LETTERS AND CORRECTIONS

Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five references may be used. Complete references must be furnished, as specified in "Information for Authors" (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: we give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style. Special Uses of Cimetidine T o T H E EDITOR: We read with interest the recent article by Swartz and colleagues that described hemodialysis with a highchloride, low-acetate dialysate as a successful treatment for metabolic alkalosis in the postoperative patient with renal failure (1). We recently treated a 37-year-old man who had suffered a gunshot wound to the abdomen that required extensive abdominal surgery. The patient subsequently developed acute renal failure and a severe metabolic alkalosis that was secondary to nasogastric suctioning. Hemodialysis with a high-chloride, lowacetate dialysate was very effective in correcting the metabolic alkalosis. Before dialysis the blood pH was 7.57 and plasma bicarbonate 42 meq/litre. After 5 h of high-chloride, low-acetate dialysis, the blood pH had fallen to 7.40 and the plasma bicarbonate to 22 meq/litre. With continuous nasogastric suctioning the metabolic alkalosis recurred rapidly. By 18 h postdialysis the blood pH and plasma bicarbonate had risen to 7.54 and 36.5 meq/litre, respectively. Because the generation and maintenance of our patient's metabolic alkalosis depended on gastric acid loss secondary to the continuous nasogastric suctioning, the use of an agent that would inhibit gastric acid secretion seemed fully rational.

A newly released drug, cimetidine (an H 2 receptor blocker), appeared suitable for this purpose because it had been shown to effectively reduce gastric acid secretion (2, 3). To attempt to prevent reoccurrence of the metabolic alkalosis, treatment with cimetidine (300 mg intravenously every 12 h) was initiated immediately after a second high-chloride, low-acetate dialysis. During cimetidine administration hemodialysis was done about

every 3 days with a conventional dialysate. The metabolic alkalosis did not recur; the plasma bicarbonate was maintained between 16.6 and 25.0 meq/litre. Gastric analysis data showed a great reduction in the 24-h hydrochloric acid production, from 563 meq before to 102 meq after the institution of cimetidine. The lack of redevelopment of metabolic alkalosis in the face of the continuous loss of small amounts of hydrochloric acid through nasogastric suctioning may be explained by intermittent hemodialysis treatments and retention of endogenously produced nonvolatile acids in the presence of renal failure. We conclude that cimetidine is a useful adjunct in the treatment of metabolic alkalosis caused by the loss of gastric secretions (nasogastric suctioning or vomiting, or both) in the presence of concomitant renal failure. N. D A B I R V A Z I R I , C Y R I L H. B A R T O N , RUSSELL NESS, KHOSROW MIRAHMADI,

M.D. M.D. M.D. M.D.

University of California Irvine Medical Center; Orange, CA 92668 REFERENCES 1. S W A R T Z RD,

R U B I N JE, B R O W N RS, Y A G E R HM,

S T E I N M A N TI,

FRA-

ZIER HS: Correction of postoperative metabolic alkalosis and renal failure by hemodialysis. Ann Intern Med 86:52-55, 1977 2. BRIMBLECOMBE RW, DUNCAN WAM: The relevance to man of preclinical data for cimetidine, in Proceedings of the Second International Symposium on Histamine H,-Receptor Antagonists. Amsterdam, Excerpta Medica, 1977, pp. 54-65 " 3. G I L B E R T OB, BANK S: Basal acid output response to cimetidine in man, in Proceedings of the Second International Symposium on Histamine H2Receptor Antagonists. Amsterdam, Excerpta Medica, 1977, pp. 110-119

T o T H E EDITOR: Cimetidine, a histamine H 2 receptor antagonist, is effective in suppressing gastric acid secretion (1). The effect of cimetidine on refractory metabolic alkalosis resulting from copious nasogastric drainage has not been described. We report our experience with cimetidine in a patient who developed severe metabolic alkalosis from nasogastric suction.

Table 1. Clinical Data Hospital Day 2

3

4

5

6

146 3.9 98 25

138 3.5 90 31

140 3.4 88 36

139 3.3 94 24

141 3.9 99 23

Serum electrolytes, meq/litre

Na K CI HC03 Arterial blood gases Pco 2 , mm Hg PH Nasogastric aspirate, meq/litre Na K CI Therapy

266

37 7.49

40 7.55

36 7.55 59 12 128

Dialysis

Dialysis NH4CI, 140 meq

NH4CI, 169 meq Cimetidine, 300 mg every 12 h

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33 7.38 113 7 129 Dialysis NH4CI, 40 meq Cimetidine, 300 mg every 12 h

38 7.38 114 9 116 Dialysis

Cimetidine, 300 mg every 12 h

Three days after intestinal resection for bowel infarction, a 74-year-old man was admitted to Indiana University Hospital with acute oliguric renal failure and profound ileus. Hypochloremic metabolic alkalosis developed secondary to hydrogen ion loss from the 2.5 to 5 litres of nasogastric suction daily. Attempts to correct the alkalosis with intravenous potassium and ammonium chloride solutions were unsuccessful. Hemodialysis, using a standard dialysate bath containing 36.6 meq/litre of acetate, had no detectable influence on the alkalosis. On the fourth hospital day, treatment with cimetidine, 300 mg intravenously every 12 h, was begun and continued throughout the hospitalization. An abrupt change in the electrolyte composition of the nasogastric aspirate occurred on the next day, after which normal acid-base homeostasis was promptly attained with ammonium chloride replacement. On the second day after the start of cimetidine therapy, ammonium chloride was no longer required. Although nasogastric suction was continued for the remainder of the hospitalization, with nasogastric outputs of 2 to 4 litres daily, metabolic alkalosis did not recur. A summary of pertinent acid-base data appears in Table 1.

Hypochloremic metabolic alkalosis is a well-documented consequence of nasogastric suction (2). Alkalosis due to hydrogen ion loss is difficult to correct by replacement of depleted volume and chloride in patients with oliguric renal failure because of their inability to excrete bicarbonate. Consequently, dilute solutions of hydrochloric acid or ammonium chloride have been used, as well as dialysis with specially prepared low acetate dialysate (3). O u r case report suggests a potential method for physiologically preventing or treating metabolic alkalosis that results from nasogastric suction. Although the hydrogen ion concentration of the nasogastric secretions was not measured directly, the change in electrolyte composition of the gastric aspirate after the initiation of cimetidine therapy, as listed in Table 1, implies that a decrease in the hydrogen ion content of the secretions occurred. This effect explains the relative ease with which alkalosis was subsequently corrected and normal acid-base homeostasis maintained in this patient. G E O R G E R. A R O N O F F , M . D . R I C H A R D J. H A M B U R G E R , M . D . , F . A . C . P .

fore the antacids leave the stomach. Possibly histamine H-2 receptor antagonist can be substituted for antacids in an attempt to neutralize stomach contents and prevent acid injury to the lungs. Side effects have been few, and the margin of safety for these compounds has been good (2). Cimetidine is known to markedly reduce gastric acidity for prolonged periods. Mean basal acid secretion has been shown to be reduced to almost zero for 5 h after a single dose (3). Data provided by the manufacturer show that even after a meal the p H of gastric contents remains at 3.1 or greater for at least 4 h. This is well above the p H of 2.5 considered critical for serious acid injury to the lungs. In addition to very effective lowering of gastric acidity and a much greater duration of action, other advantages of cimetidine over antacids for prevention of acid injury to the lungs are obvious. T h e drug comes in an intravenous form and therefore would not be included in the gastric aspirate. It may also be given to those who are comatose or otherwise unable to take oral medications. Prophylactically reducing the acidity of gastric contents with H-2 receptor antagonists might safely reduce the frequency of lung injury from aspirated acid. A clinical trial of this concept would not be difficult and should be undertaken. W.H. B E S T E R M A N , J R . , M . D .

Naval Hospital; Beaufort, SC 29902

REFERENCES

1. W Y N N E JW, M O D E L L JH: Respiratory aspiration of stomach contents. Ann Intern Med 87:466-474, 1977 2. HIRSCHOWITZ BI: Histamine H-2 receptor antagonists. Ann Intern Med 87:373-375, 1977 3. H E N N RM, ISENBERG JI, M A X W E L L V, S T U R D E V A N T RAL: Inhibition

of gastric acid secretion by cimetidine in patients with duodenal ulcer. TV Engl J Med 293:371-375, 1975

Indiana University Medical Center; Indianapolis, I N 46202 REFERENCES

Acetaminophen and the Liver

1. L O N G S T R E T H G F , G o VLW, M A L E G E L A D A J-R: Cimetidine suppression

of nocturnal gastric acid secretion in active duodenal ulcer. N Engl J Med 294:801 -804, 1976 2. W I L S O N R F , G I B S O N D, P E R C I N E L AK, A L I MA, B A K E R G, L E B L A N C

LP, LUCAS C: Severe alkalosis in critically ill surgical patients. Arch Surg 105:197-203, 1972 3. S W A R T Z R D , R U B I N JE, B R O W N RS, Y A G E R H M , STEINMAN TI, F R A -

ZIER HS: Correction of postoperative metabolic alkalosis and renal failure by hemodialysis. Ann Intern Med 86:52-55, 1977

T o T H E E D I T O R : T h e recent clinical review by Wynne and M o dell (1) addressed the perplexing problem of respiratory aspiration of gastric contents. This illness is especially disconcerting because under some conditions, mortality is very high after acid aspiration even with maximal supportive measures such as intubation, positive pressure ventilation, and administration of steroids, antibiotics, and intravenous fluids. As the authors also pointed out, the injury of acid applied to lung tissue is almost immediate, so that local measures such as endotracheal suctioning and removal of debris by bronchoscopy do little to prevent pulmonary damage by acid. The optimal approach to patients at risk for acid aspiration should be prevention. Wynne and Modell (1) have listed the clinical settings likely to be associated with aspiration, including altered states of consciousness, abnormal swallowing mechanisms, anesthesia, depressed intestinal motility, and regurgitation, as well as patients with nasogastric tubes or tracheostomies. For the prevention of injury to the lung in patients at risk for aspiration, several measures are recommended, including the administration of antacids, to reduce the acidity of gastric contents. While antacid administration is a rational step in the prevention of acid injury, it has not been shown to reduce morbidity or mortality. Further, the antacids themselves may become part of the aspirate unless the recipient is conscious, has a normal swallowing mechanism, and does not suffer aspiration be-

T o T H E E D I T O R : We are stimulated by the paper by Barker, de Carle, and Anuras ("Chronic Excessive Acetaminophen Use and Liver D a m a g e , " Ann Intern Med 87:299-301, 1977) to report the case of a patient who sustained severe liver damage from acetaminophen, not from an overdose with suicidal intent but from inappropriately heavy therapeutic use. A 30-year-old white man was admitted to Parkland Memorial Hospital in September 1977 with confusion, disorientation, jaundice, and fever. His acute illness had begun 8 weeks previously with anorexia, nausea, vomiting, dark urine, and malaise associated with severe headaches but no overt jaundice. After 3 to 4 weeks he improved and was able to return to work. Ten days before admission severe headaches recurred, again accompanied by nausea, vomiting, and dark urine. The symptoms became intractable, with onset of the mental changes he was brought to the hospital. The patient denied any exposure to hepatitis, recent blood transfusions, illicit drug use, or alcohol abuse. He denied skin rash, arthralgia, pruritus, or abdominal pain. In 1973 he was subjected to partial gastrectomy with a Billroth II anastomosis for a chronic duodenal ulcer. In 1975 he required a number of hospitalizations and, ultimately, a surgical revision to treat a marginal ulcer. During this 2-year interval he received a number of blood transfusions, and on one of these admissions his serum glutamic oxalacetic transaminase (SGOT) and serum alkaline phosphatase activities were noted to be slightly elevated. The hepatitis B surface antigen (HBsAg) was negative. Liver function test findings were within normal limits. The patient gave no other history of previous liver disease. He had been subject to severe headaches ever since he sustained a head injury at age 15. These headaches occurred in 2- to 3-week episodes and recurred every 3 to 4 months. They were frequently associated with nausea and vomiting. The patient chronically ingested two or three tablets of Darvocet N-100 and Tylenol daily but would increase his medication markedly during these episodes of severe pain. No cause for the headaches had been found during a previous extensive investigation. For the week before his current admission he was taking at least four Percodan® tablets, five Darvocet N-100 tablets, and up to 10 Tylenol tablets each day. At admission he was agitated and showed marked disturbance of concentration with flight of ideas and mild disorientation. He was febrile to 38.3 °C, his sclerae were icteric, and he had scattered spider angiomata over his chest Letters and Corrections

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267

Figure 1 . Left. Fibrotic widened centrilobular areas ( O and small inconspicuous portal tracts (P). (Hematoxylin and eosin; original magnification, x 6 6 . ) Right. Higher magnification showing central fibrosis (C) containing predominantly chronic inflammatory cells, minimal fatty metamorphosis, and a small normal portal tract (P). (Hematoxylin and eosin; original magnification, x 1 6 5 . ) and arms. No other peripheral stigmata of liver disease were apparent. Neither his liver nor spleen were palpable, but there was tenderness in both right and left upper quadrants. His liver span was only 8 cm by percussion. A metabolic flapping tremor could not be elicited, and he had no evidence of fluid retention. Initial laboratory data included a hemoglobin of 10.5 g/dl and a leukocyte count of 4600/mm 3 with 86% polymorphonuclear leukocytes and 4 % band forms. The serum bilirubin was 5.3 mg/dl (2.2 mg/dl direct reacting), the serum alkaline phosphatase 16.8 King-Armstrong (K-A) units, and the SGOT 1321 Karmen units. The prothrombin time was 25 seconds (control, 11.5 seconds), and the partial thromboplastin time was 42.5 seconds (control, 22 seconds). Blood ammonia was measured at 189 /xg/dl, and the HBsAg was negative. Unfortunately serum acetaminophen was not measured at admission. Serum electrolyte, serum creatinine, and plasma protein values were all within normal limits, as were chest roentgenogram and ECG findings. The patient was considered to be in stage I hepatic encephalopathy with acute fulminant viral hepatitis and was treated conservatively. His mental status improved over the next 3 days, with parallel improvement in liver function test findings. A percutaneous liver biopsy was done on the fifth hospital day. Two cylinders of liver parenchyma measuring 2 cm by 2 mm were obtained and examined microscopically using hematoxylin-eosin and Masson trichrome stains (Figure 1). The biopsy did not show changes consistent with a diagnosis of viral hepatitis. The architecture was disrupted by extensive centrilobular fibrosis composed of both mature collagenous and delicate reticular fibers that indicated both an acute and a more established lesion. Connective tissue septae and bridging necrosis connected some central areas and, rarely, joined central to portal structures. The centrilobular fibrous tissue contained a chronic inflammatory infiltrate with a scattering of polymorphonuclear leukocytes. The surrounding hepatocytes showed a moderate fatty metamorphosis. Rare coagulation necrosis of individual hepatocytes was seen. Balloon degeneration and Mallory's hyalin were absent. The parenchyma showed numerous plates several cells thick. The portal areas were well preserved. A slight increase in fibrous tissue and a mild chronic inflammatory infiltrate were noted in a few portal triads, but most were entirely normal. These findings were considered to be quite atypical for acute viral hepatitis and strongly suggestive of the toxic lesion induced by acetaminophen. His clinical course improved rapidly. He was discharged, asymptomatic, after 8 days, with a serum bilirubin of 1.2 mg/dl (0.7 mg/dl direct reacting), serum alkaline phosphatase of 17.4 K-A units, SGOT of 17 Karmen units, and a normal prothrombin time. We believe that this man sustained severe hepatic necrosis from excessive therapeutic use of acetaminophen. The histologic features of his liver biopsy are consistent with this proposition and suggest he may have suffered previous, less severe, episodes. Unlike one of the patients reported by Barker, de Carle, and Anuras, our patient was not exposed to a known inducer of the P-450 system. He had had a marked decrease in his nutritional intake, however, and may well have had depletion of his hepatic glutathione level. This, with injudicious dosages of the drug, produced a very severe liver lesion and illness. 268

A T H O L J. W A R E , M.B., B.S., F.R.A.C.P. K A T H E R I N E S. U P C H U R C H , M . D . E D W I N H. E I G E N B R O D T , M . D . D A N I E L A. N O R M A N , M . D . Southwestern Medical School and Veterans Administration Hospital; Dallas, TX 75235

Hepatic Granulomas and Ileal Bypass T o T H E EDITOR: Bruce and Wise (Ann Intern Med 87:574-576, 1977) have reported the occurrence of tuberculosis in four patients after ileal bypass for obesity. In two of their patients, a presumptive diagnosis of tuberculosis was made from liver biopsy showing noncaseating granulomas, with acid-fast organisms identified in one case. We agree that these two patients probably had tuberculosis, but we wish to caution against accepting hepatic granulomas as prima facie evidence for tuberculosis in ileal bypass patients. We have reviewed liver biopsies from 25 patients who had had ileal bypass surgery. Hepatic granulomas appeared in the biopsies of six patients (24%) at postbypass intervals ranging from 3 months to 3 years. This compares with an annual incidence of granulomas in 3 % of nonobesity liver biopsies and in 4% of obesity patients at the time of bypass surgery. The six patients showed no clinical evidence for tuberculosis; acid-fast stains and one biopsy culture were negative; and all patients have done well through 3 years of observation. Our findings suggest that hepatic granulomas in postbypass patients are probably most often not due to tuberculosis, but may represent a local reaction to absorbed products from the blind loop. BARBARA BANNER, M.D. Department of Pathology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL 60612 A R T H U R S. B A N N E R , M . D . Division of Pulmonary Medicine, Cook County Hospital, Chicago, IL 60612

Leukocyte Mobilization in Leukemic Reticuloendotheliosis T o T H E EDITOR: Yam, Chaudry, and Janckila (1) have recently described impaired leukocyte mobilization in leukemic reticuloendotheliosis (hairy cell leukemia). Using the skin window technique of Rebuck and Crowley (2), they showed lack of monocyte response. The authors postulate that factors other than

Annals of Internal Medicine • February 1978

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monocytopenia could explain the lack of monocyte response and suggest an intrinsic monocyte defect or a lack of chemotactic factors. We wish t o report briefly on a study that may explain some of their findings. Sera from five patients with leukemic reticuloendotheliosis were examined for the presence of chemotactic factor inactivator(s). A suspension of bacterial chemotactic factor (Escherichia coli extract) and patient's serum was incubated at room temperature for 30 min. A portion of this mixture was put in a modified Boy den chemotactic chamber (Neuroprobe, Inc., Bethesda, Maryland), against a suspension of normal mononuclear cells and incubated for 90 min. The percent inhibition was determined by calculating the ratio of normal monocyte chemotactic activity in the presence of the inactivator, and in its absence (3). All tests were done in triplicate. As controls, serums from 12 normal subjects were studied. T h e blood monocytes used were from two individuals who had normal monocyte chemotaxis. Serum from the patients with leukemic reticuloendotheliosis produced inhibition of normal monocyte chemotactic activity due to the presence of chemotactic factor inactivator(s). In contrast, none of the control subjects showed any evidence of chemotactic factor inactivation. Thus, the presence of chemotactic factor inactivator(s) in the serum of patients with leukemic reticuloendotheliosis may interfere with the ability of monocytes to reach the site of inflammation and may play a role in the increased susceptibility to infection in these patients. T h e presence of chemotactic factor inactivator(s) in malignancies has also been found in Hodgkin's disease (4) and in patients with malignant solid tumors (5).

with well-developed collateral circulation and opacification of the portal system. On 9 April 1976, the patient was readmitted with what appeared to be a massive intra-abdominal hemorrhage. She complained of dysuria and her abdomen was distended. An abdominal puncture showed the presence of uncoagulated blood. Quick's time was estimated at 2 min. After correction of coagulation defect a laparatomy showed a hematocyst filling the entire pelvis, apparently originating from the left ovary. A left adnexectomy was done, and the patient underwent an uneventful recovery. Anticoagulant therapy was restarted 8 days after surgery. One year after surgery, the nephrotic syndrome remained unchanged, without any further complication.

This case further illustrates the need for the clinician to be aware of the possibility of intrapelvic hemorrhage of genital origin associated with anticoagulant therapy in those patients being treated for renal vein thrombosis. High pressure in the left ovarian vein and the important collateral circulation raise the risk of bleeding in those sites. R. G E N I N M.D. J. M. CHALOPIN M.D. G. RIFLE M.D. Nephrology Unit, Hopital du Bocage, 21034—Dijon-Cedex, France REFERENCE 1. A P P E L GB, W I L L I A M S GS, M E L T Z E R JI, P I R A N I CL: Renal-vein throm-

bosis nephrotic syndrome and systemic lupus erythematosus. An association in four cases. Ann Intern Med 85:310-317, 1976

Folic Acid, Xanthine Oxidase, and Uric Acid

C A R L R. K J E L D S B E R G , M . D .

College of Medicine, University of Utah, Salt Lake City, U T 84113

REFERENCES 1. Y A M LT, C H A U D R Y AA, J A N C K I L A AJ: Impaired marrow granulocyte

2. 3. 4. 5.

reserve and leukocyte mobilization in leukemic reticuloendotheliosis. Ann Intern Med 87:444-446, 1977 REBUCK JW, C R O W L E Y JH: A method for studying leukocytic functions in vivo. Ann NY Acad Sci 59:757-805, 1955 BERENBERG JL, W A R D PA: Chemotactic factor inactivator in normal human serum. J Clin Invest 52:1200-1206, 1973 W A R D PA, BERENBERG JL: Defective regulation of inflammatory mediators in Hodgkin's disease. N Engl J Med 290:76-80, 1974 KJELDSBERG CR, PAY G D : A qualitative and quantitative study of monocytes in patients with malignant solid tumors. Cancer, in press

Intrapelvic Hemorrhage and Renal Vein Thrombosis T o T H E EDITOR: We have read with interest the paper by Appel and associates (1) relating to renal vein thrombosis during systemic lupus erythematosus glomerulonephritis (1). W e were particularly interested by the two cases of "laterouterine hematomas" occuring during anticoagulant therapy. We wish to add our experience with a case of intraperitoneal hematoma occuring during anticoagulant therapy for renal vein thrombosis due to extramembranous glomerulonephritis. A 29-year-old white woman was first seen at our hospital in July 1975 with typical symptoms of the nephrotic syndrome. Physical findings were unremarkable except for edema of legs. Arterial blood pressure was 120/80 mm Hg. Proteinuria (of selective glomerular type) was 5.5 g/24 h. Total serum protein was 5.8 g/dl. Creatininemia was 1 mg/dl. Renal biopsy showed extramembranous glomerulonephritis, cause unidentified. During hospitalization two episodes of pulmonary embolism occured. Inferior vena cavagraphy showed thrombosis of both left and right renal veins with extension to the inferior vena cava. Because of recurrent pulmonary emboli, a surgical operation was done on 24 September 1975. The thrombus of the inferior vena cava was removed, and a clip was placed superior to the junction of the renal veins with the inferior vena cava. Heparin therapy was started, followed by antivitamin-K therapy. Pulmonary emboli did not recur. The nephrotic syndrome remained unchanged; X-ray examination showed complete thrombosis of the inferior vena cava inferior to the clip

T o T H E EDITOR: With reference to the letter of K. A. Oster (1), we wish to report a trial of treatment with folic acid, at daily dose of 1 m g / k g body weight during 1 month, in 10 patients with gout (five with hyperuricemia and hyperuricosuria, five with isolated hyperuricosuria). In one case, an attack of gout developed on the sixth day. Blood uric acid has been determined weekly in the patients with hyperuricemia, and no change was found during the period of folic acid administration. W e observed a fall of 10% in urine uric acid excretion during the first week of treatment, with subsequent return to initial values. We conclude that folic acid, at least with a dose of 1 m g / k g body weight per day during 1 month, does not reduce uricemia or uric acid excretion. W e do not see that folic acid could replace allopurinol as the therapeutic inhibitor of xanthine oxidase.

BERNARD PLOUVIER, M.D. BERNARD DEVULDER, M.D. Service de Medecine Generate et Nephrologie B, Hopital Calmette, Centre Hospitalo—Universitaire, 59037 Lille Cedex, France. REFERENCE

1. OSTER KA: Folic acid and xanthine oxidase. Ann Intern Med 86:367, 1977

Long Half-Life for Cefazolin in Anuria T o T H E EDITOR: "Guidelines for Drug Therapy in Renal Failure" by Bennett and colleagues (1) provides valuable information to the practitioner. Individualization of drug therapy by monitoring serum levels is preferred because of the great variation among patients in pharmacokinetics. T h e following case illustrates potential problems in using average patient data when adjusting cefazolin doses in decreased renal function. A 26-year-old white man was admitted to The Ohio State University Hospitals on 18 July 1977. He gave a history of renal disease for 3 years and had been on chronic hemodialysis since April 1974. In June 1977 he underwent cadaveric transplantation but experienced numerous rejections that did not respond to therapy. Letters and

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Corrections

269

At admission the patient was acutely ill. His vital signs were a temperature of 39.4 °C, pulse 112 beats/min, respiration 24/min, and blood pressure 90/60 mmHg. A chest roentgenogram showed a left lower lobe and lingula infiltrate consistent with bacterial pneumonia. Pertinent laboratory data included blood urea nitrogen and serum creatinine levels of 48 mg/dl and 10.4 mg/dl, respectively. Sputum cultures were obtained. Treatment with intravenous cefazolin and gentamicin was started. The patient continued to spike fevers, his urine output fell to zero, and he was finally taken to surgery for nephrectomy of the transplanted kidney. Two days after surgery antibiotics were withdrawn. Before withdrawal of the antibiotics the patient had been treated for 12 days with cefazolin and gentamicin. Serum levels of cefazolin were measured 1 h after the drug was withdrawn and at 24, 72, 96, and 120 h thereafter. The patient was dialyzed between the 72-h and 96-h measurements. A microbiological method, using Bacillus subtilis as the test organism, was used to assay cefazolin levels. These decay levels were 1 h, 256 /ig/ml; 72 h, 206 jag/ml; 96 h, 128 jag/ml; and 120 h, 105 jag/ml. The patient slowly improved, but before recovery was complete he signed out of the hospital against medical advice.

The biological half-life of cefazolin in end-stage renal disease has been reported by Bennett and associates (1) to be between 18 and 36 h. Other authors cite a slightly wider range (10 to 59 h) (2-4). In our patient the half-life of cefazolin was estimated using a natural log concentration versus time plot for the levels obtained during the decay of the serum levels. A line of best fit was generated using linear regression computerization and was found to be statistically significant (r = 0.97, P = 0.025). From the line of best fit the elimination rate constant was found to be 0.007 h ' or an elimination half-life of 99 h. The single dialysis did not appear to have a significant effect on cefazolin elimination. Previous attempts to determine the kinetic properties of cefazolin have used single-dose injections. T h e effect of multiple doses on serum concentration has not been fully studied. In our patient, who had been taking cefazolin for 14 days, steady state was not reached. However, the half-life was almost three times as long as previously reported. Recently studies have cited seizures secondary to high serum and cerebrospinal fluid levels of cefazolin in renally compromised patients (5). We believe that caution must be used in the administration of cefazolin in patients with severe renal disease for multiple days. Although the literature provides rough guidelines for cefazolin dosage in the renally compromised patient, there is no substitute for measuring serum levels. T I M O T H Y D . M O O R E , B. P H A R M . S H I V K. S E T H , P H . D .

The Ohio State University Hospitals; Columbus, O H 43210

(1). Parathormone promotes renal bicarbonate wasting, renal reabsorption of hydrogen ion, and production of organic acids. As a consequence, in hypercalcemia from primary hyperparathyroidism there is a tendency to acidosis that results in the intracellular to extracellular shift of potassium and thus higher serum levels. With secondary forms of hypercalcemia, as in malignancy, there is feedback inhibition of parathormone, a tendency to alkalosis, and thus lower serum potassium levels. Second, patients with malignancy are frequently catabolic. As described in other catabolic settings (2, 3) there is loss of lean body mass, cellular breakdown, and loss of intracellular constituents including potassium. It seems reasonable, therefore, to attribute the more pronounced hypokalemia in hypercalcemia from malignancy than that of hyperparathyroidism to multiple mechanisms. These include decreased intake of potassium; gastrointestinal potassium losses; tendency to alkalosis; and increased catabolic activity. D A V I D A. N A R D O N E , M . D .

Veterans Administration Hospital; Portland, O R 97207 REFERENCES

1. BARZEL US: The differential diagnosis of hypercalcemia. Ann Intern Med 76:825-826, 1972 2. L J U N G G R E N H, IKKOS D, L U F T R: Studies on body composition. III.

Body fluid compartments and exchangeable potassium in females with anorexia nervosa. ATA Endocrinol (Kbh) 25:209-223, 1957 3. KASSIRER JP, H A R R I N G T O N JT: Diuretics and potassium metabolism: a

reassessment of the need, effectiveness and safety of potassium therapy. Kidney Int 11:505-515, 1977

T o T H E EDITOR: The discussion of "Hypokalemia with Hypercalcemia" by Aldinger and Samaan (Ann Intern Med 87:571573, 1977) concludes without mention of acid-base contributions to production of hypokalemia in the presence of hypercalemia. That metabolic alkalosis is a common concomitant of non-parathyroid hormone (PTH)-related hypercalcemia has been known for many years (1) but only recently has a likely mechanism been elucidated in animal studies (2). It is probable that elevated P T H and non-PTH-related hypercalcemias have opposite effects on proximal handling of bicarbonate, causing a depression and an elevation in the Tm H C O , , respectively. Conceivably blood p H may be one of the key determinants of serum potassium concentration in Aldinger and Samaan's patients and a factor that may partially explain the difference between the prevalence of hypokalemia in malignant ( P T H and n o n - P T H varieties) and primary hyperparathyroid hypercalemias. P A U L D. M I T N I C K , M.D.

REFERENCES 1. B E N N E T T WM, SINGER I, G O L P E R T, F E I G P, COGGINS CJ: Guidelines

Hospital of the University of Pennsylvania; Philadelphia, P A 19104

for drug therapy in renal failure. Ann Intern Med 86:754-783, 1977 2. W E L L I N G PG, C R A I G WA, A M I D O N GL, K U N I N CM: Pharmacokinetics

of cefazolin in normal and uremic subjects. Clin Pharmacol Ther 15:344353, 1974 3. L E R O Y A, C A N O N N E M-A, FILLASTRE J-P, H U M B E R T G: Pharmacoki-

netics of cefazolin, a new cephalosporin antibiotic, in normal and uraemic patients. Curr Ther Res 16:878-889, 1974 4. W E L L I N G PG, C R A I G WA, K U N I N CM: Prediction of drug dosage in

patients with renal failure using data derived from normal subjects. Clin Pharmacol Ther 18:45-52, 1975 5. YOST RL: Convulsions associated with sodium cefazolin: a case report. Am Surg 43:417-420, 1977

Hypokalemia and Hypercalcemia T o T H E EDITOR: Aldinger and Samaan in their article " H y p o kalemia with Hypercalcemia" (Ann Intern Med 87:571-573, 1977) demonstrate a higher prevalence of hypokalemia in the hypercalcemia of malignancy than in that of hyperparathyroidism. They postulate that this difference is due to decreased potassium intake either from the malignancy itself or associated chemotherapy as well as gastrointestinal losses. I suggest two additional mechanisms. The first is related to the metabolic effects of parathormone 270

REFERENCES

1. H E I N E M A N N HO: Metabolic alkalosis in patients with hypercalcemia. Metabolism 14:1137-1152,1965 2. C R U M B CK, M A R T I N E Z - M A L D O N A D O M, EKNOYAN G, SUKI W N : Ef-

fects of volume expansion, purified parathyroid extract, and calcium on renal bicarbonate absorption in the dog../ Clin Invest 54:1287-1294, 1974

Allowing or Causing Death T o T H E EDITOR: I found the article by K. Danner Clouser, "Allowing or Causing: Another Look" (Ann Intern Med 87:622-624, 1977), quite interesting. I agree with his position that the difference between "allowing to d i e " and "causing to die" is subtle. However, I object to his notion that "it is the doctor's obligation to do all he can to save," and that if the physician recedes from this, he ethically becomes a layman. It has become axiomatic in medicine that the physician will cure sometimes, but comfort always. As eloquently described by Peabody (1), the caring role of a physician is at least as important and may supersede the curative role. Following a caring role will commonly mean abandoning the curative role in terminally ill patients. This is a medical decision. I know of

Annals of Internal Medicine • February 1978

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nothing that states society has dictated that physicians should save at the expense of a caring role. Indeed I would counter Clouser's position by stating that a physician would be ethically remiss if he abandoned a caring role for his patient while seeking to save. I recently attended at the death of one of my long-term patients at his home with his family. T h e cause of death that I "allowed" to occur was pneumonia in a man who had suffered for many years with severe emphysema. At all times my supportive role was that of a physician, not a layman. Although I agree with the general message of Clouser's article, to state that "the physician has an obligation to save and is remiss if he does not t r y " is a simplistic look at the practice of medicine that leads to the inappropriate care of dying patients. J O S E P H E. S C H E R G E R , M . D .

University of Washington; Seattle, W A 98195 REFERENCE

1. PEABODY FW: The care of the patient. JAMA 88:877-882, 1927 T o T H E EDITOR: Clouser is to be commended for his courageous thoughts on a difficult problem ("Allowing or Causing: Another Look," Ann Intern Med 87:622-624, 1977). Unfortunately, his analysis is seriously marred in that it glosses over a critical point. H e repeatedly defines the physician's duty to the patient in terms of society's expectations: " . . . society's expectations of the physician toward his patient, and hence a moral obligation . . . the doctor's society-given duty to save . . . no longer a clear mandate from society as to the physician's duty Without definition of the physician's primary obligations to the patient, any analysis of the problems presented when the needs or expectations of patients and their society (or, indeed, their physicians) are in conflict must remain interesting but of little practical value. P E T E R H. ELIAS, M . D .

Central Maine Medical Center; Lewiston M E 04240

Holistic Care T o T H E EDITOR: "Major Trends in Psychosomatic Medicine" by Drs. Leigh and Reiser in the August issue {Ann Intern Med 87:233-239, 1977) is an important review of the benefits that may result from a more inclusive view of the patient and of the illness process. We, too, have been impressed by the depth and usefulness of a holistic systems model of illness that includes interacting constitutional, developmental, environmental, and interpersonal factors. We attribute much of our success in our specialty, chronic pain control, to developing as broad an understanding as possible of each patient's problem through use of a holistic approach. However, we find one aspect of the authors' discussion distressing. Drs. Leigh and Reiser ask, " W h a t . . . is the appropriate role of the general psychiatrist of the future?", and answer, ". . . there is a need for physicians who will bridge the gap between the medical and physical sciences on the one hand, and the behavioral, social sciences on the other." This tacitly assumes that only a specialist (psychiatrist) can provide holistic care for patients. Admittedly, a psychiatrist is all too often the first health professional to talk to the patient and his family about the psychosocial aspects of illness, but often this is simply through default by the referring physician. We believe that it is as inappropriate to ask a psychiatrist to perform this function as it is to refer a patient to a urologist for treatment of a simple urinary tract infection, to a proctologist for a routine admission rectal examination, or to an otolaryngologist to inquire if the patient is dizzy. People are not jigsaw puzzles that can be disassembled into component pieces. W h y do most physicians rarely include questions on employment,

finances, sleep, marriage, sexuality, and religious life as part of a routine review of systems? These questions are often more rewarding avenues for exploration than those on the endocrine, metabolic, or hematologic systems. In their defense, many physicians respond that "asking about the patient's life circumstances takes too long" and that "this is someone else's responsibility." In fact, we have found that it generally requires less time to reach an adequate understanding of the psychosocial dimension than it does to do a thorough neurologic examination or to prepare and examine a peripheral smear and a urinalysis. On deeper probing, we often find that many physicians consider the broader view of the patient as neither interesting nor directly relevant to care. Further, when unable to avoid confronting a positive psychological finding, physicians often feel profoundly helpless and quickly call for outside help, namely, the psychiatrist. This complicates the matter because the patient now has two doctors, one for the body and one for the mind. Although this commonly occurs, we believe that it is antithetical to the holistic model and represents a major failure of our medical training programs. Drs. Leigh and Reiser have offered only part of the solution. The appeal of the holistic model lies in its value to all physicians, not just consultation-liaison psychiatrists. Regardless of specialty, all health practitioners should be more fully trained to bridge the gaps between the medical-physical and social-behavioral aspects of illness. When this occurs, perhaps the emphasis of modern medicine will shift from treating diseases to treating people. JAMES G A G N E , M.D. M E L V Y N R. W E R B A C H , M . D . D A V I D E. B R E S L E R , P H . D .

U C L A Pain Control Unit; Los Angeles, C A 90024

Information on Private Practice T o T H E EDITOR: I am conducting a research project on various aspects of office practice in primary care. I am interested in communicating with physicians who have recently entered private practice. I will send a questionnaire to all physicians who contact me in order to gain more information on some of the common problems faced by physicians when they first enter practice. K E N N E T H R. D A R D I C K , M . D .

Mansfield Family Practice Associates; Storrs, C T 06268

Correction: Nafcillin Dosage T o T H E EDITOR: I wish to call your attention to a possible error in "Nafcillin Concentration in Cerebrospinal Fluid During Treatment of Staphylococcal Infections" by K a n e and colleagues in the September 1977 issue (Ann Intern Med 87:309311, 1977). Table 2 cities doses of nafcillin as m g / k g body weight • day and g/day. I believe the correct unit for the second category is g/dosage interval, otherwise the calculated weights are much too small. Please verify this and let us have a correction if one is needed. W I L L I A M J. S A N D E R S , M . D .

Cleveland 44109

Metropolitan

General

Hospital;

Cleveland,

OH

In reply: Dr. Sanders is correct about the error in Table 2. T h e unit should be g/dose, not g/day. We have been correcting all reprints that we send out. R I C H A R D H. P A R K E R , M . D .

Veterans Administration Hospital; Washington, D . C . 20422

Letters and Corrections

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Folic acid, xanthine oxidase, and uric acid.

LETTERS AND CORRECTIONS Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five r...
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