From The Connaught Hospital, London, E.I7, and The Unit for Experimental Plastic Surgery, Postgraduate Medical School, London, I~V.

Transcription

1 THE CONTROL OF POST-OPERATIVE (EDEMA: A CLINICAL CONTROLLED TRIAL OF HIGH-DOSAGE ORAL CHYMOTRYPSIN (" AVAZYME ") By N. SAAD, F.R.C.S. 1, A. HANDYSIDES, B., Ch.B., CHARLES NOON, F.R.C.S. 2 and JAMES CALNAN, R.C.P., F.R.C.S. From The Connaught Hospital, London, E.I7, and The Unit for Experimental Plastic Surgery, Postgraduate Medical School, London, I~V.I2 THE occurrence of swelling of tissues after surgical operations is common, and is one of the main causes of post-operative pain. When due to ha~matoma formation, inadequate haemostasis is usually the cause and this can be avoided. When tissue oedema is the cause there seems little one can do. In recent years systemic therapy with ~-chymotrypsin has been widely used in the prophylactic control of surgical eedema, but controlled trials have shown disappointing results. Gall and Talbot (i962) were unable to show any beneficial effect in patients undergoing thyroidectomy, on subjective assessment. Recently Calnan, Kulatilake, and Saad (I963) have shown that intramuscular chymotrypsin could prevent tissue oedema in experimental animals, and suggested that the dosage used in man was probably too small to be effective. The present controlled double-blind trial was carried out using a high-dosage oral preparation on a series of patients undergoing a standard operation for varicose veins, so that the changes in limb volume were measured accurately, and cedema assessed objectively. Material.--Thirty-one patients (nineteen females, twelve males) were admitted consecutively from the hospital waiting list and their varicose veins were treated in a standard manner. Every patient was given two tablets four times daily for five days, starting on the first post-operative day. The tablets were yellow, enteric coated and all of identical appearance. The " active" tablet contained IOO mg. of chymotrypsin (Avazyme) in a wheat and lactose base and the "blank " contained exipient only. Those patients on Avazyme thus received 8oo mg. of chymotrypsin by mouth daily, and a total of 4 g. in five days, which is five times the dose recommended by the manufacturer. Methods.--Operative Technique.--The course of the varicose veins was marked on the skin before operation which was carried out under general anaesthesia. The saphenous vein and its branches were tied off at the groin. Another incision at the ankle allowed the vein stripper to be passed up to the groin and the whole of the saphenous vein removed. During the removal of the vein the table was tilted I5 degrees in the Trendelenburg position. A firm crepe bandage was applied, immediately after the groin and ankle wounds were sutured, to both legs. The patient was then returned to the ward, and allowed up next day. Volumetric Measurements.--The volume of each leg was measured in a perspex tank 3o in. high, with internal diameter of 7½ by 7½ in. and an extension to accommodate Now Senior Registrar, Mount Vernon Hospital, Northwood, Middlesex. 2 Now Consultant Surgeon, King George V Hospital, Ilford. 245

2 246 BRITISH JOURNAL OF PLASTIC SURGERY the foot. The siphon was mounted 4 in. below the top, so that the volume of the lower 26 in. of the limb was in fact measured. The tank shown in Figure I was filled with warm water (about 34 C.) until the overflow siphon lowered the level to a constant tank volume. The patient's leg was then slowly inserted until it was resting firmly on the bottom of the tank in an upright position. The volume of water displaced by the leg was collected until the siphon FIG. I Prespex tank for measuring volume of leg. The displaced water is collected in a bucket and measured. ceased. This water was then measured to the nearest IO ml., in 2-1itre measuring jars, and the procedure then repeated. If these two separate measurements differed by less than 60 ml. the mean was taken as representing the volume of the leg. If the difference was greater than 60 ml. a third measurement of leg volume was made and the mean of all three accepted. Since the limb volume was usually between 5 and 6 litres, the error in technique of volumetric measurement was estimated at ~i-2 per cent. (i.e I00) The volumes of both legs were measured on each occasion--the day before operation and on the first, third, and fifth day after operation. When limb volumes were taken after operation the crepe bandages were removed half an hour before and reapplied to

3 THE CONTROL OF POST-OPERATIVE (EDEMA 247 both legs immediately afterwards. Nobecutane sprayed over the recent skin wounds was used to make them waterproof. The Clinical Trial.--As soon as the patient was considered suitable to enter the trial a prescription was sent to the dispensary. The pharmacist supplied either" blank" or " active " tablets, of identical appearance, according to a prepared list of treatments, allocated in random order (Fisher and Yates, I957) in groups of ten. In this way the trial was conducted " blind," and the key to the tablets was not seen until it was completed. TABLE I Patients Receiving Avazyme Tablets--Difference between Pre-operative and Post-operative Volumes of Whole leg on First, Third, and Fifth Post-operative Days Fifteen Affected Legs Thirteen Unaffected Legs Name and Age Sex Day i Day 3 Day 5 Day I Day 3 Day 5 P. R., 40 D., 44 C., 47 F. F. F. E. W., 58 F. D. H., 4 F. D. W., 38 F. J., 49 F. A. B., 56 A. H., 29 R. C., 50 G. F., 38 F. J. Y., 59 S. G., 40 H., 48 F o I4O o + 3o I5O 4o ~ i : 415 i o o O 310 ~420 2I ~I iio +io o I35 I9o I I35 I o I20 80 o II0 + IO 18o IO5 95 ~I0 55 I II0 The records of each patient contained a form on which certain observations and the limb volumes were recorded. The observer was also required to judge whether the patient had had the active or the blank tablets, and to note any unusual features. Results.--The results are recorded in Tables I to IV. Even a cursory glance at Tables I and II is sufficient to see that swelling of the affected limb is usual after operation, while loss of volume of the untreated limb is common. In both tables the total volume of each leg on admission to hospital has been accepted as the normal volume for the limb, and the subsequent alteration in volumes recorded as an increase or decrease from this original figure. The numbers therefore are absolute. It is clear, too, that there is little difference between the figures in Table I, those receiving Avazyme and, Table II, those on blank tablets. In Table III the difference between the original volume of the limb and subsequent measurements (as a plus or minus figure) on days I, 3, and 5 have been summed. The mean difference in volume of treated and untreated legs is shown for those on Avazyme or blank tablets. Again there is no significant difference for chymotrypsin although there is a significant difference between the surgically treated and untreated limbs. The means for each day measured are shown graphically in Figure 2. Table IV records the "guesstimate " for the observer, who was able to judge

4 - - 17o 248 BRITISH JOURNAL OF PLASTIC SURGERY TABLE II Patients Receiving Blank Tablets--Difference between Pre-operative and Post-operative Volumes of Whole Leg on First, Third, and Fifth Post-operative Days Nineteen Affected Legs Fifteen Unaffected Legs Name and Age Sex Day I Day 3 Day 5 Day I Day 3 Day 5 L. D., 60 B., 24 D. H., 34 A. H., 39 F. H., 65 A. B., 55 D. D., 73 G. D., 42 F. H., 65 S., 33 G. C., 32 C. L., 54 C. S., 41 A. R., 45 D., 54 L. L., 33 W. S., 49 F. ~ F. +38 F F. +75 F o F F. --7 F. + 13o ME," o FI lo ) lo9 ~ o o L3o x 190 ~37 o +410 ~8o IO ~5 o o o o o ~7 o o --18o o o +90 +iio ioo o lo5 IIO ~ o TABLE III Mean Volume of Legs after Operation in Treated and Untreated Patients, compared with Volume before O 9eration Tablets Legs Treated (Mean in ml.) Legs Untreated (Mean in ml.) Avazyme Blank o Increase in volume. - Loss of volume. TABLE IV Accuracy of Observer's Assessment (Guess) of Tablets Taken by Patients Guess Guess Treatment Right Wrong Totals Avazyme Blank Totals 21 I O 3 I X 2 =0"7971, df= I, P>O'O 5.

5 THE CONTROL OF POST-OPERATIVE (EDEMA 249 correctly which preparation had been given to the patient on 7 per cent. of occasions ; such a performance is not statistically significant LO 200 '~' --" ~ 80 = = -?*o ~: ~, -BO ~ -f20,-,- ~: ~ ?* PATIENTS : 3?, TREATED LEGS TREATED LEGS / i* //i /,o... *AVAZYME /// / BLANK UNTREATED LEGS ~.- AVAZYME jj-- - ' DLANK I I I TiME (Days) FIG. 2 Mean change in volume of legs of thirty-one patients. Side-effects.--These were minimal. One patient complained of nausea which ceased although the tablets were continued. Another had local urticaria of the treated leg possibly due to the tincture of iodine used on the skin at operation. Two other patients with a history of allergy to penicillin had no reaction from the trial tablets. DISCUSSION A double-blind controlled trial using objective methods of measurement was carried out to assess the value of oral chymotrypsin in the relief of post-operative aedema. In spite of the fact that we have used a dose of five times that normally recommended we have not been able to demonstrate any beneficial effect in preventing or diminishing oedema after operation. In this respect the hope that larger doses of chymotrypsin could reduce post-operative oedema has not been fulfilled. These drugs are expensive; thus we have calculated that the yearly bill for a hospital the size of Hammersmith Hospital, if these drugs are used routinely, would be of the order of IO,OOO a year. Even so the extra finance for any one patient would be amply covered by the saving of the cost of a hospital bed for one day. The effect of these drugs when given intramuscularly in high dosage has been proved experimentally in rats (Calnan, Kulatilake, and Saad, I963). We therefore feel that further investigation in the absorption and fate of the oral preparation is necessary in order to justify the high cost involved. The degree of swelling of a limb after removal of varicose veins is of some interest. It is clear that some 200 ml. of fluid can accumulate in a limb after operation and that one-day bed rest reduces the volume of a normal limb by 50 to zoo ml. Expressed as a percentage of the total limb volumes these quantities are very small, representing a mere 4 per cent. or less, and so virtually impossible to detect clinically.

6 250 BRITISH JOURNAL OF PLASTIC SURGERY We wish to thank Mr A. C. MacLeod, Mr J. T. Fathi, and Mr J. P. Bentley, Consulting Surgeons, for allowing us to treat patients under their care, and Mr A. E. Haynes, Chief Pharmacist, who made it possible to carry out the trial" blind." The tablets were supplied gratis by the Denver Pharmaceutical Company and the measuring tank was made in the Postgraduate Medical School Workshops (Mr C. Lordan). We are grateful to Sister S. Rynne for making the measurement of limb volume a less messy business. REFERENCES CALNAN, J. S., KULATILAKE, A. E., and SAAD, N. (I963). Brit. J. Surg., 5o, o. FISHER, R. A., and YATES, F. (I957). Statistical Tables for Biological, Agricultural and Medical Research. London : Oliver and Boyd. GALL, W. J., and TALBOT, C. H. (I96e). Brit. J. plast. Surg., x5, zo. Submitted for publication, June i965.