h y p e r a d r e n e r g i c states, t h e action of p r o p r a n o lol in reducing alcoholic w i t h d r a w a l t r e m o r m a y be by blockade of the peripheral /^-receptors. D U A N E H . Z l L M , B.A.SC, M.PHIL., D.I.C. EDWARD M. SELLERS, M.D., PH.D., F . R . C P . ( C ) STUART M . M A C L E O D , M.D., PH.D., F . R . C P . ( C ) N A E E M A DEGANI, M.B.B.S.
Clinical Institute Alcohol and Drug Addiction Research Foundation 33 Russell Street Toronto, Ontario, M5S 2S1, Canada Toronto Western Hospital 399 Bathurst Street Toronto, Ontario, M5T 2S8, Canada Departments of Pharmacology and Medicine, and The Institute of Biomedical Engineering University of Toronto Toronto, Ontario, Canada Received 27 December 1974. REFERENCES 1. GROSS MM, LEWIS E, HASTEY J: Acute alcohol withdrawal syn-
drome, in The Biology of Alcoholism, vol. 3 of Clinical Pathology, edited by KISSIN B, BEGLEITER H. New York, Plenum Press, 1974, p. 191 2. WINKLER GF, YOUNG RR: Efficacy of chronic propranolol therapy in action tremors of the familial, senile or essential varieties. N Engl J Med 290:984-988, 1974 Figure 1. Influence of intravenous propranolol on withdrawal tremor and heart rate.
3. MARSDEN CD, GIMLETTE TM, MCALLISTER RG, et al:
Letters
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of /^-adrenergic blockade on finger tremor and achilles reflex
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The Teaching of Medical History . . . the physician-professional-historian is undoubtedly the best qualified person to teach medical history (11). However, present limitations associated with admission to medical schools, the length and cost of education, an uncertain job market for historians, and the temptations of a decidedly more prosperous practice of medicine will continue to deter qualified applicants from pursuing such a dual career. Thus, professional historians should be encouraged to work and teach in fields related to medicine, especially those areas related to the social history of medicine which do not require any professional medical training. The advantage inherent in a teacher with both a medical and historical background is the capacity to better perceive the relevance of certain contemporary issues with the subsequent employment of historical antecedents to explain or clarify these questions. Therefore, it is preferable to have a physician-historian at least as the coordinator or adviser for the previously outlined teaching program. Ideally the competent teacher should be committed to the subject on a full-time basis in order to research and prepare an issue-oriented teaching program in medical history. Whether the historian heads an independent department in the medical school, is a member in a clinical department, or shares membership in a history or history of science department will depend on the particular institutional conditions and traditions. However, failure to belong in any capacity to the health sciences unit on campus would seriously hamper the teaching of health professionals. GUENTER B. RlSSE, M.D., PH.D. The Role of Medical History in the Education of the "Humanist" Physician: A Reevaluation Journal of Medical Education 50:458-465, 1975
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