Brief Communications Myopathy in Severe Asthma'>
JO A. DOUGLASS, DAVID V. TUXEN, MALCOLM HORNE, CARLOS D. SCHEINKESTEL, MAX WEINMANN, DANIEL CZARNY, and GLENN BOWES
T
he occurrence of myopathy as a complication of the therapy of severe asthma in patients requiring mechanical ventilation has been described in a number of case reports (1-10). The etiology of this syndrome has not been conclusively established. In a recent case report from this hospital, . acute profound myopathy occurred with the clinical pattern of limb weakness and the histologic changes of muscle cell vacuolation and muscle cell necrosis. The presumed cause ~ was thought to be high dose dexamethasone therapy (1). Several further case reports describing myopathy in severe asthma have suggested corticosteroids as the probable cause of either acute rhabdomyolysis (2, 3) or chronic myopathy (5, 6). In still further reports, the cause has been attributed to myorelaxant medication (7-9) or to accelerated disuse atrophy (5, 10). Myopathy has also been described as a complication of acute asthma in pediatric patients (Hopkins syndrome) (11). The present study was designed to prospectively survey the incidence of both clinical myopathy and the elevation of blood levels of creatine kinase (CK) in consecutive patients who required mechanical ventilation for severe asthma over an 18-month period. The metabolic disturbance and pharmacologic interventions occurring in these patients were documented with the aim of determining likely causative factors. Twenty-five consecutive patients who required mechanical ventilation for severe asthma (mean age, 39 ± 17 yr; five male) were studied over an 18month period. Nineteen patients reported using inhaled salbutarnol on presentation, 16 reported using oral theophylline, 11 reported using inhaled corticosteroids, and eight patients were receiving oral corticosteroid therapy (range, 5 to 50 mg of prednisolone daily). The group's preexisting health status was unremarkable, one patient was an alcoholic, and three patients were smokers. Asthma treatment followed a standard protocol of both ventilatory support and bronchodilator therapy. Ventilatory support was conducted according to the method described by Thxen and Lane (12) to minimize gas trapping but not to necessarily normalize PaC02. Patients were therapeutically paralyzed with suxamethonium to induce paralysis, and a vecuronium infusion was used to maintain paralysis in 22 patients. Bronchodilator therapy consisted of a salbutamol infusion (3 to 20 ug/rnin), nebulized salbutamol (5 mg every 2 h), aminophylline intravenously to achieve therapeutic blood levels, and corticosteroid therapy with either dexamethasone (10 mg every 8 h) or hydrocor-
SUMMARY Myopathy complicating the therapy of severe asthma has been recently described In several case reports. Twenty-five consecutive patients admitted to the intensive care unit (ICU) at this hospital for mechanical ventilation for severe asthma were studied for the Incidence of creatine kinase (CK) enzyme rise and for the development of clinical myopathy. Pharmacologic therapy was standardized, every patient receiving corticosteroids and aminophylline Intravenously and salbutamol both nebulized and intravenously. Twenty-two patients received muscle relaxant therapy with vecuronium.ln 19 of 25 (76%) of patients there was elevation of CK levels to a median of 1,575 U/L (range, 66 to 7,430) occurring 3.6 ± 1.5 days after admission. In nine patients there was clln Ically detectable myopathy. The presence of either myopathy or CK enzyme rise was associated with a significant prolongation of ventilation time. Arterial blood gas measurements on admission to the ICU revealed a pH (mean ± SO) of 7.07 ± 0.21, a PaC02 of 87.2 ± 32.7, and a Pao2 (with a high Flo2) of 129 ± 97 mm Hg; however, no correlation was found between the severity of Initial metabolic disturbance and the subsequent development of myopathy. There was no association between the type of corticosteroid administered and the subsequent development of myopathy. Patients with myopathy had received a significantly higher total dose of vecuronium when compared with those who did not develop myopathy (p < 0.001, Kruskal Wallis test). We have therefore found a surprisingly high Incidence of CK enzyme rise and myopathy in this group of mechanically ventilated patients with severe asthma. The etiology of this problem may be related to the therapeutic regimen, particularly corticosteroids or muscle-relaxant agents. AM REV RESPIR DIS 1992; 146:517-519
tisone (250 mg every 6 h). No intramuscular therapy was used and all patients underwent routine chest physiotherapy daily for the duration of their stay in the intensive care unit (ICU). Paralysis was withdrawn when controlled ventilation was no longer necessary to maintain Pao2 and PaC02. Weaning from mechanical ventilation was attempted when the patient's severe airflow obstruction had significantly resolved as determined by ventilator parameters. Physiologic disturbance was documented on admission by arterial blood gas, blood electrolyte, and CK measurements. CK was documented daily for the duration of ICU admission. Clinical myopathy was documented by scoring according to the severity of myopathy as mild (no muscle group weaker than 4/5), moderate (one or more muscle groups graded less than 4/5), and severe (all limb muscle groups scoring less than 4/5). Patients with myopathy were then reassessed at intervals during the remainder of their admission, and the duration of time elapsed before recovery was noted. EMG and muscle biopsy were performed in some cases. Results are expressed as mean ± SD. Statistical analysis was performed using the "StatWorks" (Macintosh) software package for Wilcoxon's rank sum and Kruskal Wallis tests.
CK levels above 200 U/L (normal < 180U/L) occurred in 19 patients (range, 66 to 7,430 U/L) withthe group median for all 25 patients being 1,575 U/L. The CK peak occurred an average of 3.6 ± 1.5 days after ICU admission and remained elevated for an average of 9.8 ± 5.9 days, In four patients there
was a second peak of CK levels beyond this first CK peak (range, 770 to 21,400 U/L) occurring 18.5 ± 1.9 days after ICU admission. In these four patients the prolonged elevation of CK levels was accompanied by profound muscle weakness. Myopathy was documented in nine patients, all of whom had an elevated CK (median, 3,080 U/L; range, 441 to 7,430 U/L). The clinical pattern was of generalized muscle weakness in eight patients; however, in one patient there was pronounced arm weakness, which was confined to shoulder girdle musculature. The mean duration of myopathy in all nine cases was 27 ± 12 days. Of these nine patients, four had myopathy graded as severe, and all of them had a second peak of CK levels described previously. Two patients had a myopathy graded as moderate, and three had myopathy classified as mild. EMG was performed in four patients and showed a myopathic pattern in all instances. Insertional activity was often re-
(Received in original form August 12, 1991 and in revised form November 18, 1991) 1 From the Department of Respiratory Medicine and Intensive Care, Alfred Hospital, Prahran, Australia. 2 Correspondence and reques ts for reprints should be addressed to Dr. D. V. Tuxen, Intensive Care, Alfred Hospital, Prahran, Victoria 3181 Australia.
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518
BRIEF COMMUNICATION
duced, but spontaneously active sharp waves were present in all cases in which an EMG was performed. Voluntary activated units were of low amplitude, with a tendency to early recruitment, but interference pattern was surprisingly reduced. Muscle biopsy was performed in six patients with clinically detectable myopathy, and in three it revealed rhabdomyolysis or muscle cell vacuolation; in the other three patients it revealed predominantly type 2 fiber atrophy only consistent with disuse atrophy or corticosteroid myopathy. In one patient specimens were taken at postmortem examination, revealing rhabdomyolysis in diaphragmatic muscle but not in specimens from psoas muscle. Admission blood gas analysis revealed that 23 patients had a marked hypercapnic acidosisand that four patients werehypoxic (Pao, < 65 mm Hg) despite high levelsof inspired oxygen (table 1). Seventeen patients had a coexistent respiratory and lactic acidosis. The lowest results for serum potassium (K+), calcium (Ca 2+), phosphate (P0 4 -), and magnesium (Mg2+) ions in the first 24 h of hospital admission are recorded in table 1. There was no significant association between the severity of any documented metabolic disturbance and the subsequent development of CK rise or myopathy. Examination of the patient groups with respect to pharmacologic interventions also failed to revealdifferences in either salbutamol doses or aminophylline doses and blood levels between patients who developed myopathy and those who did not. There was a significantly lowertotal dose of vecuronium used in those patients who did not develop myopathy or blood CK rise (table 1). In the three patients who did not receivevecuronium, only one developed a CK rise, and none developed myopathy. Patients who had developed myopathy were also compared with respect to which corticosteroid they received prior to their initial CK rise. Accordingly, of the nine patients with myopathy, three received hydro-
cortisone, three received dexamethasone, and three received both agents sequentially because of a change in therapy once they were admitted to ICU. In the four patients who developed profound myopathy the dose of corticosteroid was prolonged at high levels because of slow clinical improvement in their asthma. All of these patients received hydrocortisone during the later stages of their ICU admission; however, three of these patients received both corticosteroid agents sequentially in the first 72 h of their admission. Therefore, the type of corticosteroid agent used was not predictive for the subsequent occurrence of myopathy. The dose of corticosteroid employed was according to protocol in 22 patients. However, one patient receiving a smaller dose of hydrocortisone (400 mg per day) developed mild myopathy and an associated modest CK rise (peak, 441UIL), and one other patient receiving 12 mg per day of dexamethasone also developed a CK rise (peak, 569 U/L). Thus, there appears to be no association between the dose of corticosteroid and the development of myopathy or CK rise. Patients were ventilated for an average of 6.6 ± 6.6 days, and ventilation was significantly prolonged in the patients with clinical myopathy (12.9 ± 6.6 days) compared with the patients without myopathy (3.1 ± 3.1 days; p < 0.02, Wilcoxon's rank sum test). The presence of an elevated CK in the absence of clinically detectable myopathy was also significantly associated with prolongation of the time patients were ventilated. Thus, the six patients without CK rise were ventilated for 1.6 ± 0.4 days, whereas those 10 patients without myopathy but with CK rise were ventilated for 4.3 ± 3.5 days (p < 0.01, Wilcoxon's rank sum test). Three deaths occurred in the study group, one because of irreversible brain damage, one as the result of a respiratory arrest after discharge from the ICU, and one from multisystem failure, all of these having a CK rise and one having myopathy. One pa-
TABLE 1 METABOLIC DISTURBANCE AND VECURONIUM DOSAGE IN PATIENT GROUPS WITH AND WITHOUT MYOPATHY AND CREATINE KINASE (CK) ENZYME RISE· All Patients (n = 25) pH Paco2, mm Hg Pao2, mm Hg Lactate, mMolIL K+, mMolIL Ca2+, mMolIL Po 4 , mMolIL Mg2+, mMoI/L Total dose Vecuronium, mg Days paralyzed
7.07 87 129 5.4 3.3 2.18 0.82 0.84
0.21 32 97 2.7 0.6 0.05 ± 0.33 ± 0.15
± ± ± ± ± ±
492 ± 602 2.5 ± 2.5
CK Rise (n = 19)
7.05 90 122 5.4 3.4 2.17 0.79 0.84
± ± ± ± ± ± ± ±
0.20 32 103 2.7 0.6 0.24 0.36 0.16
626 ± 631 3.1 ± 2.5
No CK Rise (n = 6)
7.12 76 150 5.7 3.1 2.26 0.93 0.79
± ± ± ± ± ± ± ±
0.22 35 79 3.4 0.4 0.24 0.08 0.08
68 ± 155t 0.5 ± 0.8
Myopathy (n = 9)
7.11 84 136 5.1 3.3 2.15 0.77 0.84
± ± ± ± ± ± ± ±
0.19 29 124 2.7 0.5 0.14 0.22 0.07
1,065 ± 674t 5.4 ± 2.0
CK Rise No Myopathy (n = 10)
7.00 96 109 5.6 3.5 2.16 0.82 0.85
± ± ± ±
± ± ± ±
0.21 35 86 2.8 0.6 0.25 0.17 0.12
231 ± 163t 1.3 ± 0.9
• Values are mean ± SO. There was no significant difference in the initial metabolic disturbance between patients who developed evidence of a myopathic process and those who did not. t Patients who developed CK rise or myopathy had a significantly greater total dose of vecuronium when compared with patients who did not develop CK rise (p < 0.001, Kruskal Wallis test).
tient suffered a pneumothorax while in the ICU, but otherwise no complications suggesting barotrauma were noted.
*** The incidence of CK rises in patients ventilated for severeasthma was surprisingly high in this patient group, occurring in 19 of 25 (76(10) patients within the first 4 days after admission to the ICU. Nine patients (36(10) also developed clinically detectable myopathy. It is surprising that such a high incidence of myopathy in patients undergoing mechanical ventilation for acute asthma has not previously been documented. This may in part be due to the difficulty of collecting a large sample of patients with such severe asthma. Moreover, in patients with such life-threatening asthma the focus of therapy is on the successful management of such asthma rather than on the observation of a complication that appears to be self-limiting in the majority of patients. Certainly the frequency of myopathic complications in this study would suggest that study of a larger patient cohort is likely to reveal positive findings. A significant feature of the clinical progress of those patients who had developed myopathy or CK rise was the prolongation of mechanical ventilation. This would suggest that respiratory muscle weakness was likely to have contributed to the prolongation of the requirement for ventilation. The involvement of respiratory as well as limb muscles in the myopathic process has been documented in acute corticosteroid myopathy where diaphragmatic effects of high dose corticosteroids have been documented (13). The observation of a CK enzyme rise may therefore alert the attending physician to the potential need for prolonged ventilation in these patients. In attempting to identify causative factors for myopathy, there was no significant relationship seen in this patient group in the degree of initial metabolic disturbance and the subsequent development of myopathy or CK rise. All patients on admission to the ICU were hypokalemic. The phenomenon of hypokalemic myopathy has been previously described and has features in common with the findings in these patients of elevated blood CK levels and histologic features of myocyte vacuolation and necrosis (14). However, the degree of hypokalemia showed no significant association with the presence or severity of the ensuing myopathy, suggesting that hypokalemia is unlikely to be the sole causative agent. The various pharmacologic agents used for the therapy of acute asthma were also examined for an association with the development of myopathy. Intuitively, corticosteroids would seem likely to playa significant role in the cause of both CK elevation and myopathy. In the recent report from this hospital dexamethasone was thought to be the likely causative agent, causing relapse on rechallenge with this drug (I). However, the initial reports of myopathy as a complication of se-
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BRIEF COMMUNICATION
vere asthma suggested that high dose hydrocortisone was the most pro bable cause (2, 3) of this acute severe myopathy (14). In other reports of myopathy in patients receiving hydrocortisone, the etiology was thought to be a subacute form of chronic corticosteroidrelated myopathy (4-6). In one 0 f these studies (6) CK blood levels were elevated, a feature not usually associated with chronic corticosteroid myopathy (14). Two further studies have reported the occurrence of myopathy in patients receiving methyl-prednisolone for treatment of severe asthma (7, 10). Although some reports have suggested that the type of corticosteroid is important (1-6), in the current study both myopathy and CK rise occurred after treatment with both hydrocortisone and dexamethasone, suggesting that the occurrence of this syndrome is not related exclusivelyto any corticosteroid agent. The dose of corticosteroid used in this study was within the usual range recommended for severe asthma. The occurrence of myopathy and CK rise in two patients receiving smaller doses of corticosteroid would imply that the myopathic response to doses of corticosteroid is likely to have significant individual variability. The duration of paralysis and consequently the total dose of vecuronium received was significantly less in those patients without myopathy or CK rise when compared with other patient groups. However, the significance of this is confounded by the fact that this subgroup of patients also had a significantly shorter time in the ICU and therefore less exposure to other pharmacologic agents such as high dose intravenously administered corticosteroids and salbutamol, together with a
shorter duration of paralysis to permit the development of disuse atrophy. In this context, myopathy has been reported as a rare complication of therapeutic paralysis with pancuronium and mechanical ventilation (8). Consequently, in several case reports of myopathy in severe asthma the role of myorelaxant therapy alone, or in accelerating disuse atrophy of muscles, has been considered (5-7, 9, 10).A biochemical explanation for this may reside in the fact that inactivity is recognized to increase corticosteroid receptors in muscle (15). This issue is further complicated by the histologic similarities of chronic corticosteroid myopathy and disuse atrophy (14). The unexpectedly high incidence of myopathy observed in this patient group and its association with prolonged ventilation times, together with the possible causative roles of important therapeutic agents, necessitates further study of this problem.
References ,.1. Williams TJ, O'Hehir RE, Czarny D, Horne M, Bowes G. Acute myopathy in severe asthma treated with intravenously administered corticosteroids. Am Rev Respir Dis 1988; 137:460-3. 2. Macfarlane lA, Rosenthal FD. Severe myopathy after status asthmaticus. Lancet 1977; ii:615. 3. Van Marie W, Woods KL. Acute hydrocortisone myopathy. Br Med J 1980; 281:271-2. 4. Knox AJ, Mascie-Taylor BH, Muers ME Acute hydrocortisone myopathy in acute severe asthma. Thorax 1986; 41:411-2. 5. Bachmann P, Gaussorgues P, Piperno D, et ale Hydrocortisone and pancuronium bromide: acute myopathy during status asthmaticus. Crit Care Med 1988; 16:731. 6. Brun-Bruisson C, Gherardi R. Hydrocortisone
and pancuronium bromide: acute myopathy during status asthmaticus. Crit Care Med 1988; 16: 731-2. 7. Picado C, Montserrat J, Agusti-VidaIA. Muscle atrophy in severe exacerbation of asthma requiring mechanical ventilation. Respiration 1988; 53:201-3. 8. Op de Coul AAW, Lambregts PCLA, Koeman J, Van Puyenbroek MJE, Terlaak HJ, GabreelsFesten AAWM. Neuromuscular complications in patients given pancuronium bromide during artificial ventilation. Clin Neurol Neurosurg 1985; 87: 17-22. 9. Panacek EA, Sherman B. Hydrocortisone and pancuronium bromide: acute myopathy during status asthmaticus. Crit Care Med 1988; 16:732. 10. Kupfer Y, Okrent DG, Twersky RA, Tessler S. Disuse atrophy in a ventilated patient with status asthmaticus receiving neuromuscular blockade. Crit Care Med 1987; 15:795-6. 11. Hopkins IJ. A new syndrome: poliomyelitislike illness associated with acute asthma in childhood. Aust Paediatr J 1974; 10:273-6. 12. Thxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pressure, and circulation in mechanical ventilation of patients with severe airflow obstruction. Am Rev Respir Dis 1987; 136:872-9. 13. Ferguson GT, Irvin CG, Cherniak RM. Effect of corticosteroids on diaphragm function and biochemistry in the rabbit. Am Rev Respir Dis 1990; 141:156-63. 14. Mastaglia FL, Argov Z. Drug induced neuromuscular disorders. In: Walton J, ed. Disorders of voluntary muscle. 5th ed. Edinburgh: Churchill Livingston, 1988; 981-1014. 15. DuBois DC, Almon RR. Disuse atrophy of skeletal muscle is associated with an increase in number of glucocorticoid receptors. Endocrinology 1980; 107:1649-51.
JO A. DOUGLASS, DAVID V. TUXEN, MALCOLM HORNE, CARLOS D. SCHEINKESTEL, MAX WEINMANN, DANIEL CZARNY, and GLENN BOWES
T
he occurrence of myopathy as a complication of the therapy of severe asthma in patients requiring mechanical ventilation has been described in a number of case reports (1-10). The etiology of this syndrome has not been conclusively established. In a recent case report from this hospital, . acute profound myopathy occurred with the clinical pattern of limb weakness and the histologic changes of muscle cell vacuolation and muscle cell necrosis. The presumed cause ~ was thought to be high dose dexamethasone therapy (1). Several further case reports describing myopathy in severe asthma have suggested corticosteroids as the probable cause of either acute rhabdomyolysis (2, 3) or chronic myopathy (5, 6). In still further reports, the cause has been attributed to myorelaxant medication (7-9) or to accelerated disuse atrophy (5, 10). Myopathy has also been described as a complication of acute asthma in pediatric patients (Hopkins syndrome) (11). The present study was designed to prospectively survey the incidence of both clinical myopathy and the elevation of blood levels of creatine kinase (CK) in consecutive patients who required mechanical ventilation for severe asthma over an 18-month period. The metabolic disturbance and pharmacologic interventions occurring in these patients were documented with the aim of determining likely causative factors. Twenty-five consecutive patients who required mechanical ventilation for severe asthma (mean age, 39 ± 17 yr; five male) were studied over an 18month period. Nineteen patients reported using inhaled salbutarnol on presentation, 16 reported using oral theophylline, 11 reported using inhaled corticosteroids, and eight patients were receiving oral corticosteroid therapy (range, 5 to 50 mg of prednisolone daily). The group's preexisting health status was unremarkable, one patient was an alcoholic, and three patients were smokers. Asthma treatment followed a standard protocol of both ventilatory support and bronchodilator therapy. Ventilatory support was conducted according to the method described by Thxen and Lane (12) to minimize gas trapping but not to necessarily normalize PaC02. Patients were therapeutically paralyzed with suxamethonium to induce paralysis, and a vecuronium infusion was used to maintain paralysis in 22 patients. Bronchodilator therapy consisted of a salbutamol infusion (3 to 20 ug/rnin), nebulized salbutamol (5 mg every 2 h), aminophylline intravenously to achieve therapeutic blood levels, and corticosteroid therapy with either dexamethasone (10 mg every 8 h) or hydrocor-
SUMMARY Myopathy complicating the therapy of severe asthma has been recently described In several case reports. Twenty-five consecutive patients admitted to the intensive care unit (ICU) at this hospital for mechanical ventilation for severe asthma were studied for the Incidence of creatine kinase (CK) enzyme rise and for the development of clinical myopathy. Pharmacologic therapy was standardized, every patient receiving corticosteroids and aminophylline Intravenously and salbutamol both nebulized and intravenously. Twenty-two patients received muscle relaxant therapy with vecuronium.ln 19 of 25 (76%) of patients there was elevation of CK levels to a median of 1,575 U/L (range, 66 to 7,430) occurring 3.6 ± 1.5 days after admission. In nine patients there was clln Ically detectable myopathy. The presence of either myopathy or CK enzyme rise was associated with a significant prolongation of ventilation time. Arterial blood gas measurements on admission to the ICU revealed a pH (mean ± SO) of 7.07 ± 0.21, a PaC02 of 87.2 ± 32.7, and a Pao2 (with a high Flo2) of 129 ± 97 mm Hg; however, no correlation was found between the severity of Initial metabolic disturbance and the subsequent development of myopathy. There was no association between the type of corticosteroid administered and the subsequent development of myopathy. Patients with myopathy had received a significantly higher total dose of vecuronium when compared with those who did not develop myopathy (p < 0.001, Kruskal Wallis test). We have therefore found a surprisingly high Incidence of CK enzyme rise and myopathy in this group of mechanically ventilated patients with severe asthma. The etiology of this problem may be related to the therapeutic regimen, particularly corticosteroids or muscle-relaxant agents. AM REV RESPIR DIS 1992; 146:517-519
tisone (250 mg every 6 h). No intramuscular therapy was used and all patients underwent routine chest physiotherapy daily for the duration of their stay in the intensive care unit (ICU). Paralysis was withdrawn when controlled ventilation was no longer necessary to maintain Pao2 and PaC02. Weaning from mechanical ventilation was attempted when the patient's severe airflow obstruction had significantly resolved as determined by ventilator parameters. Physiologic disturbance was documented on admission by arterial blood gas, blood electrolyte, and CK measurements. CK was documented daily for the duration of ICU admission. Clinical myopathy was documented by scoring according to the severity of myopathy as mild (no muscle group weaker than 4/5), moderate (one or more muscle groups graded less than 4/5), and severe (all limb muscle groups scoring less than 4/5). Patients with myopathy were then reassessed at intervals during the remainder of their admission, and the duration of time elapsed before recovery was noted. EMG and muscle biopsy were performed in some cases. Results are expressed as mean ± SD. Statistical analysis was performed using the "StatWorks" (Macintosh) software package for Wilcoxon's rank sum and Kruskal Wallis tests.
CK levels above 200 U/L (normal < 180U/L) occurred in 19 patients (range, 66 to 7,430 U/L) withthe group median for all 25 patients being 1,575 U/L. The CK peak occurred an average of 3.6 ± 1.5 days after ICU admission and remained elevated for an average of 9.8 ± 5.9 days, In four patients there
was a second peak of CK levels beyond this first CK peak (range, 770 to 21,400 U/L) occurring 18.5 ± 1.9 days after ICU admission. In these four patients the prolonged elevation of CK levels was accompanied by profound muscle weakness. Myopathy was documented in nine patients, all of whom had an elevated CK (median, 3,080 U/L; range, 441 to 7,430 U/L). The clinical pattern was of generalized muscle weakness in eight patients; however, in one patient there was pronounced arm weakness, which was confined to shoulder girdle musculature. The mean duration of myopathy in all nine cases was 27 ± 12 days. Of these nine patients, four had myopathy graded as severe, and all of them had a second peak of CK levels described previously. Two patients had a myopathy graded as moderate, and three had myopathy classified as mild. EMG was performed in four patients and showed a myopathic pattern in all instances. Insertional activity was often re-
(Received in original form August 12, 1991 and in revised form November 18, 1991) 1 From the Department of Respiratory Medicine and Intensive Care, Alfred Hospital, Prahran, Australia. 2 Correspondence and reques ts for reprints should be addressed to Dr. D. V. Tuxen, Intensive Care, Alfred Hospital, Prahran, Victoria 3181 Australia.
517
518
BRIEF COMMUNICATION
duced, but spontaneously active sharp waves were present in all cases in which an EMG was performed. Voluntary activated units were of low amplitude, with a tendency to early recruitment, but interference pattern was surprisingly reduced. Muscle biopsy was performed in six patients with clinically detectable myopathy, and in three it revealed rhabdomyolysis or muscle cell vacuolation; in the other three patients it revealed predominantly type 2 fiber atrophy only consistent with disuse atrophy or corticosteroid myopathy. In one patient specimens were taken at postmortem examination, revealing rhabdomyolysis in diaphragmatic muscle but not in specimens from psoas muscle. Admission blood gas analysis revealed that 23 patients had a marked hypercapnic acidosisand that four patients werehypoxic (Pao, < 65 mm Hg) despite high levelsof inspired oxygen (table 1). Seventeen patients had a coexistent respiratory and lactic acidosis. The lowest results for serum potassium (K+), calcium (Ca 2+), phosphate (P0 4 -), and magnesium (Mg2+) ions in the first 24 h of hospital admission are recorded in table 1. There was no significant association between the severity of any documented metabolic disturbance and the subsequent development of CK rise or myopathy. Examination of the patient groups with respect to pharmacologic interventions also failed to revealdifferences in either salbutamol doses or aminophylline doses and blood levels between patients who developed myopathy and those who did not. There was a significantly lowertotal dose of vecuronium used in those patients who did not develop myopathy or blood CK rise (table 1). In the three patients who did not receivevecuronium, only one developed a CK rise, and none developed myopathy. Patients who had developed myopathy were also compared with respect to which corticosteroid they received prior to their initial CK rise. Accordingly, of the nine patients with myopathy, three received hydro-
cortisone, three received dexamethasone, and three received both agents sequentially because of a change in therapy once they were admitted to ICU. In the four patients who developed profound myopathy the dose of corticosteroid was prolonged at high levels because of slow clinical improvement in their asthma. All of these patients received hydrocortisone during the later stages of their ICU admission; however, three of these patients received both corticosteroid agents sequentially in the first 72 h of their admission. Therefore, the type of corticosteroid agent used was not predictive for the subsequent occurrence of myopathy. The dose of corticosteroid employed was according to protocol in 22 patients. However, one patient receiving a smaller dose of hydrocortisone (400 mg per day) developed mild myopathy and an associated modest CK rise (peak, 441UIL), and one other patient receiving 12 mg per day of dexamethasone also developed a CK rise (peak, 569 U/L). Thus, there appears to be no association between the dose of corticosteroid and the development of myopathy or CK rise. Patients were ventilated for an average of 6.6 ± 6.6 days, and ventilation was significantly prolonged in the patients with clinical myopathy (12.9 ± 6.6 days) compared with the patients without myopathy (3.1 ± 3.1 days; p < 0.02, Wilcoxon's rank sum test). The presence of an elevated CK in the absence of clinically detectable myopathy was also significantly associated with prolongation of the time patients were ventilated. Thus, the six patients without CK rise were ventilated for 1.6 ± 0.4 days, whereas those 10 patients without myopathy but with CK rise were ventilated for 4.3 ± 3.5 days (p < 0.01, Wilcoxon's rank sum test). Three deaths occurred in the study group, one because of irreversible brain damage, one as the result of a respiratory arrest after discharge from the ICU, and one from multisystem failure, all of these having a CK rise and one having myopathy. One pa-
TABLE 1 METABOLIC DISTURBANCE AND VECURONIUM DOSAGE IN PATIENT GROUPS WITH AND WITHOUT MYOPATHY AND CREATINE KINASE (CK) ENZYME RISE· All Patients (n = 25) pH Paco2, mm Hg Pao2, mm Hg Lactate, mMolIL K+, mMolIL Ca2+, mMolIL Po 4 , mMolIL Mg2+, mMoI/L Total dose Vecuronium, mg Days paralyzed
7.07 87 129 5.4 3.3 2.18 0.82 0.84
0.21 32 97 2.7 0.6 0.05 ± 0.33 ± 0.15
± ± ± ± ± ±
492 ± 602 2.5 ± 2.5
CK Rise (n = 19)
7.05 90 122 5.4 3.4 2.17 0.79 0.84
± ± ± ± ± ± ± ±
0.20 32 103 2.7 0.6 0.24 0.36 0.16
626 ± 631 3.1 ± 2.5
No CK Rise (n = 6)
7.12 76 150 5.7 3.1 2.26 0.93 0.79
± ± ± ± ± ± ± ±
0.22 35 79 3.4 0.4 0.24 0.08 0.08
68 ± 155t 0.5 ± 0.8
Myopathy (n = 9)
7.11 84 136 5.1 3.3 2.15 0.77 0.84
± ± ± ± ± ± ± ±
0.19 29 124 2.7 0.5 0.14 0.22 0.07
1,065 ± 674t 5.4 ± 2.0
CK Rise No Myopathy (n = 10)
7.00 96 109 5.6 3.5 2.16 0.82 0.85
± ± ± ±
± ± ± ±
0.21 35 86 2.8 0.6 0.25 0.17 0.12
231 ± 163t 1.3 ± 0.9
• Values are mean ± SO. There was no significant difference in the initial metabolic disturbance between patients who developed evidence of a myopathic process and those who did not. t Patients who developed CK rise or myopathy had a significantly greater total dose of vecuronium when compared with patients who did not develop CK rise (p < 0.001, Kruskal Wallis test).
tient suffered a pneumothorax while in the ICU, but otherwise no complications suggesting barotrauma were noted.
*** The incidence of CK rises in patients ventilated for severeasthma was surprisingly high in this patient group, occurring in 19 of 25 (76(10) patients within the first 4 days after admission to the ICU. Nine patients (36(10) also developed clinically detectable myopathy. It is surprising that such a high incidence of myopathy in patients undergoing mechanical ventilation for acute asthma has not previously been documented. This may in part be due to the difficulty of collecting a large sample of patients with such severe asthma. Moreover, in patients with such life-threatening asthma the focus of therapy is on the successful management of such asthma rather than on the observation of a complication that appears to be self-limiting in the majority of patients. Certainly the frequency of myopathic complications in this study would suggest that study of a larger patient cohort is likely to reveal positive findings. A significant feature of the clinical progress of those patients who had developed myopathy or CK rise was the prolongation of mechanical ventilation. This would suggest that respiratory muscle weakness was likely to have contributed to the prolongation of the requirement for ventilation. The involvement of respiratory as well as limb muscles in the myopathic process has been documented in acute corticosteroid myopathy where diaphragmatic effects of high dose corticosteroids have been documented (13). The observation of a CK enzyme rise may therefore alert the attending physician to the potential need for prolonged ventilation in these patients. In attempting to identify causative factors for myopathy, there was no significant relationship seen in this patient group in the degree of initial metabolic disturbance and the subsequent development of myopathy or CK rise. All patients on admission to the ICU were hypokalemic. The phenomenon of hypokalemic myopathy has been previously described and has features in common with the findings in these patients of elevated blood CK levels and histologic features of myocyte vacuolation and necrosis (14). However, the degree of hypokalemia showed no significant association with the presence or severity of the ensuing myopathy, suggesting that hypokalemia is unlikely to be the sole causative agent. The various pharmacologic agents used for the therapy of acute asthma were also examined for an association with the development of myopathy. Intuitively, corticosteroids would seem likely to playa significant role in the cause of both CK elevation and myopathy. In the recent report from this hospital dexamethasone was thought to be the likely causative agent, causing relapse on rechallenge with this drug (I). However, the initial reports of myopathy as a complication of se-
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vere asthma suggested that high dose hydrocortisone was the most pro bable cause (2, 3) of this acute severe myopathy (14). In other reports of myopathy in patients receiving hydrocortisone, the etiology was thought to be a subacute form of chronic corticosteroidrelated myopathy (4-6). In one 0 f these studies (6) CK blood levels were elevated, a feature not usually associated with chronic corticosteroid myopathy (14). Two further studies have reported the occurrence of myopathy in patients receiving methyl-prednisolone for treatment of severe asthma (7, 10). Although some reports have suggested that the type of corticosteroid is important (1-6), in the current study both myopathy and CK rise occurred after treatment with both hydrocortisone and dexamethasone, suggesting that the occurrence of this syndrome is not related exclusivelyto any corticosteroid agent. The dose of corticosteroid used in this study was within the usual range recommended for severe asthma. The occurrence of myopathy and CK rise in two patients receiving smaller doses of corticosteroid would imply that the myopathic response to doses of corticosteroid is likely to have significant individual variability. The duration of paralysis and consequently the total dose of vecuronium received was significantly less in those patients without myopathy or CK rise when compared with other patient groups. However, the significance of this is confounded by the fact that this subgroup of patients also had a significantly shorter time in the ICU and therefore less exposure to other pharmacologic agents such as high dose intravenously administered corticosteroids and salbutamol, together with a
shorter duration of paralysis to permit the development of disuse atrophy. In this context, myopathy has been reported as a rare complication of therapeutic paralysis with pancuronium and mechanical ventilation (8). Consequently, in several case reports of myopathy in severe asthma the role of myorelaxant therapy alone, or in accelerating disuse atrophy of muscles, has been considered (5-7, 9, 10).A biochemical explanation for this may reside in the fact that inactivity is recognized to increase corticosteroid receptors in muscle (15). This issue is further complicated by the histologic similarities of chronic corticosteroid myopathy and disuse atrophy (14). The unexpectedly high incidence of myopathy observed in this patient group and its association with prolonged ventilation times, together with the possible causative roles of important therapeutic agents, necessitates further study of this problem.
References ,.1. Williams TJ, O'Hehir RE, Czarny D, Horne M, Bowes G. Acute myopathy in severe asthma treated with intravenously administered corticosteroids. Am Rev Respir Dis 1988; 137:460-3. 2. Macfarlane lA, Rosenthal FD. Severe myopathy after status asthmaticus. Lancet 1977; ii:615. 3. Van Marie W, Woods KL. Acute hydrocortisone myopathy. Br Med J 1980; 281:271-2. 4. Knox AJ, Mascie-Taylor BH, Muers ME Acute hydrocortisone myopathy in acute severe asthma. Thorax 1986; 41:411-2. 5. Bachmann P, Gaussorgues P, Piperno D, et ale Hydrocortisone and pancuronium bromide: acute myopathy during status asthmaticus. Crit Care Med 1988; 16:731. 6. Brun-Bruisson C, Gherardi R. Hydrocortisone
and pancuronium bromide: acute myopathy during status asthmaticus. Crit Care Med 1988; 16: 731-2. 7. Picado C, Montserrat J, Agusti-VidaIA. Muscle atrophy in severe exacerbation of asthma requiring mechanical ventilation. Respiration 1988; 53:201-3. 8. Op de Coul AAW, Lambregts PCLA, Koeman J, Van Puyenbroek MJE, Terlaak HJ, GabreelsFesten AAWM. Neuromuscular complications in patients given pancuronium bromide during artificial ventilation. Clin Neurol Neurosurg 1985; 87: 17-22. 9. Panacek EA, Sherman B. Hydrocortisone and pancuronium bromide: acute myopathy during status asthmaticus. Crit Care Med 1988; 16:732. 10. Kupfer Y, Okrent DG, Twersky RA, Tessler S. Disuse atrophy in a ventilated patient with status asthmaticus receiving neuromuscular blockade. Crit Care Med 1987; 15:795-6. 11. Hopkins IJ. A new syndrome: poliomyelitislike illness associated with acute asthma in childhood. Aust Paediatr J 1974; 10:273-6. 12. Thxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pressure, and circulation in mechanical ventilation of patients with severe airflow obstruction. Am Rev Respir Dis 1987; 136:872-9. 13. Ferguson GT, Irvin CG, Cherniak RM. Effect of corticosteroids on diaphragm function and biochemistry in the rabbit. Am Rev Respir Dis 1990; 141:156-63. 14. Mastaglia FL, Argov Z. Drug induced neuromuscular disorders. In: Walton J, ed. Disorders of voluntary muscle. 5th ed. Edinburgh: Churchill Livingston, 1988; 981-1014. 15. DuBois DC, Almon RR. Disuse atrophy of skeletal muscle is associated with an increase in number of glucocorticoid receptors. Endocrinology 1980; 107:1649-51.
