Comments submitted for publication must be typed doublespaced, and text length must not exceed 500 words. 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. Therapy of Fluid and Electrolyte Disorders TO THE EDITOR: The paper by Lindeman and Papper {Ann Intern Med 82:64-70, 1975), a fine review of the therapy of fluid and electrolyte disorders, is unfortunately made potentially dangerous by what appear to be some gross typographical errors. I hope the following will be helpful in correcting some misinformation conveyed by an otherwise useful, and definitely much needed, paper. With regard to calcium, calcium gluconate, available as 10 ml of a 10% solution, provides approximately 4.6 meq calcium ion (Ca ++ ) per 1 g of calcium gluconate, not 50 meq of Ca++ as reported. This may be calculated as follows: C 1 2 H 2 2 Ca0 1 4 provides 9.3% Ca++ {Merck Index, 8th edition); therefore, 1 g of the drug (from 10% of 10 ml) provides about 93 mg of Ca++. meq wt of Ca~ = atomic wt of Ca in mg valence of Ca = 20 mg (1 meqCa + ")


40mg 2

Therefore, 93 mg Ca++ divided by 20 mg is 4.6 meq. (One brand of calcium gluconate injection has, in addition, about 35 mg of Ca D-saccharate per 10 ml, which supplies an additional approximately 0.2 meq Ca++ for a total of 4.8 meq.) A more direct method of calculation not requiring the percentage of Ca++ contained in the salt, follows: Calcium gluconate has a molecular weight of 430. This information is available quickly from the United States Pharmacopoeia, United States Dispensatory, Martindale: The Extra Pharmacopoeia, Merck Index, and others. meq wt of chemical compound = « o l w t of compound (in mg) valence of cation or anion therefore, 430 me meq wt of Ca gluconate = — — - = 215 mg

ministration should not exceed 50 mg of Ca gluconate per minute (that is, 0.5 ml of 10% solution; approximately 0.23 meq Ca ++ ) or a total of 2 g (approximately 9 to 10 meq Ca ++ ) without checking serum calcium concentrations, especially in patients receiving digitalis glycosides. Also, mithramycin is used to treat hypercalcemia in doses of 25 fig/'kg body weight, not 25 mg/kg body weight. The total weekly dose should not exceed about 150 /xg/kg body weight, rather than 150 mg/kg. Needless to say, a thousandfold error such as that in the paper could have undesirable results. With regard to the section on acid-base balance, the paper advises that "whenever possible, arterial blood pH, Po 2 , and Pco 2 should be determined. . . ." This was possibly intended to read "arterial blood pH, C 0 2 , and Pco 2 ." If so, however, since total C 0 2 is actually a measure of H C 0 3 - Plus P c o 2 a n d i s therefore a slightly overstated value that should be corrected (although the difference is generally not clinically significant), perhaps this sentence should more accurately read "arterial blood pH, HC0 3 ", and Pco 2 ." With regard to the use of intravenous fructose solutions, I would strongly urge the interested reader to weigh the risk/ benefit ratio before considering the administration of fructose. An excellent review may be found in a paper by Woods and Alberti entitled "Dangers of Intravenous Fructose" {Lancet 2:1354-1357, 1972). Finally, another omission: Ringer's lactate solution contains, in addition to those ions indicated in the article, our friend the Ca++ ion, about 3 meq per litre. These "hidden" ions, incidentally, are frequently responsible for many unexpected, and invisible, incompatibilities because the user is unaware, or forgets (as in this article!) that they are present. I echo the sentiment expressed by Drs. Lindeman and Papper that Ringer's lactate, with or without glucose 5%, is one of many therapeutic "cliches" that we might do well to eliminate from our armamentarium of intravenous fluids. Perhaps I am distressed most with the simple fact that this great number of errors—some potentially fatal—should appear in a single paper on such a vital area of therapy. Intravenous administration is certainly the most critical route of drug administration and remains one of the most taken-for-granted, used, and abused forms of therapy in our institutions. We vitally need excellent papers and reviews to continually educate and reawaken the practitioner to basic, and not so basic, concepts and procedures. W. ARTHUR BURKE, PHARM.D.

and, 1000 mg (Ca gluconate in 10 ml, 10%) 215 mg (meq wt of Ca gluconate

meq (Ca


So much for the calculations. The article then advises that "intravenous administration should not exceed 50 mg (2.5 meq) per minute or a total of 2 g (100 meq) without checking serum calcium concentrations. . . ." This implies that Ca++ (ion) is being discussed, whereas the sentence should probably have read as follows: "Intravenous ad844

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Department of Parenteral Nutrition and Clinical Pharmacy Services Delaware Division Wilmington Medical Center Wilmington, Delaware 19801 TO THE EDITOR: The recent paper by Drs. Robert D. Lindeman and Solomon Papper, "Therapy of Fluid and Electrolyte Disorders," contains another possible typographical error, in addition to the one that was noted in your letter

to the New England Journal of Medicine. Reference is made to the therapy of hypocalcemia with calcium gluconate. The article implies that 10 ml of a 10% calcium gluconate solution contains 50 meq of calcium. But this preparation contains only 4.5 meq of calcium. It should be remembered that percent strength in solutions includes both the cationic and anionic substituents in the solution. The preparation contains 1 g of ingredient, that is, calcium gluconate. Equivalent weight of calcium gluconate is 215.19 g. Therefore, 1 meq of calcium gluconate weighs 215.19 mg, rather than the 20 mg implied in the paper. The authors' recommendation for intravenous administration is correct in total ingredient administered, that is, 2 g, but this represents 9 meq of calcium, rather than the 100 meq indicated in the paper. Administration of 100 meq calcium, approximately 22 ampules, could place the patient in a condition of hypercalcemia and the resultant physiologic effects indicated in the paper. In clinical practice, the irritation associated with parenteral administration of calcium gluconate can be reduced by diluting the 10 ml of 10% solution in equal volumes of normal saline. I did find the paper an excellent review and commend the authors for their work. DAVID H. SCHUETZ, M . S C , PHARM.D.

School of Pharmacy University of the Pacific Stockton, California 95207 TO THE EDITOR: Drs. Lindeman and Papper have covered such a wide field in such a short compass that inevitably some errors have crept into their manuscript. In their section on hypocalcemia, they state that 10 ml of a 10% solution of calcium gluconate contains 50 meq of calcium. One gram of calcium gluconate contains only about 90 mg of calcium so that the stated quantity of solution contains approximately 4.5 meq of calcium. Their subsequent figures on rates of administration and total safe quantity require comparable modification. Similarly, 8 g of oral calcium gluconate contains only about 720 mg of calcium, a relatively small amount. If calcium alone is used to treat tetany, then normally at least 2 g a day would be required to have a significant effect. The authors refer somewhat disparagingly to those who advocate other forms of vitamin D such as dihydrotachysterol as "touts." The main advantage of dihydrotachysterol over regular vitamin D is its much more rapid onset of action. This makes it the present drug of choice for the treatment of symptomatic postsurgical hypocalcemia, which does not respond to calcium alone. An attempt to achieve a rapid response using the slow-acting vitamin D 2 inevitably leads to vitamin-D intoxication. In their discussion of hypercalcemia, the authors refer to initial therapy with saline and do not mention the need for diagnosis. The great majority of patients with hypercalcemia discovered by multichannel screening require no treatment for the hypercalcemia as such. The administration of normal saline and diuretics to mildly hypercalcemic patients is a common aberration of hospital practice that confuses the interpretation of diagnostic tests and accomplishes nothing other than a lowering of total calcium because of dilution of serum proteins. It is unfortunate that no satisfactory preparation of oral phosphate is available for general use in the United States, but of those phosphate preparations that can be used for

the treatment of hypercalcemia, Phospho-Soda® is the worst tolerated; it is intended as a laxative for which purpose it is very effective. Finally, we have yet another repetition of the entirely erroneous notion that EDTA lowers serum calcium by increasing urinary excretion: EDTA lowers ionized calcium by directly complexing the calcium in the blood. The degree of fall is a function of the dose and of the speed with which additional calcium can be mobilized from bone. At the pH of body fluids, the calcium EDTA complex is inert and cannot dissociate; normally, it is rapidly excreted in the urine. Failure to excrete the complex because of impaired renal function markedly increases the hazards of this treatment because the calcium EDTA complex is nephrotoxic, but this has no effect on EDTA's efficacy in lowering ionized calcium. Because it is the only hypocalcemic agent that works instantaneously, EDTA still has a place in the treatment of those very severely hypercalcemic patients who are likely to die from cardiac arrest within a short time. If necessary, the EDTA complex can be removed by dialysis. A. M. PARFITT, M.D.

Fifth Medical Division Henry Ford Hospital Detroit, Michigan 48202 TO THE EDITOR: In the article on fluid and electrolyte therapy by Lindeman and Papper that appeared in the lanuary issue of the Annals, the point concerning the administration of sodium lactate to a patient with lactic acidosis was not clearly made. It was stated that "patients with diverse and generally serious illness may not be able to metabolize lactate, with resultant serious lactic acidosis." Lactic acid produced in the body under anaerobic conditions dissociates in the blood to hydrogen ions and lactate ions. The hydrogen ions cause the pH to decrease. Being a proton acceptor, the lactate ion is a weak base and does not contribute to the acidosis. Lactate administered as the sodium salt contains no available hydrogen ions and, therefore, does not contribute to the acidosis. It is true that the administered sodium lactate may not be converted to bicarbonate under anaerobic conditions (1) and, thus, may not correct lactic acidosis as well as sodium bicarbonate. WAYNE S. BURKLE, PHARM.D.

School of Pharmacy State University of New York at Buffalo Buffalo, New York 14203 REFERENCE

1. SCHWARTZ W, WATERS W: Lactate versus bicarbonate. Am J Med 32:831-834, 1962 TO THE EDITOR: I would like to call attention to an error in dosage of mithramycin in the article "Therapy of Fluid and Electrolyte Disorders" by Lindeman and Papper in the lanuary issue. On page 68 the dose is given as 25 mg/kg body weight. This dose is too high and I think you would want to put in a corrective notice in the next issue. HARVEY E. FINKEL, M.D.

Oncology & Hematology Associates, Inc. Boston, Massachusetts 02118 TO THE EDITOR: In "Therapy of Fluid and Electrolyte Disorders" by Lindeman and Papper, the authors state that Comments and Corrections

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"two grams of oral sodium or potassium phosphate" daily should be the initial therapy for chronic hypercalcemia. Actually, it is 1 to 2 g of oral phosphate phosphorus that has been found necessary to treat hypercalcemia ( 1 ) . Since phosphorus constitutes approximately 20% of the formula weight of monobasic and/or dibasic sodium and/ or potassium phosphate salts, 5 to 10 g of sodium or potassium phosphate would be the required dosage. In addition, if the Neutra-Phos® powder is prepared in the manner the pharmaceutical company suggests, 10 to 20 fluid ounces orally would be the amount necessary to supply 1 to 2 g of phosphate phosphorus, not 2 teaspoonfuls a day. The dose of mithramycin should be 25 [ig/kg body weight, not 25 mg/kg body weight as stated in the article. GEORGE D. LAWRENCE, M.D., F.A.C.P.

Division of Endocrinology and Metabolism St. Agnes Hospital Baltimore, Maryland 21229 REFERENCE 1. GOLDSMITH RS, INGBAR SH: Inorganic phosphate treatment of

hypercalcemia of diverse etiologies. N Engl J Med 274:1-7, 1966

From the authors in reply: The following comments and rebuttals are our responses to the letters sent to us on 5 March.

large volume of available information into the allotted space, it was necessary to concentrate our discussion on therapy and assume that the appropriate steps were taken to establish a diagnosis. The need for therapy in mild, asymptomatic hypercalcemia picked up by screening techniques remains poorly defined. One might argue that if severe hypercalcemia leads to nephrocalcinosis and renal insufficiency, might not less severe hypercalcemia also be detrimental to renal function? We agree with Dr. Parfltt that no really satisfactory oral phosphate preparation is available in the United States. We have described what is available commercially. Finally, Dr. Parfitt correctly notes that EDTA lowers serum ionized calcium by forming a complex that is biologically inert. Although urinary excretion of calcium is increased, this is not the major reason for the therapeutic benefit. LETTER OF DR. BURKLE

Dr. Burkle's comments are correct. Reference was made in our review to the small group of patients who, after a serious illness, may develop lactic acidosis. Use of sodium lactate in such patients might not only fail to correct the acidosis but might accentuate the accumulation of lactate ion and cause the patient's condition to deteriorate. LETTER OF DR. FINKEL

Dr. Finkel's letter calls attention again to the error in mithramycin dosage. LETTER OF DR. LAWRENCE


The first section on calcium covers the errors in calculation of meq of calcium and mithramycin dosage previously observed. Under the section on acid-base balance, our intent was, as stated, to measure blood gases; that is, pH, Po 2 , and Pco 2 . With the pH and Pco 2 , total C 0 2 or H C 0 3 _ could be estimated, but this adds little to the evaluation of the patient. The comment on use of intravenous fructose solutions adds an appropriate and useful reference, pointing out potential dangers in the use of fructose ( 1 ) . Finally, although we failed to include the calcium content of Ringer's lactate, we were aware that it was present and did note that it should not be used in patients with hypercalcemia. LETTER OF DR. SCHUETZ

The letter of Dr. Schuetz again calls attention to the error in calculation of meq of calcium. The comment on dilution of intravenous calcium gluconate with normal saline to prevent venous initiation is an appropriate and useful suggestion.

Dr. Lawrence is correct when he states that initial therapy for chronic hypercalcemia should be 2 g/day of phosphate phosphorus, rather than sodium or potassium phosphate. The reference cited uses the column heading "Phosphate Therapy" in grams per day (approximate mean, 2.0 g/day) when referring to grams of phosphorus per day. The quantities of the commercial preparations necessary to provide 2 g/day of phosphate phosphorus are correct. He also notes that when Neutra-Phos® is prepared as suggested by the pharmaceutical company that 20 fluid ounces must be given, not 2 teaspoonfuls. We were referring to the 2 teaspoonfuls (10 g) of powder concentrate that would be used to prepare the solution. We are grateful for the opportunity to respond to these letters. ROBERT D. LINDEMAN, M.D. SOLOMON PAPPER, M.D.

Department of Medicine College of Medicine The University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma 73190


The letter from Dr. Parfltt makes several good points. First, he notes the error in calculation of meq of calcium. We have used the word "tout" as a verb, which means "to solicit support for or describe favorably." We did not intend to imply that persons who advocated other forms of vitamin-D therapy were "touts" defined by Webster as "persons who solicit business, employment, votes, etc., or, in horse racing terms, one who gives information for a fee." The more rapid onset of action of dihydrotachysterol would provide an advantage over regular vitamin D in treatment of postsurgical hypocalcemia. Dr. Parfitt comments on our failure to discuss the need for diagnostic evaluation of the hypercalcemic patient. To condense a 846

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Lancet 2:1354-1357, 1972

Mycobacterial Skin Infection TO THE EDITOR: I would like to draw attention to a possible relation between Feldman and Hershfleld's paper (1) and a recent paper by Schiefer, Gee, and Ward ( 2 ) . Both deal with a peculiar mycobacterial infection: a) the lesions were isolated or scattered granulomas primarily localized to the skin; b) the 29 human cases and 7 feline cases were

localized to a similar geographic locale in central and western Canada; c) biopsy confirmed foamy histiocytes containing innumerable acid-fast staining organisms; and d) the organisms could not be cultured at both 37 °C and 25 °C. Although the in-depth microbiologic studies done in the feline cases are not discussed, the clinical and histiologic similarity in the "uncharacterized disorders" suggests a possible relation between them. The feline cases might very well represent a naturally occurring animal model of a human disease much like that existing between the armadillo and leprosy. ROBERT L. ANDERTON, M.D.

Department of Dermatology School of Medicine Medical College of Georgia Augusta, Georgia 30902 REFERENCES 1. FELDMAN RA, HERSHFIELD E: Mycobacterial skin infection by an

unidentified species. A report of 29 patients. Ann Intern Med 80:445-452, 1974 2. SCHIEFER B, GEE BR, WARD GE: A disease resembling feline

leprosy in western Canada. J Am Vet Med Assoc 165:1085-1087, 1974

In comment: As indicated in the paper by Schiefer, Gee, and Ward (Reference 2, above), and mentioned by Dr. Anderton, mycobacterial infections in cats, other mammals, and other vertebrates result in histiologic changes similar to those seen with mycobacterial infections in man. Dr. William H. Feldman, in his chapter "Non-Leprous and Non-Tuberculous Mycobacterial Infections" ( 1 ) , points out the longstanding interest in learning about mycobacterial infection in man through the study of those found in animals. However, a recent review of mycobacterial infections in freeliving wild animals (2) indicates that there is little to suggest that infections in animals are associated with a serious risk to human populations and some data to suggest the opposite. When I questioned Dr. Grzybowski (3) concerning skin infections due to mycobacteria in British Columbia, and when I wrote to other mycobacteriologists in Canada, no one reported a problem similar to that seen in Manitoba. However, there were a few previous reports of cases in the north-central United States, and the cases were so scattered that not one person was aware of clustering except for Tom Semba in Minneapolis. On reviewing data on pets in the cases we described (Reference 1, above), the list includes fish, turtles, birds, cattle, dogs, rats, cats, sheep, rabbits, snakes, squirrels, horses, among others. Thirty-eight percent (8/21) of the cases involved contact with a cat; I do not have information on an equivalent control group. None of the families reported a pet with a skin infection. ROGER A. FELDMAN, M.D.

Central America Research Station Bureau of Tropical Diseases c/o U.S. Embassy APO New York, 09889 REFERENCES

1. Leprosy in Theory and Practice, edited by COCHRANE RG. Bristol, John Wright & Sons Ltd., 1964, pp. 50-68


Mycobacterial infections in free-

living wild animals. Symp Zool Soc London 24:119-131, 1968 3. ROBINSON BL, GRZYBOWSKI S, BOWMER EJ, et al: Atypical myco-

bacterial disease in British Columbia, 1960-1967. Can Med Assoc J 101:17-24, 1969

Pneumococcemia with Sarcoid-lnfiltrated Spleen TO THE EDITOR: The syndrome of asplenia, fulminant pneumococcemia, and disseminated intravascular coagulation has been described almost exclusively in association with atrophic or absent spleens ( 1 ) . The following case of fatal pneumococcemia occurred in a patient with clinically unsuspected sarcoidosis, which had completely infiltrated the spleen. A 36-year-old woman, previously well, presented with a 1day history of fever, chills, and intermittent pleuritic chest pain without cough. Except for a temperature of 40 °C [104 °F], slight tachypnea (respiratory rate of 20/min), and some wheezing in the chest, physical examination was normal with no palpable lymphadenopathy or splenomegaly. The prothrombin time was 25 seconds with a control of 11.5 seconds. The thrombin time was 21 seconds with a control of 18 seconds. The serum creatinine was 2.6 mg/100 ml, compared with 0.8 mg/ 100 ml recorded during a routine clinic visit 9 months earlier. There ensued a rapidly progressive hospital course, marked by (in chronological sequence) extreme hyperventilation, generalized muscle tenderness, mental confusion leading to obtundation, conjunctival and sternal petechiae, watery diarrhea, anuria, and shock. A lumbar puncture showed 32 erythrocytes per cubic millimetre and 3 lymphocytes per cubic millimetre. Spurting arterial bleeding developed at the lumbar puncture site. Despite high-dose intravenous penicillin, the patient died 17 hours after hospitalization. Three of three blood cultures taken on admission grew Streptococcus (Diplococcus) pneumoniae. At autopsy, there were multiple petechiae and ecchymoses of the skin, conjunctivas, pericardium, renal pelvises, and bowel. Focal adrenal hemorrhage was present. In sections of the skin petechiae, many of the capillaries in the upper dermis were occluded by fibrin thrombi, consistent with a terminal consumptive coagulopathy. No focal infectious lesions were identifiable grossly or microscopically. Extensive sarcoidosis (noncaseating granulomas, negative Ziehl-Nielson and GrocottGomori methenamine silver nitrate stains) was found infiltrating the lungs, the heart, and visceral lymph nodes. The spleen (Figure 1) was hard and nodular and weighed 300 g. There was no recognizable (grossly or microscopically) red or white pulp in multiple sections. Microscopically, hyalinized confluent granulomas had replaced the normal architecture. Infrequently, we found younger, more cellular granulomas with multinucleated giant cells. The typical rapid septic course in this previously healthy patient, the coagulation abnormalities with autopsy findings of intravascular coagulation, and the lack of an apparent original focus of infection adequately describe, we believe, a syndrome of pneumococcemia like that seen in asplenic patients. Sarcoidosis is not considered to predispose to bacterial infections ( 2 ) ; therefore, we hypothesize that our patient's susceptibility to pneumococcemia was conditioned by functional hyposplenia. (Regrettably, peripheral blood smears were not available for review.) Overwhelming pneumococcemia has been reported in young patients with sickle-cell anemia whose spleens were large and had sinusoids congested with sickle-form erythrocytes ( 3 ) . The association of pneumococcemia with neoplastic infiltration of the spleen (4, 5) is somewhat unclear because these patients may be extremely ill from their underlying disease. Our patient's case was more striking in that she was Comments and Corrections

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Seven of these 12 (58.4%) were correctly diagnosed as positive by gallium-67 scintigraphy. Of our five false-negative cases, four involved diseases in or around the liver. In our study, we correctly identified slightly over half of the deep intraabdominal infections with gallium-67. We failed to identify those in areas where gallium normally concentrates (that is, the liver). We agree that a negative gallium-67 scan does not rule out infection. On the other hand, any abnormal accumulation of intraabdominal gallium-67 must be looked upon with great suspicion, especially when the clinical picture suggests infection. We feel this approach is warranted because our false-positive rate was 4 % . Close clinical correlation is essential to properly interpret gallium-67 scintigrams. D O N A L D A. P O D O L O F F , L T COL, USAF, M C Figure 1 . Nodular spleen, 300 g, infiltrated by sarcoidosis.

apparently healthy before the onset of her catastrophic illness. JOHN R. GUYTON, M.D.

Wilford Hall U S A F Medical Center (AFSC) Lackland Air Force Base, Texas 78236 REFERENCE 1. HARVEY WC, PODOLOFF DA, KOPP DT: 67 gallium in 68 con-

secutive infection searches. J Nucl Med 16:2-4, 1975

ROSS E . ZUMWALT, M.D. Department of Internal Medicine Department of Pathology University of Texas Southwestern Medical School Dallas, Texas 75235

Non-Cholera Vibrio Septicemia and Meningoencephalitis

REFERENCES 1. BISNO AL, FREEMAN JC: The syndrome of asplenia, pneumo-

coccal sepsis and disseminated intravascular coagulation. Ann Intern Med 72:389-393, 1970 2. SONES M, ISRAEL HI: Course and prognosis of sarcoidosis. Am

J Med 29:84-93, 1960 3. KABINS SA, LERNER C: Fulminant pneumococcemia and sickle

cell anemia. JAMA 211:467-471, 1970 4. FOLLAND D, ARMSTRONG D, SEIDES S, et al:


bacteremia in patients with neoplastic disease. Cancer 33:845849, 1974 5. HAHN M, BARNES A JR, LERNER W, et al: Chronic lymphocytic

leukemia, disseminated histoplasmosis and pneumococcal septicemia. Mo Med 70:249-250, 1973

Gallium-67 and Infections TO THE EDITOR: The article on gallium-67 for localization of septic lesions written by Littenburg and associates {Ann Intern Med 79:403-406, 1973) clearly showed the usefulness of gallium-67 for the localization of septic lesions. Subsequent to the publication of the article, a letter appearing in this column by Gelrud, Milder, and Canellos {Ann Intern Med 80:775-776, 1974) made several points relevant to the diagnosis of infection using gallium-67. The authors cautioned that a negative gallium-67 study might not rule out infection and also lamented the fact that there were no prospective series with adequate bacteriologic conformation. We have recently published our results in a prospective study of 68 consecutive patients screened for infection with gallium-67 ( 1 ) . We had adequate histopathologic data in all our cases. Thirty seven of our patients were suspected of having deep intraabdominal infections. Twenty four of 25 patients (96% ) had negative gallium-67 studies and had no histopathologic evidence of infection. Twelve patients had positive histopathologic evidence of infection. 848

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TO THE EDITOR: We have read with interest the note by Fearrington and associates {Ann Intern Med 81:401, 1974) about a case of non-cholera vibrio septicemia and meningoencephalitis. We wish to report another case. A man with hepatic cirrhosis, aged 49, entered our hospital on 2 August 1973. He was febrile (38.5 °C) but showed no signs of localized infection. A blood culture was positive and the isolated organism was identified as a nonagglutinating vibrio, Heiberg type II. Four days after starting treatment with ampicillin (3000 mg/day) the fever subsided; this treatment was followed for 10 more days. Two blood cultures (one made the day after stopping the treatment, another 3 days thereafter) were negative. Although the patient apparently recovered from this infection, he died 2 months later from Klebsiella pneumoniae septicemia. Permission for necropsy was not granted. In our case, the identification of the organism was done at our premises and confirmed by Dr. Richard at the Pasteur Institute in Paris. We fail to understand how confusions such as those posed by Sands in a recent letter to the editor {Ann Intern Med 82:124, 1975) can occur because the taxonomic position of species of the Vibrio genus is well established and easy to identify and understand. Vibrio cholera is a species belonging to Vibrio genus, which is included in the family Vibrionaceae. Most strains in this species can be ascribed to one of six O antigenic groups. Biotypes cholerae and el tor, which cause cholera, are the only ones showing an 0:1 antigenic pattern. Organisms in this species not associated with clinical cholera are usually called choleralike vibrios, non-cholera vibrios, or nonagglutinating vibrios. None of them shows an 0:1 antigenic pattern, and identification is further made possible by study of acid production from sugars (Heiberg, 1935). All these above mentioned organisms are aerobic and facultative anaerobic and grow easily on MacConkey and T.C.B.S. media. On the other hand, Vibrio fetus, which is now called Campilobacter fetus, belongs to the Campilobacter genus,

included in the Spirillaceae family. This is a species quite different from V. cholerae, with regard to morphology, metabolism, and culture characteristics, and in that it shows a microaerophilic behaviour ( 1 ) . G. PRATS, M.D. B. MIRELIS, M.D. R. PERICAS, M.D. G. VERGER, M.D.

Hospital de la Santa Cruz y San Pablo Barcelona, Spain

disease as we presently understand this term. We feel more studies are needed, with particular attention to the quantification of the complex deposition by electron microscope and immunofluorescence and with careful use of antiserums to all available species of immunoglobulin and complement, before any conclusions can be justified. We say this knowing that Germuth and Pollack produced granulomatous lesions in the pulmonary veins of chronic bovine serum albumin injected rabbits, but, as in other states of antibody excess, they could not produce progressive glomerulonephritis ( 8 ) .




Bacteriology, 8th ed. Baltimore, The Williams & Wilkins Company, 1974, pp. 207, 340

JAY I. M E L T Z E R , M . D .

Nephrology Division Department of Medicine Columbia University 622 West 168th Street New York, New York 10032

Renal Lesions in Wegener's Granulomatosis TO THE EDITOR: In the N I H conference on Wegener's


granulomatosis (Ann Intern Med 81:513-525, 1974), one of the authors (Dr. Horn) concludes that the renal lesions are the result of "immune complex deposition (that) probably triggers focal and segmental injury to the glomerulus." He supports this view by citing electron microscopic findings of subepithelial deposits and immunofluorescence studies showing IgG and complement. Concerning the electron microscopic evidence, the author states that subepithelial deposits were found in only 3 of 19 specimens in their own series. This is the largest series in the literature and is not in disagreement with other findings (1). Dr. Horn does not quantitate the deposits in the 3 cases described but does say "examination of multiple sections was often required." Although quantification of deposits is not a feature of any reports in the literature, it is common experience that deposits are ubiquitous in those diseases believed to conform best with immunecomplex disease such as systemic lupus erythematosus, shunt nephritis, and the Henoch-Schonlein syndrome. Concerning the immunofluorescence evidence, no new data are given, but reference is made to one study in the literature (2) that includes only one case. We can find two other sketchy case reports with positive immunofluorescent findings (3, 4 ) . In all three of these positive findings, we have no quantification of the number and extent of immunoglobulins and complement deposited, no indication of how many glomeruli were studied, and no mention of controls. There are two studies that mention negative findings in Wegener's granulomatosis (5, 6 ) . For periarteritis nodosa, a disease that seems to be closely related to Wegener's granulomatosis, there are also two reports of negative glomerular immunofluorescence (6, 7 ) . It is not enough to note that electron microscopic deposits were found, or immunofluorescence was positive, or both, for IgG and complement. The extent and location of the deposits and immunofluorescence must reasonably account for the abnormalities observed to link them causally. Dr. Horn's data fail this important test, because a few scattered subepithelial deposits are not a reasonable cause of a virulent glomerulonephritis. Despite the probability that negative findings are less likely to be published than positive ones, the data presented in the N I H conference paper and in the rest of the literature do not justify a positive statement that the renal lesion in Wegener's granulomatosis is caused by an immune-complex

1. NORTON WL, SUKI W, STRUNK S: Combined corticosteroid and

azathioprine therapy in two patients with Wegener's granulomatosis. Arch Intern Med 121:554-560, 1968 2. FAUCI AS, WOLFF SM: Wegener's granulomatosis:

studies in

eighteen patients and a review of the literature. Medicine (Baltimore) 52:535-561, 1973 3. BARR J, DANIELSSON D, MAGNUSSON PH:



matos, 3 fall—klinik och immunofluorescens. Nord Med 86:1291, 1971 4. MGH Case Records (Case 15-1969). N Engl J Med 280:828834, 1969 5. FULLER T, OLSEN N, BLOCK A, et al: Wegener's granulomatosis

treatment with heparin in addition to azathioprine and corticosteroids. Nephron 9:225-234, 1972 6. MCINTOSH







histology in renal disease—diagnostic, prognostic, therapeutic and etiologic value and limitations. Q J Med 159:385, 1971 7. MOREL-MAROGER L, LEATHEM A, RICHET G:

Glomerular ab-

normalities in nonsystemic diseases—relationship between findings by light microscope and immunofluorescence in 433 renal biopsy specimens. Am J Med 53:170, 1972 8. GERMUTH FC, POLLACK AD: Immune complex disease III—the granulomatous lesions. Johns Hopkins Med J 121:254, 1967



Doctors Rubin, Peterson, and Meltzer challenge the interpretation that the finding of subepithelial dense deposits in the glomerular lesions of Wegener's granulomatosis is sufricient to suggest a mechanism of immune-complex mediated injury as a cause of the focal and segmental glomerulonephritis. Many experienced renal pathologists (1-3) now believe that subepithelial electron dense deposits almost invariably represent immune complexes, whereas subendothelial and mesangial densities may have other origins. These assumptions, based on a wide body of clinical and experimental information, are stated explicitly by Dr. McCluskey in Dr. Heptinstall's book ( 3 ) . Quantitation of morphologic findings is difficult. In our detailed description of the renal biopsy findings in Wegener's granulomatosis, we indicated the number of glomeruli examined in each specimen ( 4 ) . We believe that it is highly unlikely that more elaborate quantification mechanisms would show additional useful information. Immunofluorescence is of unquestioned value in the analysis of glomerulonephritis, but it is of less value in focal-segmental glomerulonephritis because of sampling Comments and Corrections

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problems and because of difficulty differentiating sparse deposits from technical artifact. Furthermore, in cases where necrotizing changes have occurred, exudation and trapping of serum proteins (including immunoglobulin) pollute the field and limit the usefulness of this method. These difficulties may have inhibited the demonstration of significant deposits of immunoglobulin in cases of necrotizing arteritis ( 5 ) , a disorder recognized to be generally immune-complex mediated. Thus, immunofluorescence data in the necrotizing glomerulitis of Wegener's granulomatosis tend to be supportive of an immune-complex pathogenesis, but this method does not afford definitive information. In contrast to the implication of the correspondents that "deposits are ubiquitous in . . . immune complex diseases," the experience of one of us ( R G H ) with approximately 250 renal biopsies examined in detail by electron microscopy corresponds to the larger experience of Burkholder (1) that in focal proliferative glomerulonephritis, including Berger's IgA-IgG nephropathy and Henoch-Schonlein syndrome, deposits are often sparse, predominantly paramesangial or subendothelial or both, and, rarely, subepithelial. In most cases of focal-segmental necrotizing glomerulonephritis that we have examined, careful examination has yielded at least a few typical subepithelial densities. It is our opinion that subepithelial deposits, when present, are a strong indication of immune-complex deposition, and it is our experience that many forms of focal-segmental glomerulonephritis contain such subepithelial deposits that will be found only after fairly prolonged search, often of many glomerular profiles. It is our hypothesis that the immune-complex deposits in Wegener's granulomatosis lead to a necrotizing inflammatory response. Thus, the sparsity of the deposits correlates with the segmentality of the lesions. That a small amount of deposits should be so damaging may be superficially surprising, but so is the variation of the inflammatory potential of the immunecomplex deposits in poststreptococcal glomerulonephritis versus the deposits in membranous nephropathy. The last sentence of the letter by Rubin, Peterson, and Meltzer is misleading because Germuth and others have shown in elaborately studied experimental models that chronic BSA injection in rabbits produces immune-complex mediated glomerulonephritis with subepithelial deposits (2).

5. MCCLUSKEY RT: Case records of the Massachusetts General Hospital. N Engl J Med 291:1079, 1974

Ethics of Renal Biopsies in Typhoid Fever TO THE EDITOR: In response to Dr. LoGerfo's comment {Ann Intern Med 81:861, 1974) on the ethical aspect of renal biopsy study in typhoid fever done by our group (Ann Intern Med 81:210-213, 1974) we wish to offer our reply. Our study was an attempt to further define the nature of typhoid fever, an apparently simple disease that needs more details in its description. It represented a model in man supporting the concept of pathogenesis of glomerulonephritis advanced from earlier studies in animals. It also brought up a hypothesis to explain proteinuria in febrile diseases long believed to be due to the nonspecific effect of fever. Although the renal biopsies were not relevant to the management of the patients under study, their findings could provide useful information for the future management of typhoid fever with significant proteinuria. Our patients were clearly informed of the renal biopsy procedure and of every possible risk, and they agreed to the study. Those who did not agree were never accepted for study. Biopsies in all cases were uneventful. In our extensive experience with renal biopsy in tropical nephrology, no serious complications have been observed. We are well aware of the ethics of clinical research. We knew the problem we were dealing with, and have been ethically very careful in our study. VlSITH SlTPRIJA, M.D., PH.D., F.A.C.P. VlCHITRA PlPATANAGUL, M.D. Department of Medicine Chulalongkorn Hospital Chulalongkorn University VlJITR BOONPUCKNAVIG, M.D. Department of Pathology Ramathibodi Hospital SOMNATE BOONPUCKNAVIG, M.D. Department of Pathobiology Faculty of Science Mahidol University Bangkok, Thailand


Department of Pathology Vanderbilt University School of Medicine Nashville, Tennessee 37232 SHELDON M. W O L F F , M.D. ANTHONY S. FAUCI, M.D. DAVID C. DALE, M.D.

Laboratory of Clinical Investigation National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland 20014 REFERENCES 1. BURKHOLDER PM: Atlas of Human Glomerular Pathology. Hagerstown, Maryland, Harper and Row, Inc., 1974 2. GERMUTH FG JR, RODRIGUEZ E: Immunopathology of the Renal Glomerulus. Boston, Little, Brown and Co., 1973 3. MCCLUSKEY RT: Immunologic mechanisms in renal disease, in Pathology of the Kidney, 2nd ed. Edited by HEPTINSTALL RH. Boston, Little, Brown and Co., 1974, p. 276 4. HORN RG, FAUCI AS, ROSENTHAL AS, et al: Renal biopsy pathology in Wegener's granulomatosis. Am J Pathol 74:423434, 1974 850

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Penicillin G Therapy in Renal Failure TO THE EDITOR: The article by Bryan and Stone (Ann Intern Med 82:189-195, 1975) is a welcome example of attempts by clinicians to apply pharmacokinetic concepts to drug use during renal failure for enhancement of efficacy with reduction in toxicity. Earlier guidelines for the use of drugs in renal impairment, as in this paper, have tended to advocate the administration of conventional or moderately reduced doses of drugs at long intervals ( 1 ) . Less attention has been paid to the effects of giving small doses of the drug at conventional intervals to maintain more constant serum levels of the drug. The most definitive means of attaining a constant level of drug in the serum is to give a loading dose followed by a continuous intravenous infusion at a rate equal to that of elimination. Because this method is technically difficult in most clinical settings, intermittent dosage regimens are generally advocated. Obviously, frequent admin-

istration of small quantities of drug at short intervals more closely resembles a continuous infusion than infrequent administration of the same total amount of drug per unit time at long intervals. The magnitude of differences between zenith and nadir concentrations of a drug in serum is directly related to the dosing interval in that the longer the time interval between doses, the greater the swings from maximum to minimum serum levels (2, 3 ) . Clinical and experimental evidence exists that supports the desirability of attaining and maintaining a level of antibiotic in serum that is in the therapeutic range for a maximal portion of the therapeutic period (or, at least, preventing prolonged periods of subinhibitory levels) (4, 5 ) . Bryan and Stone have used prior models of administration of drugs to uremic patients by recommending reduced doses of penicillin at long intervals. Consequently, as noted in their Figure 3, Patients 3 and 11 have measured serum levels of the antibiotic below their stated therapeutic goal of 20 fjg/ml during most (60% to 7 0 % ) of the time of the drug's administration. In contrast, in their Patient 3, had 250 000 units of penicillin G been given every 4 hours rather than 500 000 units every 8 hours, the same total daily dose would predictably reduce the amount of time during which the concentration of drug was below the desired therapeutic level. The administration of gentamicin to patients with impaired renal function in small doses at standard time intervals has been shown to be clinically superior to giving "normal" doses at longer intervals ( 4 ) . More studies of this type are needed with measurements of concentrations of antibiotic and, importantly, clinical efficacy to support the thesis of the advantage of short versus long dosing intervals for drug administration in patients with renal failure. I propose in the interim that a more rational guideline for the administration of penicillin G to patients with renal failure than that suggested by Bryan and Stone is to use the total dose recommended by them for any given degree of renal failure, but given in divided doses at intervals of 4, or possibly even 2, hours rather than the proposed schedule of administration every 6 to 8 hours. D. CRAIG BRATER, M.D.

Division of Clinical Pharmacology Department of Medicine University of California Medical Center San Francisco, California 94143

necessary to achieve a desired mean serum concentration. This dose can then be given by continuous infusion or can be divided into any desired number of equal portions for intermittent therapy. I am responding to Dr. Brater's preference for shorter dosing intervals. 1. That shorter dosing intervals result in higher trough (nadir) serum concentrations is well known. However, there is both clinical and experimental evidence that the risk of penicillin neurotoxicity is significantly increased by higher trough serum concentrations, possibly because these overcome the normal mechanism for removing penicillin from the cerebrospinal fluid ( 1 ) . Patient 3 (Figure 3) had trough serum concentrations of 12.5, 12.6, and 13.1 /xg/ml on a dose of only 500 000 units of penicillin G every 8 hours. These values actually exceed the limit (15 U / m l or 9.4 /xg/ml) suggested by Smith, Lerner, and Weinstein ( 1 ) . One cannot shorten the duration of time in which the serum concentration is below the desired mean level without raising the trough concentration still further. 2. The subject of optimum dosing intervals is fraught with complexities. These are, we think, no better illustrated than by the continued controversy over the relative merits of one or another guideline for gentamicin dose adjustment in renal failure. For gentamicin, also, higher trough concentrations seem to be especially related to the risk of toxicity ( 2 ) . We prefer a schedule that uses moderate increments in the dosing interval for progressive degrees of renal impairment (2) to the method of using the same dosing interval for all patients (Reference 4, above). In suggesting guidelines for safe penicillin G therapy for critically ill patients, in whom the diagnosis of penicillin neurotoxicity may be difficult, we chose dosing intervals (our Table 1) based on these principles. 3. In a previous, longer version of our paper, we stated: "The optimum dosage interval for intermittent penicillin G therapy is not well-established. For normal subjects, van Saanen (3) recently suggested a dosage interval of three hours. Mathematical models are available for calculation of dosage intervals requisite for achieving a given time-serum concentration curve; however, such calculations should be tempered by practical considerations." We thank Dr. Brater for his comments. We attempted to present both our method and our data in such a way that they might be of maximum use to others, whatever their pharmacokinetic priorities regarding the clinical use of penicillin G.


C H A R L E S S. B R Y A N , M . D .

1. BENNETT WM, SINGER I, COGGINS CH: Guide to drug usage in

adult patients with impaired renal function. A supplement. JAMA 223:991-997, 1973 2. O'GRADY F : Antibiotics in renal failure. Br Med Bull 27:142147, 1971 3. VAN GEMERT AGM, DUYFF JW: Optimal dosage of drugs. Acta Physiol Pharmacol Need 1:256-278, 1950 4. CHAN




Gentamicin therapy in

renal failure: a nomogram for dosage. Ann Intern Med 76:773778, 1972 5. EAGLE H, FLEISCHMAN

R, LEVY M: "Continuous" vs. "discon-

tinuous" therapy with penicillin. The effect of the interval between injections on therapeutic efficacy. N Engl J Med 248:481488, 1953

In comment: The purpose of our paper was to provide a method for calculation of the 24-hour maintenance dose of penicillin G

2430 Hey ward Street Columbia, South Carolina 29205 W I L L I A M J. S T O N E , M . D .

Department of Medicine Veterans Administration Hospital, and Vanderbilt University Medical Center Nashville, Tennessee 37203 REFERENCES 1. SMITH H, LERNER PI, WEINSTEIN L: Neurotoxicity and "massive"

intravenous therapy with penicillin: a study of possible predisposing factors. Arch Intern Med 120:47-53, 1967 2. MAWER GE, AHMAD R, DOBBS SM, et al: Prescribing aids for

gentamicin. Br J Clin Pharmacol 1:45-50, 1974 3. VAN SAANEN P: Kinetic studies and their value for a better dosage schedule of antibiotics. I. The penicillins. Rev Roum Med Intern 10:149-157, 1973 Comments and Corrections

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Water Intoxication and Thioridazine TO THE EDITOR: In the letter by Rao, Miller, and Moses (Ann Intern Med 82:61-63, 1975), thioridazine (Mellaril1®) was mentioned as a cause of dilutional hyponatremia. We have recently treated an institutionalized 28-year-old paranoid schizophrenic patient for inappropriate antidiuretic hormone activity (ADH) twice in a 14-day period. On the first admission, she arrived in the Emergency Room comatose with a serum sodium of 115 meq/ litre, a urinary osmolality of 408 milliosmols/kg H 2 0 , a serum osmolality of 236 milliosmols/kg H 2 0 , and a urinary sodium of 70 meq/litre. The patient had been in her usual state of health until one day before admission when she was involved in a fight that resulted in head trauma. She responded appropriately to fluid restriction and hypertonic saline and was discharged 9 days later with a diagnosis of inappropriate A D H activity secondary to head trauma, after other causes had been ruled out. The patient returned to the Emergency Room 3 days later in status epilepticus. Her serum sodium was 119 meq/litre, the urinary sodium 60 meq/litre, the urinary osmolality 290 milliosmols/kg H 2 0 , and the serum osmolality 250 milliosmols/kg H 2 0 . After careful questioning of the institution's house staff, it was learned that the patient was receiving Mellaril before her first admission. The Mellaril had been discontinued during her previous hospital stay and replaced with haloperidol (Haldol®). On returning to the institution, she was put back on Mellaril, 100 mg orally three times a day. To assess the role of thioridazine in causing inappropriate A D H activity, a controlled water loading test was done. All medications, except the mentioned dose of Mellaril, were discontinued. The patient was kept in bed without being allowed to smoke and given 4500 ml of water orally over a 2 hour and 40-minute period. Laboratory values after completing the test were a serum sodium of 137 meq/litre, urinary sodium of 19 meq/litre, urinary osmolality of 81 milliosmoles/kg H 2 0 , and a serum osmolality of 293 milliosmoles/kg H 2 0 . The patient was discharged 2 days later with a diagnosis of inappropriate ADH activity of undetermined cause. Mellaril cannot be implicated as a cause of inappropriate antidiuretic hormone secretion or dilutional hyponatremia in our patient. Until Mellaril-induced hyponatremia can be experimentally reproduced or until additional reports of water intoxication associated with Mellaril are published, the preliminary report of Rao, Miller, and Moses, must be read with guarded judgment. CHARLES M. FISCHMAN, M.D.

Jackson Memorial Hospital 1700 NW 10th Avenue Box 134 Miami, Florida 33136

the water load under the conditions of the test. The patient described by Dr. Fischman shows the problems involved in the evaluation of the patient who presents with dilutional hyponatremia. It would seem from the data of Dr. Fischman that his patient indeed had transient inappropriate A D H syndrome, which can be attributed to the prior head trauma. This may have been further aggravated by an effect of thioridazine to increase thirst and therefore water intake. At present the mechanism of the dilutional hyponatremia remains unresolved, but we still feel that the initial water intoxication was related to the administration of thioridazine, even though the abnormality could not be reproduced in a hospital setting. Perhaps other factors not evident to us, but present in the patient's environment outside the hospital, are necessary for the thioridazine effect to occur. MYRON MILLER, M.D. ARNOLD M. MOSES, M.D. K. J. RAO, M.D.

Veterans Administration Hospital Irving Avenue and University Place Syracuse, New York 13210 Diazepam or Paraldehyde for Delirium Tremens TO THE EDITOR: I take some exception to conclusions from the controlled trial of diazepam and paraldehyde for treatment of delirium tremens recently reported in this journal (Ann Intern Med 82:175-180, 1975). A year at Boston City Hospital (BCH) proved to me that the main indication for paraldehyde under the bed was to treat the patient under the bed. I believe the difference in response times for the two drugs lies in the regimen chosen. The average of 150 mg diazepam using 5 mg dose increments compares rather poorly with a mere two or three doses of paraldehyde. That is, using the described regimen at BCH, most of us gave increasing doses, adding 5 to 10 ml every 30 minutes until a response level was reached. We would reach similar dose levels with much less time. There are other advantages to paraldehyde. 1. One can always restrain the patient and give a rectal drug. One cannot always retain a reliable intravenous site before effective sedation in a patient with delirium tremens. 2. There are hazards with a largely liver-metabolized drug in a disease with a high risk of liver dysfunction. As alluded to in the report, paraldehyde can always be eliminated via the respiratory route ( 1 ) . Finally, what is meant by "potency ratios"? Does dividing apples by peaches really prove something? The paraldehyde belongs in the patient's rectum, not on the floor. Hooray for the enlightened half of your housestaff! LEWIS W. GRAY, M.D.

Framingham Union Hospital Framingham, Massachusetts

In comment: REFERENCE

As emphasized in our report, we did not find evidence of the inappropriate ADH syndrome in the patients treated with thioridazine, but rather we felt that these patients had dilutional hyponatremia due to the ingestion of water in an amount greater than the ability of the kidney to excrete the water load with resultant water intoxication. These patients have been challenged with water loads after readministration of the drug and have not shown an inability to excrete 852

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1. SHARPLESS SK: Hypnotics and Sedatives, in The Pharmacological Basis of Therapeutics, edited by GOODMAN LS, GILLMAN A. New

York, Macmillan Co., 1970, p. 127

In comment: We stated clearly in the second paragraph of the discussion that the difference between diazepam and paraldehyde was

due to the doses and routes chosen rather than to inherent differences in their sedative actions. The diazepam dose for initial calming was not 150 mg but averaged 46 mg in patients with delirium tremens alone and 89 mg in patients with other diseases as well. These doses must be compared with average paraldehyde doses of 36 ml and 88 ml. The rate of diazepam administration can be accelerated, and, in patients with extreme agitation who are refractory to usual doses, Dr. Gray's regimen is reasonable. Theoretically, if the sedative and hypopneic effects of diazepam are similar exponential functions of total dose, a progressively increasing rate of drug administration may cause linearly incremented effects. As a general therapeutic principle, however, we feel it is safer to give smaller doses (for example, of digoxin or insulin) as the end point is approached. In practice, the dose-response relations have not been established for diazepam or paraldehyde. The important consideration in initial calming of the patient with delirium tremens is the great risk of injury and death while sedating heavily a patient with variable tolerance to sedatives. This is analogous to induction of general anesthesia, and a similar degree of constant professional attention is warranted during the average of 36 or 79 minutes required for initial calming with intravenous diazepam. A reliable site of intravenous therapy is useful in the patient with delirium tremens as a route of administering saline, glucose, thiamine, and magnesium. Also, the risk of sudden death in these patients is equivalent to that of patients with acute myocardial infarction and a reliable intravenous site is of value in both groups for rapid emergency drug therapy. Ventilatory excretion of paraldehyde does not impart much safety. Initial calming, which we believe to be the time of hazardous overdosage, should be completed before much paraldehyde has been excreted. Only 7% of paraldehyde is excreted in the exhaled air of normal subjects ( 1 ) . If all other routes of elimination were first-order processes whose rates were decreased to 5 0 % , 2 5 % , and 10% of their usual rates, the paraldehyde half-time of elimination would be increased 87%, 2 3 1 % , and 5 1 5 % , respectively. In fact, liver disease and dysfunction, as measured by usual tests, do not necessarily impair drug metabolism. Diphenylhydantoin metabolism is unchanged in acute viral hepatitis ( 2 ) , and diazepam half-time of elimination is doubled by hepatic cirrhosis but increases fourfold in the elderly patient ( 3 ) . Finally, the amount of paraldehyde needed to maintain a calm state relative to the amount of diazepam was about half that needed for initial calming. This suggests that the paraldehyde doses for initial calming may have been excessive, as corroborated by three apneic episodes, and that intravenous diazepam provides a more gradual, safe, and predictable approach to the end point of alert tranquility. Perhaps paraldehyde belongs most appropriately in pharmacologic history. W. LEIGH THOMPSON, M.D. WILLIS C. MADDREY, M.D., F.A.C.P.

Department of Medicine University Hospitals Cleveland, Ohio 44106 REFERENCES 1. LANG DW, BORGSTEDT HH: Rate of pulmonary excretion of paraldehyde in man. Toxicol Appl Pharmacol 15:269-274, 1969 2. KLOTZ U, AVANT GR, HOYUMPA A, et al: The effects of age

and liver disease on the disposition and elimination of diazepam in adult man. / Clin Invest 55:347-359, 1975 3. BLASCHKE TF, MEFFIN PJ, RICE AJ, et al: Influence of acute viral hepatitis on diphenylhydantoin (DPH) elimination in man. J Clin Invest 53:8, 1974

"Concepts" in Diabetes Mellitus TO THE EDITOR: It is unfortunate that "concepts" remain entrenched in medicine while facts are ignored until they overwhelm the concept. I refer to the editorial note by Molnar and Service (1) in the December 1974 issue. In 1962 Shaw and associates (2) showed that low doses of insulin were just as effective as high doses in correcting diabetic ketoacidosis. In 1954 Smith and Martin (3) reported that the time required to lower the blood sugar to 300 mg/100 ml and to raise the serum bicarbonate to 20 meq/litre was not influenced by changes in insulin dosage from 80 to 160 to 240 units every 2 hours. In more than 750 patients with diabetic coma treated at a city hospital during the past 10 years, we too have used a low dose insulin regimen and found it safe and effective (4). There never was any evidence, in humans, that ketosis or a low pH impairs tissue insulin responsiveness, nor that large doses of insulin were necessary to treat diabetic coma —it was all a "concept"! This is not to say that there are not occasional patients with diabetic coma who will require large doses of insulin, but they are the exception rather than the rule. ROBERT MATZ, M.D., F.A.C.P.

Montefiore-Morrisania Affiliation, and Albert Einstein College of Medicine Bronx, New York 10452 REFERENCES 1. MOLNAR GD, SERVICE FJ: Low-dosage continuous insulin infusion for diabetic coma. Ann Intern Med 81:853-854, 1974 2. SHAW CE JR, HURWITZ GE, SCHMUKLER M, et al: A clinical and laboratory study of insulin dosage in diabetic acidosis: comparison with small and large doses. Diabetes 11:23-30, 1962 3. SMITH K, MARTIN HE: Response of diabetic coma to various insulin dosages. Diabetes 3:287-294, 1954 4. MATZ R: Diabetic coma: guidelines in therapy. NY State J Med 74:642-648, 1974

In comment: After receiving the copy of Dr. Matz's letter, we have further searched the literature. To this date, we have not found the evidence on which to challenge the final paragraph of his letter in which he claims that there never was any evidence in humans that ketosis or a low pH impairs tissue insulin responsiveness. G. D. MOLNAR, M.D., PH.D., F.A.C.P.

Mayo Clinic Rochester, Minnesota 55901

Raw Diet in Diabetes Mellitus TO THE EDITOR: In his recent letter (Ann Intern Med 82: 61-62, 1975), Douglass describes a decreased insulin requirement in diabetic patients placed on a diet containing an increased percentage of raw food. Although this obComments and Corrections

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servation is of interest, we believe the mechanism for this may be much more direct than his suggestions of noninactivated enzymes in raw food or a more rapid transit time. It is well known that most plant foods consist of cells surrounded by a cellulose wall that is only slightly disrupted by chewing and through which digestive enzymes do not pass. The calories in these cells are thus unavailable ( 1 ) . Cooking, however, causes the starch within the cells to swell, bursting the cell wall and making the starch and other nutrients available for digestion. Indeed, the standard "A Vegetable" exchange list limits the quantity of cooked food, but not raw food. Therefore, the efficacy of the raw diet may be solely due to its decreasing the net calories absorbed. This should not discourage further investigation of the diet, however, as any means of decreasing the caloric consumption of the obese diabetic (or nondiabetic) patient is worthy of consideration. DAVID L. HORWITZ, M.D., PH.D. LINDA SLOWIE, R.D., M.S.

Department of Medicine University of Chicago Chicago, Illinois 60637 REFERENCE 1. DAVIDSON S, PASSMORE R: Human Nutrition and Dietetics, 3rd ed. Baltimore, The Williams and Wilkins Company, 1966, p. 321

Hypokalemia in Leukemia TO THE EDITOR: In a recent paper, Mir and associates (Ann Intern Med 82:54-57, 1975) propose that the hypokalemia that often occurs in association with acute myeloid leukemia may be unrelated to levels of serum or urine lysozyme. We wish to comment on their data and draw their attention to some work in an appropriate animal model. In a study of 32 patients, the authors reported that of 18 patients with elevated serum lysozyme levels, only 9 became hypokalemic. Similarly, of 18 patients with elevated levels of urinary lysozyme, only 10 became hypokalemic. The reverse correlation showed that although 19 of 32 patients were hypokalemic at some point in their course, only 9 had elevated serum and 10 had elevated urinary lysozyme levels (their Table 1). Relative hyperkaluria was noted in all patients. The authors concluded that factors other than renal exposure to lysozyme may be important in the etiology of the hypokalemia of acute myelogenous leukemia. Although we do not disagree with this conclusion, we do suggest that additional information on the duration of serum lysozyme elevation might be helpful in interpretation of their data. Recent studies with normal and chloroleukemic rats ( 1 , 2) have shown that only prolonged elevation in serum lysozyme levels produced detectable lysozymuria with associated hyperkaluria. Acute elevations in serum lysozyme activity were not associated with urinary abnormalities ( 2 ) . Furthermore, once lysozymuria had begun, renal loss of lysozyme and potassium often persisted after serum lysozyme levels again returned to normal. We infer from our animal studies that some duration of serum lysozyme elevation may be reflected in the hyperlysozymuria and hyperkaluria of certain patients with myelogenous leukemia who have no other mechanism of renal 854

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proximal tubule damage. These animal studies may also explain the high incidence of hypokalemia and hyperlysozymuria in other patients with chronic myeloproliferative disorders terminating in acute leukemia ( 3 ) . Many of these patients had chronic serum lysozyme elevations during a prolonged course of chronic myelogenous leukemia, polycythemia vera, or myeloid metaplasia, which rose markedly during the terminal acute leukemia episode. The chronic "exposure" of the kidneys to lysozyme in these myeloproliferative disorders would be similar to that seen in chloromatous rats. In both situations, serum lysozyme elevations were observed before but not necessarily concommitant with urinary lysozyme and potassium elevations. In summary, single observations of serum and urinary lysozyme and potassium could yield a wide variety of unrelated values and still be consistent with the mechanism proposed by Muggia and associates ( 4 ) . JOEL S. GREENBERGER, M.D. DAVID S. ROSENTHAL, M.D. WILLIAM C. MOLONEY, M.D.

Division of Hematology Department of Medicine Peter Bent Brigham Hospital Boston, Massachusetts 02115 REFERENCES 1. ROSENTHAL DS, MAGLIO R, MOLONEY WC: Muramidasuria and hyperkaluria in the chloroleukemic rat. Proc Soc Exp Biol Med 141:499-500, 1972 2. GREENBERGER JS, ROSENTHAL DS, MOLONEY WC: Studies on hypermuramidasemia in the normal and chloroleukemic rat, the role of the kidney. / Lab Clin Med 81:116-121, 1973 3. SKARIN AT, MATSUO Y, MOLONEY WC: Muramidase in myeloproliferative disorders terminating in acute leukemia. Cancer 29: 1336-1342, 1972 4. MUGGIA FM, HEINEMANN HO, FARHANGI M, et al: Lysozymuria

and renal tubular dysfunction in monocytic and myelomonocytic leukemia. Am J Med 47:351-365, 1969

TO THE EDITOR: We read with interest the paper "Hypok a l e m i a in Acute Myeloid Leukaemia" by M. A. Mir and associates in the January 1975 issue of the Annals. In the past few weeks, we have seen a case of acute myelomonocytic leukemia in a 61-year-old white man with severe and persistent hypokalemia; he did not have hyperkaluria. On admission the serum K was 4.0 meq/litre with blood urea nitrogen (BUN), 13 mg/100 ml and creatinine, 0.8 mg/ 100 ml. The leukocyte count was 6700/mm3; the differential count showed 10% blast forms, 2% band, 67% lymphocytes, and 29% monocytes. Marrow aspirate had 60% to 70% blast forms with an increase in immature myeloid forms. He received cytosine-arabinoside, 180 mg intravenously daily, by continuous infusion and 5-thioguanine, 150 mg orally daily, for 4 days plus allopurinol, 100 mg three times a day orally. On the fifth hospital day our patient received carbenicillin, Keflin®, amphotericin B, isoniazid, rifampin and for 2 days gentamicin. On the third and ninth hospital days, he was transfused with a total of 4 units of packed red cells. On the tenth hospital day the serum K dropped to 1.6 meq/litre and remained between 1.4 meq/litre and 1.8 meq/litre daily despite the intravenous administration of KC1 from 100 to 240 meq/ day. The most impressive feature, however, was the relatively low urinary potassium. On the 13th hospital day while the patient was receiving 240 meq potassium daily intravenously, the serum K was 1.7 meq/litre, the urine potassium was 35 meq/total volume (total volume, 700 cm3) with BUN, 17 mg/100 ml,

creatinine, 1.1 mg/100 ml, and creatinine clearance, 13 ml/min. The arterial pH was 7.63 and bicarbonate 38 meq/litre. On this day carbenicillin was withdrawn. On the 14th hospital day he received ammonium chloride intravenously in an attempt to mobilize potassium from the cells into the intravascular department. However, the patient developed anuria and died the next day. Therefore the effect of the acidifying agent could not be evaluated. The effect of antibiotics on serum potassium ( 1 , 2) and the possible effect of lysozymes (3, 4) on the kidneys are well known. In our patient an intracellular redistribution rather than urinary loss of potassium seems to be the most likely explanation of the hypokalemia. Tattersall, Battersby, and Spiers (2) reported a patient with hypokalemia due to a similar mechanism. PARAKEVAS KOSMIDIS, M.D. MARJETA JAMSEK, M.D. ARNOLD R. AXELROD, M.D.

Department of Medicine Sinai Hospital of Detroit Detroit, Michigan 48235 REFERENCES 1. KLASTERSKY J, VANDERKELEN B, DANEAU D, et al: Carbenicillin

and hypokalemia (letter). Ann Intern Med 78:774-775, 1973 2. TATTERSALL MHN, BATTERSBY G, SPIERS ASD: Antibiotics and

hypokalaemia (letter). Lancet 1:630-631, 1972 3. MUGGIA FM, HEINEMANN HO, FARHANGI M, et al: Lysozymuria

and renal tubular dysfunction in monocytic and myelomonocytic leukemia. Am J Med 47:351-366, 1969 4. PICKERING TG, CATOVSKY D: Hypokalaemia and raised lysozyme

levels in acute myeloid leukaemia. Q J Med 42:677-682, 1973

In reply: The data presented in our study were not based on single observations as understood by Greenberger, Rosenthal, and Moloney. All patients were followed up throughout the period of the study lasting for over a year, and balance studies were conducted on each readmission to hospital. We did consider the possible role of prolonged raised lysozyme concentrations on serum K levels; but, for the reasons given below, it was not considered of sufficient importance to be discussed in a brief paper. The total glomerular filtered load of lysozyme (TFLL) was estimated in seven patients by multiplying the mean daily serum lysozyme level (g/24 h) by creatinine clearance (litres/24 h) from the day of diagnosis to the onset of hypokalaemia, or of discharge from hospital. The mean daily normal filtered load of lysozyme was calculated by doing 35 studies in seven normal subjects. The normal for seven subjects was 0.655 ± 0.0388 g/24 h ( S E M ) . As shown in Table 1, Patients 3, 8, and 17 developed hypokalaemia despite lower than normal filtered lysozyme load, while in Patient 31 there was only a slight fall in the serum K level after 28 days, in the face of a much greater TFLL. Lysozymuria did not continue in any one of these patients after the fall of serum lysozyme toward a normal level. This is contrary to the experience of Greenberger, Rosenthal, and Moloney in the chloroleukaemic rat. It is doubtful whether the results obtained in the rat can be extrapolated to apply to human leukaemic patients. With the present effective antileukaemic therapy, a rapid destruction of blast cells precedes a fall in serum lysozyme level, and patients with persistently elevated levels must be

Table 1 . Effect of Glomerular Filtered Lysozyme Load on Serum Potassium Level


1 3 8 16 17 31 32

Lysozymie Data

Serum K

Total Glomerular Filtered Load

Urinary Excretion Range




40.355 1.962 11.01 1.564 4.937 206.616 2.533

0-470 0-1.3 0-40 0-20.7 0-2.5 0-198 0-1

4.3 4.1 3.6 4.1 3.8 3.5 4.2


First Fall

Interval Between Initial and First Fall

3.1 3.4 2.8 3.6 3.3 3.4 2.7

10 5 24 16 13 28 17

rare. Our studies suggest that TFLL is probably not related to the development of hypokalaemia, but the relation of an acutely elevated load of lysozyme to hypokalaemia cannot be disregarded, because four of the five patients, with hypokalaemia on admission to hospital, had markedly elevated lysozyme levels. However, it is our submission that even this association can not be considered as proof that lysozymuria caused hypokalaemia. Recent work has suggested that a high proportion of patients with acute myeloid leukaemia, irrespective of lysozyme concentrations, develops proximal renal tubular dysfunction with aminoaciduria and with incomplete reabsorption of urate and phosphate ( 1 ) . It would seem that there are other, hitherto unrecognised, factors that impair the tubular reabsorption of a wide variety of substances. Leukaemic plasma has been shown to have a strong effect on N a / K transport in the erythrocyte ( 2 ) . It is possible that this or a similar substance may be responsible for the disordered K transport in the renal tubule. We were interested to read the case report from Kosmidis, Jamsek, and Axelrod. It adds further weight to our belief that redistribution of potassium plays an important part in causing hypokalaemia in some patients with acute myeloid leukaemia. M. A. M I R B. BRABIN O. T. TANG M. J. LEYLAND I. W. DELAMORE

University Department of Clinical Haematology Manchester Royal Infirmary Manchester M13 9WL, England, UK REFERENCES

1. MIR MA, DELAMORE IW: Hypouricaemia and proximal renal tubular dysfunction in acute myeloid leukaemia. Br Med J 3: 775-777, 1974 2. MIR MA, BOBINSKI H: Altered membrane sodium transport and the presence of a plasma ouabain-like inhibitory factor in acute myeloid luekaemia. Clin Sci Mol Med 48:213-218, 1975

Adriamycin Cardiotoxicity TO THE EDITOR: Rinehart, Lewis, and Balcerzak (1) recommend the use of systolic time intervals for the early detection of adriamycin cardiotoxicity. As they suggest, Comments and Corrections

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the early detection of significant cardiotoxicity would allow a more accurate decision on the dose limitation of adriamycin. Their Figure IA suggests a continuous increase in systolic time intervals with increasing adriamycin dose, yet they only give the data on two patients. It would be more interesting to see if a dose response curve could be formed from all their cases. In eight of their nine ( 8 9 % ) patients who received > 300 mg/m 2 body surface area of adriamycin, the authors suggest that an increase in the systolic time interval (that is, the ratio of the preejection period/left ventricular ejection time) of greater than 0.08 correlates with significant adriamycin cardiotoxicity. It is implied that detection of a significant systolic time interval increase allows for a maximum dosage of adriamycin without excessive risk of life-threatening heart failure. Without knowledge of the systolic time intervals, we gave adriamycin to 54 patients in a dose between 451 and 550 mg/m 2 body surface area. These patients have been seen for a minimum of an additional 6 months. Extrapolating from the data of Rinehart, Lewis, and Balcerzak, we would have expected 89% (or 48 of the 54 patients) to have a significant increase in the systolic time interval, but only 1 of these patients developed clinical cardiac toxicity, an incidence of only 1.8%. In the uniformly fatal malignant diseases in which it is used, adriamycin can result in frequent prolonged objective responses (2-4). The potential benefit of additional adriamycin must always be weighed against the risk of potentially fatal cardiac damage from continued administration. If the total cumulative dose of adriamycin is kept below 550 mg/m 2 body surface area and clinical indices are followed closely, the risk is quite low. Although the systolic time interval reflects left ventricular dysfunction (5, 6 ) , we believe it is too sensitive an indicator. We do not feel that a significant increase of the systolic time interval alone is an indication to discontinue adriamycin, as many patients would be deprived potential benefit from adriamycin while only a few would be spared cardiac toxicity. We also feel that systolic time interval prolongation may not give early enough warning for all patients who will develop cardiomyopathy. This toxicity may develop 1 to 6 months after withdrawal of adriamycin (7). We report below the case of a patient who developed a severe congestive heart failure 3l/z months after withdrawal of adriamycin at a total dose of 550 mg/m 2 body surface area despite a normal systolic time interval for several months before and 1 month after his last dose of adriamycin. A 30-year-old man underwent an exploratory laparotomy for intestinal obstruction. An undifferentiated retroperitoneal sarcoma with multiple abdominal metastases was found. Chemotherapy consisting of cyclophosphamide, vincristine, adriamycin, and dimethyltriazeno imidazole carboxamide was administered at 4-week intervals (8), resulting in stabilization of his disease. Monthly physical examinations, chest X-rays and electrocardiograms all showed normal findings. In addition, systolic time intervals measured 4 weeks after he had last received adriamycin at cumulative doses of 350, 450, and 550 mg/m2 body surface area were all normal. Adriamycin was withdrawn after a total dose of 550 mg/m2 body surface area. Despite this, he developed severe congestive heart failure ZVi months after his last dose of adriamycin, IVi months after a normal systolic time interval (Figure 1). His systolic time interval became abnormal and his electrocardiogram showed a marked decrease in the QRS voltage. Fortunately, 856

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Months After Initiation of Adriamycin Therapy Figure 1. Serial systolic time intervals (PEP/LVETs) in patient who developed adriamycin-induced congestive heart failure 12y2 months after initiation of adriamycin therapy.

the patient responded to digitalis diuretics and bed rest, but he still has severe exercise intolerance 7 months after developing congestive heart failure. (We believe this patient may have developed his cardiomyopathy despite following the dose-limitation because of concurrent use of cyclophosphamide, another known cardiotoxin [9].) Thus, the systolic time interval can be normal when adriamycin is withdrawn, yet cardiotoxicity may still develop. We believe that if we continued to administer adriamycin in this case until a significant increase in the systolic time interval occurred, additional cardiac damage would have developed, and the patient would probably have died from cardiomyopathy. Therefore, we cannot recommend that a normal systolic time interval alone justifies routinely exceeding the dose limitation of 550 mg/m 2 body surface area where the risk of cardiac toxicity rises to 2 7 % . Clinical criteria should still be emphasized in making decisions to withdraw adriamycin below the dose limitation. With present knowledge, measurements of the systolic time interval may be (rather than are) valuable in detecting clinically significant cardiotoxicity. It is our opinion that clinical, radiologic, and possibly echocardiographic (10, 11) and electrocardiographic (12) criteria must still be emphasized in making decisions both to discontinue below or to exceed the current adriamycin dose limitation recommendation of 550 mg/m 2 body surface area, with the measurement of the systolic time interval possibly an additional confirmatory aid. ROBERT A. M I N O W , M.D. JEFFREY A. GOTTLIEB, M.D.

Department of Developmental Therapeutics The University of Texas System Cancer Center

M.D. Anderson Hospital and Tumor Institute Houston, Texas 77025 LEON FRAZIN, M.D. EFRAIN GARCIA, M . D .

Division of Cardiology The Texas Heart Institute St. Luke's Episcopal Hospital Houston, Texas 77025 REFERENCES



toxicity in man. Ann Intern Med 81:475-478, 1974 2. BLUM RH, CARTER SK: Adriamycin: a new anticancer drug with significant clinical activity. Ann Intern Med 80:249-259, 1974 3. O'BRYAN RM, LUCE JK, TALLEY RW, et al: Phase II evaluation

of adriamycin in human neoplasia. Cancer 32:1-8, 1973 4. TAN C, ETCUBANAS E, WOLLNER N, et al: Adriamycin—an anti-

tumor antibiotic in the treatment of neoplastic diseases. Cancer 32:9-17, 1973 5. WEISSLER AM, HARRIS WS, SCHOENFELD CD: Bedside techniques

for the evaluation of ventricular function in man. Am J Cardiol 23:577-583, 1969 6. WEISSLER AM, HARRIS WS, SCHOENFELD CD: Systolic


intervals in heart failure in man. Circulation 37:149-159, 1968 7. LEFRAK EA, PITHA J, ROSENHEIM S, et al: A clinicopathologic

analysis of adriamycin cardiotoxicity. Cancer 32:302-314, 1973 8. GOTTLIEB J A, BODEY GP, SINKOVICS JG, et al: An effective new

4-drug combination regimen (CY-VA-DIC) for metastatic sarcomas. Proc Am Soc Clin Oncol 15:162, 1974 9. BUCKNER CD, RUDOLPH RH, FEFER A, et al: High dose cyclo-

phosphamide therapy for malignant disease. Cancer 29:357-365, 1972 10. JONES SE, EWY GA, GROVES BM: Echocardiographic detection

of adriamycin heart disease. Proc Am Soc Clin Oncol, in press 11. MCDONALD IG, HOBSON ER: A comparison of the relative value of noninvasive techniques—echocardiographic systolic time intervals and apex cardiography—in the diagnosis of primary myocardial disease. Am Heart J 88:454-462, 1974 12. MINOW RA, GOTTLIEB JA, FREIREICH EJ:


QRS voltage changes in adriamycin cardiomyopathy. Proc Am Assoc Cancer Res, in press

A regimen of oral nitrates, such as that used in our patient, has been presumed to be ineffective for prophylactic antianginal therapy, based on reports that the drug is rapidly converted to supposedly inactive metabolites ( 1 ) . Conclusive evidence in this regard, however, has not been presented, and indeed the efficacy or oral isosorbide dinitrate in the type of patient described above requires one to consider a possible prolonged effect of the drug or its metabolites. Rather than having a primary effect on coronary blood flow, it is probable that the extracardiac effects on afterload and preload is most beneficial in these patients. Hemodynamic evidence of the activity of isosorbide dinitrate in our patient is shown by subjective complaints of headache after ingestion of the drug. We did not, however, see a decrease in arterial blood pressure or an increase in heart rate. If the dosage used was not great enough to cause a rapid decrease in blood pressure but, rather, a decreased peripheral resistance balanced by an increased cardiac output, then the blood pressure would be maintained within normal limits. Perhaps an increased cardiac output from the oral nitrate therapy resulted in his large-volume diuresis, implying an improved functioning of the myocardium. Further work is needed to precisely elucidate the mechanism of action of oral nitrates in patients with intractable heart failure. Perhaps their efficacy is due to a metabolite, or perhaps the drug itself enhances the action of other agents like the diuretic action of furosemide. This is an area that is still speculative. R E N E E PLAWNER

Philadelphia College of Pharmacy & Science Philadelphia, Pennsylvania 19102 REFERENCE

1. NEEDLEMAN P, LANG S, JOHNSON E JR: Organic nitrates: rela-

Vasodilators in Heart Failure TO THE EDITOR: I read with great interest the paper by Cohn and associates (Ann Intern Med 81:777-780, 1974) on the use of vasodilator therapy in intractable left ventricular failure. I wish to corroborate their findings with an account of one of our cases. A 52-year-old white man had had scarlet fever at age 18. In May 1973, he was found to have congestive heart failure secondary to papillary muscle dysfunction; he was treated, and his failure was controlled with digoxin and furosemide. In November 1974, the patient noted onset of dyspnea on exertion and paroxysmal nocturnal dyspnea, which gradually increased in severity until admission on 26 December. At admission he was noted to have severe congestive heart failure secondary to mitral insufficiency. He was treated aggressively with digoxin, 0.25 mg po qd, furosemide, up to 120 mg tid po, intravenously, spironolactone, 50 to 100 mg tid, and bedrest for 2 weeks, but he did not respond. He was additionally placed on a trial of oral isosorbide dinitrate, 20 mg qid. Within 24 hours the patient voided approximately 4 litres of urine and continued to do so for several days. He had a final weight loss of 10 kg, improved greatly subjectively and objectively, and was subsequently discharged from the hospital in a stable condition. This confirms Cohn's view that oral isosorbide dinitrate does work in patients with intractable congestive heart failure, presumably by decreasing the afterload and preload on the heart and therefore allowing for increased cardiac output.

tionship between biotransformation and rational angina pectoris therapy. / Pharmacol Exp Ther 181:489-497, 1972

Heparin Therapy for Heatstroke TO THE EDITOR : In their letter Cornell and colleagues (1) express the view that disseminated intravascular dissemination rather than primary fibrinolysis contributes to the morbidity and mortality of heatstroke, and that consequently the early administration of heparin is advocated. We proposed that excessive body temperature, as implied by its term heatstroke, should be considered as the primary cause of its manifestations. Hence, heat damage to cells and enzymes should be expected to occur in all the body systems. Because of the time-intensity relation of the effects of physical agents, early and effective cooling off while preventing shivering with a "lytic cocktail" was initiated in our cases ( 2 ) . Body temperature reached the 37 °C zone within 4 to 6 hours and was not allowed to rise again. In the case of Cornell and associates the rectal temperature, 41.1 °C on admission, was still 39.5 °C after 4 hours and 38 °C after 12 hours. Because there is no evidence for adrenocortical failure in heatstroke, we did not feel obliged to administer adrenocortical hormones. We are aware that the central nervous system depressant drugs used in a "lytic cocktail," like phenothiazine and Phenergan®, have been implicated in malignant hyperthermia. However, there seems to be Comments and Corrections

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no common pathogenetic relation between the malignant hyperthermia in anesthesia and heatstroke. The main reason for writing this letter is the facile implication of disseminated intravascular coagulation in the clinical picture of heatstroke. Its possible role has been mentioned by us and others (2, 3) and was also suggested by the experimental model in dogs by measuring 131 iodine fibrinogen disappearance from the blood ( 4 ) . However, the factors responsible for the breakdown of hemostasis in heatstroke are probably even more intricate than the enigmatic relations between primary fibrinolysis and disseminated intravascular coagulation in cases other than heatstroke. In addition to these conditions, frequently discussed in connection with bleeding, the following pathophysiologic mechanisms could play a role in the breakdown of hemostasis in heatstroke: [1] thermic damage to blood vessels, to the liver and its production of clotting factors, to the bone marrow, and to the megacaryocytes (indeed, damage to blood vessels, liver, and bone marrow has been described in the pathologic picture of heatstroke); [2] thermic damage to clotting factors and thrombocytes; and [3] changes of the enzymatic activity of clotting factors due to the extreme changes in the interior milieu, such as in pH and temperature. Most of these mechanisms have not yet been investigated. We found that fibrinogen decreased its electrophoretic mobility at 43 °C, and pH-dependent changes of fibrinogenolysis have also been noted ( 5 ) . In view of these considerations we have weighed the use of heparin therapy in our heatstroke cases but always refrained from it and took refuge with replacement therapy of fresh plasma, fibrinogen, and thrombocytes. The changes in thrombocyte number and prothrombin time, like those observed by Cornell and associates (1) after heparin administration, were also often observed in our cases (2) after replacement therapy. That the administration of clotting factors had no deleterious effects in our cases is worth mentioning. If disseminated intravascular coagulation was the only cause of bleeding, addition of fresh plasma, fibrinogen, and thrombocytes should have aggravated the hemorrhagic diathesis. Instead the clinical picture was favorably influenced by replacement. We believe that use of heparin should be very cautiously weighed in heatstroke, if indeed heparin should be given at all. Fatal cases after massive bleeding and therapeutic failures are more likely to be forgotten and not published. Because the diagnosis of heatstroke calls for immediate emergency measures, the publication of observations based on controlled studies is not to be expected. Although the observation of Cornell and associates conforms with accepted views on disseminated intravascular coagulation, our doubt as to its primary importance in heatstroke is worth mentioning. Further studies on the clotting disturbances in heatstroke are warranted. SHLOMO SHIBOLET, M.D. ZVI FARFEL, M.D.

Heller Institute of Medical Research Chaim Sheba Medical Center Tel-Hashomer, Israel REFERENCES 1. C O R N E L L




B, et al:




heatstroke (letter). Ann Intern Med 81:702-703, 1974 2. SHIBOLET S, C O L L R, G I L A T T, et al: H e a t s t r o k e : its clinical pic-

ture and mechanism in 36 cases. Q J Med 36:525-548, 1967 858

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3. STEFANINI M , SPICER D D : Hemostatic breakdown, fibrinolysis and acquired hemolytic anemia in a patient with fatal heatstroke: pathogenetic mechanisms. Am J Clin Pathol 55:180-186, 1971 4. R O S E N T H A L








intravascular coagulation in experimental heatstroke. Diath Haemorrh 26:417-425, 1971 5. N A N N I N G A






Thromb and


chaelis constants during activation of profibrinolysin a n d fibrinolysis. Thromb Diath Haemorrh 19:492-498, 1968

Care of Homebound Aged TO THE EDITOR: Doctor Paul A. L. Haber, Deputy Assistant Chief Medical Director for Professional Services, and I were gratified to read the report of Brickner and colleagues in the January issue on the care of homebound aged. Doctor Philip Brickner and his colleagues have correctly pointed out the importance of this kind of program in reaching the needs of the many patients who ordinarily might not come in to any health-care delivery system until it was determined that they need long-term institutional care. The editorial in that same issue gives further evidence of need for such a program. We wish, therefore, to call your attention to the fact that the Veterans Administration has been involved in a comparable program of hospital-based home care since 1970. This program was begun originally as a pilot program and was then extended to a number of other hospitals, until, at present, it is practiced in 31 separate VA hospitals. Over 1000 patients will be treated in this program during fiscal year 1975, and 32 000 visits will be made. Three major benefits stem from this program: [1] cost saving for patients who might otherwise require continued hospitalization, [2] more effective use of inpatient beds, and [3] more rapid progression toward recovery on the part of patients who might otherwise continue to be institutionalized. We wholeheartedly agree that similar programs should be instituted, as indicated in your editorial. JOHN D. CHASE, M.D.

Department of Medicine and Surgery Veterans Administration Washington, D.C. 20420

Wanted: Case Reports on Insect Bites TO THE EDITOR: Again this year I am compiling case reports of allergic reactions to biting insects, that is, mosquitoes, fleas, gnats, kissing bugs, bedbugs, chiggers, black flies, horseflies, sandflies, and deerflies. I would like physicians to supply me with case reports of those patients who have had reactions to such insects. Include in your reports the type of reaction and complications, if any, the age, sex, and race of the patient, the site of the bite(s), the season of the year, the immediate symptoms, the skin test results, desensitization results, if any, and any associated other allergies. CLAUDE A. FRAZIER, M.D.

4-C Doctors' Park Asheville, North Carolina 28801

Correction: Designation of College Fellowship The designation F.A.C.P. was inadvertently added after Dr. Charles S. White Ill's name in his contribution to the April issue (Ann Intern Med 82:589, 1975). Dr. White is an Associate, not a Fellow, of the College. This error occurred in the editorial department.

20. BUJAK JS, OTTESEN EA, DINARELLO CA, et al: Nocardiosis in

a child with chronic granulomatous disease. J Pediatr 83:98-100, 1973 21. MARCOVITCH H, NORMAN AP: Treatment of nocardiosis. Lancet

2:362-363, 1970 22. PIER AC, THURSTON JR, LARSEN AB: A diagnostic antigen for

nocardiosis: comparative tests in cattle with nocardiosis and mycobacteriosis. Am J Vet Res 29:397-403, 1968 23. BREED RS, MURRAY EGD, HITCHENS AP: Bergey's Manual of

Determinative Bacteriology, 6th ed. Baltimore, The Williams and Wilkins Company, 1948, p. 897

Correction: References TO THE EDITOR: We have discovered a serious error in our

paper "Nocardia Infection in Heart Transplant Patients" (Ann Intern Med 82:18-26, 1975). References 20 through 24 are incorrect and should read as follows:

24. NELSON E, HENRICI AT: Immunologic studies of actinomycetes,

with special reference to the acid-fast species. Proc Soc Exp Biol Med 19:351-352, 1922 J A M E S A. K R I C K , M.D.

Palo Alto Medical Research Foundation 860 Bryant Street Palo Alto, California 94301

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Letter: Penicillin G therapy in renal failure.

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