RHABDOMYOLYSIS btly Dr Tanisha Baladia medicine

RHABDOMYOLYSIS
DR TANISHA BALADIA

Understanding Rhabdomyolysis: Muscle Cell
Leakage and Systemic Complications
• Rhabdomyolysis is a condition characterized by the leakage of muscle cell contents
into the bloodstream.
• Leads to systemic complications such as acute kidney injury, electrolyte imbalance,
and disseminated intravascular coagulation.
• The muscle injury (trauma, exercise, thermal dependent syndromes) or lack of ATP
(Medicines, electrolytes, hereditary and metabolic disorders, intense exercise,
ischemia) in a muscle cell results in intracellular sodium and calcium influx.
• Water is drawn into the cell along with sodium, causing cell swelling and
disruption of intracellular and membraneous structures. Excessive intracellular
calcium leads to activation of actin-myosin cross-linkage, myofibrillar contraction,
and depletion of ATP.

• Excessive intracellular calcium also activates calcium-dependent
phospholipases and proteases, promoting cell membrane dissolution
and disruption of ion channels (Na+K+ pump and Na+Ca2+
exchangers).
• With reperfusion, leukocytes migrate into the damaged muscle and
cause an increased number of cytokines, prostaglandins, and free
radicals, causing further myolysis, necrosis of muscle fibers, and
release muscle breakdown products like potassium and myoglobin,
creatine kinase, phosphate, uric acid, and various organic acids into
the bloodstream.

• This leads to the complications of hyperkalemia and
hyperphosphatemia.
• In rhabdomyolysis, hypocalcemia is observed initially, followed by
hypercalcemia. This is because calcium first moves into the myocyte
during injury, and then it leaks out into extracellular spaces after cell
lysis.
• Disseminated intravascular coagulation (DIC) is thought to be due to
thromboplastin released during muscle injury.

• Myoglobinuria is only seen in rhabdomyolysis.
• Myoglobin is freely filtered through the glomerulus and reabsorbed in the
renal tubule by endocytosis in a normal, healthy state.
• Myoglobin has no nephrotoxic effect in the tubules in alkaline urine.
• The proximal convoluted tubule (PCT) of the kidney has limited ability to
convert iron to ferritin. Urine acidification in rhabdomyolysis and excess
myoglobin delivery to PCT causes ferrihemate accumulation. The globin chain
readily dissociates from the iron-containing ferrihemate portion of myoglobin
and is rapidly converted to ferritin.
• Ferritin generates oxygen-free radicals, leading to excess oxidative stress and
Proximal convoluted tubular cell injury.

• The reabsorption of excess myoglobin is limited in distal convoluted
tubule (DCT) in rhabdomyolysis.
• The presence of vasoconstriction and hypovolemia with excess water
reabsorption in DCT further concentrates myoglobin in DCT; all of
these promote cast formation and obstruction of DCT.

• Acute kidney injury (AKI) from rhabdomyolysis is multifactorial.
Muscle breakdown and water sequestration within the muscle cause
volume depletion and activation of the Renin-angiotensin-aldosterone
and antidiuretic hormone secretion.
• Excess myoglobin released from rhabdomyolysis causes oxidative
injury to lipids. It allows the excess release of endothelin,
thromboxane A2, necrotic tumor factor-alpha, isoprostanes
(vasoconstrictors), and decreased nitric oxide (vasodilators), resulting
in direct renal vasoconstriction.

• Excess myoglobinuria during rhabdomyolysis exceeds the renal
metabolic threshold and manifests as brown-reddish tea-colored
urine called myoglobinuria.
• The presence of volume depletion, intrarenal vasoconstriction,
ischemia, direct cellular injury in PCT, and precipitation of the Tamm–
Horsfall protein–myoglobin complex obstructing DCT all play a role in
developing the AKI.

• Persistently raised compartment pressure may lead to irreversible
peripheral nerve palsy.
• Compartment pressure of more than 30 mmHg produces significant
muscle ischemia, and measurement of compartmental pressure is
helpful in decision-making for fasciotomy.
• Rhabdomyolysis victims with severe blood loss and hypotension are at
increased risk for muscle ischemia even with lesser compartment
pressures.

When to suspect rhabdomyolysis
• Rhabdomyolysis should be suspected in patients presenting with the
triad of muscle pain, weakness, and dark-colored urine, but few
patients have all three classic symptoms
• Thus, a diagnostic evaluation should be performed in individuals with
both myalgias and pigmenturia

Muscle — When present, muscle symptoms of rhabdomyolysis may develop
over hours to days.
• Pain
• Weakness
• Swelling –Swelling may be due to either:
• Myoedema, which is nonpitting and is apparent at presentation or develops
after rehydration
• Peripheral edema, which is pitting and occurs with rehydration (particularly
in patients with AKI)
• Limb induration is occasionally present.

• Urine — Dark-colored urine (red to brown, "tea-colored," "cola-colored") is one of the
classic signs of rhabdomyolysis but it occurs in ≤10 percent of cases.
• Urinalysis is required to distinguish myoglobinuria (from rhabdomyolysis) from
hematuria.
• Myoglobin, a heme-containing respiratory protein, is released from damaged muscle in
parallel with CK. It appears in the urine when the plasma concentration exceeds 1.5
mg/dL. Visible changes in the urine only occur once urine levels exceed from
approximately 100 to 300 mg/dL, although it can be detected by the urine
(orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL
• Hemoglobin, the other heme pigment capable of producing pigmented urine, is much
larger (a tetramer) than myoglobin and is protein bound. As a result, much higher
plasma concentrations are required before red to brown urine is seen, resulting in a
change in plasma color

• Skin — Skin changes caused by ischemic tissue injury, such as
discoloration or blisters, may also be seen but are present in <10
percent of patients
• Systemic — Additional symptoms that are more common in severely
affected patients include malaise, fever, tachycardia, nausea and
vomiting, and abdominal pain

Fluid and electrolyte abnormalities
• Hypovolemia results from "third-spacing" due to the influx of
extracellular fluid into injured muscles and increases the risk of AKI.
• Hyperkalemia and hyperphosphatemia result from the release of
potassium and phosphorus from damaged muscle cells. Hypocalcemia,
which can be extreme, occurs in the first few days because of entry into
damaged myocytes and both deposition of calcium salts in damaged
muscle and decreased bone responsiveness to parathyroid hormone.
• Severe hyperuricemia may develop because of the release of purines
from damaged muscle cells and from reduced urinary excretion if AKI
occurs.

• Acute kidney injury can be from hypovolemia, drugs, dehydration,
hypoperfusion, pigment induced distal tubular damage.
• The risk of AKI is less in patients with CPK levels less than 20,000 IU/L.
Patients with CK levels of more than 40,000 IU/L have an increased
risk of acute kidney injury.
• The best predictors for developing acute kidney injury appear to be
high initial serum creatine, low serum bicarbonate, low serum
calcium, and increased serum phosphate.
• Hypoalbuminemia and increased BUN have also been associated with
the development of acute kidney injury.

• Compartment syndrome — Compartment syndrome may develop
after fluid resuscitation, with worsening edema of the limb and
muscle.
• Compartment syndrome can also be a cause of rhabdomyolysis, as
may occur after traumatic bone fracture or prolonged limb
compression.
• Capillary ischemia in compartment syndrome exacerbates muscle and
nerve tissue injury.

• History and examination — The history should focus on factors that
may cause or predispose to rhabdomyolysis, including traumatic,
nontraumatic exertional, and nontraumatic nonexertional etiologies

Traumatic or direct muscle injury
Crush syndrome
Prolonged immobilization (eg, coma, sedation)
Compression of blood vessels (eg, tourniquets)
Surgery with prolonged immobilization or vascular
occlusion
Compartment syndrome
Electrical injury
Burn injury
Physical restraint
Causes
of
muscle
injury
(rhabdomyolysis)

Nontraumatic
Exertional
Normal muscle
Prolonged, strenuous, and/or unaccustomed exertion
Eccentric exercise
Environmental heat illness
Impaired heat loss due to reduced sweating
Hyperkinetic states (eg, convulsive seizures, delirium tremens, psychotic
agitation)
Sickle cell trait
Abnormal muscle
Metabolic myopathies
Pseudometabolic myopathies*
Mitochondrial myopathies
Malignant hyperthermia
Neuroleptic malignant syndrome
Nonexertional
Alcoholism
Drugs, including prescription medications (eg, statins) and illicit substances (eg,
cocaine, amphetamines, heroin)
Toxins (eg, carbon monoxide)
Infections (eg, influenza virus, HIV, COVID-19, Legionella species)
Electrolyte abnormalities (especially hypokalemia)
Endocrinopathies
Inflammatory myopathies
Miscellaneous

Laboratory Investigations
• Complete blood count, differential, and platelet count, for evidence of infection or hemolysis
• Blood urea nitrogen, and creatinine, for renal function and evidence of acute kidney injury (AKI)
• Routine electrolytes plus calcium and phosphate, for hyperkalemia, hypocalcemia, and
hyperphosphatemia
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) for evidence of hepatic
impairment, though both AST and ALT elevations can suggest release from muscle due to
rhabdomyolysis
• Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, and fibrinogen, for
evidence of disseminated intravascular coagulation
• Arterial blood gas, for metabolic acidosis
• Serum albumin, for hypoalbuminemia, which can be seen with systemic capillary leak syndrome
• Electrocardiography, for cardiac dysrhythmias secondary to hyperkalemia and hypocalcemia

Creatine kinase elevation
• The serum CK level at presentation of rhabdomyolysis is usually at
least five times the upper limit of normal, but ranges from
approximately 1500 to over 100,000 units/L.
• Serum CK is typically >5000 units/L with nonexertional
rhabdomyolysis and >10,000 units/L with exertional rhabdomyolysis.
Of note, an asymptomatic CK elevation of >2000 units/L can occur as
a transient physiologic response to vigorous exercise.

• The serum CK begins to rise within 2 to 12 hours following the onset
of muscle injury and reaches its maximum within 24 to 72 hours
• A decline is usually seen within three to five days of cessation of
muscle injury. CK has a serum half-life of approximately 1.5 days and
declines at a relatively constant rate of approximately 40 to 50
percent of the previous day's value
• In patients whose CK does not decline as expected, continued muscle
injury, an underlying muscle disease, or the development of a
compartment syndrome may be present.

Urine findings and myoglobinuria
• Evidence of myoglobinuria should be sought by routine urine dipstick
evaluation combined with microscopic examination of the urinary
sediment.
• Testing of the unspun urine or the supernatant of the centrifuged
urine will be positive for heme on dipstick if myoglobinuria is present,
even if red to reddish-brown urine is not evident macroscopically.
• However, a positive dipstick for heme may result not only from free
myoglobin but also from urinary red blood cells (RBCs) or free
hemoglobin.

TREATMENT
In addition to treating the underlying rhabdomyolysis or hemolysis, the
general goals for prevention of AKI in all patients at risk for heme
pigment-induced AKI are :
• Correction of volume depletion if present
• Prevention of intratubular cast formation

Volume administration
• The mainstay of AKI prevention in patients with rhabdomyolysis or
hemolysis is early and aggressive volume administration with crystalloid
fluids.
• IV crystalloid maintains or enhances kidney perfusion, thereby minimizing
ischemic injury, and increases the urine flow rate, which will limit
intratubular cast formation by diluting the concentration of heme
pigment within the tubular fluid and wash out partially obstructing
intratubular casts.
• Choice of IV fluids — For patients with rhabdomyolysis or hemolysis, we
suggest initial volume administration with isotonic saline rather than
other intravenous (IV) fluids.

Rate of fluids — Isotonic saline should be administered as soon as possible after
the onset of muscle injury/rhabdomyolysis or detection of hemolysis.
• Initial rate – The rate of initial fluid administration differs depending on whether
the patient has rhabdomyolysis or hemolysis. Initial fluid requirements are
generally more for patients with rhabdomyolysis, who often present with
substantial volume depletion due to the sequestration of significant amounts of
fluid within damaged muscle.
• In patients with rhabdomyolysis, initiate isotonic saline at a rate of 1 to 2 L/hour.
• In patients with hemolysis, initiate isotonic saline at a rate of 100 to 200
mL/hour. A higher initial rate (200 to 300 mL/hour) may be appropriate in
patients with more severe hemolysis.

• Volume replete and producing urine – For patients with
rhabdomyolysis or hemolysis who are volume replete and are
producing urine, we titrate the rate of intravenous fluids to target a
goal urine output of approximately 200 to 300 mL/hour while avoiding
volume overload. For patients with rhabdomyolysis, this usually means
decreasing the amount of administered fluid.
• Unless the patient develops signs of volume overload, intravenous
fluids should be continued until the muscle injury or hemolysis has
largely resolved. Among patients with rhabdomyolysis, fluid repletion
should be continued until plasma CK levels decrease to ≤5000 units/L
and continue to fall.

• For patients with rhabdomyolysis or hemolysis who are volume replete but
remain oligoanuric after an aggressive course of initial IV fluid administration
(eg, 6 liters for rhabdomyolysis or 3 liters for hemolysis), we decrease
intravenous fluids to a rate sufficient only to maintain circulatory support.
• Fluid administration totals may need to be adjusted in patients with heart
failure, and signs and symptoms of volume overload should be assessed
frequently in such patients.
• Patients who are volume replete but do not produce urine after an adequate
volume challenge should be considered to have established acute kidney
injury. These patients should be closely followed for indications to initiate
dialysis.

• In rhabdomyolysis, substantial peripheral edema may be present in
the absence of volume overload due to third-space fluid
sequestration.
• Volume overload in these patients is better assessed by signs of
pulmonary congestion or via central hemodynamic monitoring. Loop
diuretics may be employed to control volume overload.

Bicarbonate in selected patients —
• Patients with rhabdomyolysis may benefit from urinary alkalinization with bicarbonate
therapy with appropriate monitoring. After an adequate diuresis has been established
with isotonic saline we generally administer a bicarbonate infusion to patients who
have severe rhabdomyolysis, such as those with a serum CK level above 5000 units/L
or clinical evidence of severe muscle injury (eg, crush injury) and a rising serum CK
level, regardless of the initial value.
In such patients, bicarbonate may be given, provided that the following conditions are
met:
• Hypocalcemia is not present
• Arterial pH is less than 7.5
• Serum bicarbonate is less than 30 mEq/L

Administration – Among patients with rhabdomyolysis, we infuse isotonic sodium
bicarbonate (150 mEq of sodium bicarbonate added to 1 L of 5 percent dextrose or
water) via an intravenous line separate from that used for the isotonic saline infusion.
The initial rate of infusion is 200 mL/hour; the rate is adjusted to achieve a urine pH of >6.5.
• Continue bicarbonate therapy until the plasma CK level decreases to less than 5000
units/L or until the development of alkalemia, hypocalcemia, or symptomatic fluid
overload.
• Monitoring – If bicarbonate is given, the arterial pH and serum calcium should be
monitored every two hours during the infusion.
• The bicarbonate infusion should be discontinued if the urine pH does not rise above 6.5
after three to four hours, if the patient develops symptomatic hypocalcemia, if the
arterial pH exceeds 7.5, or if the serum bicarbonate exceeds 30 mEq/L.

• A forced alkaline diuresis, in which the urine pH is raised to above 6.5, may diminish the kidney
toxicity of heme pigments. In theory, urine alkalinization prevents heme-protein precipitation
with Tamm-Horsfall protein and therefore intratubular pigment cast formation.
• Alkalinization may also decrease the release of free iron from myoglobin, the formation of
vasoconstricting F2-isoprostanes, and the risk for tubular precipitation of uric acid

Metabolic abnormalities
• Plasma potassium, calcium should be monitored several times daily
until stable in patients with rhabdomyolysis and hemolysis.
• Hyperkalemia – Hyperkalemia should be anticipated and may occur
even in the absence of severe AKI. Hyperkalemia should be
aggressively treated with standard medical management. Dialysis may
be required to treat severe hyperkalemia
• Hyperuricemia – Patients who develop hyperuricemia should be
treated with allopurinol. Allopurinol should be given orally at 300 mg
if uric acid levels are >8 mg/dL (476 micromol/L) or if there is a 25
percent increase from baseline.

Established AKI —
• The initiation of dialysis may be necessary for control of volume
overload, hyperkalemia, severe acidemia, and uremia.

DIFFERENTIAL DIAGNOSIS
• Strenuous or unaccustomed muscular activity – The line between a normal physiologic response to
exercise and clinically meaningful rhabdomyolysis is not clear, as CK elevation up to and exceeding
2000 units/L and myalgias commonly occur after certain types of prolonged or strenuous exercise
• Delayed-onset muscle soreness (DOMS) – Approximately two to three days after strenuous exercise
or typically unaccustomed or eccentric exercise, pain can be severe with potentially extensive
myofiber damage. Symptoms resolve five to seven days postexercise
• Myocardial infarction – Although serum CK also rises acutely with myocardial infarction, patients
with rhabdomyolysis alone do not have ischemic chest pain or electrocardiogram (ECG) signs of
myocardial infarction. Additionally, the CK-MM fraction is elevated, while little or no CK-MB is
present. Assays for cardiac troponins (both the I and T isoforms) are highly sensitive and specific for
cardiac muscle injury, although both isoforms can sometimes be elevated in patients with
rhabdomyolysis
• Hematuria and hemoglobinuria
• Inflammatory myopathy

RHABDOMYOLYSIS btly Dr Tanisha Baladia medicine

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