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Home , Crush injury, Crush syndrome, Major trauma

13 May 2016 No.11

Rhabdomyolysis: Making sense of the metabolic mayhem

ED SWART

Moderator: D Skinner

School of Clinical Medicine Discipline of Anaesthesiology and Critical Care

CONTENT

RHABDOMYOLYSIS: MAKING SENSE OF THE METABOLIC MAYHEM ...... 3 INTRODUCTION AND HISTORY ...... 3 AETIOLOGY ...... 4 PATHOPHYSIOLOGY ...... 4 Pathogenesis of reperfusion ...... 8 RISK ASSESSMENT...... 9 PROGNOSIS ...... 10 MANAGEMENT ...... 11 Management of in the acute phase ...... 11 Fluids and diuresis ...... 11 Electrolytes ...... 13 Disseminated intravascular coagulation ...... 13 ...... 13 Dantrolene ...... 14 Preservation of renal function ...... 14 Super high flux continuous veno-venous hemofiltration ...... 14 Management of acute injury and renal failure ...... 14 N-acetyl cysteine ...... 15 CONCLUSION ...... 15 REFERENCES ...... 16

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RHABDOMYOLYSIS: MAKING SENSE OF THE METABOLIC MAYHEM

INTRODUCTION AND HISTORY

By Dr Euodia D. Swart

Rhabdomyolysis is a condition as old as humanity itself. The Israelites were traveling to the promised land when they were struck with a very great plaque after consuming quail1, 2. One of the theories is that the great plague was caused by rhabdomyolysis. During late winter and early spring large numbers of quail migrate from Northern Africa to Europe and the Middle East to breed3. During this time hemlock seeds (Conium maculatum) form part of the quail’s diet and consumption of quail meat can lead to Hemlock poisoning4.

Figure 1: Quail Migration and Israelites leaving Mount Sinai

Hemlock is an alkaloid toxin (coniine) that acts as a nicotinic cholinergic agonist and GABA antagonist. This causes vomiting, abdominal pain, fasciculations, tremors, seizures, , , respiratory failure and . To this day there are case reports of rhabdomyolysis secondary to coturnism5.

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AETIOLOGY

There are multiple factors that can initiate rhabdomyolysis (Table 1) but the most common cause is traumatic rhabdomyolysis (crush syndrome) and the focus of this review. Crush syndrome really came to the forefront during manmade and natural disasters. One of the biggest advances in rhabdomyolysis was made during the London Blitz (Battle of Britain 1941)6. A rheumatologist, Dr. E. G. L. Bywaters7, noted that buried under rubble for several hours developed swelling of the limbs, dark tea coloured urine and despite recovering initially, died suddenly a few days later.

He noticed that there was a rise in their serum potassium and creatinine levels and that they developed hypertension after presenting the first few days with low . The revealed necrotic and degenerative renal changes with casts containing brown pigment8. Earthquakes have very high incidence of crush syndrome victims. It has been estimated that between 3-20% of earthquake victims will develop traumatic rhabdomyolysis. The victims are sometimes trapped for days underneath rubble of collapsed multi-story buildings. An example of the devastating consequences of crush syndrome was when a 7.8 Richter scale earthquake hit Tangshan (near Beijing). There were 242 769 of which 20% were because of crush syndrome9.

Africa is a continent with little seismic activity but crush syndrome is still a common condition seen in African hospitals. The most common presentation in an African is after severe beatings10. The South African overloaded judicial system created vigilante community groups who administer corporal punishment to criminals. This is a common cause of traumatic rhabdomyolysis in the rural South African population. Perpetrators are repeatedly beaten with a sjambok that leads to extensive muscle damage. Patients present to hospital with tramline bruising and widespread ecchymosis over large muscle groups11. Anaesthesia-induced rhabdomyolysis is a rare cause of rhabdomyolysis. It is most commonly seen during the administration of suxamethonium (nicotinic cholinergic agonist) in patients with an undiagnosed myopathy12, 13.

PATHOPHYSIOLOGY

There is a wide variety of conditions that can cause rhabdomyolysis. Anything that interferes with skeletal cellular can lead to cellular destruction14-16 (Figure 2).

Figure 2: Mechanism of rhabdomyolysis

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Category Examples Direct muscle Crush and crush syndrome, , electrical injuries including injury lightning strikes and /cardioversion

Excessive Tonic- clonic seizure, intense physical activity physical activity

Muscle ischaemia Generalized ischaemia – states Localised ischaemia – compartment syndrome, arterial or venous occlusion, , tourniquets17

Temperature Extreme cold or heat - , heat stroke18, malignant hyperthermia

Electrolyte and Chronic hypokalaemia, hypophosphatemia, sodium disturbances, osmolality hyperosmolar states abnormalities

Endocrine Hypermetabolic states – thyroid storm, pheochromocytoma Electrolyte abnormalities - DKA, Addison disease, hyperaldosteronism

Genetic and Muscular dystrophies, polymyositis, dermatomyositis autoimmune

Infections Bacterial – pneumococcal , staphylococcus aureus sepsis, salmonella , listeria infections, leptospirosis, legionella, tetanus, necrotizing fasciitis Parasitic - malaria Viral - Influenza, Varicella- Zoster, HIV, enteroviruses

Drugs, toxins Heroin, , N-methyl-D-aspartate19, caffeine, aminophylline, phencyclidine, hemlock, toxic mushrooms, snake venoms, , , immune-suppressants, narcotic analgesia, salicylates, statins13, paralytics, , antidepressants, antipsychotics, thrombolytics, chemotherapy, metformin, ACE inhibitors20.

Table 1: Aetiology of rhabdomyolysis

There is an important relationship between intracellular and extracellular electrolytes which is maintained by the cell membrane, sodium-potassium ATPase pump and the sarcoplasmic reticulum21. The intracellular concentration of sodium is kept low by the Na/K ATPase pump (primary transport). This creates an electrochemical gradient that favours the efflux of calcium ions through the sodium-calcium exchange secondary transport22.

Remaining calcium ions are transported actively into the sarcoplasmic reticulum which leads to a very low intracellular calcium concentration. Calcium is used by cells as a physiological trigger and is an essential ion for muscle contraction, clotting, membrane excitation, release of neurotransmitters, hormones and numerous intracellular processes including numerous pathological processes23.

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Ion Extracellular concentration Intracellular concentration (mmol/L) (mmol/L) Sodium 140 15 Potassium 4 135 Calcium 2 <0,5 Magnesium 1 20 Chloride 120 4 Bicarbonate 24 10 Phosphate 1.3 6.5 Table 2: Extracellular and Intracellular ion concentrations

If any of the mechanisms that maintain the homeostasis (cell membrane, Na-K ATPase pump, sarcoplasmic reticulum) are damaged or dysfunctional, that can lead to rhabdomyolysis. This causes the following (Figure 3): 1) An influx of sodium, chloride, calcium and water that leads to cellular oedema. 2) An efflux of potassium, phosphate, organic acids, thromboplastin and .

Influx Efflux

Figure 3: Influx and efflux of electrolytes

The influx of calcium increases the release of Ca2+ from the sarcoplasmic reticulum (calcium- mediated calcium release) and the increased intracellular calcium ions activate numerous cytolytic enzymes like neutral proteases, calcium dependant phosphorylases, nucleases and lipid peroxidation (figure 4).

Figure 4: Activation of cytolytic enzymes

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This aggravates the damage to the cellular membrane, oedema and cell destruction. The rapid rise of plasma K+ with hypocalcaemia will predispose the heart to arrhythmias especially sudden ventricular dysrhythmias and . This predisposition will be worsened by the secondary to the release of organic acids that increases the release of intracellular potassium and that lowers the plasma Ca2+ by inhibiting 1,25 dihydroxycholecalciferol.

Disseminated intravascular coagulation (DIC) is caused by thromboplastin release 24. The intravascular formation of fibrin results in thrombotic occlusions with depletion of and clotting factors. The thrombotic occlusions promote organ dysfunction and failure while the results in .

Creatine kinase is an enzyme found in three isomers (CK-BB, CK-MB and CK-MM). Cellular damage causes its release and it is as a helpful diagnostic and risk assessment tool.

Myoglobin is released into plasma, binds to haptoglobin and alpha-2 globulin and then transported to the reticuloendothelial system. If the haptoglobin and alpha-2 globulin is exhausted the myoglobin will be freely filtered by the kidneys.

Tamm Horsfall proteins are found in the ascending loop of Henle and distal tubules 25, 26. These glycoproteins have an important immunological function and provide protection against urinary tract infections especially against E.coli infections27.

Free myoglobin is filtered by Decrease glomerular filtrate Myoglobin binds to Tamm the kidneys flow Horsfall proteins = Tamm Horsfall proteins in the Decrease urine pH cast formation ascending loop of Henle and distal tubules

Figure 5: Cast formation during rhabdomyolysis28

The urine pH is decreased secondary to the organic acids that are excreted via the kidneys and the glomerular filtrate flow rate lowers because of hypovolaemia. The intracellular movement of water depletes the intravascular volume and the consequences of hypovolaemia are29: 1) Renal vasoconstriction via sympathetic stimulation and vasoconstrictor release. 2) Concentrated urine with lower volumes because of the activation of the renin- angiotensin-aldosterone system.

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This creates the perfect environment for myoglobin to precipitate with Tamm Horsfall proteins. The myoglobin casts obstruct the renal distal tubules and promote transtubular leakage of glomerular filtrate. Another reason for myoglobinuria nephrotoxicity is the toxic effect of myoglobin30-32. A myoglobin molecule consists of a haem group that causes oxidative to the renal tubules, promotes the formation of free radicals and activates lipid peroxidation (Figure 4). The end result is dark tea colour urine, oliguria and (AKI).

Pathogenesis of reperfusion injury

Clamped/Blocked artery Return of flow Activation of lipid peroxidase and rhabdomyolysis in other cells

Figure 6: Reperfusion injury

During prolonged compression or vascular injury there is decreased delivery of oxygen to cells with anaerobic metabolism and limited ATP availability. The consequence of a lack of ATP is a dysfunctional Na/K ATPase pump, increase H+ formation, accumulation of intracellular Ca2+ and activation of cytolytic enzymes. When vascular integrity is regained, the blood flow leads to an -reperfusion injury. High concentrations of potassium and hydrogen ions enter the bloodstream. The delivery of oxygen, hypoxanthine and activated neutrophils activate lipid peroxidation, increase cell membrane leakiness and worsen cellular oedema (see Flow diagram 1) 22.

Delivery of activated neutrophils, oxygen and hypoxanthine. Oxygen and hypoxanthine is converted to xanthine and superoxide anions by xanthine oxidase. Superoxide anions is highly reactive free radicals

The activated neutrophils and free radicals damage lipid bilayer (lipid peroxidation)

Cell membrane damage results in cellular oedema, increased intracellular Ca2+ and activation of cytolytic enzymes with cell lysis

Flow diagram 1: Reperfusion injury steps

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RISK ASSESSMENT

The biggest threat to a with crush syndrome’s life is during the first 3-4 days and then around 2 weeks after the injury. The most common reasons for in the first few days are hypovolaemia, hyperkalaemia and circulatory shock. If the patient survives the first insult they are faced with a second mortality spike around 14 days after the injury. The main cause of death shifts to multi-organ dysfunction with renal failure, hyperkalaemia and sepsis. The degree of muscle injury determines the risk for the development of crush syndrome and its complications. The best markers for measuring muscle injury in use are kinase, - 33-35 myoglobin and venous HCO3 .

Figure 7: Myoglobin levels peak at 30 hours versus the 72 hours of .

Creatine Kinase (CK) is the most commonly used marker. Myoglobin is the main causative protein for developing AKI-associated rhabdomyolysis and has a faster pharmacokinetics (half-life 2-3 hours) than creatine kinase (half-life 1.5 days) but because CK is more economical and readily available, it became the biomarker used to guide diagnosis and therapy.

A CK value above 5000 U/L have been accepted as a very strong risk for developing AKI (acute kidney injury), but even more than 1000 U/L has a threefold higher odd for developing 34 - AKI . Another valuable predictor for AKI is venous HCO3 . Muckart et al. illustrated venous - HCO3 of <17 mmol/L to be an indicator of extensive muscle injury and a strong predictor for the development of AKI35, 36. This was supported by other studies and considered as a robust predictor as CK37.

Body surface area (BSA) can also be used to predict the extent of the muscle injury. Smith found in blunt injury a linear correlation between BSA >18% and development of renal impairment37. The BSA appeared valuable in the “aerobic” group (example sjambok injuries) were caused direct muscle injury with muscle lysis. The BSA is not as helpful in the “anaerobic” injury group were the main drive for the crush syndrome is a reperfusion injury (example vascular injuries).

As AKI develops the creatinine starts to rise38. The severity of the AKI can be classified by using the RIFLE classification (Risk, Injury, Failure, Loss of Kidney function, End- stage renal failure). Once renal failure is established, dialysis must be considered as a treatment option. Other indications for dialysis are refractory hyperkalaemia, acidosis, high urea levels and fluid overloaded (rare because large amount of fluid sequester into muscle)29. Page 9 of 18

Class GFR criteria Urine output criteria Risk ↑sCr x 1.5 <0.5ml/kg/hr x 6hr Injury ↑sCr x 2 <0.5ml/kg/hr x 12hr Failure ↑sCr x 3 <0.3ml/kg/hr x 24hr or anuria x 12hr Loss of Kidney Complete loss of kidney function for 4 function weeks End-stage kidney Complete loss of kidney function > disease 3months Table 3: RIFLE classification

(sCR - serum creatinine, GFT - glomerular filtration rate, ↑ Increase, ↓ Decrease)39, 40

PROGNOSIS

An observational study done at Inkosi Albert Luthuli Central Hospital found that the overall mortality secondary to trauma related acute kidney injury (AKI) was 57%41.

The following risk factors for the development of AKI in trauma patients were identified:  Advanced age (Odds ratio (OR) of 2.6 in the age group 30-50 in comparison to an OR of 9.4 in patients older than 50 years)  BE <-12  Blunt trauma  Administration of IV contrast

This study also illustrated a lower mortality in the rhabdomyolysis patients with acute renal failure compared to other trauma related AKI with failure (23% versus 64%). This significant mortality difference supports early renal replacement therapy for rhabdomyolysis patients with severe acute kidney injury since they appear to have a significantly better prognosis.

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MANAGEMENT

The anaesthesia plan will be greatly influenced by the stage of the crush syndrome.

Figure 8: Different focus points

The “new” crush syndrome patient requires aggressive fluid while this treatment can lead to fluid overloading in the same patient with an established renal injury. The best management plan for rhabdomyolysis patient remains filled with controversies and lack of level 1 evidence42. Despite this, there as important aspects of the management that can improve the outcome for these patients especially in the acute phase.

Management of crush syndrome in the acute phase Fluids and diuresis

The first couple of hours after the insult are crucial. Sequestration of fluid into myocytes and surrounding tissue leads to hypovolaemia and circulatory shock. The release of myoglobin and organic acids in the presence of decrease urine output leads to cast formation. Fluid resuscitation is required to correct hypovolaemia and promote diuresis with a urine output goal of more than 1.5mls/kg/hr9, 42. If the patient present 6-12 hours after the insult, the aggressive fluid resuscitation may be ineffective and can lead to fluid overloading because the acute kidney injury is already established (see management of acute kidney injury and renal replacement therapy).

The best choice of fluid therapy is still an ongoing controversy. In most guidelines and studies regarding rhabdomyolysis normal is used as resuscitation fluid. Resuscitation with normal saline versus a balanced salt solution (like ringer’s lactate) has a couple important side effects against the use of normal saline. A couple of studies illustrated better outcomes for patients receiving a balanced salt solution regarding blood loss, blood product requirements, acidosis (hyperchloraemic acidosis) and urine output (because of normal saline’s higher osmolality)43-45. The biggest theoretical concerns regarding the use of ringer’s lactate is that it can contribute to hyperkalaemia and if lactate clearance is impaired (like with liver failure patients) it can lead to lactic acidosis9.

There is a lot of debate regarding the use of diuretics ( and furosemide) to promote diuresis. Mannitol is an osmotic diuretic which is commonly used for its postulated renal protective qualities in rhabdomyolysis: 1. Improves renal perfusion by the expansion of the intravascular compartment 2. Improves diuresis and prevent cast formation 3. Free radical scavenger that protects tubular cells against lipid peroxidation Page 11 of 18

A 20% mannitol solution is used and 0,5g/kg is given over 15 min followed by 0,1kg/hr as an infusion but should be avoided in patients that are known with cardiac failure and oliguria42. A randomised control trail found no benefit in the prevention of the development of acute kidney injury in patients who were treated with mannitol and normal saline versus only normal saline administration despite these so called renal protective qualities46. The use of other diuretics also remains controversial. Furosemide (40-120mg IV) is thought to assist with renal vasodilation, renal tubular flow and renal oxygen demands but can increase the acidity of the urine which will increase cast formation9, 14.

The use of for urine alkalisation is also questionable and there is no class 1 evidence to support its use22, but if you consider the presence of and hyperkalaemia, it might be a good treatment option to add. Acetazolamide (carbonic anhydrase inhibitor) can be added if the serum pH >7.45 or urinary pH <6.042.

Sodium bicarbonate can be administered as follows: 1. Remove 50mls from 1L of 0.45% saline and add 50 mEq of sodium bicarbonate (50mls of 8.4% Sodium bicarbonate) 2. Alternate fluid administration between 1 and ringer’s lactate 3. If pH is >7.5 add acetazolamide to promote diuresis, excrete bicarbonate, increase urine pH and improve alkalosis.

Despite the above mentioned postulated benefits, mannitol with bicarbonate therapy does not prevent renal failure, need for dialysis or improves mortality in patients with a CK <30 000 U/L. Brown and colleagues illustrated possible benefit for the use of mannitol with bicarbonate if the CK >30 000 U/L, but the study population was small and the finding was not statistically significant47.

The take home message is that there is no benefit in using a diuretic with fluid resuscitation versus fluid resuscitation on its own46 and if the intravascular compartment is further depleted by forced diuresis, it may even be harmful. A fluid management plan is outlined below:

Acute crush syndrome patient

Fluid challenge 30mls/kg

Normal volume status with Low volume status: Continue fluid improvement in urine output: Normal or high volume resuscitation with close monitoring of Continue fluid @ 1-2mls/kg/hr, status with oliguria /anuria: electrolytes, volume status and urine monitor electrolytes and volume Referral to unit with RRT output status

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Electrolytes

Hyperkalaemia with cardiac arrhythmias is one of the leading causes of mortality in the first 24-72hours. The risk for and cardiac arrest is further increased with the presence of hypocalcaemia. The first line of treatment for severe hyperkalaemia is which presents a problem with crush syndrome. The raised intracellular calcium ions are the centre of pathological process of rhabdomyolysis. Increasing the intracellular Ca++ will fuel the cytolic enzyme activation and worsen the rhabdomyolysis. Supplemental calcium administration should be omitted in the acute phase of rhabdomyolysis except in the presence of arrhythmias secondary to the hyperkalaemia.

Especially considering that at 3-4 days the serum calcium will improve (movement back into intravascular compartment)22. The diuresis because of the fluid resuscitation should also assist with lowering the plasma potassium and phosphate levels. Any drugs that will increase plasma potassium (like suxamethonium) and lower plasma calcium should be avoided. The focus of the management of hyperkalaemia should be on intracellular shift of potassium where the administration of sodium bicarbonate will be beneficial and diuresis secondary to adequate fluid resuscitation22.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) can be caused by the widespread activation of coagulation secondary to thromboplastin and cytokines release48, 49. The key to the management is vigorous treatment of the underlying condition, but supportive treatment will most likely be required. Bleeding is one of the biggest intra-operative challenges. The administration of blood products (, plasma, clotting factors and fibrinogen) and antifibrinolytics will frequently be indicated.

Compartment syndrome

Acute compartment syndrome and intra-abdominal compartment syndrome is a severe that can develop because of the fluid sequestration. The risk factors commonly found in crush syndrome patients are 50, 51:

 Young men with /radius factors (large muscle volumes with inelastic facial envelope)  Acidosis   Massive (10u packed cells/ 24hours)  Coagulopathy (platelets <55, INR >1.5)  Mechanical ventilation  Use of positive end expiratory pressure  Massive fluid resuscitation (>5l colloid or crystalloid in 24 hours)  Intra-abdominal , damage control

A very high index of suspicion for compartment syndrome is mandatory in patients with traumatic rhabdomyolysis.

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Dantrolene

Dantrolene is the cornerstone treatment of malignant hyperthermia, but has also been used in other cases of rhabdomyolysis19, 52. Dantrolene sodium is a hydantoin derivative that inhibits the release of Ca2+ from the sarcoplasmic reticulum and has previously been marketed as a muscle relaxant18. It is currently used in hypermetabolic, hyperthermia states where the excessive release of Ca2+ is attenuated.

Examples of causes of rhabdomyolysis where dantrolene can be beneficial are:  Severe sepsis (Especially staphylococcus aureus toxic shock syndrome)  Heat stroke  Malignant hyperthermia  (Ecstasy, theophylline, caffeine)

The dose required to reduce the temperature varies greatly. In a case report involving a patient with an ecstasy overdose, a dose of 3mg/kg within an hour was required before a decrease in temperature was noted19.

Preservation of renal function

Preservation of renal function is important determinant of morbidity and mortality. The anaesthetist should be conscious of this and potential nephrotoxic drugs like aminoglycosides, nonsteroidal anti-inflammatory drugs and contrast should be avoided especially if AKI is present41, 53.

Super high flux continuous veno-venous hemofiltration

Myoglobin is one of the key contributing factors for AKI development. If myoglobin can be removed from the circulation without being filtered by the kidneys, it can theoretically improve the outcome of crush syndrome victims. Conventional haemodialysis and plasma exchange have limited success, because of the size of the molecules allowed through the membrane (cut off point 20kDa). The molecular weight of myoglobin is 16.7kDa. But a treatment modality that can be considered is super high flux continuous veno-venous hemofiltration with a membrane that allows up to 100kDa molecules to pass54, 55.

In a case report of severe rhabdomyolysis, super high flux continuous veno-venous hemofiltration was used and they had significantly higher clearance of myoglobin. The myoglobin clearance was 39,2mls/min with an ultrafiltration rate of 4l/hr in comparison to <8mls/min with an ultrafiltration rate of 2l/hr seen with conventional dialysis54. A big adverse effect is the loss of serum albumin which worsens intravascular oncotic pressure and cellular oedema. In the above mentioned case report the administration of supplemental albumin was required.

Management of acute kidney injury and renal failure

Once the renal injury has occurred, the goal shifts to avoiding further renal insults (like nephrotoxic drugs) and maintaining isovolaemia, adequate and renal perfusion pressure56.

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The 5 indications for renal replacement therapy (RRT) are: 1. Volume overload 2. Hyperkalaemia 3. Severe metabolic acidosis 4. Symptomatic uraemia 5. Intoxication of dialyzable substances

The two basic modes of RRT are: 1. Intermittent haemodialysis 2. Peritoneal dialysis

N-acetyl cysteine

N-acetyl cysteine is a free radical oxygen scavenger that has been advocated in the prevention of contrast-induced nephropathy56. Although some studies results sound promising, the clinical efficacy is still not proven and a few meta-analysis showed no benefit in preventing acute renal failure57, 58.

CONCLUSION

Rhabdomyolysis (especially trauma related rhabdomyolysis) is a common condition in a South Africa community where violent crimes and mine accidents are part of daily life. The anaesthesia plan might be influenced by fluid status, electrolyte abnormalities, acidosis, coagulation, compartment syndromes and preservation of renal function. It must be highlighted that the crush syndrome patient will require adequate planning, preparation and knowledge of rhabdomyolysis pathogenesis. A vigilant monitoring for expected complications is of utmost importance.

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REFERENCES

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