COMPLICATIONS OF POISONING

Rhabdomyolysis

dipstick for haem but no red cells on microscopic examination of

urine also supports the diagnosis.
In addition, hyperkalaemia (which may precipitate fatal dysrhythmias), hypocalcaemia (due to calcium binding by damaged
muscle proteins and phosphates), hyperuricaemia (>750 micromol/litre), hyperphosphataemia (>2.5 mmol/litre) and an increase in aminotransferase, lactic dehydrogenase and aldolase
activities may be present due to the release of these enzymes
from damaged muscle. More general manifestations include
malaise, fever, tachycardia, nausea and vomiting.
Two clinically important complications are observed: acute
renal failure (which may be non-oliguric)1 and peripheral nerve
damage (secondary to compartment syndrome), resulting predominantly in wrist drop (Figure 1) or foot drop (Figure 2).
Rhabdomyolysis accounts for 5e9% of all cases of acute renal
failure,4,5 and 5e30% of patients with rhabdomyolysis develop
acute renal failure.6,7

Allister Vale

Abstract
Non-traumatic rhabdomyolysis may be caused by a direct insult to the
cell membrane, affecting its ability to maintain ion gradients, or be secondary to local muscle compression as a result of coma or seizures.
Acute renal failure and peripheral nerve damage are the two most
common and important complications observed, although hyperkalaemia leading to a dysrhythmia is the main cause of death.

Keywords creatine kinase; myoglobin; myoglobinuria; peripheral

nerve damage; renal failure

Introduction
Pathogenesis of rhabdomyolysis-induced renal failure

Rhabdomyolysis is a condition in which there is dissolution of

striated muscle fibres, with leakage of muscle cell contents (enzymes, myoglobin, potassium, phosphate). The mechanisms
involved in the pathogenesis of rhabdomyolysis have been
reviewed,1 and include an increase in free (ionized) calcium in
the cytoplasm. The increased cytoplasmic calcium initiates a
complex network of intracellular processes, such as the activation of phospholipase A2, prolonged contraction of muscle cells,
mitochondrial dysfunction and production of reactive oxygen
species; these processes eventually promote muscle cell damage
and the release of various substances into the systemic circulation, thereby leading to the clinical manifestations of
rhabdomyolysis.1,2
In patients who are poisoned, non-traumatic rhabdomyolysis
may be caused by a direct insult to the cell membrane, affecting
its ability to maintain ion gradients, or be secondary to local
muscle compression as a result of coma or seizures. Several
hundred drugs have been found to be associated with the onset
of rhabdomyolysis: opioids, benzodiazepines and antipsychotics
were the most common drugs involved in a recent series of 114
patients treated in Iran.3

Three main mechanisms are involved.1,8 First, tubular necrosis

occurs by free radical-mediated lipid peroxidation. This involves
redox cycling between two oxidation states of myoglobin haem:
Fe3 (ferric) and ferryl (Fe4).9 The formation of ferryl
myoglobin requires the presence of lipid hydroperoxide (LOOH).
Once formed, the ferryl species react with lipids and LOOH
moieties to form lipid alkyl (LOO*) and lipid peroxyl (L*) radicals that progressively damage renal tubular membranes. Thus,
ferryl myoglobin can initiate lipid peroxidation.
Second, renal vasoconstriction occurs due to activation of the
sympathetic nervous system and the renineangiotensin system
in response to reduced effective circulating blood volume, scavenging of the vasodilator nitric oxide by myoglobin and the
release of isoprostanes (particularly 15-F2t and 15-E2t, which are
potent vasoconstrictors), formed as a result of free radical damage to phospholipid membranes.
Third, tubular obstruction occurs due to the formation of
tubular casts by binding of free myoglobin to the TammeHorsfall
protein (uromodulin), a renal glycoprotein,10 and as a result of
urate crystal deposition.

Management

Features

Management is predominantly supportive, including treatment of

the intoxication, early correction of potentially lethal electrolyte
disorders (e.g. severe hyperkalaemia) and metabolic acidosis,
and measures to prevent and then treat rhabdomyolysis-induced
renal failure and the compartment syndrome.

The key to making the diagnosis is to detect increased creatine

kinase activity in the plasma or myoglobin in the urine. The
creatine kinase activity must be at least five times normal (CKMB fraction <5%) 2e12 hours after the precipitating cause, but
is often several thousand units per litre; the creatine kinase activity may continue to rise for more than 24 hours. This is
associated with a transient increase in serum myoglobin and
visible (tea- or cola-coloured urine) myoglobinuria. The absence
of myoglobinuria does not exclude the diagnosis. A positive urine

Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS FBPhS FEAPCCT is
Director of the National Poisons Information Service (Birmingham
Unit) at City Hospital, Birmingham, and Honorary Professor, University
of Birmingham, UK. Competing interests: none declared.

MEDICINE 44:2

Figure 1 Wrist drop resulting from peripheral nerve damage.

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2016 Published by Elsevier Ltd.

COMPLICATIONS OF POISONING

2 Chatzizisis YS, Misirli G, Hatzitolios AI, Giannoglou GD. The

syndrome of rhabdomyolysis: complications and treatment. Eur J
Intern Med 2008; 19: 568e74.
3 Mousavi SR, Vahabzadeh M, Mahdizadeh A, et al. Rhabdomyolysis in 114 patients with acute poisonings. J Res Med Sci 2015;
20: 239e43.
4 Grossman RA, Hamilton RW, Morse BM, Penn AS, Goldberg M.
Nontraumatic rhabdomyolysis and acute renal failure. N Engl J
Med 1974; 291: 807e11.
5 Thomas MAB, Ibels LS. Rhabdomyolysis and acute renal failure.
Aust N Z J Med 1985; 15: 623e8.
6 Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore) 1982; 61: 141e52.
7 Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Arch Intern Med 1988; 148: 1553e7.
8 Holt SG, Moore KP. Pathogenesis and treatment of renal
dysfunction in rhabdomyolysis. Intensive Care Med 2001; 27:
803e11.
9 Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis:
the role of myoglobin. Exp Nephrol 2000; 8: 72e6.
10 Zager RA. Studies of mechanisms and protective maneuvers in
myoglobinuric acute renal injury. Lab Invest 1989; 60: 619e29.
11 Moore KP, Holt SG, Patel RP, et al. A causative role for redox
cycling of myoglobin and its inhibition by alkalinization in the
pathogenesis and treatment of rhabdomyolysis-induced renal
failure. J Biol Chem 1998; 273: 31731e7.
12 Brown CVR, Rhee P, Chan L, Evans K, Demetriades D,
Velmahos GC. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?
J Trauma 2004; 56: 1191e6.
13 Homsi E, Leme Barreiro MFF, Orlando JMC, Higa EM. Prophylaxis
of acute renal failure in patients with rhabdomyolysis. Ren Fail
1997; 19: 283e8.
14 Eneas JF, Schoenfeld PY, Humphreys MH. The effect of infusion
of mannitol-sodium bicarbonate on the clinical course of myoglobinuria. Arch Intern Med 1979; 139: 801e5.
15 Thomas R, Cox J. Rhabdomyolysis and the use of sodium bicarbonate and/or mannitol. Emerg Med J 2010; 27: 305e8.
m A, Kyla
vainio V, Honkanen E, Pettila
V. The
16 Peltonen S,

Ahlstro
effect of combining intermittent hemodialtration with forced
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Figure 2 Foot drop resulting from peripheral nerve damage.

Experimentally, urine alkalinization has been shown to suppress the rate of conversion of ferryl myoglobin to ferric
myoglobin, particularly at urine pH greater than 7.0. Thus,
alkalinization inhibits the cyclical formation of lipid peroxide
radicals and limits lipid peroxidation,11 thereby reducing tubular
damage. Isoprostane release is also reduced by alkalinization,
thereby lessening vasoconstriction. In addition, binding of
myoglobin to TammeHorsfall protein is reduced under alkaline
conditions, so that tubular casts are not formed.10
However, limited experimental and clinical data12e15 suggest
that early volume replacement is at least as important, if not
more important, than urine alkalization in preventing
rhabdomyolysis-induced renal failure. The administration of sodium bicarbonate (8.4%, 225 ml) should produce urine alkalinization; further boluses of sodium bicarbonate will be required to
maintain the urine pH above 7.5. It has been shown that haemodialfiltration can remove myoglobin from the circulation
effectively and that, when combined with alkalinization of the
urine, it is more effective than urine alkalinization alone.16 A
REFERENCES
1 Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney
injury. N Engl J Med 2009; 361: 62e72.

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2016 Published by Elsevier Ltd.