Rhabdomyolysis

Dr. Osama El-Shahat Head of Nephrology Department

New Mansoura General Hospital (international)ISN Educational Ambassador

WEEKLY SCIENTIFIC MEETING

Nephrology Department New Mansoura General Hospital

(international)

Definition

Destruction or disintegration of striated

muscle resulting in the leakage of the

intracellular muscle constituents into the

circulation and extracellular fluid

Causes

Exertional & Traumatic

Inherited metabolic

Miscellaneous Acquired metabolic

Hypoxia / Ischemia

Drugs

Etiology of rhabdomyolysisPhysical Causes

Trauma & Compression• Traffic or working accidents• Disasters• Torture• Abuse• Long term confinement to the same

position Occlusion or hypo perfusion of muscular

Vs• Thrombosis• Embolism• Vs clamping • Shock

Electric current• High voltage electric injury• Lightening• Cadioversion

Straining muscular exercise• Exercise• Epilepsy• Psychiatric agitation• Delirium tremens• Tetanus• Amphetamine overdose• Ecstasy• Status asthmatics

Temperature related• Exercise• High ambient temperature• Sepsis• Narcoleptic malignant syndrome• Malignant hyperthermia

Critical care 2005 – 9,158-169

Non physical causes

Metabolic myopathies• McArdle disease• Mitochondrial respiratory chain

enzyme deficiencies• Carnitine palmitoyl transferas

deficiency• Myoadenlyate deaminase

deficiency• Phosphofructokinase deficiency•

Drug & toxins• Regular & illegal drugs• Toxins• Snake & insect venom

Polymyositis/dermatomyositis Infections

• Local and metastatic infections

Endocrinolgic cause• Hyper/hypothyrodism

Systemic effect• Toxic shock syndrome• Influenza• HIV• Herpes viruses• Coxsackie virus

Electrolyte abnormalities• Hypokalemia• Hypocalcaemia• Hyponatremia &

hypernatremia• Hypophosphatemia• Hyper osmotic conditions

Critical care 2005 – 9,158-169

Drugs that may induce

rhabdomyolysis

Statin related rhabdomyolysis

Directly or indirectly impairs the production or use of ATP by skeletal muscle

Increases energy requirements that exceed the rate of ATP production

Interfere with ATP production by reducing levels of coenzyme Q, chronic myositis syndrome

Risk factors: high dosages, increasing age, female, renal and hepatic insufficiency, DM and concomitant therapy with drugs such as fibrates

Exertional Rhabdomyolysis

Exercise beyond physical capabilitiesATP demand outweighs supply resulting in

cellular membrane breakdown Intense exercise in normal individuals Grand mal seizure Delirium tremens Physical abuse Contact sports Crush injury Compression

Factors in the development ofExertional Rhabdomyolysis

Fitness levelExperience with the type of exercise being

PerformedIntensity of exerciseType of exercise (eccentric vs concentric)Ambient temperatureHydration levelFastingAssociated illness

Causes of Cellular Destruction in Rhabdomyolysis

Direct injury to cell membrane (ex. crushing, tearing, burning..)

Severe electrolyte disturbance disrupting sodium-potassium pump

Muscle cell hypoxia leading to depletion of ATP

Patho-

Physiology

Physical injury Compression Ischemia Excessive contractions Electric injury Hyperthermia

Non physical injury• Metabolic myopathies• Drug & toxins• Infection • Electrolyte• Endocrine disorder

Decrease intracellular

ATPSarcoplasmic Ca++ influx

Reperfusion injury

Compartment syndrome

• Increase phospholipase A2

• Increase Ca++ dependent phosphorylases

• Increase nucleases• Increase proteases• Increase free radicals• Increase local BMN

cells

Rhabdomyolysis

Primary cellular injury inrcease intracellular Ca++ secondary injury Activation Goldman: Cecil Medicine 23rd ed

Patho-physiology

Etiology of acute renal injury with rhabdomyolysis

Acute kidney injury

Direct toxicity of myoglobin in tubular cells

Hypovolemia and decrease renal

perfusion

Cast formation decreasing

tubular flow

Cellular Patho-physiology

Influx of extra cellular contents (sodium, water, chloride, calcium)

Efflux from damaged muscle cells(potassium, phosphates, lactic acid and other

organic acids, purines, myoglobin,thromboplatin, creatinine, creatine kinase)

Influx and Efflux of Extra and Intra CellularFluids During Cellular Destruction

Chemical composition

Extracellular (mEq/L)

Intracellular (mEq/L)

Sodium 142 10Potassium 4 140Calcium 2.4 0.0001Magnesium 1.2 58Chloride 103 4Bicarbonate 28 10Protein ( myoglobin, CKetc) 5 40

Myocyte Injury

zHours of ischemia

0 2 4 6

Tolerable-no permanent histological

changes

Irreversible anatomic and

functional changes

Muscle necrosis

When to Suspect Rhabdo

Occurs in up to 85% of patients with traumatic injuries. Those with severe injury who develop rhabdomyolysis-

induced renal failure have a 20% mortality rate

Multiple orthopedic injuries

Crush injury to any part of the body (eg: hand)

Laying on limb for long period of time –patient “found down”

Long surgeryBrown urine

AXIOM

Sudden collapse during physical exertion carried out

under warm climatic conditions should be primarily

diagnosed as

rhabdomyolysis

)unless and until proven otherwise(

What to Watch for if you suspect Rhabdo:

Clinical: Ms pain, weakness, dark urine

Hypovolemia, shock

Electrolyte abnormalities : ↑K+, ↓ Ca++

(sequestered in injured tissues)

Early Signs and Symptoms

weaknessfatigueheadacheslowed

mentation

thirstmuscle

crampsnausea,

vomitingdiarrhea

Causes of reddish-brown discoloration of the urine

Characteristics of urine and plasma in the different conditions that may cause red discoloration of the

urine

Characteristic

Rhabdomyolysis

Haemolysis

Hematuria

Red discoloration

plasmaPositive benzidine dipstick

Presence of erythrocyte by

urine microscopyElevated CK

concentration in the blood

Approach to the patient with red or brown urine

Diagnosis Serum CKMM

Correlates w/severity of rhabdoNormally 145-260 U/L100,000’s not uncommonhigh t(1/2): 1.5 daysRises within 12 hours of the onsetPeaks in 1–3 days, and declines 3–

5 days5000 U/l or greater is related to

renal failure

Serum myoglobint(1/2) 2-3 hExcreted in bile

sample UA

uric acid crystals

Creatine kinase(CK);CPK ( 38-174U/L for M

26-140 U/L for F )

CPK can be divided to 3 isoenzymes:

1-MM or CK3 96-100%(Skletal muscle and cardiac)

is the isoenzyme that constitutes almost all the

circulatory enz. In the healthy person

2-BB or CK1 0%(brain,GIT,Genitourinary)

3MB or CK2 0-6%

Creatine kinase(CK);CPK CK levels rise within 12 hours of muscle injury,

peak in 24-36 hours, and decrease at a rate of 30-40% per day.The serum half-life is 36 hours. CK levels decline 3-5 days after resolution of muscle injury ; failure of CK levels to decrease suggests ongoing muscle injury or development of a compartment syndrome. The peak CK level, especially when it is higher than 15,000 U/L, may be predictive of renal failure.

Myoglobin(5-70ng/ml)

Plasma myoglobin measurements are not

reliable, because myoglobin has a half-life

of 1-3 hours and is cleared from plasma in

the urine within 6 hours. Urine myoglobin

measurements are therefore preferable.

UA-myoglobinuriadipstick will be (+) for

hemoglobin, RBC’s and myoglobin

Microscopy: no RBC’s, brown casts, uric acid crystals

Other measures: carbonic anhydrase III, aldolase

Serum creatinine : disproportionate to BUN

Uric acid

Leucocytosis

Hypoalbuminemia

Haematocrite

Urine Na +

K +

Ca + +

Po4 Gluc.in urine Pigment casts

(+) for blood

Clinical Manifestations & Complications

Early signs:ɚ Hyperkalemia, ɚ Hypocalcemia,ɚ Hyperphosphatemia, ɚ Hyperuricemia ,

ɚ AcidosisEarly complications:

ɚ Cardiac arrhythmia

up to cardiac arrest & deathɚ HypovolemiaLate complications:ɚ Acute renal failure ɚ DICɚ Compartment syndrome ɚ Hypercalcemiaɚ Infection ɚ MOSF ɚ ARDSɚ Fascial compartment compression syndrome

American Family Physician (2002) 65:907-912

TREATMENT

Fluid Resuscitation

Is the cornerstone of treatment and must be

initiated as soon as possible. No

randomized trials of fluid repletion

regimens in any age group have been done.

Patients with a CK elevation in excess of 2-3 times the

reference range, appropriate clinical history, and risk

factors should be suspected of having

rhabdomyolysis. For adults, administer isotonic

fluids at a rate of approximately 400 mL/h (may

be up to 1000 mL/h based on type of condition

and severity) and then titrate to maintain a urine

output of at least 200 mL/h or 3 ml per kilogram

Because injured myocytes can sequester large volumes of ECF, crystalloid requirements may be surprisingly large. Consider central venous pressure measurement or Swan-Ganz catheterization in patients with cardiac or renal disease. Repeat the CK assay every 6-12 hours to determine the peak CK level.

The composition of repletion fluid is

controversial and may also include

sodium bicarbonate, esp. in NS is used.

To prevent renal failure, many authorities

advocate urinary alkalization, mannitol, and

loop diuretics. Check urine pH. If it is less

than 6.5, alternate each liter of normal

saline with 1 liter of 5% dextrose plus 100

mmol of bicarbonate.

Alkalinization of urine benefits:-

1-Decrease precipitationof the Tamm–Horsfall

protein–myoglobin complex

2- Inhibits reduction–oxidation (redox)cycling of

myoglobin and lipid peroxidation , thus

ameliorating tubule injury.

3- Counteract VC

Dirutics Remains controversial, but it is clear that it should be

restricted to patients in whom the fluid repletion has been achieved.Mannitol may have several benefits: as an osmotic diuretic, it increases urinary flow and the flushing of nephrotoxic agents through the renal tubules; as an osmotic agent, it creates a gradient that extracts fluid that has accumulated in injured muscles and thus improves hypovolemia; finally,it is a free-radical scavenger

During the time mannitol is being administered, plasma osmolality and the osmolal gap (i.e., the difference between the measured and calculated serum osmolality) should be monitored frequently and therapy discontinued if adequate diuresis is not achieved or if the osmolal gap rises above 55 mOsm per kilogram

Late Treatment

Dialysis –◦ intermitted preferred to

continuous Reduce use of anticoagulants in

trauma patients◦Peritoneal dialysis is

inadequate

◦The removal of myoglobin by plasma exchange has not demonstrated any benefit

Take Home Message

Impairment of the production or use of ATP is the basic cause.

Most useful laboratory findings are elevated CK(> 5000U/L related to ARF), initial detection of myglobolin.

Management: Aggressive hydration, diuresis, urine alkalinzation, free-radical scavengers, dialysis.

Do not treat hypocalcemia unless symptom developed.

Conditioning by regular exercise to prevent ″white-collar rhabdomyolysis ″ .

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