CORRESPONDENCE
tween patient age and the number of doses of benzodiazepine hypnotic drugs prescribed at a single physician visit. The hospital in which this study was performed, however, had no such limitations on minimum quantities prescribed. ANDREW LLOYD, M.B., B.S. We did not intend our findings IAN HICKIE, M.D. to implicate community physiDENIS WAKEFIELD,M.D. cians, but our results suggest that JOHN D WYER,M.B., B.S.,ph.0 Sydney, Australia the prescribing of sedative-hypnotic drugs should be studied in 1. Oxtoby A, Jones A, Robinson M. Is your ‘doubleblind’ design truly double-blind? Br J Psychiatry other outpatient settings.
I was particularly disturbed by the addendum to the article in which the authors indicate that they have discontinued the evaluation of pulse cyclophosphamide therapy in WG. What the Hoffman study illustrates is that patients with relapsing disease may respond poorly to pulse cyclophosphamide. There is inadequate information to extend this conclusion to patients who present with new-onset disease. Because long-term, oral cyclophos1989; 155: 700-l. RONALD I. SHORR,M.D.,MS. phamide may be quite toxic, I am Nashville, Tennessee disappointed that Dr. Hoffman C.SETHLANDEFELD,M.D. Cleveland, Ohio has elected to discontinue evaluOVERPRESCRIBINGOF STEVENF. BAUWENS,P~~~~.D. ating pulse cyclophosphamide. In South Bend, Indiana an earlier report by Fauci et al BENZODIAZEPINEHYPNOTIC [2], 34% of recipients of oral cyDRUGSIN THE ELDERLY To The Editor: clophosphamide were noted to PULSECYCLOPHOSPHAMIDE develop cystitis. In a more recent In the December 1990 issue, THERAPYFORWEGENER’S Shorr et al [l] went to great study, 47% of patients with WG who received long-term cyclolengths to demonstrate that ben- GRANULOMATOSIS phosphamide developed microzodiazepine hypnotic drugs are To The Editor: being overprescribed in the elderHoffman and associates [l] re- scopic hematuria [3]. In addition port that intermittent high-dose to hemorrhagic cystitis, longly. Their data suggest the elderly (pulse) cyclophosphamide does term cyclophosphamide adminisreceive quantitatively larger prescriptions for these drugs. not induce lasting remissions in tration is clearly associated with I suggest they have overlooked Wegener’s granulomatosis (WG). urothelial neoplasms [4]. This prospective, noncontrolled The present study by Hoffman an important factor. Prescripquestions retions plans that mandate that 3 trial evaluated 14 patients, 12 of raises important months’ supply of medicine be whom were being retreated in a garding management of relapsing prescribed are much more ramsalvage protocol. In fact, eight of WG. To suggest that pulse cyclopant amongst the elderly. It is an 14 (57%) of the patients were said phosphamide should not be evalunfortunate fact that prescripto have relapsing WG. Their uated for efficacy as an initial study indicated that when this treatment of patients with WG is tion design is often dictated by these prescription plans. Their group of patients was treated inappropriate based on the preindictment of the physician com- with pulse cyclophosphamide, an sented data. This study raises immunity is probably incorrect. initial response was frequently portant questions regarding the NICHOLASJ.BELITSOS,M.D., followed by a relapse of WG. use of intravenous versus oral cyF.A.C.G. They concluded that “daily lowclophosphamide, but the findings Baltimore, Maryland dose cyclophosphamide and glu- do not warrant suspending the 1. Shorr RI. Bauwens SF, Landefeld CS. Failure to cocorticoids remain the treatevaluation of pulse cyclophoslimit quantities of benzodiazepine hypnotic drugs for ment of choice for this disease.” phamide for initial management outpatients: placing the elderly at risk. Am J Med 1990; 89: 725-32. What this study does indicate is of WG. that patient8 with relapsing WG JOHNS. COWDERY,M.D. Submitted January 4. 1991, and accepted March University of Iowa College of 13. 1991 may be unresponsive to pulse cyMedicine clophosphamide administration. Iowa City, Iowa The Reply: Treatment was categorized as 1. Hoffman GS, Leavitt RY. Fleisher TA, Manor JR, We appreciate Dr. Belitsos’ com- having failed in the two patients Fauci AS. Treatment of Wegener’s granulomatosis ments. We agree that if our study with new-onset WG. The authors with intermittent high-dose intravenous cyclophoshad been performed in a commuindicate that treatment was con- phamide. Am J Med 1990; 89: 403-10. nity setting, membership in cer- sidered to have failed after 3 2. Fauci AS, Hayes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective and therapeutic expetain prescription plans would be weeks in these two patients. This rience with 85 patients for 21 years. Ann Intern Med an important potential conmay be too early to make a final 1983; 98: 76-85. founder in the relationship be- assessment. 3. Stillwell TJ. Benson RC Jr, DeRemee RA. McDoncompletion of treatment, a time point specifically chosen to allow resolution of the transient adverse effects, to minimize placebo response, and to provide a conservative estimate of the beneficial effect of immunoglobulin therapy.
September 1991 The American Journal of Medicine
Volume 91
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CORRESPONDENCE
mg/dL. We did not believe that pursuing additional treatment with a regimen of unproven efficacy (pulse cyclophosphamide) would be ethical in view of such progression. Both patients subseSubmitted November 29, 1990, and accepted March 13, 1991 quently improved and achieved The Reply: remission after treatment with Dr. Cowdery’s letter regarding daily cyclophosphamide. Howour recent publication on the use ever, since our report has been of pulse cyclophosphamide in the published, both patients have treatment of WG includes interalso experienced cyclophosphapretation of data that requires mide toxicity, hemorrhagic cystifurther clarification. He notes tis, and transitional cell carcinothat 12 of our 14 patients were ma of the bladder, which has led part of a “salvage” arm of our to placement on alternative inprotocol. In fact, only four were vestigational protocols. salvage patients, who we indicatDr. Cowdery concludes that ed were so classified because of our study indicates that patients the inability to achieve complete with relapsing WG may be unreremission with daily cyclophossponsive to pulse cyclophosphaphamide treatment or were re- mide. We in fact observed that 13 moved from such treatment be- of 14 (93%) patients did have uncause of toxicity. The other eight equivocal improvement, but in 11 patients who had previously been patients, improvement was not treated for WG had excellent re- sustained with continued pulse sponses to daily cyclophosphatherapy. mide and glucocorticoids, had We agree with Dr. Cowdery’s sustained complete remission for observations that daily cycloabout 5 years, and were not re- phosphamide is associated with ceiving any immunosuppressive serious toxicity. These observamedications for a mean of 3.3 tions provide our rationale for years (1 to 6.5 years) prior to re- this study and other ongoing inlapse. These patients could have vestigations designed to identify been retreated with daily cyclo- effective alternative approaches phosphamide rather than pulse to the treatment of WG and other cyclophosphamide and therefore vasculitides. were not considered salvage paWe have previously indicated tients. The two patients who had that the investigation of rare disbeen newly diagnosed and treateases, such as WG, suffers from ed with pulse cyclophosphamide the inability to gather large numwere stated by Cowdery to have bers of previously untreated pahad pulse treatment classified as tients [l]. If one were to justify a approach to a failure prematurely, as they costly multicenter were removed from the study af- solve this problem, pilot studies ter 3 weeks. He suggests that such as ours with pulse cyclo“ . . . this may be too early to make phosphamide would have to be a final assessment.” We did indimore encouraging. GARY S. HOFFMAN, M.D. cate that both of these patients RANDI Y. LEAVITT, M.D., Ph.D. had unequivocal life-threatening ANTHONY S. FAUX, M.D. progression of disease within 3 National Institute of Allergy and Infectious Diseases weeks following pulse therapy. In Bethesda, Maryland one case, diffuse pulmonary hemorrhage led to prolonged use of Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, mechanical ventilation, and in 1.Fauci AS. Treatment of Wegener’s granulomatosis the other, the serum creatinine with intermittent high-dose intravenous cyclophoslevel increased from 3.3 to 5.5 phamide. Am J Med 1990; 89: 403-10. ald TJ, Weiland LH. Cyclophosphamide-induced bladder toxicity in Wegener’s granulomatosis. Arthritis Rheum 1988; 31: 465-70. 4. Fairchild WV, Spence CR, Solomon HD. Gangai MP. The incidence of bladder cancer after cyclophosphamide therapy. J Urol 1979: 122: 163-4.
322
September 1991 The American Journal of Medicine
Volume 91
NEUROLEPTICMALIGNANT SYNDROMEVERSUS MALIGNANT HYPERTHERMIA To the Editor: As an anesthesiologist who has treated several cases of malignant hyperthermia (MH), I read with interest the case report concerning rhabdomyolysis-induced hypercalcemia by Lane et al [l]. They describe a patient who, after anesthesia and the postoperative administration of neuroleptic agents, developed hyperthermia, rhabdomyolysis, and renal failure. The diagnosis was neuroleptic malignant syndrome (NMS). Although the authors rejected the possible diagnosis of MH, it may be important for the subsequent care of this and other patients to point out the similarities between the two entities. In each, fever and muscle rigidity/weakness result from prolonged, generalized muscle contracture. Elevated cytoplasmic calcium levels in response to psychotropic drugs or anesthetic agents produce the muscle contractures. In NMS, the defect in calcium metabolism is believed to be central or presynaptic; in MH, it is peripheral or postsynaptic
PI.
The treatment of both NMS and MH is similar: supportive therapy and dantrolene sodium. Dantrolene has markedly reduced the morbidity and mortality of MH episodes, and has proven to be effective in NMS as well. Was dantrolene used in the case under discussion? Early intervention with dantrolene may have reduced the extent of rhabdomyolysis and consequent renal failure. In addition, although the authors state that there is no therapy preventing calcium deposition, a number of studies suggest that dantrolene prevents calcium release from the sarcoplasmic reticulum and limits calcium accumulation in the myoplasm. Dantrolene may act as a nonspecific antidote to hypercatabolism
tween patient age and the number of doses of benzodiazepine hypnotic drugs prescribed at a single physician visit. The hospital in which this study was performed, however, had no such limitations on minimum quantities prescribed. ANDREW LLOYD, M.B., B.S. We did not intend our findings IAN HICKIE, M.D. to implicate community physiDENIS WAKEFIELD,M.D. cians, but our results suggest that JOHN D WYER,M.B., B.S.,ph.0 Sydney, Australia the prescribing of sedative-hypnotic drugs should be studied in 1. Oxtoby A, Jones A, Robinson M. Is your ‘doubleblind’ design truly double-blind? Br J Psychiatry other outpatient settings.
I was particularly disturbed by the addendum to the article in which the authors indicate that they have discontinued the evaluation of pulse cyclophosphamide therapy in WG. What the Hoffman study illustrates is that patients with relapsing disease may respond poorly to pulse cyclophosphamide. There is inadequate information to extend this conclusion to patients who present with new-onset disease. Because long-term, oral cyclophos1989; 155: 700-l. RONALD I. SHORR,M.D.,MS. phamide may be quite toxic, I am Nashville, Tennessee disappointed that Dr. Hoffman C.SETHLANDEFELD,M.D. Cleveland, Ohio has elected to discontinue evaluOVERPRESCRIBINGOF STEVENF. BAUWENS,P~~~~.D. ating pulse cyclophosphamide. In South Bend, Indiana an earlier report by Fauci et al BENZODIAZEPINEHYPNOTIC [2], 34% of recipients of oral cyDRUGSIN THE ELDERLY To The Editor: clophosphamide were noted to PULSECYCLOPHOSPHAMIDE develop cystitis. In a more recent In the December 1990 issue, THERAPYFORWEGENER’S Shorr et al [l] went to great study, 47% of patients with WG who received long-term cyclolengths to demonstrate that ben- GRANULOMATOSIS phosphamide developed microzodiazepine hypnotic drugs are To The Editor: being overprescribed in the elderHoffman and associates [l] re- scopic hematuria [3]. In addition port that intermittent high-dose to hemorrhagic cystitis, longly. Their data suggest the elderly (pulse) cyclophosphamide does term cyclophosphamide adminisreceive quantitatively larger prescriptions for these drugs. not induce lasting remissions in tration is clearly associated with I suggest they have overlooked Wegener’s granulomatosis (WG). urothelial neoplasms [4]. This prospective, noncontrolled The present study by Hoffman an important factor. Prescripquestions retions plans that mandate that 3 trial evaluated 14 patients, 12 of raises important months’ supply of medicine be whom were being retreated in a garding management of relapsing prescribed are much more ramsalvage protocol. In fact, eight of WG. To suggest that pulse cyclopant amongst the elderly. It is an 14 (57%) of the patients were said phosphamide should not be evalunfortunate fact that prescripto have relapsing WG. Their uated for efficacy as an initial study indicated that when this treatment of patients with WG is tion design is often dictated by these prescription plans. Their group of patients was treated inappropriate based on the preindictment of the physician com- with pulse cyclophosphamide, an sented data. This study raises immunity is probably incorrect. initial response was frequently portant questions regarding the NICHOLASJ.BELITSOS,M.D., followed by a relapse of WG. use of intravenous versus oral cyF.A.C.G. They concluded that “daily lowclophosphamide, but the findings Baltimore, Maryland dose cyclophosphamide and glu- do not warrant suspending the 1. Shorr RI. Bauwens SF, Landefeld CS. Failure to cocorticoids remain the treatevaluation of pulse cyclophoslimit quantities of benzodiazepine hypnotic drugs for ment of choice for this disease.” phamide for initial management outpatients: placing the elderly at risk. Am J Med 1990; 89: 725-32. What this study does indicate is of WG. that patient8 with relapsing WG JOHNS. COWDERY,M.D. Submitted January 4. 1991, and accepted March University of Iowa College of 13. 1991 may be unresponsive to pulse cyMedicine clophosphamide administration. Iowa City, Iowa The Reply: Treatment was categorized as 1. Hoffman GS, Leavitt RY. Fleisher TA, Manor JR, We appreciate Dr. Belitsos’ com- having failed in the two patients Fauci AS. Treatment of Wegener’s granulomatosis ments. We agree that if our study with new-onset WG. The authors with intermittent high-dose intravenous cyclophoshad been performed in a commuindicate that treatment was con- phamide. Am J Med 1990; 89: 403-10. nity setting, membership in cer- sidered to have failed after 3 2. Fauci AS, Hayes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective and therapeutic expetain prescription plans would be weeks in these two patients. This rience with 85 patients for 21 years. Ann Intern Med an important potential conmay be too early to make a final 1983; 98: 76-85. founder in the relationship be- assessment. 3. Stillwell TJ. Benson RC Jr, DeRemee RA. McDoncompletion of treatment, a time point specifically chosen to allow resolution of the transient adverse effects, to minimize placebo response, and to provide a conservative estimate of the beneficial effect of immunoglobulin therapy.
September 1991 The American Journal of Medicine
Volume 91
321
CORRESPONDENCE
mg/dL. We did not believe that pursuing additional treatment with a regimen of unproven efficacy (pulse cyclophosphamide) would be ethical in view of such progression. Both patients subseSubmitted November 29, 1990, and accepted March 13, 1991 quently improved and achieved The Reply: remission after treatment with Dr. Cowdery’s letter regarding daily cyclophosphamide. Howour recent publication on the use ever, since our report has been of pulse cyclophosphamide in the published, both patients have treatment of WG includes interalso experienced cyclophosphapretation of data that requires mide toxicity, hemorrhagic cystifurther clarification. He notes tis, and transitional cell carcinothat 12 of our 14 patients were ma of the bladder, which has led part of a “salvage” arm of our to placement on alternative inprotocol. In fact, only four were vestigational protocols. salvage patients, who we indicatDr. Cowdery concludes that ed were so classified because of our study indicates that patients the inability to achieve complete with relapsing WG may be unreremission with daily cyclophossponsive to pulse cyclophosphaphamide treatment or were re- mide. We in fact observed that 13 moved from such treatment be- of 14 (93%) patients did have uncause of toxicity. The other eight equivocal improvement, but in 11 patients who had previously been patients, improvement was not treated for WG had excellent re- sustained with continued pulse sponses to daily cyclophosphatherapy. mide and glucocorticoids, had We agree with Dr. Cowdery’s sustained complete remission for observations that daily cycloabout 5 years, and were not re- phosphamide is associated with ceiving any immunosuppressive serious toxicity. These observamedications for a mean of 3.3 tions provide our rationale for years (1 to 6.5 years) prior to re- this study and other ongoing inlapse. These patients could have vestigations designed to identify been retreated with daily cyclo- effective alternative approaches phosphamide rather than pulse to the treatment of WG and other cyclophosphamide and therefore vasculitides. were not considered salvage paWe have previously indicated tients. The two patients who had that the investigation of rare disbeen newly diagnosed and treateases, such as WG, suffers from ed with pulse cyclophosphamide the inability to gather large numwere stated by Cowdery to have bers of previously untreated pahad pulse treatment classified as tients [l]. If one were to justify a approach to a failure prematurely, as they costly multicenter were removed from the study af- solve this problem, pilot studies ter 3 weeks. He suggests that such as ours with pulse cyclo“ . . . this may be too early to make phosphamide would have to be a final assessment.” We did indimore encouraging. GARY S. HOFFMAN, M.D. cate that both of these patients RANDI Y. LEAVITT, M.D., Ph.D. had unequivocal life-threatening ANTHONY S. FAUX, M.D. progression of disease within 3 National Institute of Allergy and Infectious Diseases weeks following pulse therapy. In Bethesda, Maryland one case, diffuse pulmonary hemorrhage led to prolonged use of Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, mechanical ventilation, and in 1.Fauci AS. Treatment of Wegener’s granulomatosis the other, the serum creatinine with intermittent high-dose intravenous cyclophoslevel increased from 3.3 to 5.5 phamide. Am J Med 1990; 89: 403-10. ald TJ, Weiland LH. Cyclophosphamide-induced bladder toxicity in Wegener’s granulomatosis. Arthritis Rheum 1988; 31: 465-70. 4. Fairchild WV, Spence CR, Solomon HD. Gangai MP. The incidence of bladder cancer after cyclophosphamide therapy. J Urol 1979: 122: 163-4.
322
September 1991 The American Journal of Medicine
Volume 91
NEUROLEPTICMALIGNANT SYNDROMEVERSUS MALIGNANT HYPERTHERMIA To the Editor: As an anesthesiologist who has treated several cases of malignant hyperthermia (MH), I read with interest the case report concerning rhabdomyolysis-induced hypercalcemia by Lane et al [l]. They describe a patient who, after anesthesia and the postoperative administration of neuroleptic agents, developed hyperthermia, rhabdomyolysis, and renal failure. The diagnosis was neuroleptic malignant syndrome (NMS). Although the authors rejected the possible diagnosis of MH, it may be important for the subsequent care of this and other patients to point out the similarities between the two entities. In each, fever and muscle rigidity/weakness result from prolonged, generalized muscle contracture. Elevated cytoplasmic calcium levels in response to psychotropic drugs or anesthetic agents produce the muscle contractures. In NMS, the defect in calcium metabolism is believed to be central or presynaptic; in MH, it is peripheral or postsynaptic
PI.
The treatment of both NMS and MH is similar: supportive therapy and dantrolene sodium. Dantrolene has markedly reduced the morbidity and mortality of MH episodes, and has proven to be effective in NMS as well. Was dantrolene used in the case under discussion? Early intervention with dantrolene may have reduced the extent of rhabdomyolysis and consequent renal failure. In addition, although the authors state that there is no therapy preventing calcium deposition, a number of studies suggest that dantrolene prevents calcium release from the sarcoplasmic reticulum and limits calcium accumulation in the myoplasm. Dantrolene may act as a nonspecific antidote to hypercatabolism
