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Chapter X

Contents

CHAPTER X

Sulfonamides in Relation to "Shock Kidney"

No discussion of renal failure in the wounded of World War II would be complete without consideration of the possible role of sulfonamide injury of the kidneys. Two forms of this type of injury are generally recognized. One is the purely mechanical process of crystalluria, with precipitation of the crystals in the ureters, renal pelves, and perhaps in some instances in the collecting tubules. The second is a more complex process involving true parenchymal damage to the kidney; it appears to be relatively independent of dosage and is believed by many to belong in the category of hypersensitive reactions along with other recognized sulfonamide lesions such as dermatitis, myocarditis, and pneumonitis.

The problem is difficult because this renal lesion is a characteristic lower nephron nephrosis, usually although not invariably associated with the precipitation of hemoglobin-like products in the tubules and hence indistinguishable from transfusion kidney, crush kidney, or shock kidney. With present knowledge, distinction is impossible on the basis of renal morphology.

Sulfonamide Therapy in Battle Casualties

During the period in which the cases studied by the Board were collected, sulfonamides were still extensively used in forward installations (aid stations, collecting stations, and clearing stations) in the Fifth Army Area, although their use in hospitals had greatly diminished with the arrival of large supplies of penicillin. In the aid stations a sulfonamide dressing almost universally was applied. This might or might not be supplemented by indeterminate amounts of sulfonamide powder dusted onto or into the wounds, and more of the drug by mouth, the most frequent total oral dose being 4 grams. In the field and evacuation hospitals, sulfonamide therapy usually was stopped and penicillin sub-


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stituted. Notable exceptions, however, were in some cases of abdominal wounds with incipient peritonitis. Many surgeons placed from 5 to 10 Gm. of sulfadiazine in the abdominal cavity before closing it, and some continued sulfonamide treatment by mouth for several days. There was no standard practice since this was considered a matter for individual surgical judgment.

Blood Sulfonamide Levels

Relationship to Sulfonamide Intake

Blood sulfonamide levels were determined in 50 of our patients. The tests were made for free sulfonamide only, whereas the total of free and acetylated blood sulfonamide would probably have been a more valuable index of sulfonamide retention by the kidney. As would be expected, there seemed to be a general relationship between the blood levels of the drug and the quantity administered, as shown in Table 94. However, the fluctuations within each group are too great and the number of cases is too small to justify further analysis. It is noteworthy that no patient tested failed to show at least a trace of sulfonamide in the blood stream, and in two of six patients with no recorded chemotherapy, levels of 7.0 and 10.6 mg. per 100 cc. were observed. Furthermore, characteristic sulfonamide crystals were found at necropsy in the renal tubules in several other patients with no history of exposure to sulfonamide

TABLE 94.-BLOOD SULFONAMIDE LEVELS IN 50 PATIENTS


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and no records of chemical tests for it. The only possible conclusions are that the records were grossly unreliable so far as sulfonamide therapy was concerned, and that, regardless of their histories, virtually all of these patients must have received some sulfonamide therapy.

Relationship to Renal Insufficiency

The 50 patients on whom blood sulfonamide levels were determined were classified on the basis of urinary suppression and nonprotein nitrogen level (with or without high azotemia). In the upper two quarters of Chart 38 the patients have been divided into those with normal urinary output and those with oliguria. In the lower two the separation is on the basis of nitrogen retention.

CHART 38. BLOOD SULFONAMIDE LEVELS IN 50 PATIENTS CLASSIFIED ACCORDING TO URINE OUTPUT AND NITROGEN RETENTION


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It is evident that blood sulfonamide levels above 8 mg. per 100 cc. were observed only in patients suffering from oliguria, or high azotemia, or both. Attempts at closer analysis are disappointingly inconclusive. The average blood sulfonamide level in 36 azotemic patients was 5.7 mg. per 100 cc. as compared with 2.3 mg. per 100 cc. in the control group of 14, but again the variations are too wide in proportion to the number of samples to warrant statistical analysis. The mean blood sulfonamide level in 38 oliguric patients was 5.4 and in 12 without oliguria, 2.5 milligrams per 100 cubic centimeters.

The results are similar when the cases are divided, in an attempt to exclude the influence of variation in dosage, into two groups as follows: Group A, those patients who had external medication only, and Group B, those who received internal medication (oral, intraperitoneal, or intravenous). Eight patients could not be classified because of inadequate information regarding therapy. Of the 18 patients in Group A, 12 were azotemic, 6 were not. The mean blood sulfonamide level in the former was 1.7 mg. per 100 cc., with a standard error of ± 1.1; of the latter 1.32 with a standard error of ± 0.8. Obviously the difference is not significant. In Group B, 17 azotemic patients showed a mean blood sulfonamide level of 7.8 mg. per 100 cc., with a range of 0.4 to 39; and 7 patients with no azotemia, a level of 3.7 mg. per 100 cc., with a range of 0.2 to 7.8. With a range of this magnitude in such a small number of cases, the calculation of standard errors has little meaning. Similar results followed efforts to establish any correlation of average blood sulfonamide levels with oliguria.

Very high blood sulfonamide levels (10 mg. per 100 cc. or higher) were seen only in patients with symptoms of renal insufficiency. Nothing in this relationship serves to distinguish between cause and effect. It is obvious, however, that with continued administration of a drug eliminated almost solely by the kidney, its level in the blood must mount with the onset of renal insufficiency. Two cases are worthy of individual attention.

Cases in Point

Case 21.-This patient was not a battle casualty. As treatment for a urethral discharge, the patient medicated himself with 12 Gm. of sulfathiazole in 24 hours. The following day ureteral colic developed. Crystalline concretions were observed in both ureteral orifices on cystoscopy. He was treated by pelvic lavage and had no further symptoms. It is evident that his trouble was purely mechanical.

Case 90.-This patient was a battle casualty; a severe abdominal wound had resulted in evisceration of several loops of bowel, perforation of the diaphragm, and lacerations of


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the liver and right kidney. The patient was in moderate shock on entry to the hospital. For the first week postoperatively he voided adequate quantities of urine and did not show nitrogen retention, but he was febrile. On the ninth day signs of consolidation developed in the lower lobe of the left lung. He was given 66 Gm. of sulfadiazine between the seventh and twelfth days. Within 24 hours the plasma nonprotein nitrogen level rose to 143 mg. per 100 cc. and later to 166 mg. per 100 cc., and the blood sulfonamide level to 51.6 mg. per 100 cc. (free sulfonamide 34.4, acetylated 17.2). Following cessation of sulfonamide therapy, the nonprotein nitrogen level fell to 41 mg. per 100 cc. in the course of 17 days. Oliguria did not develop during the period of nitrogen retention. It is possible that this may have been a case of sulfonamide injury of the renal parenchyma, but the relative importance of the simultaneous spreading infection cannot be assessed.

One other line of argument must be explored before conclusion. As was stated in the introduction, there are reasons for believing that the sulfonamide form of lower nephron nephrosis is dependent upon hypersensitivity. One reason for this belief is the frequent association of this lesion with inflammatory lesions of other tissues and organs; for example, dermatitis, myocarditis, interstitial pancreatitis, hepatitis, arteritis, and a form of pneumonitis. In the present series of cases, the only such associated lesion observed was pneumonitis. It is the personal opinion of the writer (T.B.M.) that pneumonitis can occur in uremia independently of sulfonamide treatment and that, therefore, its presence cannot be accorded great diagnostic weight.

SUMMARY

Grounds have been found for believing that the records of sulfonamide therapy in the group of battle casualties upon which this report is based were grossly inaccurate, but that it is a reasonable assumption that few if any patients escaped exposure to the drug. Very high blood sulfonamide levels were observed only in patients with renal insufficiency. Except for these extreme instances, the variation in the blood sulfonamide levels was too great in all categories studied to yield reliable correlation between blood level and renal insufficiency. In only two cases did clinical evidence point toward a sulfonamide etiology. A strong argument against such a causative mechanism was the failure to observe any instance of other forms of sulfonamide injury such as arteritis, myocarditis, dermatitis, hepatitis, or pancreatitis.

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