COMMENTS AND CORRECTION
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. Unapproved Uses of Drugs TO THE EDITOR: All my enthusiasm for the excellent article "Naloxone" by Dr. Martin in the December issue {Ann Intern Med 85:765-768, 1976) evaporated when I came to the words "unapproved uses." Why is this admonition included? Does this imply that I should not use the drug, permitting a patient to die and be guilty of murder? If this is so, my reading the article is an academic exercise in futility. The detail man, as well as the Physicians' Desk Reference, has given me all of the approved indications, and the practice of reading journals the past 46 years for the latest therapy has become superfluous. Does the editor have little or no trust in his judgment to select articles for publication, or is the author some scoundrel not to be trusted, and, like Pilate, the editor washes his hands of the affair and places upon me the task of making a choice for which I am not prepared? Is the editor implying that if I use the drug properly, I am guilty of some unspecified horror by not paying obeisance to the Food and Drug Administration ( F D A ) ? I will never bend my knee to anyone who makes the statement that if every physician in the United States finds a drug useful, and he dissents, his dissent overrides the findings of all of them. What ukase feeds his cacoethes [an insatiable desire] for unlimited power? Should God move over and bow to this man Crout? When the editor permits the FDA to use him, he becomes a policeman and relinquishes his objectivity as an editor. Those who bow to the dictates of the FDA do not need to read journals. The remainder care nothing for what the FDA approves or disapproves. J . G . BOHORFOUSH, M.D., F.A.C.P.
811 North Cobb St. Milledgeville, GA 31061
In comment: The role of the package insert in medicine is an important issue on which we receive many inquiries from physicians. In commenting on Dr. Bohorfoush's letter, may I quote from a previous paper on this subject ( 1 ) . Not too long ago, package inserts were wholly ignored by the medical profession, and, of course, until the New Drug Amendments of 1962 they deserved to be ignored, since most were simply promotional brochures. In the past decade, however, the scientific quality of package inserts 652
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has improved remarkably. Today, many package inserts are excellent resource documents for information not summarized elsewhere, and some are even readable! The package insert is (intended to be) a summary of the essential scientific and medical information about a drug which the physician should know in order to use the drug safely and effectively for the listed indications. The Food, Drug, and Cosmetic Act is quite clear in requiring that these indications be supported by "substantial evidence" consisting of "adequate and well-controlled trials." This means that such evidence must be obtained through systematic clinical research, and it must be presented to the FDA and be acted upon, before new information can be added to the labeling. Given this system, it is evident that a time lag will occur between the publication of studies providing substantial evidence for a claim and the actual appearance of that claim in the package insert. In other instances, a claim made in a published paper may fall by the wayside after additional studies. Poorly documented therapeutic claims are widespread in the medical literature, and it would be folly to catalogue all such "information" in the package insert If information in the package insert is based on substantial evidence, it follows that the physician can use the insert as an authoritative reference source for drug usage in the care of patients. However, as mentioned previously, it also follows that the package insert may not contain the most up-to-date information about the drug. Thus, the physician must be free to use the drug for an indication not in the package insert when such usage is part of the practice of medicine and for the benefit of the patient. When such usage is done as part of a research project on a marketed drug, however, it is still permissible but should be done under an IND. The above paragraph is completely in line with announced FDA policy on this matter. Nevertheless, there continues to be enormous concern among physicians that mere usage of a drug for an indication not in the package insert is in some way illegal and that, by itself, may open the physician to some form of legal jeopardy. This is not true, but in Government we have not yet been able to impart this message credibly to physicians. The world we want is one in which the physician welcomes a well-documented package insert because he finds it useful, and he finds it useful because the information in it is supported by substantial evidence. Such a package insert would be unique among medical documents. The physician can already ascertain from the medical literature new and interesting proposed uses for marketed drugs, and he can discover at any medical meeting the many innovative ways in which experts use drugs in patient care, some of which are not in the package insert. The physician does not need yet another document which enumerates these newer drugs. The package insert's most important educational value derives from the fact that it is a wellreviewed, authoritative document. However, to achieve this world we want, it is essential that those of us in regulatory agencies and in the legal profession not take offense at drug usage outside the package insert merely because it is occurring. We must understand how our drug labeling system works and recognize that such usage will occur as a necessary part of the practice of good medicine; and the more current the physician
is in his practice, the more often it will occur. Understanding this, we in Government and in law cannot threaten to use the package insert as a tight regulatory standard for the practice of medicine. Such a threat would do nothing beneficial for patient care and would serve only to antagonize the medical profession for no good purpose. Any attempt to compel a physician not to use a drug for the good of his patient merely because the drug firm was slow in presenting the evidence in an approvable form to the FDA or because of the normal lag time required for processing the application should properly be resisted by physicians and patients alike. In presenting these views, I am not endorsing the notion that a physician can, with impunity, use a drug simply as he pleases. The physician has a responsibility always to be well informed about the drugs he prescribes. Use of a drug for a purpose not in the package insert, when done, should be based on a firm scientific rationale and on medical evidence. Also, the physician should be aware of the information in the package insert, including appropriate warnings, precautions, and dosage. Congress intended that the courts not the FDA, judge whether a physician has met his obligations in the event of patient harm from a marketed drug. In making this determination, the courts have found that the package insert, along with medical literature and expert opinion, may constitute evidence of the proper practice of medicine, but it alone is not controlling on this issue. J. RICHARD CROUT, M.D., F.A.C.P.
Director, Bureau of Drugs Food and Drug Administration Rockville, MD 20857 REFERENCE
1. CROUT JR: In praise of the lowly package insert. Food Drug Cosmet Law J 29:139-145, 1974
to private patients. In my view, it might better serve the patient's overall needs as well as those of the profession if the concept of the teaching hospital and the role and value of the resident's involvement in patient care was also addressed in this section of the standard. The practitioner must acknowledge that for residents to effectively learn in the clinical setting they must be directly and actively involved in making decisions and delivering care to patients. This system does not, and should not, exclude the attending staff. By accepting a staff appointment in a teaching hospital, the attending has a responsibility to actively participate in this system. In fact, they represent the role-models for the physician-in-training. Each person involved in the health-care team must accommodate to the teaching model. Communication coupled with intellectual curiosity and honesty are the threads that bind them together. Teaching hospitals have various fail-safe mechanisms that insure the rights and needs of the patient and the practitioner: [1] any physician may direct care in an emergency; [2] in many institutions the private physician or patient may elect not to have resident-staff coverage (here the attending assumes complete responsibility for the patient's care); and [3] the private attending physician has the final legal and professional responsibility for the patient. The extension of the teaching of the clinical disciplines into the community hospitals will likely continue. These institutions are needed to insure adequate clinical exposure for students and residents in training. It is the patient who will benefit most when care is delivered in a system where a fiduciary relation exists between the physician-in-training and other members of the health-care team, particularly the senior physician staff. RUDOLPH J. NAPODANO, M.D.
Accreditation Standards and House-Staff Teaching TO THE EDITOR: The Board of Commissioners of the Joint Commission on Hospital Accreditation recently adopted changes in the wording of Standard VII of the Medical Staff Section: "Where there is a medical staff policy that permits patient care orders to be written by the house staff, the policy must not be extended to prohibit orders being written by the patient's private physician without his agreement. This should be made clear in the medical staff by-laws, rules and regulations'^ 1). This standard does protect the rights and privileges of the medical attending staff and also, seemingly, those of the patient. Although I concur with the general sense of the standard, I anticipate variations in its interpretation by members of the profession. A liberal view of this could understandably result in a private attending physician's writing orders, whenever he or she elects, on a patient who is also being cared for by assigned resident staff. Even if this action occurs infrequently, it may, and in most instances will, nullify a fundamental principle in the clinical training of medical residents: a physician-in-training must share in the decision making process relating to a patient's diagnosis and management. As a program director, I am concerned when a national accrediting body adopts in its standards a manner of phrasing that could have potential far-reaching effects on undergraduate and postgraduate medical educational programs, particularly in the community teaching hospital. I recognize that there is concern in the private sector with the role of the physician-in-training in the delivery of care
Department of Medicine St. Mary's Hospital Rochester, NY 14611 REFERENCE
1. JOINT COMMISSION ON ACCREDITATION OF HOSPITALS: Perspectives
on accreditation. March-April 1976, no. 2
Coronary Care Units TO THE EDITOR: The paper "Effectiveness of Coronary Care Units in Small Community Hospitals" by Stross and associates {Ann Intern Med 85:709-713, 1976) indicates that the worst, or least effective, coronary care units, those with less than 60 patients with myocardial infarction admitted per year, have succeeded in cutting mortality rates in half. They therefore do seem effective, although some coronary care units seem more effective, by their measuring standards, than others. My questions are several. First, is death in the hospital a good outcome measure for judging one coronary care unit against another? Do we have a Cancer Ward phenomenon (1) in university and urban hospitals? Do they discharge patients who are very ill to die at home? Would it not have been better to use mortality statistics that included death in the immediate postdischarge period? Further, Stross himself (2) has shown that in at least one setting, cardiopulmonary arrest is a more sensitive, critical event than cause-specific death rates in determining the need for modification of care delivery. It would be helpful to know how many episodes of cardiopulmonary resuscitaComments and Correction
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tion there were per patient in relation to the number of deaths. Conceivably in the small hospitals, the ratio would be the same as in the large hospitals. The article also points out a lack of quality control in physician education. In the newly established coronary care units, nurses were only permitted to work in those units after achieving certain scores on certain tests. There were no apparant evaluable criteria by which a physician's fitness to work in a coronary care unit could be judged. Do the authors suppose that this might be a factor contributing to increased death rates in small coronary care units? It would be very helpful in my evaluation of the article to know the authors' opinions about these questions. FRANK MITCHELL, M.D.
Department of Medicine University of Washington Seattle, WA 98195 REFERENCES 1. SOLZHENITSYN A: Cancer Ward. New York, Farrar, Straus, & Giroux, 1969 2. STROSS JK, SHASBY DM, HARLAN WR: An epidemic of mysterious cardiopulmonary arrests. N Engl J Med 295:1107-1110, 1976
In reply: In-hospital death was the major outcome measure used in this study for several reasons. It was available, measurable, and the state of the art at the onset of the project (1969) did not allow for others to be used. If death is to be used, correction for the severity of illness must be undertaken as well as corrections for immediate postCoronary Care Unit (CCU) deaths. We do not believe that a Cancer Ward phenomenon (1) exists, as there is no evidence that patients are sent home to die. We do not have data on posthospitalization deaths, but post-CCU deaths were infrequent and had no effect on the points we were stating. Dr. Mitchell raises an excellent point in his discussion on the need to monitor critical events, an issue we have also stressed recently ( 2 ) . We do not have available the number of cardiopulmonary arrests per patient in relation to the number of deaths. We do know the ratio was higher in the large hospitals, which is a function of the patient population in those units. The inability to monitor physicians' fitness to work in a CCU is definitely a factor contributing to the increased death rate. Physicians participated in educational programs, but no tests of competence were given. It is the responsibility of the individual hospital and its medical staff to delineate hospital privileges, and this was a difficult area for us to deal with. The use of standard protocols on whom to treat, when to transfer, and similar variables have been useful in some community hospitals. JEOFFREY K. STROSS, M.D. PARK W. WILLIS, HI, M.D.
University Hospital Ann Arbor, MI 48109 REFERENCES 1. SOLZHENITSYN A: Cancer Ward. New York, Farrar, Straus, & Giroux, 1969 2. STROSS JK, SHASBY DM, HARLAN WR: An epidemic of mysterious cardiopulmonary arrests. N Engl J Med 295:1107-1110, 1976 654
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Angiography in Diabetic Patients TO THE EDITOR: I am writing with reference to the article by Weinrauch and associates ( 1 ) , "Coronary Angiography and Acute Renal Failure in Diabetic Azotemic Nephropathy." As a practicing clinical nephrologist, I wonder how any further information obtained from these dye studies could have been used for the future management of the unfortunate patients. Was coronary bypass surgery contemplated for the patients with severe angina? We were not informed of angina in any of these patients. In my opinion, no information not already known clinically would have excluded these patients from regular hemodialysis therapy. Atherosclerosis is accelerated by hemodialysis therapy, probably more so than by renal transplantation. Finding obstructions in the coronary arteries would not therefore be a contraindication to renal transplant and may in fact be a relative indication for renal transplantation. So, to what useful information are the authors referring? If the information is academic, then it should be labeled as such, and the patients should be so informed. I ask that the authors inform their readers of the therapeutic implications of ventriculography, which, as mentioned, required a larger dose of dye and therefore presented a greater risk of developing renal failure. I am flabbergasted that 13 patients could have been subjected to angiography, when resulting renal failure must have been obvious long before all 13 were studied. In fact, two patients had suffered from acute renal failure from previous dye infusions! Can we know what the 12th and 13th patients were told before they were studied? I am deeply ashamed of this series of studies because we all share a collective responsibility to these patients, and I am unable to justify the series of events as described. I would be very interested to hear the authors' comments, and could we be informed of the ultimate renal function after the episodes of acute renal failure in these patients? DESMOND J. SHAPIRO, M.D., C.H.P., M.R.C.P.
Community Hemodialysis Center 431 Doyle Park Drive Santa Rosa, CA 95405 REFERENCE 1. WEINRAUCH LA, HEALY RW, LELAND OS JR, et al: Coronary angiography and acute renal failure in diabetic azotemic nephroppathy. Ann Intern Med 86:56-59, 1977
f o THE EDITOR: I read with astonishment and distress the report by Weinrauch and colleagues (Ann Intern Med 86:56-59, 1977) of acute renal failure after coronary angiography in 12 of 13 patients with azotemic nephropathy from juvenile-onset diabetes. We are told the patients were studied "to assess expected patient survival" but are subsequently told that the patients were studied to ascertain the cause of pulmonary edema, to differentiate those with "fluid overload from those with true myocardial ischemia." Whatever the reasons, they appeared rather hazy to me. What remains inexplicable is how the authors persisted with the study despite an appalling 92% occurrence of renal failure, which must have been vividly apparent before all 13 patients had undergone coronary angiography and which should have prompted early cessa-
tion of the study. The authors themselves were aware they were dealing with a high-risk group, for they quoted previous reports dealing precisely with the risk of contrast studies in azotemic diabetic patients. One is left with the feeling that serious ethical considerations were neglected with continuation of an extremely high-risk procedure that was primarily elective. RAYMOND D. ADELMAN, M.D.
Sacramento Medical Center 4301 X Street Sacramento, CA 95817
brief, three of the four deaths resulted from severe coronary artery disease not detectable by noninvasive methods currently available. In summary, prospective renal allograft recipients and donors were actively engaged in decision-making by means of studies designed to elucidate the risks of surgery and to determine those patients in whom asymptomatic coronary artery disease might jeopardize longevity and raise serious doubts as to the wisdom of transplantation. L. A. WEINRAUCH, M.D. R. W. HEALY, M.D. O. S. LELAND, J R . , M.D. H. H . GOLDSTEIN, M.D. S. D. KASSISSIEH, M.D.
In reply:
J. A . LlBERTINO, M.D. F . J. T A K A C S , M . D . , F . A . C . P .
We feel compelled to correct some misapprehensions that are raised in the letters of Drs. Shapiro and Adelman. All of our patients were juvenile-onset diabetic patients with terminal renal failure and could be expected to need dialysis in less than 12 months ( 1 ) . The rationale for cardiac studies before a decision on ultimate therapy (liverelated or nonliving-related transplantation, or hemodialysis alone) is to define those patients at highest risk of nonsurvival due to cardiovascular mortality. Our experience and that of other major centers (2) suggest that the mortality in this population is largely accounted for by pre-existent coronary-artery heart disease. Because no clinical, laboratory, or noninvasive test is definitive in identifying which patients have underlying coronary heart disease (none had angina) ( 3 ) , we continue to believe that coronary angiography is needed. Dealing with living-related transplantation involves the need to provide enlightened parents and siblings with objective data on expected recipient survival before they can possibly donate a vital organ in a truly informed manner. This is not to say that nonliving-related transplantation should be done indiscriminately. Misuse of a cadaveric organ should be avoided as well, since the kidney wasted in a foolhardy surgical endeavor might have provided another person with a life free of hemodialysis. We hope that studies such as this will enable us to differentiate reliably between candidates for living-related versus nonliving-related transplantation. The references that we have cited have uniformly considered angiography and urography as low-risk procedures even in diabetics. In addition, no previous study had correlated degree of toxicity with volume of contrast (4, 5 ) . Because our studies documented an average increment in creatinine of 3 mg/dl in diabetics with end-stage renal failure, our present practice is to defer angiography until an access for dialysis has been established and to eliminate ventriculography in some instances. At 6-month follow-up, one nontransplanted patient with severe three-vessel coronary artery disease had died from a myocardial infarction, four patients were on maintenance dialysis, and seven patients had undergone successful renal transplantation from living-related donors. The 13th patient, who had not suffered acute renal damage, had also been successfully transplanted from a living-related donor by that time. Two-year follow-up revealed three additional deaths: two from myocardial infarctions in maintenance dialysis patients with severe three-vessel coronary artery disease, and the third from postimmunosuppression sepsis. Three patients were alive on chronic dialysis. The remaining six patients were alive with functioning allografts. In
J. A . D ' E L I A , M . D . , F . A . C . P .
New England Deaconess Hospital 185 Pilgrim Road Boston, M A 02215 REFERENCES 1. KUSSMAN MJ, GOLDSTEIN HH, GLEASON RE: The clinical course
of diabetic nephropathy. JAMA 236:1861-1863, 1976 2. SHIDEMAN JR, BUSELMEIER TJ, KJELLSTRAND CM: Hemodialysis
in diabetics, complications in insulin-dependent patients accepted for renal transplantation. Arch Intern Med 136:1126-1130, 1976 3. WEINRAUCH LA, HEALY RW, D'ELIA JA, et al: Coronary and
ventricular angiographic findings in azotemic juvenile type diabetics evaluated for renal transplantation (abstract). Circulation 54 (suppl2):163, 1976 4. DOUST BD, REDMAN HC: Myth of 1 ml/kg in angiography:
study to determine relationship of contrast medium dosage to complications. Radiology 104:557-560, 1972 5. OLDER RA, MILLER JP, JACKSON DC, et al:
Angiographically
induced renal failure and its radiographic detection. Am J Roentgenol 126:1039-1045, 1976
Adriamycin and Radiation Reactions TO THE EDITOR: In the September issue {Ann Intern Med 85:294-298, 1976) Greco and associates reported that combination chemotherapy with adriamycin enhanced radiation reactions in skin and esophagus in 10 patients receiving concurrent therapy for small-cell anaplastic carcinoma of the lung. These observations were made in 1975. Two other reports have been published on these same patients, plus about 12 others from the National Institutes of Health (NIH) ( 1 , 2 ) . These reports and unpublished results from 48 patients treated at Vanderbilt University Medical Center help shed additional light on the true frequency, severity, and cause of esophageal and skin reactions. Merrill and associates (1) reported a high occurrence rate of anorectal inflammatory disease ( 3 2 % ) and sepsis in the same 22 patients from the N I H treated for smallcell carcinoma of the lung. The authors thought that the degree of granulocytopenia induced by the chemotherapy was the major predisposing factor in these patients. The first 10 of these patients were the same patients described by Greco and associates in the September issue of Annals of Internal Medicine. Johnson, Brereton, and Kent (2) later reported therapeutic results in 21 patients (including the original 10 patients) and again mentioned the enhanced radiation reactions of skin and esophagus and anorectal inflammatory complications. The therapeutic regimen was intensive and included radiation therapy to the bulk disease plus prophylactic whole-brain radiotherapy concurrently Comments and Correction
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with a cyclic combination of Cytoxan® (usually 1500 mg/m 2 intravenously), adriamycin (40 mg/m 2 intravenously) and vincristine (2 mg). The mean interval between cycles was 20.5 (=t 3.7) days. The doses were not usually attenuated but given as soon as the total leukocyte count exceeded 3500 cells/ mm3. The hematologic toxicity was "considerable," with a mean neutrophil nadir of 85/mm 2 (range, 0 to 300). Although toxicity was "appreciable," their results may be a therapeutic advance in patients without demonstrable metastasis outside the chest or supraclavicular areas. We have used a similar regimen at Vanderbilt, but we have given chemotherapy only after a 21-day interval and have adjusted dosages downward at this time depending on the blood counts. Treatment of 48 consecutive patients with small-cell carcinoma in this fashion has resulted in no unusual esophageal or skin reactions. The tumor response rate is similar to that of Johnson and associates (2), but it is too early to evaluate survival. Therefore, in addition to the radiosensitizing effect of adriamycin and scheduling of radiotherapy, the intensity of the chemotherapy was probably a major factor responsible for the enhanced radiation reactions in esophagus and skin as reported in the September issue. F. ANTHONY GRECO, M.D. ROBERT K. OLDHAM, M.D.
Division of Oncology Vanderbilt University Medical Center Nashville, TN 37232 REFERENCES 1. MERRILL J, BRERETON HD, KENT CH, et al: Anorectal disease in patients with non-haematologized malignancy. Lancet 1:11051107, 1976 2. JOHNSON RE, BRERETON HD, KENT CH: Small-cell carcinoma of the lung: attempt to remedy causes of past therapeutic failure. Lancet 2:289-291, 1976
Deoxycholate or Amphotericin B in Chemotherapy Sensitization TO THE EDITOR: The use of amphotericin B as a sensitizing
agent during combination chemotherapy in human neoplasia has been reported by Presant, Klahr, and Santala (1). An implication of the lack of an important control population in this study deserves comment. The commercial preparation of amphotericin B, Fungizone® (E. R. Squibb, Princeton, New Jersey), is prepared with 41 mg of sodium deoxycholate to every 50 mg of amphotericin B. The deoxycholate is used to form a colloidal dispersion because crystalline amphotericin B is insoluble in water. Both amphotericin B and deoxycholate have cell-membrane altering effects that can increase the uptake of certain antitumor drugs. The synergistic effect seen with Fungizone and BCNU against AKR leukemia was attributed to the amphotericin B by Medoff and associates (2). However, Kessel (3) reported that the increased uptake of dactinomycin in LI210 cells was due to the detergent effect of deoxycholate. Similarly, daunorubicin uptake in Chinese hamster cells resistant to daunorubicin was increased when the cells were treated with the nonionic detergent Tween 80® (polysorbate 80). Because it is not clear from investigation done in vitro which agent would be responsible for changes in antitumor activity of a drug combination in vivo, it is perhaps premature to recommend the addition of Fungizone to a 656
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chemotherapeutic regimen as suggested by Presant and associates. Life-threatening reactions from Fungizone occur with sufficient frequency to make it unwise to administer it if deoxycholate alone could produce similar results. I suggest that Presant and associates plan to include as a control population in their future studies patients who would receive deoxycholate plus chemotherapy to assess the role of deoxycholate in the sensitizing effects of Fungizone. STEVEN D. REICH, M.D.
Departments of Pharmacology and Medicine Northwestern University Chicago, IL 60611 REFERENCES 1. PRESANT CA, KLAHR C, SANTALA R: Amphotericin B induction of sensitivity to adriamycin, 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU) plus cyclophosphamide in human neoplasia. Ann Intern Med 86:47-51, 1977 2. MEDOFF G, VALERIOTE F, LYNCH RG, et al: Synergistic effect of amphotericin B and 1,3-bis (2-chloroethyl)-l-nitrosourea against a transplantable AKR leukemia. Cancer Res 34:974-978, 1974 3. KESSEL D: Alteration of cell permeability barriers by amphotericin B-deoxycholate (Fungizone) in vitro. Biochem Pharmacol 25: 483-485, 1976 4. RIEHM H, BIEDLER JL: Potentiation of drug effect by Tween 80 in Chinese hamster cells resistant to actinomycin D and daunomycin. Cancer Res 32:1195-1200, 1972
In comment: The comments by Dr. Reich are appropriate because Fungizone is a mixture of amphotericin B plus sodium deoxycholate. However, no data exist to conclusively identify which of the two chemicals is related to the clinical effect observed in our studies (1, 2 ) . The data of Kessel (3) are confusing. A careful analysis of his data shows that Fungizone produced a much greater increase in uptake of dactinomycin by LI210 cells than did either "pure" amphotericin B or deoxycholate at a concentration equal to that in the Fungizone. This greater effect by the combination of chemicals in Fungizone might be expected if deoxycholate increased the availability of amphotericin B. Only in concentrations two and a halffold higher did the deoxycholate produce an enhancement of dactinomycin uptake quantitatively similar to that observed with lower doses of Fungizone. Similar experiments on dactinomycin uptake in dactinomycin-resistant HeLa cells have produced contradictory results (4). Dactinomycin uptake, dactinomycin inhibition of RNA synthesis, and dactinomycin-induced morphologic changes were enhanced by the addition of Fungizone but not by two-fold higher concentrations of deoxycholate. Other data make it less likely that the effect we observed in vivo is due to deoxycholate. Cures of mice with LI210 leukemia were observed with Fungizone plus BCNU. These cures were not observed with deoxycholate plus BCNU (5). In addition, cures were observed with BCNU plus amphotericin methyl ester, a water-soluble form of amphotericin B that does not include deoxycholate (MEDOFF G, VALERIOTE F, unpublished observations). Furthermore, the immunopotentiation induced in mice by Fungizone is also seen with the use of amphotericin methyl ester but is not observed with either deoxycholate or photoinactivated amphotericin B (LITTLE JR, BLANKE TJ, VALERIOTE F et
al: Immunoadjuvant properties of amphotericin B, in Modulation of Host Immune Resistance in the Prevention or
Treatment of Induced Neoplasias, edited by CHIRIGOS MA. New York, Raven Press, 1977, in press). In addition we have studied in-vitro nitrogen mustard uptake by human ovarian carcinoma cells obtained from ascites fluid. Fungizone enhanced nitrogen mustard uptake by these cells in a dose-dependent fashion, but deoxycholate did not increase nitrogen mustard accumulation in tumor cells (PRESANT C, CARR D, submitted for publication). Possibly the clinical effects observed by us (1, 2) are mediated by deoxycholate. Further experimental trials are first needed to define the frequency of improvement induced by Fungizone. If a frequent effect is confirmed, trials would be indicated to determine whether amphotericin B or deoxycholate was the effective agent. In such trials, one should select the agent most likely to produce the effect. The experimental data cited above indicate that amphotericin B rather than deoxycholate is likely to be the active ingredient. Amphotericin methyl ester, which is water soluble, might be the more suitable drug form for such a trial. CARY A. PRESANT, M.D. CAROL KLAHR, M.S., R.N. ROGER SANTALA, M.D.
The Jewish Hospital of St. Louis 216 South Kings Highway St. Louis, MO 63110 REFERENCES
1. PRESANT CA, KLAHR C, SANTALA R: Amphotericin B induction
of sensitivity to adriamycin, 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU) plus cyclophosphamide in human neoplasia. Ann Intern Med 86:47-51, 1977 2. PRESANT CA, KLAHR C, OLANDER J, et al: Amphotericin B plus
1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU-NSC No. 409962) in advanced cancer. Cancer 38:1917-1921, 1976 3. KESSEL D: Alteration of cell permeability barriers by amphotericin B-deoxycholate (Fungizone) in vitro. Biochem Pharmacol 25:483-485, 1976 4. MEDOFF J, MEDOFF G, GOLDSTEIN MN, et al: Amphotericin B
induced sensitivity to actinomycin D in drug-resistant HeLa cells. Cancer Res 35:2548-2552, 1975
three more aspirations during the next 4 weeks yielded E. coli. On the 46th hospital day leukemic remission occurred, after which the cellulitis rapidly resolved. A 27-year-old man undergoing treatment of acute myelogenous leukemia had shown no evidence of infection, despite profound granulocytopenia. Six days after insertion of a heparin-lock needle, he experienced pain at the site and the device was removed. Within 4 h the site had become erythematous, swollen, and exquisitely tender, and he was febrile (39.5 °C). An aspirate showed few leukocytes but sheets of large-Gram-negative bacilli on smear. Cultures of the aspirate and blood were subsequently positive for Klebsiella pneumoniae. Despite treatment with cephalothin and gentamicin, leukocyte infusions, and two attempts at surgical drainage, the area of cellulitis progressively increased in size, and the patient died of refractory infection and active leukemia 50 days after the onset of infection. Clearly no type of vascular cannula is absolutely safe, especially in highly susceptible patients such as those of the two cases presented. In each instance, the heparin-lock needle had been in place for more than 72 h and sepsis was heralded by local pain. Available data suggest that continuous intravenous therapy with small metal needles is substantially safer than with plastic catheters, even when the cumulative daily incidence of infection is analyzed; about two needles per 1000 infusions produce septicemia (2, 3 ) . However, needle-related septicemia appears to be more frequent in patients with cancer or those otherwise significantly immunocompromised ( 3 ) . Concerning risk of infection, heparin-locks are probably equivalent to continuous infusion therapy through scalp-vein needles. The risk of septicemia and phlebitis (1) caused by heparin-lock needles also rises with increasing duration of use. Thus the safest course when using heparin-locks, especially in patients who are neutropenic or otherwise highly susceptible, is to rotate the site every 48 to 72 h routinely (2, 3 ) . Pain or other signs of inflammation, unexplained fever, or signs of sepsis should prompt immediate removal and culture of the needle. WILLIAM A. AGGER, M.D. DENNIS G. MAKI, M.D., F.A.C.P.
5. MEDOFF G, VALERIOTE F, LYNCH RG, et al: Synergistic effect
of amphotericin B and 1,3-bis (2-chloroethyl)-l-nitrosourea against a transplantable AKR leukemia. Cancer Res 34:974-978, 1974
Septicemia from Heparin-Lock Needles TO THE EDITOR: Heparin-lock needles are widely used for intravenous administration of antineoplastic drugs. Until the report by Ferguson and associates ( 1 ) , no information was available on the safety of these devices. These investigators encountered no systemic infections with 221 heparin-locks in 78 patients, but most of their patients were not immunosuppressed. We report two cases of patients with leukemia in whom cellulitis and septicemia developed with infection derived from heparin-lock needles. An 82-year-old man receiving chemotherapy for treatment of acute myelogenous leukemia was severely granulocytopenic ( 104 meq/litre and serum phosphate < 3 . 5 mg/dl correctly predicted the diagnosis of primary hyperparathyroidism in 29 of the 34 patients ( 8 5 % ) , without any false-positive diagnosis. A similar result is achieved, when these limits are applied to the values of the patients reported by Palmer and associates ( 3 ) . We later studied two further patients with paraneoplastic hyperparathyroidism. Both of them showed serum chloride and phosphate levels similar to those found in primary hyperparathyroidism. We thus conclude that in a substantial fraction of the hypercalcemic patients with normal renal function the diagnosis of primary hyperparathyroidism can be predicted by the simple screening method of measuring the serum chloride and phosphate concentrations. The differentiation between primary hyperparathyroidism and other causes of hypercalcemia seems to be almost complete, except for paraneoplastic hyperparathyroidism, which cannot be distinguished from primary hyperparathyroidism. A N T T I ARO, M.D.
Department of Medicine University of Kuopio SF-70210Kuopio21 Finland Hypercalcemia: Serum Chloride and Phosphate
RISTO PELKONEN, M.D.
Third Department of Medicine TO THE EDITOR: In the December 1976 issue Pak
and
Townsend (1) questioned the usefulness of the serum chloride/phosphate ratio in the diagnosis of primary hyperparathyroidism. Our experience indicates that the measurement of serum chloride and phosphate concentrations is of diagnostic value in hypercalcemia, even though the chloride/phosphate ratio has proved ineffective also in our practice. We recently studied a series of 64 patients with hypercalcemia for a review article published in Finnish ( 2 ) . Included were 40 patients with surgically proven primary hyperparathyroidism, 17 with malignant disease, most of them with skeletal involvement, four with vitamin D intoxication, and three with sarcoidosis. The serum chloride (in meq/litre)/phosphate (in mg/dl) ratio was less than 33, a limit initially suggested (3, 4 ) , in five (12.5%) of the hyperparathyroid patients, whereas the ratio exceeded this limit in eight (47%) of the patients with malignant disease. The results thus are in agreement with those of Pak and Townsend (1) in that there is a wide overlap of values, which limits the usefulness of the chloride/phosphate ratio in the differential diagnosis of hypercalcemic states. Serum chloride and phosphate concentrations are, however, of diagnostic importance, when the results are interpreted in another way, by looking at the combination of the individual values, as expressed in Figure 1. A serum chloride concentration exceeding 104 meq/litre together with a serum phosphate concentration of less than 3.5 mg/dl was found in 32 of the 40 patients with primary hyperparathyroidism whereas only two patients with malignant disease, both showing impaired renal function, showed a similar pattern. One of the two patients had multiple myeloma and severe renal failure and had been treated by peritoneal dialysis. She had serum chloride of 119 meq/litre and phosphate of 3.1 mg/dl. The other patient had primary carcinoma of the liver; the hypercalcemia 664
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University of Helsinki SF-00290 Helsinki 29 Finland A R T O SIVULA, M . D .
Second Department of Surgery University of Helsinki SF-00290 Helsinki 29 Finland REFERENCES
1. PAK CYC, TOWNSEND J: Chloride/phosphorus in primary hyperparathyroidism. Ann Intern Med 85:830, 1976 2. ARO A: Differential diagnosis of hypercalcaemia. Duodecim (Helsinki) 91:436-447, 1975 3. PALMER FJ, NELSON JC, BACCHUS H: The chloride-phosphate
ratio in hypercalcemia. Ann Intern Med 80:200-204, 1974 4. REEVES CD, PALMER F, BACCHUS H, et al: Differential diagnosis
of hypercalcemia by the chloride/phosphate ratio. Am J Surg 130:166-171, 1975
Thyroid Hormones in Chronic Renal Failure TO THE EDITOR: In their recently published paper Spector
and associates (1) report on thyroid function and metabolic state in chronic renal failure. In their uremic patients they found low serum 3, 5, 3'-triiodothyronine (T3) and low serum free T3 in contrast to normal free thyroxine (T4) and thyroid-stimulating hormone (TSH) serum levels. Total serum T4 concentrations were in the lower normal range. They point out the similarity of these findings with the results reported for hepatic cirrhosis and various other severe nonthyroidal illnesses in which serum T3 levels are markedly decreased in spite of normal total T4 serum concentrations. This is apparently a result of diminution of peripheral conversion of T4 to T3, which can be due either to a shift of T4 conversion from T3
Table 1. Serum Concentrations of Thyroid Hormones in Uremic Patients Total T4
Total T3
rT3
TSH
ng/dl
ng/dl
nV/ml
~M/dl Controls (n = 30) Mean ± SD 8.2 ± 2.0 124 ± 46 Range 4.0 - 12.5 70 - 190 Uremic patients (n = 14) Mean ± SD 6.0 ± 2.0 81 ± 33 Range 3.3 - 10.4 37 - 133
21.9 + 2.7 3.1 ± 2.0 15.9 - 25.2 0.9 - 8.7 13.0 ± 7.0 2.6 ± 1.6 1.0 - 22.8 0.9 - 4.6
towards reverse T 3 ( 3 , 3'^'-triiodothyronine = r T 3 ) ( 2 )
or to a decrease in the overall deiodinative metabolism of T4 (3). To further elucidate this abnormality in peripheral hormone metabolism we have additionally measured rT3 serum levels in 14 uremic patients on chronic intermittent hemodialysis (Table 1). As can be seen from this table our mean total T3, total T4, and TSH serum levels correspond well with the data reported by Spector and associates. The mean rT3 serum level is markedly reduced in our uremic patients compared with the control level. This excludes a shift of T4 conversion towards rT3 and indicates a decrease in overall deiodinative metabolism of T4 in uremia, because both products of monodeiodination of T4 (T3, rT3) are diminished. This is in contrast to the situation found in most of the diseases Spector and associates refer to, where a shift of T4 conversion towards rT3 is suggested by low total T3 and high rT3 serum levels. MICHAEL WEISSEL, M.D. H. KRISTER STUMMVOLL, M.D. AXEL WOLF, M.D. HEINZ FRITZSCHE, M.D.
Department of Nuclear Medicine, Division of Nephrology Second Medical Department University of Vienna A-1090, Vienna Austria
radiotherapists would consider that dosages of 2400 to 3000 rad to the pituitary at the normal rate of 1000 rad per week are therapeutically inadequate. Thus two of these subjects cannot be properly evaluated. These patients were presented against a background of the suggestion that irradiation to the pituitary before bilateral adrenalectomy may prevent Nelson's syndrome, in part predicated on the findings of Orth and Liddle (2). These latter investigators had treated 19 patients with pituitary irradiation before total adrenalectomy and in none did Nelson's syndrome ensue. In view of the paucity of data available in this regard, we wish to bring to the authors' and readers' attention the report of Wild and associates (3) in 1972, which Moore and colleagues inadvertently overlooked in their review of the literature. Wild and associates reported a patient with Cushing's syndrome treated with 4500 rad who developed Nelson's syndrome after bilateral adrenalectomy and refer briefly to two other such instances available. Wild and associates pointed out that "although the experience to date indicates pituitary irradiation may reduce the incidence of Nelson's syndrome, its effectiveness has not been precisely established. For this reason, failures of such therapy should be reported. This may also clarify whether there is a point of time in the course of the treatment of Cushing's syndrome when pituitary irradiation is most effective". J. L. GABRILOVE, M.D. G. L. NlCOLIS, M.D., PH.D. Mount Sinai School of Medicine • City University of New York New York, N Y 10029 REFERENCES 1. MOORE TJ, DLUHY RG, WILLIAMS GH, et al:
Nelson's syn-
drome: frequency, prognosis and effect of prior pituitary irradiation. Ann Intern Med 85:731-734, 1976 2. ORTH DN, LIDDLE GW: Results of treatment in 108 patients with Cushing's syndrome. N Engl J Med 285:243, 1971 3. WILD W, NICOLIS GL, GABRILOVE JL: Appearance of Nelson's
syndrome despite pituitary irradiation prior to bilateral adrenalectomy for Cushing's syndrome. M Sinai J Med NY 40:68, 1973
REFERENCES 1. SPECTOR DA, DAVIS PJ, HELDERMAN JH, et al: Thyroid function
and metabolic state in chronic renal failure. Ann Intern Med 85:724-730, 1976 2. CHOPRA IJ, CHOPRA U, SMITH SR, et al: Reciprocal changes in
serum concentrations of 3,3',5'-triiodothyronine (Reverse T3) and 3,3',5'-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab 41:1043-1049, 1975 3. NICOD P, BURGER A, STAEHELI V, et al: A radioimmunoassay for
3,3',5'-triiodo-L-thyronine in unextracted serum: method and clinical results. J Clin Endocrinol Metab 42:823-829, 1976
Nelson's Syndrome
From their study of Nelson's syndrome Moore and colleagues (1) reported nine patients with the disorder out of 120 patients treated for Cushing's syndrome. Of these nine only two had received prior pituitary irradiation; one having received 3000 rad, the other 5000. They cite a case from Salassa's and associates' series of pituitary tumors in patients with Cushing's syndrome who was reported without comment to have developed a pituitary tumor subsequent to pituitary irradiation with 2400 rad and bilateral subtotal adrenalectomy. Most TO THE EDITOR:
Jake Walk in Vietnam
The recent paper by Morgan and Tuloss, 'The Jake Walk Blues" (Ann Intern Med 85:804-808, 1976) on paralytic disease caused by poisoning with triortho-cresyl phosphate, reminded me of tragic outbreaks of this affliction that occurred in the Quang Tri Province of Viet Nam during 1970-71. While serving with a medical assistance team, (Navy MILPHAP N-4), assigned to work within the local health care system in the northernmost province of South Vietnam, I observed small clusters of Vietnamese patients with newly developing spastic quadriplegia. This epidemic paralysis peculiarly attacked family groups. As noted by Morgan and Tuloss, muscle pain was a common feature of the syndrome (in its early course), there was little or no sensory deficit, and the resulting spastic gait had a jerky, stumbling character. Some persons with the condition associated its onset with preceding use of a "black market" cooking oil, which on investigation proved to be a tri-ortho-cresyl containing U.S. military aviation lubricant supplied to South Vietnamese helicopter units. TO THE EDITOR:
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Notification of U.S. and South Vietnamese military authorities of the problem had little effect, and sporadic outbreaks occurred in the area throughout 1970-71. The widening use of helicopters in underdeveloped areas among unsophisticated peoples, particularly in situations of disaster when basic food commodities are in short supply, may lead to similar sad outbreaks in the future. DAVID T. DENNIS, M.D.
U.S. Naval Medical Research Unit No. 2 Jakarta Detachment APO San Francisco, CA 96356
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Correction: Misspelled Name The editorial office is responsible for a misspelled name in the March issue of Annals of Internal Medicine. On pages 267, 303, and 322, the name should have read Alexander Solomon Wiener.
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. Unapproved Uses of Drugs TO THE EDITOR: All my enthusiasm for the excellent article "Naloxone" by Dr. Martin in the December issue {Ann Intern Med 85:765-768, 1976) evaporated when I came to the words "unapproved uses." Why is this admonition included? Does this imply that I should not use the drug, permitting a patient to die and be guilty of murder? If this is so, my reading the article is an academic exercise in futility. The detail man, as well as the Physicians' Desk Reference, has given me all of the approved indications, and the practice of reading journals the past 46 years for the latest therapy has become superfluous. Does the editor have little or no trust in his judgment to select articles for publication, or is the author some scoundrel not to be trusted, and, like Pilate, the editor washes his hands of the affair and places upon me the task of making a choice for which I am not prepared? Is the editor implying that if I use the drug properly, I am guilty of some unspecified horror by not paying obeisance to the Food and Drug Administration ( F D A ) ? I will never bend my knee to anyone who makes the statement that if every physician in the United States finds a drug useful, and he dissents, his dissent overrides the findings of all of them. What ukase feeds his cacoethes [an insatiable desire] for unlimited power? Should God move over and bow to this man Crout? When the editor permits the FDA to use him, he becomes a policeman and relinquishes his objectivity as an editor. Those who bow to the dictates of the FDA do not need to read journals. The remainder care nothing for what the FDA approves or disapproves. J . G . BOHORFOUSH, M.D., F.A.C.P.
811 North Cobb St. Milledgeville, GA 31061
In comment: The role of the package insert in medicine is an important issue on which we receive many inquiries from physicians. In commenting on Dr. Bohorfoush's letter, may I quote from a previous paper on this subject ( 1 ) . Not too long ago, package inserts were wholly ignored by the medical profession, and, of course, until the New Drug Amendments of 1962 they deserved to be ignored, since most were simply promotional brochures. In the past decade, however, the scientific quality of package inserts 652
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has improved remarkably. Today, many package inserts are excellent resource documents for information not summarized elsewhere, and some are even readable! The package insert is (intended to be) a summary of the essential scientific and medical information about a drug which the physician should know in order to use the drug safely and effectively for the listed indications. The Food, Drug, and Cosmetic Act is quite clear in requiring that these indications be supported by "substantial evidence" consisting of "adequate and well-controlled trials." This means that such evidence must be obtained through systematic clinical research, and it must be presented to the FDA and be acted upon, before new information can be added to the labeling. Given this system, it is evident that a time lag will occur between the publication of studies providing substantial evidence for a claim and the actual appearance of that claim in the package insert. In other instances, a claim made in a published paper may fall by the wayside after additional studies. Poorly documented therapeutic claims are widespread in the medical literature, and it would be folly to catalogue all such "information" in the package insert If information in the package insert is based on substantial evidence, it follows that the physician can use the insert as an authoritative reference source for drug usage in the care of patients. However, as mentioned previously, it also follows that the package insert may not contain the most up-to-date information about the drug. Thus, the physician must be free to use the drug for an indication not in the package insert when such usage is part of the practice of medicine and for the benefit of the patient. When such usage is done as part of a research project on a marketed drug, however, it is still permissible but should be done under an IND. The above paragraph is completely in line with announced FDA policy on this matter. Nevertheless, there continues to be enormous concern among physicians that mere usage of a drug for an indication not in the package insert is in some way illegal and that, by itself, may open the physician to some form of legal jeopardy. This is not true, but in Government we have not yet been able to impart this message credibly to physicians. The world we want is one in which the physician welcomes a well-documented package insert because he finds it useful, and he finds it useful because the information in it is supported by substantial evidence. Such a package insert would be unique among medical documents. The physician can already ascertain from the medical literature new and interesting proposed uses for marketed drugs, and he can discover at any medical meeting the many innovative ways in which experts use drugs in patient care, some of which are not in the package insert. The physician does not need yet another document which enumerates these newer drugs. The package insert's most important educational value derives from the fact that it is a wellreviewed, authoritative document. However, to achieve this world we want, it is essential that those of us in regulatory agencies and in the legal profession not take offense at drug usage outside the package insert merely because it is occurring. We must understand how our drug labeling system works and recognize that such usage will occur as a necessary part of the practice of good medicine; and the more current the physician
is in his practice, the more often it will occur. Understanding this, we in Government and in law cannot threaten to use the package insert as a tight regulatory standard for the practice of medicine. Such a threat would do nothing beneficial for patient care and would serve only to antagonize the medical profession for no good purpose. Any attempt to compel a physician not to use a drug for the good of his patient merely because the drug firm was slow in presenting the evidence in an approvable form to the FDA or because of the normal lag time required for processing the application should properly be resisted by physicians and patients alike. In presenting these views, I am not endorsing the notion that a physician can, with impunity, use a drug simply as he pleases. The physician has a responsibility always to be well informed about the drugs he prescribes. Use of a drug for a purpose not in the package insert, when done, should be based on a firm scientific rationale and on medical evidence. Also, the physician should be aware of the information in the package insert, including appropriate warnings, precautions, and dosage. Congress intended that the courts not the FDA, judge whether a physician has met his obligations in the event of patient harm from a marketed drug. In making this determination, the courts have found that the package insert, along with medical literature and expert opinion, may constitute evidence of the proper practice of medicine, but it alone is not controlling on this issue. J. RICHARD CROUT, M.D., F.A.C.P.
Director, Bureau of Drugs Food and Drug Administration Rockville, MD 20857 REFERENCE
1. CROUT JR: In praise of the lowly package insert. Food Drug Cosmet Law J 29:139-145, 1974
to private patients. In my view, it might better serve the patient's overall needs as well as those of the profession if the concept of the teaching hospital and the role and value of the resident's involvement in patient care was also addressed in this section of the standard. The practitioner must acknowledge that for residents to effectively learn in the clinical setting they must be directly and actively involved in making decisions and delivering care to patients. This system does not, and should not, exclude the attending staff. By accepting a staff appointment in a teaching hospital, the attending has a responsibility to actively participate in this system. In fact, they represent the role-models for the physician-in-training. Each person involved in the health-care team must accommodate to the teaching model. Communication coupled with intellectual curiosity and honesty are the threads that bind them together. Teaching hospitals have various fail-safe mechanisms that insure the rights and needs of the patient and the practitioner: [1] any physician may direct care in an emergency; [2] in many institutions the private physician or patient may elect not to have resident-staff coverage (here the attending assumes complete responsibility for the patient's care); and [3] the private attending physician has the final legal and professional responsibility for the patient. The extension of the teaching of the clinical disciplines into the community hospitals will likely continue. These institutions are needed to insure adequate clinical exposure for students and residents in training. It is the patient who will benefit most when care is delivered in a system where a fiduciary relation exists between the physician-in-training and other members of the health-care team, particularly the senior physician staff. RUDOLPH J. NAPODANO, M.D.
Accreditation Standards and House-Staff Teaching TO THE EDITOR: The Board of Commissioners of the Joint Commission on Hospital Accreditation recently adopted changes in the wording of Standard VII of the Medical Staff Section: "Where there is a medical staff policy that permits patient care orders to be written by the house staff, the policy must not be extended to prohibit orders being written by the patient's private physician without his agreement. This should be made clear in the medical staff by-laws, rules and regulations'^ 1). This standard does protect the rights and privileges of the medical attending staff and also, seemingly, those of the patient. Although I concur with the general sense of the standard, I anticipate variations in its interpretation by members of the profession. A liberal view of this could understandably result in a private attending physician's writing orders, whenever he or she elects, on a patient who is also being cared for by assigned resident staff. Even if this action occurs infrequently, it may, and in most instances will, nullify a fundamental principle in the clinical training of medical residents: a physician-in-training must share in the decision making process relating to a patient's diagnosis and management. As a program director, I am concerned when a national accrediting body adopts in its standards a manner of phrasing that could have potential far-reaching effects on undergraduate and postgraduate medical educational programs, particularly in the community teaching hospital. I recognize that there is concern in the private sector with the role of the physician-in-training in the delivery of care
Department of Medicine St. Mary's Hospital Rochester, NY 14611 REFERENCE
1. JOINT COMMISSION ON ACCREDITATION OF HOSPITALS: Perspectives
on accreditation. March-April 1976, no. 2
Coronary Care Units TO THE EDITOR: The paper "Effectiveness of Coronary Care Units in Small Community Hospitals" by Stross and associates {Ann Intern Med 85:709-713, 1976) indicates that the worst, or least effective, coronary care units, those with less than 60 patients with myocardial infarction admitted per year, have succeeded in cutting mortality rates in half. They therefore do seem effective, although some coronary care units seem more effective, by their measuring standards, than others. My questions are several. First, is death in the hospital a good outcome measure for judging one coronary care unit against another? Do we have a Cancer Ward phenomenon (1) in university and urban hospitals? Do they discharge patients who are very ill to die at home? Would it not have been better to use mortality statistics that included death in the immediate postdischarge period? Further, Stross himself (2) has shown that in at least one setting, cardiopulmonary arrest is a more sensitive, critical event than cause-specific death rates in determining the need for modification of care delivery. It would be helpful to know how many episodes of cardiopulmonary resuscitaComments and Correction
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tion there were per patient in relation to the number of deaths. Conceivably in the small hospitals, the ratio would be the same as in the large hospitals. The article also points out a lack of quality control in physician education. In the newly established coronary care units, nurses were only permitted to work in those units after achieving certain scores on certain tests. There were no apparant evaluable criteria by which a physician's fitness to work in a coronary care unit could be judged. Do the authors suppose that this might be a factor contributing to increased death rates in small coronary care units? It would be very helpful in my evaluation of the article to know the authors' opinions about these questions. FRANK MITCHELL, M.D.
Department of Medicine University of Washington Seattle, WA 98195 REFERENCES 1. SOLZHENITSYN A: Cancer Ward. New York, Farrar, Straus, & Giroux, 1969 2. STROSS JK, SHASBY DM, HARLAN WR: An epidemic of mysterious cardiopulmonary arrests. N Engl J Med 295:1107-1110, 1976
In reply: In-hospital death was the major outcome measure used in this study for several reasons. It was available, measurable, and the state of the art at the onset of the project (1969) did not allow for others to be used. If death is to be used, correction for the severity of illness must be undertaken as well as corrections for immediate postCoronary Care Unit (CCU) deaths. We do not believe that a Cancer Ward phenomenon (1) exists, as there is no evidence that patients are sent home to die. We do not have data on posthospitalization deaths, but post-CCU deaths were infrequent and had no effect on the points we were stating. Dr. Mitchell raises an excellent point in his discussion on the need to monitor critical events, an issue we have also stressed recently ( 2 ) . We do not have available the number of cardiopulmonary arrests per patient in relation to the number of deaths. We do know the ratio was higher in the large hospitals, which is a function of the patient population in those units. The inability to monitor physicians' fitness to work in a CCU is definitely a factor contributing to the increased death rate. Physicians participated in educational programs, but no tests of competence were given. It is the responsibility of the individual hospital and its medical staff to delineate hospital privileges, and this was a difficult area for us to deal with. The use of standard protocols on whom to treat, when to transfer, and similar variables have been useful in some community hospitals. JEOFFREY K. STROSS, M.D. PARK W. WILLIS, HI, M.D.
University Hospital Ann Arbor, MI 48109 REFERENCES 1. SOLZHENITSYN A: Cancer Ward. New York, Farrar, Straus, & Giroux, 1969 2. STROSS JK, SHASBY DM, HARLAN WR: An epidemic of mysterious cardiopulmonary arrests. N Engl J Med 295:1107-1110, 1976 654
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Angiography in Diabetic Patients TO THE EDITOR: I am writing with reference to the article by Weinrauch and associates ( 1 ) , "Coronary Angiography and Acute Renal Failure in Diabetic Azotemic Nephropathy." As a practicing clinical nephrologist, I wonder how any further information obtained from these dye studies could have been used for the future management of the unfortunate patients. Was coronary bypass surgery contemplated for the patients with severe angina? We were not informed of angina in any of these patients. In my opinion, no information not already known clinically would have excluded these patients from regular hemodialysis therapy. Atherosclerosis is accelerated by hemodialysis therapy, probably more so than by renal transplantation. Finding obstructions in the coronary arteries would not therefore be a contraindication to renal transplant and may in fact be a relative indication for renal transplantation. So, to what useful information are the authors referring? If the information is academic, then it should be labeled as such, and the patients should be so informed. I ask that the authors inform their readers of the therapeutic implications of ventriculography, which, as mentioned, required a larger dose of dye and therefore presented a greater risk of developing renal failure. I am flabbergasted that 13 patients could have been subjected to angiography, when resulting renal failure must have been obvious long before all 13 were studied. In fact, two patients had suffered from acute renal failure from previous dye infusions! Can we know what the 12th and 13th patients were told before they were studied? I am deeply ashamed of this series of studies because we all share a collective responsibility to these patients, and I am unable to justify the series of events as described. I would be very interested to hear the authors' comments, and could we be informed of the ultimate renal function after the episodes of acute renal failure in these patients? DESMOND J. SHAPIRO, M.D., C.H.P., M.R.C.P.
Community Hemodialysis Center 431 Doyle Park Drive Santa Rosa, CA 95405 REFERENCE 1. WEINRAUCH LA, HEALY RW, LELAND OS JR, et al: Coronary angiography and acute renal failure in diabetic azotemic nephroppathy. Ann Intern Med 86:56-59, 1977
f o THE EDITOR: I read with astonishment and distress the report by Weinrauch and colleagues (Ann Intern Med 86:56-59, 1977) of acute renal failure after coronary angiography in 12 of 13 patients with azotemic nephropathy from juvenile-onset diabetes. We are told the patients were studied "to assess expected patient survival" but are subsequently told that the patients were studied to ascertain the cause of pulmonary edema, to differentiate those with "fluid overload from those with true myocardial ischemia." Whatever the reasons, they appeared rather hazy to me. What remains inexplicable is how the authors persisted with the study despite an appalling 92% occurrence of renal failure, which must have been vividly apparent before all 13 patients had undergone coronary angiography and which should have prompted early cessa-
tion of the study. The authors themselves were aware they were dealing with a high-risk group, for they quoted previous reports dealing precisely with the risk of contrast studies in azotemic diabetic patients. One is left with the feeling that serious ethical considerations were neglected with continuation of an extremely high-risk procedure that was primarily elective. RAYMOND D. ADELMAN, M.D.
Sacramento Medical Center 4301 X Street Sacramento, CA 95817
brief, three of the four deaths resulted from severe coronary artery disease not detectable by noninvasive methods currently available. In summary, prospective renal allograft recipients and donors were actively engaged in decision-making by means of studies designed to elucidate the risks of surgery and to determine those patients in whom asymptomatic coronary artery disease might jeopardize longevity and raise serious doubts as to the wisdom of transplantation. L. A. WEINRAUCH, M.D. R. W. HEALY, M.D. O. S. LELAND, J R . , M.D. H. H . GOLDSTEIN, M.D. S. D. KASSISSIEH, M.D.
In reply:
J. A . LlBERTINO, M.D. F . J. T A K A C S , M . D . , F . A . C . P .
We feel compelled to correct some misapprehensions that are raised in the letters of Drs. Shapiro and Adelman. All of our patients were juvenile-onset diabetic patients with terminal renal failure and could be expected to need dialysis in less than 12 months ( 1 ) . The rationale for cardiac studies before a decision on ultimate therapy (liverelated or nonliving-related transplantation, or hemodialysis alone) is to define those patients at highest risk of nonsurvival due to cardiovascular mortality. Our experience and that of other major centers (2) suggest that the mortality in this population is largely accounted for by pre-existent coronary-artery heart disease. Because no clinical, laboratory, or noninvasive test is definitive in identifying which patients have underlying coronary heart disease (none had angina) ( 3 ) , we continue to believe that coronary angiography is needed. Dealing with living-related transplantation involves the need to provide enlightened parents and siblings with objective data on expected recipient survival before they can possibly donate a vital organ in a truly informed manner. This is not to say that nonliving-related transplantation should be done indiscriminately. Misuse of a cadaveric organ should be avoided as well, since the kidney wasted in a foolhardy surgical endeavor might have provided another person with a life free of hemodialysis. We hope that studies such as this will enable us to differentiate reliably between candidates for living-related versus nonliving-related transplantation. The references that we have cited have uniformly considered angiography and urography as low-risk procedures even in diabetics. In addition, no previous study had correlated degree of toxicity with volume of contrast (4, 5 ) . Because our studies documented an average increment in creatinine of 3 mg/dl in diabetics with end-stage renal failure, our present practice is to defer angiography until an access for dialysis has been established and to eliminate ventriculography in some instances. At 6-month follow-up, one nontransplanted patient with severe three-vessel coronary artery disease had died from a myocardial infarction, four patients were on maintenance dialysis, and seven patients had undergone successful renal transplantation from living-related donors. The 13th patient, who had not suffered acute renal damage, had also been successfully transplanted from a living-related donor by that time. Two-year follow-up revealed three additional deaths: two from myocardial infarctions in maintenance dialysis patients with severe three-vessel coronary artery disease, and the third from postimmunosuppression sepsis. Three patients were alive on chronic dialysis. The remaining six patients were alive with functioning allografts. In
J. A . D ' E L I A , M . D . , F . A . C . P .
New England Deaconess Hospital 185 Pilgrim Road Boston, M A 02215 REFERENCES 1. KUSSMAN MJ, GOLDSTEIN HH, GLEASON RE: The clinical course
of diabetic nephropathy. JAMA 236:1861-1863, 1976 2. SHIDEMAN JR, BUSELMEIER TJ, KJELLSTRAND CM: Hemodialysis
in diabetics, complications in insulin-dependent patients accepted for renal transplantation. Arch Intern Med 136:1126-1130, 1976 3. WEINRAUCH LA, HEALY RW, D'ELIA JA, et al: Coronary and
ventricular angiographic findings in azotemic juvenile type diabetics evaluated for renal transplantation (abstract). Circulation 54 (suppl2):163, 1976 4. DOUST BD, REDMAN HC: Myth of 1 ml/kg in angiography:
study to determine relationship of contrast medium dosage to complications. Radiology 104:557-560, 1972 5. OLDER RA, MILLER JP, JACKSON DC, et al:
Angiographically
induced renal failure and its radiographic detection. Am J Roentgenol 126:1039-1045, 1976
Adriamycin and Radiation Reactions TO THE EDITOR: In the September issue {Ann Intern Med 85:294-298, 1976) Greco and associates reported that combination chemotherapy with adriamycin enhanced radiation reactions in skin and esophagus in 10 patients receiving concurrent therapy for small-cell anaplastic carcinoma of the lung. These observations were made in 1975. Two other reports have been published on these same patients, plus about 12 others from the National Institutes of Health (NIH) ( 1 , 2 ) . These reports and unpublished results from 48 patients treated at Vanderbilt University Medical Center help shed additional light on the true frequency, severity, and cause of esophageal and skin reactions. Merrill and associates (1) reported a high occurrence rate of anorectal inflammatory disease ( 3 2 % ) and sepsis in the same 22 patients from the N I H treated for smallcell carcinoma of the lung. The authors thought that the degree of granulocytopenia induced by the chemotherapy was the major predisposing factor in these patients. The first 10 of these patients were the same patients described by Greco and associates in the September issue of Annals of Internal Medicine. Johnson, Brereton, and Kent (2) later reported therapeutic results in 21 patients (including the original 10 patients) and again mentioned the enhanced radiation reactions of skin and esophagus and anorectal inflammatory complications. The therapeutic regimen was intensive and included radiation therapy to the bulk disease plus prophylactic whole-brain radiotherapy concurrently Comments and Correction
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with a cyclic combination of Cytoxan® (usually 1500 mg/m 2 intravenously), adriamycin (40 mg/m 2 intravenously) and vincristine (2 mg). The mean interval between cycles was 20.5 (=t 3.7) days. The doses were not usually attenuated but given as soon as the total leukocyte count exceeded 3500 cells/ mm3. The hematologic toxicity was "considerable," with a mean neutrophil nadir of 85/mm 2 (range, 0 to 300). Although toxicity was "appreciable," their results may be a therapeutic advance in patients without demonstrable metastasis outside the chest or supraclavicular areas. We have used a similar regimen at Vanderbilt, but we have given chemotherapy only after a 21-day interval and have adjusted dosages downward at this time depending on the blood counts. Treatment of 48 consecutive patients with small-cell carcinoma in this fashion has resulted in no unusual esophageal or skin reactions. The tumor response rate is similar to that of Johnson and associates (2), but it is too early to evaluate survival. Therefore, in addition to the radiosensitizing effect of adriamycin and scheduling of radiotherapy, the intensity of the chemotherapy was probably a major factor responsible for the enhanced radiation reactions in esophagus and skin as reported in the September issue. F. ANTHONY GRECO, M.D. ROBERT K. OLDHAM, M.D.
Division of Oncology Vanderbilt University Medical Center Nashville, TN 37232 REFERENCES 1. MERRILL J, BRERETON HD, KENT CH, et al: Anorectal disease in patients with non-haematologized malignancy. Lancet 1:11051107, 1976 2. JOHNSON RE, BRERETON HD, KENT CH: Small-cell carcinoma of the lung: attempt to remedy causes of past therapeutic failure. Lancet 2:289-291, 1976
Deoxycholate or Amphotericin B in Chemotherapy Sensitization TO THE EDITOR: The use of amphotericin B as a sensitizing
agent during combination chemotherapy in human neoplasia has been reported by Presant, Klahr, and Santala (1). An implication of the lack of an important control population in this study deserves comment. The commercial preparation of amphotericin B, Fungizone® (E. R. Squibb, Princeton, New Jersey), is prepared with 41 mg of sodium deoxycholate to every 50 mg of amphotericin B. The deoxycholate is used to form a colloidal dispersion because crystalline amphotericin B is insoluble in water. Both amphotericin B and deoxycholate have cell-membrane altering effects that can increase the uptake of certain antitumor drugs. The synergistic effect seen with Fungizone and BCNU against AKR leukemia was attributed to the amphotericin B by Medoff and associates (2). However, Kessel (3) reported that the increased uptake of dactinomycin in LI210 cells was due to the detergent effect of deoxycholate. Similarly, daunorubicin uptake in Chinese hamster cells resistant to daunorubicin was increased when the cells were treated with the nonionic detergent Tween 80® (polysorbate 80). Because it is not clear from investigation done in vitro which agent would be responsible for changes in antitumor activity of a drug combination in vivo, it is perhaps premature to recommend the addition of Fungizone to a 656
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chemotherapeutic regimen as suggested by Presant and associates. Life-threatening reactions from Fungizone occur with sufficient frequency to make it unwise to administer it if deoxycholate alone could produce similar results. I suggest that Presant and associates plan to include as a control population in their future studies patients who would receive deoxycholate plus chemotherapy to assess the role of deoxycholate in the sensitizing effects of Fungizone. STEVEN D. REICH, M.D.
Departments of Pharmacology and Medicine Northwestern University Chicago, IL 60611 REFERENCES 1. PRESANT CA, KLAHR C, SANTALA R: Amphotericin B induction of sensitivity to adriamycin, 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU) plus cyclophosphamide in human neoplasia. Ann Intern Med 86:47-51, 1977 2. MEDOFF G, VALERIOTE F, LYNCH RG, et al: Synergistic effect of amphotericin B and 1,3-bis (2-chloroethyl)-l-nitrosourea against a transplantable AKR leukemia. Cancer Res 34:974-978, 1974 3. KESSEL D: Alteration of cell permeability barriers by amphotericin B-deoxycholate (Fungizone) in vitro. Biochem Pharmacol 25: 483-485, 1976 4. RIEHM H, BIEDLER JL: Potentiation of drug effect by Tween 80 in Chinese hamster cells resistant to actinomycin D and daunomycin. Cancer Res 32:1195-1200, 1972
In comment: The comments by Dr. Reich are appropriate because Fungizone is a mixture of amphotericin B plus sodium deoxycholate. However, no data exist to conclusively identify which of the two chemicals is related to the clinical effect observed in our studies (1, 2 ) . The data of Kessel (3) are confusing. A careful analysis of his data shows that Fungizone produced a much greater increase in uptake of dactinomycin by LI210 cells than did either "pure" amphotericin B or deoxycholate at a concentration equal to that in the Fungizone. This greater effect by the combination of chemicals in Fungizone might be expected if deoxycholate increased the availability of amphotericin B. Only in concentrations two and a halffold higher did the deoxycholate produce an enhancement of dactinomycin uptake quantitatively similar to that observed with lower doses of Fungizone. Similar experiments on dactinomycin uptake in dactinomycin-resistant HeLa cells have produced contradictory results (4). Dactinomycin uptake, dactinomycin inhibition of RNA synthesis, and dactinomycin-induced morphologic changes were enhanced by the addition of Fungizone but not by two-fold higher concentrations of deoxycholate. Other data make it less likely that the effect we observed in vivo is due to deoxycholate. Cures of mice with LI210 leukemia were observed with Fungizone plus BCNU. These cures were not observed with deoxycholate plus BCNU (5). In addition, cures were observed with BCNU plus amphotericin methyl ester, a water-soluble form of amphotericin B that does not include deoxycholate (MEDOFF G, VALERIOTE F, unpublished observations). Furthermore, the immunopotentiation induced in mice by Fungizone is also seen with the use of amphotericin methyl ester but is not observed with either deoxycholate or photoinactivated amphotericin B (LITTLE JR, BLANKE TJ, VALERIOTE F et
al: Immunoadjuvant properties of amphotericin B, in Modulation of Host Immune Resistance in the Prevention or
Treatment of Induced Neoplasias, edited by CHIRIGOS MA. New York, Raven Press, 1977, in press). In addition we have studied in-vitro nitrogen mustard uptake by human ovarian carcinoma cells obtained from ascites fluid. Fungizone enhanced nitrogen mustard uptake by these cells in a dose-dependent fashion, but deoxycholate did not increase nitrogen mustard accumulation in tumor cells (PRESANT C, CARR D, submitted for publication). Possibly the clinical effects observed by us (1, 2) are mediated by deoxycholate. Further experimental trials are first needed to define the frequency of improvement induced by Fungizone. If a frequent effect is confirmed, trials would be indicated to determine whether amphotericin B or deoxycholate was the effective agent. In such trials, one should select the agent most likely to produce the effect. The experimental data cited above indicate that amphotericin B rather than deoxycholate is likely to be the active ingredient. Amphotericin methyl ester, which is water soluble, might be the more suitable drug form for such a trial. CARY A. PRESANT, M.D. CAROL KLAHR, M.S., R.N. ROGER SANTALA, M.D.
The Jewish Hospital of St. Louis 216 South Kings Highway St. Louis, MO 63110 REFERENCES
1. PRESANT CA, KLAHR C, SANTALA R: Amphotericin B induction
of sensitivity to adriamycin, 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU) plus cyclophosphamide in human neoplasia. Ann Intern Med 86:47-51, 1977 2. PRESANT CA, KLAHR C, OLANDER J, et al: Amphotericin B plus
1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU-NSC No. 409962) in advanced cancer. Cancer 38:1917-1921, 1976 3. KESSEL D: Alteration of cell permeability barriers by amphotericin B-deoxycholate (Fungizone) in vitro. Biochem Pharmacol 25:483-485, 1976 4. MEDOFF J, MEDOFF G, GOLDSTEIN MN, et al: Amphotericin B
induced sensitivity to actinomycin D in drug-resistant HeLa cells. Cancer Res 35:2548-2552, 1975
three more aspirations during the next 4 weeks yielded E. coli. On the 46th hospital day leukemic remission occurred, after which the cellulitis rapidly resolved. A 27-year-old man undergoing treatment of acute myelogenous leukemia had shown no evidence of infection, despite profound granulocytopenia. Six days after insertion of a heparin-lock needle, he experienced pain at the site and the device was removed. Within 4 h the site had become erythematous, swollen, and exquisitely tender, and he was febrile (39.5 °C). An aspirate showed few leukocytes but sheets of large-Gram-negative bacilli on smear. Cultures of the aspirate and blood were subsequently positive for Klebsiella pneumoniae. Despite treatment with cephalothin and gentamicin, leukocyte infusions, and two attempts at surgical drainage, the area of cellulitis progressively increased in size, and the patient died of refractory infection and active leukemia 50 days after the onset of infection. Clearly no type of vascular cannula is absolutely safe, especially in highly susceptible patients such as those of the two cases presented. In each instance, the heparin-lock needle had been in place for more than 72 h and sepsis was heralded by local pain. Available data suggest that continuous intravenous therapy with small metal needles is substantially safer than with plastic catheters, even when the cumulative daily incidence of infection is analyzed; about two needles per 1000 infusions produce septicemia (2, 3 ) . However, needle-related septicemia appears to be more frequent in patients with cancer or those otherwise significantly immunocompromised ( 3 ) . Concerning risk of infection, heparin-locks are probably equivalent to continuous infusion therapy through scalp-vein needles. The risk of septicemia and phlebitis (1) caused by heparin-lock needles also rises with increasing duration of use. Thus the safest course when using heparin-locks, especially in patients who are neutropenic or otherwise highly susceptible, is to rotate the site every 48 to 72 h routinely (2, 3 ) . Pain or other signs of inflammation, unexplained fever, or signs of sepsis should prompt immediate removal and culture of the needle. WILLIAM A. AGGER, M.D. DENNIS G. MAKI, M.D., F.A.C.P.
5. MEDOFF G, VALERIOTE F, LYNCH RG, et al: Synergistic effect
of amphotericin B and 1,3-bis (2-chloroethyl)-l-nitrosourea against a transplantable AKR leukemia. Cancer Res 34:974-978, 1974
Septicemia from Heparin-Lock Needles TO THE EDITOR: Heparin-lock needles are widely used for intravenous administration of antineoplastic drugs. Until the report by Ferguson and associates ( 1 ) , no information was available on the safety of these devices. These investigators encountered no systemic infections with 221 heparin-locks in 78 patients, but most of their patients were not immunosuppressed. We report two cases of patients with leukemia in whom cellulitis and septicemia developed with infection derived from heparin-lock needles. An 82-year-old man receiving chemotherapy for treatment of acute myelogenous leukemia was severely granulocytopenic ( 104 meq/litre and serum phosphate < 3 . 5 mg/dl correctly predicted the diagnosis of primary hyperparathyroidism in 29 of the 34 patients ( 8 5 % ) , without any false-positive diagnosis. A similar result is achieved, when these limits are applied to the values of the patients reported by Palmer and associates ( 3 ) . We later studied two further patients with paraneoplastic hyperparathyroidism. Both of them showed serum chloride and phosphate levels similar to those found in primary hyperparathyroidism. We thus conclude that in a substantial fraction of the hypercalcemic patients with normal renal function the diagnosis of primary hyperparathyroidism can be predicted by the simple screening method of measuring the serum chloride and phosphate concentrations. The differentiation between primary hyperparathyroidism and other causes of hypercalcemia seems to be almost complete, except for paraneoplastic hyperparathyroidism, which cannot be distinguished from primary hyperparathyroidism. A N T T I ARO, M.D.
Department of Medicine University of Kuopio SF-70210Kuopio21 Finland Hypercalcemia: Serum Chloride and Phosphate
RISTO PELKONEN, M.D.
Third Department of Medicine TO THE EDITOR: In the December 1976 issue Pak
and
Townsend (1) questioned the usefulness of the serum chloride/phosphate ratio in the diagnosis of primary hyperparathyroidism. Our experience indicates that the measurement of serum chloride and phosphate concentrations is of diagnostic value in hypercalcemia, even though the chloride/phosphate ratio has proved ineffective also in our practice. We recently studied a series of 64 patients with hypercalcemia for a review article published in Finnish ( 2 ) . Included were 40 patients with surgically proven primary hyperparathyroidism, 17 with malignant disease, most of them with skeletal involvement, four with vitamin D intoxication, and three with sarcoidosis. The serum chloride (in meq/litre)/phosphate (in mg/dl) ratio was less than 33, a limit initially suggested (3, 4 ) , in five (12.5%) of the hyperparathyroid patients, whereas the ratio exceeded this limit in eight (47%) of the patients with malignant disease. The results thus are in agreement with those of Pak and Townsend (1) in that there is a wide overlap of values, which limits the usefulness of the chloride/phosphate ratio in the differential diagnosis of hypercalcemic states. Serum chloride and phosphate concentrations are, however, of diagnostic importance, when the results are interpreted in another way, by looking at the combination of the individual values, as expressed in Figure 1. A serum chloride concentration exceeding 104 meq/litre together with a serum phosphate concentration of less than 3.5 mg/dl was found in 32 of the 40 patients with primary hyperparathyroidism whereas only two patients with malignant disease, both showing impaired renal function, showed a similar pattern. One of the two patients had multiple myeloma and severe renal failure and had been treated by peritoneal dialysis. She had serum chloride of 119 meq/litre and phosphate of 3.1 mg/dl. The other patient had primary carcinoma of the liver; the hypercalcemia 664
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University of Helsinki SF-00290 Helsinki 29 Finland A R T O SIVULA, M . D .
Second Department of Surgery University of Helsinki SF-00290 Helsinki 29 Finland REFERENCES
1. PAK CYC, TOWNSEND J: Chloride/phosphorus in primary hyperparathyroidism. Ann Intern Med 85:830, 1976 2. ARO A: Differential diagnosis of hypercalcaemia. Duodecim (Helsinki) 91:436-447, 1975 3. PALMER FJ, NELSON JC, BACCHUS H: The chloride-phosphate
ratio in hypercalcemia. Ann Intern Med 80:200-204, 1974 4. REEVES CD, PALMER F, BACCHUS H, et al: Differential diagnosis
of hypercalcemia by the chloride/phosphate ratio. Am J Surg 130:166-171, 1975
Thyroid Hormones in Chronic Renal Failure TO THE EDITOR: In their recently published paper Spector
and associates (1) report on thyroid function and metabolic state in chronic renal failure. In their uremic patients they found low serum 3, 5, 3'-triiodothyronine (T3) and low serum free T3 in contrast to normal free thyroxine (T4) and thyroid-stimulating hormone (TSH) serum levels. Total serum T4 concentrations were in the lower normal range. They point out the similarity of these findings with the results reported for hepatic cirrhosis and various other severe nonthyroidal illnesses in which serum T3 levels are markedly decreased in spite of normal total T4 serum concentrations. This is apparently a result of diminution of peripheral conversion of T4 to T3, which can be due either to a shift of T4 conversion from T3
Table 1. Serum Concentrations of Thyroid Hormones in Uremic Patients Total T4
Total T3
rT3
TSH
ng/dl
ng/dl
nV/ml
~M/dl Controls (n = 30) Mean ± SD 8.2 ± 2.0 124 ± 46 Range 4.0 - 12.5 70 - 190 Uremic patients (n = 14) Mean ± SD 6.0 ± 2.0 81 ± 33 Range 3.3 - 10.4 37 - 133
21.9 + 2.7 3.1 ± 2.0 15.9 - 25.2 0.9 - 8.7 13.0 ± 7.0 2.6 ± 1.6 1.0 - 22.8 0.9 - 4.6
towards reverse T 3 ( 3 , 3'^'-triiodothyronine = r T 3 ) ( 2 )
or to a decrease in the overall deiodinative metabolism of T4 (3). To further elucidate this abnormality in peripheral hormone metabolism we have additionally measured rT3 serum levels in 14 uremic patients on chronic intermittent hemodialysis (Table 1). As can be seen from this table our mean total T3, total T4, and TSH serum levels correspond well with the data reported by Spector and associates. The mean rT3 serum level is markedly reduced in our uremic patients compared with the control level. This excludes a shift of T4 conversion towards rT3 and indicates a decrease in overall deiodinative metabolism of T4 in uremia, because both products of monodeiodination of T4 (T3, rT3) are diminished. This is in contrast to the situation found in most of the diseases Spector and associates refer to, where a shift of T4 conversion towards rT3 is suggested by low total T3 and high rT3 serum levels. MICHAEL WEISSEL, M.D. H. KRISTER STUMMVOLL, M.D. AXEL WOLF, M.D. HEINZ FRITZSCHE, M.D.
Department of Nuclear Medicine, Division of Nephrology Second Medical Department University of Vienna A-1090, Vienna Austria
radiotherapists would consider that dosages of 2400 to 3000 rad to the pituitary at the normal rate of 1000 rad per week are therapeutically inadequate. Thus two of these subjects cannot be properly evaluated. These patients were presented against a background of the suggestion that irradiation to the pituitary before bilateral adrenalectomy may prevent Nelson's syndrome, in part predicated on the findings of Orth and Liddle (2). These latter investigators had treated 19 patients with pituitary irradiation before total adrenalectomy and in none did Nelson's syndrome ensue. In view of the paucity of data available in this regard, we wish to bring to the authors' and readers' attention the report of Wild and associates (3) in 1972, which Moore and colleagues inadvertently overlooked in their review of the literature. Wild and associates reported a patient with Cushing's syndrome treated with 4500 rad who developed Nelson's syndrome after bilateral adrenalectomy and refer briefly to two other such instances available. Wild and associates pointed out that "although the experience to date indicates pituitary irradiation may reduce the incidence of Nelson's syndrome, its effectiveness has not been precisely established. For this reason, failures of such therapy should be reported. This may also clarify whether there is a point of time in the course of the treatment of Cushing's syndrome when pituitary irradiation is most effective". J. L. GABRILOVE, M.D. G. L. NlCOLIS, M.D., PH.D. Mount Sinai School of Medicine • City University of New York New York, N Y 10029 REFERENCES 1. MOORE TJ, DLUHY RG, WILLIAMS GH, et al:
Nelson's syn-
drome: frequency, prognosis and effect of prior pituitary irradiation. Ann Intern Med 85:731-734, 1976 2. ORTH DN, LIDDLE GW: Results of treatment in 108 patients with Cushing's syndrome. N Engl J Med 285:243, 1971 3. WILD W, NICOLIS GL, GABRILOVE JL: Appearance of Nelson's
syndrome despite pituitary irradiation prior to bilateral adrenalectomy for Cushing's syndrome. M Sinai J Med NY 40:68, 1973
REFERENCES 1. SPECTOR DA, DAVIS PJ, HELDERMAN JH, et al: Thyroid function
and metabolic state in chronic renal failure. Ann Intern Med 85:724-730, 1976 2. CHOPRA IJ, CHOPRA U, SMITH SR, et al: Reciprocal changes in
serum concentrations of 3,3',5'-triiodothyronine (Reverse T3) and 3,3',5'-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab 41:1043-1049, 1975 3. NICOD P, BURGER A, STAEHELI V, et al: A radioimmunoassay for
3,3',5'-triiodo-L-thyronine in unextracted serum: method and clinical results. J Clin Endocrinol Metab 42:823-829, 1976
Nelson's Syndrome
From their study of Nelson's syndrome Moore and colleagues (1) reported nine patients with the disorder out of 120 patients treated for Cushing's syndrome. Of these nine only two had received prior pituitary irradiation; one having received 3000 rad, the other 5000. They cite a case from Salassa's and associates' series of pituitary tumors in patients with Cushing's syndrome who was reported without comment to have developed a pituitary tumor subsequent to pituitary irradiation with 2400 rad and bilateral subtotal adrenalectomy. Most TO THE EDITOR:
Jake Walk in Vietnam
The recent paper by Morgan and Tuloss, 'The Jake Walk Blues" (Ann Intern Med 85:804-808, 1976) on paralytic disease caused by poisoning with triortho-cresyl phosphate, reminded me of tragic outbreaks of this affliction that occurred in the Quang Tri Province of Viet Nam during 1970-71. While serving with a medical assistance team, (Navy MILPHAP N-4), assigned to work within the local health care system in the northernmost province of South Vietnam, I observed small clusters of Vietnamese patients with newly developing spastic quadriplegia. This epidemic paralysis peculiarly attacked family groups. As noted by Morgan and Tuloss, muscle pain was a common feature of the syndrome (in its early course), there was little or no sensory deficit, and the resulting spastic gait had a jerky, stumbling character. Some persons with the condition associated its onset with preceding use of a "black market" cooking oil, which on investigation proved to be a tri-ortho-cresyl containing U.S. military aviation lubricant supplied to South Vietnamese helicopter units. TO THE EDITOR:
Comments and Correction
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Notification of U.S. and South Vietnamese military authorities of the problem had little effect, and sporadic outbreaks occurred in the area throughout 1970-71. The widening use of helicopters in underdeveloped areas among unsophisticated peoples, particularly in situations of disaster when basic food commodities are in short supply, may lead to similar sad outbreaks in the future. DAVID T. DENNIS, M.D.
U.S. Naval Medical Research Unit No. 2 Jakarta Detachment APO San Francisco, CA 96356
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Correction: Misspelled Name The editorial office is responsible for a misspelled name in the March issue of Annals of Internal Medicine. On pages 267, 303, and 322, the name should have read Alexander Solomon Wiener.
