١ RHABDOMYOLYSIS: AN EVALUATION OF 56 HOSPITALIZED INTOXICATED PATIENTS * Hossein Hassanian-Moghaddam, Seyed Reza Mousavi. Shaheed Beheshti Medical University,Iran. Department of Clinical Toxicology & Forensic medicine ABSTRACT: Background: Rhabdomyolysis results from acute muscle fibers necrosis with leakage of muscle constituents into blood. It is a common and potentially lethal clinical syndrome. Acute renal failure (ARF) which appears in 15%-33% of patients with rhabdomyolysis is due to the Myoglobinuria. Intoxications, inherited diseases, muscle compression or overexertion, or inflammatory processes, are among other disorders cause rhabdomyolysis. No cause is found in some cases. To determine the most common etiologic factors underlying development of rhabdomyolysis and related complications in poisoned patients the present study was carried out. Material: We describe 56 patients who were hospitalized in toxicology ICU of "Loghman Hakim Hospital", the biggest toxicology unit in the world, between February 2002 and March 2003. Of 813 patients, 56 patients with an acute overdose and serum creatine kinase (CK) more than 5 times the upper limit of normal (>975 IU/L) were included. Patients with recent myocardial infarction or stroke were excluded. For all, the highest values of serum CK, serum creatinine, and urine hemoglobin, and red blood cells were recorded. Results: Of the 56 patients, 5 were female and 51 were male (median age, 32 yr; range, 16-76yr).The most common intoxication responsible for rhabdomyolysis, included opium(42.5% ), tricyclic antidepressants(19.5% ), and benzodiazepines(9% ). In 5%, no cause was found. Acute renal failure (ARF) was present in 16 (29%) patients, of whom 15 were male. Five male subjects with ARF required hemodialysis which all of them died (9%). Hemodialysed ARF had a significant correlation with death. Urine dipstick for heme was positive in 96.5%. Conclusion: Patients using illicit drugs were at risk for rhabdomyolysis. With appropriate care for prevention of ARF, death is rare. Key words: Rhabdomyolysis, ARF, Intoxication * Corresponding Author: Loghman-Hakim Poison Center, Kamali Street. South Karegar Avenue, Tehran, IRAN Tel/Fax: +9821 55409534 PO Box: 13185-494 Email: hassanian@sbmu.ac.ir ١
٢ INTRODUCTION Rhabdomyolysis is a clinical and biochemical syndrome that results from acute necrosis of skeletal muscle fibers and consequent leakage of muscle constituents into the circulation. Myoglobinuria is the most significant consequence of the muscle breakdown and is reported to cause renal failure in 15%-33% of cases [1]. Rhabdomyolysis is the cause of renal failure in 5%- 25% of all cases of acute renal failure (ARF) [2]. In addition, rhabdomyolysis leads to death in about 10% of cases [3]. The term myoglobinuria is generally used as a synonym for rhabdomyolysis. Rhabdomyolysis is, however, the preferred term, given that the fundamental problem concerns the muscle, and not the presence of myoglobin in the urine [4, 5]. In the United States, about 26,000 cases of rhabdomyolysis are reported annually in the national hospital discharged patients database [1]. Reported etiologies of rhabdomyolysis include alcohol abuse, muscle compression, muscle overexertion, and inherited disorders of muscle metabolism [6]. In a significant proportion of patients, however, especially those with recurrent episodes, no cause can be identified [7]. Although many reviews on rhabdomyolysis etiologies and pathogenic mechanisms have been published, to date few data from large population studies are available. In particular, little is known about the actual frequency of the different etiologies causing rhabdomyolysis. Moreover, many studies have been conducted among patients with rhabdomyolysis-induced ARF. Therefore, for the present study we examined a large population of hospitalized patients with rhabdomyolysis, independent from ARF, and analyzed the incidence of different etiologies, the characteristics of patients with rhabdomyolysis, the laboratory variables in detecting the disorders, and the incidence of complications. PATIENTS AND METHODS 813 patients who admitted to toxicology ICU of Loghman-Hakim Poison Hospital for intoxication between February 2002 and March 2003 evaluated for presence of rhabdomyolysis. The diagnosis of rhabdomyolysis was considered if the serum creatine kinase (CK) value greater than 5 times the upper limit of normal (>975 IU/L). For all patients, the highest value of serum CK, serum creatinine, urine hemoglobin and red blood cells were recorded. All complication of rhabdomyolysis including ARF and death were recorded. ARF was defined as an increase in serum creatinine above the upper limit of normal (>2 mg/dl). Patients with recent evidence of myocardial infarction, stroke or cardiopulmonary resuscitation (CPR) were excluded. Data are expressed as mean values +SD and we used X 2 -test, and difference were considered significant when P<0.05. The protocol for the research project has been approved by Ethic Committee of Shaheed Beheshti Medical University. ٢
٣ RESULTS 56 patients, 5 females (9%) and 51 males (91%) were included in the study. The median age was 32 years (range 16-76 yr). ARF was present in 16 patients (29%), and death secondary to rhabdomyolysis occurred in 5 patients (9%) ARF was present in 16 (29%) patients, 15 were male. Five male subjects with ARF required hemodialysis which all of them died (9%). Hemodialysed ARF had a significant correlation with death. The mean creatine kinase was 17,964 (range 1100-31400). Urine dipstick for heme was positive in 96.5%. Frequencies for each of the eleven main etiologic factors are listed in Table 1. In all categories men were affected more frequently than women. No significant differences were found between the serum CK values in the different etiologic groups. Opium and tricyclic antidepressants (TCA) were the most common cause of rhabdomyolysis. In 3 patients (5%), no cause was identified. Mortality was high in this group (100%). Urine hemoglobin was positive in 54 patients (96.5%). DISCUSSION The most common cause of rhabdomyolysis in this series was overdose of opium, TCAs and benzodiazepines. We describe the characteristics of 11 etiologic factors associated with rhabdomyolysis. Few large population studies on rhabdomyolysis have been reported (Table 2) [8-10]. In most of them, ARF and the biochemical and clinical parameters related to it have been the main concern. The different design of our study can explain the large number of intoxication etiologies that have been considered. Similar to ours, 3 previous studies [3, 11, 12] have shown illegal drug abuse as the most frequent causes of rhabdomyolysis. This result is also confirmed by a recent publication on the annual incidence of ARF due to rhabdomyolysis associated with drug abuse: it showed a 3-fold increase in the period 1987-1997 in an urban area in Scotland. The demographic distribution in our study had overall similar characteristics to those previously reported, with males predominantly affected and the mean age of onset in the fourth decade of life (see Table 2). Differences in the reported studies may be due to differing inclusion and exclusion criteria. The current study differs from previous studies, because this study includes patients with rhabdomyolysis with and without ARF, while previous series were usually collections of patients with rhabdomyolysis-induced ARF only [11-13]. Among toxic cases caused by medical drugs, the largest number of episodes was caused by TCAs. ARF, the most serious complication of rhabdomyolysis, developed in 29% of patients, which is similar to previously reported in general reviews (15%-33%) [3, 14]. The exact mechanism or mechanisms of ARF in rhabdomyolysis are not completely clear. Some of the proposed mechanisms include mechanical injury to the tubules caused by myoglobin precipitation, direct toxic effect of free chelatable iron on tubules, and hypovolemia [1]. Since it has been shown that the amount of myoglobin released in the blood correlates with the serum CK [15], if myoglobin precipitation is related to ARF, higher levels of CK should be present in the setting of ARF. Indeed, we found a highly significant association between serum creatinine values, as a marker of renal function, and CK values. ٣
٤ Only five out of 56 patients died as a result of rhabdomyolysis. A clear correlation was found between ARF and death. In conclusion, rhabdomyolysis is common in intoxication. The most common myotoxins are opium, TCAs and benzodiazepines. ARF is a frequent complication and develops in a larger portion of patients than previously reported. REFERNCES: 1. Sauret JM, Marinides G, Wang JK. Rhabdomyolysis. Am Fam Physician. 2002; 65: 907-912. 2. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve. 2002; 25: 332-347. 3. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore).1982; 61: 141-152. 4. Bowden DH, Fraser D, Jackson SH, Walker NF. Acute recurrent rhabdomyolysis (paroxysmal myohaemoglobinuria): a report of three cases and a review of the literature. Medicine (Baltimore).1956; 35: 335-353. 5. Poels PJ, Gabreels FJ. Rhabdomyolysis: a review of the literature. Clin Neurol Neurosurg. 1993; 95: 175-192. 6. Tonin P, Lewis P, Servidei S, Di Mauro S. Metabolic causes of myoglobinuria. Ann Neurol. 1990; 27: 181-185. 7. Lofberg M, Jankala H, Paetau A, Harkonem M, Somer H. Metabolic causes of recurrent rhabdomyolysis. Acta Neurol Scand. 1998; 98: 268-275. 8. Blanco JR, Zabalza M, Salcedo J, Echeverria L, Garcia A, Vallejo M. Rhabdomyolysis of infectious and noninfectious causes. South Med J. 2002; 95: 542-544. 9. Veenstra J, Smit WM, Krediet RT, Arisz L. Relationship between elevated creatine phosphokinase and the clinical spectrum of rhabdomyolysis. Nephrol Dial Transplant.1994; 9: 637-641. 10. Melli G,Chaudhry V,Cornblath DR. Rhabdomyolysis :An Evaluation of 475 Hospitalized Patients. Medicine. 2005; 84: 377-385. 11. Eneas JF, Schoenfeld PY, Humphreys MH. The effect of infusion of mannitol-sodium bicarbonate on the clinical course of myoglobinuria. Arch Intern Med. 1979; 139: 801-805. 12. Koffler A, Friedler RM, Massry SG. Acute renal failure due to nontraumatic rhabdomyolysis. Ann Intern Med.1976; 85: 23-28. 13. Grossman RA, Hamilton RW, Morse BM, Penn AS, Goldberg M. Nontraumatic rhabdomyolysis and acute renal failure. N Engl J Med. 1974; 291: 807-811. 14. Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med. 1988; 148: 1553-1557. 15. Beetham R. Biochemical investigation of suspected rhabdomyolysis. Ann Clin Biochem. 2000; 37: 581-587. ٤
٥ Table 1 Toxic Agents & Drug Underlying Developement of Rhabdomyolysis Drug / Toxin No. of patients (%) Opium 24(42.5) TCAs 11(19.5) Benzodiazepines 5(9) Phenobarbital 4(7) Carbamazepine 2(3.5) Carbon Monoxide 2(3.5) Methanol 1(2) Arsenic 1(2) Hydrocarbons 1(2) Organophosphate 1(2) Strychnine 1(2) Unknown 3(5) Total 56(100) ٥
٦ TABLE 2. Patient Characteristics and Etiology, present and previous studies of Rhabdomyolysis Present report (2007) Melli (2005) Blanco (2002) Veenstra (1994) Gabow (1982) Eneas (1979) Koffler (1976) Grossman (1974) NO. of patients Male (%) Age in year, Mean(range) CK(IU/L)(range) ARF (%) Illicit drugs & alcohol (%) 56 91 32 (16-76) 1100-31400 29 44.5 5 475 68 47 (4-95) 2975-250,000 46 34 7 Unknown (%) 52 80 60 (16-93) NR NR 15 NR 93 81 NR 5000-25,000 51 30 1 77 86 48 (21-85) 500-238,000 33 82 3 20 90 36 (19-63) 1000-95,000 NR 65 NR 21 90 34 (22-63) 2608-24,000 100 85 5 15 86 40 (18-77) 370-120,000 100 20 13 Abbreviations: NR = not reported ٦