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Rabdomiolisis

Rhabdomyolysis is a condition characterized by the breakdown of muscle tissue, leading to the release of intracellular components into the bloodstream, which can result in complications such as acute kidney injury (AKI). Diagnosis is confirmed with elevated serum creatine kinase levels, and treatment primarily involves addressing the underlying cause and ensuring aggressive fluid replacement to prevent AKI. Prognosis is generally favorable with early intervention, although the condition can lead to severe complications if not recognized and treated promptly.
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0% found this document useful (0 votes)
10 views21 pages

Rabdomiolisis

Rhabdomyolysis is a condition characterized by the breakdown of muscle tissue, leading to the release of intracellular components into the bloodstream, which can result in complications such as acute kidney injury (AKI). Diagnosis is confirmed with elevated serum creatine kinase levels, and treatment primarily involves addressing the underlying cause and ensuring aggressive fluid replacement to prevent AKI. Prognosis is generally favorable with early intervention, although the condition can lead to severe complications if not recognized and treated promptly.
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Disease-a-Month 66 (2020) 101015

Contents lists available at ScienceDirect

Disease-a-Month

journal homepage: www.elsevier.com/locate/disamonth

Rhabdomyolysis
Brian Michael I. Cabral, MD, FASN, FPCP, FPSN, MMM a,∗,
Sherida N. Edding, MD b, Juan P. Portocarrero, MD c,
Edgar V. Lerma, MD, FACP, FASN, FPSN (Hon) d
a
Clinical Associate Professor, Department of Medicine, Section of Nephrology, University of the Philippines –
Philippine General Hospital, Manila, Philippines
b
Resident Physician, Department of Internal Medicine, St. Luke’s Medical Center – Global City, Taguig City,
Philippines
c
Resident Physician, Department of Internal Medicine, Macneal Hospital, Berwyn, Illinois
d
Clinical Professor of Medicine, Section of Nephrology, University of Illinois at Chicago College of Medicine/Advocate
Christ Medical Center, Oak Lawn, Illinois

a r t i c l e i n f o a b s t r a c t

Rhabdomyolysis is caused by the breakdown and necrosis of


muscle tissue and the release of intracellular content into
the blood stream. There are multiple and diverse causes of
rhabdomyolysis but central to the pathophysiology is the de-
struction of the sarcolemmal membrane and release of intra-
cellular components into the systemic circulation. The clin-
ical presentation may vary, ranging from an asymptomatic
increase in serum levels of enzymes released from damaged
muscles to worrisome conditions such as volume depletion,
metabolic and electrolyte abnormalities, and acute kidney in-
jury (AKI). The diagnosis is confirmed when the serum cre-
atine kinase (CK) level is > 10 0 0 U/L or at least 5x the
upper limit of normal. Other important tests to request in-
clude serum myoglobin, urinalysis (to check for myoglobin-
uria), and a full metabolic panel including serum creatinine
and electrolytes. Prompt recognition of rhabdomyolysis is im-
portant in order to allow for timely and appropriate treat-
ment. A McMahon score, calculated on admission, of 6 or
greater is predictive of AKI requiring renal replacement ther-
apy. Treatment of the underlying cause of the muscle in-


Contact Author: Brian Michael I. Cabral, MD, 558 Country Club Drive, Ayala Alabang Village, Muntinlupa City, Philip-
pines, 1780
E-mail address: [email protected] (B.M.I. Cabral).

https://doi.org/10.1016/j.disamonth.2020.101015
0011-5029/© 2020 Elsevier Inc. All rights reserved.
2 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015

sult is the first component of rhabdomyolysis management.


Early and aggressive fluid replacement using crystalloid solu-
tion is the cornerstone for preventing and treating AKI due to
rhabdomyolysis. Electrolyte imbalances must be treated with
standard medical management. There is, however, no estab-
lished benefit of using mannitol or giving bicarbonate infu-
sion. In general, the prognosis of rhabdomyolysis is excellent
when treated early and aggressively.
© 2020 Elsevier Inc. All rights reserved.

Outline
1
What is Rhabdomyolysis?
2
Epidemiology
3
Etiology/Common Causes
4
Pathophysiology
5
Histopathology in Rhabdomyolysis
6
Clinical Manifestations
7
Diagnosis
a Laboratory Tests
b Diagnostic Approach
8 Differential Diagnosis
9 Rhabdomyolysis-Induced AKI
a Pathophysiology
b McMahon Score
c Prevention and Treatment
i Volume Replacement
ii Urine Alkalinization
iii Mannitol
iv Treatment of Metabolic Abnormalities
v Treatment of Established AKI
10 Prognosis

Introduction – What is Rhabdomyolysis?


Rhabdomyolysis (rhabd/o, my/o, -lysis) literally means dissolution of striated muscle. It is
caused by the breakdown and necrosis of muscle tissue and the release of intracellular content
into the blood stream. It usually results from traumatic or non-traumatic injury to skeletal mus-
cle. Since skeletal muscle comprises about 40% of body mass, such an insult can result in the
accumulation of cellular contents that could eventually overwhelm the underlying elimination
mechanism [1].
The first ever description of rhabdomyolysis can be seen in some chapters of the Bible, more
specifically in the Book of Exodus, when a population of Jews was exposed to certain toxic sub-
stances like hemlock herbs during their migration from Egypt [2].
Typical clinical manifestations are muscle weakness, pain and dark tea-colored urine. Clinical
presentation can vary from a subclinical elevation of serum enzyme levels, e.g., creatine kinase
(CK), lactate dehydrogenase (LDH), or aspartate aminotransferase (AST), to acute kidney injury
(AKI).

Epidemiology

Rhabdomyolysis can occur in all age groups and both sexes. Its exact incidence is difficult to
determine because of the lack of prospective studies and underreporting of many mild cases [3].
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 3

Table 1
Etiology of Rhabdomyolysis

Acquired Genetic

Traumatic Disorders of lipid metabolismDisorders of carbohydrate metabolism

• Crush injuries • McArdle’s disease


• Compression • Tarui’s disease
• Electrical injury Mitochondrial disordersPentose phosphate pathwayPurine nucleoside
• Vascular or orthopedic surgery cycleMyositis

Coma/Prolonged immobilization
Non-traumaticExertional

• Strenuous activities
• Seizures
• Sickle cell trait
• Exposure to extreme heat
• Malignant hyperthermia
• Neuroleptic Malignant
Syndrome (NMS)

Non-exertional

• Alcohol
• Drugs/Toxin
• Infections
• Electrolyte imbalance

The disease appears more frequent amongst males, African-Americans, those aged <10 and >60
years old, and in persons with body mass index >40 kg/m2 [4]. The etiology of rhabdomyolysis
may also vary depending on the age. Among adults the most commonly cited causes are trauma
and drugs, meanwhile in the pediatric age group infection accounts for 1/3 of the cases [4].
The most feared complication of rhabdomyolysis is development of AKI. It is estimated that
roughly 10–40% of cases of rhabdomyolysis lead to AKI, while 5–15% of AKI cases are attributed
to rhabdomyolysis. Patients who develop AKI have an increased mortality rate as high as 80%
[5].

Etiology/Common Causes

There are multiple and diverse causes of rhabdomyolysis which can be classified as acquired
and genetic (see Table 1).
Acquired causes may be due to trauma and exertion, hypoxic injury, infections, hyperthermia
and drugs and toxins. Genetic causes include those with enzyme deficiencies (for carbohydrate
or lipid metabolism) and myopathies.

Trauma

Trauma and crush injuries following natural calamities, vehicular accidents and multiple ca-
sualty disasters are common causes of rhabdomyolysis.
The classic description and the identification of the pathophysiological mechanism of myo-
globinuric AKI is based on the 1941 publication of Bywaters and Beal, as it alluded to the London
bombing during World War II [6].
At least nine major earthquakes occurred that have involved numerous casualties complicated
by acute kidney injury or the need for dialysis (see Table 2).
4 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015

Table 2
Major Earthquakes in the Past 3 Decades [7]

Location and Year Deaths Overall Number of Crush Victims Dialysis


Spitak, Armenia, 1988[8] 25,0 0 0 600 225-385
Northern Iran, 1990[9] >40,0 0 0 ? 156
Kobe, Japan, 1995[10] 5,0 0 0 372 123
Marmara Region, Turkey, 1999[11] >17,0 0 0 639 477
Chi-Chi, Taiwan, 1999[12] 2,405 52 32
Gujarat, India, 2001[13] 20,023 35 33
Boumerdes, Algeria, 2003[14] 2,266 20? 15?
Bam, Iran, 2003[15] 26,0 0 0 124 96
Kashmir, Pakistan, 2005[16] >80,0 0 0 118 65
Total >2170 0 0 >1900 >1200

Rhabdomyolysis is actually noted to occur only once the acute compression is relieved due
to release of necrotic debris into the circulation [17].
The compression of blood vessels (application of tourniquets, splints, pneumatic compres-
sion device, clamping during surgery) can result in muscle ischemia and interfere with oxy-
gen delivery to the cells [17]. Prolonged immobilization (e.g., coma, sedation, surgery) can also
cause rhabdomyolysis due to unrelieved pressure on gravity-dependent areas. Risk factors in-
clude: body weight more than 30% above ideal body weight, immobilization/compression for
more than 5-6 hours, extracellular volume loss, pre-existing azotemia, diabetes and hyperten-
sion [17].
Rhabdomyolysis occurs in at least 10% of subjects surviving a high-voltage electrical injury.
The myolysis that occurs is secondary to electrical disruption and formation of pores on the
sarcolemmal membranes, with subsequent massive calcium influx [18].

Exertional Non-Traumatic Causes

Strenuous muscular activity, such as sporadic strenuous exercise, as well as seizures and/or
status epilepticus, may cause rhabdomyolysis. The more strenuous or prolonged the activity, the
more damage there is. The pathogenesis of rhabdomyolysis appears to be due to a combination
of mechanical and thermal muscle injury, and ATP depletion. Factors predisposing to exertional
rhabdomyolysis are hypokalemia, extreme heat and humidity, sickle-cell trait, exercise-induced
asthma or pre-exertion fatigue [17,19].
The human thermal maximum, defined as the maximum magnitude and duration of heat the
cells can endure before becoming damaged, has been established as a core body temperature of
42 degrees for 45 minutes to 8 hours. [20] Exposure to extreme heat (heat stroke, neurolep-
tic malignant syndrome and malignant hyperthermia) may cause muscle damage. Aside from
rhabdomyolysis, typical symptoms include fever, and generalized muscle contraction or rigid-
ity. Neuroleptic malignant syndrome is an idiosyncratic reaction to antipsychotic agents such as
phenothiazide and haloperidol. Malignant hyperthermia is an inheritable condition, and occurs
within an hour after administration of anesthetic agents, most commonly succinylcholine and
halothane [19].

Non-Exertional Non-Traumatic Causes

Drugs/Toxins

Medications and recreational drugs are important causes of rhabdomyolysis (see Table 3).
Drug-induced rhabdomyolysis encompasses a large group of substances that can affect muscles
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 5

Table 3
Most Commonly Reported Drugs Causing Rhabdomyolysis

Medications Illicit Drugs


• Lipid-lowering agents (statins, fibrates) • Cocaine
• Psychiatric medications (antipsychotics like haloperidol, • Amphetamines/Methamphetamines
SSRIs, lithium, valproic acid)
• Antimicrobials (protease inhibitors, TMP-SMX, quinolones, • Hallucinogens
amphotericin B)
• Anesthetics/Paralytics (succinylcholine, propofol) • Heroin
• Antihistamines • LSD
• Others (sunitinib, erlotinib, narcotics, vasopressin,
colchicine, glucocorticoids, aminocaproic acid)

Note: list is not exhaustive

either through interfering with ATP production or by increasing permeability of the sarcolemma
permitting leakage of intracellular contents.
Perhaps the most frequent cause of drug-induced rhabdomyolysis today is the administration
of HMG-CoA reductase inhibitors or statins. Rhabdomyolysis may develop 2-3 weeks after ini-
tiating therapy [19]. Immediate withdrawal of these drugs is mandatory if patients complain of
muscle problems or if CK rises to more than three times above normal levels. The risk of drug-
induced muscle disease is aggravated by simultaneous administration of danazol, nicotinic acid,
cyclosporine, itraconazole, or erythromycin. The combination of HMG-CoA reductase inhibitors
with gemfibrozil also carries a high risk of myotoxicity.

Infections

Numerous bacterial, viral, fungal and protozoal infections can lead to rhabdomyolysis. The
proposed mechanisms for infection-induced rhabdomyolysis include tissue hypoxia, direct bac-
terial invasion of muscle, low oxidative and glycolytic enzyme activity, activation of lysosomal
enzymes and mechanisms implicating endotoxins [19,21].

Electrolyte Imbalances

Hypokalemia, hypocalcemia, hypophosphatemia, hyponatremia, and particularly, hyperna-


tremia and hyperosmotic conditions all have been associated with rhabdomyolysis. Any con-
dition that produces major electrolyte losses, such as diuretic abuse, use of cathartic drugs or
hyperemesis gravidarum, can be associated with rhabdomyolysis [17,19,22].

Genetic Causes

A number of genetic disorders can cause rhabdomyolysis. These conditions normally present
in childhood with the patient experiencing recurrent episodes of rhabdomyolysis, usually pre-
cipitated by mild exertion or starvation. These also include disorders of enzyme deficiency (of
carbohydrate or lipid metabolism) and myopathies, with the final common pathway being defi-
cient delivery of ATP [17,22].

Pathophysiology

Despite the diverse causes of rhabdomyolysis, the cascade of pathophysiologic events follows
a common pathway. With muscle injury, there is sarcolemmal membrane destruction and ATP
6 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015

depletion causing intracellular calcium to increase, leading to cell lysis and the release of intra-
cellular components into the systemic circulation.
Under physiologic conditions, the sarcolemmal membrane is lined with different pumps,
channels and exchangers. The most important of which is the Na-K-ATP-ase pump, which ac-
tively transports 3 sodium (Na+ ) out of the cell in exchange for every 2 potassium (K+ ) trans-
ported intracellularly to maintain a negative membrane potential. This negative potential draws
Na+ inside, in exchange for calcium (Ca2+ ) via the Na+ /Ca2+ exchanger, thus maintaining low
intracellular Ca2+ concentration. Tightly regulated calcium homeostasis is essential for proper
cell function – to maintain low levels of calcium when the muscle is at rest and to allow the
increase that is necessary for actin–myosin binding and muscle contraction [17,23,24].
Note that central in the pathophysiology of rhabdomyolysis is influx of calcium into the cell
brought about by cell membrane destruction and ATP depletion. Damage to the cell membrane,
whether from traumatic, hereditary or biochemical factors, leads directly to the influx of calcium
ions into the cell [25].
ATP depletion from anaerobic metabolism from muscle ischemia increases intracellular cal-
cium in an indirect manner. It impairs the function of the Na-K-ATP-ase channel, causing in-
tracellular Na+ to increase, which activates the Na+ /Ca2+ exchanger. This causes an increase in
sarcoplasmic calcium leading to persistent muscle contraction, energy depletion and the activa-
tion of calcium-dependent proteolytic enzymes [26]. The end result is destruction of membrane
proteins and disintegration of the myocyte.
Most of the damage occurs after blood flow is restored to the injured site (reperfusion injury).
In addition to delivering activated neutrophils to previously ischemic tissue, reperfusion leads
to the generation of highly reactive oxygen-derived free radicals capable of damaging the lipid
bilayer of cell membranes via lipid peroxidation [23].
As the myocyte degenerates, large quantities of intracellular substances particularly potas-
sium, myoglobin and CK leak into the circulation. If more than 100 grams of skeletal muscle
is damaged, the circulating myoglobin levels will exceed the protein-binding capacity of the
plasma and can precipitate in the glomerular filtrate. Excess myoglobin may thus cause renal
tubular obstruction, direct nephrotoxicity, and acute renal failure [22,25,26].

Histopathology in Rhabdomyolysis

Muscle biopsies, though rarely necessary, may be used to confirm the diagnosis of rhabdomy-
olysis. Histochemical, immunohistochemical, and mitochondrial respiration studies performed on
a muscle-biopsy specimen may yield a specific diagnosis. It is important to wait several weeks
or months after the clinical event to perform a biopsy, because the results of a biopsy will typ-
ically be uninformative at an early stage. The specimen may appear normal or show no specific
findings other than necrosis during and early after the acute episode of rhabdomyolysis. [22].
A muscle biopsy should be performed if metabolic myopathies are clinically suspected. Spe-
cial stains can be used depending on the suspected cause. Periodic acid-Schiff (PAS) and H&E
staining may demonstrate the presence of increased glycogen or glycogen-containing vacuoles,
which can point to the diagnosis of glycogen storage disease. Increased lipid content in my-
ofibers may suggest a disorder of fatty acid oxidation or mitochondrial cytopathy. If indicated,
immunohistochemistry techniques can be used to identify particular enzyme deficiencies [27].

Clinical Manifestations - Symptoms and Physical Findings

The clinical presentation of rhabdomyolysis varies widely depending on the extent and sever-
ity of muscle damage – ranging from an asymptomatic increase in serum levels of enzymes
released from muscle cells, e.g., CK, LDH, AST, to worrisome conditions associated with severe
intravascular volume depletion, metabolic acidosis, multiple electrolyte abnormalities, including
hyperkalemia, hyperphosphatemia, and hypocalcemia, and AKI.
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 7

Table 4
Classification of Rhabdomyolysis based on CK level [36]

Diagnosis CK level Clinical Significance Treatment Needed


Normal CK level ∼40-200 U/L
Mild rhabdomyolysis 1,0 0 0-5,0 0 0 U/L Low risk for kidney injury Possible Depends on context
Moderate rhabdomyolysis 5,0 0 0 0-15,0 0 0 U/L Increased risk of renal injury Yes
Severe rhabdomyolysis >15,0 0 0 U/L Increased risk of dialysis Yes

Many symptoms are non-specific. The “classic” triad of symptoms includes muscle pain,
weakness and dark-colored urine. However, this triad is only observed in less than 10% of pa-
tients [3,19]. Patients primarily complain of muscle pain, swelling, stiffness or cramping. The
most frequently involved muscles are those in the proximal muscle groups, such as the thighs,
calves and the lower back. In some patients, pain and swelling only manifest after repletion
of volume status. Skin changes, such as discoloration or blisters, indicative of pressure necrosis
may also be seen but only in less than 10% of patients [17,19,27]. Still, in more severe cases,
compartmental compression syndromes are characterized by significant neurovascular compro-
mise, necessitating emergent fasciotomies, have been described [30].
Systemic symptoms such as malaise, fever, abdominal pain, nausea and vomiting, are also fre-
quently seen. Cardiovascular symptoms can stem from associated electrolyte abnormalities (i.e.,
potassium, calcium, phosphate) [5]. Discolored urine (ranging from pink-tinged to tea-colored or
dark black) suggests significant myoglobin excretion.

Diagnosis

Laboratory Tests

In rhabdomyolysis, as with other diseases, a thorough history and physical examination will
provide important clues. However, laboratory tests are still required to confirm the diagnosis.

Creatine Kinase (CK)

Serum CK level is the cornerstone of rhabdomyolysis diagnosis. Serum CK levels, mainly the
CK-MM subtype, are the most sensitive indicator of skeletal muscle injury [19]. CK levels typi-
cally rise within 12 hours of the onset of muscle injury; it peaks within 24-72 hours, and nor-
malizes around 5 days after the cessation of muscle injury [29]. The half-life of CK is approxi-
mately 48 hours, and levels decline by 40–50% each consecutive day [31].
The increase in the CK level correlates very well with degree of muscle injury or development
of compartment syndrome, but only correlates marginally with the development of AKI [32,33].
Normal CK enzyme levels are usually <100 U/L. A systematic review revealed that most stud-
ies diagnose rhabdomyolysis by referring to a specific CK cutoff value, majority of which is a CK
level >10 0 0 U/L or at least 5x the upper limit of normal [34,35]. The following categorization
(Table 4) scheme based on CK levels is consistent with the majority of current literature [36].
The Clinical Advisory on Statins defines statin-induced rhabdomyolysis as muscle symptoms
with marked CK elevation greater >10 times the upper limit of normal, accompanied by creati-
nine elevation consistent with pigment nephropathy and myoglobinuria [37,38].
Serial CK measurements should be monitored; increasing levels, or failure of levels to decline
despite therapy, suggest ongoing muscle injury or the development of renal failure [39].
8 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015

Table 5
Urine Findings in Rhabdomyolysis

General Urinalysis
Dipstick
Heme/blood Positive (3+ or 4+)
pH Acidic (5-6)
Proteins Positive
Color Reddish-brown
Microscopic analysis Absent or few red blood cells
Urine sediment Myoglobin casts, dead epithelial cells

Table 6
Other Important Diagnostic Tests

Arterial blood gas Evaluate acid-base balance


ECG Evaluate cardiac dysrhythmias related to hyperkalemia and hypocalcemia
CBC Check for signs of hemolysis, infection
PT, aPTT, D-dimer, fibrinogen DIC can ensue secondary to release of thromboplastin
Serum albumin Hypoalbuminemia = poor prognostic sign; represents capillary rupture with leakage
Toxicological screen If drugs are the suspected causal agents

Table 7
Summary of Biochemical Changes in Rhabdomyolysis

Myoglobin

Myoglobin is released from damaged muscle together with CK. It is normally bound to
plasma proteins and is rapidly excreted in the urine, imparting a red to brown color. After devel-
opment of rhabdomyolysis, levels of plasma myoglobin (>1.5 mg/dL) exceed the binding capacity
of plasma globulins. Visible changes in the urine only occur once urine levels exceed 100 mg/dL
[28].
Myoglobin has a short half-life (1–3 hours) and may return to normal within 6–8 hours [39].
Estimation of myoglobin in serum and urine is useful, particularly in the early phases of the
disease [19]. But it becomes less sensitive especially when disease presentation is delayed. It
appears in the plasma before CK elevation occurs and resolves while CK is still elevated or rising.

Urine Dipstick and Urinalysis

Myoglobinuria is suspected when the patient’s urine dipstick detects “blood” with micro-
scopic evaluation, in contrast showing less than 5 RBCs per high-power field. Combined with el-
evated plasma CK levels, myoglobinuria confirms the diagnosis of rhabdomyolysis [24]. However,
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 9

Table 8
Calculation of the McMahon Risk Score

Variable Points
Age, years ≤50 0
51-70 1.5
71-80 2.5
>80 3
Sex Male 0
Female 1
Initial Creatinine <1.4 mg/dL (<124 μmol/L) 0
1.4-2.2 mg/dL (124-195 1.5
μmol/L)
>2.2 mg/dL (>195 μmol/L) 3
Initial Calcium <7.5 mg/dL (1.88 mmol/L) No 0
Initial CK > 40 0 0 0 U/L Yes 2
No 0
Yes 2
Rhabdo secondary to seizures, syncope, exercise, statins Yes 0
or myositis
No 3
Initial Phosphate <4.0 mg/dL (<1.0 mmol/L) 0
<4.0-5.4 mg/dL (1.0-1.4 1.5
mmol/L)
>5.4 mg/dL (>1.4 mmol/L) 3
Initial Bicarbonate <19 mEq/L (19 mmol/L) No 0
Yes 2

it is not considered as an essential diagnostic test because of its poor sensitivity and specificity
[39].
Early in the presentation, a particular finding of rhabdomyolysis-induced kidney injury can be
a fractionated excretion of sodium (FeNa%) of less than 1%, explained by the tubular occlusion
[26].
The urine pH tends to be acidic. Urine sediment analysis will show myoglobin casts and dead
epithelial cells. Proteinuria, coming from the globin component of myoglobin, is present in up to
45% of cases. However, urine testing was shown to be positive in only 19% of cases and so the
absence of urine myoglobin does not rule out rhabdomyolysis [41].

Fluid and Electrolyte Abnormalities

Various electrolyte abnormalities are associated with rhabdomyolysis. A metabolic panel that
includes electrolytes (potassium, calcium, phosphorous) and assessment of renal function should
be obtained routinely. It is important to screen for hypokalemia and hypophosphatemia as po-
tential causes, and to identify potentially life-threatening hyperkalemia.
Hyperkalemia and hyperphosphatemia result from the release of potassium and phospho-
rus from damaged muscle cells. Even an acute necrosis of only 100 grams of muscular mass
could increase potassium by 1.0 mEq/L [40]. Hyperkalemia should be identified and addressed
promptly as it can precipitate severe arrhythmia or even cardiac arrest. ECG studies may be
considered to detect abnormalities secondary to electrolyte disturbances.
Calcium levels are often low initially, secondary to calcium influx, the precipitation of cal-
cium with phosphates in damaged muscles, and the decreased bone responsiveness to parathy-
roid hormone [42,43]. During the recovery phase, serum calcium levels should return to normal.
However, levels may also become significantly elevated due to calcium mobilization from dam-
aged muscles, mild secondary hyperparathyroidism from the acute renal failure and an increase
in calcitriol [42,43].
Both BUN and creatinine levels are increased. There will be a disproportionate rise in crea-
tinine early in the course of the disease due to metabolism of large amounts of CK released by
10 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015

the injured muscles [22]. This causes the blood urea nitrogen-to-creatinine ratio to be as low as
5:1 or even less [24].
The anion gap in rhabdomyolysis is often increased more than expected for the degree of
AKI due to the phosphates and organic acids released from muscle [22]. Hyperuricemia may
also develop, secondary to the release of muscle purines and reduced urinary excretion if AKI
occurs [28].

Other Diagnostic Tests

Listed below are other important laboratory tests that may provide information regarding the
complications, prognosis and possible etiology of rhabdomyolysis.

Diagnostic Approach

Prompt recognition of rhabdomyolysis is important in order to allow for timely and appropri-
ate treatment. Rhabdomyolysis should be highly suspected in patients presenting with muscle
pain, weakness and tea-colored urine. A careful history and physical examination may reveal
the underlying etiology of rhabdomyolysis and is important for the proper selection of the sub-
sequent diagnostic tests. It is important to ask about provoking factors such as presence of infec-
tion, seizure episodes, the intensity and duration of exercise, exposure to extreme temperature,
general anesthesia, immobilization, medication history and use of alcohol or drugs. It is also im-
portant to ask for a history of recurrent symptoms as this may imply the presence of genetic
causes.
Basic diagnostic tests to be considered include serum CK levels, urinalysis (dipstick and mi-
croscopy), serum creatinine, potassium, phosphate, calcium and uric acid.

Differential Diagnosis

The diagnosis of rhabdomyolysis should be considered in patients who are noted to have a
combination of its pathognomonic features. These include the symptoms of muscle pain and
dark urine, as well as measurable laboratory values (elevated CK and other muscle enzymes),
particularly in the acute setting.
However, when these features are taken individually or in a different combination, the differ-
ential diagnoses can be fairly extensive. For example, in patients presenting with dark-colored
urine, it is important to differentiate between hematuria and myoglobinuria. Examination of the
urine red blood cells as well as serum test for hemolysis can help distinguish these conditions.
Inflammatory myopathies, such as dermatomyositis, may also present with myalgia and el-
evated CK levels. However, these patients will have a protracted disease course that develops
over weeks to months with accompanying systemic features. These patients may have relatively
subtle laboratory abnormalities with distinct electromyographic (EMG) or histologic changes.
It is important to promptly investigate the underlying cause of rhabdomyolysis, since they
must be addressed to avoid further progression of the disease. Some of the common causes have
already been discussed above with the most common causes including trauma/compression, vas-
cular occlusion, hyperthermia, metabolic myopathies, drugs and toxins and infection.

Rhabdomyolysis-Induced AKI

Acute kidney injury (AKI) can occur in 7-10% of all patients who have rhabdomyolysis. [3] The
exact mechanism by which rhabdomyolysis impairs glomerular filtration rate is unclear, but
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 11

there is growing evidence that suggest the following mechanisms (Figure 3): 1. Renal vasocon-
striction; 2. Direct and ischemic tubule injury and 3. Tubular obstruction [5,19,22,26].

Pathophysiology

Renal vasoconstriction is a characteristic feature of rhabdomyolysis-induced AKI and is the


result of various combinations of several mechanisms. Fluid sequestration in injured muscle
induces intravascular volume depletion and subsequent homeostatic activation of the renin–
angiotensin system (RAS), antidiuretic hormone (ADH) and the sympathetic nervous system
(SNS), all favoring vasoconstriction and renal water and salt retention. Another mechanism in-
volves the scavenging effect of myoglobin in the renal microcirculation increasing the release of
vasoconstrictors and a decrease in vasodilators [19,26].
Myoglobin is a protein that is normally freely filtered by the glomerulus and is then metab-
olized. When its concentration exceeds the renal threshold it appears, making the color of the
urine reddish-brown. In the presence of dehydration and renal vasoconstriction, tubular flow de-
creases, water reabsorption increases and myoglobin precipitates and interacts with the Tamm–
Horsfall protein causing tubular obstruction - a process precipitated by acidic urine. Tubule ob-
struction occurs principally at the level of the distal tubules, and direct tubule cytotoxicity occurs
mainly in the proximal tubules [5,22,26].

McMahon Score

The McMahon Score is a scoring system calculated on admission for the prediction of risk
of renal failure requiring renal replacement therapy (RRT) or mortality in patients with rhab-
domyolysis [44]. The variables included are age, gender, underlying etiology, and initial labora-
tory values (i.e., calcium, CK, phosphate, and bicarbonate). The advantage of this scoring system
is that it prognosticates patients without waiting for the CK levels to increase above 50 0 0 U/L
prior to initiation of therapy, by telling us more of the biological substrate on which the insult
is encountered as well as giving us an idea of the physiological reserve of the patient [44]. This
scoring system has been validated in two studies at different institutions.
The main limitations of these studies are their retrospective nature and absence of data re-
garding resuscitation fluid volumes, urinary output and fluid balance. The timing of the insult
was also not ascertained, and patients may have presented at varying intervals following injury.
Hence, further prospective validation studies may be informative. [44,45]
A McMahon score of 6 or greater had greater sensitivity and specificity (86% vs 83% and 68%
vs 55%, respectively) than CK level >50 0 0 U/L in predicting risk of RRT [44,45].
A McMahon score <5 indicates a 2-3% risk of either need for RRT or death, whereas a score
>10 indicates a 52-61.2% risk of RRT or death. A score of 6 or greater indicates risk of acute
kidney injury or dialysis, hence renal protective therapies should be considered in all patients
with this score [44,45].

Prevention and Treatment

Treatment of the underlying cause of the muscle insult is the first component of rhabdomy-
olysis management. Furthermore, it is equally important to institute measures to prevent AKI
and the associated metabolic abnormalities.
The general goals for preventing AKI are adequate hydration and the prevention of formation
of intratubular casts. It is important to note that the underlying conditions and factors leading
to rhabdomyolysis must be addressed so as to avoid the continuous release of myoglobin. This
12 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015

may include cessation of a potentially harmful drug, control of patient temperature, treatment
of underlying infections, and more.
A meta-analysis which included 27 studies, mostly retrospective and case series, suggested
the following recommendations to prevent rhabdomyolysis-induced AKI [46,47]:

• Fluid administration should be initiated as soon as possible, preferably within the first 6
hours after muscle injury (grade D).
• Fluids should be administered at a rate that maintains a urine output of 300 mL/h or more
for at least the first 24 hours, unless a medical condition precludes giving enough fluids to
meet this goal (grade D).
• Intravenous sodium bicarbonate should be administered only if necessary to correct systemic
acidosis; the amount and rate should be individualized based on the patient’s size and med-
ical condition (grade D).
• Mannitol should be administered only if needed to maintain desired urine output of 300
mL/h or more despite adequate fluid administration (grade D).

Volume Replacement

Early and aggressive fluid replacement is the cornerstone for preventing and treating AKI
due to rhabdomyolysis. The goals of fluid repletion are to restore renal perfusion, thereby mini-
mizing ischemic injury, and to increase glomerular filtration and urine flow, which should limit
the formation of intratubular casts. Studies have shown that the development of AKI is directly
proportional to the timing of fluid administration, i.e. the longer it takes for hydration to be ini-
tiated, the more likely that AKI will develop [48]. Prompt IV fluid administration is associated
with better outcomes. Patients often require as high as 10 liters of fluid per day [26], depending
on the severity of rhabdomyolysis.
Although the importance of volume repletion is clearly established, standardized guidelines
for fluid therapy have yet to be set in terms of composition, volume, and time of initiation. There
are no randomized controlled trials that can offer definitive guidance in treatment. Most recom-
mendations are based on observational or retrospective studies, case reports, and case series,
which describe diverse and often simultaneous medical treatments for this syndrome.
A study by Cho et al. compared the effects of Lactated Ringer’s (LR) vs normal saline (NS)
in patients diagnosed with rhabdomyolysis secondary to doxylamine overdose. Serum and urine
pH were higher in the LR group 12 hours after infusion. Large amounts of NS infusion induced
mild metabolic acidosis in contrast with mild metabolic alkalosis induced by LR infusion. The
acidosis may cause impaired cardiac performance, decreased responsiveness to cardiac inotropic
drugs and decreased renal perfusion [49].
Initial fluid resuscitation may be given at a rate of 1 to 2 L/hour. Normally, hydration is main-
tained until the resolution of rhabdomyolysis or until plasma CK levels decrease to <50 0 0 U/L.
A lower likelihood of AKI is expected when peak CK levels are under 50 0 0 to 10,0 0 0 U/L [28].
Serial CK measurements are helpful in adjusting therapeutic hydration parameters.
The volume status should be carefully assessed and urine output monitored. Fluid rates
should be adjusted as necessary, paying particular attention to any signs of volume overload.
If adequate diuresis is established, fluids are titrated to maintain a urine output of 200 to 300
mL/hour [50].

Urine Alkalinization

Although primarily anecdotal, some patients with rhabdomyolysis have been shown benefit
from bicarbonate therapy. The principles of urine alkalinization are based on studies in animal
models and include the following: 1. Tamm-Horsfall protein-myoglobin complex precipitation is
increased in acidic urine, hence alkalinization prevents intratubular pigment cast formation; 2.
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 13

Redox cycling of myoglobin and lipid peroxidation is inhibited by alkaline urine, thus decreasing
tubular damage; and 3. Myoglobin-induced vasoconstriction is observed only in acidic medium
[26].
The principal disadvantage of alkalinization is the reduction in ionized calcium, which can
exacerbate the symptoms of the initial hypocalcemic phase of rhabdomyolysis.
In general, bicarbonate infusion is given to patients with severe rhabdomyolysis, such as
those with a serum CK above 50 0 0 U/L or with clinical evidence of severe muscle injury (e.g.,
crush injury) and a rising serum CK, regardless of the initial value. In such patients bicarbonate
may be given, provided the following conditions are met [50]:
• Hypocalcemia is not present
• Arterial pH is less than 7.5
• Serum bicarbonate is less 30 mEq/L
The initial rate of infusion is 200 mL/hour; the rate is adjusted to achieve a urine pH of >6.5.
The arterial pH and serum calcium should be monitored every two hours during the infusion.
The bicarbonate infusion should be discontinued and volume repletion continued with iso-
tonic saline alone if any of the following occur [50]:
• Urine pH does not rise above 6.5 after 3-4 hours
• Development of symptomatic hypocalcemia
• Arterial pH exceeds 7.5
• Serum bicarbonate exceeds 30 mEq/L
Despite the potential theoretical benefits, there is no clear clinical evidence that alkaline di-
uresis is more effective than saline diuresis in preventing AKI [19]. A study of Brown, et. al.,
found that among patients with CK greater than 5,0 0 0 U/L, there was no difference in the rates
of AKI, dialysis, or mortality between those who received combination bicarbonate/mannitol in-
fusion and those who didn’t. [51]. The only data supporting the use of alkaline diuresis is derived
from an uncontrolled case series in which benefit was demonstrated among patients with severe
rhabdomyolysis [50].

Mannitol

Mannitol is an osmotic agent that attracts the fluid from the interstitial space, offsetting hy-
povolemia which may reduce muscular swelling. As a diuretic agent, mannitol increases urinary
flow and prevents intrarenal heme pigment trapping, decreasing cast formation.
The benefit of mannitol in rhabdomyolysis is however, not established. Available retrospective
series report conflicting results regarding the effectiveness of combined administration of bicar-
bonate and mannitol in preventing heme pigment-induced acute tubular necrosis (ATN) [50].
Unless the patient is carefully monitored and losses replaced when appropriate, mannitol can
lead to both volume depletion and, since free water is lost with mannitol, hypernatremia. In high
doses (>200 grams of mannitol per day) or in those with renal insufficiency, mannitol can cause
hyperosmolality, volume expansion, and hyperosmolar hyponatremia. Hyperosmolality can cause
passive movement of potassium out of cells and raise the plasma potassium concentration [49].
The use of mannitol administration may be of benefit in patients with markedly severe rhab-
domyolysis (CK >30,0 0 0 U/L); however the true benefit associated with mannitol administration
remains undefined [50].

Treatment of Metabolic Abnormalities

Patients with rhabdomyolysis are prone to developing metabolic abnormalities such as hyper-
kalemia, hypocalcemia, hyperphosphatemia and hyperuricemia, and must be treated promptly
with standard medical management.
14 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015

Figure 1. Pathophysiology of Rhabdomyolysis


B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 15

Figure 2. Suggested Diagnostic Approach in Rhabdomyolysis


16 B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015
Figure 3. Pathophysiology of AKI in Rhabdomyolysis
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015
Figure 4. Approach to Diagnosing and Stratifying Rhabdomyolysis using the McMahon Scoring System, reprinted with permission from Farkas, J. 2016 [36]

17
18
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015
Figure 5. Suggested Algorithm for Fluid Resuscitation, reprinted with permission from Farkas, J. 2016 [36]
B.M.I. Cabral, S.N. Edding and J.P. Portocarrero et al. / Disease-a-Month 66 (2020) 101015 19

The correction of hyperkalemia, which occurs early in the course of the disease, is especially
important since hyperkalemic cardiac arrest/arrhythmia is a life-threatening early complication.
Dialysis may be required to treat severe hyperkalemia. Because of a very large potassium load,
patients may develop post-dialysis “rebound” hyperkalemia, hence the need for frequent potas-
sium monitoring even after dialysis [52].
On the other hand, correction of hypocalcemia should be avoided, unless the patient is symp-
tomatic, not only to minimize risk of calcium phosphate precipitation in injured muscle but also
20-30% of patients will develop hypercalcemia during the recovery phase [19].

Treatment of Established AKI

There is no specific therapy once the patient develops AKI. Initiation of dialysis may be nec-
essary for control of volume overload and correction of intractable and severe metabolic abnor-
malities.
Daily hemodialysis or continuous hemofiltration may be required initially to remove urea
and potassium that are released from damaged muscles [19]. Peritoneal dialysis is inadequate
to remove the large solute loads in patients with rhabdomyolysis-induced AKI [19]. In patients
deemed to require renal replacement therapy, peritoneal dialysis should only be considered until
hemodialysis can be started.

Prognosis

The prognosis of rhabdomyolysis is heavily dependent upon the underlying etiology and the
associated comorbidities. Despite the lack of any well-organized randomized controlled studies,
the available evidence from case reports and small retrospective studies suggests that rhabdomy-
olysis has an excellent prognosis when treated early and aggressively [53].
There is a wide variation in the reported mortality rate of patients with severe injury devel-
oping rhabdomyolysis-induced AKI, anywhere between 7-80% [5]. Patients with rhabdomyolysis-
induced AKI consequently require longer hospital stays. Dialysis is necessary in about 85% of
patients with oliguric AKI and in 30% of patients with non-oliguric AKI, whereas the mortality
rate in patients with AKI who require dialysis is between 50% and 80% [5]. Fortunately, in most
cases, the AKI is completely reversible and most patients recover function within a few months
(Figs. 1, 2, 4 and 5 and Tables 5–8).

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