Letters and Corrections
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Aerosolized Pentamidine and Conjunctivitis
To the Editor: Pentamidine is commonly used to treat patients with Pneumocystis carinii pneumonia. Al-though often effective, the drug is frequently associat-ed with adverse effects when administerassociat-ed parenteral-ly. These effects include an elevation of transaminase levels, nausea, vomiting, hypoglycemia, azotemia, ane-mia, fever, and leukopenia; pain at the injection site or sterile abscess formation can occur when the drug is given intramuscularly ( 1 ) . The incidence of these side effects has ranged from 5 0 % to 8 3 % ( 1 , 2 ) . Aerosol-ized pentamidine therapy has been found efficacious in less severe cases of P. carinii pneumonia, and signifi-cantly fewer adverse effects have been reported (2, 3 ) . Coughing and bronchospasm appear to be the com-monest adverse effects, although neutropenia, rash, fe-ver, and hypoglycemia have been reported (2, 4 ) . We report a case of chemical conjunctivitis associated with aerosolized pentamidine therapy. To our knowledge, this adverse effect has not been reported previously.
A 31-year-old man previously diagnosed as having the acquired immunodeficiency syndrome had a cough and hypoxia, and lung infiltrates were seen on a chest roentgenogram. Pneumocystis carinii pneumonia was diagnosed on the basis of findings from bronchoaveo-lar lavage. Because of a history of sulfa intolerance, the patient was treated with intravenous pentamidine. He responded well to therapy, and after 7 days,
thera-py was administered by the aerosol route to complete a 21-day course. Four days after the aerosol therapy was begun, the patient had blurry vision, eye discom-fort, and conjunctival erythema without a purulent ex-udate. A n ophthalmologist felt that the patient had chemical conjunctivitis. During aerosol therapy, the patient often removed the mouthpiece of his nebulizer
(Respigard II, Marquest Medical Products, Inc., En-glewood, Colorado) from his mouth to talk with oth-ers in the rooms; this removal resulted in the misdirec-tion of the aerosol mist toward his face. The exposure of his eyes to this mist may have been the source of the conjunctival irritation. When this practice was stopped, the conjunctivitis gradually resolved without specific therapy, despite continued pentamidine ministration. Chemical conjunctivitis is a possible ad-verse effect of aerosolized pentamidine therapy, and should be avoided by minimizing the exposure of the eyes to the nebulized mist.
D. Alec Lindley, MD Charles J. Schleupner, MD
University of Virginia School of Medicine Veterans Administration Medical Center Salem, VA 24153
References
1. Andersen R, Boedicker M, Ma M, Goldstein EJC. Adverse reactions associated with pentamidine isethionate in AIDS patients: recommenda-tions for monitoring therapy. Drug Intel] Clin Pharm. 1986;20:862-8. 2. Conte JE Jr, Hollander H, Golden JA. Inhaled or reduced-dose
in-travenous pentamidine for Pneumocystis carinii pneumonia. Ann Intern Med. 1987;107:495-8.
3. Montgomery AB, Luce JM, Turner J, et al. Aerosolized pentamidine as sole therapy for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet. 1987;2:480-3. 4. Karboski JA, Godley PJ. Inhaled pentamidine and hypoglycemia
[Letter]. Ann Intern Med. 1988;108:490.
Vibrio vulnificus and Pulmonary Infection
To the Editor: I read with interest the article by Klontz and colleagues (1) on syndromes of Vibrio
vulnificus infections. In August 1986, a 60-year-old man with a history of alcoholism fell into the waters of the Inner Harbor in Baltimore after having a cardio-pulmonary arrest. H e was successfully revived and ad-mitted to a community hospital. On his second day of hospitalization, he had a fever of 40 °C. The leukocyte count was 16 000 mm3, with a profound left shift (69 band forms). A chest roentgenogram showed infil-trates in his right lower lobe and left upper lobe. H e also had transient diarrhea for 72 hours. Sputum
cul-tures grew Vibrio cholerae and Vibrio vulnificus, and
blood cultures, Vibrio species. After he was treated with tetracycline and gentamicin for 14 days, the pul-monary infiltrates resolved. His stool cultures were negative for organisms.
Ramesh Sabapathi, MD
Columbia, M D 21044 Reference
1. Klontz KC, Lieb S, Schreiber M, Janowski HT, Baldy LM, Gunn RA. Syndromes of Vibrio vulnificus infections: clinical and epidemio-logic features in Florida cases, 1981-1987. Ann Intern Med. 1988;109:318-23.
Placement of Peritoneal Catheters
To the Editor: The position (1) paper on clinical com-petence in acute peritoneal dialysis urges that bedside techniques for placing peritoneal catheters be prac-ticed in nephrology programs. Like clinicians in many, if not most, larger nephrology programs, we prefer placing soft "chronic" peritoneal catheters rather than the more rigid stylet catheters for treating patients with acute renal failure as discussed elsewhere ( 2 ) . Briefly, use of such placement avoids repeated abdom-inal punctures for intermittent therapies, allows great-er mobility and comfort during the treatment, pgreat-ermits the use of continuous peritoneal dialysis (even ambu-latory in some patients), and eases the transition to chronic care if necessary. The increasing interest in continuous peritoneal dialysis for treating patients with hypercatabolic acute renal failure was neglected in the paper ( 3 ) .
Bedside techniques for placing " c h r o n i c " catheters exist and, in experienced hands, such techniques can yield good results. At most medical centers, however, catheters are usually placed by surgeons in the operat-ing room settoperat-ing. In the position paper, placoperat-ing a cath-eter is described as "relatively simple"; in contrast, most clinicians who are experienced in the field believe that the proper placement of a " c h r o n i c " catheter with one or two cuffs requires an experienced operator to avoid cuff extrusion, exit-site problems, and catheter migration ( 4 ) .
In the beginning of the paper, the authors explain that catheter placement may involve the surgical inser-tion of a Tenckhoff catheter into the abdomen and that one physician may place the catheter and another physician may manage the dialysis. They even state, " I n such cases, staff privileges should be granted ac-cordingly." Paradoxically, they later state, "Beginning in 1988, certification in the subspecialty of nephrology by the American Board of Internal Medicine implies competence in the cognitive and technical skills required to do acute peritoneal dialysis." The summa-rized technical skills include the ability to place a peri-toneal catheter. Thus, the authors recognize that ne-phrologists may not be involved in catheter placement at some centers, and yet they later mandate such train-ing.
Blood access for extracorporeal blood purification through subclavian and femoral cannulations makes the utilization of hemodialysis, continuous arteriove-nous hemofiltration, slow continuous ultrafiltration, and continuous arteriovenous hemofiltration with he-modialysis popular choices in very ill patients. Perito-neal dialysis is no longer the only choice for rapid initiation of treatment ( 5 ) .
My concern is that in programs in which bedside techniques are not routinely used, (probably for good reasons based on local experience and talents) stylet catheter placements or bedside catheter placements will be used to treat patients not because they are the best choice for the patient, but because trainees must satisfy board requirements ( 5 ) .
In many medical centers, the placement of a perito-neal catheter is a surgical procedure and should not be mandated for nephrology training any more than should kidney transplantation, the creation of an ar-teriovenous fistula, or an open renal biopsy.
Karl D. Nolph, MD
University of Missouri, Health Sciences Center Columbia, M O 65212
References
1. Health and Public Policy Committee, American College of Physi-cians. Clinical competence in acute peritoneal dialysis. Ann Intern Med. 1988;108:763-5.
2. Nolph KD. Peritoneal dialysis in acute renal failure. In: Brenner BM, Lazarus JM, eds. Acute Renal Failure. New York: Churchill Living-stone; 1988:809.
3. Katirtzoglov A, Kontesis P, Myopoulou-Symvoulidis D, et al. Con-tinuous equilibration peritoneal dialysis ( C E P D ) in hypercatabolic renal failure. Perit Dial Bull. 1983;3:178.
4. Twardowski ZJ, Nolph KD, Khanna R, Prowant BF, Ryan LP, Nich-ols WK. The need for a "swan neck" permanently bent, arcuate peri-toneal dialysis catheter. Perit Dial Bull. 1985;5:219-23.
5. Twardowski ZJ, Nolph KD. Blood purification in acute renal failure (editorial). Ann Intern Med. 1984;100:447-9.
Cefuroxime Dosage in Renal Failure
To the Editor: Drug Prescribing in Renal Failure by
Bennett and colleagues (1) possibly contains a mis-print. This excellent reference provides dosage recom-mendations for various drugs when prescribed for pa-tients with differing degrees of renal dysfunction.
For patients with an estimated glomerular filtration rate of less than 10 m L / m i n , Bennett and colleagues recommend 5 % - 1 0 % of the usual intravenous cefu-roxime dosage. If the usual dose of 750 mg is given every 8 hours, patients will receive 112 to 225 mg dai-ly. Ten percent of the dosage for life-threatening infec-tions (1.5 g every 6 hours) provides 600 mg daily. In contrast, the manufacturer of cefuroxime (Zincef, Glaxo, Research Triangle Park, N o r t h Carolina) rec-ommends a daily dose of 750 mg for these pa-tients ( 2 ) .
The two studies ( 3 , 4) of cefuroxime cited by Ben-nett and colleagues also support a daily dose of 750 mg. Chan and colleagues ( 3 ) describe the pharmaco-kinetics of cefuroxime in 16 patients on peritoneal di-alysis who received a single dose of 15 m g / k g body
weight. Because of the serum concentrations and elim-ination half-lives of cefuroxime measured in these pa-tients, the authors conclude that 15 m g / k g • d is suffi-cient to treat most gram-positive infections (except for peritonitis). In a patient who weighs 70 kg, a 15-mg/ kg dose provides 1050 mg of cefuroxime, an amount clearly higher than 10% of the usual recommended dose. Obviously, this study of cefuroxime in single doses cannot rule out the accumulation of the drug with continued dosing.
In the other study (4) by Walstad and colleagues, five patients with renal dysfunction were treated with cefuroxime for urinary tract infections. Patients with a creatinine clearance of 20 m L / m i n or greater were prescribed 750 mg twice daily while those with a creat-inine clearance of less than 20 m L / m i n were given 750 mg daily (two patients had a creatinine clearance of 10 m L / m i n or less). All patients had a satisfactory response to treatment without side effects. Serum cefu-roxime concentrations obtained on the first day and on the sixth or seventh day of therapy showed no accu-mulation of the drug.
These data suggest that a single daily 750-mg dose of cefuroxime is appropriate for treating patients with a creatinine clearance of less than 10 m L / m i n . If the dosage recommended in the handbook is an error, cli-nicians should be notified because this reference is widely used in many hospitals.
Thomas G. Cantu, PharmD DavidFantozzi, RPh
Johns Hopkins Hospital Baltimore, M D 21205 References
1. Bennett WM, Aronoff GR, Golper TA, Morrison G, Singer I, Brater DC. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. Philadelphia: American College of Physicians; 1987. 2. Glaxo. Zincef. In: Physician's Desk Reference. Oradell, New Jersey:
Medical Economics Company, Inc.; 1988.
3. Chan MK, Browning AK, Poole CJ, Matheson LA, Li CS, Baillod RA. Cefuroxime pharmacokinetics in continuous and intermittent peritoneal dialysis. Nephron. 1985;41:161-5.
4. Walstad RA, Nilsen OG, Berg KJ. Pharmacokinetics and clinical effects of cefuroxime in patients with severe renal insufficiency. Eur J Clin Pharmacol. 1983;24:391-8.
In response: The dosage recommended in Drug Pre-scribing in Renal Failure (1) was calculated by
com-paring the cefuroxime elimination rate in patients with normal renal function with that measured in patients with impaired renal function. Walstad and colleagues (2) determined the correlation between the total cefu-roxime clearance and creatinine clearance in five pa-tients with a creatinine clearance of less than 25 m L / min. F r o m their data, cefuroxime clearance in anuric patients is 5 % of that predicted for patients with nor-mal renal function. Similarly, cefuroxime clearance in patients with a creatinine clearance of 10 m L / m i n is 1 3 % of that predicted for patients with normal renal function. These data corroborate those of Buntzen and coworkers ( 3 ) , who found that the cefuroxime elimi-nation rate constant in anuric subjects was 10% of the elimination rate shown for patients with normal renal function.
Cefuroxime, like many other beta-lactam antibiotic agents, has a wide therapeutic range. The pharmacoki-netic data support the dose reduction recommendation
in Drug Prescribing in Renal Failure that 5% to 10%
of the normal dose be given to patients with renal fail-ure. We doubt that the manufacturer's recommenda-tion for these patients, which is 1 3 % of that recom-mended for persons with normal renal function, would result in toxic drug accumulation. In fact, because the antibiotic agent is packaged in mg vials and 750-mg infusion packs, a single daily dose of 750 750-mg in patients with renal failure would be convenient.
Our dosage recommendations are based on the
pharmacokinetic data. As we emphasize in the intro-duction of the book, these dosage tables should not be considered as a fixed approach but as an initial at-tempt to arrive at an effective dosage. The appropriate use of our reference requires that physicians use sound clinical judgment in caring for patients with renal dis-ease, evaluate each situation, choose a drug regimen on the basis of all of the factors, and continually reevaluate patients' response to therapy.
George R. Aronoff, MD
University of Louisville Louisville, K Y 40292
William M. Bennett, MD
Oregon Health Sciences University Portland, O R 97201
References
1. Bennett WM, Aronoff GR, Golper TA, Morrison G, Singer I, Brater DC. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. Philadelphia: American College of Physicians; 1987. 2. Walstad RA, Nilsen OG, Berg KJ. Pharmacokinetics and clinical
effects of cefuroxime in patients with severe renal insufficiency. Eur J Clin Pharmacol. 1983;24:391-8.
3. Buntzen RW, Toothaker R, Nielson OS, Madsen PO, Welling PG, Craig WA. Pharmacokinetics of cefuroxime in normal and impaired renal function: comparison of high pressure liquid chromatography and microbiological assays. Antimicrob Agents Chemother. 1981;19:443-9.
Death with Dipyridamole-Thallium Imaging
Dipyridamole-thallium 201 cardiac imaging is a sensi-tive and specific test for detecting coronary artery dis-ease in patients unable to exercise effectively (1-3). Minor side effects from dipyridamole administration are common; however, morbidity is rare, and death has never been reported.
A 77-year-old woman was hospitalized for increas-ingly severe, atypical chest pain. Her medical history showed hypertension and calf claudication. The re-sults of recent echocardiographic study had shown concentric left ventricular hypertrophy, with normal contractility and aortic valve thickening. The peak aortic gradient was 20 m m Hg by Doppler study. Physical examination showed bilateral carotid bruits and fine bibasilar rales. Heart sounds were normal, except for an apical S4 and a grade 2 / 6 systolic mur-m u r at the base. Peripheral pulses were absent. The resting electrocardiogram showed left ventricular
hy-pertrophy, with secondary ST segment and T-wave ab-normalities.
The patient's chest pain spontaneously abated, and an acute myocardial infarction was ruled out. After she was given dipyridamole, 400 mg orally, thallium imaging was done to further assess chest pain. The baseline blood pressure was 138/70 m m Hg, and the pulse rate, 103 beats/min. After 20 minutes, the blood pressure fell to 124/80 m m Hg, and the pulse rate increased to 135 beats/min. ST segment depression 3 to 4 m m below baseline appeared in leads II, III, and V4-V6 in association with substernal chest pain. The imaging study was aborted after 45 minutes when the patient developed cardiovascular collapse. Initially, she was refractory to treatment with intraveous ami-nophylline, dopamine, atropine, and saline solution. After her hemodynamic condition transiently stabi-lized, terminal electromechanical dissociation devel-oped. Permission for a postmortem examination was denied.
After the oral administration of 200 to 400 mg of dipyridamole preparatory to thallium imaging, chest pain has developed in 2 0 % to 2 7 % of patients, and ischemic ST segment changes in 10% to 14% of pa-tients (1-3). Theophylline, an effective antidote, may be needed in 4 % to 2 7 % of patients to abort major or prolonged symptoms. Complex ventricular arrhythmi-as, an infrequent complication, are generally transient and readily treated (4, 5 ) .
Because the severity of aortic stenosis in elderly per-sons may be clinically difficult to quantify, an underes-timated valvular obstruction may have contributed to the fatal outcome of our patient. Patients presenting with suspected coronary artery disease in the setting of aortic stenosis may be at increased risk for life-threatening complications from oral dipyridamole and should be preferentially referred to cardiac catheter-ization.
Harold Z. Friedman, MD ScotF. Goldberg, MD Andrew M. Hauser, MD
William W. O'Neill, MD
William Beaumont Hospital Royal Oak, M I 48072
References
1. Homma S, Callahan RS, Ameer B, et al. Usefulness of oral dipyrid-amole suspension for stress thallium imaging without exercise in the detection of coronary artery disease. Am J Cardiol. 1986;57:503-8. 2. Taillefer R, Lette J, Phaneuf D, Leveille J, Lemire F, Essiambre R.
Thallium-201 myocardial imaging during pharmacologic coronary vasodilatation: comparison of oral and intravenous administration of dipyridamole. J Am Coll Cardiol. 1986;8:76-83.
3. Borges-Neto S, Mahmarian J J, Jain A, Roberts R, Verani M S . Quantitative thallium-201 single photon emission computed tomogra-phy after oral dipyridamole for assessing the presence, anatomic loca-tion and severity of coronary artery disease. / Am Coll Cardiol. 1988;11:962-9.
4. Bayliss J, Pearson M, Sutton GC. Ventricular dysrhythmias follow-ing intravenous dipyridamole durfollow-ing "stress" myocardial imagfollow-ing. Br J Radiol. 1983;56:686.
5. Blumenthal MS, McCauley CS. Cardiac arrest during dipyridamole imaging. Chest. 1988;93:103-4.
Numeric Discrepancies in Article on Myocardial Ischemia
To the Editor: I would like to bring to your attention the following errors in the article by Nesto and col-leagues ( 1 ) . These errors are in addition to the one already noted in the previous erratum ( 2 ) .
On page 172, the authors state, "Twenty-five pa-tients were treated with insulin, and 25 were treated with oral agents." In contrast, Table 4 shows that 38 of the diabetic patients were receiving insulin and 12 were receiving oral agents.
Table 1 shows the findings in 38 male diabetic pa-tients and 12 female diabetic papa-tients. In Table 4, how-ever, 39 of the diabetic patients are male and 13 fe-male. Table 4 also shows that 38 (29 + 9) diabetic patients did not have angina, whereas the correct number should be 36, as indicated in the footnote to Table 4 and elsewhere in the paper.
In Table 1, 30 diabetic patients are shown as having hypertension, but in Table 4, only 29 diabetic patients are listed as having hypertension. Table 1 shows that 22 of the diabetic patients smoke, whereas Table 4 shows that 23 of the diabetic patients smoke.
In Table 1, 12 of the diabetic patients are shown as having anterior Q waves, and 11 as having inferior Q waves by electrocardiography. Table 4, however, shows
10 diabetic patients as having anterior Q waves and 13 as having inferior Q waves by electrocardiography.
These inconsistencies stand in marked contrast to the near perfect matching in clinical characteristics, indications for testing, and results of testing between the diabetic and nondiabetic groups of patients. For example, 4 4 % of patients in both groups smoked; 2 4 % and 2 6 % were female, 2 8 % and 2 6 % had hyper-lipidemia, and 8 % and 6 % previously had coronary artery bypass grafting or percutaneous transluminal coronary angioplasty. I am uncertain why a relatively small series of consecutive patients should be nearly identical.
The diabetic patients did have a higher prevalence of hypertension, but had no difference in the extent of ischemia and infarction compared with the nondiabet-ic patients as shown in Table 3. It seems unusual that the diabetic patients with a higher prevalence of hy-pertension had no more ischemia and infarction than the nondiabetic patients.
The clinical characteristics of the diabetic patients with and without angina as shown in Table 4 are also remarkably similar. F o r example, 6 4 % of both groups have a positive family history (9 of 14 patients and 23 of 36 patients), and 14% have retinopathy (2 of 14 patients and 5 of 36 patients). It is surprising that a small group of diabetic patients compared on the basis of whether or not they had angina on a positive thalli-um exercise test should be so closely matched.
T h e thallium results in Table 3 are, as the authors state, "identical" for all the groups compared. Howev-er, there seems to be less statistical variation than might be expected.
The previously published correction ( 2 ) should have caused the authors to search the paper for other
errors, which they apparently did not do. A t the least, the authors have not been responsible authors as de-fined by H u t h ( 3 ) .
Lee C. Abel, MD
University of Arkansas for Medical Sciences Little Rock, A R 72205
References
1. Nesto RW, Phillips RT, Kett KG, et al. Anginal and exertional myo-cardial ischemia in diabetic and nondiabetic patients: assessment by exercise thallium scintigraphy. Ann Intern Med. 1988;108:170-5. 2. Huth EJ. Correction: angina in exertional myocardial ischemia in
diabetic and nondiabetic patients [Letter]. Ann Intern Med. 1988;108:646.
3. Huth EJ. Authorship from the reader's side. Ann Intern Med. 1982;97:613-4.
Adult T-cell Leukemia and Interferon-Alpha
To The Editor: We report a case of adult-T-cell leuke-mia in a patient successfully treated with natural inter-feron-alpha.
A 37-year-old woman was hospitalized in March 1986 for nodular erythemas of the chest, abdomen, and extremities. The results of peripheral blood stud-ies showed leukocytosis (20 0 0 0 / m m3) , with convo-luted lymphocytes ( 7 0 % ) , positive anti-human T-cell lymphotropic virus (HTLV)-I-antigen antibody, and a high C D 4 : C D 8 ratio. Convoluted lymphocytes also infiltrated in bone marrow ( 2 6 . 4 % ) . She was diag-nosed as having adult-T-cell leukemia. The repeated administration of combination chemotherapy with cy-clophosphamide, doxorubicin, vincristine, and prednis-olone failed to achieve a remission. She was hospital-ized in November 1987 because the erythema wors-ened and the number of leukemic cells increased. Three million units of natural human interferon-alpha was injected intramuscularly everyday. Seven days af-ter inaf-terferon-alpha therapy had been initiated, erythe-mas faded and only pigmentation remained. The ab-normal cells in the peripheral blood disappeared, and the C D 4 : C D 8 ratio returned to normal. Abnormal cells occupied less than 5 % of the cells in bone mar-row. After remission was achieved, 6 million units of interferon-alpha was injected three times a month. She has been in remission for more than 10 months.
The therapy for patients with adult-T-cell leukemia has not yet been established ( 1 ) . Various chemothera-py regimens seldom result in remission. Moreover, im-munosuppression often occurs, which results in severe infections. The use of interferon therapy for patients with adult T-cell leukemia is controversial ( 2 ) . As our case shows, however, this therapy is occasionally effec-tive. We recommend interferon-alpha as the first choice for treating patients with this disease.
Yoshiaki Ohbayashi, MD Akio Urabe, MD
Kazuo Niitani, MD
K a n t o Teishin Hospital, Tokyo 141, Japan
References
1. Uchiyama T, Yodoi J, Sagawa K, et al. Adult T cell leukemia: clinical and hematological features of 16 cases. Blood. 1977;50:481-91. 2. Tamura K, Makino S, Araki Y, et al. Recombinant interferon beta
and gamma in the treatment of adult T-cell leukemia. Cancer. 1987;59:1059-62.
Tamoxifen and Premenopausal Breast Cancer
To the Editor: In his excellent review (1) of tamoxifen in the treatment of breast cancer, Legha concludes that "adjuvant use of tamoxifen in premenopausal women with stage II breast cancer has not been shown to be useful and should be avoided." As the author himself has noted, the Nolvadex Adjuvant Treatment Organization ( N A T O ) and Scottish Cancer Trial G r o u p have shown that the adjuvant use of tamoxifen improved the disease-free and overall survival of pre-menopausal women (2, 3 ) . T h e number of premeno-pausal patients with stage II breast cancer in the Scot-tish trial was not stated; however, all premenopausal women in the N A T O trial had stage II disease.
Legha's concern may not have been questioned if he had cautioned against the use of tamoxifen as adjuvant therapy for premenopausal patients with estrogen-receptor-negative and node-positive tumors because the likelihood that patients with receptor-negative tu-mors would respond to tamoxifen therapy is less than
10% ( 4 ) . The reason to withhold tamoxifen therapy, however, in premenopausal patients with estrogen- or progesterone-receptor-positive tumors who have posi-tive axillary lymph nodes is not clear. Legha warned against the possible detrimental effect of tamoxifen therapy in such situations, especially when used with chemotherapy. Perhaps he could have discussed this important point in greater detail. W h a t should be the ideal initial adjuvant therapy for premenopausal pa-tients with node-positive, receptor-positive tumors? Should tamoxifen therapy be given (for several years or indefinitely) with chemotherapy when a relapse oc-curs, or should combination chemotherapy be given as advocated by National Institutes of Health Consensus Development Conference ( 5 ) ? Also, has a prospec-tive, randomized study addressed this question?
Amin U. Hag, MD
Veterans Administration Medical Center East Orange, N J 07019
References
1. Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med. 1988;109:219-28.
2. Nolvadex Adjuvant Trial Organization. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer. Lancet. 1985;1:836-9.
3. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Adjuvant tamoxifen in the man-agement of operable breast cancer: the Scottish Trial. Lancet. 1987;2:171-5.
4. McGuire WL, Horwitz KB, Pearson OH, Segaloff A. Current status of estrogen and progesterone receptors in breast cancer. Cancer. 1977;39:2934-47.
5. Consensus conference: adjuvant chemotherapy for breast cancer. JAMA. 1985;254:3461-3.
In response: H a q has correctly stated that adjuvant therapy with tamoxifen was shown to be useful in the trial carried out by the Nolvadex Adjuvant Trial Or-ganization ( N A T O ) in premenopausal women with node-positive tumors, regardless of their estrogen-receptor status. His statement that the adjuvant use of tamoxifen in the Scottish trial also improved the dis-ease-free and overall survival of premenopausal wom-en with stage II breast cancer, however, is incorrect. Patients with node-positive tumors were excluded from this trial, which largely comprised postmenopau-sal women with stage I and stage II breast cancer. Premenopausal women were included only if they had negative axillary nodes. Thus, although both of these British trials have reported a beneficial effect from ad-juvant tamoxifen therapy in patients with node-negative tumors, regardless of their receptor status, the usefulness of tamoxifen therapy in premenopausal women with positive axillary nodes has only been ob-served in the single ( N A T O ) trial and remains to be confirmed.
A c c o r d i n g l y , t h e current therapy r e c o m m e n d e d for
premenopausal women with node-positive and recep-tor-positive tumors is combination chemotherapy, as indicated by the recent update of the recommenda-tions of the National Institutes of Health consensus conference ( 1 ) . Whether therapy with tamoxifen alone will prove as effective as chemotherapy remains to be established by the results of ongoing trials com-paring these two treatment options. On the other hand, the preliminary results of an ongoing study
(B-14) by the National Surgical Adjuvant Breast and Bowel Project ( N S A B P ) show a significant increase in the disease-free survival of premenopausal patients with stage I disease and estrogen-receptor-positive tu-mors who were treated with tamoxifen. (Unpublished data.) It is very likely that tamoxifen will be useful in treating patients with node-positive tumors as well, but this theory remains to be established beyond doubt.
Sewa S. Legha, MD
M . D . Anderson Cancer Center Houston, T X 77030
Reference
1. Glick JH. Commentary: meeting highlights: adjuvant therapy for breast cancer. JNCI. 1988;80:471-5.
Repeated Fetal Losses and the Lupus Anticoagulant
To the Editor: Combined therapy with prednisone and low doses of aspirin has been reported to reduce the risk for fetal loss in women with the lupus anticoagu-lant ( 1 , 2 ) . We report a case in which a woman with the lupus anticoagulant had had three successive fetal losses while receiving this combined therapy. The out-come of a fourth pregnancy was favorable when she was given high-dose intravenous polyvalent immuno-globulin therapy.
A 24-year-old woman had episodes of deep venous thrombosis and pulmonary embolism when she was 18, 19, and 22 years of age. She was found to have the lupus anticoagulant but no other evidence of autoim-mune disease was noted. The patient was hospitalized in the second month of her first pregnancy for throm-bocytopenia (platelets, 20 X 1 09/ L ) . She received therapy with prednisone (1.5 m g / k g body weight • d ) and with heparin of low-molecular weight, which had no effect on the activated partial thromboplastin time and the platelet count. Fetal death occurred in the fourth month of this pregnancy.
In October 1985 and April 1986, two other preg-nancies ended by spontaneous abortion after she had had amenorrhea for 10 weeks, despite treatment with prednisone, low-molecular weight heparin, and aspirin since the first month. Thereafter, she received predni-sone (10 m g / d ) for recurrent thrombocytopenia.
At the beginning of her fourth pregnancy in March 1987, the activated partial thromboplastin time was prolonged 2.8-fold. Despite treatment with prednisone (0.75 m g / k g • d ) , the platelet count decreased 1 month later. After administration of intravenous poly-valent immunoglobulin (400 m g / k g • d for 5 d ) , a transient rise in the platelet count and a decrease in the activated partial thromboplastin time occurred. A persistent increase in the platelet count (140 X 109/ L ) and a less than 1.8-fold prolongation in the activat-ed partial thromboplastin time were achievactivat-ed with the repeated administration of polyvalent immunoglobulin twice a week.
In October 1987, the patient had a caesarean section because of preeclampsia; she gave birth to a male child weighing 2.1 kg. Her platelet count and activated par-tial thromboplastin time were normal for the term of her pregnancy. The cessation of polyvalent immuno-globulin and maintenance of prednisone therapy re-sulted in the immediate reappearance of a 2.7-fold pro-longation of the activated partial thromboplastin time and a drop in the platelet count (9 X 1 09/ L ) .
High-dose polyvalent immunoglobulin has been ad-ministered before to pregnant women without harmful side effects to the women and fetuses ( 3 ) . Some pa-tients with autoimmune disorders have been success-fully treated by immunoglobulin (4, 5 ) . In our pa-tient, we believe that the polyvalent immunoglobulin therapy played a key role in her successful fourth pregnancy because combined prednisone and aspirin therapy was inefficient during her three previous preg-nancies and the hemostatic abnormalities recurred af-ter the immunoglobulin was discontinued.
In our patient, the activated partial thromboplastin time and platelet count returned to the pretherapy lev-els within 5 days after the infusion of polyvalent im-munoglobulin. The need for such a high dosage of the agent is unknown, but the association with prednisone may have been important. High-dose intravenous po-lyvalent immunoglobulin may be the optimal and saf-est therapy for patients with the lupus anticoagulant who have had repeated fetal losses while receiving combined treatment with prednisone and aspirin.
Be-cause of our findings, trials of high-dose polyvalent immunoglobulin should be carried out.
Anne Francois, MD
Hopital Broussais 75014 Paris, France
Marc Freund, MD Fernand Daffbs, MD
Hopital Notre D a m e de Bon Secours 75014 Paris, France Philippe Remy, MD Martine Aiach, MD Christian Jacquot, MD Hopital Broussais 75014 Paris, France References
1. Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric com-plications associated with the lupus anticoagulant. N Engl J Med. 1985;313:1322-6.
2. Lubbe WF, Butler WS, Palmer SJ, Liggins CG. Fetal survival after prednisone suppression of maternal lupus anticoagulant. Lancet. 1983;1:1361-3.
3. Levery JP, Koontz WL, Liu YK, Howell R. Immunological throm-bocytopenia in pregnancy: use of antenatal immunoglobulin therapy; case report and review. Obstet Gynecol. 1985;66:415-35.
4. Imbach P, Baradun S, D'Apuzzo V, et al. High dose intravenous gamma-globulin for idiopathic thrombocytopenic purpura in child-hood. Lancer. 1981;1:1228-31.
5. Leickly F, Buckley RH. Successful treatment of autoimmune hemo-lytic anemia in common variable immunodeficiency with high-dose intravenous gamma globulin. Am J Med. 1987;82:159-62.
Dementia and Hypoxia
To the Editor: Clarfield (1) listed Alzheimer disease, multi-infarct, depression, alcohol, and drugs as impor-tant causes of the dementias. The causes of the revers-ible dementias were drugs, depression, and metabolic conditions. I report a case that shows an additional cause for reversible dementia.
A n 82-year-old man with a history of excised colon-ic carcinoma and angina was hospitalized after having had weight loss and progressive mental confusion for 3 months. A comprehensive evaluation showed no evi-dence of metastatic disease, metabolic disease, a struc-tural neurologic abnormality, or medication effect. A neurologic consultation concluded that he had a "de-generative syndrome" of unknown cause.
Even though the patient had normal blood gas val-ues on room air ( P 02, 82 m m Hg; P C 02, 36 m m Hg;
p H , 7.46), overnight oximetry was done. The results of this study showed that his oxygen saturation de-creased to between 70 and 79 m m H g while he was asleep. A sleep electroencephalogram failed to docu-ment apnea. Oxygen, 2 L / m i n , was given while the patient was asleep. In a 5-day period, his mental status dramatically improved. H e was discharged and his in-tellectual function showed a complete return to base-line levels. Nocturnal oxygen treatment was continued at home. After an 8-month follow-up, he regained his lost weight and is mentally normal.
Unfortunately, there were no predictors in this case that nocturnal hypoxia was present. Arterial blood
gases, a chest roentgenogram, the results of pulmo-nary function tests, and a sleep electroencephalogram were all normal. Only the results of the overnight oxi-metry study documented the problem. Thus, over-night oximetry must be added to the work-up of patients with dementia because noctunal hypoxia is a potentially reversible cause of dementia.
Michael R. Sand berg, MD
Beth Israel Hospital Boston, M A 02215 Reference
1. Clarfield AM. The reversible dementias: do they reverse? Ann Intern Med. 1988;109:476-86.
Bohr's Principle of Complementarity
To the Editor: In their editorial, Bloom and Kissick (1) invoke Bohr's principle of complementarity in dealing with the socioeconomics of health care. As is often the case with the social sciences, a concept from the physical sciences is exploited for its metaphorical content, while its actual meaning is trivialized, ig-nored, or even worse, misunderstood. The authors maintain that Bohr posited this principle as a "theory" to explain the behavior of "light as a wave or a pulse." This description is incomplete and incorrect.
Complementarity is not so much a theory as it is a principle or dogma posited by Bohr to reconcile seem-ingly contradictory results in the early days of quan-t u m mechanics. These resulquan-ts involved quan-the behavior of fundmental particles of matter under different experi-mental conditions. The dual nature of light—that it behaved both as a wave of energy and as a particle— was a familiar notion by 1922, having been known at least since Lorentz's work before 1900. However, studies of the elementary particles of matter in the early 1920s showed that they also exhibited a dual nature, in that they manifested properties of both a wave or particle, depending on the experimental ditions. Previously, matter and energy had been con-sidered relatively discrete categories, energy being constituted as waves, and matter as particles. The wave-particle duality of light had been tolerated, but these new results from quantum mechanics showed that wave-particle duality was fundamental and irrec-oncilable. Physics faced a theoretical impasse. In 1922, Bohr presented the "Copenhagen interpretation" to find a way out of these straits. According to this "dog-m a , " the wave and particle results were not contradic-tory, but rather complementary: they expressed differ-ent aspects of a single unitary phenomenon that could not be described completely as either a wave or parti-cle, but instead exhibited the properties of both. This principle constituted a profound break with previous epistemology, for it asserted that the experimental re-sults expressed not artifactual contradictions resulting from our own imperfect perceptions, but were rather expressions of a fundamental duality in nature itself.
This principle was a staggering departure from the previous unitary, Platonic drive that underlay three centuries of Western science.
Unfortunately, when Bohr subsequently attempted to explain this principle, he likened it to Eastern concepts of yin and yang, for it imported into the dis-cussion tendency towards glib metaphoric generaliza-tions. This tendency has been given greatest rein out-side the physical sciences themselves, where earnest social scientists, philosophers, and pundits have com-bined an enthusiasm for the metaphoric power of 20th-century physics with an imperfect understanding of its true context and meaning. This tendency is espe-cially unfortunate in instances such as the editorial in question, in which an important concept in physics is invoked gratuitously and incorrectly to impart a false import and sophistication to an otherwise mundane but respectable discussion of health care economics. The author's argument for a catholic tolerance of dif-ferent interpretations of medicine's economic structure is in no way akin to Bohr's bold but necessary asser-tion of complementarity as a saving principle to deliv-er physics from the profoundest of epistemologic dilemmas. T h e authors trivialize Bohr's work by at-tempting to make such comparisons and bring no ad-ditional power to their already cogent discussion. Stephen J. Clark, MD
Birmingham, A L 35294 Reference
1. Bloom BS, Kissick WL. Marxism, the theory of complementarity, and medical care [Editorial]. Ann Intern Med. 1988;109:446-8.
Physicians and the Economics of Practice
To the Editor: Povar and Moreno's article ( l ) o n health maintenance organizations ( H M O s ) was sheer misrepresentation, hyperbole, and bias. This article would have been justified only if it were an editorial. I fail to see how this article passed critical review.
The article misrepresented reality by defending H M O s on the basis of the "staff model," which, in reality, is the model for only a minority of operating H M O s . By their own admission, the authors state that the "independent practice model" is much harder to defend and is fraught with ethical pitfalls. Yet, this model is by far the most prevalent one in operation.
Also misrepresented is the idea that "not-for-profit" systems exist. Not-for-profit systems are such only through the distribution of excess funds through bo-nuses or secondary gains (that is, admissions to hospi-tal-based H M O s ) providing hidden profits. T h e per-sons running these systems are not philanthropists, but business persons intent only on turning a profit.
The authors use hyperbole to suggest that an H M O may save 999 of 1000 patients from unnecessary test-ing. This statement is preposterous. I challenge the authors to name one clinical examination done by fee-for-service physicians that is negative 999 times out of
1000. This statement is obviously intended to preju-dice readers, especially health care administrators, leg-islators, and consumers.
The article is biased. It portrays the fee-for-service physicians as money-grabbing capitalists w h o weigh the value of every test on a monetary scale. I could portray the H M O physicians as underqualified, semi-incompetent persons who could not practice on their own. This viewpoint may be commonly held but is no more accurate than the suggestions of Povar and Moreno.
Finally, I suggest the authors purchase a Webster's dictionary. Something that imposes itself along a path (health care) or between two objects (doctor-patient) is not an advocate. It is an obstacle.
I a m a fee-for-service physician who also treats pa-tients covered by H M O (not by choice). I do not con-sider gains or losses when I order tests. I concon-sider value. Too often I am forced to offer less value and less service to my patients with H M O coverage.
Charles E. Andrews, Jr., MD
W e s t F o r t W o r t h D i a l y s i s Center
Fort Worth, T X 76109 References
1. Povar G, Moreno J. Hippocrates and the health maintenance organiza-tion: a discussion of ethical issues. Ann Intern Med. 1988;109:419-24.
To the Editor: Himmelstein and Woolhandler ( 1 ) are to be congratulated for their thoroughly researched and well-written article. Although Marxism may be as unable as any other philosophical or economic system to describe reality completely (as Bloom and Kissick suggest in their editorial [ 2 ] , many of M a r x ' and En-gels' insightful observations do directly pertain to the
field o f m e d i c i n e .
The modern physician may now, more than in any other period in the history of our profession, be con-sidered a laborer. T h e fact accounts for much of the dissatisfaction within our profession ( 3 ) . As Himmel-stein and Woolhandler state, "physicians [now] find many satisfying aspects of their traditional role chal-lenged" in this process of "proletarianization" ( 1 ) .
Whenever society chooses to regard any profession primarily in economic terms (and the authors have outlined well the recent events most responsible for this modern attitude toward medicine), a loss of re-spect for that profession inevitably follows. T h e theo-retical origin of such an outlook is not in the writings of Marx, but in the famous distinction made by A d a m Smith (a man to whom Marx refers extensively in his writings) between productive and unproductive labor
( 4 ) . Unproductive laborers are those whose labor is "unproductive of any value'' (that is, any "vendible commodity" surviving the laboring process itself). Thus, Smith classifies "churchmen, lawyers, physi-cians, men of letters of all kinds" with "players, buf-foons, musicians" and "menial servants."
A society deriving its system of values primarily from economic considerations degrades all human
ac-tivities to the level of market, or labor, value. Thus, whether that society be composed of Marxists or mod-ern capitalists, it will show little appreciation for or understanding of the greatness that was once part and parcel of the professional life.
John L. Graner, MD
Hines Veterans Administration Hines, I L 60141
References
1. Himmelstein DU, Woolhandler S. The corporate compromise: a Marxist view of health maintenance organizations and prospective payment. Ann Intern Med. 1988;109:494-501.
2. Bloom BS, Kissick WL. Marxism, the theory of complementarity, and medical care. Ann Intern Med. 1988;109:446-8.
3. Graner JL. The primary care crisis. II: Physician as laborer. Humane Med. 1987;3:20-5.
4. Smith A. Of the accumulation of capital, or of productive and unpro-ductive labour. In: Smith A. An Inquiry Into the Nature and Causes of the Wealth of Nations. New York: P.F. Collier & Son Corp.; 1937:258-77.
Financial Help for Housestaff
To the Editor: In the article (1) on stress and impair-ment during residency training, many important issues were raised. The article correctly emphasizes the fi-nancial pressures of student indebtedness on work habits, personal life, and professional choice. Unfortu-nately, the indebtedness of housestaff begins long be-fore the first day of internship. Heavy loan burdens, relatively low salaries, loan deferments, and delayed personal needs lead to a period of negative amortiza-tion during residency training.
As a result, financial advocacy, services, and plan-ning for both medical students and housestaff should be provided to prevent inevitable financial distress. Specifically, financial counseling by properly trained and empowered financial advisors should be given continually from the premedical years through fellow-ship training.
A recent federal program promoting student credit unions could provide continuous financial advocacy services and counseling on a self-supporting and not-for-profit basis from the first year of college to the end of fellowship training. Full services can also be provid-ed to alumni of mprovid-edical schools and residency programs.
Student credit unions, which are being developed at 26 leading U.S. universities and business schools, are federally insured institutions chartered to provide full but educationally oriented financial services to stu-dents, financial counseling to indebted students and alumni, and savings programs for education. These credit unions give students a voice in their financial affairs. The services are financed through interest on deposits, appropriate service fees, and seed deposits by third parties. Credit unions can raise capital at market or submarket rates, accept contributions from third parties, serve as vendors or group purchasers of finan-cial services, and collect loans in a timely fashion.
Because a recent federal ruling reclassified house-staff as full-time, nonpaying students, it has become highly feasible to provide continuous financial advoca-cy services and planning from college through fellow-ship training and beyond under this umbrella pro-gram.
The medical education community should evaluate this program because of the rapidly declining number of applications to medical schools and the loss of inter-est in cognitive specialties.
Bohdan A. Oryshkevich, MD, MPH
Albany, N Y 12208 Reference
1. Resident Services Committee, Association of Program Directors in Internal Medicine. Stress and impairment during residency training: strategies for reduction, identification, and management. Ann Intern Med. 1988;109:154-61.
SI Units in Hematology
To the Editor: In the article by Bach and Colleagues (1) on odynophagia from aphthous ulcers of the phar-ynx and esophagus in the acquired immunodeficiency syndrome ( A I D S ) , the C D 4 cell counts were incor-rect. For Patients 1, 2, and 3, the counts were listed as 12 X 10VL, 383 X 10VL and 97 X 10VL, respec-tively. These counts should no doubt be 0.012 X 10VL, 0.383 X 10VL, and 0.097 X 10VL, or 12 X 10VL, 383 X 10VL, and 97 X 10VL, re-spectively. Errors of this type almost inevitably arise from the conversion of these counts from cell counts per cubic millimetre to cell counts per litre in SI units.
The actual unit to be used for expressing lympho-cyte subsets per unit of blood is somewhat ambiguous. In an article on SI units ( 2 ) , the SI unit of measure for the blood leukocyte count was 109 per litre whereas that for the spinal fluid leukocyte count was 106 per litre. The article also mentions using the conversion factor of 106 as part of the unit, that is times 106 per litre for cell count values. Because lymphocyte subset counts fall between the levels of spinal fluid and blood leukocyte counts, expressing these counts in units of 106 per litre would be more useful. Using this unit of measure would maintain the current numerical values expressed as per cubic millimeter and would thus make the transition to SI units easier.
Thomas J. Spira, MD
Centers for Disease Control Atlanta, G A 30333
References
1. Bach MC, Valenti A J, Howell DA, Smith TJ. Odynophagia from ahpthous ulcers of the pharynx and esophagus in the acquired immu-nodeficiency syndrome ( A I D S ) . Ann Intern Med. 1988;109:338-9. 2. Young DS. Implementation of SI units for clinical laboratory data.
In response: We thank Dr. Spira for noticing the error in our presentation of C D 4 cell counts and agree that the actual values should be 12 X 106/L, 383 X 10VL, and 97 X 106/L. This error shows our continued
con-fusion with the transition to SI units.
Michael C. Bach, MD August J. Valenti, MD Douglas A. Howell, MD
Thomas J. Smith, MD
Portland, M E 04102
Correction: Letter on Primary Sclerosing Cholangitis
In the last paragraph of the letter by Verresen and
colleagues ( 1 ) , the abbreviation PSC was incorrectly written out as "primary sclerosing nephropathy." The first, third, sixth, and seventh sentences of this para-graph should instead refer to "primary sclerosing cho-langitis." The editorial office accepts responsibility for this mistake and apologizes for it.
Also, the end of the fourth paragraph should read, "no reports describe primary sclerosing cholangitis as-sociated with membranous nephropathy," instead of " n o reports describe primary biliary cirrhosis associat-ed with membranous nephropathy."
Reference
1. Verresen L, Waer M, Verberckmoes R, Morias P, Michielsen P. Primary sclerosing cholangitis associated with membranous nephrop-athy [Letter]. Ann Intern Med. 1988;108:909-10.
Correction: Ray, Not Bay
To the Editor: Ewy (1) clearly shows the use of the abdominojugular test in evaluating an increased
cen-tral blood volume in patients. Although the article by Burch and Ray ( 2 ) on the suggested mechanism of the hepatojugular reflux in congestive heart failure is correctly referenced, Dr. Ray is incorrectly referred to as Bay several times in the discussion of this important diagnostic maneuver. As a physician who continues to uphold a tradition of excellence in clinical medicine, Dr. Ray would surely appreciate this correction.
N. Kevin Krane, MD
Tulane University Medical Center New Orleans, L A 70112
References
1. Ewy GA. The abdominojugular test: technique and hemodynamic correlates. Ann Intern Med. 1988;109:456-60.
2. Burch GE, Ray CT. Mechanism of the hepatojugular reflux test in congestive heart failure. Am Heart J. 1954;48:373-82.
Correction: Reference in Article on Chronic Fatigue
To the Editor: I would like to correct reference 13 in my article (1) on the frequency of the chronic fatigue syndrome. In this reference, the name of the journal, the year of publication, and the page numbers should have been / Infect. 1985;10:211-22, not / Infect Dis.
1958;10:212-27!
Peter Man u, MD
University of Connecticut Health Center Farmington, C T 06032
Reference
1. Manu P, Lane TJ, Matthews DA. The frequency of the chronic fa-tigue syndrome in patients with symptoms of persistent fafa-tigue. Ann Intern Med. 1988;109:554-6.
