Renal replacement therapy Durka, Anestezjologia

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Anestezjologia i Ratownictwo 2009; 3: 354-357
Anestezjologia • Ratownictwo • Nauka • Praktyka / Anaesthesiology • Rescue Medicine • Science • Practice
ARTYKUŁ POGLĄDOWY/REVIEW PAPER
Submitted: 26.01.2009 • Corrected: 28.02.2009 • Accepted: 01.03.2009
© Akademia Medycyny
Renal replacement therapy in crush
syndrome
Anna Durka
1
, Waldemar Machała
2
1
StudenckieKołoNaukoweAnestezjologii,IntensywnejTerapii
iMedycynyRatunkowejprzyIIZakładzieAnestezjologii
iIntensywnejTerapiiUSKnr2im.WAMwŁodzi;Opiekun:dr
hab.n.med.WaldemarMachała
2
IIZakładAnestezjologiiiIntensywnejTerapii,Uniwersytet
MedycznywŁodzi
Summary
Crush syndrome (CS) is deined as a severe systemic multi-organ failure resulting from a massive mechanical
injury of skeletal muscles. It occurs ater trauma, muscle compression during prolonged lying, alcohol poisoning,
cocaine overdose, adverse efects of some drugs as well as bacterial, viral infections, hyperthermia, hypothermia
and frostbite. he basis of pathophysiology is rhabdomyolysis i.e. increased permeability of damaged myocyte
cell membrane, resulting in the release of toxic substances from muscle ibers cells into the bloodstream. It fre-
quently leads to acute renal failure, hypovolemia and shock. Recognition of crush syndrome requires early luid
resuscitation, ICU treatment and implementation of Renal Replacement herapy (RRT) simultaneously with urine
alkalization. Continuous veno-venous hemoiltration (CVVH) is also recommended as it improves the transfer of
iltered myoglobin molecules. A multitude of related clinical problems with various etiology, pathogenesis, courses
as well as the complicated and multidimensional therapy contribute to the complexity of a presented problem.
Anestezjologia i Ratownictwo 2009; 3: 448-453.
Keywords: rhabdomyolysis, myoglobin, acute renal failure, renal replacement therapy, haemodialysis, hemoiltration
Contents
literature in 1881. he cause-and-efect relationship
between injury as a crush factor and following acute
renal failure was described in 1909 ater the Messina
earthquake in Sicily. However, the best sources of
information on crush syndrome are the papers of two
English scientists (Bywasters, Beall, 1941) from the
times of II World War, in which they describe injuries
of London bombing victims. A few reports appeared
also in Japan ater the atomic bomb explosion over
Hiroshima and Nagasaki [1,3].
In the 80’s of the 20th century research results
devoted to pathophysiology of crush syndrome were
published. Three theories were formulated (toxic,
neurorelective and plasma loss) and they explained
Muscles comprise about 40% of the body weight
and contain about 75% of total potassium. herefore, it
is commonly known that the consequences of massive
muscle damage and other diseases resulting in their
destruction are very dangerous.
he word „crush” is deined as pressing or squeez-
ing two bodies resulting in injury or breaking. No won-
der this term is oten used in traumatology in order to
deine aetiology and/or mechanisms of various injuries,
mainly accidents and disasters leading to massive and
severe damage [1,2].
Crush syndrome was irst reported in the German
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Anestezjologia • Ratownictwo • Nauka • Praktyka / Anaesthesiology • Rescue Medicine • Science • Practice
the mechanisms of systemic failures in rhabdomyolysis
[4]. As the term crushed wound” refers only to injury,
the term “crush syndrome” (CS-Crush Syndrome) is
much wider. It describes severe, systemic consequences
of mechanical damage to striated muscles [1].
Skeletal muscles are 100–1000 times more sensi-
tive to tension and compression than skin. When they
are excessively pressed, swelling and hypoxia appear,
which results in necrosis and myocyte lysis and the
release of their catabolites. he process is called rhab-
domyolysis i.e. the rapid breakdown of striated muscles.
Rhabdomyolysis is the basis for the pathophysiology of
crush syndrome resulting from trauma as well as the
damage following it [1,2].
Crush sy ndrome is most ly the consequence
of extensive crushed wounds e.g. when people are
crushed by falling walls in construction disasters, mine
accidents, armed conlicts or natural disasters (earth-
quakes, hurricanes, typhoons, etc.). It is considered to
be one of the most severe conditions, especially when
it is combined with detonation and blow syndrome. It
can be observed as a result of disequilibrium between
energy produced and used by skeletal muscles. It
also occurs in case of muscle compression during
prolonged lying (e.g. coma, tight fascial compartment
syndrome), status epilepticus, too exhausting physical
exercise, myocardial infarction, alcohol poisoning,
drug overdose: cocaine, heroine, amphetamine, as
well as in hyperthermia and burns, hypothermia and
limb frostbite. Among other causes of rhabdomyolysis
we can distinguish: side efects of therapy with statin
drugs, ibrate drugs, theophylline, cyclosporine A;
muscular dystrophy, muscle inlammatory conditions,
carbon monoxide poisoning, rhabdomyosarcoma and
other malignant neoplasms iniltrating and destroying
striated muscles, thrombotic/embolic disease, meta-
bolic and electrolyte disorders, such as hypokalemia,
hypophosphatemia, hyponatremia, diabetes, bacterial
and viral infections, such as inluenza A, mononu-
cleosis, tetanus, sepsis, Legionnaires’ disease, Rocky
Mountains spotted fever. Intense and prolonged muscle
compression results in ischemia and necrosis, which
lead to local and systemic complications [1,3,5-7].
Removing a damage factor is necessary before
implementing advanced rescue activ ities. They
restore tissue metabolic activity, but inevitably lead
to occurrence and intensiication of complications.
his a peculiar paradox evoked by a sudden release of
metabolites of reactions occurring under anaerobic
conditions in crushed muscles [6]. he consequence
of crush syndrome is the increase of permeability of
cell membranes of damaged myocytes and the release
of toxic substances into the bloodstream. hey include
myoglobin, creatinine, potassium released during
muscle breakdown. It is accompanied by decrease in
calcium concentration in blood <8 mg/dl (<2 mmol/l),
anion gap metabolic acidosis and a signiicant increase
in potassium concentration (>6 mmol/l), uric acid
>8 mg/dl (>475,8 µmol/l) and phosphates >8 mg/dl
(>2,6 mmol/l). Concentration of creatinine in plasma
and non-protein nitrogen in blood (BUN - Blood
Urinal Nitrogen) may increase rapidly and reach the
levels of >2,0 mg/dl (176,8 µmol/l) and >40 mg/dl
(>14,3 mmol/l )
[1,3].
During prolonged compression
skeletal muscles are exposed to oxygen deicit, which
results in increased lactate production, decrease
in blood pH and occurrence of metabolic acidosis.
Moreover, increase of activity of, so-called, muscle
enzymes in serum is noted. he enzymes include:
creatinine kinase (CPK), lactate dehydrogenase (LDH),
aldolase, alanine and aspartate aminotransferase
(ALAT) and (AspAT). Hepatotoxic adenine nucle-
otides are released from damaged muscles, which
cause increased production of uric acid by a liver
and marked hyperuricemia [3]. In the initial stage of
crush syndrome hypocalcaemia occurs, which a result
of Ca2+ ions is moving inside damaged muscle cells.
A big amount of free calcium ions in myocytes causes
increase of permeability of cell membrane to sodium
and at the same time it increases the threshold of cell
excitability. It also causes muscle ibre contraction
that exhausts muscle energy resources. As the disease
progresses hypocalcaemia intensiies due to irrevers-
ibility of calcium ion binding during calciic myonecro-
sis. However, during the recovery stage hypercalcemia
can be observed, which is an efect of parathormone
and the increased production of 1,25-dihydroxychole-
calciferol. Hypercalcemia is more oten observed in
patients whose therapy included calcium supplementa-
tion, so the supply of calcium is recommended only in
case of convulsions or cardiac arrhythmia caused by
hypocalcaemia [2,6,7,8].
Myoglobin – a heme pigment – can be found in
skeletal muscles and a heart muscle. It is similar to
haemoglobin as it can also bind oxygen reversely and
serves as its reserve source. Myoglobin has a molecular
weight of 18800 Daltons and it accounts only for ¼ of
haemoglobin weight. herefore, it is small enough to
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permeate through renal glomerular vessels to urinifer-
ous tubules. In case of chronic hypoxia the amount of
myoglobin in muscles increases. Its presence in urine
indicates signiicant muscle damage. It is assumed that
the breakdown of about 200 g of muscles may result in
myoglobinuria [1,3]. Normal myoglobin concentration
is estimated at 10-46 µg/l (28-72 ng/ml). Renal thresh-
old is 15 mg/100 ml. When myoglobin concentration
in plasma reaches the level of 0,03 mg/dl, iltration
takes place in renal corpuscles. In acid plasma and
urine environment a myoglobin ion is transformed
from anion to cation. hen the conversion to acid ferro-
hematin takes place and it reacts with Tamm–Horsfall
proteins. It causes precipitation of conglomerates in
proximal tubules and as a result their obturation [1].
Myoglobin shows nephrotoxic activity when it afects
tubular epithelial cells. Moreover, it shrinks renal
vessels, which additionally reduces iltration ability
and leads to acute renal failure (ARF - Acute Renal
Failure) [3].
his is a pathologic condition character-
ised by a sudden decrease in urination, which does
not allow removing toxic products of metabolism.
In majority of cases it does not exceed 50 ml a day
[9,10]. Research shows that acute renal failure occurs
together with metabolic acidosis and when urine pH is
<6 [1]. Hypovolemia and reduced low of blood in renal
tubules intensify renal damage. Renal failure can be
prevented by urine alkalization (pH >6,5) and imple-
menting forced diuresis [1,3]. Myoglobin that is iltered
into Bowman’s space is reabsorbed in proximal tubules.
Porphyrine ring is metabolized in tubular cells and Fe
2+
ions are freed. In physiological conditions free iron is
quickly bound by ferritin and ferroprotein complexes
are created. In rhabdomyolysis, however, when big
amounts of ionized iron are freed to uriniferous tubule
lumen, exhaustion of enzymes is observed. Fe
2+
cations,
through free radical catalysis during lipid oxidation,
inactivate intravascular nitrogen oxide NO, which
results in blood vessel contraction. his phenomenon is
intensiied when it is accompanied by hypotension and
hypovolemia [1,3]. Remarkable amounts of thrombo-
plastin, which is present in circulatory system, generate
intravascular coagulation together with thrombuses
in renal corpuscles [7,9]. Rhabdomyolysis activates
freeing of proinlammatory mediators and hormones,
such as angiotensine II, endoteline, tromboxan – A
2
,
vasopresine and catecholamine. It also contributes to
intensiication of hypovolemia and renal vessel con-
traction, and thus it decreases renal iltration [1].
he pathogenesis of crush syndrome should be
considered on the basis of two processes: rhabdomy-
olysis and acute renal failure resulting directly from
it. Signiicant loss of plasma in the course of skeletal
muscle crush (amounting even to 10 litres per damaged
limb) reduces circulating blood volume, condenses it
and leads to hypovolemia and shock. Blood is saturated
with products that are normally excreted, such as urea,
bilirubin, potassium and phosphorus. Urea is the main
end product of protein metabolism. About ½ of urea
iltered in renal corpuscles is absorbed reversibly in
kidneys, the rest is excreted with urine. Urea nitrogen
accounts for 50% of non-protein nitrogen, and in renal
failure even for 95% [1].
Pain irritation, caused by relex contraction of
blood vessels, induces dysfunctions of respiratory
and circulatory systems. Pain disrupts functions of
respiratory and circulatory systems. Frequently repor-
ted symptoms are: relex contraction of blood vessel,
decrease in diuresis, blood condensation and decrease
in immunity as well as sensitiveness to blood loss.
Electrolyte disorders and hypovolemia are the main
causes of acute heart failure [5].
During reperfusion in damaged skeletal muscles
leukocytes with polymorphic nuclei are accumulated
and they pour into the bloodstream. hey produce
free radicals and secrete myeloperoxidase i.e. enzyme
catalizing reactions producing potentially cytotoxic
oxidants of hypochloraus acid and N-chloramine.
he presence of activated neutrophilic granulocytes
may also result in damaging epithelial cells because
they produce active oxygen metabolites: peroxides and
hydro-oxygen radicals, which increase permeability of
surface epithelial layer. Leukocytes with polymorphic
nuclei pay a very important role in multi-organ damage
caused by reperfusion [1,6].
All pathogenic mechanisms in crush syndrome are
reciprocally intensiied and afect negatively the whole
organism. When a patient survives a shock caused by
trauma, crush syndrome symptoms appear ater a few
hours ater action of inducing factor. Initially general
condition of injured people is good. Clinical picture
develops slowly and it resembles a post-traumatic shock
but it is not the case. here are three stages of crush
syndrome: early, intermediate and late. In an early
stage, which lasts 3-4 days ater trauma, oedema and
lividity of an injured limb or other part of the body
are observed. Bladders illed with serous or serosan-
guineous liquid appear on the skin. In peripheral parts
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of a limb iliform pulse and increased pulse rate are
noted, ater some time it becomes impalpable. Arterial
blood pressure decreases to about 80/60 mmHg. If
crush syndrome exacerbates, patient’s condition
deteriorates. Patient becomes apathetic, reacts poorly
to the surroundings, nausea and vomiting appear.
Blood coagulability is disturbed. From the 2
nd
or 3
rd
day of post-traumatic circulation decompensation
increase in thrombotic readiness is observed, which
is a result of penetration of excessive amount of tissue
thromboplastin. It includes: decrease in free heparin
concentration, increase in plasma tolerance to hepa-
rin and increase in plasma ibrinogen concentration.
Urine is dark red and sediment contains albumins,
erythrocytes, haematin, myoglobin and granular
casts [1,4,8].
In the intermediate stage, during which both
improvement and deterioration can be observed,
oedema of crushed limb exacerbates, causing severe
pain. Apparent improvement may occur in spite of
observed oliguria. Intensive medical treatment and
renal replacement therapy conducted at this stage may
equalize kidney activity 8-12 days ater the trauma.
From the 7
th
day hypocoagulation condition develops,
which results from consumption of blood coagulation
factors in the body. his condition leads to dissemi-
nated intravascular coagulation (DIC – Disseminated
Intravascular Coagulation) and thrombosis of small
blood vessels of internal organs. In venous blood,
especially the blood lowing away from site of crush,
a marked change in parameters related to acid-base
equilibrium is noted. hen blood pH decreases from
7,05 (directly ater crush) to 6,87 in the sixth hour.
Alkaline deiciency amounts to 6,6-21 mmol/l, which
causes acidosis in ischemic tissues ater crush. From
the very beginning it resembles metabolic acidosis
that intensiies markedly during a sudden decom-
pression of a swollen limb or other parts of the body.
Accompanying symptoms of infection in the site of
trauma greatly deteriorate the prognosis [1,6,8].
In the late stage of crush syndrome (from 10-20 to
45-60 days ater trauma) ater controlling acute renal
failure and without noticing any septic or respiratory
complications, clinical picture shows prevailing local
regressive symptoms of crush syndrome. hey include:
oedema, limb movement restriction, dysesthesia, muscu-
lar atrophy resulting from primary injuries. Generally,
patients who survived the intermediate stage of crush
syndrome, have good chance of recovery [1,5,6].
Clinical picture is strictly related to patient’s
general condition, strength and duration of crush
trauma, as well as to damage of internal organs, blood
vessels, nerves, fractures and others [5].
he pace of
crush syndrome development is reversely proportio-
nate to the time of proper therapy implementation
and it depends on the kind of applied treatment. Bad
prognostic factors that deepen pathology of rhabdo-
myolysis are severe infections, sepsis, multiple organ
dysfunction (MODS – Multiple Organ Dysfunction
Syndrome), disseminated intravascular coagulation
(DIC), hyperphosphatemia and hyperuricemia [1,7].
In case of lack of help or its ineiciency majority of
seriously ill patients die due to severe heart failure.
In less serious cases circulatory disturbances may be
minor and pass unnoticeably
[
6,8].
Prehospital procedures include maintaining
victim’s vital functions and preventing complications
and crush syndrome occurrence. Rapid initiation of
luid replacement is necessary to maintain functions
of circulatory system and to counteract hypovolemia.
Immediately ater releasing a victim, if not possible
earlier, it is required to insert a cannula into peripheral
vein and transfuse 0,9% NaCl
or Ringer’s solution in
volume of 1500 ml/an hour. Shock-controlling procedu-
res include also application of analgesics. Recognition
of crush syndrome indicates rapid implementation of
shock-controlling procedures and renal replacement
therapy, simultaneously with urine alkalization [3].
It is
very important to continue luid replacement therapy.
Fluid losses can be remarkable, e.g. in case of a limb
they may amount to 10 l. It is a result of luids moving
inside damaged muscles. Fluid replacement therapy
undertaken at a site of accident allows complementing
intravascular volume, which is prophylaxis against
acute prerenal failure. It is crucial to keep a positive
luid balance during irst 2-3 days of treatment i.e.
provide about 12 litres of luid per day. During such
intense hydration it is necessary to measure central
venous pressure or pulmonary capillary wedge pressure
(PCWP). Fluids administered intravenously should be
supplemented with sodium bicarbonate (NaHCO
3
) in
dose of 100 mmol/l due to the risk of severe acidosis
and accompanying hyperkalemia. Sodium bicarbonate
is not only used in treatment of metabolic acidosis,
but it also alkalizes urine. Maintaining urine pH at
≥ 6,5 enables to avoid formation of uric acid crystals
and moreover, it increases dissolution of myoglobin,
inhibiting precipitation and deposition of its conglome-
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rates in uriniferous tubules [3]. Administering sodium
bicarbonate potentially exposes a patient to the risk
of metabolic alkalosis, which causes precipitation of
calcium-phosphate concrements. It can be regulated
with acetazolamide; its application may be required
when pH > 7,45. However, the risk of metabolic alka-
losis is less dangerous than acidosis, hypokaliemia and
kidneys deprived of protection against toxic efect of
myoglobin and uric acid [3,6].
A drug considered to be efective in ARF preven-
tion in rhabdomyolysis is mannitol [3,6].
Having a variety of uses it is protective against
crush syndrome complications. It induces movement
of intravascular and extracellular luid, which reduces
blood viscosity and greatly improves kidney perfusion.
Mannitol prevents contraction of renal vessels and as
an osmotic diuretic it reduces oncotic pressure and
increases intraurethral pressure, at the same time
increasing glomerular iltration. It also prevents renal
tubule blocking, myoglobin precipitation, pigmented
cast formation as well as it reduces endocytosis and
heme uptake in proximal renal tubule. It demonstrates
cytoprotective action because it increases uptake of
free radicals, not inhibiting their production. Mannitol
shows also positive extrarenal action, e.g. decrease in
muscle oedema, increase in mean arterial pressure and
improvement of cardiac muscle contractility. Mannitol
administration is recommended when diuresis is mai-
ntained at 4 l/a day. Mannitol as an osmotic diuretic
does not lower urine pH [3,10].
Administration of loop diuretics is not recom-
mended. They may induce dehydration and urine
acidiication – conditions that should be prevented
during the whole treatment process [10].
he efective method of treatment and preventing
acute renal failure in rhabdomyolysis is renal repla-
cement therapy [3]. Indications for renal replacement
therapy are:
− oliguria (200 ml/12 hours)
− anuria (do 50 ml/12 hours)
− increase in urea concentration >35 mmol/l.
− increase in creatinine concentration >400 µmol/l.
− increase in potassium concentration >6,5 mmol/l
or its rapid rise
− increase in sodium concentration >160 mmol/l or
its decrease <110 mmol/l.
− pulmonary oedema not responding to diuretic
agents
− decompensated metabolic acidosis (pH >7,1).
− severe uraemia (encephalopathy, miopathy, ure-
mic neuropathy and pericarditis).
− body temperature >40
o
C.
− intoxication with toxins that can be removed dur-
ing dialysis.
Renal replacement therapy should be considered
when one of the criteria mentioned above occurs, but
it should be implemented immediately when two of
them are observed [11]. Two main assumptions of
renal replacement therapy are removing excess of
luids (water) and toxic substances they contain (acid
metabolites, urea, potassium, etc.) [11].
Classic haemodialysis is based on two physi-
cochemical principles. he process responsible for
removal of excess body water is called ultrailtration
and it is based on the difference between trans-
membrane pressure at both sides of semipermeable
membrane (analogically to physiological glomerular
iltration). he rate of ultrailtration depends on the dif-
ference in hydrostatic and oncotic pressure. As plasma
water is iltered, oncotic pressure increases because
plasma protein concentration rises. his phenomenon
plays a remarkable role in case of related methods,
such as hemoiltration and hemodiailtration [10,12].
Removing toxic substances (endo– or exogenous) from
intrasystemic luids is called difusion and its driving
force is the diference between blood pressure and
dialysis luid at both sides of dialysis membrane [10,12].
he rate of difusion (according to Fick’s law) depends
on molecular mass of dissolved substance, type of
protein bonds, size of semipermeable membrane pores,
the rate of blood and dialysis luid low and intermem-
brane pressure gradient [11,13]. In standard low-lux
cellulose membrane medium-sized molecules or those
Table 1. Recommended composition and volume
of intravenous infusion luid administered
in crush syndrome. he procedure corrects
hyperkalemia and prevents acute renal
failure.
Glucose 5%
1000 ml
NaHCO
3
100 mmol
NaCl
140 mmol
Mannitol 20%
10 g
24-hourluidsupply:
12 litres
24-hour diuresis:
8 litres
To prevent acute renal failure in crush syndrome
maintaining pH >6,5 is recommended.
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