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Rhabdomyolysis and drugs of abuse
The Journal of Emergency Medicine, Vol. 19, No. 1, pp. 51–56, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/00 $–see front matter
PII S0736-4679(00)00180-3
Selected Topics: Toxicology
RHABDOMYOLYSIS AND DRUGS OF ABUSE John R. Richards,
MD
Division of Emergency Medicine, University of California, Davis Medical Center, Sacramento, California Reprint Address: John R. Richards, MD, Division of Emergency Medicine, UC Davis Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817
e Abstract—Rhabdomyolysis is a disorder in which injury to muscle results in leakage of myocyte intracellular contents into the plasma. It has been associated with a tremendous number and diversity of clinical conditions and substances. Several physiological and biochemical mechanisms for this syndrome have been described. The most likely etiology of rhabdomyolysis in patients presenting to the emergency department is ingestion of drugs of abuse, most commonly ethanol, heroin, amphetamines, cocaine, and other sedatives or stimulants. In this article, the association between rhabdomyolysis and drugs of abuse is explored, as well as its diagnosis and treatment. © 2000 Elsevier Science Inc.
veloped acute renal failure (4). It is estimated rhabdomyolysis is responsible for 8 –15% of all cases of acute renal failure (5). In this article the association between rhabdomyolysis and drugs of abuse is investigated, and its diagnosis and treatment reviewed.
PATHOPHYSIOLOGY Rhabdomyolysis is characterized by myocyte membrane rupture with release of intracellular contents, which include creatine phosphokinase (CK), lactate dehydrogenase, aldolase, myoglobin, purines, potassium, and phosphates. Creatine phosphokinase is an enzyme that catalyzes the conversion of creatine phosphate to creatine and transfers the high energy phosphate bond to adenosine diphosphate (ADP) to form adenosine triphosphate (ATP). Creatine kinase is present in large quantities in the myocyte and is 100% sensitive as a marker of rhabdomyolysis (6). Any impairment of muscle ATP production or utilization, or ATP consumption greater than production may result in rhabdomyolysis (7). Depletion of ATP results in loss of membrane transporter function, such as the ATP-dependent sodium–potassium and sodium– calcium pumps (8). Subsequently, increasing intracellular calcium concentration results in activation of phospholipases, which further damage myocyte membranes. Myoglobin is a 17.8 kDa protein unique to myocytes and, like hemoglobin, is capable of oxygen transport by a heme group within the protein. It is an earlier marker for rhabdomyolysis than CK (9,10).
e Keywords—rhabdomyolysis; drug abuse; ethanol; heroin; amphetamine; cocaine
INTRODUCTION Rhabdomyolysis is a common clinical condition characterized by injury to myocytes and release of intracellular contents into the extracellular space (1). The first description of possible rhabdomyolysis appears in the Bible in the Book of Numbers (2). Several Israelites developed dark urine and died after eating quail during their exodus from Egypt. These quail are known to feed on hemlock seeds, which are myotoxic. Suspected rhabdomyolysis from crush injuries with myoglobinuria was first reported in World War II during the Nazi bombing of London (3). There are many causes of rhabdomyolysis (4,5). In one study, drugs and alcohol were responsible for 81% of cases of rhabdomyolysis, and one-third of patients de-
RECEIVED: 7 September 1999; FINAL ACCEPTED: 8 February 2000
SUBMISSION RECEIVED:
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52
J. R. Richards
Hypocalcemia has been associated with rhabdomyolysis (11,12). The proposed mechanism is precipitation of serum calcium salts in necrotic muscle. This initial hypocalcemia may be followed by hypercalcemia, as the metastatic calcium salts are liberated from the necrotic muscle and return to the serum (13). Gabow and colleagues report 63% of patients admitted for rhabdomyolysis to be hypocalcemic (4). Serum calcium should be routinely measured in all patients with rhabdomyolysis. Derangement in serum potassium is common in patients with muscle injury, and may predispose patients to life-threatening dysrhythmia (9). Damaged muscle releases intracellular potassium, and this results in hyperkalemia (1). Diminished glomerular filtration rate, dehydration, and acute renal failure further exacerbate hyperkalemia associated with rhabdomyolysis (11,14). Conversely, hypokalemia has been demonstrated to provoke rhabdomyolysis (15). Knochel and Schlein demonstrated that skeletal muscle releases very little potassium during contraction in potassium-depleted animals (15). Furthermore, exertion in their animal model was not accompanied by a normal hyperemic response, but instead a relative ischemia. This may account for the rhabdomyolysis observed in athletes or others participating in intense physical training with eventual potassium depletion (16). Patients with prolonged tonic-clonic seizures are also at risk for rhabdomyolysis. Chesson and colleagues demonstrated that an elevation in CK is directly proportional to number, length, and intensity of seizures (17). Excessive muscle activity may lead to hyperthermia, although there is no evidence that hyperthermia is directly toxic to myocytes (16,18). Hyperthermia, however, does increase the energy requirements of muscle (1). Rhabdomyolysis patients are also at risk for disseminated intravascular coagulation (DIC) as thromboplastin is released from damaged myocytes (9). As such, prothrombin time, partial thromboplastin time, and platelet count also should be measured in these patients.
DIAGNOSIS AND TREATMENT The diagnosis of non-traumatic rhabdomyolysis relies on clinical history and specific laboratory tests. Patients who present to the emergency department (ED) obtunded or agitated are at greatest risk for rhabdomyolysis. Physical examination is often unrevealing, as focal or diffuse muscle tenderness or edema is a rare finding. Dark urine suggests myoglobinuria and should be evaluated further. The diagnosis is confirmed by serum elevations of intracellular proteins unique to myocytes, specifically CK and myoglobin. The level of CK that defines rhabdomyolysis is controversial. Gabow and colleagues propose a CK level greater than 5 times the upper limit of normal (⬎ 1,000
U/L), while others have utilized lower levels (4). Creatine kinase levels have been reported in previous studies to peak between 24 and 48 h even with aggressive hydration, and to decline at a rate approximately 39% of the previous day’s level (1,5,9). Serial measurement of CK may reveal persistent or increasing serum CK despite hydration, which suggests ongoing myocyte damage and possible renal failure. The urine dipstick, which utilizes the orthotolidine method of detecting hemoglobin and myoglobin, is a convenient and rapid method for screening for myoglobinuria. Levels detected with the dipstick approach those observed with immunodiffusion (5–10 mg/L) (9). Myoglobin is cleared from the plasma in 1– 6 h by renal excretion and by hepatic metabolism to bilirubin (10). As such, a negative test for myoglobin does not rule out rhabdomyolysis. One study reports only 50% of patients with rhabdomyolysis and no hematuria had urine that was orthotolidine-positive (4). Microscopic hematuria results in a false positive orthotolidine test for myoglobinuria. However, myoglobinuria as an early marker of rhabdomyolysis may be useful in patients presenting to the ED in an agitated state, before renal clearance is complete. Early detection and treatment of rhabdomyolysis is necessary to minimize kidney damage. Rhabdomyolysis is implicated in up to 10% of acute renal failure cases (12). The development of renal failure in patients with rhabdomyolysis has been linked to renal tubular damage from the toxicity of myoglobin and hemoglobin decomposition products such as ferrihemate, and tubular obstruction by myoglobin and urate crystals (5,16). The incidence of renal failure is increased in patients with high serum CK (⬎ 15,000 U/L), but only myoglobin, not CK or other intracellular contents, has been demonstrated to be directly nephrotoxic (12). Renal ischemia from vasoconstrictive mediators also has been described (1,19). Dehydration and acidic urine exacerbates this condition (5,16). At urine pH ⱕ 5.6, myoglobin dissociates into ferrihemate and globin (19). Therefore, aggressive hydration with intravenous (i.v.) crystalloid such as normal saline or lactated Ringer’s solution at a rate of 500 cc/h in an adult is essential to elevate glomerular filtration rate, improve oxygen delivery to the renal tubules, and dilute toxins. To maintain a neutral or alkaline urine pH, sodium bicarbonate may be added to a hypotonic solution and infused. A typical regimen would be one ampule (44 meq) in one liter of 0.45 normal saline or 2–3 ampules in a liter of D5W at a rate of 100 cc/h. Care must be taken not to produce an iatrogenic hypernatremia from excessive sodium bicarbonate. Mannitol (1 g/kg) also may be added after sufficient rehydration for diuresis. Loop diuretics such as furosemide (20 – 40 mg i.v.) also may be added to enhance this diuresis. Target urine output should be at least 200 cc/h. Serial
Rhabdomyolysis and Drugs of Abuse
measurements of serum CK and electrolytes, including potassium and calcium, should be checked often to monitor renal function. Patients who fail to respond to these measures may require temporary or permanent dialysis. Ward investigated predictive factors for the development of acute renal failure in rhabdomyolysis and reports associations with degree of CK and potassium elevation, albumin depletion, dehydration at presentation, and sepsis (11). Gabow et al. identify an association between acute renal failure in patients with rhabdomyolysis and elevated potassium levels (4). Early treatment of rhabdomyolysis with mannitol, bicarbonate, and large i.v. infusions of crystalloid has been associated with good outcome (20,21). One study reports a mortality rate of approximately 5% for patients with serious rhabdomyolysis (9). Veenstra and colleagues demonstrate a higher mortality rate in rhabdomyolysis patients with accompanying acute renal failure (12). Indications for dialysis include worsening renal failure, persistent hyperkalemia despite treatment, refractory pulmonary edema, and serious acid-base disorders. There are no studies comparing aggressive versus non-aggressive hydration for prevention of renal failure in patients with rhabdomyolysis. Compartment syndrome also may be a complication of rhabdomyolysis, and its presentation may be subtle (7). Patients abusing myotoxic drugs, such as ethanol and heroin, are usually immobile for long periods of time, thus sustaining direct pressure on muscles. The edema accompanying rhabdomyolysis may also raise the fascial compartment pressure, with compression of adjacent vessels and nerves. When this pressure exceeds arterial pressure, ischemic necrosis and widespread muscle destruction ensues. At this point urgent fasciotomy is required. ASSOCIATION WITH SPECIFIC DRUGS OF ABUSE The following drugs of abuse have been associated with rhabdomyolysis and have a variety of related mechanisms as outlined in Figure 1.
53
oxidative phosphorylation and directly compromises ATP production (22,23).
Ethanol Alcoholics are particularly at risk for rhabdomyolysis (6,24). Delerium tremens results in elevated CK and may reflect prolonged tremor and increased muscle tone (6). Ethanol also has direct myotoxicity and has been demonstrated to produce muscle damage in healthy volunteers (25). Other proposed mechanisms of ethanol myotoxicity include inhibition of calcium accumulation by the sarcoplasmic reticulum, alteration of membrane viscosity with derangement of membrane ion transporters, and aberration in myocyte carbohydrate metabolism (1,6). Intoxication from ethanol leads to periods of immobilization with pressure myonecrosis (9,26). Alcoholics are often malnourished, with resultant diminished glycogen storage and ATP reserve. Ethanol consumption leads to dehydration from its antagonism of antidiuretic hormone, which increases risk of renal failure. These patients frequently have deficiencies of potassium, magnesium, and phosphorus, which may also precipitate or exacerbate rhabdomyolysis (24,27).
Heroin Richter et al. describe an association between heroin injection and rhabdomyolysis that is linked to adulterants such as quinine (28). Narcotics also may have direct cell toxicity and alter membrane transport (29). After injecting, heroin users tend to lie stationary for prolonged periods of time or become comatose, placing them at further risk to develop rhabdomyolysis (30). During these periods, food and fluid intake is often neglected, leading to diminished ATP production, dehydration, and subsequent increased risk of rhabdomyolysis.
Cocaine Tobacco Tobacco smoking may be a cofactor in the development of rhabdomyolysis. The carboxyhemoglobinemia produced by chronic heavy smoking results in impaired oxygen delivery to tissue, and this may increase risk of rhabdomyolysis (22). Furthermore, myoglobin, which is present only within myocytes, has an even stronger affinity for carbon monoxide than hemoglobin (23). The production of carboxymyoglobinemia leads to diminished oxygen delivery to mitochondria within myocytes. Carbon monoxide is also a metabolic poison that disrupts
Rhabdomyolysis from cocaine abuse has been widely reported (31–34). Counselman and colleagues calculate a mean CK of 1,071 U/L in patients presenting with cocaine-related complaints (31). Welch and coworkers demonstrated that 24% of cocaine users have accompanying rhabdomyolysis (32). Cocaine appears to have direct toxicity to skeletal muscle as well as vasoconstrictive properties, which lead to muscle ischemia (33,34). Adulterants used to “cut” cocaine may be directly myotoxic (32). Pagala and colleagues determined cocaine directly causes myocytes to leak CK but were unable to
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J. R. Richards
Figure 1. Mechanisms of rhabdomyolysis and association with drugs of abuse.
identify a precise mechanism (33). Brody et al. identify a subgroup of cocaine-toxic patients who are at high risk for rhabdomyolysis, with clinical features of seizure, coma, dysrhythmia, hypotension, and cardiac arrest (34). Cocaine blocks dopamine reuptake, leading to depletion of both dopamine and norepinephrine (NE) (34,35). Chronic cocaine use may lead to down-regulation of postsynaptic dopamine receptors in the basal ganglia in a manner similar to amphetamine derivatives, predisposing patients to dystonia and hyperthermia (36,37). This may also contribute to the degree of rhabdomyolysis.
Amphetamines The association between rhabdomyolysis and amphetamines has been described in case reports and has many proposed mechanisms (18,38 – 40). The first report of a fatal amphetamine ingestion was in 1963 (38). Kendrick and coworkers report shock, rhabdomyolysis, myoglobinuria, DIC, and azotemia in a series of five amphetamine injectors (39). Amphetamine and its derivatives, like cocaine, have vasoconstrictive properties that cause myocytes and the renal medulla to become ischemic and
Rhabdomyolysis and Drugs of Abuse
hypoxic (41). Amphetamines have not been proven to be directly nephrotoxic (5,9,41). Hyperthermia with DIC and tubular necrosis with amphetamine use has been described (18). Amphetamine abusers frequently present to the ED agitated and require physical and chemical restraint (42,43). In this situation, rhabdomyolysis may occur in a fashion similar to the exertional rhabdomyolysis seen in military recruits and athletes after exhaustive physical exercise (16). The uncontrolled choreiform movements associated with acute amphetamine toxicity may also cause rhabdomyolysis (44). Weis demonstrates in an animal model that hyperthermia induced by toxic amphetamine ingestion is not prevented by decapitation (45). Zalis and colleagues successfully antagonized the hyperthermia and lethality of toxic doses of amphetamine with curare (46). These studies suggest the origin of hyperthermia is from direct muscle activity and not CNS thermoregulatory aberration. Amphetamine abusers frequently don’t sleep for long periods of time, and this may also predispose them to rhabdomyolysis (47). Kupfer and colleagues demonstrate elevations in serum muscle enzyme levels with sleep deprivation in the absence of agitation (48). Amphetamines cause elevated levels of serum NE and dopamine, which result in an increasing ATP demand (49 –51). This results in the overstimulation of the sympathetic nervous system, with eventual depletion of NE and dopamine, and may explain the profound sleep into which abusers lapse after a binge (50,51). Furthermore, amphetamine abusers frequently neglect eating and drinking (47,52). The combination of decreased intake of calories resulting in limited ATP supply coupled with dehydration may result in rhabdomyolysis. Amphetamines are directly neurotoxic, with both permanent and transient structural changes in pre- and post-synaptic dopamine transporters (53,54). This may explain the Parkinson-like state seen in some chronic users, characterized by uncontrolled choreiform movements (44,55).
Phencyclidine Phencyclidine (PCP), a common drug of abuse in the late 1970s, is a potent sympathomimetic that has largely disappeared from the illicit drug scene (56). The rhabdomyolysis accompanying PCP abuse appears to be from excessive physical activity. It is unclear if this drug is directly myotoxic (56,57). Kuncl and Meltzer demonstrated that elevations of CK are 100 times normal when PCP-treated animals are physically restrained, with myofibrillar disruption from intense isometric contraction (57).
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Septic Causes from i.v. Use Intravenous drug abusers expose themselves to a long list of medical problems, including endocarditis, hepatitis, human immunodeficiency virus (HIV), anaphylaxis, intracerebral hemorrhage and stroke, and necrotizing vasculitis (58 – 60). Vasculitis, described in a previous report, may induce ischemic muscle injury (58). Rhabdomyolysis may also be caused by sepsis (1). The bacteriologic contents of injectable street drugs can contain a wide variety of organisms, such as Eikenella corrodens, which may cause considerable tissue damage through various proteases (59,60). Any organism that affects muscle may result in elevated CK, such as myotoxin-producing clostridia. Organisms such as streptococci, staphylococci, and Gram-negative bacteria may also cause rhabdomyolysis (61). It is also proposed that cytokines, such as tumor necrosis factor (TNF) and interleukins, which accompany these types of infections, are involved in the development of rhabdomyolysis (62). These “evil humors” result in alteration of myocyte membrane ion permeability and are directly cytotoxic.
SUMMARY Rhabdomyolysis has a varied presentation and should be suspected in intoxicated patients presenting to the ED agitated or immobile. Routinely testing urine for myoglobin and measuring serum CK levels for this subgroup of patients will detect occult rhabdomyolysis. In addition, screening for drugs of abuse in patients with rhabdomyolysis of unclear etiology is also warranted, as well as for occult infection.
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56 11. Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med 1988;148:1553–7. 12. Veenstra J, Smit WM, Krediet RT, Arisz L. Relationship between elevated creatine phosphokinase and the clinical spectrum of rhabdomyolysis. Nephrol Dial Transplant 1994;9:637– 41. 13. Meroney WH, Arney GK, Segar WE, et al. The acute calcification of traumatized muscle, with particular reference to post-traumatic renal insufficiency. J Clin Invest 1957;36:825–32. 14. Koffler A, Freidler RM, Massry SG. Acute renal failure due to nontraumatic rhabdomyolysis. Ann Intern Med 1976;85:23– 8. 15. Knochel JP, Schlein E. On the mechanism of rhabdomyolysis in potassium depletion. J Clin Invest. 1972;51:1750 – 8. 16. Knochel JP, Dotin LN, Hamburger RJ. Heat stress, exercise, and muscle injury: effects on urate metabolism and renal function. Ann Intern Med 1974;81:321– 8. 17. Chesson AL, Kasarskis EJ, Small VW. Postictal elevation of serum creatine kinase level. Arch Neurol 1983;40:315–7. 18. Ginsberg MD, Hertzman M, Schmidt-Nowara WW. Amphetamine intoxication with coagulopathy, hyperthermia, and reversible renal failure. A syndrome resembling heatstroke. Ann Intern Med 1970; 73:81–5. 19. Bunn HF, Jandl JH. Exchange of heme among hemoglobin molecules. Proc Natl Acad Sci USA 1966;56:974 – 8. 20. Eneas JF, Schoenfeld PY, Humphreys MH. The effect of infusion of mannitol-bicarbonate on the clinical course of myoglobinuria. Arch Intern Med 1979;139:801–5. 21. Ron D, Taitelman U, Michaelson M, et al. Prevention of acute renal failure in traumatic rhabdomyolysis. Arch Intern Med 1984; 144:277– 80. 22. Finley J, VanBeek A, Glover JL. Myonecrosis complicating carbon monoxide poisoning. J Trauma 1977;17:536 – 40. 23. Coburn RF. The carbon monoxide body stores. Ann NY Acad Sci 1970;174:11–22. 24. Haller RG, Knochel JP. Skeletal muscle disease in alcoholism. Med Clin North Am 1984;68:91–103. 25. Song SK, Rubin E. Ethanol produces muscle damage in human volunteers. Science 1972;175:327– 8. 26. Bessa O. Alcoholic rhabdomyolysis: a review. Conn Med 1995; 59:519 –20. 27. Anderson R, Cohen M, Haller R, et al. Skeletal muscle phosphorus and magnesium deficiency in alcoholic myopathy. Miner Electrolyte Metab 1980;6:106 –12. 28. Richter RW, Challenor YB, Pearson J, et al. Acute myoglobinuria associated with heroin addiction. JAMA 1971;216:1172– 6. 29. Simon EJ. The effects of narcotics on cells in tissue culture. In: Clouet D, ed. Narcotic drugs: biochemical pharmacology. New York: Planum Press; 1971:248 –59. 30. D’Agostino RS, Arnett EN. Acute myoglobinuria and heroin snorting. JAMA 1979;241:277. 31. Counselman FL, McLaughlin EW, Kardon EM, Bhambhani-Bhavnani AS. Creatine phosphokinase elevation in patients presenting to the emergency department with cocaine-related complaints. Am J Emerg Med 1997;15:221–3. 32. Welch RD, Todd K, Krause GS. Incidence of cocaine-associated rhabdomyolysis. Ann Emerg Med. 1991;20:154 –7. 33. Pagala M, Amaladevi B, Azad D, et al. Effect of cocaine on leakage of creatine kinase from isolated fast and slow muscles of rat. Life Sci 1993;52:751– 6. 34. Brody Sl, Wrenn KD, Wilber MW, et al. Predicting the severity of cocaine-associated rhabdomyolysis. Ann Emerg Med 1990;19: 1137– 43. 35. Daras M, Kakkouras L, Tuchman AJ, Koppel BS. Rhabdomyolysis and hyperthermia after cocaine abuse: a variant of the neuroleptic malignant syndrome? Acta Neurol Scanda 1995;92:161–5. 36. Cappon GD, Morford LL, Vorhees CV. Ontogeny of methamphetamine-induced neurotoxicity and associated hyperthermic response. Brain Res 1997;103:155– 62. 37. Marshall JF, O’Dell SJ, Weimuller FB. Dopamine-glutamate interactions in methamphetamine-induced neurotoxicity. J Neur Transm 1993;91:241–54.
J. R. Richards 38. Zalis EG, Parmley LF. Fatal amphetamine poisoning. Arch Intern Med 1963;112:822– 6. 39. Kendrick WC, Hull AR, Knochel JP. Rhabdomyolysis and shock after intravenous amphetamine administration. Ann Intern Med 1977;86:381–7. 40. Lehmann ED, Thom CH, Croft DN. Delayed severe rhabdomyolysis after taking “ectasy.” Postgrad Med J 1995;71:186- 7. 41. Scandling J, Spital A. Amphetamine-associated myoglobinuric renal failure. South Med J. 1982;75:237– 40. 42. Ellinwood E. Assault and homicide associated with amphetamine abuse. Am J Psychiatry. 1971;127:90 –5. 43. Richards JR, Derlet RW, Duncan DR. Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone. Eur J Emerg Med 1997;4:130 –5. 44. Sperling LS, Horowitz JL. Methamphetamine-induced choreoathetosis and rhabdomyolysis. Ann Int Med 121:986. 45. Weis J. On the hyperthermic response to D-amphetamine in the decapitated rat. Life Sci 1973;13:475– 84. 46. Zalis EG, Kaplan G, Lundberg GD. Acute lethality of amphetamines in dogs and its antagonism by curare. Proc Soc Exp Biol Med. 1965;118:557– 61. 47. Morgan P, Beck JE. The legacy and the paradox: hidden contexts of methamphetamine use in the United States. In: Klee H, ed. Amphetamine misuse: international perspectives on current trends. Amsterdam: Harwood Publishers; 1997:135– 62. 48. Kupfer DJ, Meltzer HY, Wyatt RJ. Serum enzyme changes during sleep deprivation. Nature 1970;228:768 –70. 49. Segal DS, Kuczenski R. Repeated binge exposures to amphetamine and methamphetamine: behavioral and neurochemical characterization. J Pharm Exp Ther 1997;282:561–73. 50. Stephans S, Yamamoto B. Effect of repeated methamphetamine administrations on dopamine and glutamate efflux in rat prefrontal cortex. Brain Res 1995;700:99 –106. 51. Wilson J, Kalasinsky K, Levey A, et al. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 1996;2:699 –703. 52. Iyo M, Namba H, Yanagisawa M, Hirai S, Yui N, Fukui S. Abnormal cerebral perfusion in chronic methamphetamine abusers: a study using 99MTc-HMPAO and SPECT. Prog NeuroPsychopharm Biol Psych 1997;21:789 –96. 53. Fleckenstein AE, Metzger RR, Wilkins DG, et al. Rapid and reversible effects of methamphetamine on dopamine transporters. J Pharm Exp Ther 1997;282:834 – 8. 54. Villemagne V, Yuan J, Wong DF, et al. Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [C-11]WIN-35,428 positron emission tomography studies. J Neurosci 1998;18:419 –27. 55. Rhee K, Alberton TE, Douglas J. Choreoathetoid disorder associated with amphetamine-like drugs. Am J Emerg Med 1988;6: 131–3. 56. Cogen FC, Rigg G, Simmons JL, Domino EF. Phencyclidineassociated acute rhabdomyolysis. Ann Intern Med 1978;88:210 –2. 57. Kuncl RW, Meltzer HY. Pathologic effect of phencyclidine and restraint on rat skeletal muscle: prevention by prior denervation. Exp Neurol 1974;45:387– 402. 58. Koff RS, Widrich WC, Robbins AH. Necrotizing angiitis in a methamphetamine user with hepatitis B—angiographic diagnosis, five month follow up results and localization of bleeding site. N Engl J Med 1973;288:946 – 8. 59. Brooks GF, O’Donoghue JM, Rissing JP, et al. Eikenella corrodens, a recently discovered pathogen: infections in medical-surgical patients and in association with methylphenidate abuse. Medicine 1974;53:325– 42. 60. Tuazon CU, Hill R, Sheagren JN. Microbiologic study of street heroin and injection paraphernalia. J Infect Dis. 1974;129:327–329. 61. Christin L, Sarosi G. Pyomyositis in North America: case reports and review. Clin Infect Dis 1992;15:668 –77. 62. Tracey K, Lowry S, Beutler B, et al. Cachectin/TNF mediates changes of skeletal muscle plasma membrane potential. J Exp Med 1986;164:1368 –73.
PII S0736-4679(00)00180-3
Selected Topics: Toxicology
RHABDOMYOLYSIS AND DRUGS OF ABUSE John R. Richards,
MD
Division of Emergency Medicine, University of California, Davis Medical Center, Sacramento, California Reprint Address: John R. Richards, MD, Division of Emergency Medicine, UC Davis Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817
e Abstract—Rhabdomyolysis is a disorder in which injury to muscle results in leakage of myocyte intracellular contents into the plasma. It has been associated with a tremendous number and diversity of clinical conditions and substances. Several physiological and biochemical mechanisms for this syndrome have been described. The most likely etiology of rhabdomyolysis in patients presenting to the emergency department is ingestion of drugs of abuse, most commonly ethanol, heroin, amphetamines, cocaine, and other sedatives or stimulants. In this article, the association between rhabdomyolysis and drugs of abuse is explored, as well as its diagnosis and treatment. © 2000 Elsevier Science Inc.
veloped acute renal failure (4). It is estimated rhabdomyolysis is responsible for 8 –15% of all cases of acute renal failure (5). In this article the association between rhabdomyolysis and drugs of abuse is investigated, and its diagnosis and treatment reviewed.
PATHOPHYSIOLOGY Rhabdomyolysis is characterized by myocyte membrane rupture with release of intracellular contents, which include creatine phosphokinase (CK), lactate dehydrogenase, aldolase, myoglobin, purines, potassium, and phosphates. Creatine phosphokinase is an enzyme that catalyzes the conversion of creatine phosphate to creatine and transfers the high energy phosphate bond to adenosine diphosphate (ADP) to form adenosine triphosphate (ATP). Creatine kinase is present in large quantities in the myocyte and is 100% sensitive as a marker of rhabdomyolysis (6). Any impairment of muscle ATP production or utilization, or ATP consumption greater than production may result in rhabdomyolysis (7). Depletion of ATP results in loss of membrane transporter function, such as the ATP-dependent sodium–potassium and sodium– calcium pumps (8). Subsequently, increasing intracellular calcium concentration results in activation of phospholipases, which further damage myocyte membranes. Myoglobin is a 17.8 kDa protein unique to myocytes and, like hemoglobin, is capable of oxygen transport by a heme group within the protein. It is an earlier marker for rhabdomyolysis than CK (9,10).
e Keywords—rhabdomyolysis; drug abuse; ethanol; heroin; amphetamine; cocaine
INTRODUCTION Rhabdomyolysis is a common clinical condition characterized by injury to myocytes and release of intracellular contents into the extracellular space (1). The first description of possible rhabdomyolysis appears in the Bible in the Book of Numbers (2). Several Israelites developed dark urine and died after eating quail during their exodus from Egypt. These quail are known to feed on hemlock seeds, which are myotoxic. Suspected rhabdomyolysis from crush injuries with myoglobinuria was first reported in World War II during the Nazi bombing of London (3). There are many causes of rhabdomyolysis (4,5). In one study, drugs and alcohol were responsible for 81% of cases of rhabdomyolysis, and one-third of patients de-
RECEIVED: 7 September 1999; FINAL ACCEPTED: 8 February 2000
SUBMISSION RECEIVED:
29 December 1999; 51
52
J. R. Richards
Hypocalcemia has been associated with rhabdomyolysis (11,12). The proposed mechanism is precipitation of serum calcium salts in necrotic muscle. This initial hypocalcemia may be followed by hypercalcemia, as the metastatic calcium salts are liberated from the necrotic muscle and return to the serum (13). Gabow and colleagues report 63% of patients admitted for rhabdomyolysis to be hypocalcemic (4). Serum calcium should be routinely measured in all patients with rhabdomyolysis. Derangement in serum potassium is common in patients with muscle injury, and may predispose patients to life-threatening dysrhythmia (9). Damaged muscle releases intracellular potassium, and this results in hyperkalemia (1). Diminished glomerular filtration rate, dehydration, and acute renal failure further exacerbate hyperkalemia associated with rhabdomyolysis (11,14). Conversely, hypokalemia has been demonstrated to provoke rhabdomyolysis (15). Knochel and Schlein demonstrated that skeletal muscle releases very little potassium during contraction in potassium-depleted animals (15). Furthermore, exertion in their animal model was not accompanied by a normal hyperemic response, but instead a relative ischemia. This may account for the rhabdomyolysis observed in athletes or others participating in intense physical training with eventual potassium depletion (16). Patients with prolonged tonic-clonic seizures are also at risk for rhabdomyolysis. Chesson and colleagues demonstrated that an elevation in CK is directly proportional to number, length, and intensity of seizures (17). Excessive muscle activity may lead to hyperthermia, although there is no evidence that hyperthermia is directly toxic to myocytes (16,18). Hyperthermia, however, does increase the energy requirements of muscle (1). Rhabdomyolysis patients are also at risk for disseminated intravascular coagulation (DIC) as thromboplastin is released from damaged myocytes (9). As such, prothrombin time, partial thromboplastin time, and platelet count also should be measured in these patients.
DIAGNOSIS AND TREATMENT The diagnosis of non-traumatic rhabdomyolysis relies on clinical history and specific laboratory tests. Patients who present to the emergency department (ED) obtunded or agitated are at greatest risk for rhabdomyolysis. Physical examination is often unrevealing, as focal or diffuse muscle tenderness or edema is a rare finding. Dark urine suggests myoglobinuria and should be evaluated further. The diagnosis is confirmed by serum elevations of intracellular proteins unique to myocytes, specifically CK and myoglobin. The level of CK that defines rhabdomyolysis is controversial. Gabow and colleagues propose a CK level greater than 5 times the upper limit of normal (⬎ 1,000
U/L), while others have utilized lower levels (4). Creatine kinase levels have been reported in previous studies to peak between 24 and 48 h even with aggressive hydration, and to decline at a rate approximately 39% of the previous day’s level (1,5,9). Serial measurement of CK may reveal persistent or increasing serum CK despite hydration, which suggests ongoing myocyte damage and possible renal failure. The urine dipstick, which utilizes the orthotolidine method of detecting hemoglobin and myoglobin, is a convenient and rapid method for screening for myoglobinuria. Levels detected with the dipstick approach those observed with immunodiffusion (5–10 mg/L) (9). Myoglobin is cleared from the plasma in 1– 6 h by renal excretion and by hepatic metabolism to bilirubin (10). As such, a negative test for myoglobin does not rule out rhabdomyolysis. One study reports only 50% of patients with rhabdomyolysis and no hematuria had urine that was orthotolidine-positive (4). Microscopic hematuria results in a false positive orthotolidine test for myoglobinuria. However, myoglobinuria as an early marker of rhabdomyolysis may be useful in patients presenting to the ED in an agitated state, before renal clearance is complete. Early detection and treatment of rhabdomyolysis is necessary to minimize kidney damage. Rhabdomyolysis is implicated in up to 10% of acute renal failure cases (12). The development of renal failure in patients with rhabdomyolysis has been linked to renal tubular damage from the toxicity of myoglobin and hemoglobin decomposition products such as ferrihemate, and tubular obstruction by myoglobin and urate crystals (5,16). The incidence of renal failure is increased in patients with high serum CK (⬎ 15,000 U/L), but only myoglobin, not CK or other intracellular contents, has been demonstrated to be directly nephrotoxic (12). Renal ischemia from vasoconstrictive mediators also has been described (1,19). Dehydration and acidic urine exacerbates this condition (5,16). At urine pH ⱕ 5.6, myoglobin dissociates into ferrihemate and globin (19). Therefore, aggressive hydration with intravenous (i.v.) crystalloid such as normal saline or lactated Ringer’s solution at a rate of 500 cc/h in an adult is essential to elevate glomerular filtration rate, improve oxygen delivery to the renal tubules, and dilute toxins. To maintain a neutral or alkaline urine pH, sodium bicarbonate may be added to a hypotonic solution and infused. A typical regimen would be one ampule (44 meq) in one liter of 0.45 normal saline or 2–3 ampules in a liter of D5W at a rate of 100 cc/h. Care must be taken not to produce an iatrogenic hypernatremia from excessive sodium bicarbonate. Mannitol (1 g/kg) also may be added after sufficient rehydration for diuresis. Loop diuretics such as furosemide (20 – 40 mg i.v.) also may be added to enhance this diuresis. Target urine output should be at least 200 cc/h. Serial
Rhabdomyolysis and Drugs of Abuse
measurements of serum CK and electrolytes, including potassium and calcium, should be checked often to monitor renal function. Patients who fail to respond to these measures may require temporary or permanent dialysis. Ward investigated predictive factors for the development of acute renal failure in rhabdomyolysis and reports associations with degree of CK and potassium elevation, albumin depletion, dehydration at presentation, and sepsis (11). Gabow et al. identify an association between acute renal failure in patients with rhabdomyolysis and elevated potassium levels (4). Early treatment of rhabdomyolysis with mannitol, bicarbonate, and large i.v. infusions of crystalloid has been associated with good outcome (20,21). One study reports a mortality rate of approximately 5% for patients with serious rhabdomyolysis (9). Veenstra and colleagues demonstrate a higher mortality rate in rhabdomyolysis patients with accompanying acute renal failure (12). Indications for dialysis include worsening renal failure, persistent hyperkalemia despite treatment, refractory pulmonary edema, and serious acid-base disorders. There are no studies comparing aggressive versus non-aggressive hydration for prevention of renal failure in patients with rhabdomyolysis. Compartment syndrome also may be a complication of rhabdomyolysis, and its presentation may be subtle (7). Patients abusing myotoxic drugs, such as ethanol and heroin, are usually immobile for long periods of time, thus sustaining direct pressure on muscles. The edema accompanying rhabdomyolysis may also raise the fascial compartment pressure, with compression of adjacent vessels and nerves. When this pressure exceeds arterial pressure, ischemic necrosis and widespread muscle destruction ensues. At this point urgent fasciotomy is required. ASSOCIATION WITH SPECIFIC DRUGS OF ABUSE The following drugs of abuse have been associated with rhabdomyolysis and have a variety of related mechanisms as outlined in Figure 1.
53
oxidative phosphorylation and directly compromises ATP production (22,23).
Ethanol Alcoholics are particularly at risk for rhabdomyolysis (6,24). Delerium tremens results in elevated CK and may reflect prolonged tremor and increased muscle tone (6). Ethanol also has direct myotoxicity and has been demonstrated to produce muscle damage in healthy volunteers (25). Other proposed mechanisms of ethanol myotoxicity include inhibition of calcium accumulation by the sarcoplasmic reticulum, alteration of membrane viscosity with derangement of membrane ion transporters, and aberration in myocyte carbohydrate metabolism (1,6). Intoxication from ethanol leads to periods of immobilization with pressure myonecrosis (9,26). Alcoholics are often malnourished, with resultant diminished glycogen storage and ATP reserve. Ethanol consumption leads to dehydration from its antagonism of antidiuretic hormone, which increases risk of renal failure. These patients frequently have deficiencies of potassium, magnesium, and phosphorus, which may also precipitate or exacerbate rhabdomyolysis (24,27).
Heroin Richter et al. describe an association between heroin injection and rhabdomyolysis that is linked to adulterants such as quinine (28). Narcotics also may have direct cell toxicity and alter membrane transport (29). After injecting, heroin users tend to lie stationary for prolonged periods of time or become comatose, placing them at further risk to develop rhabdomyolysis (30). During these periods, food and fluid intake is often neglected, leading to diminished ATP production, dehydration, and subsequent increased risk of rhabdomyolysis.
Cocaine Tobacco Tobacco smoking may be a cofactor in the development of rhabdomyolysis. The carboxyhemoglobinemia produced by chronic heavy smoking results in impaired oxygen delivery to tissue, and this may increase risk of rhabdomyolysis (22). Furthermore, myoglobin, which is present only within myocytes, has an even stronger affinity for carbon monoxide than hemoglobin (23). The production of carboxymyoglobinemia leads to diminished oxygen delivery to mitochondria within myocytes. Carbon monoxide is also a metabolic poison that disrupts
Rhabdomyolysis from cocaine abuse has been widely reported (31–34). Counselman and colleagues calculate a mean CK of 1,071 U/L in patients presenting with cocaine-related complaints (31). Welch and coworkers demonstrated that 24% of cocaine users have accompanying rhabdomyolysis (32). Cocaine appears to have direct toxicity to skeletal muscle as well as vasoconstrictive properties, which lead to muscle ischemia (33,34). Adulterants used to “cut” cocaine may be directly myotoxic (32). Pagala and colleagues determined cocaine directly causes myocytes to leak CK but were unable to
54
J. R. Richards
Figure 1. Mechanisms of rhabdomyolysis and association with drugs of abuse.
identify a precise mechanism (33). Brody et al. identify a subgroup of cocaine-toxic patients who are at high risk for rhabdomyolysis, with clinical features of seizure, coma, dysrhythmia, hypotension, and cardiac arrest (34). Cocaine blocks dopamine reuptake, leading to depletion of both dopamine and norepinephrine (NE) (34,35). Chronic cocaine use may lead to down-regulation of postsynaptic dopamine receptors in the basal ganglia in a manner similar to amphetamine derivatives, predisposing patients to dystonia and hyperthermia (36,37). This may also contribute to the degree of rhabdomyolysis.
Amphetamines The association between rhabdomyolysis and amphetamines has been described in case reports and has many proposed mechanisms (18,38 – 40). The first report of a fatal amphetamine ingestion was in 1963 (38). Kendrick and coworkers report shock, rhabdomyolysis, myoglobinuria, DIC, and azotemia in a series of five amphetamine injectors (39). Amphetamine and its derivatives, like cocaine, have vasoconstrictive properties that cause myocytes and the renal medulla to become ischemic and
Rhabdomyolysis and Drugs of Abuse
hypoxic (41). Amphetamines have not been proven to be directly nephrotoxic (5,9,41). Hyperthermia with DIC and tubular necrosis with amphetamine use has been described (18). Amphetamine abusers frequently present to the ED agitated and require physical and chemical restraint (42,43). In this situation, rhabdomyolysis may occur in a fashion similar to the exertional rhabdomyolysis seen in military recruits and athletes after exhaustive physical exercise (16). The uncontrolled choreiform movements associated with acute amphetamine toxicity may also cause rhabdomyolysis (44). Weis demonstrates in an animal model that hyperthermia induced by toxic amphetamine ingestion is not prevented by decapitation (45). Zalis and colleagues successfully antagonized the hyperthermia and lethality of toxic doses of amphetamine with curare (46). These studies suggest the origin of hyperthermia is from direct muscle activity and not CNS thermoregulatory aberration. Amphetamine abusers frequently don’t sleep for long periods of time, and this may also predispose them to rhabdomyolysis (47). Kupfer and colleagues demonstrate elevations in serum muscle enzyme levels with sleep deprivation in the absence of agitation (48). Amphetamines cause elevated levels of serum NE and dopamine, which result in an increasing ATP demand (49 –51). This results in the overstimulation of the sympathetic nervous system, with eventual depletion of NE and dopamine, and may explain the profound sleep into which abusers lapse after a binge (50,51). Furthermore, amphetamine abusers frequently neglect eating and drinking (47,52). The combination of decreased intake of calories resulting in limited ATP supply coupled with dehydration may result in rhabdomyolysis. Amphetamines are directly neurotoxic, with both permanent and transient structural changes in pre- and post-synaptic dopamine transporters (53,54). This may explain the Parkinson-like state seen in some chronic users, characterized by uncontrolled choreiform movements (44,55).
Phencyclidine Phencyclidine (PCP), a common drug of abuse in the late 1970s, is a potent sympathomimetic that has largely disappeared from the illicit drug scene (56). The rhabdomyolysis accompanying PCP abuse appears to be from excessive physical activity. It is unclear if this drug is directly myotoxic (56,57). Kuncl and Meltzer demonstrated that elevations of CK are 100 times normal when PCP-treated animals are physically restrained, with myofibrillar disruption from intense isometric contraction (57).
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Septic Causes from i.v. Use Intravenous drug abusers expose themselves to a long list of medical problems, including endocarditis, hepatitis, human immunodeficiency virus (HIV), anaphylaxis, intracerebral hemorrhage and stroke, and necrotizing vasculitis (58 – 60). Vasculitis, described in a previous report, may induce ischemic muscle injury (58). Rhabdomyolysis may also be caused by sepsis (1). The bacteriologic contents of injectable street drugs can contain a wide variety of organisms, such as Eikenella corrodens, which may cause considerable tissue damage through various proteases (59,60). Any organism that affects muscle may result in elevated CK, such as myotoxin-producing clostridia. Organisms such as streptococci, staphylococci, and Gram-negative bacteria may also cause rhabdomyolysis (61). It is also proposed that cytokines, such as tumor necrosis factor (TNF) and interleukins, which accompany these types of infections, are involved in the development of rhabdomyolysis (62). These “evil humors” result in alteration of myocyte membrane ion permeability and are directly cytotoxic.
SUMMARY Rhabdomyolysis has a varied presentation and should be suspected in intoxicated patients presenting to the ED agitated or immobile. Routinely testing urine for myoglobin and measuring serum CK levels for this subgroup of patients will detect occult rhabdomyolysis. In addition, screening for drugs of abuse in patients with rhabdomyolysis of unclear etiology is also warranted, as well as for occult infection.
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