Granulocytopenia complicating sulfadiazine therapy in a severe intestinal injury

GRANULOCYTOPENIA COMPLICATING SULFADIAZINE THERAPY IN A SEVERE INTESTINAL INJURY REPORT

OF A CASE IN WHICH PENICILLIN WAS EMPLOYED THERAPEUTIC MEASURES COLONEL JAMES E. FISH AND MAJOR

TO SUPPLEMENT

HAROLD A.

OTHER

CONRAD

MEDICAL CORPS, ARMY OF THE UNITED STATES

T

because of the following interesting features : ( 1) Multiple perforations of both the large and small intestine from a So-calibre machinegun bullet were successfuIIy handied in accordance with generally accepted surgical principIes. (2) The comphcating peritonitis, secondary to widespread soiling of the peritoneum, was successfully combated by means of combined sulfonamide and penicillin therapy without a residua1 abscess formation or comphcating wound infection. (3) An unusua1 urinary tract

HIS

case is reported

comphcation, due to coincidenta injury of the parasympathetic nerves in the sacra1 plexus, was encountered. (4) A severe granulocytopenia developed as a complication of the sulfonamide therapy. (3) Penicillin was employed as an adjunct to other therapeutic measures in the management of the complicating agranulocytosis. CASE REPORT A twenty&e year old soldier was admitted to this hospital at 9 P.M. on December 29, 1943, because of intra-abdominal injuries sustained two hours previously from accidental shooting with a 3o-calibre machinegun bullet fired at point blank range. Physica examination reveaIed a patient in severe shock. The pulse rate was 136 and quite thready. The blood pressure at first could not be registered, but after a short time was recorded at 90 systolic and 60 diastoIic. The wound of entrance was a ragged hole about 1.0 cm. in diameter in the right lower quadrant of the abdomen from which came a moderate bloody ooze. The wound of exit was in the left sacral region, where there was another ragged hole approximately 1.5 cm. in diameter. After the administration of two units ($00

cc.) of plasma, his condition had improved to the point where it was believed that surgery couId be instituted. At that time his pulse rate was 104 and the blood pressure was IOO systolic and 70 diastolic; 500 cc. of titrated whole bIood was administered during the operative procedure as we11as one additional unit (230 cc.) of plasma. Under ether anesthesia, the abdominal cavity was entered through a right lower paramedian incision. Hemorrhage had been profuse, due to bleeding from several large vessels in the mesentery of the terminal ileum and sigmoid. There was also a moderately severe ooze from the retroperitoneal wound deep in the hollow of the sacrum. Examination showed one perforation in the cecum, three in the terminal ileum, two in the sigmoid coIon, and two in the rectum just above the peritoneal reflection. (Fig. I.) There was gross feca1 contamination, and a considerabIe quantity of fecal material was removed from the peritoneal cavity during the course of the operation. The perforations in the rectum, cecum, and ileum were cIosed using atraumatic No. o chromic catgut. The damaged mesentery of the ileum was a1so repaired. The involved sigmoid loop was exteriorized after approximation of the proximal and distal limbs to facilitate the later appIication of a spur crushing clamp. The colostomy loop was brought out through the main incision. Tw.0 cigarette drains were inserted into the retroperitonea1 wound, and two additional cigarette drains placed in the bottom of the pelvis. These were brought out through the lower angle of the operative incision. Prior to cIosure, 12 Gm. of sulfanilamide powder were placed in the peritoneal cavity. The wounds of entrance and exit were then debrided and packed loosely with Vaseline gauze. At the conclusion of the operation, which took one and three-quarter hours, the pulse rate was 128 and the blood pressure was 108 systoIic and 58 diastoIic.

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American Journal of Surgery

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Conrad-IntestinaI

After removal to the ward, he was placed in an oxygen tent. A Levine tube was passed into the stomach and connected to a constant

FIG. I. Diagram missiIe through organs involved.

iltustrating the course of the the peritoneal cavity and the

suction apparatus. An additiona 300 cc. of titrated whoIe blood and two units (500 cc.) of plasma were given during the day following operation. A blood sulfanilamide IeveI taken twelve hours after operation showed only a trace (less than 1.0 mg. per cent). AccordingIy he was given intravenously 3 Gm. of sodium sulfadiazine in distiIIed water. His pulse rate varied from 124 to 160 during the day. AIthough his temperature was onIy IOI.O’F. by rectum, he appeared extremely toxic and was irrational most of the time. Penicillin, at that time available only in very Iimited quantities, was started eighteen hours after operation, I 2,500 units being given intramuscuIarIy every two hours. The condition of the patient improved considerabIy during the second postoperativeday. He appeared much less toxic and there was a slowing of the puIse rate. A blood suIfaniIamide IeveI taken thirty-six hours after operation was reported as 20.6 mg. per cent. The plasma protein Ievel was 6.75 per cent. The peniciIIin dosage was reduced to 8,740 units every two hours. An adequate fluid intake was provided

Injury

OcroeEn,*9+5

by the administration of glucose and saIine, and glucose and distiIIed water intravenously. Thiamin chIoride and vitamin c (cenolate), 1.0 cc. of each, were given intramuscuIarly daiIy. There was no abdomina1 distention. The continuous suction functioned effrcientIy. About I ,000 cc. of drainage were returned in a twentyfour hour period. By the third postoperative day a11 signs indicated continued improvement. He was irrationa1 only at rare intervals. Peristalsis could be heard on abdomina1 auscuItation. He was started on two ounces of water an hour. The constant suction tube was Ieft in pIace but was cIamped off for several hours at a time with no ill effects. He was again given $00 cc. of whole titrated bIood. The blood suIfadiazine IeveI was 7.8 mg. per cent and he was given intravenously another 3 Gm. of sodium suIfadiazine. The p$se showed further improvement. He remained out of the oxygen tent for severa hours. He continued to gain during the next several days. The colostomy began functioning ninety-six hours after operation. He was pIaced on a semi-soft diet on the tenth postoperative day. The penicillin dosage was gradually reduced and discontinued entirely after the fourth postoperative day. He had received a tota of 300,000 units during that time. No sulfonamide was administered on the third postoperative day, but with this exception he received 3 Gm. of sodium sulfadiazine intravenousJy from the second to the tweIfth days incIusive. From the thirteenth to the eighteenth days incIusive he received I Gm. of suIfadiazine oraIIy four times daily. The blood sulfonamide Ievel foIIowing the peak of 20.6 varied from 7.8 on the fourth to 1.9 on the ninth, and 4.3 mg. per cent on the eighteenth postoperative day. (Fig. 2.) The Ieucocyte count was folIowed at two-day intervals. Following a Iow of 6,000 on the fifth postoperative day, there was a rise to 14,000 on the twelfth postoperative day. By the nineteenth postoperative day, it had falIen to 4,000 with 68 per cent poIymorphonuclear ceIIs. No sulfonamide was administered after the eighteenth postoperative day. Two days Iater his Ieucocyte count had falIen to 1,200 with 99 per cent Iymphocytes. The erythrocyte count was 2,800,000 and the hemogIobin 85 per cent. He again appeared critically iI1. A diagnosis of agranuIocytosis secondary to the administra-

Now

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tion of suIfadiazine was made. Repeated transfusions of 250 cc. titrated whole blood were instituted. Liver extract was aIso given in

FIG. z. A chart of the temperature,

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American

Journal

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the leucocyte count with an increasing percentage of neutrophiles. FortunateIy, in this case the bone marrow recovery was swift and

puke, leucocyte counts and blood sulfonamide IeveIs folIowing operation.

daily doses of 1.0 cc. intramuscularly. Pentnucleotide was started on the day foIlowing recognition of his agranulocytosis, with the intramuscuIar injection of 40 cc. In addition to the above measures, penicillin was resumed on the third day of his agranulocytosis as a prophyIactic measure. This was to boIster the body defenses against anticipated pyogenic complications pending the restoration of a normal granuIocyte reaction. The leucocyte count two days following onset was 600 with a differentia1 of 2 per cent neutrophiles and 95 per cent Iymphocytes. A day Iater the Ieucocyte count was 400 with IOO per cent lymphocytes. On the folIowing day, however, the first encouraging response in the Ieucocyte count was noted when it showed 850 ce1I.s with a differentia1 count of I neutrophile, 90 lymphocytes, 7 monocytes, and 2 basophiles. From this time on there was a gradua1 but steady increase in

it &as possible to discontinue the peniciIIin on the seventh day following recognition of the agranulocytosis. Pentnucleotide was also discontinued after a tota of I IO cc. had been administered. At that time the Ieucocyte count was 10,500 with 16 per cent neutrophiles and 30 per cent lymphocytes, the balance being immature forms. At no time during this serious compIication was there any indication of acute pharyngitis, mucosal ulcerations, or a latent pyogenic infection. A coIostomy spur crushing cIamp was appIied on the fortieth postoperative day. Two days later there was some bIeeding from the bowe1 edge which was controIIed by the appIication of MonseIl’s solution. A Ieucocyte count taken at this time is of interest in that it was found to be 24,000 with 96 per cent neutrophiIes. The spur was compIeteIy cut through in one week foIlowing appIication of the clamp. At this time

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American

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Conrad--Intestinal

he began to complain of considerable dysuria and his urine, heretofore grossly bloody. The question

FIG. 3. Cystogram

opaque kidney

media peIvis.

normai, became immediately arose

show& reflux of the up each ureter and into the

as to the possibility of a beginning vesicorecta1 fistma. A fecal odor to the urine was not noted and the patient denied the passage of any gas through the urethra. The urine continued to be grossly bIoody, but cultures were steriIe. Bieeding and cIotting times were normaI. The patient voIunteered the information that when he urinated his “bladder didn’t seem to contract like it did before his injury but just foIded up.” Urologica consultation was secured and cystoscopy showed a loss of bladder tone with marked redundancy of the bIadder mucosa. No evidence of a vesicorectai fistuIa was seen. A cystogram was taken and reveaIed a diIated bIadder with a reffux of the opaque media up each ureter and into the kidney peivis. (Fig. 3.) The ureters were somewhat dilated. In the opinion of the uroIogist, this condition represented a neurogenic bladder, resulting from injury to the sacral plexus. It was believed that the bfeeding was due to congestion of the redundant bIadder mucosa. The patient was encouraged to void frequentIy. The urine remained uninfected and the hematuria gradualIy subsided.

Injury

OLTOBBH, I(r-li

CIosure of the coIostomy sodium second

pentotha1 anesthesia day following the

was done under on the eightyoriginal injury.

FIG. 4. Cystogram taken two months later showing normal bladder and no demonstrabIe reflux up either ureter.

SuIfaniIamide was not used in the wound, which heaIed solidly and rapidiy without incident. The convaIescence from this point on was uneventfu1. A cystogram was repeated by the uroIogica1 service two months after the original attack of hematuria, and a series of cystometric readings were taken. The residua1 urine was found to be less than 20 cc. and the study indicated that the bladder was regaining norma tone. There was no reflux of the opaque media up either ureter. (Fig. 4.) At the time of his discharge from the hospita1, he was fuily ambulant. He had gained steadiIy in weight and was feeling and Iooking very weI1. He was returned to the maimand for sick leave, foIIowing which it appeared that he would be able to return to full duty.

COMMENT

The continuance of the sulfonamide therapy in this instance may appear to have been unnecessariIy proIonged. It shouId be pointed out that the fecal contamination was extremeIy widespread, and

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the subsequent peritonitis very severe. The continuation was dictated, in our opinion, in light of past experiences in which a number of cases of apparently “recovered” peritonitis developed residual abscesses foIlowing the early withdrawal of the drug. The absence of pyogenic complications during and following the agranulocytosis may have been attributable to the relatively brief duration of this condition. On the other hand, the agranulocytosis, although of brief duration, was of great severity and the absence of pyogenic sequalae is noteworthy. ‘I’here are two schools of thought in regard to therapy in agranuIocytosis due to drug sensitivity. The first is expressed by Dameshek:’ “ If the bone marrow Ieucocytes are not irretrievabIy damaged, the patient wiI1 recover; otherwise the effects of therapy in a given case are very dubious.” The second is expressed by Jackson2s3 who has stated: “ I n seventy-two personaI1y collected cases of extreme agranulocytosis (without anemia of moment) due to sulfonamide compounds or other drugs, recovery occurred in but 30 per cent of these in which withdrawal of the drug was the only measure taken. In twenty-six similar cases in which the drug was withdrawn and adequate amounts of pentnucIeotide (40 cc. daily) were given, recovery occurred in

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American Journal <,ISurgery

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66 per cent. The series is small, but the resuhs are suggestive. In any event, daiIy leucocyte and differentia1 counts should be done on all cases suspected of having agranulocytosis, and energetic measures should be taken immediatelyafter the diagnosis is estabIished.” We chose to treat this case “energetically.” In addition to stopping the drug, transfusions, liver extract, and pentnucleotide were employed. For the purpose of suppressing pyogenic infection pending the resumption of normal bone marrow activity, we believed that penicillin on theoretical grounds shouId be inchided in the energetic measures empIoyed in the management of this case. There is some evidence for the belief that it was of definite benefit. The inclusion of this drug among the “energetic” measures to be employed in the treatment of agranuIocytosis is recommended pending further evamation of the many factors involved in this condition. REFERENCES 1. DAMESHEK, WILLIAM. Report on medical progress; hematology. New England J. Med., 222: IOOO1010, 1940. 2. JACKSON, H. JR. Leukemias. New England J. Med., 222:22-28, 1940. 3. JACKSON, H. JR. Report on medica progress; leukemia, agranulocgtosis. New England J. Med., 225: 978-982, 1941.