Prevention of Urinary Catheter Incrustations by Acetohydroxamic Acid

0022-534 7/84/1323-0455$02.00/0

THE

Vol. 132, September

JOURNAL OF UROLOGY

Copyright © 1984 by The Williams & Wilkins Co.

Printed in U.S.A.

PREVENTION OF URINARY CATHETER INCRUSTATIONS BY ACETOHYDROXAMIC ACID JOHN R. BURNS

AND

JAMES F. GAUTHIER

From the Department of Surgery, Division of Urology, University of Alabama, Veterans Administration Hospital, Birmingham, Alabama

ABSTRACT

Acetohydroxamic acid was administered in 5 patients to determine its effect in reducing urinary catheter incrustations. All patients had chronic indwelling catheters that required frequent changes because of severe incrustations and catheter occlusion. Incrustations were analyzed chemically for calcium, magnesium, ammonia nitrogen and phosphorus. The degree of incrustation before and during acetohydroxamic acid therapy was compared in each patient and was decreased significantly (average 81 per cent) during therapy (p less than 0.05). Catheter changes were required less frequently during therapy in all patients. Acetohydroxamic acid is effective in preventing catheter incrustations and should be considered in patients with this problem. Incrustation and the development of bladder calculi constitute a problem in some patients maintained on long-term catheter drainage. The use of silicone catheters has decreased incrustation but some patients continue to require frequent catheter changes. Infection-induced calculi (carbonate apatite and struvite) form in the urinary tract because of a urea-splitting bacterial infection, which results in the formation of alkaline urine with ammonium ion in high concentration. These changes in the urinary environment cause supersaturation and crystallization of struvite and carbonate apatite. Acetohydroxamic acid is a specific inhibitor of bacterial urease and prevents growth of infection -induced calculi in the upper urinary tract. We report on the effectiveness of acetohydroxamic acid in reducing catheter incrustation associated with chronic urinary tract infection. MATERIALS AND METHODS

We studied 5 patients with indwelling urethral (4) or suprapubic (1) urinary catheters. Bladder dysfunction resulted from a spinal cord lesion in 4 patients and multiple sclerosis in 1. All patients had at least a 6-month history of chronic catheter incrustation, which required frequent catheter changes (~1 every 2 weeks). Additional criteria for selection were the presence of a urease-producing bacterial urinary infection and adequate renal function (serum creatinine concentration <2.5 mg./dl.). All patients signed an informed consent form before assignment to the study. During the study the interval between catheter changes (operational cycle) was determined for each patient by history and remained constant throughout the study. The catheter was changed at the end of each cycle. Catheter incrustation rates were analyzed for each patient during 6 cycles: baseline incrustation rates were determined for 3 cycles, with each cycle followed by a cycle during which acetohydroxamic acid was administered. Patients were given acetohydroxamic acid orally based on body weight: patients weighing >70 kg. received 250 mg. 4 times daily, those between 50 and 70 kg. received 250 mg. 3 times daily and those <50 kg. received 15 mg./kg. daily in 3 doses. Acetohydroxamic acid was not administered on the day of a catheter change, which allowed sufficient washout time before the next baseline cycle began according to the reported kinetics of acetohydroxamic acid. 1 Accepted for publication March 23, 1984. Supported by the Veterans Administration. 455

The material and size of the catheter lumina varied among the patients. Incrustation rates depend partially on catheter material,2 so that patients were not allowed to change the type of catheter used until the study ended. Before the study each patient underwent a serum creatinine determination, serum electrolyte test, complete blood count, reticulocyte count, and urine culture and sensitivity tests. Urease activity was determined for each organism revealed by the culture. A plain radiograph of the pelvis was made to determine whether any large bladder calculi were present. The blood studies were repeated on alternate visits. The presence of adverse effects was recorded at the time of each catheter change. After a catheter change the proximal 6 cm. of the old catheter was saved for analysis. The catheter tip was dried at lOOC for several hours and then weighed (initial dry weight). Incrustations then were eluted from the catheter tip by placing it in 100 ml. 1 M. hydrochloric acid for 1 hour and then in 100 ml. 10 per cent ammonium hydroxide for 1 hour to remove alkalinesoluble incrustations. After elution the catheter tip was dried and weighed. When elution was complete no visible incrustations remained on any of the catheters tested. Samples of the solutions then were aspirated through a 0.22 µm. Millipore filter and the aspirates were analyzed for calcium, magnesium, phosphorus and urea nitrogen. Calcium and magnesium were analyzed by atomic absorption spectrophotometry, phosphorus by the method of Fiske and Subbarow,3 and urea nitrogen by the indophenol reaction. 4 Lanthanum oxide was used in the calcium and magnesium determinations. Because the degree of incrustation is correlated with the presence of urinary infection antibiotics were not given to any patient during the study. RESULTS

All patients had urinary tract infections that persisted throughout the study. Most urine cultures yielded multiple organisms and ~1 organisms in each culture were identified as being able to split urea (that is positive for urease). The most common urea-splitting organism identified was Proteus mirabilis. The amount of incrusted material on each catheter tip was defined as the decrease in dry weight of the catheter tip after the elution process. The amount of incrusted material that formed while a patient was not on acetohydroxamic acid therapy was compared to the amount that formed during therapy using Student's t test. The effect of acetohydroxamic acid in decreasing catheter incrustation is shown in the table. In each

456

BURNS AND GAUTHIER

Degree of incrustation and recovery rate with and without acetohydroxamic acid therapy Pt. No.

Degree of Incrustation (mg. per day ± standard deviation) Baseline

1 2 3 4 5

28.4 ± 41.7 ± 11.6 ± 16.1 ± 9.4 ±

10.7 13.9 1.9 9.1 6.1

Therapy* 3.2 4.7 3.0 1.4 3.7

± ± ± ± ±

1.4 1.2 2.4 0.4 1.3

Dry Weight of Incrusted Material Recovered (%±standard deviation) Baseline 43.5 40.9 39.7 48.5 56.0

± ± ± ± ±

8.5 1.4 6.8 3.5 15.7

Therapyt 40.0 30.5 34.7 37.3 50.3

± ± ± ± ±

5.7 10.6 13.7 11.5 14.7

* p <0.05 compared to baseline values. t p >0.10 compared to baseline rates.

patient acetohydroxamic acid reduced significantly the quantity of incrusted material by 61 to 91 per cent (average 81 per cent, p <0.05). In patients with chronic indwelling catheters incrustations usually consist of carbonate apatite and struvite. 5 Measurement of calcium, magnesium, phosphorus and urea nitrogen accounted for an average of 42.9 per cent of the dry weight of the incrusted material. This percentage was defined as the recovery rate and did not differ significantly between cycles with and without acetohydroxamic acid (see table). Adverse effects of acetohydroxamic acid therapy were minimal: 1 patient complained of headaches, which resolved spon. taneously after 3 days of therapy and all patients suffered mild reticulocytosis, although the hematocrit did not decrease. None of the reported major complications, such as deep venous thrombosis, pulmonary emboli and severe anemia, occurred during this study. DISCUSSION

Infection-induced carbonate apatite and struvite calculi form in the urinary tract because of a urea-splitting bacterial infection. Splitting of urinary urea results in the formation of alkaline urine with ammonium ion in high concentration, which causes supersaturation and crystallization of struvite and carbonate apatite. In patients on catheter drainage the crystals adhere to the catheter surface and crystal growth ensues, resulting in catheter incrustation and bladder calculi. Acetohydroxamic acid, an effective inhibitor of bacterial urease, prevents alkalization of urine and halts the formation of infection-induced calculi. Stone growth ceases even in the presence of a continuing bacterial urinary tract infection. The usefulness of acetohydroxamic acid in the treatment of upper urinary tract infection calculi has been well described6 • 7 but its application in treating catheter incrustation and bladder calculi has not been documented. Because these calculi usually are composed of struvite and carbonate apatite acetohydroxamic acid should be an ideal agent for preventing catheter incrustation. All of our patients had a marked decrease in the degree of incrustation while on acetohydroxamic acid therapy. The severity of catheter incrustation depends on several factors. The rate of incrustation is correlated directly to the degree of roughness of the catheter surface. 8 Because of the relatively smooth surface silicone catheters have a lower rate of incrustation than latex catheters. 2 However, all of our patients still had substantial incrustation despite the use of silicone catheters. Calcium, magnesium, phosphorus and urea nitrogen accounted for an average of 42.9 per cent (range 30.5 to 56.0 per

cent) of the dry weight of the incrusted material. The rate of recovery did not differ significantly between control and acetohydroxamic acid cycles. Therefore, acetohydroxamic acid must act by decreasing the quantity of incrustation without altering its composition. In theory, diet should have a role in determining incrustation rate. High urinary magnesium and phosphorus concentrations should increase the relative supersaturation of urine with respect to struvite and carbonate apatite. However, in a previous study no correlation was found between the concentration of urinary solutes and incrusted material. 9 During our study patients received no dietary instructions and even if changes in urinary magnesium or phosphorus concentration did occur they probably would have averaged out over 3 control and 3 therapy intervals. It seems unlikely that the decrease in incrustation rates noted in this study is related to changes in diet. Before the use of acetohydroxamic acid is recommended for all patients with chronic catheter incrustation the risk-tobenefit ratio should be considered. The morbidity of catheter incrustation and bladder calculi is far less than that of upper tract infection-induced calculi. Other therapy, such as routine catheter irrigation with hemiacidrin solution, can be effective in reducing catheter incrustation. However, irrigating solutions are effective only while retained in the bladder (60 to 90 minutes daily). Moreover, cumbersome irrigating techniques in many patients result in poor compliance. Oral administration of acetohydroxamic acid produces therapeutic urinary concentrations throughout much of the day and patient compliance usually is high because adverse effects are minimal. Although none of our patients experienced any major adverse effects the potential for severe problems remains. We have instructed our patients to reduce the daily dose of acetohydroxamic acid in an attempt to achieve a satisfactory clinical result with minimal side effects. In 2 patients maintained on a lower dosage catheter changes have been required only once a month. Acetohydroxamic acid is an effective drug to prevent catheter-induced incrustation and should be considered in patients who require frequent catheter changes. The usefulness of acetohydroxamic acid in reducing the incidence of bladder calculi remains unknown. However, bladder calculi often result from catheter incrustation. By reducing incrustation, acetohydroxamic acid should be effective in reducing the formation of bladder calculi. REFERENCES 1. Feldman, S., Putcha, L. and Griffith, D. P.: Pharmacokinetics of

2. 3. 4. 5. 6. 7. 8. 9.

acetohydroxamic acid. Preliminary investigations. Invest. Urol., 15: 498, 1978. Srinivasan, V. and Clark, S. S.: Encrustation of catheter materials in vitro. J. Urol., 108: 473, 1972. Fiske, C. H. and Subbarow, Y.: The colorimetric determination of phosphorus. J. Biol. Chem., 66: 375, 1925. Chaney, A. L. and Marbach, E. P.: Modified reagents for determination of urea and ammonia. Clin. Chem., 8: 130, 1962. Burr, R. G.: Urinary calculi composition in patients with spinal cord lesions. Arch. Phys. Med. Rehab., 59: 84, 1978. Griffith, D. P.: Struvite stones. Kidney Int., 13: 372, 1978. Griffith, D. P. and Musher, D. M.: Prevention of infected urinary stones by urease inhibition. Invest. Urol., 11: 228, 1973. Axelsson, H., Schonebeck, J. and Winblad, B.: Surface structure of unused and used catheters. A scanning electron microscopic study. Scand. J. Urol. Nephrol., 11: 283, 1977. Bruce, A. W., Sira, S. S., Clark, A. F. and Awad, S. A.: The problem of catheter encrustation. Canad. Med. Ass. J., 111: 238, 1974.