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Non-traumatic rhabdomyolysis: Background, laboratory features, and acute

clinical management

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DOI: 10.1016/j.clinbiochem.2017.02.016

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Clinical Biochemistry xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Clinical Biochemistry

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Review

Non-traumatic rhabdomyolysis: Background, laboratory features, and

acute clinical management
Gianfranco Cervellin a,⁎, Ivan Comelli a, Mario Benatti a, Fabian Sanchis-Gomar b,c,
Antonella Bassi d, Giuseppe Lippi e
a
Emergency Department, Academic Hospital of Parma, Parma, Italy
b
NYU Langone Medical Center, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, USA
c
Department of Physiology, Faculty of Medicine, University of Valencia and Fundación Investigación Hospital Clínico Universitario de Valencia, Instituto de Investigación INCLIVA, Valencia, Spain
d
Laboratory of Clinical Chemistry and Hematology, University Hospital of Verona, Verona, Italy
e
Section of Clinical Chemistry, University of Verona, Verona, Italy

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

Article history: Rhabdomyolysis is a relatively rare condition, but its clinical consequences are frequently dramatic in terms of
Received 24 January 2017 both morbidity and mortality. Although no consensus has been reached so far about the precise definition of
Received in revised form 20 February 2017 this condition, the term rhabdomyolysis describes a rapid breakdown of striated, or skeletal, muscle. It is hence
Accepted 20 February 2017
characterized by the rupture and necrosis of muscle fibers, resulting in release of cell degradation products and
Available online xxxx
intracellular elements within the bloodstream and extracellular space. Notably, the percentage of patients with
Keywords:
rhabdomyolysis who develop acute kidney injury, the most dramatic consequence, varies from 13% to over
Rhabdomyolysis 50% according to both the cause and the clinical and organizational setting where they are diagnosed. Despite di-
Crush syndrome rect muscle injury (i.e., traumatic rhabdomyolysis) remains the most common cause, additional causes, frequent-
Myopathy ly overlapping, include hypoxic, physical, chemical or biological factors. The conventional triad of symptoms
Creatine kinase includes muscle pain, weakness and dark urine. The laboratory diagnosis is essentially based on the measure-
Myoglobin ment of biomarkers of muscle injury, being creatine kinase (CK) the biochemical “gold standard” for diagnosis,
and myoglobin the “gold standard” for prognostication, especially in patients with non-traumatic rhabdomyoly-
sis. The essential clinical management in the emergency department is based on a targeted intervention to man-
age the underlying cause, combined with infusion of fluids and eventually sodium bicarbonate. We will present
and discuss in this article the pathophysiological and clinical features of non-traumatic rhabdomyolysis, focusing
specifically on Emergency Department (ED) management.
© 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Contents

1. Historical background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Definition and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
5. Clinics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
6. Laboratory diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
7. Emergency department treatment and management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author at: Emergency Department, Academic Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy.
E-mail address: gcervellin@ao.pr.it (G. Cervellin).

http://dx.doi.org/10.1016/j.clinbiochem.2017.02.016
0009-9120/© 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Please cite this article as: G. Cervellin, et al., Non-traumatic rhabdomyolysis: Background, laboratory features, and acute clinical management, Clin
Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.016
2 G. Cervellin et al. / Clinical Biochemistry xxx (2017) xxx–xxx
1. Historical background
The first “reference” on rhabdomyolysis is thought to be found in the
Pentateuch, the first five books of the Bible, which describes an episode
of mass poisoning afflicting the Jews soon after the ingestion of quails
caught during their staying in the Sinai desert (“And while the flesh
was yet between their teeth, ere it was chewed, the wrath of the Lord was
kindled against the people, and the Lord smote the people with a very
great plague”; Numbers 11.33) [1]. The description is somehow consis-
tent with rhabdomyolysis. It is well-known that during their spring mi-
gration across Northern Africa, quails can feed on large amounts of
hemlock (Conium maculatum), a notoriously toxic herbaceous plant,
the toxin of which (cicutoxin) typically causes rhabdomyolysis, usually
associated with renal failure [2].
The second “reference” on rhabdomyolysis is probably associated
with the description of the execution of Socrates by the Athenian state
in 399 BCE. Despite Plato's dialogue “Phaedo” insinuates that Socrates
may have died after drinking an extract of hemlock, doubts remain
about the true nature of the poison. In fact, the major clinical findings re-
ported in the Phaedo cannot be explained only by hemlock poisoning,
and it seems more reasonable that the great philosopher died after
drinking a mixture of poisons, probably including hemlock [3].
The third “reference”, which actually represents the first medical de-
scription of the syndrome, is dated back to the early 1900s, describing
the clinical pictures of survivors of the tremendous earthquake followed
by a tsunami which destroyed Messina and Reggio Calabria in Southern
Italy and caused N 100.000 victims, on December 28, 1908. Three Au-
thors, one German and two Italian surgeons, described almost at the
same time the Crush syndrome, but only the Italian surgeon Antonino
d'Antona reported the presence of shock and uremia associated with
traumatic injuries [4–6].
The pathophysiological mechanisms, however, were first identified
by Bywaters et al. in 1941, when the traumatic form of rhabdomyolysis
was accurately described in the victims of the bombing of London. Myo-
globin released from traumatized muscles was identified as the main
substance responsible for kidney failure which, due to the lack of renal
dialysis at that time, caused the majority of fatalities [7].
Traumatic rhabdomyolysis is extensively discussed in some excel-
lent articles and reviews [8–10], and hence will not be treated in this ar-
ticle. Non-traumatic rhabdomyolysis represent a rapidly growing field
of knowledge, as demonstrated by the increasing number of publica-
tions on this topic: N350 new articles have been published in 2016
(source: PubMed). We will present and discuss in this article the path-
ophysiological and clinical features of non-traumatic rhabdomyolysis,
focusing specifically on the management in the Emergency Department
(ED).
2. Definition and epidemiology
Although there is no consensus on the precise definition of this con-
dition, the term rhabdomyolysis describes the rapid breakdown of stri-
ated, or skeletal, muscle. It is hence characterized by the rupture and
necrosis of muscle fibers, resulting in release into the bloodstream and
extracellular space of cell products. Since skeletal muscles comprises
~ 40% of body weight (i.e., several kg), and the destruction of just
100 g of muscle tissue is capable to induce the clinical syndrome of
rhabdomyolysis, it is easy to understand that this “breakpoint” can be
reached quite easily [11].
The precise knowledge on the actual incidence of rhabdomyolysis is
limited, mainly due to the fact that many mild (i.e., oligo-symptomatic
or asymptomatic) cases probably go unrecognized. Nevertheless, it
has been reported that approximately 26.000 cases of rhabdomyolysis
are hospitalized every year in the United States [12]. Rhabdomyolysis
occurs with a wide spectrum of signs and symptoms, ranging from a
completely asymptomatic increase of plasma creatine kinase (CK),
through massive increases in blood levels of acute kidney injury (AKI)
Please cite this article as: G. Cervellin, et al., Non-traumatic rhabdomyolysis: Background, laboratory features, and acute clinical management, Clin
Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.016
biomarkers, severe alterations of electrolyte balance and, in the most se-
vere cases, disseminated intravascular coagulation (DIC) [9]. The litera-
ture evidence reports that the percentage of patients developing AKI
secondary to rhabdomyolysis varies from 13% to over 50%, mainly de-
pending on the clinical and organizational setting where it is diagnosed
[9]. Notably, an important distinction should be made between the
terms rhabdomyolysis, crush injury, compartment syndrome and
crush syndrome [8,13]. The first term describes the damage to striated
muscle cells or fibers; the second describes all those injuries occurring
as consequence of crushing of bodily parts (usually a limb); the third de-
scribes the complications developing for increased pressure inside one
or more muscular compartments (where rhabdomyolysis may, or may
not, have occurred) which can cause interruption in the regional circu-
lation and ischemic injury to nerves and muscles; the fourth describes
the complex pathophysiological consequences caused by massive rhab-
domyolysis, mainly involving both kidneys and coagulation system.
There is frequent overlapping or subsequent evolution between the
four aforementioned conditions. Others commonly used terms in this
field are: i) myalgia, i.e., muscle ache or weakness without increases of
CK, and ii) myositis, i.e., inflammatory process that includes muscle
symptoms with increased CK activity. They both differ from rhabdomy-
olysis, which encompasses muscle symptoms associated with marked
increases in CK [typically N 5–10 times the upper limit of normal
(ULN)] and often increased creatinine levels (usually accompanied
with brown urine due to myoglobinuria) [14].
Interestingly, humans are not the only mammals affected by rhabdo-
myolysis. It has been demonstrated that up to 3% of exercising horses
may be affected by this disorder, showing similar signs and etiologies
[15].
3. Etiology
Direct muscle injury remains the most common cause of rhabdomy-
olysis, although the etiology includes up to four leading mechanisms,
that are frequently overlapped: i) hypoxic, ii) physical, iii) chemical,
iv) biological. Each one of these etiologic categories may have intrinsic
or extrinsic causes, as follows (only citing the most frequent). Hypoxic
mechanisms: i) extrinsic (carbon monoxide or cyanide poisoning), ii) in-
trinsic (compartment syndrome; compression; immobilization; vascu-
lar occlusion due to thrombosis or vasculitis). Physical mechanisms: i)
extrinsic (trauma; burns; electrocution; hypo/hyperthermia); ii) intrin-
sic (exertion; seizures; status asthmaticus; agitation; malignant hyper-
thermia). Chemical mechanisms: i) extrinsic (environmental toxins,
alcohol; drugs or substances of abuse); ii) intrinsic, mainly represented
by electrolyte disorders (hypokalemia; hypophosphatemia; hypocalce-
mia; hypo/hypernatremia). Biologic mechanisms: i) extrinsic (infections
from bacteria, viruses, parasite; preformed organic toxins); ii) intrinsic
(dermatomyositis/polymyositis; endocrinopathies, mainly thyroid dys-
function) [16].
Road accidents are the most frequent direct traumatic causes, al-
though entrapment in collapsed buildings poses the greatest challenge
for emergency services due to the number of victims, which is often
considerable. During some of the most recent catastrophes (i.e., the
1988 Armenian earthquake, and the 1999 earthquake which hit the
Turkish region of Marmara) hundreds of victims required hemodialysis.
Notably, hospitals are usually impacted by the earthquakes, since they
can be at least in part damaged or even completely destroyed. After
the earthquake in Kobe Japan) in 1995, 42–69% of the local hospital per-
sonnel was unavailable, either because direct victim or unable to travel
due to collapsed roads [10]. It is now well recognized that late mortality
in earthquake victims is primarily due to crush syndrome complicated
by acute kidney injury (AKI) [9,10]. A frequent mechanism causing
rhabdomyolysis is prolonged compression during immobility. This is
usually due to stroke in elderly patients, time consuming surgery with-
out adequate periodic patient mobilization, self-induced intoxication
(with the concomitant effects of immobilization and toxicity from
 G. Cervellin et al. / Clinical Biochemistry xxx (2017) xxx–xxx
substances). This mechanism contributes to a significant percentage of
cases treated in the ED. In general, 1 h of compression might be suffi-
cient, but cases of rhabdomyolysis have also been described when com-
pression lasted ~20 min [17].
Excessive muscular activity can also cause rhabdomyolysis [18],
both due to strenuous sports activities (typically in marathon runners)
and combined with some medical conditions such as epilepsy, delirium
tremens and tetanus, often associated with extreme muscular activity
[19–21]. An interesting report on exercise-induced rhabdomyolysis
from India recently described the cases of 27 young and apparently
healthy subjects, who were affected by severe rhabdomyolysis with
AKI after a pilgrimage. All these subjects were “Dak-Bum”, representing
a special category of devotees who travel a long distance in short pe-
riods. They usually visit a holy site in the month of Shravan during
July and August to offering holy water they carry from the small town
of Bihar. These devotees cover a distance of 105 km on foot, in fasting
state, in 24 h [22]. Also, a recently diffused gym activity, the so called
“spinning,” has been described as a possible cause of rhabdomyolysis
[23].
Electrical injuries are a frequent cause of rhabdomyolysis due to the
combination of tetanic contraction of the muscles and direct effects of
electricity on muscle fibers [19].
Among medical causes, drugs and toxic substances play a pivotal
role, with opioids [24], alcohol [25], cocaine and other substances of
abuse [26–29], among the most frequent. All these compounds directly
trigger rhabdomyolysis, i.e., through toxic effect on muscle fibers, or in-
directly, i.e., through immobilization-compression or muscular hyper-
activity [30,31]. The adverse effects of ethanol on muscles have been
experimentally described several decades ago. Alcohol can induce rhab-
domyolysis by inhibiting calcium accumulation into the sarcoplasmic
reticulum, disrupting muscle cell membranes, and inhibiting the sodi-
um-potassium ATPase pump which helps maintaining cellular integrity
[32]. Other causes may coexist in the same patient, so increasing the
likelihood of rhabdomyolysis. These especially include delirium
tremens and/or alcohol withdrawal seizures, muscle hypoxia due to
prolonged immobilization and limb compression, hypoperfusion fol-
lowing volume depletion, and hypokalemia and hypophosphatemia
that frequently occurs in poorly nourished alcoholic patients [33]. Sev-
eral cases of cocaine-induced rhabdomyolysis have been described in
the past decades, and the severity of muscle injury seemingly parallel
the severity of cocaine intoxication. Studies of cocaine-intoxicated pa-
tients observed in the ED revealed a 5–24% incidence of increased CK ac-
tivity. These patients may develop rhabdomyolysis in association with
other causes, such as seizures, excessive muscle activity, hyperthermia,
tissue hypoxia from limb compression following loss of consciousness
and hypovolemia. However, cocaine has also been implicated in trigger-
ing acute myocardial infarction (MI) in patients with or without under-
lying coronary atherosclerosis. Thus, the partial contribution of CK
isoenzyme MB (CK-MB) in increasing CK activity cannot be excluded
[34–36], and the specificity of CK-MB in diagnosing MI is heavily chal-
lenged by the overlap with rhabdomyolysis [37].
Recently, synthetic cannabinoids have been added to the list of sub-
stances capable to induce rhabdomyolysis [38].
An increasing number of drugs is currently recognized as a possible,
or even well established, cause of rhabdomyolysis, both as single thera-
py or in various associations. The case of statins is certainly the best
known. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibi-
tors decrease cholesterol serum levels by inhibiting the enzyme that
catalyzes the rate limiting step in cholesterol synthesis. However, the
mechanisms by which statins can induce muscle injury are not well
established, and are probably multifactorial. Interestingly, statins may
reduce both selenoprotein and ubiquinone levels, so suggesting that
these effects may be partly responsible for the statins-induced rhabdo-
myolysis [39]. Some studies described an association between some ge-
netic polymorphisms and the risk of developing statin-induced
rhabdomyolysis [40–42]. The clinical spectrum of statin-induced
Please cite this article as: G. Cervellin, et al., Non-traumatic rhabdomyolysis: Background, laboratory features, and acute clinical management, Clin
Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.016
3
myopathy ranges from asymptomatic elevations of serum CK levels
without muscle pain, muscle pain or weakness, to rhabdomyolysis
with muscle symptoms, elevated serum levels of CK, and renal damage
(Table 1).
The risk of rhabdomyolysis is significantly increased when statins
are used in association with fibrates. Beginning with the first case de-
scribed in association with clofibrate in 1968, it was then reported
that all fibrates (including gemfibrozil) can induce myopathy, probably
by a direct toxic effect on muscles. Because fibrates are excreted by the
kidney, the risk of myopathy increases exponentially in patients with
impaired renal function [44]. Statins-associated rhabdomyolysis may
also be modulated by physical exercise [45]. Notably, cerivastatin was
withdrawn from the market in 2001, when its used was strongly associ-
ated with rhabdomyolysis, leading to 31 deaths, 12 of which had in-
volved the concomitant use of gemfibrozil.
A large number of additional drugs have been implicated, or at least
suspected, of causing rhabdomyolysis (see Table 2 for a summary). The
most recent warning regard the widely-used proton pump inhibitors
[46], levofloxacin [47], caffeine [48,49], mefloquine [50], pregabalin
[51], and sildenafil [52], among others. Interestingly, antipsychotic
drugs have been implicated in the risk of developing rhabdomyolysis,
when associated with neuroleptic malignant syndrome or not [53,54].
Other important medical causes of rhabdomyolysis include malig-
nant hyperthermia and neuroleptic malignant syndrome [55], heat-
stroke and hypothermia [56], severe electrolytes alterations (e.g.,
severe hypokalemia, hypophosphatemia and hyponatremia), diabetic
ketoacidosis and non-ketotic hyperosmolar coma, and severe hypo- or
hyperthyroidism [30]. Recently, licorice-induced pseudoaldosteronism
has been implicated as a potential cause of rhabdomyolysis, probably
mediated by the severe electrolyte imbalance [57]. Hyperemesis
gravidarum has also been recently implicated in rhabdomyolysis, prob-
ably mediated by hypokalemia and hypophosphatemia [58].
Among the infective diseases that have been associated with devel-
opment of rhabdomyolysis, the most documented include some bacte-
rial (e.g., Legionnaire's disease or sepsis caused by other bacteria even
in the absence of direct muscle infection) and viral infections (e.g., influ-
enza A and B, Coxsackievirus, Epstein-Barr-virus, adenovirus, echovirus,
HIV, and cytomegalovirus) [30,59–61]. Among parasites, malaria repre-
sent a particularly interesting issue, since both the disease itself and
some medications frequently used to treat malaria have been associated
with rhabdomyolysis [50,62–64].
Various natural substances can also trigger rhabdomyolysis. The best
known is cicutoxin, a mixture of at least eight different alkaloids present
at varying concentrations in different species of hemlock (poison hem-
lock – Conium maculatum – but also lesser hemlock – Aethusa cynapium
– and water hemlock – Cicuta virosa). In the Mediterranean region, cases
of rhabdomyolysis are still observed in patients who have eaten quail
[2]. In 2001, 12 cases of rhabdomyolysis, three of which fatal, were de-
scribed in France after consumption of large amounts of Tricholoma
equestre, a mushroom generally considered as edible. The syndrome
was subsequently reproduced in laboratory animals treated with ex-
tracts of the same mushroom. The molecular structure of the specific
Table 1
Phenotypes classification of statin-induced myotoxicity (SIM). Adapted from [43]
Classification Phenotype Incidence
SIM
SIM 0 CKN4x upper threshold of 1.5–26%
normality
SIM 1 Tolerable myalgia 190/100.000 patients/year;
0.3–33%
SIM 2 Intolerable myalgia 0.2–2/1000
SIM 3 Myopathy 5/100.000
SIM 4 Severe myopathy 0.11%
SIM 5 Rhabdomyolysis 0.1–8.4/100.000 patients/year
SIM 6 Necrotizing myositis ~2/million patients/year
4 G. Cervellin et al. / Clinical Biochemistry xxx (2017) xxx–xxx

Table 2
Selected drugs that have been associated with rhabdomyolysis.

Antipsychotics and antidepressants Abuse substances Other medicines: miscellaneous

Amitriptyline Alcohol Amphotericin B

Amoxapine Amphetamine/metamphetamine (MDMA, ecstasy) Azathioprine
Chloropromazine Caffeine Corticosteroids
Doxepin Cocaine Colchicine
Fluphenazine Heroin Epsilon-aminocaprioc acid
Fluoxetine Lysergic acid diethylamide (LSD) Fluorochinolones
Fluphenazine Mephedrone Halothane
Haloperidol Methadone Macrolides
Lithium Methanol Moxalactam
Olanzapine Phencyclidine Oxprenolol
Protriptyline Sintetic cannabinoids Paracetamol
Perphenazine Toluene (“glue sniffing”) Penicillamine
Promethazine Alcohol Pentamidine
Risperidone Phenylpropanolamine
Trifluoperazine Quinidine
Salicylates
Succinylcholine
Theophylline
Terbutaline
Thiazides
Trimethoprim-sulfamethoxazole
Vasopressin

Hypnotics and sedatives Antihistamines Anti-hyperlipidemic agents

Diazepam Diphenhydramine Lovastatin
Nitrazepam Doxylamine Pravastatin
Flunitrazepam Simvastatin
Lorazepam Fluvastatin
Propofol Atorvastatin
Triazolam Rosuvastatin
Barbiturates Cerivastatin (withdrawn)
Clofibrate
Bezafibrate
Fenofibrate
Gemfibrozil

myolytic toxin contained in Tricholoma equestre has not yet been identi-
fied, nor classified [65]. At least one species of Russula mushroom (i.e.,
Russula subnigricans) has been reported to provoke rhabdomyolysis
and causing at least two deaths [66,67]. Viper venom frequently causes
rhabdomyolysis and compartment syndrome. This may be due to
edema, myotoxic agents and hemorrhagic factors, which are ultimately
responsible for two types of potentially fatal complications, i.e., AKI and
hyperkalemia [68]. Another species of snake belonging to the Viperidae
family, i.e., Protobothrops Flavoviridis (also classified as Trimeresurus
flavoviridis), endemic in the Ryukyu Islands of Japan, has recently been
associated with several cases of rhabdomyolysis [69]. Eating fish has
been recognized as a potential cause of rhabdomyolysis, and the so-
called Haff disease (from the German word “Haff”, meaning “Lagoon”),
has been described nearly a century ago in the Baltic region [70]. The
fish species involved are, to the best of current knowledge, buffalo
fish, crawfish, salmon, parrotfish, crayfish, and carp fish. Although the
toxins involved remain unknown, several candidates have recently
emerged [71,72]. Multiple bee stings have been described as a cause of
rhabdomyolysis, recognizing multifactorial pathophysiology, both toxic
and allergic, and provoking even potentially lethal damage [73–75].
In cases of severe carbon monoxide (CO) poisoning, rhabdomyolysis
can occur through the dual mechanism of hypoxic muscular damage
and compression especially when the victim remains unconscious on
the ground for long periods [76].
Hereditary enzyme disorders are rare, and of minor interest for the
Emergency Physicians (EPs), but also deserve to be mentioned. The most
frequent condition is McArdle's disease (congenital myophosphorylase de-
ficiency), followed by Tarui disease (phosphofructokinase deficiency),
phosphoglycerate mutase deficiency, and carnitine palmitoyltransferase
deficiency [30]. Patients with these pathologies are usually aware of their
condition, and may be brought to the ED following traumatic, medical or
toxic events.
4. Pathophysiology
All the aforementioned mechanisms capable to produce muscle
damage converge in a final common pathway that triggers a cascade
of events leading to a rapid influx of calcium ions into muscle cells.
This fact can trigger the pathophysiological cascade, resulting in a path-
ological interaction between actin and myosin and activation of cell pro-
tease, with subsequent necrosis of muscle fibers, and release of
intracellular metabolites (potassium, phosphates, and urates) and intra-
cellular proteins (myoglobin, creatine kinase, aldolase, lactate dehydro-
genase, among others) in the extracellular space and bloodstream. In
normal conditions, myoglobin is bound to plasma globulins. However,
the destruction of just 100 g of muscle tissue is capable to overwhelm
this binding capacity, and myoglobin can thus precipitate in the glomer-
ular filtrate, particularly in an acidic environment, finally causing tubu-
lar occlusion and severe kidney damage [11]. Additional mechanisms
causing renal damage include (i) a direct cytotoxic effect of myoglobin
on renal cells, (ii) urate precipitation, leading to intraluminal casts, in-
creased intratubular pressure and subsequent decreased glomerular fil-
tration rate, (iii) renal vasoconstriction and ischemia due to the heme
group of myoglobin causing activation of the cytokine cascade, and
(iv) oxidant injury through heme-induced reactive oxygen species
such as superoxide anion, hydrogen peroxide, or hydroxyl radicals caus-
ing direct oxidative damage to renal tissue [14,17]. Pigmented myoglo-
bin casts, characteristic of rhabdomyolysis syndrome, are the result of
the interaction between myoglobin and Tamm-Horsfall protein in an
acid environment [9]. There is an inverse relationship between urine
pH and the percentage of precipitated myoglobin, at any protein con-
centration. For example, when the urine pH is b5, 73% of myoglobin pre-
cipitates, whereas at a pH of 6.5 only 4% of myoglobin precipitates [9]. In
the case of traumatic rhabdomyolysis, other key aspect is the hypovole-
mia and/or shock that frequently accompanies this condition, with the

Please cite this article as: G. Cervellin, et al., Non-traumatic rhabdomyolysis: Background, laboratory features, and acute clinical management, Clin
Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.016
 G. Cervellin et al. / Clinical Biochemistry xxx (2017) xxx–xxx
subsequent effects of renal hypoperfusion and acidemia and aciduria.
AKI thus represents a feared and common complication of rhabdomyol-
ysis, occurring in 13% to 50% of patients [77,78] and influencing
mortality.
5. Clinics
The classic triad of symptoms of rhabdomyolysis includes muscle
pain, weakness and dark urine. Muscle weakness and muscle pain can
occur in any body region, but the muscle groups mostly involved are
those of the proximal leg, calf and lumbar region [17,31]. These muscles
may appear tense and swollen, sometimes associated with bed sores.
However, this classic triad is observed in b 10% of patients only, and up
to 50% of the patients do not complain of muscle pain or weakness,
only complaining for non-specific symptoms. In these cases, the first
sign may be the appearance of dark urine (from pink to brown to
black), that rises the problem of a differential diagnosis with hematuria
[17,31]. The clinician must hence have a high index of suspicion, primar-
ily based on the history of the event. Systemic manifestations include
fever, general malaise, tachycardia, nausea and vomiting. The clinical
manifestations of AKI, DIC and multiorgan failure may appear later
[17,31]. Notably, patients with traumatic rhabdomyolysis who develop
AKI have much higher mortality compared with those who do not
(59% vs. 22%) [79,80]. Regardless of the underlying causes, the overall
mortality rate due to rhabdomyolysis is still as high as 8% [77]. Recently,
a clinical prediction score capable to accurately identify patients at high
risk for renal failure and death has been described, and this approach
may be useful for risk stratification in the ED, early establishment of ag-
gressive therapy and monitoring [80,81].
6. Laboratory diagnostics
The laboratory diagnosis of rhabdomyolysis is still essentially based
on the measurement of serum or plasma CK, which is considered the
most sensitive test despite being only regarded as a “surrogate” marker.
Although there is no established cut-off threshold, a concentration five
to ten times the URL (i.e., ~1000 U/L) is commonly used [17,82]. In the
case of a single event (i.e., mostly trauma), CK levels tend to rise in the
first 12 h, peak on the second or third day and return to baseline 3–
5 days later. CK values are generally considered to predict the likelihood
of developing AKI, with a concentration N5000 U/L thought to be closely
associated with development of kidney damage. Nevertheless, this as-
sumption has recently been challenged by the evidence that myoglobin
is the crucial player in the pathogenesis of myoglobinuric AKI, has a
more rapid kinetics than CK, so that its monitoring over time may
allow to mirror disease activity and define therapeutic efficiency better
than using CK [83]. More specifically, CK has a half-life of 1.5 days. As a
consequence, blood levels remain increased longer than for myoglobin,
which has a half-life of 2–4 h. Myoglobin values tend to normalize with-
in 6–8 h following the event [17,84,85]. Strong evidence has emerged
that peak values of myoglobin in serum or plasma could be better pre-
dictors of AKI than CK values [86–89]. These data have been recently
supported by a meta-analysis of 18 studies, concluding that AKI occur-
rence was significantly predicted by CK value in patients with crush-in-
duced rhabdomyolysis, but not in those with other causes of
rhabdomyolysis [90]. Unlike serum or plasma myoglobin assessment,
there is inconclusive data supporting the use of urine myoglobin mea-
surement as a predictor of AKI in patients with suspected rhabdomyol-
ysis. Importantly, the traditional dipstick methods do not differentiate
between hemoglobin, myoglobin, or red blood cells. Since the presence
of hematuria is very frequent in patients with rhabdomyolysis, this
might be a serious limitation, so potentially causing false positive results
and leading to inappropriate therapeutic management. Falsely low or
false negative results can especially occur in the presence of ascorbic
acid, high nitrite concentrations, or high specific gravity. Cardiac
troponins might also be occasionally increased in patients with
Please cite this article as: G. Cervellin, et al., Non-traumatic rhabdomyolysis: Background, laboratory features, and acute clinical management, Clin
Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.016
5
rhabdomyolysis (up to 17% of cases) [91,92], although data are lacking
about differences between “classical” troponins and high-sensitivity
troponins in this clinical context. It may hence be concluded that CK
should still be considered the biochemical “gold standard” for diagnos-
ing rhabdomyolysis, whereas myoglobin should be considered the “gold
standard” in prognostication, especially in patients with non-traumatic
rhabdomyolysis. Given that troponins are now widely accepted as the
unique biochemical “gold standard” for diagnosing acute coronary syn-
dromes, CK and myoglobin have been erased from admission test panels
of the vast majority of EDs. Troponin concentrations, on the contrary,
can be increased in case of severe rhabdomyolysis, possibly reflecting
associated myocardial damage [93], so challenging to the accurate diag-
nosis of rhabdomyolysis in the ED, especially in absence of obvious
causes.
The assessment of severity and progression of the syndrome should
entail serial monitoring of renal function and electrolytes, as well as co-
agulation testing in order to promptly reveal the presence of early coag-
ulopathy or DIC. Unfortunately, blood creatinine and blood urea
nitrogen values are late markers of kidney damage. Other than renal
damage, they often reflect the gradual deterioration of renal function.
Recent focus has been placed on innovative biomarkers of kidney injury,
in particular N-GAL (neutrophil gelatinase associated lipocalin), a 178
AA polypeptide which is rapidly released from the kidney after an ische-
mic and/or nephrotoxic event [94,95]. Urine and serum NGAL concen-
trations increase 2 h after an ischemic renal event (e.g., coronary
artery by-pass surgery), displaying 95% sensitivity and 99% specificity
for identifying patients who later develop AKI. This protein, which mea-
surement is also available on the market as “point-of-care” testing, may
be useful for rapid identification of patients requiring more aggressive
monitoring and treatment. Nevertheless, despite mounting evidence
about its clinical usefulness, a universally accepted maker of AKI, i.e., a
desirable “kidney troponin”, is still lacking [96].
7. Emergency department treatment and management
After establishing a definitive diagnosis of rhabdomyolysis, or even
when is strongly suspected it (e.g., in case of crush syndrome), fluid in-
fusion should be promptly initiated, with the goal of maintaining a uri-
nary flow of 200–300 mL/h. In order to avoid volume overload, it is
highly recommended to alternate 500 mL of sterile saline solution
with 500 mL of 5% glucose solution, adding 50 mmol of sodium bicar-
bonate for each subsequent 2–3 L of solution (usually 200–300 mmol
on the first day) and maintaining the urine pH above 6.5 and plasma
pH below 7.50 (8,9,13). The speed of infusion should be ~ 500 mL/h,
while hemodynamic parameters and urine output should be monitored
closely. The role of osmotic agents (i.e., mannitol) or loop diuretics (i.e.,
furosemide) was never proven to be useful and should hence be dis-
couraged [8,10,13]. Especially in traumatic forms, up to 12 L of fluid
can be sequestered in the damaged tissue in the first 48 h, so explaining
the imbalance (sometimes exceeding 4 L) between the administered
fluids and urine output. In elderly patients, or in those with pre-existent
heart disease, intravenous fluid therapy must be personalized and care-
fully monitored due to the risk of fluid overload and pulmonary edema.
It is still of outmost importance to recognize that the treatment bench-
mark is aggressive forced hydration by means of sterile saline and glu-
cose solutions, since studies in humans show that alkalinization add
little to the beneficial effect of hydration [8,10,13]. It should also be con-
sidered that sodium bicarbonate, targeting urine alkalinization around a
pH of 6.5, prevent myoglobin precipitation into the renal tubuli, but may
also help managing of one of the most frequent complications, i.e.,
hyperkalemia associated or not with metabolic acidosis [9,97]. Forced
hydration should be continued until disappearance of myoglobinuria,
which typically occurs in the third day. Hyperkalemia must be managed
using the usual techniques, considering that treatment with glucose and
insulin may be ineffective in this setting due to inability of damaged
muscle tissues to capture potassium from the extracellular liquid, so
6 G. Cervellin et al. / Clinical Biochemistry xxx (2017) xxx–xxx
enhancing the importance of administering sodium bicarbonate. It is
often necessary to treat severe hyperkalemia with hemodialysis. Hypo-
calcemia, secondary to sequestration of calcium into damaged muscle
cells, must not be uncritically treated. The administration of intravenous
calcium (both chloride and gluconate) should be used only to treat life-
threatening ECG alterations, secondary to hyperkalemia or extreme hy-
pocalcemia [13].
Certainly, precipitating conditions must be promptly managed,
whenever possible, with high priority, encompassing suspension of
the suspected drugs, normalization of thermal, endocrino-metabolic or
electrolyte disorders, and surgical debridement of involved tissues
(considering timely fasciotomy when compartment syndrome is
suspected).
8. Conclusions
Overall, rhabdomyolysis remains a relatively rare condition, but it
clinical consequences are frequently dramatic in terms of both morbid-
ity and mortality. Unlike many other human diseases the triggering fac-
tors are often unrecognized, so that clinical prevention strategies are
frequently ineffective. Therefore, a deepened knowledge of triggering
factors, clinical and laboratory features along with the appropriate treat-
ment in the ED remains pivotal for the clinical management of patients
with this condition. One of the main new features in the clinical man-
agement of this disorder is the different meaning tribute to the two bio-
markers of muscle injury, i.e., CK, that should still be considered the
biochemical “gold standard” for diagnosing rhabdomyolysis, and myo-
globin, that should be considered the “gold standard” in prognostica-
tion, especially in patients with non-traumatic forms.
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