Rhabdomyolysis is a potentially life-threatening syndrome characterised by the breakdown of skeletal muscle cells and the subsequent release into the circulation of toxic sarcoplasmic contents such as potassium and myoglobin, along with other intracellular proteins and electrolytes.1 The acute clinical picture of severe rhabdomyolysis is dominated by electrolyte disturbances (hyperkalaemia, hyperphosphataemia, and hypocalcaemia), life-threatening arrhythmias and haemodynamic instability. Acute kidney injury (AKI) ensues as a result of combined ischaemic tubular injury (prerenal injury) and direct myoglobin toxicity (renal injury). The reported prevalence of AKI following rhabdomyolysis ranges from 13% to 50%.2,3
Creatine kinase is a biomarker of muscle injury and is widely used for laboratory confirmation of rhabdomyolysis. It is widely accepted that creatine kinase levels greater than five times the normal limit (creatine kinase > 1000 Ul−1) in the presence of skeletal muscle injury constitutes a diagnostic confirmation of rhabdomyolysis. Creatine kinase is not directly implicated in the pathogenesis of AKI following rhabdomyolysis, yet creatine kinase levels in excess of 5000 Ul−1 have been associated with the onset of renal failure and the need for renal replacement therapy (RRT) following crush injuries.4–6
Renoprotective treatment for the prevention of AKI in patients with confirmed rhabdomyolysis for as long as creatine kinase remained in excess of 2000 Ul−1 was introduced into clinical practice in our Neurosciences and Trauma Critical Care Unit (NCCU). The treatment consisted primarily of liberal fluid resuscitation with 0.9% sodium chloride. Diuretic therapy was considered when urinary output remained below 150 ml h−1 despite positive fluid balance. Sodium bicarbonate was administered to alkalinise urine when urinary pH remained less than 7 despite adequate volume resuscitation and diuresis. It must be pointed out that there is little evidence supporting the use of bicarbonate in this context and that it has been suggested that large volume infusion of crystalloid alone creates a solute diuresis sufficient enough to alkalinise the urine.7 Renal replacement therapy (continuous veno-venous haemodiafiltration) is not used as a preventive measure and its use is restricted to patients with established renal failure and/or refractory hyperkalaemia, acidosis, or fluid overload not responsive to pharmacological therapy.
In view of the emerging body of evidence linking positive fluid balance with increased mortality8–14 and a paradoxical increase in the risk of developing AKI and its progression,15–18 we elected to audit the appropriateness of using creatine kinase (a surrogate marker of renal risk) for the instigation of potentially harmful ‘renoprotective’ treatments. The main aim of this retrospective service evaluation is the identification of robust creatine kinase thresholds that could be used to guide clinical management of rhabdomyolysis safely. Finally, we sought to evaluate the prognostic performance of the McMahon score,19 a recently introduced risk prediction score for the aggregate outcome of kidney failure and mortality following rhabdomyolysis (Table 1).
This was a retrospective observational study. Data were collected as part of a service evaluation registered and approved by the NCCU Audit Committee at Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust 1 June 2013 (PRN 4656), and as such no further ethical approval was required.
Patients were identified in the local Intensive Care National Audit & Research Centre (ICNARC) database. Search criteria were: age at least 18 years, admission to NCCU between 2002 and 2012 and a diagnosis of rhabdomyolysis (creatine kinase ≥ 1000 Ul−1). Patient identification was followed by review of individual case records and laboratory findings. Data collection included: patient characteristics and admission diagnoses, APACHE II score, daily serum creatine kinase levels (including: ADMISSION creatine kinase, maximum recorded creatine kinase (PEAK creatine kinase) and the day in which PEAK creatine kinase was recorded, and the number of days a patient's creatine kinase level remained in excess of 2000 Ul−1), daily creatinine, phosphate, calcium and bicarbonate (Table 2). Outcome variables included: in-hospital mortality, ICU, length of stay (LOS) ventilator-days, renal failure and the need for RRT. Renal failure was defined using a modified Risk, Injury, Failure; Loss, End Stage Renal Disease (RIFLE) classification system with omission of urine output criteria. The baseline levels of creatinine were compared with the maximum creatinine level during ICU stay. Patients were stratified as ‘at risk’ if their maximum value was 1.5 times greater than baseline, ‘injury’ if it was two times greater, and ‘failure’ if it was three times greater than baseline creatinine.20 Baseline creatinine was determined by reference to previous admission creatinine results, clinical records or whether creatinine returned to within normal limits. The McMahon score is calculated on the day of admission based on personal variables and biochemical markers, according to the methodology described in McMahon et al. 2013. This involves calculating a risk score based on admission variables and personal factors shown in Table 1.19
Receiver Operating Characteristics (ROC) curves were produced to assess the sensitivity and specificity of ADMISSION creatine kinase, PEAK creatine kinase and McMahon Score for the prediction of development of AKI, requirement for RRT, mortality and the aggregate of the three adverse outcomes. For each patient, the ADMISSION and PEAK creatine kinase were recorded and the McMahon Score was calculated. These variables were used to determine the sensitivity and specificity of having a positive result of either AKI, RRT or death. Statistical software SPSS v 21.0 (Armonk, New York, USA: IBM Corp.) was used to produce the ROC curves, AUC and confidence intervals based on methodology described by Hanley et al.21 Between group differences in creatine kinase levels (ADMISSION creatine kinase and PEAK creatine kinase) between patients experiencing adverse outcomes (either as individual outcomes or as composite outcome) were evaluated using the unpaired t-test. Differences in mortality rates between groups stratified based on adverse renal outcomes were evaluated using Fisher's exact test. Correlations between variables (creatine kinase levels and LOS) were described using Pearson's correlation analysis. Continuous variables are reported as mean (range). Discrete variables are reported as median (interquartile range, IQR), and range. Statistical analysis was performed using SPSS v 21.0 Statistical software.
A total of 232 patients [M/F = 180/52; age 40 (IQR 25–58) years] that fulfilled the inclusion criteria were identified. The causes of rhabdomyolysis were trauma in 76% of cases, medical causes (15%, which included 1 patient with myocardial infarction, 1 patient with a perioperative cardiac event and two out of hospital cardiac arrests) and perioperative complications (9%). The majority of the latter (9/21, 43%) were associated with major vascular emergencies such as ruptured abdominal aortic aneurysm repair. Median APACHE II score was 12 (range 0–42). Median LOS was 9.6 (IQR 4.6–21.6) days. Overall ICU mortality was 37% (n = 86).
Creatine kinase time trends
Average initial creatine kinase for all patients was 5009 (range 69–157 860) Ul−1, with creatine kinase values remaining in excess of 2000 Ul−1 for an average duration of 3 days (range 1–10 days) (Fig. 1). Delayed increases in creatine kinase were common especially in patients with ADMISSION creatine kinase less than 2500 Ul−1 (n = 72/232, 31%). In this subgroup, 17 (24%) patients experienced a delayed increase in creatine kinase in excess 5 000 Ul−1. In the whole cohort, PEAK creatine kinase was recorded most commonly on the day of admission (median day 2), although in 9% of cases PEAK creatine kinase was recorded later than 72 h after admission (Fig. 2).
Nineteen percent (n = 45/232) of patients developed kidney ‘failure’ during their ICU admission. We could not clarify the extent of renal impairment in 13 patients (13/232, 0.05%) because of lack of a baseline creatinine. Mortality in the subgroup of patients with renal failure was 62% (n = 28/45), compared with an 18% mortality in the rest of the cohort [2 × 2 comparison by χ2, odds ratio 7.3, 95% confidence interval (CI) 3.4–15.9, P < 0.0001]. Two patients developed chronic renal failure (CRF), defined by RIFLE as persistent acute renal failure for more than 4 weeks. The mean ADMISSION creatine kinase of patients developing renal impairment was 7210 Ul−1, whereas the ADMISSION creatine kinase for those who developed CRF was 4713 and 157 860 Ul−1, respectively. ROC curves revealed that neither PEAK creatine kinase nor ADMISSION creatine kinase were sensitive or specific for predicting kidney ‘failure’ (AUC 0.658 ± 0.05; 95% CI 0.559–0.758, P < 0.01 and AUC 0.618 ± 0.05; 95% CI 0.520–0.716, P < 0.014).
Renal replacement therapy
Twenty-nine (12.5%) patients required RRT during their ICU stay. Patients requiring RRT had a higher PEAK creatine kinase (32 354 Ul−1) when compared with patients who did not need RRT (PEAK creatine kinase 7353 Ul−1; mean difference 25 000 Ul−1; P = 0.001). A PEAK creatine kinase of at least 5 000 Ul−1 is 83% sensitive and 55% specific for the prediction of need for RRT. Local guidelines state that RRT be commenced for potassium levels greater than 6.0 mmol l−1, hydrogen ions greater than 80 nmol l−1 or doubling of creatinine. However, initiation for other indications such as severe initial creatine kinase is at the discretion of the treating clinician.
Length of stay and mortality
There was no statistically significant correlation between LOS and creatine kinase. We corrected for skewed outliers (Pearson's correlation 0.06), up to a maximum stay of 4 weeks, after which any creatine kinase rise is unlikely to be because of the initial injury, (Pearson's correlation −0.042). We compared LOS with the number of days creatine kinase was more than 2000 Ul−1(Pearson's correlation −0.041) and there was no correlation. PEAK creatine kinase was higher in patients with fatal outcome (n = 72; PEAK creatine kinase 15 044 Ul−1) when compared with patients that survived (n = 160; PEAK creatine kinase 7 789 Ul−1; mean diff. 7255 Ul−1; P = 0.011). ROC curves reveal that PEAK creatine kinase is neither a sensitive nor specific predictor of mortality (AUC 0.594 ± 0.04; 95% CI 0.516–0.672, P < 0.017). For the aggregates of adverse outcomes (AKI, RRT and mortality) a PEAK creatine kinase at least 5000 Ul−1 had a sensitivity and specificity below 60%.
ROC analysis revealed that a McMahon Score of at least 6, calculated on admission, is 86% sensitive and 68% specific for the identification of patients who will require RRT (Fig. 3). A McMahon Score of 5 or less is associated with a 3% risk of developing AKI requiring RRT. The ROC curves suggest that use of the McMahon Score is a better predictor of RRT and mortality in our patient cohort and has the advantage that it can be calculated on day of admission (AUC 0.775 ± 0.05; CI 0.678–0.873, P < 0.00 and AUC 0.681 ± 0.037; CI 0.607–0.754, respectively).
This retrospective observational study was designed to determine robust creatine kinase thresholds for the identification of patients at high risk of adverse outcomes following rhabdomyolysis, a life-threatening disorder with multiple causes that include traumatic and vascular muscle injury, myotoxic drugs and toxins, infective or autoimmune myositis and malignant hyperthermia. Whatever the mechanism of injury, the final common pathway of muscle necrosis is a critical increase in intracellular calcium resulting in a pathological interaction of actin and myosin, myocyte energy failure, activation of intracellular proteases, increased cellular permeability and capillary leak.22–24 Skeletal muscle necrosis results in leakage of creatine kinase into the blood. Serum creatine kinase begins to rise approximately 2–12 h after the onset of muscle injury, peaks within 24–72 h and then declines at the relatively constant rate of approximately 40% of the previous day's value.25 It is creatine kinase that is commonly measured, however it is not directly implicated in the pathogenesis of rhabdomyolysis, rather it is myoglobin.
Myoglobin is a cytoplasmic haemoprotein found in skeletal and cardiac myocytes. Myoglobin reversibly binds oxygen by its haeme residue, a porphyrin ring – iron ion complex. Functionally, myoglobin is an oxygen-storage protein, capable of releasing oxygen during periods of relative hypoxia or anoxia.26 Following muscle necrosis, myoglobin is released into the circulating blood volume. Myoglobinuria occurs when serum myoglobin exceeds 85.65–171.3 nmol l−1.5 Myoglobin is directly involved in the pathogenesis of AKI following rhabdomyolysis via three synergistic mechanisms. Firstly, myoglobin can cause renal vasoconstriction and can precipitate ischaemic renal injury in hypotensive or hypovolaemic patients. Secondly, within the renal tubular system, in acidic pre-urine myoglobin dissociates into ferrihaemate and globin. Ferrihaemate has a direct cytotoxic effect on the epithelial cells of the proximal convoluted tubules, causing acute tubular necrosis. Thirdly, myoglobin binds Tamm-Horsfall proteins in acidic pre-urine, causing cast formation and distal tubular obstruction. The latter phenomenon is pH-dependent, with myoglobin precipitation rate in excess of 70% at urinary pH 5 or less, compared with a precipitation rate of less than 5% when urinary pH exceeds 6.5.1,2,6,22,24,27,28 On all three accounts, ‘myoglobin nephrotoxicity is exacerbated by hypovolaemia, hypotension and acidosis’.
There are theoretical concerns regarding the prognostic validity of creatine kinase time trends, along with an emerging body of evidence pointing toward a detrimental effect of liberal fluid administration. These led us to question our local policy that triggered liberal fluid resuscitation in patients with rhabdomyolysis whilst creatine kinase remained in excess of 2000 Ul−1. The available evidence supports liberal fluid resuscitation aimed at high-volume urinary output to be achieved within the first 6 h of admission to minimise the risk of AKI.29
Our results confirm that creatine kinase has limited prognostic value. Although a PEAK creatine kinase ≥ 5,000 Ul−1 is a sensitive (if not specific) marker of kidney failure requiring RRT, PEAK creatine kinase remains a poorly specific prognostic marker and it often is a delayed finding. Our interpretation of these data is that PEAK creatine kinase may be increasing after renal injury has already occurred, limiting its usefulness in guiding care in the individual patient.
The McMahon Score is a scoring system calculated on admission for the prediction of risk of renal failure requiring RRT or mortality in patients with rhabdomyolysis, first described in 2013. The McMahon risk prediction model does include admission creatine kinase (extreme elevations in excess of 40 000 Ul−1 confer 2 points), along with other indicators of severity (hypocalcaemia, hyperphosphataemia and acidosis) and patient variables (gender, age and type of injury).19 A McMahon score less than 5 indicates a 3% risk of either need for RRT or death, whereas a score more than 10 indicates a 52% risk of RRT or death. When applied to our patient cohort, a McMahon score of at least 6 would have allowed for a more sensitive, specific and timely identification of patients at risk of adverse outcomes when compared with PEAK creatine kinase or creatine kinase time trends. This is because the McMahon score tells us a lot more about the biological substrate on which the insult is encountered, as some of its variables (age and admission creatinine) are markers of generally reduced physiological reserve.
The implications of these results are twofold. On one hand, a relatively low admission creatine kinase is often falsely reassuring and should not delay the instigation of renoprotective therapy in high-risk patients identified by a high McMahon score. Although physiological targets and resuscitation volumes need to be tailored, based on a risk-benefit estimation which takes into account the functional reserve of the individual patient, delaying aggressive fluid resuscitation to support renal perfusion and alkaline diuresis may result in preventable AKI in patients with a high McMahon score.30–35 It should be emphasised that fluid balance, haemodynamic variables, respiratory function and acid base status remain the most relevant factors guiding fluid resuscitation strategies. The main conclusion of this study is that a high McMahon score (but not admission creatine kinase) informs the decision making process by identifying patients at risk of renal injury in whom aggressive fluid resuscitation targeting alkaline polyuria may be justified despite perceived haemodynamic stability, euvolaemia and satisfactory acid-base status. On the other hand, the finding of a protracted elevation in creatine kinase in a patient who is otherwise at low risk of renal injury should probably not warrant, by itself, aggressive fluid administration. The latter point was a specific concern in our patient cohort, as the local adult ICU policy instigated liberal fluid resuscitation in all patients with creatine kinase at least 2000 Ul−1, irrespective of duration and actual renal risk. An emerging body of evidence highlighting the potential detrimental effects of large volume resuscitation made us hypothesise that patients with creatine kinase more than 2000 Ul−1 for longer periods would be receiving higher volumes of fluids and experience worse outcomes. We were unable to confirm such a hypothesis, as there was no correlation between the number of days with recorded creatine kinase of at least 2000 Ul−1 and LOS, mortality or any other adverse outcome. The main limitations of this study are the retrospective nature and absence of data regarding resuscitation fluid volumes, urinary output and fluid balance. Although we were unable to demonstrate a correlation between the number of days with elevated creatine kinase and any adverse outcomes (including ventilator days and ICU LOS), the assumption of a protractedly elevated creatine kinase being associated with higher volume of fluids in this patient group may not hold true: a recent local audit revealed that clinicians tended to be much more restrictive with fluid administration than the local rhabdomyolysis management policy dictated.
Overall mortality was 37% (n = 86/232), with a threefold increased risk of a fatal outcome in patients developing renal failure. The development of CRF in this patient cohort was 0.8% (n = 2/232), confirming that renal injury associated with rhabdomyolysis is often reversible in patients that survive the acute phase.
The McMahon score should be calculated on admission for all patients admitted with rhabdomyolysis. Renal protective therapies should be considered in all patients deemed to be at high risk (score ≥6), irrespective of admission creatine kinase. A prospective trial would need to be undertaken to determine if this will alter prognosis in these individuals. Renal protective therapy should include fluid resuscitation targeting euvolaemia and urinary output of at least 1–2 ml Kg−1 h−1 in accordance with well documented evidence. Fluid balance should be carefully followed to prevent a positive fluid balance or fluid overload. Creatine kinase remains a relevant biomarker in the management of rhabdomyolysis and creatine kinase levels should be obtained for up to a week post injury for the following reasons: ADMISSION creatine kinase more than 1000 Ul−1 provides laboratory confirmation of the clinical diagnosis, ADMISSION creatine kinase of at least 40 000 Ul−1 is used to calculate the McMahon score and delayed increase in creatine kinase are common and may reveal delayed deterioration that may otherwise go undetected.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: preliminary data for this study were presented as a poster presentation at the International Symposium on Intensive Care and Emergency Medicine, 17–20 March 2015, Brussels.
1. Bosch X, Poch E, Grau JM. Rhabdomyolysis and Acute Kidney Injury. N Engl J Med
2. Holt S, Moore K. Pathogenesis and treatment of renal dysfunction in rhabdomyolysis. Intensive Care Med
2001; 27:803–811. http://link.springer.com/10.1007/s001340100878
3. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore)
2005; 84:377–385. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00005792-200511000-00005
4. Brown CVR, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol Mmke a difference? J Trauma Inj Infect Crit Care
2004; 56:1191–1196. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00005373-200406000-00004
5. Brochard L, Abroug F, Brenner M, et al. An Official ATS/ERS/ESICM/SCCM/SRLF Statement: prevention and management of acute renal failure in the ICU patient: an international consensus conference in intensive care medicine. Am J Respir Crit Care Med
2010; 181:1128–1155. http://www.ncbi.nlm.nih.gov/pubmed/20460549
6. El-Abdellati E, Eyselbergs M, Sirimsi H, et al. An observational study on rhabdomyolysis in the intensive care unit. Exploring its risk factors and main complication: acute kidney injury. Ann Intensive Care
7. Of O. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl [Internet]. 2013; 3(1):4-4. Available from: http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO
CKD-MBD GL KI Suppl 113.pdf\nhttp://www.nature.com/doifinder/10.1038/kisup.2012.73\nhttp://www.nature.com/doifinder/10.1038/kisup
8. Bellomo R, Cass A, Cole L, et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med
9. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care
10. Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int
11. Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med
12. Goldstein SL, Somers MJG, Baum MA, et al. Pediatric patients with multiorgan dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int
13. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol
14. Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int
15. Legrand M, Dupuis C, Simon C, et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit Care
16. Van Biesen W, Yegenaga I, Vanholder R, et al. Relationship between fluid status and its management on acute renal failure (ARF) in intensive care unit (ICU) patients with sepsis: a prospective analysis. J Nephrol
2005; 18:54–60. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Retrieve&list_uids=15772923&dopt=abstractplus\npapers://347a0d64-8b48-4dcf-b0a7-00f094a7599b/Paper/p2054
17. Raimundo M, Crichton S, Syed Y, et al. Reduced systemic oxygen delivery and low blood pressure on day of early AKI increase the risk of progression to severe AKI in critically ill patients. Nephrol Dial Transplant
2012; 27 (suppl 2):ii348–ii377.
18. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol
19. McMahon GM, Zeng X, Waikar SS. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med
2013; 173:1821–1828. http://www.ncbi.nlm.nih.gov/pubmed/24000014
20. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care
21. Hanley AJ, McNeil JB. The Meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology
1982; 143:29–36. http://radiology.rsna.org/content/143/1/29.full.pdf
22. Criddle LM. Rhabdomyolysis. Pathophysiology, recognition, and management. Crit Care Nurse
23. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis: an overview for clinicians. Crit Care
2005; 9:158–169. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1175909&tool=pmcentrez&rendertype=Abstract
24. Chatzizisis YS, Misirli G, Hatzitolios AI, Giannoglou GD. The syndrome of rhabdomyolysis: complications and treatment. Eur J Intern Med
2008; 19:568–574. http://www.ncbi.nlm.nih.gov/pubmed/19046720
26. Ordway GA, Garry DJ. Myoglobin: an essential hemoprotein in striated muscle. J Exp Biol
27. de Meijer AR, Fikkers BG, de Keijzer MH, et al. Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey. Intensive Care Med
2003; 29:1121–1125. http://www.ncbi.nlm.nih.gov/pubmed/12768237
28. Boutaud O, Jackson Roberts IIL. Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure. Free Radic Biol Med
29. Zager RA. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney international
30. Scharman EJ, Troutman WG. Prevention of kidney injury following rhabdomyolysis: a systematic review. Ann Pharmacother
2013; 47:90–105. http://www.ncbi.nlm.nih.gov/pubmed/23324509
31. Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med
32. Cushner HM, Barnes JL, Stein JH, Reineck HJ. Role of volume depletion in the glycerol model of acute renal failure. Am J Physiol
33. Reineck HJ, O’Connor GJ, Lifschitz MD, Stein JH. Sequential studies on the pathophysiology of glycerol-induced acute renal failure. J Lab Clin Med
34. Knottenbelt JD. Traumatic rhabdomyolysis from severe beating–experience of volume diuresis in 200 patients. J Trauma
35. Iraj N, Saeed S, Mostafa H, et al. Prophylactic fluid therapy in crushed victims of Bam earthquake. Am J Emerg Med