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on 17 Oct 2017

January 2016

Rhabdomyolysis- Causes, presentation, work up and treatment

Esther Jackson-Taylor MBBCh Hons, FY1 and Alexandra Vaughan MBBCh, FY1.  

[Edited by Yogita Aggarwal, SpR Renal Medicine] 

 

Introduction 

Rhabdomyolysis is a clinical condition in which skeletal muscle is damaged and broken down, resulting in the release of toxic intracellular components into the circulation.  It is an important clinical consideration as it is associated with several important complications, such as AKI, arrhythmias, volume depletion and DIC.  AKI occurs in approximately one third to one half of patients with rhabdomyolysis, and thus a high index of suspicion and knowledge of the complications of rhabdomyolysis and their treatment is crucial (A).  

The case presented is that of a gentleman who developed rhabdomyolysis and haematuria following extreme muscle exertion during personal training sessions.  This case highlights the importance of recognising rhabdomyolysis, and will discuss the pathophysiology and management of AKI with rhabdomyolysis. 

 

The Case 

The History 

A 32 year old gentleman was referred by his GP to the AMU with a two day history of “treacle coloured urine”.  From the history, it was evident that for the last two days the first void of urine had been “treacle coloured”, with subsequent voids light brown in colour.  Aside from this, he had no other symptoms to report apart from extreme muscle pain and stiffness. His urine output had been normal since the onset of symptoms and he had no other urinary or systemic symptoms.  During the 4 days prior to the onset of symptoms, he had started weight training for the first time with a personal trainer.   

 

Past Medical History 

He was usually fit and well, with no regular prescribed or over-the-counter medications. 

 

Social History 

He lived with his wife and children, was a non-smoker and drank 6 units of alcohol every other week on a night out. 

 

On Examination 

  • Observations were stable on admission and he was afebrile. 
  • Chest was clear. 
  • Abdomen was soft, non-tender with no obvious organomegaly.  
  • He was euvolaemic, with moist mucous membranes, JVP not raised, normal capillary refill time and no signs of peripheral oedema. 
  • The patient was tender to palpation of muscles all over body. 

 

Investigations 

  • Urine Dip: +++ for protein, +++ for blood, negative for leucocytes and nitrites. 
  • Blood Glucose: within normal range 
  • VBG: pH normal, lactate raised. 
  • Urine MCS: RBC 30, Casts  1, WBC   3 
  • Urine Myoglobin Levels: Raised. 
  • Urine PCR: 103 mg/mmol (raised). 
  • Urine Total Protein: 0.71 g/L (raised). 
  • Hepatitis Viral Serology: -ve 
  • EBV IgG: -ve 
  • CMV IgM: -ve 
  • ECG – normal  
  • USS Abdomen: liver normal size with no hepatic lesions.   R + L kidney or normal size with no hydronephrosis or abnormality of urinary tract visible. 

 

Diagnosis 

The patient was diagnosed with rhabdomyolysis secondary to excessive muscle damage. 

 

Management 

  • The patient was admitted for treatment with IV fluids for 48 hours; initially 1L every 4 hours for 24 hours to drive polyuria and then decreasing to 1L in 8 hours as the renal profile and CK improved.  He had regular monitoring of his U&Es and CK. 
  • The Renal Association Guideline 3.4-AKI* advise fuid resuscitation with 0.9% sodium chloride at a rate of 10-15ml/kg/hr to achieve high urinary flow rates (>100ml/hr), with the cautious addition of sodium bicarbonate 1.4% to maintain urinary pH> 6.51.
  • Throughout this process the patient's volume status must be carefully evaluated and once the patient has been adequately fluid resuscitated care must be taken not to precipitate pulmonary oedema.
  • During his inpatient stay, CK remained > 42640 for 3 days and then decreased to 32466 on the 4th day and 15494 on the 5th day following admission.  
  • Throughout his inpatient stay, U&Es remained normal and he retained adequate urine output. 
  • Additionally, his ALT decreased to 344. 
  • He was then discharged, with GP to follow-up and check bloods the following week. 
  • Proteinuria was due to tubular damage and completely settled on repeat 1 month later. 

* 2011 Renal Association AKI Guidelines by Dr Andrew Lewington & Dr Suren Kanagasundaram found at http://www.renal.org/guidelines/modules/acute-kidney-injury#sthash.EYKmoWxI.dpbs

Discussion

A key part of diagnosis is in the history, and patients will usually recall an event that could lead to muscle damage.  Definitive diagnosis can be made by raised CK levels and myoglobinuria.   

 

Pathophysiology 

  • The sarcolemma, the membrane surrounding striated muscle fibers, contains many pumps that regulate cellular electrochemical gradients.  
  • The Na/K-ATPase pump is located in the sarcolemma, and is necessary for pumping Na+ across the cell membrane to the exterior, thus resulting in a net intracellular negative charge. 
  • The negative intracellular charge generates a gradient down which calcium is exchanged over the sarcolemma and then once again into the sarcoplasmic reticulum and mitochondria.  ATP is required for these processes. 
  • In rhabdomyolysis, ATP is depleted.   
  • Increased intracellular calcium results in the activation of proteases, mitochondrial dysfunction and the generation of free oxygen radicals; which go on to cause damage to myofilaments and injure membrane phospholipid with leakage of intracellular contents into plasma. These contents include potassium, phosphate, CK, urate, and myoglobin. 

 

AKI and Rhabdomyolysis 

AKI is a severe and common complication of rhabdomyolysis.  The pathophysiology of AKI due to rhabdomyolysis is complex, not fully understood, and involves several mechanisms of action.  Following muscle cell damage, potassium, phosphate, myoglobin, CK, LDH and aldolase are released into the circulation.  The primary insult to the kidneys in rhabdomyolysis is thought to be due to volume depletion and the direct impact of myoglobin via three mechanisms on the kidney: renal vasoconstriction due to cytokine release, formation of intra-tubular casts and direct toxicity to the tubular cells.  The following diagram depicts the way in which rhabdomyolysis can cause AKI via these mechanisms (B).

 

Picture taken from  (G) Petejova and Martinek, Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Critical Care 2014, 18:224  doi:10.1186/cc13897

 

Causes 

There are multiple potential causes of rhabdomyolysis [C, D, E] can be catagorised as follows: 

  • Traumatic or muscle compression 
  • Non-traumatic exertional  
  • Non-traumatic non exertional 

Work Up 

  • Symptoms and Clinical signs 

The classical triad of symptoms in rhabdomyolysis is muscle pain, weakness and dark urine, though patients can be asymptomatic.  The muscle groups usually involved are the large proximal girdle muscles, and may be tender and/or swollen in clinical examination. Depending on the severity of presentation, patients may also complain of constitutional upset, and an altered metal state.  

 

Diagnostic tests 

  • CK, Myoglobinuria and Myoglobinaemia 

The most sensitive indicator of muscle damage is CK (more specifically CKMM), thus being the gold-standard investigation: serum levels begin to rise 2-12 hours post muscle injury, peaking at 24-72 hours and then decreasing gradually in 7-10 days (A).  A threshold level for CK has not yet been established, but many physicians take a level of five times the normal value to be diagnostic (I).   

Another finding suggestive of rhabdomyolysis is the presence of myoglobin in urine, although not all patients urine will be discoloured (B).  However, urinary and serum levels return to normal much more rapidly than CK (within 6 hours).  A negative serum or urine myoglobin test maybe falsely reassuring,   thus CK is more reliable than myoglobin in assessing the presence and extent of muscle damage and rhabdomyolysis (B).   

 

Supporting findings: 

  • AKI.
  • Hyperkalaemia and Hyperphosphataemia:  Potassium and phosphate are released from muscle breakdown and are excreted in the urine.  Hyperkalaemia and hyperphosphataemia may occur in the presence in extreme muscle breakdown or AKI.    
  • Hypocalcaemia:   Hypocalcaemia can occur in the initial stages due to entry into damaged myocytes, calcium deposition in to damaged muscles and decreased bony responsiveness to parathyroid hormone.  During the recovery stages, hypercalcaemia ay result as calcium is released from injured muscle and mild secondary hyperparathyroidism and increased 1,25-dihydroxyvitamin D levels.
  • Hyperuricaemia:   Hyperuricaemia may occur as uric acid is released from purines derived from damaged muscle cells and is prominent in AKI.
  • Metabolic acidosis 
  • DIC can occur due to the release of thromboplastin and other prothrombotic substances from damaged muscle.  

 

Further investigations to assess for complications of rhabdomyolysis are also necessary so that they can be treated accordingly: 

  • ECG to assess for arrhythmias. 
  • ABG to detect metabolic/lactic acidosis. 
  • Urea and creatinine to assess for AKI (A). 

 

Following this, if the cause for rhabdomyolysis is unclear, investigations to determine this will be required (A).  

In young patients with rhabdomyolysis muscle biopsy to test for muscular dystrophy and investigations to test for metabolic myopathies are useful. 

  • FBC to detect infection. 
  • Endocrinological tests if thought to be a possible underlying cause. 
  • Toxicology screen (A). 

 

Complications 

  • There are several important and severe complications that can occur with rhabdomyolysis, and thus regular monitoring and early intervention with any complications is important.   
  • AKI - very common in patients with Rhabdomyolysis, with between 30-50% of patients developing AKI. It may not occur for several days following the initial muscle damage, and so regular monitoring of U&Es is required (C).  The risk of developing this is related to the CK level and greatest when CK is over 15-20,000u/l (J). 
  • Arrhythmias - due to electrolyte abnormalities, thus it is necessary to monitor these throughout treatment. 
  • Volume Depletion - fluid accumulates in muscle tissue due to deranged electrolytes.  Hypovolaemia can be severe with extensive rhabdomyolysis, leading to hypovolaemic shock. 
  • Compartment Syndrome – an elevation in intracompartmental pressure leading to arteriolar collapse, muscle hypoperfusion and muscle cells necrosis.  

 

Treatment and Management of Rhabdomyolysis  

  • This focuses on supportive therapy, elimination of the underlying cause and prevention of complications.  The overall aims of treatment revolve around the following three aspects: 
  • Treatment/ prevention of hypovolaemic shock, and thus AKI, with fluid administration and correction of electrolyte and acid-base balance. 
  • Decompression of muscle compartments by reducing intramuscular oedema, thus protecting muscle integrity. 
  • Promotion of urine alkalinisation to protect against nephrotoxic effects of myoglobinuria (I). 
  • Additionally, it is important to prevent AKI associated with rhabdomyolysis due to hypovolaemia, aciduria, free radical release and tubular obstruction by myoglobin casts (B). 

 

Prevention of AKI 

  • Hypovolaemic AKI can be prevented by early, aggressive fluid resuscitation, with avoidance of fluids containing lactate or potassium due to the risk of lactic acidosis and hyperkalaemia with rhabdomyolysis (A).   
  • Urinary alkalisation with sodium bicarbonate is often used to help prevent AKI through aciduria.  However, the efficacy of this is yet to be proven by studies (G). 
  • Mannitol, an osmotic diuretic, can also be used to help prevent AKI through increasing renal blood flow and glomerular filtration (G).  A study by bragadottir et al (2012) that studied the effects of mannitol on renal blood flow and GFR has shown that mannitol can redistribute blood flow to the kidneys, induce renal vasodilatation and increase renal blood flow by up to 61 % (H).  Furthermore, mannitol is an osmotic agent that can cause shift of fluid from the interstitial compartment leading to decreased muscular swelling and correcting hypovolaemia (B). 
  • Drugs that are known to be risk factors for rhabdomyolysis, such as statins, and those that are nephrotoxic should be stopped immediately (I).   
  • Those who have already developed AKI from rhabdomyolysis will need additional treatment, possibly including renal replacement therapy (G).  Fluid regimens and other management will need to be individualised for patients depending on their age, comorbidities and severity of AKI and other complications of rhabdomyolysis. Kidney Disease Improving Global Outcomes Guidelines (KIDGO) have developed the following guidance for treatment of rhabdomyolysis and associated AKI (see figure below) (G). 

 

 

With Relevance to this Patient 

As demonstrated with this case, it is possible to avoid the occurrence of AKI with rhabdomyolysis if effective management with IV fluids is initiated early. 

 

Learning Points 

  • AKI is a common complication of rhabdomyolysis. Thus, regular monitoring of renal function is necessary in these patients in order to detect decline in renal function. 
  • Once a diagnosis of rhabdomyolysis is made, patients should be managed accordingly in order to prevent the onset or the further deterioration of AKI.   
  • Discussion with renal specialists is advised if kidney function is abnormal as renal replacement therapy may be required. 
  • Typical management for rhabdomyolysis includes aggressive fluid resuscitation for hypovolaemia; urine alkalinisation to protect the kidneys from myoglobin; mannitol to increase perfusion to the kidneys and decrease muscle oedema. 

 

References 

A.  Keltz E, Khan F, and Mann G.  Rhabdomyolysis: the role of diagnostic and prognostic factors. Muscles Ligaments Tendons J. 2013 Oct-Dec; 3(4): 303–312.  

B.  Vanholder R, Sever M†, Erek E and Lameire N. Rhabdomyolysis. JASN August 1, 2000:11;1553-1561. 

C.  Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore) 1982; 61:141. 

D.  Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore) 2005; 84:377. 

E.  Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care 2005; 9:158. 

F.  Miller M.  Causes of rhabdomyolysis. Up-to-date.  Found at http://www.uptodate.com/contents/causes-of-rhabdomyolysis as last accessed on Sept 19, 2014. 

G.  Petejova N and Martinek A.  Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Critical Care 2014, 18:224. 

H.  Bragadottir G, Redfors B, and Ricksten SE.  Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study.  Crit Care 2012, 16:R159. 

I.  Torres P, Helmstetter J, Kaye A.  Rhabdomyolysis: Pathogenesis, Diagnosis, and Treatment.  Ochsner J. 15(1): 58–69. 

J.  Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009 Jul 2;361(1):62-72. doi: 10.1056/NEJMra0801327. 

K.  KDIGO Clinical Practice Guideline for Acute Kidney Injury.  http://www.kidney-international.org as last accessed on 1st Dec 2015. 

Also see:

2011 Renal Association AKI Guidelines by Dr Andrew Lewington & Dr Suren Kanagasundaram found at http://www.renal.org/guidelines/modules/acute-kidney-injury#sthash.EYKmoWxI.dpbs

 

 

 

 

 



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