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
CORRESPONDENCE
and, as such, may have many uses in addition to the treatment of MH and NMS [3]. Finally, the similarities between NMS and MH suggest that this patient may be susceptible to MH during subsequent administration of anesthetics. Caroff et al [4] reported that muscle biopsies from NMS survivors were positive for MH susceptibility in five of seven cases. It will be important for the future anesthetic care of this patient that her physicians be able to choose anesthetic agents that do not “trigger” MH episodes. CECELIAHARD, M.D. Pasadena, California
1. Lane JT. Boudreau RJ, Kinlaw WB. Disappearance of muscular calcium deposits during resolution of prolonged rhabdomyolysis-induced hypercalcemia. Am J Med 1990; 89: 523-5. 2. Guze BH. Baxter LR. Neuroleptic malignant syndrome. N Engl J Med 1985; 313: 163-6. 3. Britt B. editor. Malignant hyperthermia. Boston: Martinus Nijhoff Publishing, 1987: 326-67. 4. Caroff SN, Rosenberg H. Fletcher JE. HeimanPatterson TD. Mann SC. Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 1987; 67: 20-5. Submitted
January 4, 1991, and accepted
March 18. 1991
The Reply: Dr. Hard makes the point that administration of dantrolene could have ameliorated the clinical course of our patient. Unfortunately, we were not asked to see her until after the development of hypercalcemia. We agree that
September
1991 The American
preemptive use of dantrolene could conceivably have reduced the extent of her rhabdomyolysis, and therefore may have reduced the mass of calcium deposited. This would require very early recognition of the syndrome. We are unaware of reports of efficacy of dantrolene or other compounds in the treatment of established hypercalcemia following the resolution of rhabdomyolysis-induced renal failure. JAMES T. LANE, M.D. Universitv of Minnesota ROBERTJ. &O~DREAU,M.D. University of Minnesota Minneapolis, Minnesota WILLIAM B. KINLA w III, M.D. Dartmouth Medical School Hanover, New Hampshire
Journal
of Medicine
Volume
91
323
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
CORRESPONDENCE
and, as such, may have many uses in addition to the treatment of MH and NMS [3]. Finally, the similarities between NMS and MH suggest that this patient may be susceptible to MH during subsequent administration of anesthetics. Caroff et al [4] reported that muscle biopsies from NMS survivors were positive for MH susceptibility in five of seven cases. It will be important for the future anesthetic care of this patient that her physicians be able to choose anesthetic agents that do not “trigger” MH episodes. CECELIAHARD, M.D. Pasadena, California
1. Lane JT. Boudreau RJ, Kinlaw WB. Disappearance of muscular calcium deposits during resolution of prolonged rhabdomyolysis-induced hypercalcemia. Am J Med 1990; 89: 523-5. 2. Guze BH. Baxter LR. Neuroleptic malignant syndrome. N Engl J Med 1985; 313: 163-6. 3. Britt B. editor. Malignant hyperthermia. Boston: Martinus Nijhoff Publishing, 1987: 326-67. 4. Caroff SN, Rosenberg H. Fletcher JE. HeimanPatterson TD. Mann SC. Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 1987; 67: 20-5. Submitted
January 4, 1991, and accepted
March 18. 1991
The Reply: Dr. Hard makes the point that administration of dantrolene could have ameliorated the clinical course of our patient. Unfortunately, we were not asked to see her until after the development of hypercalcemia. We agree that
September
1991 The American
preemptive use of dantrolene could conceivably have reduced the extent of her rhabdomyolysis, and therefore may have reduced the mass of calcium deposited. This would require very early recognition of the syndrome. We are unaware of reports of efficacy of dantrolene or other compounds in the treatment of established hypercalcemia following the resolution of rhabdomyolysis-induced renal failure. JAMES T. LANE, M.D. Universitv of Minnesota ROBERTJ. &O~DREAU,M.D. University of Minnesota Minneapolis, Minnesota WILLIAM B. KINLA w III, M.D. Dartmouth Medical School Hanover, New Hampshire
Journal
of Medicine
Volume
91
323
