SPONTANEOUS CHANGE IN FREQUENCYOF DEEP-VEIN THROMBOSIS
DETECTED BY ULTRASOUND
J. M. LITTLEMARGARET BINNS
Department of Surgery, University of Sydney at the RoyalPrince Alfred Hospital, Sydney, New South Wales, Australia
Summary A Doppler ultrasonic flow detector hasbeen used to screen 459 patients in one
surgical service over a twenty-one-month period. Thesurvey has shown a significant fall in the frequency ofDoppler-detected deep-vein thrombosis. No specialprophylactic regimen has been adopted during thisperiod. The frequency of clinically detected deep-veinthrombosis and of lung-scan-confirmed pulmonaryembolism also fell during this period.
MANY workers believe that 125I-labelled fibrinogenuptake is the best available screening test for deep-veinthrombosis. There are, however, several disadvantages. 1Iodine premedication is necessary. The test is contra-indicated in pregnancy. It is inaccurate in the veinsof the upper thigh and pelvis. It cannot be used in thepresence of trauma to the leg. The half-life of theisotope would make repeated administration of labelledfibrinogen necessary if screening is to continue formore than about ten days. The cost of the equipmentand the technical staff is high, making the cost ofscreening all patients prohibitive.
Intravenous phlebography is logistically difficultand time consuming, but is accepted as the standardagainst which other techniques are assessed. Clinicalexamination will have an accuracy of 60 % 2 at best,and 25% is more usual. 3 Ultrasound has achievedsome popularity, but it too has drawbacks. However,with fresh thrombus in or above the level of the
popliteal vein a high degree of accuracy can beachieved 4,5; and, since these " axial vein thromboses "produce the greatest morbidity, there is some valuein screening patients with ultrasound.
Since July, 1970, all patients admitted to one surgicalward at the Royal Prince Alfred Hospital have beenexamined with a Doppler ultrasound flow detector forevidence of venous thrombosis. The technique 2 is basedon that described by Sigel and his colleagues and by Evansand Cockett. 4 Patients were examined every second day,and were included in the survey if more than two Doppler
DR. CANELLOS, DR. WHANG-PENG: REFERENCEScontinued
4. Fialkow, P. J., Gartler, S. M., Yoshida, A. Proc. natn. Acad. Sci.,U.S.A. 1967, 58, 1468.
5. Fitzgerald, P. H., Pickering, A. F., Eiby, J. R. Br. J. hmat. 1971,21, 473.
6. Whang-Peng, J., Canellos, G. P., Carbone, P. P., Tjio, J. H.Blood, 1968, 32, 755.
7. Ezdinli, E. Z., Sokal, J. E., Crosswhite, L., Sandberg, A. A. Ann.intern. Med. 1970, 72, 175.
8. Whang-Peng, J., Henderson, E., Knutsen, T., Freireich, E. J.,Gart, J. J. Blood, 1970, 36, 448.
9. Boneen, P., Lee, C. S. Bull. Johns Hopkins Hosp. 1963, 113, 1.10. Kiossoglou, K. A., Mitus, W. J., Dameshek, W. Lancet, 1965, ii,
655.11. Sandberg, A. A., Hassfeld, D. K., Ezdinli, E. Z., Crosswhite,
L. H. Cancer, 1971, 27, 176.
examinations were recorded. During the first six monthsof the survey, the Parkes Electronic Laboratories model802 Doppler machine was used. Since then the E.M.I.type 64 machine has been used. Patients having venousthrombosis at the time of hospital admission have beenexcluded from the series. A change in venous performancefrom one day to the next is taken as the most importantdiagnostic criterion.By the end of March, 1972, 459 patients had been
examined-80 (17-5%) developed evidence of venousthrombosis at some time during their hospital stay. Thiswould not be remarkable were it not for the striking fallin frequency since the first study period (see figure). At
Falling frequency of Doppler-detected venous thrombosis.
The vertical bars represent 95% confidence limits. The figuresin parentheses show numbers of patients tested.
the same time fewer clinically diagnosed thromboses wererecorded-8 among the 122 patients examined betweenJuly and December, 1970, and only 1 among the 61 patientsexamined between January and March, 1972. The fre-quency of lung-scan-confirmed pulmonary embolism alsofell from 5 emboli in the first 122 patients to 1 in thelast 61.
The results of the first part of the survey (July toDecember, 1970) have been described elsewhere. 3 Thefindings differed from those made by clinicians usinglabelled fibrinogen. 6 Advancing age did not seem tobe a major determinant; nor did particular underlyingdisease states seem to predispose to thrombosis; ifa patient was sick enough to come into hospital, heseemed to be at definite risk regardless of his age orunderlying lesion. Venous thrombosis seemed tooccur as part of a complex of complications, and therewas a high incidence amongst patients who stayed forthree weeks or more in hospital. These last twofactors, when taken together, simply indicated that thesicker patient ran a higher risk of developing venousthrombosis.
This fall in frequency is difficult to explain. Thetechnical staff did the tests in the same way, using thesame criteria, and the two makes of Doppler machineproduce similar results and have similar performancecharacteristics. The pattern of surgery in the wardhas not changed, nor has there been any change in
prophylactic methods. Indeed a trial of subcutaneouslow-dose heparin has been undertaken in another wardin the hospital, and the frequency of Doppler-detectedthrombi has been the same in the two wards.The clinical significance of " 125I-detectable throm-
bus " in calf veins is still uncertain, so it is difficult toassess the real benefit of prophylactic programmeswhich lower the incidence of this form of thrombosis.Prophylactic anticoagulants have their risks,8 and theiradministration is logistically difficult and expensive.Low-dose subcutaneous heparin seems to be safe,9 butthere is the risk of accidental overdosage. Assessmentof benefit may well be complicated by spontaneousfluctuations in frequency, as we have found.
Requests for reprints should be addressed to J. M. L.
1. Browse, N. L. Archs Surg., Chicago, 1972, 104, 160.2. Hall, C. M., Clark, C. G. Br. J. Surg. 1971, 58, 101.3. Little, J. M. Med. J. Aust. 1971, ii, 561.4. Evans, D. S., Cockett, F. B. Br. med. J. 1969, ii, 802.5. Evans, D. S. Br. J. Surg. 1970, 57, 826.6. Kakkar, V. V., Howe, C. T., Flanc, C., Clarke, M. B. Lancet, 1969,
ii, 230.7. Sigel, B., Popky, G., Wagner, D., Boland, J., Mapp, E., Feigl, P.
Surgery Gynec. Obstet. 1968, 127, 339.8. Skinner, D. D., Salzman, E. W. ibid. 1967, 125, 741.9. Kakkar, V. V., Field, E. S., Nicolaides, A. M., Flute, P. T., Wessler,
S., Yin, E. T. Lancet, 1971, ii, 669.
TREATMENT OF SMALLPOX
WITH CYTOSINE ARABINOSIDE
M. S. HOSSAIN
W. HRYNIUKJ. FOERSTERL. G. ISRAELS
Department of Medicine,University of Manitoba,
and Manitoba Institute of Cell Biology,Winnipeg, Canada
A. S. CHOWDHURY M. K. BISWAS
District and Subdivisional Health Offices,Faridpur, Peoples Republic of Bangladesh
Summary During the recent outbreak in Bangla-
desh, nine patients with smallpox weretreated with cytosine arabinoside in an uncontrolledtrial. Prompt clinical responses were seen in mostpatients, and only one patient died. In contrastforty-two out of ninety-seven untreated patients inthe same district died. No patients had clinicallydetectable adverse effects from the drug. In view ofthe encouraging findings a controlled trial seemsindicated.
THE incidence of smallpox has declined sharplyin recent years, largely due to the intensified programmeof smallpox eradication launched by the World HealthOrganisation in 1966.1 Nevertheless smallpox con-tinues to be endemic on the Indian subcontinent,in East Africa, and in South Africa, and mortalityfigures remain high.2-4 Outbreaks in Europe havefocused attention on the danger of smallpox to sus-
ceptible individuals living in non-endemic areas.5Thus there is a need for effective drugs in the treatmentof smallpox. Unfortunately, no good chemotherapyhas so far been reported, although modest claims havebeen made for the antimetabolite, azauridine.6
Cytosine arabinoside (ara-C), an inhibitor of D.N.A.synthesis, may be useful in the treatment of D.N.A.virus infections, especially herpes zoster and vari-cella.1-13 Other D.N.A. viruses, including the vacciniavirus, are sensitive to ara- C in vitro 15 and it, therefore,seemed reasonable to assume that the drug mightalso be active in vivo against the related virus, variola.During the recent outbreak of variola major in Bangla-desh we treated nine smallpox patients with cytosinearabinoside.
PATIENTS AND METHODS
All patients came from small, scattered villages of ThanaBangha, an administrative unit of Faridpur, Bangladesh.Because of problems of transport, all patients had to betreated at home, usually under less than ideal circumstances.No laboratory facilities were available.The diagnosis was made on clinical and epidemiological
grounds alone by one physician (M. S. H.) and confirmedby another (A. S. C.) who, as the district health officer, hashad much experience in the diagnosis of smallpox. Allcases reported during our presence in the district weresought out and were treated unless they were women ofchildbearing age or had passed the pustular stage of thedisease. The only exception to this rule was a sister ofpatient 8 who had developed smallpox simultaneously withher sibling, but was not treated.The drug schedule was similar to that used in patients
with herpes virus infections.8,16 Treatment was startedwith an intravenous or subcutaneous injection of cytosinearabinoside at a dose of 60 mg. per sq.m. and was followedby a continuous infusion of the drug at a dose of 60 mg.per sq.m. 24 hours for 2 days, and then a reduced dose of30 mg. per sq.m. per 24 hours for an additional 2 days.Because continuous medical supervision was not possible,the drug was dissolved in 5% dextrose in water and given bycontinuous subcutaneous clysis, rather than intravenously.The smallpox incidence and mortality figures were
derived from official reports of the District Health Officer,Faridpur, and cover the period of April 1 to July 1, 1972,for Thana Bangha. All patients were treated during Apriland May of 1972.
Case 1.-Male, age 7, no primary vaccination. Highfever with headache, myalgia, and prostration; macularrash appeared on day 4. Seen on day 6 with typical lesionsof the skin and mucous membranes, most of which werestill papular. Further lesions appeared on the next day andara-C was started on day 7. Within 24 hours no furtherlesions appeared and those already present became duskyin appearance. Very few papules progressed to the vesicularstage, and within 72 hours most lesions had progressed todry, black scabs without any evidence of putrefaction;many of these scabs were shed within 5 days of the startof therapy, leaving behind superficial scars. The patientsgeneral condition improved dramatically within 48 hoursof the start of therapy, and there was no secondary elevationof temperature. There were no apparent ill-effects fromtherapy. Shortly before this patient was seen by us, hisyounger brother had died of smallpox.
Case 2.-Female, age 7, no primary vaccination. Firstseen on day 9 when most lesions were vesiculopustular.