Rhabdomyolysis is a syndrome resulting from skeletal muscle injury that leads to the release of harmful intracellular contents into the plasma, potentially causing severe renal complications. Key symptoms include muscle weakness, myalgias, and dark urine; however, not all symptoms may present together, particularly in children. Prognosis varies based on the underlying cause, with a mortality rate of approximately 5%, but early intervention can significantly improve outcomes.

1. Rhabdomyolysis
R.Srihari

2. Topics for discussion
• Background
• Pathophysiology
• Etiology
• Prognosis
• Clinical Features
• Differential Diagnosis
• Management

3. Background
• Rhabdomyolysis (literally, “dissolution of skeletal muscle”) is a
syndrome caused by injury to skeletal muscle and involves leakage
of large quantities of potentially toxic intracellular contents into
plasma.
• First described in the victims of crush injury during World War II.
Bywaters made the first association between ARF and crush injury
during the London Blitz when he noted dark brown urinary casts in
four patients who developed ARF after entrapment
• It is a final pathway of diverse processes and insults.The final
common pathway of rhabdomyolysis may be a disturbance in
myocyte calcium homeostasis.

6. • In adults, rhabdomyolysis is characterized by the triad of
muscle weakness, myalgias, and dark urine.
• In many children with this condition, however, all 3 symptoms
may not be seen together. Myalgias and generalized muscle
weakness are the most common presenting symptoms.
• Life-threatening renal failure and disseminated intravascular
coagulation (DIC) are dreaded complications that appear to be
more common in adults.

7. Pathophysiology
• Mechanisms of cell destruction in rhabdomyolysis include
– cellular membrane injury
– muscle cell hypoxia
– adenosine triphosphate (ATP) depletion
– electrolyte disturbances that cause perturbation of sodium-potassium
pumps
– generation of oxidative free radicals

9. • The sarcolemma, a thin membrane that encloses striated
muscle fibers, contains numerous pumps that regulate cellular
electrochemical gradients.
• The intercellular sodium concentration is normally maintained
at 10 mEq/L by a sodium-potassium adenosine triphosphatase
(Na/K-ATPase) pump located in the sarcolemma

10. • The Na/K-ATPase pump actively transports sodium from
the interior of the cell to the exterior.
• As a result, the interior of the cell is more negatively
charged than the exterior because positive charges are
transported across the membrane.
• The gradient pulls sodium to the interior of the cell in
exchange for calcium through a protein carrier exchange
mechanism. In addition, an active calcium exchanger
promotes calcium entry into the sarcoplasmic reticulum and
mitochondria.
• These processes depend on ATP as a source of energy.
• ATP depletion appears to be the end result of most causes of
rhabdomyolysis. This depletion disrupts cellular transport
mechanisms and alters electrolyte composition

11. • An increase in intracellular calcium levels results in
hyperactivity of proteases and proteolytic enzymes
and generation of free oxygen radicals
• These enzymes and substances increasingly degrade
myofilaments and injure membrane phospholipid
with leakage of intracellular contents into plasma
• These contents include potassium, phosphate, CK,
urate, and myoglobin.

12. • Excess fluid may also accumulate within affected muscle
tissue.
• The action of phospholipases in insect and snake venom may
cause hemolysis, muscle damage, endothelial necrosis,
rhabdomyolysis, and acute kidney injury (AKI)
• Additionally, muscle damage is amplified by infiltration of
activated neutrophils
• An inflammatory cascade and reperfusion injury sustains
muscle damage and degeneration

13. • Myoglobin is an important myocyte compound
released into plasma
• After muscle injury, massive plasma myoglobin
levels exceed protein binding (of haptoglobin) and
can precipitate in glomerular filtrate.
• Excess myoglobin may thus cause renal tubular
obstruction, direct nephrotoxicity (ischemia and
tubular injury), intrarenal vasoconstriction, and acute
kidney injury

14. • AKI is believed to be due to
– decreased extracellular volume, which results in renal
vasoconstriction.
– due to ferrihemate, which is formed from myoglobin at a pH level of
5.6 or less. Ferrihemate produces free hydroxy radicals and causes
direct nephrotoxicity, often through lipid peroxidation. These heme-
proteins may enhance vasoconstriction through interactions with nitric
oxide (NO) and endothelin receptors
– Renal vasoconstriction and ischemia deplete tubular ATP formation and
enhance tubular cell damage.
– Myoglobin precipitation in renal tubules causes formation of
obstructive casts. AKI rarely occurs in patients with chronic
myopathies unless it is triggered by a second inciting event.
– The risk of renal injury is low when initial CK levels are lower than
15,000-20,000 U/L. Lower CK levels may lead to renal injury in
patients with sepsis, dehydration, or acidosis.

15. • Gastrointestinal (GI) ischemia is common in
patients with fluid and electrolyte imbalances
This ischemia leads to endotoxin absorption,
cytokine production, and perpetuation of the
systemic inflammatory response.

16. Etiology
 trauma
 burns
 compression syndrome
 infection
 seizures
 heat intolerance
 heat stroke

17.  vascular occlusion
 prolonged shock
 electrolyte disorders
 low phosphate levels
 shaking chills

18. • Electrolyte derangement:
– hypophosphatemia is believed to cause
rhabdomyolysis because of the resulting shortage
of phosphate necessary for the production of ATP.
– Hypokalemia creates a negative potassium
balance, which causes rhabdomyolysis.
– Hypokalemia due to dehydration and exercise may
also cause rhabdomyolysis
– Hyponatremia and hypernatremia have also been
associated with rhabdomyolysis.

19. • Drugs of abuse:
– Ethanol
– Methanol
– Ethylene glycol
– Isopropanol
– Heroin
– Methadone
– Barbiturates
– Cocaine
– Amphetamines
– Ketamine hydrochloride
– Phencyclidine
– 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)
– Lysergic acid diethylamide (LSD)

20. • Rhabdomyolysis may also result from the use of
prescription and nonprescription medications, including
the following :
– Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors)
– Antihistamines (particularly in children)
– Salicylates
– Caffeine
– Fibric acid derivatives (eg, bezafibrate, clofibrate,
fenofibrate, and gemfibrozil)
– Neuroleptics/antipsychotics
– Anesthetic and paralytic agents (malignant hyperthermia
syndrome)
– Amphotericin B
– Quinine

21. – Corticosteroids
– Colchicine
– Theophylline
– Cyclic antidepressants
– Selective serotonin reuptake inhibitors (the
serotonin syndrome)
– Propofol (continuous infusion)
– Protease inhibitors

22. Prognosis
• The overall mortality for patients with rhabdomyolysis is
approximately 5%
• However, the risk of death for any single patient is dependent on the
underlying etiology and any existing comorbid conditions that may be
present and may be significantly higher in patients with AKI and
extremely elevated CPK levels.
• Rapid intervention and appropriate supportive treatment of
rhabdomyolysis-related kidney injury and renal failure improve
outcomes in traumatic crush injuries.
• If treatment modalities are implemented early, many patients recover
completely.

23. Clinical Features
• The classic triad of rhabdomyolysis comprises the
following:
– Myalgias
– Generalized weakness
– Darkened urine
• In practice, however, the presentation of rhabdomyolysis
varies considerably.
• The classic triad is actually seen in only about 50% of adult
patients, and it may be even less common in children.
• Additional nonspecific symptoms include fevers, nausea,
and vomiting.

24. • Patients may have muscular pain and tenderness,
decreased muscle strength, soft tissue swelling,
and skin changes consistent with pressure
necrosis
• The most commonly involved muscle groups in
adults include the calves and the lower back.
• Back, chest, and calf pain often mimics other
common conditions such as deep vein thrombosis
or angina.

25. Complications
• Electrolyte abnormalities are prominent
features of rhabdomyolysis:
– Hyperphosphatemia
– hyperkalemia
– hypocalcemia (early)
– hypercalcemia (late)
– Hyperuricemia
– hypoalbuminemia

26. • Hyperkalemia may be a result of both muscle
injury and renal insufficiency or failure.
• This abnormality may cause life-threatening
arrhythmias and should be immediately
addressed.

27. • Hypocalcemia is another common metabolic abnormality, resulting
from deposition of calcium phosphate.
• It may also be due to a decreased level of 1,25-
dihydroxycholecalciferol in patients with renal failure.
• Severe hypocalcemia may lead to cardiac arrhythmias, muscular
contractions, and seizures. These events may further damage
affected muscles.
• Late findings of hypercalcemia may be related of Ca leakage from
damaged muscles and poor clearance if the case is complicated by
kidney injury.

28. • Compartment syndrome may be either a
complication of or the inciting cause of
rhabdomyolysis.
• If muscle injury has occurred, measure
compartment pressures; if the pressure is
higher than 30 mm Hg, fasciotomy is
indicated.

29. • Acute kidney injury (AKI) occurs in 17-35% of adult
patients and in 5-42% in 2 pediatric case series.
• Etiologies of AKI may be related to hypovolemia,
vasoconstriction, and myoglobin toxicity.

30. • AKI and disseminated intravascular coagulation
(DIC, a late complication) are the most severe
complications of rhabdomyolysis, often developing
12-72 hours after initial muscle damage.
• AKI may account for as many as 35% of adult cases.

31. • Renal failure may also develop in patients treated
with optimal measures.
• Mechanisms of renal injury are multifactorial and
may include
– renal vasoconstriction
– intraluminal myoglobin cast formation
– heme-protein cellular toxicity
– Myoglobin and hemoglobin toxic effect on the
glomerulus are enhanced by aciduria and hypovolemia.

32. Differential Diagnosis
• Traumatic injuries (including nonaccidental abuse in children)
• Viral infections
• Myalgias from other etiologies
• Bacterial infections
• Cold exposure
• Malignant hyperthermia
• Muscle phosphorylase deficiency
• Phosphofructokinase deficiency
• Carnitine palmityl transferase deficiency
• Phosphoglycerate mutase deficiency
• Hyperosmotic conditions
• Guillain-Barré syndrome
• Inflammatory myositis

33. Management-Investigations
• Complete blood count (CBC), including hemoglobin, hematocrit,
and platelets
• Serum chemistries, including blood urea nitrogen (BUN), creatinine,
glucose, calcium, potassium, phosphate, uric acid, and liver function
tests (LFTs)
• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT) – Thromboplastin
released from injured myocytes can cause disseminated
intravascular coagulation (DIC)
• Serum aldolase
• Lactate dehydrogenase (LDH)

34. • Creatine kinase
• The diagnosis of rhabdomyolysis can be confirmed using certain laboratory
studies
• The most reliable and sensitive indicator of muscle injury is creatine kinase
(CK). Assessing CK levels is most useful because of its ease of detection in
serum and its presence in serum immediately after muscle injury.
• CK levels rise within 12 hours of muscle injury, peak in 24-36 hours, and
decrease at a rate of 30-40% per day.

35. • 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.
• Total CK elevation is a sensitive but nonspecific marker for
rhabdomyolysis. CK levels 5 times the reference range suggest
rhabdomyolysis, though CK levels in rhabdomyolysis are frequently
as high as 100 times the reference range or even higher

36. • Myoglobin:
• Plasma myoglobin measurements are not reliable, because
myoglobin has a half-life of 1-3 hours and is cleared from
plasma within 6 hours.
• Myoglobin levels not measured at the right time may
produce a false-negative result, though a positive result may
help confirm the diagnosis.
• Urine myoglobin measurements are therefore preferable.
• A urine myoglobin assay is helpful in patients with
coexisting hematuria (confirmed with microscopic
examination) when the presence of myoglobin is suspected.

37. • A urine dipstick test for blood that has positive findings
in the absence of red blood cells (RBCS) suggests
myoglobinuria
• Myoglobinuria may be sporadic or resolve early in the
course of rhabdomyolysis.
• Urine dipstick findings are positive in fewer than 50%
of patients with rhabdomyolysis; thus, a normal test
result does not rule out this condition.

38. • MRI is the imaging modality of choice for
evaluating the distribution and extent of injury of
affected muscles, especially when fasciotomy or
involvement of deep compartments is considered
• ECG should be performed early in the course of
evaluation to evaluate for cardiac dysrhythmias
related to hyperkalemia or hypocalcemia

39. Management
• Assess the ABCs
(A irway, B reathing, C irculation), and provide
supportive care as needed
• Ensure adequate hydration, and record urine
output.
• Insert a Foley catheter for careful monitoring of
urine output.
• Identify and correct the inciting cause of
rhabdomyolysis (eg, trauma, infection, or toxins)

40. • General recommendations for the treatment of
rhabdomyolysis include fluid resuscitation and
prevention of end-organ complications (eg, acute
renal failure [ARF])
• Other supportive measures include correction of
electrolyte imbalances.

41. • Serial physical examinations and laboratory
studies are indicated to monitor for
– compartment syndrome
– hyperkalemia
– acute oliguric or nonoliguric renal failure
– disseminated intravascular coagulation (DIC).

42. • Compartment syndrome necessitates immediate
orthopedic consultation for fasciotomy.
• DIC should be treated with fresh frozen plasma,
cryoprecipitate, and platelet transfusions.
• Monitor cardiac function.
• Monitor creatine kinase (CK) levels to show
resolution of rhabdomyolysis.

43. • Fluid Resuscitation:
• Expansion of extracellular volume is the cornerstone of treatment and must
be initiated as soon as possible.
• Retrospective studies of patients with severe crush injuries resulting in
rhabdomyolysis suggest that the prognosis is better when prehospital
personnel provide fluid resuscitation
• Support of intravascular volume increases the glomerular filtration rate
(GFR) and oxygen delivery and dilutes myoglobin and other renal tubular
toxins.
• Obtain intravenous (IV) access with a large-bore catheter. 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
• Because injured myocytes can sequester large volumes of extracellular
fluid, crystalloid requirements may be surprisingly large.

44. • In patients with CK levels of 15,000 IU/L or greater,
higher volumes of fluid, on the order of at least 6 L in
adults, are required
• Consider central venous pressure measurement or Swan-
Ganz catheterization in patients with cardiac or renal
disease. These invasive studies can assist in the
assessment of the intravascular volume
• Repeat the CK assay every 6-12 hours to determine the
peak CK level.

45. • Aggressive and early hydration with isotonic sodium
chloride solution is important for the prevention of
pigment-associated renal failure.
• The composition of repletion fluid is controversial and
may also include sodium bicarbonate.
• Initial fluid use in young children has been
recommended to be 20 mL/kg; in adolescents, 1-2 L/h
has been recommended. Subsequent hydration at a level
2-3 times maintenance may be sufficient

46. • Prevention of AKI:
– Alkalization of urine is believed to be helpful and is based
on the observation that acidic urine is necessary to cause
ATN.
– Alkalinization may also reduce the occurrence of cast
formation (ferrihemate and myoglobin).
– Some authorities believe that aggressive hydration
sufficiently causes a solute diuresis that alkalizes the urine.

47. • Urinary alkalization should be considered earlier in patients with
– acidemia
– dehydration
– underlying renal disease.
• A suggested regimen for adult patients is isotonic sodium chloride solution
(0.9% NaCl) with 1 ampule of sodium bicarbonate administered at 100
mL/h.
• Sodium bicarbonate is used with care because it may potentiate
hypocalcemia.
• The IV bicarbonate concentration is often adjusted to achieve a urine pH
higher than 6.5-7.0. This level of alkalization inhibits precipitation of
myoglobin and hemoglobin in the tubules.
• If the pH of urine less than 6.5, alternate each liter of normal saline with 1
L of 5% dextrose plus 100 mmol of bicarbonate.

48. • If urine output is adequate, consider the use of diuretics
such as mannitol (in adults) and furosemide
• Mannitol, acting as an osmotic diuretic, is thought to
increase urinary flow and reduce myoglobin cast
obstruction in renal tubules
• Loop diuretics such as furosemide may be used to enhance
urinary output in patients who are oliguric despite adequate
intravascular volume.
• It is recommended that aggressive volume expansion is to
be maintained until myoglobinuria is cleared.

49. • Correction of Acid-Base imbalance ,
electrolyte imbalance and Metabolic
abnormalities:
– Hyperkalemia
– Hypocalcemia
– Hypercalcemia
– Hyperuricemia
– Metabolic acidosis

50. • Other Medical Therapy:
– Dialysis may be required in patients with oliguric
renal failure, persistent hyperkalemia, other
electrolyte abnormalities, pulmonary edema,
congestive heart failure, and persistent metabolic
acidosis.

51. – The role of free-radical scavengers and
antioxidants in rhabdomyolysis (eg, pentoxifylline,
vitamin E, and vitamin C) has been studied in
animal models of ischemia-reperfusion injuries.
– Controlled studies evaluating the efficacy of these
agents have not been performed, and their clinical
use remains unclear

52. • With adequate hydration ensured, no specific
outpatient medications are needed. Inciting myotoxic
agents should be stopped.

53. Thank You