ORIGINAL CONTRIBUTION cocaine, rhabdomyolysis; rhabdomyolysis, cocaine
Incidence of Cocaine-Associated Rhabdomyolysis Study hypothesis: R h a b d o m y o l y s l s is a c o m m o n c o m p l i c a t i o n of cocaine use. and m u s c l e s y m p t o m s fail to predict its development. Study population: A prospective, convenience s a m p l e of p a t i e n t s presenting to the emergency department of a large inner-city hospital w i t h complaints related to cocaine use were eligible for inclusion. Patients were excluded i f they had other potential causes of elevated creatme kinase (CK) levels or rhabdomyolysis. A control group comprised patients w h o were n o t cocaine users and satisfied the exclusion criteria. Sixty-eight patients were studied. Methods: Initial evaluation i n c l u d e d determination of the presence of m u s c l e pare or swelling and total CK levels. Patients with a CK level of more than 800 U/L h a d additional tests, including a urine myoglobin, urine drug screen, and s e r u m phosphorus. R h a b d o m y o l y s i s was defined by a s e r u m CK level of more than 1,000 U/L fmore than fivefold that of normalj. CK levels were compared by t w o - t a i l e d Student's r test. M u s c l e s y m p t o m s were compared w i t h the d e v e l o p m e n t of r h a b d o m y o l y s i s b y Fisher's exact test. Results: The CK level in the cocaine group was 931 -c 1.785 U/L rmean ~_ 1 SD,. The CK level in the control group was 242 ~_ 168 U/L /P - .028). Of the cocaine users, 24% /eight of 34) had rhabdomyolysis; one developed multiorgan failure and died. No patient in the control group h a d a CK level of more than 1,000 U/L. O n l y one cocaine user w h o developed rhabdomyoIysis had m u s c l e s y m p t o m s . Three cocaine users h a d m u s c l e s y m p t o m s but did not develop rhabdomyolysis. No patient in the control group h a d m u s c l e s y m p t o m s or developed rhabdomyolysis. Muscle s y m p t o m s did not predict the CK level (P = .55). Conclusion: This s t u d y revealed that 24% of the cocaine users h a d rhabdomyolysis. M a n y of the cases of rhabdomyolysis were not predictable from h i s t o r y or physical examination, m a k i n g laboratory evaluation essential. [Welch RD, Todd K, Krause GS." Incidence of cocaine-associated rhabdomyolysis. A n n Emerg M e d February 1991;20:154-157.]
Robert D Welch, MD, FACEP Keir Todd. PA-C Gary S Krause. MD, MS, FACEP Detroit. Michigan From tne Department of Emergency Medicine Wayne State University School of Medicine, Detroit, Michigan. Received for publication May 24, 1990. Revision received July 17, 1990. Accepted for publication July 31, 1990. Presentea at the Society for Academic Emergency Medicine Annual Meeting in Minneapolis. Minnesota, May 1990. Address for reprints: Robert D Welch, MD, FACER Department of Emergency Medicine. Detroit Receiving Hospital, 4201 St Antoine. Detroit, Michigan 48201.
INTRODUCTION
Cocaine has become a major drug of abuse in recent years. Between 1982 and 1985, the n u m b e r of cocaine users increased by 38%, and the number of deaths related to cocaine increased 300%.] The life-threatening complications of cocaine abuse reported in the literature are most often related to the cardiovascular and central nervous systems. 2-6 More recently, the syndrome of cocaine-associated rhabdomyolysis has been described in several case reports and two retrospective studies. 7-16 The incidence and clinical significance of rhabdomyolysis in cocaine users remain unknown. We prospectively studied the incidence of rhabdomyolysis in patients who sought medical attention for symptoms of cocaine use and the clinical characteristics that may predict its occurrence. METHODS
This study was reviewed by the Wayne State University Human and Animal Investigation Committee and was deemed exempt. A convenience sample of adult patients presenting to the emergency department of an urban inner-city hospital during a six-month period with a complaint re-
66/154
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lated to cocaine use was eligible for inclusion into this study (Table); patients with other potential causes of rMbdomyolysis were excluded (Figure). The control group comprised randomly selected nondrug-using patients who met the exclusion criteria and were less than 45 years old. Sixty-eight patients were entered into the study. A detailed examination was performed with specific a t t e n t i o n to muscle swelling or tenderness or a history consistent with myocardial infarction, cerebrovascular accident, other drug abuse, or trauma. Laboratory evaluation included serum electrolytes, BUN, creatinine, creatine kinase (CK) (Paramax ® Analytic Systems, Baxter Healthcare Co, Irving, California) and CK isoenzyme electrophoresis f r a c t i o n a t i o n (Cardiotrac®-CK, C o r n i n g Medical, Palo Alto, California), and urinalysis. All patients with a CK level of more than 800 U/L underwent further laboratory examination to exclude other potential causes of rhabdomyolysis. This e x a m i n a t i o n included serum phosphorus, urine myoglobin (BioAmerica, Newport Beach, California), and a urine drug screen for opiates, cocaine metabolites, barbiturates, benzodiazepines, amphetamines, propoxyphene, cannabinoids, and phencyclidine (EMIT d.a.u. Monoclonal Assay, Syva Co, Palo Alto, California}. In our laboratory, the upper limit of a normal CK level is 224 U/L for men and 173 U/L for women (mean, 199 U/L). We defined rhabdomyolysis as a total CK level more than fivefold that of the mean high level (more than 1,000 U/L), as suggested by Gabow et al. 17 The two groups were compared for total CK and age using the two-tailed Student's t test, and sex was compared by X2 with Yates' correction. Fisher's exact test was used to examine the relationship between muscle swelling and tenderness and the development of acute rhabdomyolysis among the cocaine users. Statistical significance was set at ~ < .05. TM
RESULTS Sixty-eight patients were enrolled in this study, 34 in each group. There was no difference between the groups for age (cocaine users, 30.6 -+ 8.4 years; control group, 29.8 + 10.0 years; P = .74) or sex (cocaine users, 20:2 February 1991
FIGURE. Study exclusion criteria. 27 men; control group, 24 men; P = .58). The alkaloid preparation of coc a i n e w i t h the s t r e e t n a m e of "crack" was the drug used by all patients. Two patients reported oral ingestion of the drug, whereas the remaining 32 patients smoked crack. Of 12 urine toxicologic screens, 11 were positive for cocaine, and two were positive for cocaine and marijuana. One of the samples was negative for cocaine, but on further questioning the patient confirmed that he had been using cocaine the previous day. No other drugs were detected by the toxicologic screen. BUN on admission was 14 ___ 7 mg/dL (mean --_ SD), creatinine was 1.2 _+ 0.7 mg/dL, and potassium was 3.9 +- 0.5 mmol/L. Cocaine users had CK levels of 931 --_ 1,785 U/L (mean _+ SD), whereas the control group had CK levels of 242 _+ 168 U/L (P = .028). Among the cocaine users, the mean CK-MB fraction was 1.0 +_ 1.0% of the total. CK levels of more than 1,000 U/L, indicating acute rhabdomyolysis, were present in 24% (eight of 34) of cocaine users, whereas no patient in the control group had a CK level of more than 1,000 U/L (P = .008). Six of eight patients with rhabdomyolysis were male. One had a positive urine myoglobin, and three had a positive test for hemoglobin. Five patients without rhabdomyolysis had hemoglobinuria, but three of these had unexplained hematuria; none had myoglobinuria. Four cocaine users developed muscle s y m p t o m s , but only one had rhabdomyolysis. No patient in the control group had muscle symptoms. There was no relationship between muscle symptoms and the development of rhabdomyolysis among cocaine users (P = .55). Of the eight patients with rhabdomyolysis, four were treated and discharged from the ED when CK levels began to decrease and there were no signs of impending complications. Of the other four patients admitted to the hospital, two were referred to the psychiatric unit after medical clearance and had no further complications. One of the remaining two patients was admitted for evaluation of cerebellar dysfunction and encephalopaAnnals of Emergency Medicine
Alcohol use within three days Trauma or compression of muscle tissue within three days Seizures (generalized) within three days Other street drug used within three days (excluding marijuana smoking) Temperature more than 38.5 C or less than 35 C from sources other than cocaine Acute intluenzalike illness Acute sepsis History of neuromuscular disorders Serum potassium less than 2 mEq/L Serum phosphorus less than 2 mg/dL Acute myocardial infarction Acute cerebrovascular accident Diabetic ketoacidosis
TABLE. Chief complaints among cocaine tzseTs Complaint
Chest pain Hallucinations or agitation Difficulty breathing Palpitations or rapid heartbeat Abdominal pain Unresponsive Slurred speech Ingested crack Nervous and jittery Headache
No. of Patients (%)
17 (50,0) 5 (14.7) 3 (8.8) 2 (5,9) 2 (5.9) 1 (2.9) 1 (2.9) 1 (2.9) 1 (2.9) 1 (2.9)
thy. This patient had an initial CK l e v e l of 1,444 U / L and a p e a k CK level of 2,890 U/L. He did not develop any complications of rhabd o m y o l y s i s and was u l t i m a t e l y discharged with a diagnosis of rhabdomyolysis and drug-induced encephalopathy. The last patient with rhabdomyolysis was admitted to the ICU with an initial CK level of 10,403 U/L. He was brought to the ED with a history of bizarre behavior after s m o k i n g crack all day. He had a temperature of 41.6 C and was h y p o t e n s i v e , tachycardic, delirious, and agitated. The initial diagnosis was neuroleptic malignant hyperthermia syndrome and rhabdomyolysis. The patient was treated with a cooling blanket, ag155/67
RHABDOMYOLYSIS Welch, Todd & Krause
gressive hydration, sodium bicarbonate, and dantrolene. C u l t u r e s of blood, cerebrospinal fluid, urine, and sputum were negative. Despite intensive medical therapy, his CK level peaked at 263,800 U/L. This patient developed renal failure, liver failure, and disseminated intravascular coagulation, and died. Of the 34 cocaine users, 12 (35%) were admitted to the hospital. Four patients had myocardial infarction ruled out, two were admitted for pneumonitis, one was admitted for treatment of a complete right pneumothorax, and three were admitted to the psychiatric unit. The remaining two patients have been discussed. Fifty percent of our patients had a chief complaint of chest pain, but none had a diagnosis of myocardial ischemia or infarction. DISCUSSION Rhabdomyolysis is defined as a syndrome resulting from skeletal muscle injury and the subsequent release of muscle cell contents into the serum. 17 It may result from either primary skeletal muscle disease or one of the many systemic diseases that affect skeletal muscles. The many causes of rhabdomyolysis can be conveniently divided into a few fundamental groups: an imbalance between muscle energy consumption and production, primary muscle injury, decreased muscle oxygenation, infection, and toxins.a8 The earliest reports of rhabdomyolysis in the English language came from Great Britain during World War II and were the result of trauma. 19 Since then, many other causes of rhabdomyolysis have been described, including alcohol or other drugs, seizures, viral illness, electrolyte disorders, genetic disorders, ischemia, and others.17, 2°-22 The pathophysiology that results in acute rhabdomyolysis in cocaine users is unknown. Roth et al hypothesized cocaine-induced vasoconstriction with resultant ischemia, hypotension, malignant hyperthermia, or a direct toxic effect of cocaine on m y o c y t e s . 7 K o s t e n and K l e b e r t h o u g h t t h a t some of the deaths among cocaine users may have been the result of a syndrome similar to the neuroleptic malignant syndrome, which also can result in rhabdomyolysis. 23 It is possible that rhabdomyolysis in cocaine users is the result of more than one pathologic process. 68/156
The relationship between cocaine and rhabdomyolysis is determined by excluding other potential etiologies of rhabdomyolysis. Patients were not entered into this study if they had histories that suggested muscle damage (eg, n e u r o m u s c u l a r disease, trauma, muscle compression, or seizures), infection (eg, fever, sepsis, influenzalike illness), toxins (eg, alcohol or other street drugs), electrolyte disorders (eg, p o t a s s i u m or phosphorus), or other sources of CK (eg, heart or brain). Our study carefully ruled out other potential causes of rhabdomyolysis and suggests a link between cocaine use and rhabdomyolysis. The classic signs and symptoms of rhabdomyolysis include nausea, vomiting, myalgias, muscle swelling and tenderness, and weakness. ~4 In m a n y cases, some or all of these signs may be absent. In our study, only 13% of patients (one of eight) with r h a b d o m y o l y s i s experienced any muscle signs or symptoms. In their report of patients with rhabdomyolysis, Gabow et al noted that 50% had muscle pain, and only four of 87 (4.6%) exhibited muscle swelling or tenderness. 17 Koffler et a] found that 52% of patients with nontraumatic rhabdomyolysis had muscle swelling. 24 Knochel also noted that many cases of rhabdomyolysis are subclinical and are recognized only by finding elevated levels of skeletal muscle enzymes in the serum. 2s In a group of patients with renal failure as a result of rhabdomyolysis, m u s c l e swelling was more c o m m o n and severe among the patients with oliguric renal failure than in those with nonoliguric renal failure; fluid r e t e n t i o n m a y have accounted for the difference. 22 The diagnosis of rhabdomyolysis depends on laboratory evaluation. Serum CK and urinary myoglobin are the most useful tests. Elevated levels of serum CK, in the absence of CK from other sources (brain or hearta6), are thought to be the most sensitive indicator of muscle injury. 17 Some investigators have relied solely on CK elevation to diagnose rhabdomyolysis because myoglobinuria was not present in every case.7,16,17,24 We chose to use the definition of Gabow et al, who defined rhabdomyolysis as a CK level of more than fivefold that of the upper limit of normal. 17 Others have used CK levels of 1.5Annals of Emergency Medicine
fold the upper limit of normal as their definition of rhabdomyolysis. 16 Using this latter definition, Rubin and coworkers identified seven cases of rhabdomyolysis related to cocaine use. All of these patients were admitted to exclude myocardial infarction as the cause of an elevated CK. No patient had a myocardial infarction, but the authors could not exclude the possibility that myocardial ischemia c o e x i s t e d w i t h rhabdomyolysis. Their group of patients did not experience any of the complications of rhabdomyolysis. Had we used their increase in CK as our definition of rhabdomyolysis, we would have diagnosed 20 cocaine users and seven control cases as having rhabdomyolysis. In the absence of other clinical findings, this degree of CK elevation does not appear to pr0duce complications of rhabdomyolysis. Minor degrees of CK elevation in the cocaine user may lead one to consider myocardial infarction as the cause. As we and o t h e r s 16 have shown, this can be misleading, and one must consider rhabdomyolysis in the differential diagnosis. Myoglobinuria may also be an indicator of rhabdomyolysis. The urine dipstick is a simple procedure and has been found to be a sensitive test for myoglobinuria in the absence of h e m a t u r i a or hemoglobinuria.17,25 The orthotolidine reaction (MultiStix ®, Miles Inc, Elkhart, Indiana) detects the presence of the heine radical but does not differentiate between hemoglobin and myoglobin. However, myoglobin is cleared from the plasma in one to six hours by renal excretion and by metabolism to bilirubin.a7, 27 A negative test for myoglobin does not eliminate the p o s s i b i l i t y of r h a b d o m y o l y s i s as rapid clearance may result in missing the presence of m y o g l o b i n in the urine.aT,24, 2s Of our eight patients with rhabdomyolysis, one had myog l o b i n u r i a and t h r e e had hemoglobinuria without myoglobinuria. It appears that urine myoglobin and hemoglobin are poor screening tests for rhabdomyolysis. It is i m p o r t a n t to diagnose and treat rhabdomyolysis to prevent the morbidity and mortality that can result. The complications observed in p a t i e n t s w i t h cocaine-associated rhabdomyolysis include renal failure, hepatic damage, disseminated intravascular coagulation, elevated uric 20:2 February 1991
RHABDOMYOLYSIS Welch, Todd & Krause
acid levels, h y p e r k a l e m i a , hypocalcemia, m e t a b o l i c acidosis, and death.7q6 They also have been described in patients with rhabdomyolysis from other causes.17,21,25, 28 Thirteen percent of our patients /0he of eight) with rhabdomyolysis developed the full-blown syndrome of oliguric renal failure and died. This is similar to the experience of Roth et al, who found that six of 39 patients (15%) died due to rhabdomyolysis. 7 Severity of the illness was predictable in our case and in those reported by Roth et al. Patients who developed renal failure tended to have the highest CK levels and were often hypotensive. Our patients also were diagnosed as having many of the other diseases that have been associated with cocaine use (ie, pneumothorax, pneumonia, possible cardiac disease, and neurologic or psychiatric complications).6 Our study points out that physicians must search for many different complicating diseases w h e n treating cocaine users. Cocaine u s e has m a r k e d l y increased since 1982, and m a n y patients seek medical care for symptoms related to cocaine use. Some authors have recommended that all patients w i t h these complaints be evaluated for rhabdomyolysis. 29 It is not known whether this recommendation is practical or cost effective. This study suggests that clinical signs and symptoms of the disease may be absent, making laboratory evaluation an essential diagnostic step.
20:2February 1991
CONCLUSION This study revealed that 24% of the cocaine users w h o presented to an ED had rhabdomyolysis. Many cases of rhabdomyolysis are subclinical, but some may be fatal. The majority of our cases had no clinical predictor for the presence of rhabdomyolysis, which made laboratory evaluation essential.
REFERENCES
caine-associated rhabdomyolysis. A m J Med Sci I989; 297:334-336. 14. Lombard J, Wong B, Young JH~ Acute renal failure due to rhabdomyolysis associated with cocaine toxicity. West J Med 1988;148:466-46K 15. Reinhart WH, Stricker H: Rhabdoruyolysis after intravenous cocaine. A m J Med 1988;85:579. 16. Rubin RB, Neugarten J: Cocaine-induced rhabdomyolysis masquerading as myocardial ischemia. A m f Med 1989;86:551-553. 17. Gabow PA, Kaehny WD, Kelleher SP: The spectrum of rhabdomyolysis. Medicine 1982;61:141-152. 18. Glassock RJ: Hematuria and pigruentnria, in Massry SG, Glassok RJ (eds): Textbook of Nephrology. Baltimore, Maryland, Williams & Wilkins, voi 1, 1983, p 4.14-4.24.
1. MacDonald DI: National survey of drug abuse. JAMA 1986;256:320i.
19. Bywaters EGL, Beall D: Crush injuries with impairment of renal function. Br Med J 1941;1:427-432.
2. Isner JM, Estes NAM I]I, Thompson PD, et al: Acute cardiac events temporally related to cocaine abuse. N EngI J Med 1986;315:1438-1443.
20. Anderson RJ, Schrier RW: Acute tubular necrosis, in Schrier RW, Gottschalk CG leds): Diseases of the Kidney. Boston, Little, Brown and Co, vol 2, 1988, p 1418-1441.
3. Cregler LL, Mark H: Cardiovascular dangers of cocaine abuse. A m J CardioI 1986;57:1185-1186. 4. Jonsson S, O'Meara M, Young JB: Acute cocaine poisoning: The importance of treating seizures and acidosis. A m J Med 1983;75:1061-1064. 5. Mittleman RE, Wetli CV: Death caused by recreational c o c a i n e use: An update. J A M A 1984;252: 1889-1893.
21. Grossman RA, Hamilton RW, Morse BM, et al: Nontrauruatic rhabdornyolysis and acute renal failure. N Engl J Med 1974;291:807-811. 22. Candnapaphornchai P, Taher S, McDonald FD: Acute drug-associated rhabdomyolysis: An examination of its diverse renal manifestations and complications A m J Med Sci 1980;280:66-72.
6. Cregler LL, M a r k H: Medical complications of cocaine abuse. N Engl J ivied 1986;315:1495-1500.
23. Kosten TR, Kleber HD: Rapid death during cocaine abuse: A variant of the nenroleptic malignant syndrome? A m J Drug Alcohol Abuse 1988;14:335-346.
7. Roth D, Alarcon FJ, Fernandez JA, et ah Acute rhabdomyolysis associated with cocaine intoxication. N EngI J Med 1988~319:673-677.
24. Koffler A, Friedler RM, Massry SG: Acute renal failure due to nontraumatic rhabdomyolysis. Ann Intern Med 1976;85:23-28.
8. Menashe PI, Gottlieb JE: Hypertherruia, rhabdomyolysis and myoglobinuric renal failure after recreational use of cocaine. South Med J 1988;81:379-380.
25. Knochel JP: Rhabdoruyolysis and myoglobinuria. Annu Rev Med 1982;33:435-443.
9. Herzlich BC, Arsura EL, Pagala M, et al: Rhabdoruyolysis related to cocaine abuse. Ann Intern Med 1988; 109:335-336.
26. Hess JW, MacDonald RP, Frederick RJ, et al: Serum creatine phosphokinase (CPK) activity in disorders of heart and skeletal muscles. A n n Intern Med 1964;61: 1015-1028.
10. Sklnth HA, Clark JE, Ehringer GL: RhabdoruyolysJs associated with cocaine intoxication. Drug Intell Clin Pharm 1988;22:778-780. 11. Pogue VA, Nurse HM: Cocaine-associated acute ruyoglobinuric renal failure. A m J Med 1989;86:183-186. 12. Anand V, Siami G, Stone WJ: Cocaine-associated rhabdoruyolysis and acute renal failure. South Med J 1989;82:67-69. 13. Parks JM, Reed G, Knochel JP: Case report: Co-
Annals of Emergency Medicine
27. Koskelo P, Kekki M, Wagner O: Kinetic behaviour of 131I-labeled myoglobin in human beings. ClJn Chim Acts 1967;17:339-347. 28. Cogen FC, Rigg G, S i m m o n s JL, et al: Phencyclidine-associated acute rhabdomyolysis. Ann Intern Med 1978;88:210-212. 29. Another deadly danger of cocaine (editoriall. Eruerg Med 198%21:100-102.
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Incidence of Cocaine-Associated Rhabdomyolysis Study hypothesis: R h a b d o m y o l y s l s is a c o m m o n c o m p l i c a t i o n of cocaine use. and m u s c l e s y m p t o m s fail to predict its development. Study population: A prospective, convenience s a m p l e of p a t i e n t s presenting to the emergency department of a large inner-city hospital w i t h complaints related to cocaine use were eligible for inclusion. Patients were excluded i f they had other potential causes of elevated creatme kinase (CK) levels or rhabdomyolysis. A control group comprised patients w h o were n o t cocaine users and satisfied the exclusion criteria. Sixty-eight patients were studied. Methods: Initial evaluation i n c l u d e d determination of the presence of m u s c l e pare or swelling and total CK levels. Patients with a CK level of more than 800 U/L h a d additional tests, including a urine myoglobin, urine drug screen, and s e r u m phosphorus. R h a b d o m y o l y s i s was defined by a s e r u m CK level of more than 1,000 U/L fmore than fivefold that of normalj. CK levels were compared by t w o - t a i l e d Student's r test. M u s c l e s y m p t o m s were compared w i t h the d e v e l o p m e n t of r h a b d o m y o l y s i s b y Fisher's exact test. Results: The CK level in the cocaine group was 931 -c 1.785 U/L rmean ~_ 1 SD,. The CK level in the control group was 242 ~_ 168 U/L /P - .028). Of the cocaine users, 24% /eight of 34) had rhabdomyolysis; one developed multiorgan failure and died. No patient in the control group h a d a CK level of more than 1,000 U/L. O n l y one cocaine user w h o developed rhabdomyoIysis had m u s c l e s y m p t o m s . Three cocaine users h a d m u s c l e s y m p t o m s but did not develop rhabdomyolysis. No patient in the control group h a d m u s c l e s y m p t o m s or developed rhabdomyolysis. Muscle s y m p t o m s did not predict the CK level (P = .55). Conclusion: This s t u d y revealed that 24% of the cocaine users h a d rhabdomyolysis. M a n y of the cases of rhabdomyolysis were not predictable from h i s t o r y or physical examination, m a k i n g laboratory evaluation essential. [Welch RD, Todd K, Krause GS." Incidence of cocaine-associated rhabdomyolysis. A n n Emerg M e d February 1991;20:154-157.]
Robert D Welch, MD, FACEP Keir Todd. PA-C Gary S Krause. MD, MS, FACEP Detroit. Michigan From tne Department of Emergency Medicine Wayne State University School of Medicine, Detroit, Michigan. Received for publication May 24, 1990. Revision received July 17, 1990. Accepted for publication July 31, 1990. Presentea at the Society for Academic Emergency Medicine Annual Meeting in Minneapolis. Minnesota, May 1990. Address for reprints: Robert D Welch, MD, FACER Department of Emergency Medicine. Detroit Receiving Hospital, 4201 St Antoine. Detroit, Michigan 48201.
INTRODUCTION
Cocaine has become a major drug of abuse in recent years. Between 1982 and 1985, the n u m b e r of cocaine users increased by 38%, and the number of deaths related to cocaine increased 300%.] The life-threatening complications of cocaine abuse reported in the literature are most often related to the cardiovascular and central nervous systems. 2-6 More recently, the syndrome of cocaine-associated rhabdomyolysis has been described in several case reports and two retrospective studies. 7-16 The incidence and clinical significance of rhabdomyolysis in cocaine users remain unknown. We prospectively studied the incidence of rhabdomyolysis in patients who sought medical attention for symptoms of cocaine use and the clinical characteristics that may predict its occurrence. METHODS
This study was reviewed by the Wayne State University Human and Animal Investigation Committee and was deemed exempt. A convenience sample of adult patients presenting to the emergency department of an urban inner-city hospital during a six-month period with a complaint re-
66/154
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20:2 February 1991
RHABDOMYOLYSIS Welch, Todd & Krause
lated to cocaine use was eligible for inclusion into this study (Table); patients with other potential causes of rMbdomyolysis were excluded (Figure). The control group comprised randomly selected nondrug-using patients who met the exclusion criteria and were less than 45 years old. Sixty-eight patients were entered into the study. A detailed examination was performed with specific a t t e n t i o n to muscle swelling or tenderness or a history consistent with myocardial infarction, cerebrovascular accident, other drug abuse, or trauma. Laboratory evaluation included serum electrolytes, BUN, creatinine, creatine kinase (CK) (Paramax ® Analytic Systems, Baxter Healthcare Co, Irving, California) and CK isoenzyme electrophoresis f r a c t i o n a t i o n (Cardiotrac®-CK, C o r n i n g Medical, Palo Alto, California), and urinalysis. All patients with a CK level of more than 800 U/L underwent further laboratory examination to exclude other potential causes of rhabdomyolysis. This e x a m i n a t i o n included serum phosphorus, urine myoglobin (BioAmerica, Newport Beach, California), and a urine drug screen for opiates, cocaine metabolites, barbiturates, benzodiazepines, amphetamines, propoxyphene, cannabinoids, and phencyclidine (EMIT d.a.u. Monoclonal Assay, Syva Co, Palo Alto, California}. In our laboratory, the upper limit of a normal CK level is 224 U/L for men and 173 U/L for women (mean, 199 U/L). We defined rhabdomyolysis as a total CK level more than fivefold that of the mean high level (more than 1,000 U/L), as suggested by Gabow et al. 17 The two groups were compared for total CK and age using the two-tailed Student's t test, and sex was compared by X2 with Yates' correction. Fisher's exact test was used to examine the relationship between muscle swelling and tenderness and the development of acute rhabdomyolysis among the cocaine users. Statistical significance was set at ~ < .05. TM
RESULTS Sixty-eight patients were enrolled in this study, 34 in each group. There was no difference between the groups for age (cocaine users, 30.6 -+ 8.4 years; control group, 29.8 + 10.0 years; P = .74) or sex (cocaine users, 20:2 February 1991
FIGURE. Study exclusion criteria. 27 men; control group, 24 men; P = .58). The alkaloid preparation of coc a i n e w i t h the s t r e e t n a m e of "crack" was the drug used by all patients. Two patients reported oral ingestion of the drug, whereas the remaining 32 patients smoked crack. Of 12 urine toxicologic screens, 11 were positive for cocaine, and two were positive for cocaine and marijuana. One of the samples was negative for cocaine, but on further questioning the patient confirmed that he had been using cocaine the previous day. No other drugs were detected by the toxicologic screen. BUN on admission was 14 ___ 7 mg/dL (mean --_ SD), creatinine was 1.2 _+ 0.7 mg/dL, and potassium was 3.9 +- 0.5 mmol/L. Cocaine users had CK levels of 931 --_ 1,785 U/L (mean _+ SD), whereas the control group had CK levels of 242 _+ 168 U/L (P = .028). Among the cocaine users, the mean CK-MB fraction was 1.0 +_ 1.0% of the total. CK levels of more than 1,000 U/L, indicating acute rhabdomyolysis, were present in 24% (eight of 34) of cocaine users, whereas no patient in the control group had a CK level of more than 1,000 U/L (P = .008). Six of eight patients with rhabdomyolysis were male. One had a positive urine myoglobin, and three had a positive test for hemoglobin. Five patients without rhabdomyolysis had hemoglobinuria, but three of these had unexplained hematuria; none had myoglobinuria. Four cocaine users developed muscle s y m p t o m s , but only one had rhabdomyolysis. No patient in the control group had muscle symptoms. There was no relationship between muscle symptoms and the development of rhabdomyolysis among cocaine users (P = .55). Of the eight patients with rhabdomyolysis, four were treated and discharged from the ED when CK levels began to decrease and there were no signs of impending complications. Of the other four patients admitted to the hospital, two were referred to the psychiatric unit after medical clearance and had no further complications. One of the remaining two patients was admitted for evaluation of cerebellar dysfunction and encephalopaAnnals of Emergency Medicine
Alcohol use within three days Trauma or compression of muscle tissue within three days Seizures (generalized) within three days Other street drug used within three days (excluding marijuana smoking) Temperature more than 38.5 C or less than 35 C from sources other than cocaine Acute intluenzalike illness Acute sepsis History of neuromuscular disorders Serum potassium less than 2 mEq/L Serum phosphorus less than 2 mg/dL Acute myocardial infarction Acute cerebrovascular accident Diabetic ketoacidosis
TABLE. Chief complaints among cocaine tzseTs Complaint
Chest pain Hallucinations or agitation Difficulty breathing Palpitations or rapid heartbeat Abdominal pain Unresponsive Slurred speech Ingested crack Nervous and jittery Headache
No. of Patients (%)
17 (50,0) 5 (14.7) 3 (8.8) 2 (5,9) 2 (5.9) 1 (2.9) 1 (2.9) 1 (2.9) 1 (2.9) 1 (2.9)
thy. This patient had an initial CK l e v e l of 1,444 U / L and a p e a k CK level of 2,890 U/L. He did not develop any complications of rhabd o m y o l y s i s and was u l t i m a t e l y discharged with a diagnosis of rhabdomyolysis and drug-induced encephalopathy. The last patient with rhabdomyolysis was admitted to the ICU with an initial CK level of 10,403 U/L. He was brought to the ED with a history of bizarre behavior after s m o k i n g crack all day. He had a temperature of 41.6 C and was h y p o t e n s i v e , tachycardic, delirious, and agitated. The initial diagnosis was neuroleptic malignant hyperthermia syndrome and rhabdomyolysis. The patient was treated with a cooling blanket, ag155/67
RHABDOMYOLYSIS Welch, Todd & Krause
gressive hydration, sodium bicarbonate, and dantrolene. C u l t u r e s of blood, cerebrospinal fluid, urine, and sputum were negative. Despite intensive medical therapy, his CK level peaked at 263,800 U/L. This patient developed renal failure, liver failure, and disseminated intravascular coagulation, and died. Of the 34 cocaine users, 12 (35%) were admitted to the hospital. Four patients had myocardial infarction ruled out, two were admitted for pneumonitis, one was admitted for treatment of a complete right pneumothorax, and three were admitted to the psychiatric unit. The remaining two patients have been discussed. Fifty percent of our patients had a chief complaint of chest pain, but none had a diagnosis of myocardial ischemia or infarction. DISCUSSION Rhabdomyolysis is defined as a syndrome resulting from skeletal muscle injury and the subsequent release of muscle cell contents into the serum. 17 It may result from either primary skeletal muscle disease or one of the many systemic diseases that affect skeletal muscles. The many causes of rhabdomyolysis can be conveniently divided into a few fundamental groups: an imbalance between muscle energy consumption and production, primary muscle injury, decreased muscle oxygenation, infection, and toxins.a8 The earliest reports of rhabdomyolysis in the English language came from Great Britain during World War II and were the result of trauma. 19 Since then, many other causes of rhabdomyolysis have been described, including alcohol or other drugs, seizures, viral illness, electrolyte disorders, genetic disorders, ischemia, and others.17, 2°-22 The pathophysiology that results in acute rhabdomyolysis in cocaine users is unknown. Roth et al hypothesized cocaine-induced vasoconstriction with resultant ischemia, hypotension, malignant hyperthermia, or a direct toxic effect of cocaine on m y o c y t e s . 7 K o s t e n and K l e b e r t h o u g h t t h a t some of the deaths among cocaine users may have been the result of a syndrome similar to the neuroleptic malignant syndrome, which also can result in rhabdomyolysis. 23 It is possible that rhabdomyolysis in cocaine users is the result of more than one pathologic process. 68/156
The relationship between cocaine and rhabdomyolysis is determined by excluding other potential etiologies of rhabdomyolysis. Patients were not entered into this study if they had histories that suggested muscle damage (eg, n e u r o m u s c u l a r disease, trauma, muscle compression, or seizures), infection (eg, fever, sepsis, influenzalike illness), toxins (eg, alcohol or other street drugs), electrolyte disorders (eg, p o t a s s i u m or phosphorus), or other sources of CK (eg, heart or brain). Our study carefully ruled out other potential causes of rhabdomyolysis and suggests a link between cocaine use and rhabdomyolysis. The classic signs and symptoms of rhabdomyolysis include nausea, vomiting, myalgias, muscle swelling and tenderness, and weakness. ~4 In m a n y cases, some or all of these signs may be absent. In our study, only 13% of patients (one of eight) with r h a b d o m y o l y s i s experienced any muscle signs or symptoms. In their report of patients with rhabdomyolysis, Gabow et al noted that 50% had muscle pain, and only four of 87 (4.6%) exhibited muscle swelling or tenderness. 17 Koffler et a] found that 52% of patients with nontraumatic rhabdomyolysis had muscle swelling. 24 Knochel also noted that many cases of rhabdomyolysis are subclinical and are recognized only by finding elevated levels of skeletal muscle enzymes in the serum. 2s In a group of patients with renal failure as a result of rhabdomyolysis, m u s c l e swelling was more c o m m o n and severe among the patients with oliguric renal failure than in those with nonoliguric renal failure; fluid r e t e n t i o n m a y have accounted for the difference. 22 The diagnosis of rhabdomyolysis depends on laboratory evaluation. Serum CK and urinary myoglobin are the most useful tests. Elevated levels of serum CK, in the absence of CK from other sources (brain or hearta6), are thought to be the most sensitive indicator of muscle injury. 17 Some investigators have relied solely on CK elevation to diagnose rhabdomyolysis because myoglobinuria was not present in every case.7,16,17,24 We chose to use the definition of Gabow et al, who defined rhabdomyolysis as a CK level of more than fivefold that of the upper limit of normal. 17 Others have used CK levels of 1.5Annals of Emergency Medicine
fold the upper limit of normal as their definition of rhabdomyolysis. 16 Using this latter definition, Rubin and coworkers identified seven cases of rhabdomyolysis related to cocaine use. All of these patients were admitted to exclude myocardial infarction as the cause of an elevated CK. No patient had a myocardial infarction, but the authors could not exclude the possibility that myocardial ischemia c o e x i s t e d w i t h rhabdomyolysis. Their group of patients did not experience any of the complications of rhabdomyolysis. Had we used their increase in CK as our definition of rhabdomyolysis, we would have diagnosed 20 cocaine users and seven control cases as having rhabdomyolysis. In the absence of other clinical findings, this degree of CK elevation does not appear to pr0duce complications of rhabdomyolysis. Minor degrees of CK elevation in the cocaine user may lead one to consider myocardial infarction as the cause. As we and o t h e r s 16 have shown, this can be misleading, and one must consider rhabdomyolysis in the differential diagnosis. Myoglobinuria may also be an indicator of rhabdomyolysis. The urine dipstick is a simple procedure and has been found to be a sensitive test for myoglobinuria in the absence of h e m a t u r i a or hemoglobinuria.17,25 The orthotolidine reaction (MultiStix ®, Miles Inc, Elkhart, Indiana) detects the presence of the heine radical but does not differentiate between hemoglobin and myoglobin. However, myoglobin is cleared from the plasma in one to six hours by renal excretion and by metabolism to bilirubin.a7, 27 A negative test for myoglobin does not eliminate the p o s s i b i l i t y of r h a b d o m y o l y s i s as rapid clearance may result in missing the presence of m y o g l o b i n in the urine.aT,24, 2s Of our eight patients with rhabdomyolysis, one had myog l o b i n u r i a and t h r e e had hemoglobinuria without myoglobinuria. It appears that urine myoglobin and hemoglobin are poor screening tests for rhabdomyolysis. It is i m p o r t a n t to diagnose and treat rhabdomyolysis to prevent the morbidity and mortality that can result. The complications observed in p a t i e n t s w i t h cocaine-associated rhabdomyolysis include renal failure, hepatic damage, disseminated intravascular coagulation, elevated uric 20:2 February 1991
RHABDOMYOLYSIS Welch, Todd & Krause
acid levels, h y p e r k a l e m i a , hypocalcemia, m e t a b o l i c acidosis, and death.7q6 They also have been described in patients with rhabdomyolysis from other causes.17,21,25, 28 Thirteen percent of our patients /0he of eight) with rhabdomyolysis developed the full-blown syndrome of oliguric renal failure and died. This is similar to the experience of Roth et al, who found that six of 39 patients (15%) died due to rhabdomyolysis. 7 Severity of the illness was predictable in our case and in those reported by Roth et al. Patients who developed renal failure tended to have the highest CK levels and were often hypotensive. Our patients also were diagnosed as having many of the other diseases that have been associated with cocaine use (ie, pneumothorax, pneumonia, possible cardiac disease, and neurologic or psychiatric complications).6 Our study points out that physicians must search for many different complicating diseases w h e n treating cocaine users. Cocaine u s e has m a r k e d l y increased since 1982, and m a n y patients seek medical care for symptoms related to cocaine use. Some authors have recommended that all patients w i t h these complaints be evaluated for rhabdomyolysis. 29 It is not known whether this recommendation is practical or cost effective. This study suggests that clinical signs and symptoms of the disease may be absent, making laboratory evaluation an essential diagnostic step.
20:2February 1991
CONCLUSION This study revealed that 24% of the cocaine users w h o presented to an ED had rhabdomyolysis. Many cases of rhabdomyolysis are subclinical, but some may be fatal. The majority of our cases had no clinical predictor for the presence of rhabdomyolysis, which made laboratory evaluation essential.
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