COMMENTS

Comments submitted for publication must be typed doublespaced. Text length must not exceed 500 words, and no more than five references may be used. Complete references must be furnished, as specified in "Information for Authors" (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: we give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style. Diazoxide Therapy: Use and Risks TO THE EDITOR: The recent paper by Kanada and associates (1) describing an angina-like syndrome after diazoxide therapy is of concern to all physicians who treat hypertensive crises. We wish to comment on the high prevalence of diazoxide-induced angina-like side effects reported by Kanada and colleagues and to relate our recent experience with fatal myocardial infarction in a patient who received diazoxide. The frequent occurrence of angina-like symptoms after diazoxide administration is contrary to our experience and to that of other investigators (2, 3 ) . Frequently patients complain of a sensation of internal warmth located in the thorax and abdomen. Symptoms of substernal tightness or chest discomfort have been extremely rare in our patients, and we wonder if the discomfort described by the authors might be the sensation of internal warmth associated with potent vasodilator administration. Except for the one patient with a myocardial infarction, Kanada and associates describe chest pain, substernal tightness, or electrocardiographic ST-T wave changes only in the patients who had received the higher doses of intravenous furosemide. The authors lead us to believe that the patients with and without electrocardiographic changes were clinically similar since they had no significant difference between pretreatment blood pressure values; however, none of the patients who received pretreatment with 40 mg of furosemide had any electrocardiographic ST segment depression. This observation can be interpreted in two ways: furosemide in 80- to 120-mg intravenous doses was responsible for the ST-T wave changes noted; or different clinical characteristics led to the use of higher doses of furosemide in the patients who subsequently developed ST-T wave changes or chest discomfort. For various reasons we favor the latter explanation, but it is certainly possible that the higher doses of furosemide led to greater electrolyte changes and therefore to more pronounced ST-T wave changes. Of grave concern to us is the occurrence of myocardial infarction in Patient 14, who was notably older than the rest of the patients and who had a history of previous angina pectoris. A recent catastrophic event after diazoxide administration in our laboratory prompts us to report another case of probable diazoxide-induced myocardial infarction. A 54-year-old black man came to the Hypertension Clinic having been out of medication for 1 week. He denied any

history of previous angina pectoris, myocardial infarction, or significant chest discomfort; he had a 35-year-history of hypertension, which was considered severe for at least the past 3 years. His previous medications included furosemide, 80 mg twice daily; methyldopa, 500 mg four times daily; hydralazine, 25 mg four times daily; propranolol, 10 mg four times daily; and KC1 elixir, 13 meq twice daily. The patient's blood pressure was 224/156 mm Hg sitting and 226/160 mm Hg standing. He received intravenous diazoxide, 300 mg, rapidly, and his blood pressure decreased to 210/115 mm Hg. Approximately 30 minutes later, his blood pressure was 210/130 mm Hg, and he received a second ampule of diazoxide with no apparent response. At this time, the patient began to complain of a dull, constricting, anterior precordial chest pain and was given nitroglycerin, 0.4 mg, sublingually. Approximately 10 minutes later he developed a hypotensive reaction associated with cold clammy skin and no detectable blood pressure. A metaraminol infusion promptly restored his blood pressure to 130/90 mm Hg, and he was subsequently admitted to the coronary care unit where an electrocardiogram showed a pattern of an extensive anterior wall myocardial infarction. The patient subsequently had recurrent ventricular arrhythmias and developed circulatory collapse with ventricular fibrillation. He was pronounced dead approximately 15 h after the initial administration of diazoxide. An autopsy was not done. It is noteworthy that this patient had no history of previous chest pain or myocardial infarction. Although we have reservations about the interpretation of the high prevalence of electrocardiographic changes described by Kanada and associates ( 1 ) , apparently acute hypotensive episodes after diazoxide administration may be associated with the development of a myocardial infarction ( 4 ) . We conclude, therefore, that it is probably hazardous to administer diazoxide to patients with known coronary artery disease and that diazoxide administration in patients who are above middle age and who might have subclinical coronary artery disease should be considered with great care. WILLIAM J. MROCZEK, M.D., F.A.C.C. W O N R O L E E , M.D.

Georgetown University Medical Division D.C. General Hospital Washington, D.C. 20003 REFERENCES 1. KANADA SA, KANADA DJ, HUTCHINSON RA, et al: Angina-like syndrome with diazoxide therapy for hypertensive crisis. Ann Intern Med 84:696-699, 1976 2. MROCZEK WJ, DAVIDOV ME, GAVRILOVICH L, et al: The value of aggressive therapy in the hypertensive patient with azotemia Circulation 40:893-904, 1969 3. MILLER WE, GIFFORD RW, HUMPHREY DC, et al: Management of severe hypertension with intravenous injections of diazoxide. Am J Cardiol 24:870-875, 1969 4. KUMAR GK, DASTOOR FC, ROBAYO JR, et al: Side effects of

diazoxide. JAMA 235:275-276, 1976 TO THE EDITOR: We read with interest the paper by Kanada and associates, "Angina-Like Syndrome with Diazoxide Therapy for Hypertensive Crisis" (Ann Intern Med 84: 696-699, 1976). Further evaluation of their data would indicate, however, that the combination of the higher doses of furosemide (80 mg or more) with the diazoxide

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may have been the cause of the angina-like signs and symptoms in their patients. The authors did not evaluate this combination of furosemide and its possible relation to angina in their study. The data showed that 4 3 % (6 of 14) of the patients developed substernal discomfort. The fact was not mentioned that of the seven patients who received 40 mg of furosemide plus 300 mg of diazoxide, only one ( 1 4 % ) had substernal discomfort, whereas, of the seven patients who received 80 mg or more of furosemide plus 300 mg of diazoxide (including the patient that received 200 mg of diazoxide), five ( 7 1 % ) experienced these symptoms (P < 0.01). This indicates that the dosage of furosemide received by each patient may be a major factor in the occurrence of these symptoms. Because the dosage of diazoxide was constant at 300 mg (except for one case at 200 mg), it may be concluded that in the use of the combination diazoxide and furosemide, the dosage of the latter at or above 80 mg may cause angina symptoms due to its additive hypotensive effects. The additive hypotensive effects are a reasonable explanation because the times of onset of action with intravenous furosemide and diazoxide are virtually the same (2 to 10 minutes) ( 1 ) . This effect is also evident from the following: in those patients receiving 80 mg or more of furosemide plus the 300 mg of diazoxide, a 27% drop in systolic and a 4 6 % drop in diastolic blood pressure was seen; in those patients receiving 40 mg of furosemide plus the 300 mg of diazoxide, a 24% drop in systolic and 36% drop in diastolic blood pressure was seen (our calculations). We conclude from these data that in treating hypertensive crisis with the combination of diazoxide and furosemide, if the dosage of the latter equals or exceeds 80 mg, there is an increased additive hypotensive effect that may result in an angina-like syndrome.

versus the higher dose combination: with 40 mg of Lasix® plus 300 mg of diazoxide, ST-T wave changes are seen in three of seven patients; with 80 mg of Lasix plus 300 mg of diazoxide, changes are seen in four of seven patients. While we cannot exclude the possibility that the dosage of furosemide administered may be a factor in the occurrence of chest discomfort, we can exclude it as being a factor in the occurrence of ST-T wave changes after administration of furosemide and diazoxide. We would like to point out that the calculations of Dr. Greenlaw and associates on the percentage drop in systolic and diastolic pressures after 80 mg of furosemide plus 300 mg of diazoxide and 40 mg of furosemide plus 300 mg of diazoxide are incorrect. The actual percent blood pressure drops are as follows: in those patients receiving 40 mg of Lasix plus 300 mg of diazoxide, a 28% drop in systolic and a 37% drop in diastolic blood pressure was seen; in those receiving 80 mg of Lasix plus 300 mg of diazoxide, a 34% drop in systolic and a 4 3 % drop in diastolic blood pressure was seen. This difference in blood pressure drop between the higher dose furosemidediazoxide combination and the lower dose furosemidediazoxide combination is not statistically significant (/-test, P > 0.05). Hence 80 mg of furosemide did not render a significantly greater hypotensive effect than 40 mg of furosemide. In view of an earlier report of diazoxide-induced myocardial infarction (1) and the catastrophic experience of Drs. Mroczek and Lee, we emphasize again the importance of avoiding the use of diazoxide in persons with evidence of coronary artery disease, that is, past history of myocardial infarction or angina pectoris. We urge that caution in the use of diazoxide be extended to those patients who may have occult coronary artery disease.

CAL GREENLAW, PHARM.D. PATRICK T. PAULSON, M.S., R.PH. LARRY W. N U L L II, PHARM.D.

SHIRLEY A. KANADA, PHARM.D. DANIEL J. KANADA, M.D. D E L O N W U , M.D.

Holy Cross Hospital Fort Lauderdale, FL 33307 REFERENCE 1. GOODMAN LS, GILMAN A: The Pharmacological Basis of Thera-

peutics, 5th ed. New York, Macmillan Co., 1975, p. 833

University of Illinois Chicago, IL 60612 REFERENCE

1. KUMAR GK, DASTOOR FC, ROBAYO JR, et al: Side effects of

diazoxide. JAMA 235:275-276, 1976

In comment: As Dr. Mroczek and Dr. Lee have pointed out, the sensation of internal warmth is a fairly frequent complaint after diazoxide administration, and several of our patients did develop this sensation. However, the symptoms of substernal tightness and pain reported in our study were ischemic in character and distinctly different from the sensation of warmth associated with potent vasodilatation. The uncommon occurrence of chest discomfort observed by other investigators may be explained by the fact that patients frequently will not report adverse effects of drugs unless specifically questioned. Both Dr. Mroczek and Dr. Greenlaw and their associates have pointed out that the presence of chest discomfort appears to be related to the higher furosemide dose of 80 mg or more. However, when electrocardiographic changes, which are objective finding of ischemic effects, are evaluated, we find no statistically significant difference between the lower dose furosemide-diazoxide combination 530

TO THE EDITOR: We believe that the criteria for use of diazoxide for "hypertensive crisis" as reported in the article by Kanada and associates (Ann Intern Med 84:696-699, 1976) must be critically reviewed. Their criteria were (A) diastolic blood pressure equal to or greater than 130 mm Hg; (B) no history of active angina pectoris, myocardial infarction, or aortic dissection; and (C) no history of hypersensitivity to diazoxide. As (C) had to be present for use of the drug and as (B) lists those conditions in which the use of diazoxide is relatively contraindicated, the apparent only real criterion as reported was a diastolic pressure equal to or greater than 130 mm Hg. This alone must be considered inadequate for diagnosis of "hypertensive crisis" since the sine qua non is, in addition to severe elevation of arterial pressure, end-organ damage as manifest by one or more of the following: encephalopathy, neuroretinitis, renal failure, and left ventricular failure ( 1 ) . An examination of the cases included in this study reveals several interesting aspects. First of all, one subject,

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Patient 10, did not even meet the originally established criteria in that his diastolic blood pressure was 120 mm Hg. Another, Patient 2, had a diastolic blood pressure of 135 mm Hg, considered by at least some reliable sources to be below the level considered consistent with accelerated hypertension ( 2 ) . Of the remaining 12 patients, nine had a diagnosis of chronic renal failure complicating their hypertension. It has been stated that treatment of hypertension in patients with renal failure is generally more difficult than in patients without chronic renal failure because of various problems, including overexpansion of the extracellular fluid volume and the increased incidence of drug toxicity secondary to retention of the drugs ( 3 ) . Hence, these patients did not meet the criteria of hypertensive crisis, and in the majority of instances they suffered from chronic renal failure as well. The indication for use of diazoxide in the control of hypertension in these patients is not clear. If the requirement to lower the blood pressure is not immediate, as the authors state in their discussion, then this particular antihypertensive medication is not indicated. Certainly other effective programs are available for the control of significant diastolic hypertension, which would result in effective lowering of blood pressure over periods of several hours to 1 or 2 days, and these would be preferred in patients who did not meet the criteria for hypertensive crisis. Therefore, although electrocardiographic changes associated with angina-chest pain did occur in these patients, we find it difficult to accept the conclusion that these findings are applicable to patients with true hypertensive crisis, in whom a recognized need for diazoxide therapy exists. CARL E. ORRINGER, M.D. LAURENCE B. GARDNER, M.D.

Department of Medicine University of Miami Affiliated Hospitals Miami, FL 33152 REFERENCES

1. KOCH-WESER J: Hypertensive emergencies. N Engl J Med 290: 211-214, 1974 2. HURST J (editor): The Heart, 3rd ed. New York, McGraw-Hill Co., 1974, pp. 1242-1243 3. STRAUSS M, WELT L (editors): Diseases of the Kidney, 2nd ed.

Boston, Little, Brown and Co., 1971, p. 254

In comment: Although it was not the purpose of our study to establish criteria for what constitites a case of "hypertensive crisis," we agree with Drs. Orringer and Gardner that our criteria may have been misleading. Except for the two patients with diastolic pressures of 120 and 135 mm Hg, the patients had diastolic blood pressures of 140 mm Hg or greater and had retinopathy, which to most clinicians would meet the criteria of "accelerated hypertension." Hence, from the clinical condition and blood pressures of these patients, the attending physician deemed it necessary to lower their blood pressures rapidly. The absence or presence of certain features of "hypertensive crisis" should not alter the conclusions on the cardiovascular effects of diazoxide. The high incidence of renal insufficiency complicating our hypertensive patients is not unusual, as it is these patients with long-standing hypertension who are at risk of developing "hypertensive crisis." Moreover, diazoxide

would in principal be an appropriate agent in these accelerated hypertensive patients with renal insufficiency, as the drug will not further decrease the glomerular filtration rate or the renal plasma flow. SHIRLEY A. KANADA, PHARM.D. D A N I E L J. K A N A D A , M . D . D E L O N W U , M.D.

University of Illinois Chicago, IL 60612

Prothrombin Complex Concentrates and Coagulation TO THE EDITOR: I write with reference to "Intravascular Coagulation With Use of Human Prothrombin Complex Concentrates," the paper by Cederbaum, Blatt, and Roberts in the June issue (Ann Intern Med 84:683-687, 1976). Although I quite agree with Dr. Cederbaum and coauthors' conclusions that the prothrombin complex product should not be used in nonhemophilic patients when therapeutic alternatives are available, the doses administered to the patients cited in their paper were considerably higher than what is ordinarily recommended by the manufacturer for replacement therapy in hemophilia. The doses described are similar to those used to initiate disseminated intravascular coagulation in dogs ( 1 ) ; a consistent disseminated intravascular coagulation pattern can be obtained with the administration of 100 factor TX units per kilogram of body weight. It would not seem surprising that similar results can be achieved in the somewhat less coagulable human system. The authors' discussion of the "safer" product described by Green and colleagues (2) does not mention the possibility that a lower dose was used; unfortunately Green and co-authors do not indicate the quantity of procoagulant activity infused into their patients, but the circulating factor VII levels identified are considerably less than would be expected with the doses of Konyne® and Proplex® used in the cases under discussion. With respect to the thrombogenic properties of these concentrates, elimination of the activated factors by incubation with antithrombin III before administration of the product has failed to eliminate the coagulopathy in the dog model. This suggests that activated factors are not entirely responsible for the effect on the coagulation system, and perhaps total procoagulant activity or the presence of unidentified prothrombin intermediates may be responsible for this complication ( 3 ) . JOHN A. P E N N E R , M.D.

Department of Internal Medicine University Hospital Ann Arbor, MI 48104 REFERENCES 1. HEDNER U, NILSSON I, BERGENTZ S-E: Various prothrombin com-

plex concentrates and their effect on coagulation and fibrinolysis in vivo. Thromb Haemostasis 35:386-395, 1976 2. GREEN G, DYMOCK IW, POLLER L, et al: Use of factor-VII rich

prothrombin complex concentrate in liver disease. Lancet 1:13111314, 1975 3. PENNER JA: Activated prothrombin complex concentrates in congenital and acquired hemorrhagic disorders. Semin Thromb Hemostasis, 1976, in press

In comment: There can be no disagreement that the dose of prothrombin Comments

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complex concentrates might well affect the occurrence of disseminated intravascular coagulation. However, we should point out that the doses of Konyne and Proplex were calculated to raise the patients to about 100%. The invivo recovery of factor IX is less than one would expect from the units of factor IX stated on the product insert. More importantly, however, the same amounts of Konyne or Proplex given to most patients without liver disease did not result in disseminated intravascular coagulation. Moreover, factor IX concentrates from around the world have been shown to possess various activities ( 1 , 2 ) , and disseminated intravascular coagulation from the products has been shown to occur with European (3) as well as American (4) products. Thus, it would probably be overly simplistic to assume that factor IX concentrates could be made completely safe simply by lowering the dose. The fact that preincubation of a concentrate with antithrombin III failed to eliminate the coagulopathy in the dog model of Dr. Penner is not especially surprising. The explanation of this phenomenon may well be related, as suggested by Dr. Penner, to "total procoagulant activity" or other prothrombin intermediates. We stated quite clearly in our discussion that the "thrombogenicity" of factor IX concentrates was most likely multifactorial. However, some of the thrombogenicity is likely due to activated serine proteases that are inhibited by antithrombin III. Thus, part of the thrombogenic substances may be neutralized by antithrombin HI. The mechanism of prothrombin complex concentrate-induced coagulopathy is still not precisely elucidated, and, as we implied in our article, more work in this area is needed. Most important, however, users of prothrombin complex concentrates should continue to recognize that the concentrates are potentially dangerous and that the danger is enhanced in patients with liver disease. This is the major point of our paper that Dr. Penner's comments do not alter. As a result of observations from around the world, producers of prothrombin complex concentrates in this country are making a great effort to improve the final product. Perhaps, soon, Factor IX concentrates free of thrombogenic materials will be available.

PHILIP M. BLATT, M.D.

Department of Medicine University of North Carolina Chapel Hill, N C 27514 REFERENCES 1. BLATT PM, LUNDBLAD RL, KINGDON HS, et al: Thrombogenic

materials in prothrombin complex concentrates. Ann Intern Med 81:766-770, 1974 2. KINGDON HS, LUNDBLAD RL, VELTKAMP JJ, et al:

Potential

thrombogenic materials in Factor IX concentrates. Thromb Diath Haemorrh 33:617-631, 1975 3. GUILLIN MC, MENACHE D, BARGE JR, et al: Les troubles de

l'hemostase au cours des hepatites virales graves: e etude clinique, anatomique et biologique. Ann Med Interne (Paris) 122:605-615, 1972 4. CEDERBAUM Al, BLATT PM, ROBERTS HR: Intravascular coagula-

tion with use of human prothrombin complex concentrates. Ann Intern Med 84:683-687, 1976

Hairy Cells in Long-Term Cultures TO THE EDITOR: The derivation of hairy cells is unsettled because arguments can be put forward for both monocytic and lymphocytic origins. In a recent report ( 1 ) , lymphocytic derivation of hairy cells was suggested on the basis of short term in-vitro cultures of these cells. However, established long-term cultures of hairy cells are available (2), and these cells behave like lymphoid cells of B lineage. These cells stain for surface immunoglobulin IgG, are positive for tartrate-resistant acid phosphatase, and contain herpes virus particles resembling those of the EpsteinBarr virus (Figure \A). In addition, these cells have unusually long and numerous surface villi (Figure IB). Human lymphocytes have receptors for the Epstein-Barr virus; thus it is essential to identify the virus carried by our cell line. Preliminary studies suggest that a convalescent serum from a patient with recent infectious mononucleosis did stain the cytoplasm, or nuclei, or both of the cultured hairy cells in an indirect immunofluorescent assay, but another serum from a physician recovering from "cytomegalovirus mononucleosis" did not. Because the fluores-

Figure 1 . Left. Intranuclear and cytoplasmic (in groups of three or more) herpes-type virus particles in a hairy cell cultured from the spleen of a patient with leukemic reticuloendotheliosis. (Electron microscopy; original magnification, X 36 000.) Right. Numerous surface villi of lymphoid cells cultured from the spleen of a patient with leukemic reticuloendotheliosis. (Electron microscopy; original magnification, X 15 000.) 532

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Chronic Granulocytic Leukemia: Hypokalemia in Acute Blastic Crisis

cent antihuman globulin immune serum fluoresces with the membranes of hairy cells due to immune globulin production by the hairy cells themselves, further tests are needed to identity definitively the herpes type virus carried by these cells. Other investigators have observed type A oncornaviruslike particles in plasma cells obtained directly from patients with hairy cell leukemia ( 3 ) . We have seen tubuloreticular structures in the cultured hairy cells, but oncornavirus particles have not as yet been discovered in our preparations. Because it is quite easy to culture B lymphocytes from the spleens of patients with various lymphoproliferative diseases ( 4 ) , it is possible that our cell line does not represent the malignant clone. We plan to inoculate nude athymic mice with our cell line. B lymphocytes grown from the spleens of patients with lymphoproliferative diseases other than leukemic reticuloendotheliosis (hairy cell leukemia) do not have the unusually long and numerous surface villi that our cultured cells have, but they produce immune globulins and are often infected with a herpes type virus ( 4 ) .

TO THE EDITOR: Mir and associates (1) noted the presence of hypokalemia (serum K, < 3.5 meq/litre) at some stage of the disease in 59% of 32 consecutive cases of acute myeloid leukemia and its variants. However, this abnormality has not been reported in chronic granulocytic leukemia. Recently, we have observed two patients with chronic granulocytic leukemia who developed hypokalemia during the acute blastic crisis. Their clinical features and laboratory data are summarized in Table 1. The mechanism of the hypokalemia associated with acute myeloid leukemia and its variants has not been fully elucidated. By balance studies, Muggia and co-workers (2) first showed that the hypokalemia is mainly due to inappropriate renal potassium loss and suggested a renal tubular dysfunction caused by hyperlysozymuria. However, Mir and associates (1) failed to find any correlation between the serum and urinary lysozyme values and the hypokalemia. Mir and Delamore (3) reported that a high proportion of patients with acute myeloid leukemia, irrespective of lysozyme concentrations, developed proximal tubular dysfunction that resulted in incomplete reabsorption of urate and phosphate, hypouricemia, and aminoaciduria. Kosmidis, Jamsek, and Axelrod (4) studied a patient who had acute myelomonocytic leukemia associated with severe and persistent hypokalemia and disclosed that an intracellular redistribution rather than urinary loss of potassium was the major cause of the hypokalemia. Mir and Bobinski (5) showed that the plasma of patients with acute myeloid leukemia has a strong effect on NaVK + transport in the erythrocyte membrane. A similar substance might be responsible for the disordered K+ transport in the renal tubules. Rarely, hypokalemia associated with striking muramidasuria may occur in patients with polycthemia vera and agnogenic myeloid metaplasia terminating in acute leukemia. However, hypokalemia has not been reported in

JOSEPH G. SINKOVICS, M.D., F.A.C.P. FERENC GYORKEY, M.D. PHYLLIS GYORKEY, B.S. CHIU-HWA WANG, M.D.

The University of Texas System Cancer Center, M.D. Anderson Hospital and Veterans Administration Hospital Houston, TX 77030 REFERENCES

1. GOLDE D W , Q U A N SG, C L I N E M J : Hairy cell leukemia: in-vitro culture studies. Ann Intern Med 85:78-79, 1976 2. SINKOVICS J G , W A N G

CH,

GYORKEY

F:

Hairy

cells in

culture.

Lancet 1:749-750, 1975 3. PEDIO G, R U T T N E R J R , SPYCHER M A , et al: Virus-bearing plasma

cells in peripheral blood of a patient with "hairy cell" leukemia. Acta Haematol 54:297-305, 1975 4. W A N G C H , SINKOVICS J G , K A Y H D , et al: G r o w t h of

permanent

lymphoid cell cultures from h u m a n source: tenth anniversary. Tex Rep Biol Med 33:213-250, 1975

Table 1 . Clinical Features and Laboratory Data in Two Cases of Chronic Granulocytic Leukemia With Hypokalemia*

Case 2

Case 1 At Onset 12/73 Palpable hepatomegaly, cm Palpable splenomegaly, cm Hemoglobin, g/dl Leukocytes, 103/mm* Platelets, 103/mm3 Bone marrow blasts, % Ph1 chromosome LAP score Serum Bi2, pg/ml Blood urea nitrogen, mg/dl Arterial blood pH Serum K, meq/litre Serum Na, meq/litre Serum lysozyme, ng/ml] Urine lysozyme, mg/24 /zf Diuretics Chemotherapy Antibiotics Daily KC1 supplement, intravenously, meq

Chronic 12/74

2 0 5 0 13.2 18.4 103.8 7.1 562.0 190 3.0 4.0 Pos Pos 5 ... > 20 000 ... 14 14 . . . . . . 4.6 4.5 141 140 ... ... ... ... No No No Busulfan No No No No

Blastic Crisis 3/75

At Onset 3/71

Chronic 6/74

Blastic Crisis 8/74

5 4 5.8 32.6 63.0 63.0 Pos 33 818 13 7.42 2.8 134 5.4 1.6 No OAP Kf, Gm, Car 80

2 0 9.6 90.0 30.0 10.0 ... ... ... ... ... ... ... ... ... No No No No

0 0 10.5 39.6 105.0 4.0 ... 50 1550 16 ... 4.1 139 ... ... No Melphalan No No

0 0 9.0 0.8 48.0 66.0 Neg 801 24 7.45 3.1 128 5.6 2.76 No OAP Kf, Gm 60-90

* Pos = positive; Neg = negative; OAP = vincristine, cytosine arabinoside, and prednisone; Kf = cephalothin; Gm = gentamicin; Car = carbenicillin. t Normal values: for serum lysozyme, 4 to 12 ng/ml; for urine lysozyme, < 3 mg/24 h. Comments

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533

chronic granulocytic leukemia with acute blastic crisis. Our two cases had no diuretic administration, vomiting, diarrhea, or renal disease to account for the hypokalemia. The normal serum and urine lysozyme values support the observation by Mir and colleagues (1) that factors other than hyperlysozymuria contribute to the development of hypokalemia in leukemia. Our patients did receive cephalothin and gentamicin, one with and one without carbenicillin; these antibiotics may rarely cause hypokalemia. However, this exposure to antibiotics cannot explain the hypokalemia, because Mir and associates had observed that hypokaluria and hypokalemia occurred in patients with acute myeloid leukemia who did not receive these antibiotics and persisted in others despite the withdrawal of antibiotics. We believe that there are unexplored factors that may cause hypokalemia in acute myeloid leukemia as well as in acute blastic crisis of chronic granulocytic leukemia. KAI-YlU YEUNG, M.D., F.A.C.P., F.R.C.P.(c) Hematology-Oncology Section Veterans Administration Center Hampton, V A 23667 A R T H U R A. T R O W B R I D G E , M.D.

Hematology-Oncology Section Scott and White Clinic Temple, T X 76501 REFERENCES 1. M I R MA, BRABIN B, TANG OT, et al: Hypokalemia in acute

myeloid leukaemia. Ann Intern Med 82:54-57, 1975 2. 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 3. MIR MA, DELAMORE 1W: Hypouricaemia and proximal renal tubular dysfunction in acute myeloid leukaemia. Br Med J 3: 775-777, 1974 4. KOSMIDIS P, JAMSEK M, AXELROD AR: Hypokalemia in leukemia

(letter). Ann Intern Med 82:854-855, 1975 5. MIR MA, BOBINSKI H: Altered membrane sodium transport and the presence of a plasma ouabain-like inhibitory factor in acute myeloid leukaemia. Clin Sci Mol Med 48:213-218, 1975

Creatinine Clearance and Age TO THE EDITOR: Rowe and colleagues are fortunate to have the Baltimore Longitudinal Study of Aging (BLSA) available to provide the data from which to construct the ageadjusted standards for creatinine clearance {Ann Intern Med 84:567-569, 1976). This is a unique population of middle-class, well-educated male volunteers who receive regular medical care and who are, in addition, concerned enough about the study of aging phenomena to adhere faithfully to various protocols. However, before the published nomogram finds routine use by other health professionals, several caveats deserve emphasis. Because the function of a body system such as the urinary tract depends on a complex nexus of both genetic and environmental factors, individuals or populations under sufficiently divergent genetic and environmental influences may have significantly different renal function. Thus, renal function within the bounds of "normal" in a given population may be considered "abnormal" in another, even though both populations are "healthy," The BLSA shows a high degree of genetic (race and sex) and environmental (economic and educational and, by inference, nutritional) homogeneity. Plotting the creatinine clearance and the age of nonwhite, economically disadvantaged women could yield a markedly different nomogram. Malnutrition, for 534

example, of a degree resulting in hypoproteinemia, is associated in most studies with a reduction in glomerular filtration rate ( 1 ) . The following comments touch on dilemmas common to much gerontologic research but which, nonetheless, must be acknowledged in relation to this study of Rowe and associates. Because disorders of diverse organ systems may affect renal function as measured by creatinine clearance, these investigators have attempted to isolate the effect of aging by including only participants from the BLSA who satisfy certain prerequisites. Having screened their population by means of routine noninvasive procedures, the resulting study group is declared "normal." While the testing described could only be expected to uncover "overt abnormalities" in organ system function, the authors apparently believe these methods insufficient when applied in other studies. If "debilitated, chronically ill" subjects can pass this battery of screening tests and have no "overt abnormalities" of renal function, then why cannot such populations be termed "normal" as well? This raises a more fundamental issue. In attempting to exclude abnormalities, screening tests as well as the history and physical examination rely on arbitrary limits for specifying the abnormal, defined in part by the distribution of data within a population as well as the sensitivities of the tests. Two conclusions follow. First, some of the men whose creatinine clearances were used to create the nomogram do have significant renal, cardiovascular, and other organ disease that statistically escaped detection. Second, since hardly any noninvasive test is sufficiently sensitive to detect microscopic subclinical disease, many of the study participants could and likely do harbor many of the cellular and organ changes we associate with various diseases. The creatinine clearance is then seen to be a function not only of "aging" but also of a complex summation of subclinical pathologic alterations—unless, of course, one chooses to define these changes as being part of the aging process itself. Either way, we have to assume that subclinical changes, present in some but not all organs and individuals, will contribute to a decline in renal function. If more sensitive and specific screening procedures were used to isolate a "normal" population within the BLSA, the resulting creatinine clearance versus age nomogram might be different from the one published. The results of Rowe and co-workers may be proved to be generally applicable and useful; however, the theoretical and practical criticisms described here should be recognized by those using the nomogram. I acknowledge enlightening discussions of these issues with Drs. H. S. Solomon and B. M. Brenner. R E E D E. P Y E R I T Z , M.D., PH.D.

Department of Medicine Peter Bent Brigham Hospital Boston, M A 02115 REFERENCE

1. KLAHR S, ALLEYNE GAO: Effects of chronic protein-calorie malnutrition on the kidney. Kidney Int 3:129-141, 1973

In comment: Dr. Pyeritz raises issues that are relevant not only to our study but also to most medical literature. Population selection and description is a source of concern for all investigators working with animals or human subjects. N o one

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would hold that results from one population are necessarily applicable to a group with different genetic or environmental composition. Nevertheless, we require standards, and these cannot practically be determined on all groups. Investigators and clinicians must consider how their subjects and patients compare with the population on which standards are based and decide whether important differences exist. The responsibility of those who provide the normative data is thus clear. We must describe in detail the population on which the data are based so that the appropriate comparisons can be made. We have described our population extensively, not only in our recent paper, but to even greater detail previously (Reference 3, by Stone and Norris, in our "Annals" paper). We do not claim general applicability for our results but simply present normative data based on a well-described population and hope clinicians and investigators find our nomogram useful. Dr. Pyeritz goes on to deal with a very familiar problem. Clinical investigators are aware of the issue of separating normal from abnormal. Gerontologists and, we hope, other clinical investigators are sensitive to the need to separate normal aging from concurrent disease. The accomplishment of this difficult task is ultimately based on arbitrary decisions. We have attempted to screen our subjects thoroughly to clarify the presence or absence of disease. Our efforts in this area have a major advantage over those made in previous studies of the influence of age on renal function. In our longitudinal study each subject has been seen an average of four times. This means four complete histories, four physical examinations, four glucose tolerance tests, four exercise tolerance tests, and so on. We agree that the limitation of the application of invasive techniques to normal subjects may lead to failure to classify some disease as well as some subclinical changes. However, repeated observations of an individual and application of diverse screening procedures designed to determine the presence of disease have provided a better classification than is usually available. Interestingly, Dr. Pyeritz could have directed his letter to any of a large number of papers. It is instructive to review just the issue in which our paper appeared. Of the 12 major articles or brief communications in that issue, eight dealt with normal subjects or normal ranges for data. Three of these presented data for "normal" or "healthy" subjects without note of the source of the subjects or any details of their selection. Two of the papers presented "normal" ranges for their data without any reference to the source of their normal ranges. JOHN W. R O W E , M.D. REUBIN ANDRES, M.D. JORDAN D. TOBIN, M.D. ARTHUR H. NORRIS, M.S. NATHAN W. SHOCK, PH.D.

Gerontology Research Center National Institute on Aging National Institutes of Health at the Baltimore City Hospitals Baltimore, MD 21224 TO THE EDITOR: In a recent paper in this journal Rowe and associates (1) comment on our proposal (2) for predicting an individual's endogenous creatinine clearance from his age, sex, body weight, and serum creatinine concentration. They state that the creatinine clearance cannot be reasonably predicted because of the great variation in the urinary excretion of creatinine per 24 h even among individuals of the same sex and age group.

It is well known that the excretion of urinary creatinine shows a large variation. However, the influence of this variation may be minimized, as there often exists a positive correlation between the urinary excretion of creatinine and the serum creatinine concentration for a fixed glomerular filtration rate. This may in part explain the acceptable correlation that has been reported in several recent papers between the measured values of creatinine clearance and the values predicted from our nomogram (3-5). No computations can ever completely take the place of correct measurement of a biological variable, but our nomographic method of predicting endogenous creatinine clearance has been useful in several drug-dosing situations, excluding those where patients with severe uremia or cardiac failure, marked obesity, or muscular abnormalities are considered (6,7). The authors present a nomogram for ascertaining ageadjusted percentile rank in endogenous creatinine clearance without paying attention to the variation in serum creatinine in the normal concentration range. No validation of the nomogram is given, as the authors do not include an independent comparison between measured and predicted values of creatinine clearance. It has yet to be proved that a nomogram disregarding body weight and serum creatinine is superior to methods including these variables. JENS P. KAMPMANN, K A J SIERSBAEK-NIELSEN, JENS M 0 L H O L M HANSEN, MOGENS KRISTENSEN, Clinical Pharmacology-Toxicology Center University of Kansas Medical Center Kansas City, KS 66103 and Medical Department E, Frederiksberg Hospital, Medical Department F, Herlev Hospital and Medical Department, Diakonissestiftesen Copenhagen, Denmark REFERENCES 1. Row JW, ANDRES R, TOBIN JD, et al: Age-adjusted standards for creatinine clearance. Ann Intern Med 84:567-569, 1976 2. SIERSBAEK-NIELSEN K, M0LHOLM HANSEN J, KAMPMANN JP, et al: Rapid evaluation of creatinine clearance. Lancet 1:1133-1134, 1971 3. JELLIFFE RW: Creatinine clearance: bedside estimate. Ann Intern Med 79:604-605, 1973 4. COCKCROFT DW, GAULT MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 5. DOBBS SM, MAWER GE, RODGERS EM, et al: Can digoxin dose requirements be predicted. Br J CJin Pharmacol 3:231-237, 1976 6. CHRISTIANSEN NJB, K0LENDORF K, SIERSBAEK-NIELSEN K, et al: Serum digoxin values following a dosage regimen based on body weight, sex, age and renal function. Acta Med Scand 194:257259, 1973 7. LUMHOLTZ B, KAMPMANN JP, SIERSBAEK-NIELSEN K, et al: Dose regimen of kanamycin and gentamicin. Acta Med Scand 196: 521-524, 1974

In comment: Several points made by Dr. Kampmann and colleagues suggest that they require clarification of the computation of creatinine clearance and the construction and purpose of our nomogram. Three major points deserve comment. 1. They state that "there often exists a positive correlation between the urinary excretion of creatinine and the serum creatinine concentration for a fixed glomerular filtration rate." This is really a tautomerism. Any renal clearComments

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ance is computed as urinary excretion, divided by plasma concentration, ( U V / P ) ; thus if clearance is fixed, UV and P must vary in exactly equal proportions. It is impossible for them ever to disagree under this condition. There is nothing in the computation of clearance, however, that validates attempts such as Dr. Kampmann and colleagues espouse to predict one of these variables (creatinine clearance) based on a knowledge of another variable (serum creatinine) without measuring the third variable (creatinine excretion) if the third variable is not constant. We have shown by our previous analysis of Dr. Kampmann's own data that there is considerable variation in creatinine excretion. 2. Dr. Kampmann's criticism that our nomogram "was constructed without paying attention to the variation in serum creatinine" and that we disregarded "body weight and serum creatinine" is simply incorrect. We presented a nomogram for standard clearance (ml/1.73 m 2 • min) that was constructed for individually computed clearances on 548 subjects. The data used to compute each clearance are, of course, 24-h urinary creatinine excretion, serum creatinine concentration, height and weight (from which surface area was computed). 3. Dr. Kampmann states that we do not provide validation of our nomogram, that is, a comparison of measured and predicted creatinine clearance values. We point out that our nomogram does not represent a prediction of creatinine clearance but is a mathematical expression of the actual data we collected on our subjects. The purpose of our nomogram is to determine the age-adjusted percentile rank of a patient once age and creatinine clearance are known. JOHN W. R O W E , M.D. REUBIN ANDRES, M.D. JORDAN D. TOBIN, M.D. ARTHUR H. NORRIS, M.S. NATHAN W. SHOCK, PH.D.

Gerontology Research Center National Institute on Aging National Institutes of Health at the Baltimore City Hospitals Baltimore, MD 21224

Urinary Dilution in Hyponatremia TO THE EDITOR: DeFronzo, Goldberg, and Agus have expanded on the question of the osmostat with an interesting study on urinary dilution in hyponatremia (Ann Intern Med 84:538-542, 1976). There are three points that I should like them to clarify. Was an attempt made to correct the hyponatremia with a low sodium diet and KC1? Laragh (authors' reference 18) studied normokalemic hyponatremic subjects with a variety of diagnoses who corrected to normal serum sodium concentrations when fairly modest potassium deficits were replaced. The reduction in creatinine clearances (75, 82, 95, and 99 ml/min) and the overnight maximal urinary concentrations (560, 602, 606, and 685 mosmol/kg) could possibly be a consequence of potassium depletion. The data on arginine vasopressin radioimmunoassay need some clarification. In the article by Robertson and co-workers (author's reference 6 ) , the arginine vasopressin levels were higher in normals than in the present Patient 2. In Robertson's Figure 8, nine observations were made in normal subjects with urine osmolalities between 500 and 536

700 mosmol/kg. Recalculating from their Figure 8, the mean arginine vasopressin concentration was 2.62 ± 0.51 (SD) pg/ml; the level in Patient 2, 1.48 pg/ml, was more than two standard deviations below the mean of these nine observations. Patient 2 may have an abnormal sensitivity to arginine vasopressin leading to prolonged hyponatremia rather than a reset osmostat or the syndrome of inappropriate secretion of antidiuretic hormone ( A D H ) . Correction with fluid restriction is a hallmark of the syndrome of inappropriate secretion of ADH. It would have strengthened the authors' argument if they had demonstrated persistent hyponatremia with a fall in body weight and an increase in urinary osmolality during fluid restriction. This maneuver together with the tests of urinary dilution would have further helped to rule out the syndrome of inappropriate secretion of ADH. Have they water-restricted any of these subjects? MARK A. NEEDLE, M.D.

Department of Medicine St. Joseph's Hospital and Medical Center Paterson, NJ 07503

In response: First, as discussed in our paper (page 540), we acknowledge and discuss the possibility that potassium depletion with a resultant shift of sodium into cells could play some role in the development of the hyponatremia. It is unlikely that the reduction in creatinine clearance observed in our subjects was secondary to potassium deficiency since such changes have been observed only after severe, long-standing potassium deficiency and have been associated with significant hypokalemia ( 1 ) . None of our patients received any supplemental potassium during their hospitalization and at no time were they noted to be hypokalemic. The modest decrease in urinary concentrating ability is most likely secondary to the well-described effect of protein malnutrition and decreased medullary urea content ( 2 ) . Second, plasma arginine vasopressin levels differ considerably among individuals, and we have not infrequently observed normal subjects with arginine vasopressin levels of 1.5 ng/ml (unpublished observations). Furthermore, it is unlikely that abnormal sensitivity to arginine vasopressin alone could lead to prolonged stable hyponatremia. As water was retained, the resultant serum hypotonicity would be expected to inhibit antidiuretic hormone (ADH) release and return the serum osmolality and sodium concentrations to normal as long as the osmoreceptor itself was intact. Furthermore, one would expect to see an exaggerated response to arginine vasopressin after its elevation with hypertonic saline; such was not the case in the two patients so tested. Third, fluid intake was not restricted in our patients, and we believe that the response would not have helped to exclude the syndrome of inappropriate secretion of ADH. Any subject (including normals, patients with a reset osmostat, and those with the syndrome of ADH) would be expected to develop an increase in serum sodium concentration with water deprivation if the free water intake is less than electrolyte free water excretion.

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RALPH D E F R O N Z O , M.D.

Department of Medicine Yale University School of Medicine New Haven, CT 06510

Z A L M A N S. A G U S , M . D .

Department of Medicine University of Pennsylvania School of Medicine Philadelphia, PA 19104 REFERENCES 1. SCHWARTZ WB, RELMAN AS: Effects of electrolyte disorders on

renal structure and function. N Engl J Med 276:383-389, 1967 2. JAMISON RL: Urinary concentration and dilution, in The Kidney, edited by BRENNER BM, RECTOR FC. Philadelphia, W. B. Saun-

ders Co., 1976, pp. 429-433

Rhabdomyolysis and Renal Failure TO THE EDITOR: In light of the patient population at San Francisco General Hospital, we read with interest the recent article on renal failure and rhabdomyolysis by Koffler, Friedler, and Massry (Ann Intern Med 85:23-28, 1976). The magnitude of hyperuricemia is an aspect of this syndrome we have seen in several patients. The mechanism postulated by the authors for the elevated serum level, that is, "increased liberation of adenine nucleotides by muscle," is plausible in view of a concomitant 24-h hyperuricosuria in patients with heat stress, exercise, and muscle injury as described by Knochel, Dotin, and Hamburger ( 1 ) . Elevated urinary excretion of uric acid was not documented in the study by Koffler and associates. Although there does not appear to be a perfect reciprocal relationship between serum bicarbonate and uric acid levels in their study, the possibility of underlying metabolic acidosis and organic acidemia affecting urate excretion should be considered. Without objective proof of hyperuricosuria and without verification of normal hepatic purine metabolism, the authors cannot exclude the possibility of organic acid inhibition of urate excretion. The last phenomenon is well recognized in other clinical settings of metabolic acidosis, that is, ketoacidosis (2) and lactic acidosis ( 3 ) . The authors mention that elevated uric acid levels were not found in a population of patients with nonmyoglobinuric acute renal failure; it would be of interest to know whether or not these patients had evidence of metabolic acidosis. We suggest that the hyperuricemia seen with renal failure in association with rhabdomyolysis can be explained by at least two mechanisms: increased purines from muscle breakdown and organic acid inhibition of renal secretion of uric acid. MARK D. FISCHER, M.D.

lation of organic acids can interfere with uric acid secretion by the kidney and, hence, contribute to hyperuricemia. However, we would like to remind Drs. Fischer and Williams that the hyperuricemia in our patients occurred when they were in the oliguric phase of acute renal failure. At this state of the disease both glomerular filtration and tubular functions are extremely impaired. It is, therefore, reasonable to assume that impairment in renal uric acid secretion by organic acids did not contribute substantially to the hyperuricemia in our patients. Furthermore, patients with acute renal failure of other causes have similar acidosis without marked hyperuricemia. ALAN K O F F L E R , M.D. ROBERT M. FRIEDLER, M.D. SHAUL G. MASSRY, M.D.

Division of Nephrology University of Southern California School of Medicine Los Angeles, CA 90033

Data on Therapy in Lupus Nephritis TO THE EDITOR: The article by Hahn, Kantor, and Osterland (1) in the November 1975 issue does not quote accurately the results of a study by Cade and associates ( 2 ) . Dr. Hahn states that Cade's data failed to demonstrate improvement in overall survival with combination azathioprine and prednisone compared with prednisone alone. This point is restated in a reply to my letter in the March 1976 issue. I refer the readers of this journal to Table I in the article by Cade and colleagues ( 2 ) , which clearly shows that the group receiving prednisone alone had 13 deaths out of 15 patients (86% mortality), while the group receiving prednisone plus azathioprine had six deaths out of 13 patients (46% mortality). GARY S. H O F F M A N , M.D., MC

Letterman Army Medical Center Presidio of San Francisco, CA 94129 REFERENCES 1. HAHN BH, KANTOR OS, OSTERLAND CK, et al: Azathioprine plus

prednisone compared with prednisone alone in the treatment of systemic lupus erythematosus. Report of a prospective controlled trial in 24 patients. Ann Intern Med 83:597-605, 1975 2. CADE R, SPOONER G, SCHLEIN E, et al: Comparison of azathio-

prine, prednisone and heparin alone or combined in treating lupus nephritis. Nephron 10:37-56, 1973

HIBBARD E. WILLIAMS, M.D.

Medical Service San Francisco General Hospital and Department of Medicine University of California San Francisco, CA 94110 REFERENCES 1. KNOCHEL JP, DOTLIN LN, HAMBURGER RJ: Heat stress, exer-

cise, and muscle injury: effects on urate metabolism and renal function. Ann Intern Med 81:321-328, 1974 2. LECOCQ FR, MCPHAUL JJ J R : The effects of starvation, high fat

diets, and ketone infusions on uric acid balance. Metabolism 14: 186-197, 1965 3. STEELE TH: Control of uric acid excretion. N Engl J Med 284: 1193-1196, 1971

In comment: We certainly agree that acidosis secondary to the accumu-

Lysozyme from Bone? TO THE EDITOR: In a recent letter to this journal, Goldstein and colleagues (1) reported the occurrence of elevated serum lysozyme activity in hypercalcemic patients. Because increased serum lysozyme activity has previously been described in animals injected with either parathyroid extract (2) or vitamin D ( 3 ) , and because we have encountered a similar phenomenon in man, we welcome this documentation in the literature. On the basis of experimental studies, the authors suggest that this may be due to the selective release of lysozyme from leukocytes caused by elevated concentrations of ionized calcium. This hypothesis is both reasonable and well founded. There is, however, an equally plausible explanation that could at least partly account for the inComments

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creased serum lysozyme activity. Lysozyme is not restricted to blood cells. Indeed Fleming, who discovered lysozyme, found that cartilage contained more of this substance than any other tissue ( 4 ) . Chondrocytes synthesize lysozyme and rapidly export it to the extracellular space without significant storage in intracellular granules ( 5 ) . There are temporal changes in serum and tissue lysozyme activities in animals injected with parathyroid extract, suggesting the increment in serum activity is of skeletal origin ( 2 ) . Thus, an alternative or additive source in hypercalcemic patients could be the skeleton. If this is so, increased lysozyme activities would be expected in normocalcemic patients with rapid skeletal turnover. In this regard, we have found in very preliminary studies of a few patients that elevated serum lysozyme activity may be present in patients with very active Paget's disease without hypercalcemia and in chronic dialysis patients with secondary hyperparathyroidism and hypocalcemia. REUBIN EISENSTEIN, M.D.

Northwestern Memorial Hospital Chicago, IL 60611 KLAUS E. K U E T T N E R , PH.D.

Rush Medical College Chicago, IL 60612 REFERENCES 1. GOLDSTEIN IM, HORN JK, KAPLAN HB, et al: Hypercalcemia: a

possible cause for elevated serum lysozyme levels. Ann Intern Med 84:445-446, 1976 2. WOLINSKY I, COHN DV: Bone lysozyme: partial purification, properties, and depression of activity by parathyroid extract. Nature 210:413-414, 1966 3. EISENSTEIN R, SORGENTE N, ARSENIS C, et al: Vitamin D effects

on tissue and serum lysozyme. Arch Pathol 94:479-485, 1972 4. FLEMING A, ALLISON VD:

Bacteriolytic substance

(lysozyme)

found in secretions and tissues. Br J Exp Pathol 3:252-260, 1922 5. KUETTNER KE, EISENSTEIN R, SORGENTE N : Lysozyme in calcify-

ing tissues. Clin Orthop 112:316-339, 1975

Asthma, Steroid Therapy, Isoniazid TO THE EDITOR: In a recent paper in this journal, Schatz and associates (1) suggest that routine isoniazid preventive therapy for asthmatics on steroids be dispensed with. While their aim is laudable in that the actual relation of steroid treatment to tuberculous disease does need to be proved and quantified, the data acquisition, study design, control, and interpretation of data do not provide an adequate basis for their conclusions or recommendations. Asthmatics were skin tested by the Mantoux technique with self-reading. Self-reading, however, has never been validated for the Mantoux test. The authors state, "Although this approach may not be as accurate as physician reading of the skin test, this method has proved to be reliable," citing Magbool, Asnes, and Grebin ( 2 ) . This reference, however, considers only pediatric self-reading with the Lederle self-reading card. This is an entirely different, unrelated situation. Most medical school faculty know well the difficulty of teaching house staff to read induration rather than erythema, so one would expect even less control with an inexperienced, lay population. The authors state that all patients were X rayed at some time during the study. Unless X rays are done systematically at the end of a study, no true assessment can be made about the presence of pulmonary lesions. Steroid treatment can mask symptoms of tuberculous disease ( 3 ) . To confidently assess the effect of any variable on a 538

clinical outcome, one must be aware of the expected outcome in the absence of the variable. If the variable under the study is found to be related to a significantly different outcome than expected, it is evidence of an effect. In Schatz and associates' study, patients were followed for 620 corticosteroid years of experience. It is known, however, that positive- and negative-reacting individuals are at entirely different risks of developing tuberculous disease (4), the clinical outcome, and therefore must be considered separately: Persons with negative skin tests are estimated by the Center for Disease Control to have a 0.03% per year risk of becoming infected. Those who become infected then have, in the first year after infection, risk of 4.2% of contracting manifest tuberculosis disease ( 4 ) . The incidence of becoming infected and then diseased without steroids is thus about 1.2 per 100 000 population per year. The observed 0 per 620 patient years on steroids are not enough data to warrant any conclusion about these patient's risk. In other words, patients who start out with a negative skin test, whether they are on steroids or not, with the data at hand, must be considered to be at extremely low risk of getting tuberculous disease, and studying small numbers of them is not productive. The 37 patients who had a positive skin test are in a different situation. Since persons with a positive skin test are by definition infected and are thought to have a greater chance of getting tuberculosis disease ( 4 ) , it is these patients who must be studied. Proving a negative result is difficult, but it can be approached in the following way: since there are no data as to what an expected case rate is for tuberculous disease in infected steroid recipients, a high risk situation can be assumed, and the difference between the number of cases expected in that high risk situation and the number of cases actually observed in the study situation can be assessed. A rate of 0.5% per year is considered a high risk of tuberculous-infected individuals becoming diseased ( 5 ) . Assuming that infected steroid recipients may have this 0.5% per year chance of developing tuberculous disease, and studying the 37 infected patients for an average of 5.1 years (188.7 patient years of steroid treatment), only one case of tuberculous disease in the study group would be expected. The observed frequency of 0 is well within chance for this number of observations, so a much larger population must be studied to reach any conclusions. There is no question that physicians must be able to address themselves to possible unnecessary treatment with any potentially harmful drug. Only a carefully designed prospective study, with a sufficient number of patients and with careful initial skin testing and periodic clinical and radiographic evaluations, can provide enough evidence to lead to conclusions with unknown long-term consequences that, because of their widespread distribution in a prestigious journal, may be confidently accepted and used by the medical community. L E E B. R E I C H M A N , M . D . , M . P . H . , F . A . C . P . W A Y M A N C. L A T T I M O R E , M.D. R E Y N A R D J. M C D O N A L D , M . D .

College of Medicine and Dentistry of New Jersey New Jersey Medical School Martland Medical Center Newark, NJ 07107 REFERENCES 1. SCHATZ M, PATTERSON R, KLONER R, et al: The prevalence of

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tuberculosis and positive tuberculin skin tests in a steroid-treated asthmatic population. Ann Intern Med 84:261-265, 1976 2. MAGBOOL S, ASNES RS, GREBIN B: Tine test compliance in a

clinic setting. Pediatrics 55:338-391, 1975 3. EDITORIAL: Deleterious affect of ACTH and cortisone on tuberculosis. N Engl J Med 245:662-664, 1951 4. EDWARDS PQ: Screening for tuberculosis. Chest (suppl) 68:451455, 1975 5. JOHNSTON RF, WILDRICK KH: "State of the Art" review. The

impact of chemotherapy on the care of patients with tuberculosis. Am Rev Respir Dis 109:641-664, 1974

should receive prophylactic isoniazid. We are recommending that the routine use in this situation be discontinued and that the decision to use isoniazid in a corticosteroidtreated asthmatic patient be individualized according to such factors as corticosteroid regimens and dosages. L T COMDR MICHAEL SCHATZ, MC, USNR

Department of Medicine Naval Regional Medical Center San Diego, C A 92134 ROY PATTERSON, M.D., F.A.C.P.

In comment: We are in sympathy with Drs. Reichman, Lattimore, and McDonald in their desire for the perfect study in this difficult area. We disagree, however, either partially or totally with their criticisms of our paper. Although self-reading of tuberculin skin tests in the manner used in our study has not specifically been validated, we believe that the article of Magbool, Asnes, and Grebin (1) to which they and we referred validates the concept of self-reading and is thus applicable to our data. Moreover, the very significant association in our study of tuberculin-positivity with increased age, a finding that exists in the general conventionally tested population, tends to indirectly validate our methods. Our data were collected over several months. It was during this period of time, generally at the same time that the individual skin test and clinical data were obtained, that chest X rays were done on all patients. We submit that this data does allow a "true assessment. . . about the presence of pulmonary lesions." Moreover, the article to which they referred that suggested that corticosteroid treatment could mask symptoms of tuberculous disease (2) did not suggest that corticosteroids could mask the radiologic manifestations. We agree that, if tuberculin reactivity were known before starting corticosteroid treatment, our patients with negative skin tests would be subject to different risk analysis than our patients with positive skin tests. However, because many of our patients were on corticosteroid therapy when initially seen, and because all of them needed continuous corticosteroid therapy for their clinical wellbeing, we are not certain which or how many of our patients were truly not previously infected and which had their evidence of such prior infection suppressed. We do not agree that patients with negative skin tests due to corticosteroid suppression have the same low risk of developing tuberculosis as to untreated patients with negative tests. As we have stated previously in this section ( 3 ) , the data suggesting an interrelation between steroid regimens that preserve cell-mediated immunity and the risk of infection may indicate that these suppressed patients are even at a higher risk of developing active tuberculosis than are our patients with positive skin tests. Thus, we do not believe the risk analysis suggested by Drs. Reichman, Lattimore, and McDonald is appropriate for interpreting our data. We certainly agree that further prospective studies are necessary and that optimal clinical practice must be based on the best clinical data possible. However, we believe that neither our data nor the data presently in the literature support the routine use of isoniazid in steroid-treated asthmatics, when its potentially serious and not uncommon side effects are considered. We again emphasize that we are not saying that no corticosteroid-treated asthmatic

Department of Medicine Northwestern University Medical School Chicago, IL 60611 REFERENCES 1. MAGBOOL S, ASNES RS, GREBIN B: Tine test compliance in a

clinic setting. Pediatrics 55:388-391, 1975 2. EDITORIAL: Deleterious effect of ACTH and cortisone on tuberculosis. N Engl J Med 245:662-664, 1951 3. SCHATZ M, PATTERSON R: Tuberculosis and isoniazid in steroid-

treated asthmatic patients. Ann Intern Med 85:129, 1976

Rifampin-Amphotericin B Synergism? TO THE EDITOR: I have read with interest the "Drugs Five Years Later" paper on rifampin by Dr. Sanders in the July 1976 issue (Ann Intern Med 85:82-86, 1976). With reference to his perhaps incomplete statements regarding the use of rifampin with amphotericin B in the treatment of fungal diseases in man, I wish to call attention to a paper from our group. The point made in the last sentence of the abstract (excerpted below) of that paper may be pertinent to use of rifampin: A case of disseminated histoplasmosis resembling miliary tuberculosis is reported from a geographic area in which tuberculosis of all types is common but histoplasmosis unusual. The source of the infection is uncertain; although the patient traveled through areas in which histoplasmosis is endemic, he also self-injected narcotics of unknown purity. . . . Treatment included amphotericin B together with antituberculosis drugs. Our patient left the hospital apparently cured before receiving one third of the recommended dose of amphotericin B, raising the possibility that concomitant rifampin medication might have acted synergistically. I have added the italics for emphasis. L. F R E D AYVAZIAN, M.D., F.A.C.P.

Veterans Administration Hospital East Orange, NJ 07019 Methyl Iodide Toxicity TO THE EDITOR: The case report of methyl iodide intoxication by Appel and colleagues (Ann Intern Med 82:534536, 1975) is a useful description of a complex illness, all of the features of which were apparently due to the agent cited. Some current and future readers may find the report confusing, however, in its mention of congestive changes in the lungs as a characteristic of poisoning with methyl iodide, as stated in the report's abstract. Such characterization is not well supported by the references cited by the authors, and not at all by the case summary. We are further puzzled in that the summary presents findings of a marked respiratory alkalosis, in a patient who was Comments

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otherwise lethargic. Was alveolar hyperventilation due to lung damage not evident by the usual clinical, laboratory, and roentgenographic criteria? Was lung damage present at all? If not, does methyl iodide (or a metabolite) stimulate respiratory neurons, while depressing cerebral and cerebellar cortical function? We leave this case report unconvinced that pulmonary congestion is a hallmark of methyl iodide intoxication, but would welcome any additional information in support of such a view. ORR M. COBB, M.D. LAWRENCE W. RAYMOND, M.D., F.A.C.P.

Pulmonary Branch, Department of Internal Medicine National Naval Medical Center Bethesda, MD 20014 Publication of this letter was delayed by loss in the mails of its first copy to the Editor.

linoleic acid ( 2 ) . This fact accounts for the use of the a) 9-C 20:3/a) 6-C 20:4 ratio as an index of essential fatty acid deficiency ( > 0.4) ( 2 ) . Further, in none of Connor's experimental subjects did the plasma C 2 0 : 3 / c 20:4 ratio exceed 0.4 at 14 days. We can draw on our own experience (4-6); we have followed in two patients cycles of development and regression of essential fatty acid deficiency during 8- and 3-year periods while maintaining the patients on total parenteral nutrition (5, 6 ) . In these patients, though early biochemical changes occurred in the plasma, they were not detectable clinically. However, once they became depleted, clinical manifestations appeared within days of institution of a fat-free regimen. We do not oppose the principle of preventive nutritional practice, but we do protest the overinterpretation of the data and the panic consequent in the absence of more convincing evidence at a structural or functional level. RICHARD C. BOZIAN, M.D., F.A.C.P. JOSEPH L. PIEPMEYER, R.D.

Division of Nutrition Department of Medicine University of Cincinnati College of Medicine Cincinnati, OH 45267

Fatty Acid Deficiency TO THE EDITOR: We write to comment on Dr. William Connor's editorial on essential fatty acid deficiency in man {Ann Intern Med 83:895-896, 1975). In another paper (1) Dr. Connor and his associates report the appearance of essential fatty acid deficiency immediately upon initiating a fat-free regimen in healthy subjects, orally or parenterally, and consider the syndrome a common and significant clinical problem. In that study there was an early decrease in linoleic and arachidonic acids (^ 6 acids)* with increased eicosatrienoic, oleic, and palmitoleic acids ( w 9 acids)* in plasma cholesterol esters, phospholipids and triglycerides. Whereas the phospholipid arachidonate levels did decrease in the first 2 weeks, they rose in the next 14 days even though the fat-free regimen was continued. A distinction must be made between a deficient intake and a deficiency state: essential fatty-acid deficiency syndrome is seen in growing animals and children or adiposedepleted adults on a fat-free regimen. On the other hand, changes in the experiments cited are the reflection of a changing fuel mixture in the plasma compartment: a compartment with component half-lives measured in minutes to hours, which is in equilibrium with cellular membranes, organelles, and tissues with half-lives measured in weeks and months. It presupposes further that the high insulin levels associated with the fat-free regimen shuts off completely the process of lipolysis with its large supply of linoleic acid. The shut-off is in reality a net decrease and not an absolute change; lipolysis continues. These plasma changes in the normal adult no more represent an essential fatty-acid deficiency state than do decreased insulin, blood sugar, and increased free fatty acids and ketone bodies represent an insulin deficiency state in fasting normal adults. By definition, linoleic acid is an essential nutriment because it is not synthesized by the organism, but it is biochemically essential by virtue of its role as a precursor of arachidonic acid, prostaglandins, and longer chain polyenoic acids; all membranes of the