Rhabdomyolysis is a common and potentially life-threatening syndrome characterized by breakdown of skeletal muscle, and leakage of intracellular substances such as myoglobin and creatine kinase (CK) into the circulation [1–4]. The aetiological spectrum of rhabdomyolysis is extensive [15–14], and the clinical spectrum may vary from a transient subclinical increase in CK activity to acute kidney injury (AKI) as a serious complication . Rhabdomyolysis is sometimes a complication for other underlying disorders or can be considered as a separate disease entity. In this study, we chose to describe the syndrome as a complication associated with possible aetiological factors.
Among reviews and smaller retrospective cohort studies, only two larger retrospective studies have been published on rhabdomyolysis: Melli et al. , including 475 patients with CK more than 975 U/l, and McMahon et al. , including 2371 patients with CK more than 5000 U/l.
Our aim was to perform a 10-year retrospective study of patients treated for rhabdomyolysis at our medical department with focus on the levels of CK, myoglobin and creatinine (as a marker of renal function and thereby AKI) and in determining whether the myoglobin/CK ratio predicts the development of AKI. Clinical characteristics were also registered.
Patients and methods
Medical records of patients admitted to Oslo University Hospital Ulleval, between January 2003 and December 2012 were reviewed, and the following diagnoses were included according to the International Classification of Diseases (ICD), version 10 : T79.6, Traumatic ischaemia of muscle; M62.8, Other specified disorders of muscle and R82.1, Myoglobinuria. In addition to the search in the hospital’s electronic medical records, a manual search in each department unit’s log books was performed to make sure that patients classified with incorrect ICD codes were not missed. Oslo University Hospital Ulleval is the main acute hospital in the capital of Norway, but the Norwegian system requires referral either from paramedics or a general practitioner. The population of Oslo in 2012 was 613 285, of whom 161 522 belonged to Oslo University Hospital Ulleval as their primary hospital. In addition, seriously ill patients could be referred from smaller hospitals in the region as well. Rhabdomyolysis was defined as serum CK activity more than five times the upper reference limit [1812–14]: 1050 U/l for females, 2000 U/l for males aged 18–49 years, and 1400 U/l for males aged older than 49 years .
Trauma and surgical patients were treated in another department and were therefore not included. Patients with cardiac arrest or stroke were included provided that they otherwise fulfilled the criteria for rhabdomyolysis. Patients with myocardial infarction as the main diagnosis – that is, transmural infarctions, were excluded. Four patients diagnosed with myocardial infarction were included; three had subendocardial infarction and one had type 2 infarction, but the main contributing factor for rhabdomyolysis was immobilization.
More than one aetiological factor could be registered per patient. Immobilization was registered if the patient was found lying on the floor and had been there for several hours. Medications known to be associated with rhabdomyolysis in other studies/reports were registered . Use of illicit drugs and/or alcohol was registered if used within 1 day before admission. Other clinical characteristics were noted according to general clinical criteria.
AKI was defined as an increase in serum creatinine concentration above the reference range: more than 90 μmol/l for females, and more than 105 μmol/l for males . Maximum serum creatinine concentration was registered, and estimated glomerular filtration rate was calculated on the basis of age and sex (reference range: >90 ml/min/1.73 m2) . Chronic kidney disease before hospitalization was present in 19 patients; they were only included if creatinine concentration increased more than 1.5 times from baseline values (eight patients).
For all patients, the maximum serum CK activity during their hospital stay was recorded. Maximum serum myoglobin concentration was recorded when available.
This research was done in compliance with the Helsinki Declaration. The Ombudsman at Oslo University Hospital granted approval for this study, and the need for informed consent was waived. All data were unidentified before analysis.
Statistical analyses were performed using SPSS software (version 22.0; IBM Corp., Armonk, New York, USA). Categorical variables are expressed as a percentage. Continuous variables are expressed as the median and interquartile range as appropriate. χ2-tests were used to assess differences in percentages for categorical data, and a t-test was used for normally distributed continuous variables. Spearman’s correlation was used to evaluate the relationships between CK, myoglobin and creatinine values, and only used for patients in whom all three variables were present – that is, 63% (n=214). CK and myoglobin values and the myoglobin/CK ratio were classified into quartiles from the lowest to highest values. The lowest quartile was used as the reference. Logistic regression analyses were used to investigate whether CK or myoglobin values and/or the myoglobin/CK ratio predicted AKI. Sex, age, CK and myoglobin values were split into quartiles and tested as independent variables. Only variables that made a statistically significant contribution to the model were included and tested against each other – that is, CK and myoglobin. Myoglobin/CK ratio was tested separately. Both unadjusted and adjusted results are presented. Intercollinearity was checked. As variance inflating factor was found to be less than 5, we concluded that collinarity was not invalidating the model. P values less than 0.05 were considered to be significant.
Table 1 presents a summary of the 341 patients diagnosed with rhabdomyolysis syndrome during the study period. We registered 24 aetiological factors associated with rhabdomyolysis and immobilization (204, 60%); use of prescription drugs (178, 52%) and use of illicit drugs or alcohol (118, 35%) were the most common factors (see
appendix Table A1 for more information). Multiple aetiologies were registered in 279 (82%) patients.
AKI developed in 173 (51%) patients and 35 (10%) were in need of dialysis. Average serum creatinine concentration in the patients with AKI was 333 μmol/l. Estimated glomerular filtration rate was measured in all patients and 12 (7%) patients was in stadium 2 (60–90 ml/min/1.73 m2), 81 (47%) in stadium 3 (30–59 ml/min/1.73 m2), 30 (17%) in stadium 4 (15–29 ml/min/1.73 m2) and 50 (29%) in stadium 5 (<15 ml/min/1.73 m2).
Twelve (4%) patients died during hospitalization. Immobilization contributed to a majority of the fatalities: eight were elderly who were found immobilized at home and two were because of intoxication. Two of the patients were critically ill because of an acute bacterial infection (see appendix Table A2). Average CK and creatinine values in these patients were 27 680 U/l and 367 μmol/l, respectively. Overall, rhabdomyolysis was part of multiorgan failure and not the underlying cause of death. The mortality rate in the patient group with AKI was 6%.
Average maximum serum CK and myoglobin values in the cohort were 33 454 U/l and 10 649 ng/ml. In the patients with AKI, the similar values were 42 776 U/l and 16 568 ng/ml, which were both significantly higher than the values in patients without AKI (P=0.002 and P<0.001, respectively). Myoglobin concentration was available for 214 (63%) patients.
CK and creatinine values were significantly correlated (P=0.005), although the Spearman’s correlation coefficient of 0.19 [95% confidence interval (CI): 0.06–0.32] was relatively low. The same was true for myoglobin and creatinine concentrations (P<0.001), but the Spearman’s correlation coefficient was higher at 0.49 (95% CI: 0.39–0.59).
CK and myoglobin values and the myoglobin/CK ratio were classified into quartiles from the lowest to highest values (Table 2 and Fig. 1). There was a significant correlation between AKI and the four quartiles of CK activity, myoglobin concentration and the myoglobin/CK ratio (P=0.02, P<0.001, P<0.001, respectively). Logistic regression (Tables 3 and 4) showed that only the fourth quartile with the highest CK activity was a significant predictor of AKI (P=0.001). For myoglobin concentration, the two highest quartiles appeared to be a significant predictor of AKI (P=0.02 and P<0.001, respectively). However, when both CK and myoglobin values were included in the analysis, only myoglobin concentration remained a significant predictor of AKI. The two highest quartiles of the myoglobin/CK ratio were significant predictors of AKI (P=0.001 and P<0.001, respectively). The cutoff value between quartiles 2 and 3 was 0.2. Thus, patients with a myoglobin/CK ratio more than 0.2 were significantly more likely to develop AKI than those with a lower ratio.
Correlations between maximum serum CK, myoglobin and creatinine values were highly significant for patients with rhabdomyolysis, as has been shown for the correlation between CK activity and AKI in previous studies . A recent systematic review by Safari et al.  reported a significant correlation between serum CK activity and AKI, especially in traumatic cases. Other studies have reported a weak  or no correlation . In the present study, the myoglobin/CK ratio was a good predictor of the development of AKI. Few studies have examined the correlation between myoglobin concentration and AKI, although serum myoglobin plays a dominant role in the pathogenesis of rhabdomyolysis-induced AKI . A small prospective study reported that peak myoglobin was a better predictor for AKI than was serum CK activity . On the basis of our results, we recommend that the myoglobin concentration should be measured as soon as possible after admission.
It is debatable whether rhabdomyolysis is a disease entity in itself or a complication of other diseases, although rhabdomyolysis is diagnosed and treated irrespective of the underlying disorder. In the clinical setting, it is useful to view all patients with rhabdomyolysis as a common group, even though different aetiologies can be identified. This allows the clinician to compare laboratory values and risk for AKI for all patient groups, but it complicates the evaluation of mortality data.
Immobilization was associated with rhabdomyolysis in 60% of the patients in our study, a higher percentage than previously reported. Immobilization was also the most common medical aetiology in the study by McMahon et al. , who reported a frequency of 18%. Melli et al.  reported immobilization as the eighth most common aetiology with a 2% frequency. The lower frequencies reported in these studies probably reflect the fact that only one main aetiological factor was registered. However, immobilization appears to be a crucial contributing factor.
Many reports have noted an association between the use of prescription drugs and rhabdomyolysis, but few studies have reported the actual frequency . Antidepressants, antipsychotics and statins were the most frequently used medications in our study, as in the study by Melli et al. . However, the importance of their contributing effects in each case is not known.
AKI is the most serious complications of rhabdomyolysis and ranges from 17 to 65% in previous studies [5–1419]. The wide range probably reflects differences in the definitions of AKI, patient cohorts or inclusion criteria. In the current study, 51% of the patients developed AKI; this percentage is similar to the frequencies reported in the two larger US studies of 46 and 48% . The observation that about half of the patients with rhabdomyolysis develop AKI highlights the severity of the syndrome. As a note, the cause of AKI is multifactorial, so it can be difficult to determine the exact contribution of rhabdomyolysis in the development of AKI.
The mortality associated with rhabdomyolysis ranges from 3 to 46% in different studies [56810–1319]. Mortality in patients treated for rhabdomyolysis is closely related to the underlying cause or concomitant disease, as discussed above. In the current study, mortality was 4%. Melli et al.  found a mortality rate of 3.4%, and McMahon et al.  found a 14% mortality rate. The latter included patients with higher CK activity and, therefore, more severe rhabdomyolysis, which could explain the difference in mortality between studies. Our study found that immobilization contributed in the majority of the fatalities, although multiorgan failure was the main cause of death.
There are limitations to the present study. First, this was a retrospective study, and larger prospective studies are required. Second, because of a small number of patients the CIs in the logistic regression analysis is wide; the association could be weaker but also stronger. Third, myoglobin concentration was not always measured (37% missing variables), and the results should therefore be interpreted with caution. However, the distribution of myoglobin values was because of less availability mainly during the first years of the study period and was not biased for specific patient groups. The distribution was therefore thought to be representative. Whereas CK activity was part of a routine work-up, myoglobin had to be requested by the treating physician if the CK activity was elevated. Because myoglobin has a short half-life , the measured peak myoglobin concentration could be too low. If that is the case, the association between myoglobin and AKI may be even stronger. Finally, the number of patients included in the study and the results may have been different if we had included trauma and surgical patients, and it does not allow extrapolating results for emergency patients. However, trauma patients often have other mechanisms causing rhabdomyolysis, for example, crush syndrome, and could be viewed as another entity.
Larger prospective studies are needed to assess the relationships between AKI and serum CK and myoglobin values. Further studies are also needed to evaluate whether serum myoglobin concentration and the myoglobin/CK ratio could be good predictors of the development of AKI and whether or not it could be used to guide the direction of treatment.
Serum myoglobin concentration was a better predictor of the development of AKI than was serum CK activity. A high myoglobin/CK ratio increased the likelihood of developing AKI. Our results suggest that the myoglobin/CK ratio may be a valuable tool in the assessment of patients with rhabdomyolysis.
The authors thank Professor Leiv Sandvik, Department of Statistics, Oslo University Hospital, for statistical advice.
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
acute kidney injury; creatine kinase; myoglobin; rhabdomyolysis