RHABDOMYOLYSIS &
COMPARTMENT SYNDROME
Trevor Langhan PGY-1
May 20, 2004
OBJECTIVES
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Compartment syndrome review
Review rhabdomyolysis
Controversies in management
Measuring compartments
CASE
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24 Y Male fell 20 feet while rock climbing
isolated right leg tib/fib fracture
injury at 14:00 near Canmore
transport time one hour
Arrives in department at 15:45
Compartment syndrome
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A limb and life threatening condition
Perfusion pressure falls below tissue pressure in a closed
anatomic space
Untreated leads to:
• tissue necrosis
• permanent functional impairment
• possible renal failure
• death
Compartment syndrome
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1872 - Richard vonVolkmann
• documented nerve injury and contracture following
supra-condylar fracture
• known now as Volkmann’s contracture
Usually associated with long bone fractures
May be secondary to vascular injury
Compartment syndrome
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1930’s Jepson described ischemic contractures in dog
hind legs after limb hypertension 20 to venous
obstruction
1941 Bywaters and Beall reported crush injuries after
London Blitz
1970’s began to measure compartmental pressures
Compartment syndrome
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Elevated pressures can be noted wherever a
compartment is present:
• hand
• forearm
• upper arm
• abdomen
• buttock
• entire lower extremity
Compartment syndrome
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Similar to herniation syndromes in cranium
Fascial compartment acts as a closed space
Fluid is introduced into fixed volume, so pressure rises
As tissue pressure increases, perfusion pressure
decreases
Oxygen unavailable for cellular metabolism
Compartment syndrome
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Increased fluid content:
• intensive muscle use
(tetany, seizures,
exercise)
• burns
• Intra-arterial injection
• envenomation
• hemorrhage
• decreased serum
osmolarity
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Decreased compartment
size:
• burns
• casts
• military anti-shock
trousers
Compartment syndrome
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Tissue perfusion determined by:
• CPP - IFP = 18 mmHg
Cell metabolism needs 5-7 mmHg
Usual cap perf pressure 25 mmHg
Interstitial fluid pressure 4-6 mmHg
With rising interstitial pressure compromise of perfusion
pressure
Compartment syndrome
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Matsen et al. Diagnosis and management of compartmental syndrome.
J Bone Joint Surg 1980; 62A:286-91.
Intra-compartmental pressure rises
Venous pressure rises
Venous P > CPP = capillary collapse
Intervention indicated if compartment pressure > 30
mmHg
Compartment syndrome
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Capillaries collapse and oxygen delivery compromised
Hypoxic cell injury causes cells to release vasoactive
substances (histamine, serotonin)
Increases endothelial permeability
Continued fluid leakage from capillaries into
compartment
pH falls due to anaerobic metabolism
Compartment syndrome
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Mortality/morbidity related to time of injury to
intervention
Rorabeck and Macnab reported almost complete recovery of
limb function if fasciotomy within 6 hours
Matsen et al. found necrosis after 6 hours of ischemia considered upper limit of tissue viability
Multiple studies looking at limb function with delayed
fasciotomy
• High incidence of sepsis and amputation
• Creates open wound from a closed one
• Necrotic tissue in fascia is in sterile environment
• Don’t do fasciotomy after 6 hours
Compartment syndrome
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Suspect CS whenever significant pain occurs following
an injury
Pressure increases and ischemia begins - nerves
malfunction
Pain typically out of proportion to exam findings
Burning sensation or tightness
Compartment syndrome
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Traditional signs are not reliable
Symptoms assume a conscious patient with normal
sensorium
5 P’s
• pain
• parasthesia
• pallor
• poikilothermia
• pulselessness
Compartment syndrome
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Determine mechanism
• long bone fractures
• high-energy trauma
• penetrating injuries - arterial injury
• venous injuries - don’t be misled by pulses
• crush injuries
Compartment syndrome
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DVT prophylaxis?
Anticoagulation significantly increases the risk of CS
Case report of fasciotomy after simple venous puncture
in anti-coagulated patient
CS found in athletes and soldiers without overt trauma
Injury secondary to vigorous exercise
Compartment syndrome
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Pain and burning, decreased strength and eventually
paralysis
Limb may feel tense or hard
Pain at rest or with passive movement are red flags
Sensory nerves lose conductive ability before motor
nerves
• Ant. compartment of lower leg
• check superficial peroneal nerve
• lost sensation to web of 1st two toes
Compartment syndrome
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Clinical diagnosis in most cases
Obtunded patients or equivocal physical exam may
warrant pressure measurement
Typically diagnoses at pressures between 30-40 mmHg
Only recognized treatment is fasciotomy and release of
pressure
Delay leads to necrosis and permanent disability
Vaillancourt et al. 2001 published in CJEM mean time of
injury to ED presentation was 9 hours
Compartment syndrome
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Old belief that muscle was OK until 6 hours after
ischemia
• Based on tourniquet extrapolated studies
Animal research in dogs
• Experimental ACS versus ischemia from a
tourniquet showed greater level of muscle
necrosis
Compartment syndrome
Vaillancourt C et al. Acute compartment syndrome: How long before muscle
necrosis occurs? Can J Emerg Med 2004;6(3):147-54.
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Historical cohort analysis of all fasciotomies done for ACS
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Clinical Dx or by measured compartment pressures
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Pathologic Dx of necrosis by path reports and surgeon OR
protocols
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N = 76 (most young men with trauma 82%)
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49% suffered some muscle necrosis (1/3 of these lost >25% of
muscle belly)
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2/4 cases that had OR within 3 hours of injury had necrosis, and
11 had necrosis within 6 hours
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But 11 had injury to OR time >24 with no necrosis
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Fancy stats showed that 37% of ACS develop necrosis within 3
hours
Compartment syndrome
Hope MJ, McQueen MM. Acute Compartment Syndrome in the Absence of
Fracture. J Orthop Trauma. 2004 Apr;18(4):220-4.
 N = 164 (13 excluded)
 Compared presence of a fracture
• time to fasciotomy and patient demographics
• 38 of 151 had no fracture
 ACS with no fracture were:
• Older (p <0.05)
• More co-morbidities (p<0.001)
• Greater time to OR (mean 12.4 hours, p<0.05)
• 20% had muscle necrosis vs. 8% in # group
Compartment syndrome
Compartment syndrome
Compartment syndrome
Compartment syndrome
Uliasz A, Ishida JT, Fleming JK, Yamamoto LG. Comparing the methods of
measuring compartment pressures in acute compartment syndrome. Am J
Emerg Med. 2003 Mar;21(2):143-5.
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(1) Stryker
(2) manometric IV pump
(3) Whitesides method
“standard pressure” model using column of water and
beef muscle
• 22, 33, 44, 55, and 66 mmHg
3 separate days using a different muscle slab
9 measurements for each method at each “standard
pressure” level (45 measurements for each device)
Compartment syndrome
Compartment syndrome
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Unable to reliable measure pressure with Whitesides
method (9 step process)
Stryker instrument and IV pump
• both found to be fairly accurate and reliable methods
of measuring the intramuscular pressure of our model
• The Stryker instrument is expensive
• $1575, plus $66 disposable unit per use
Compartment syndrome
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STRYKER METHOD
(1) Fill the Stryker
instrument with normal
saline
(2) zero the Stryker
instrument
(3) insert the needle into
the area of measurement
(4) inject 0.3 cc normal
saline
(5) read the pressure
measurement
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IV PUMP METHOD
(1) Set the IV pump to
manometry mode
(2) zero the IV pump
(3) insert the needle into
the tissue being
measured
(4) infuse 0.3 cc normal
saline at a slow infusion
rate
(5) read the pressure
measurement.
Compartment syndrome
Heemskerk J, Kitslaar P. Acute compartment syndrome of the lower leg:
retrospective study on prevalence, technique, and outcome of fasciotomies.
World J Surg. 2003 Jun;27(6):744-7. Epub 2003 May 13
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August 1994 to August 2000, a total of 36 patients were
treated for the clinical diagnosis of acute compartment
syndrome
• Fracture
• blunt trauma
• reperfusion after treatment for acute arterial
obstruction
• excessive physical training
• long-term surgery in the lithotomy position
• after use of an intra-aortic balloon pump
Compartment syndrome
therapy-associated data
• number of opened
compartments
• prophylactic or therapeutic
fasciotomy
• Complications
• significant wound
infection
• Hematoma
• nerve damage
• postoperative pain
• laboratory parameters
(serum CK and creatinine)
• clinical outcome (death,
amputation, leg dysfunction
analyzed for patient
characteristics
• Sex
• Age
• admission periods
• cause of the
compartment
syndrome
Compartment syndrome
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18/40 had limb with good function at 1 year
11/40 dysfunctional limb
After fasciotomy, mortality rates of 11%–15%
amputation rates of 11%–21%
creatinine over 120 mol/l (normal 53–110 mol/l) at the
time of fasciotomy was a predictor of poor outcome (p =
0.026)
Older age also a predictor of bad outcome
RHABDO
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Clinical syndrome caused by injury to skeletal muscle
Release of cellular contents into ECF and circulation
Diagnosis by measuring cellular contents in plasma and
urine
ARF is most serious complication
• 5-15% of U.S. pts with ARF needing admission have
rhabdo as an etiology
RHABDO
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Bywaters’ and Beal’s description of trapped WWII victims
• Five victims all entrapped below rubble
• Extremity injuries
• All five presented in shock with dark urine
• Progressed to ARF
• Histology showed tubular necrosis and pigmented
casts
Bywaters and Stead identified myoglobin as the urinary
pigment in 1944
RHABDO
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Tonnes of anecdotal mass casualty case reports of ARF
after earthquakes, beatings, collapse of mines
U.S. most common cause of rhabdo is prolonged muscle
compression following alcohol bingeing
Creatine Kinase (CK) levels correlate with degree of
muscle injury
ARF may occur in 4-33% of cases with a mortality
ranging from 3-50%
5-7% of ARF admissions in the U.S.
RHABDO
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Several studies to predict who’s at risk of progressing to
ARF from crush injuries
Oda et al. Analysis of 372 patients with crush syndorme caused by the HanshinAwafi earthquake. Journal of Trauma-Injurey Infection & Critical Care
1997;42(3):470-5.
• Significant correlation between CK levels and number
of limbs crushed
• CK > 75 000 U/L higher rate of ARF and mortality (84%
vs. 39%, p<0.01, and 4% vs. 17%)
Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Ardch Intern
Med 1988;148(7):1553-7.
• Peak serum CK >16 000 U/L highest risk of ARF and
death
• 90% of pts had peak CK level within 24 hours
RHABDO
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By definition: is the liberation of components of injured
skeletal muscle into circulation
Direct compression of muscle leading to local crush
injury
Don’t forget vascular causes – thrombus, embolus,
traumatic interruption or external compression
Tissue pressure > capillary perfusion pressure
With relief of compression – re-perfusion of muscle
Fundamental pathophysiology is ischemia followed by reperfusion
RHABDO
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Other etiologies:
• Direct compression (ischemia/re-perfusion)
• Multi-trauma
• Prolonged immobility
• Seizures
• Lightning strike
• Vascular compromise
• Steroids
• Neuromuscular blockade
• Congenital enzyme disorders
• Prolonged exercise
• Soft tissue infections
RHABDO
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Muscle compression leads to mechanical stress
Opens stretch reactive channels that allow influx of fluid
and lytes into cell (including Na+ and Ca++)
Cells swell and intra-cellular Ca++ rises
• Causes increased activity of proteases and
degradation of myofibrillar proteins
• Ca++ dependant phosphorylases are activated and
cell membranes degraded
• ATP production lowered b/c anaerobic not aerobic
Neutrophil migration into cells and release of proteolytic
enzymes and free radicals
• Causes micro-vascular vasoconstriction and
worsening ischemia
PATHOPHYSIOLOGY
RHABDO
Cell membrane function is impaired
 Further influx of Na+ and Ca++
 Water follows Na+ into cell causing edema and finally
complete lysis of cell releasing contents into circulation
 Large volumes of intra-vascular fluid sequestered in
injured extremities
 Hypovolemia 1st manifestation of crush syndrome
Bywaters and Popjak Experimental crushing injury: peripheral circulatory
collapse and other effects of muscle necrosis in the rabbit. Surg
Gynecol Obstet 1942;75:612-27.
• showed ischemia in animal limbs using a touniquet
• injury was tolerated by the animals without causing
hypovolemia and systemic effects until reperfusion
• Rabbits then died of hypovolemic shock
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RHABDO
Oda et al. Analysis of 372 patients with crush syndrome caused by the HanshinAwaji earthquake. Journal of Trauma-Injury Infection & Critical Care
1997;42(3):470-5.
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35 deaths out of 372 crush syndrome victims
23/35 (66%) cause of death was hypovolemic shock
Most common cause of death in first 4 days
Additionally to hypovolemia
• Subject to large toxin load
• May develop life-threatening electrolyte abnormalities
RHABDO
Agent
Effect
Potassium
Hyperkalemia
cardiotoxicity, provoked by
hypocalcemia and hypovolemia
Phosphate
Hyperphosphatemia
worsening of hypocalcemia,
and metastatic calcification
Organic acids
Metabolic acidosis and
aciduria
Myoglobin
Myoglobinuria and
nephrotoxicity
Creatine kinase (CK)
Elevation of serum CK levels
Thromboplastin
Disseminated intravascular
coagulation
RHABDO
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4-33% of pts with rhabdo develop ARF (mortality 3-50%)
Three main mechanisms
• Decreased renal perfusion
• Cast formation with tubule obstruction
• Direct toxic effect of myoglobin
RHABDO
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Decreased renal perfusion
• From hypotension
• Renin-angiotensin
• Myoglobin causes release of endothelins
• Decrease GFR by vasoconstriction of af and ef
arterioles
• Rat model showed giving bosentan (endothelin-R
antagonist prevent ARF, no human trials)
RHABDO
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Myoglobinemia and subsequent myoglobinuria
• Respiratory pigment comprising 1-3% of wet weight of
skeletal muscle
• Single heme group in centre
• Low circulating levels easily bound by haptoglobin
and cleared by reticuloendothelial system
• At elevated levels binding capacity is saturated – free
myoglobin levels rise
• Plasma levels >0.5 to 1.5 mg/dL filtered by KD –
measurable in urine (dipstick +ve RBC/microscopy 0
RBC)
• Myoglobin is not reabsorbed in the tubueles
• H20 reabsorbed as pt is hypovolemic
• Results in dark pigmented urine
RHABDO
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Cast formation and tubular obstruction occur in acidic
urine with high myoglobin concentration
Reacts with Tamm-Horsfell protein and ppts forming
casts
Animal models have shown alkaline urine reduces cast
formation
Hypothesis that casts obstruct urine flow in tubules
RHABDO
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Direct toxic effect of myoglobin main component of renal
failure
Increasing evidence of free radical mediated injury
Endogenous renal scavenging agents depleted in
myoglobinuria-induced renal failure
In acidic urine myoglobin dissociated to protein and
ferrihemate
Iron catalyzes the formation of free radicals
This reactivity is decreased in an alkaline environment
Animal model has shown desferrioxamine (chelating
agent) protects vs. renal failure in rhabdo
RHABDO
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Early diagnosis is crucial in pts with rhabdo
Significant soft-tissue injuries or ischemia-reperfusion
injuries are at highest risk
Present often with painful, swollen limbs and should be
observed for compartment syndrome
Phys exam more difficult in the intoxicated, CNS injured
patient
Dark, tea-colored urine dipstick +ve for blood with
absence of RBC on microscopy is suggestive
Cheap screen test is serum CK level
Monitor urine output and do serial CK
RHABDO
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Several studies to predict who’s at risk of progressing to
ARF from crush injuries
Oda et al. Analysis of 372 patients with crush syndorme caused by the HanshinAwafi earthquake. Journal of Trauma-Injurey Infection & Critical Care
1997;42(3):470-5.
• Significant correlation between CK levels and number
of limbs crushed
• CK > 75 000 U/L higher rate of ARF and mortality (84%
vs. 39%, p<0.01, and 4% vs. 17%)
Ward MM. Factors predictive of acute renal failure in rhabdomyolysis. Ardch Intern
Med 1988;148(7):1553-7.
• Peak serum CK >16 000 U/L highest risk of ARF and
death
• 90% of pts had peak CK level within 24 hours
RHABDO
Feinfeld et al. A prospective study of urine and serum myoglobin levels in patients
with acute rhabdomyolysis. Clin Nephrol 1992;38(4):193-5.
• Try to predict ARF with serum/urine myoglobin
• N=8
• 4/5 pts with urine myoglobin >1000 ng/mL developed ARF
• 0/3 pts with urine myoglobin <300 ng/mL
• In this study initial CK was not predictive of development of
ARF
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CK vs. myoglobin measurement:
• CK levels known within 1 hour, easily available, less
expensive (15$ vs. 97$ U.S.)
• Serum and urine myoglobin may take >24 hours
• Myoglobin has faster elimination kinetics
• Time to 50% level for myoglobin 12 hours
• Time to 50% level for CK 42 hours
• Current practice and recommendations are to use CK
RHABDO
Odeh M. The role of reperfusion-induced injury in the pathogenesis of the crush
syndrome. N Engl J Med 1991;324(20):1417-22.
• Early, vigorous fluid resuscitation key to management
• Start therapy in field, even before pt extraction
Better et al. showed early therapy beneficial by comparing two
groups in mass casualty setting
• Building collapse in 1979 and 1982
• N = 15 with roughly same degree of crush injury (~12 hours)
• 1979 – 7 men, no fluid until 6 hours post-injury, then vigorous
fluids (mean of 11 L), all 7 men developed ARF
• 1982 – 7 of 8 men received IV fluid before extraction and
received mannitol/alkaline diuresis within 2 hours, none
developed ARF, one of 8 had delayed therapy and developed
ARF
• No conclusion forced diuresis vs. aggressive fluid therapy
RHABDO
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Several experimental studies have shown mannitol to be
beneficial
Acts as osmotic diuretic, increasing U/O and washout of
tubular myoglobin
May cause volume overload in pts with ongoing ARF and
cardiac dysfunction
Do not start osmotic diuresis until U/O has been
established
In dog models, mannitol diuresis also has beneficial
effects on reducing intra-compartmental pressures
Mannitol also acts as a free-radical scavenger that may
protect KD from oxidant injury
RHABDO
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Alkalinization of the urine with sodium-bicarb supported
by numerous:
• Animal studies
• Case reports
• Retrospective clinical studies
Alkaline environment decreases cast formation and
Moore 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(48):31731-7.
• lessens toxic effects of myoglobin
• Myoglobin induce renal vasoconstriction and
hypoperfusion only occurred at acidic pH
RHABDO
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Ron et al. Prevention of acute renal failure in traumatic rhabdomyolysis. Arch
Intern Med 1984;144(2):277-80
• Large amount of bicarb needed to alkalinize the urine
• Average of 685 mEq of bicarb during first 60 hours of
treatment to have urine pH >6.5
• Pts required acetazolamide to avoid alkalemia
• Average of 1.5 doses of 250 mg to keep plasme pH less than
7.45
Others have argued that large volume crystalloid can cause
sufficient solute diuresis to produce alkaline urine
• Knottenbelt JD. Traumatic rhabdomyolysis from severe beating –
experience of volume diuresis in 200 patients. Journal of Trauma-Injury
Infection & Critical Care 1994;37(2):214-9.
• Knochel FP. Rhabdomyolysis and myoglobinuria. Annu Rev Med
1982;33:435-43.
RHABDO
Homsi et al. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren
Fail 1997;19(2):283-8.
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• Retrospective review of 24 non-random pts
• saline, mannitol, bicarb (group 1) vs. saline (group 2)
• Concluded that mannitol and bicarb were not
necessary
• None of 24 pts developed renal failure
• Low degree of muscle injury (CK = 2750 U/L)
• Not powerful enough to conclusively endorse or
negate use of alkaline diuresis
No Class I evidence to support bicarb
• But in crush injuries can be protective for
hyperkalemia and acidosis
RHABDO
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Experimental stuff:
• Free radical scavengers decrease amount of tissue
necrosis in reperfusion injuries
• Antioxidants – glutathione, Vit E improve renal
function in experimental models
• Desferrioxamine and endothelin-R antagonist
(bosentan) shown to reduce direct toxic effects in
experimental models of ARF
RHABDO
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Daily hemodialysis or continuous hemodialysis to correct
fluid and electrolyte abnormalities
Less fluid shifts and hypotension with continuous
hemodialysis
Hyperkalemia and acidosis – refractive to bicarb and
volume expansion main threats to survival
Hypocalcemia of rhbdomyolysis should not be treated
unless risk of cardiac toxicity from K+
• Infused Ca++ will deposit in injured muscle
• Aggravate rhabdo
• Metastatic calcifications
RHABDO
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Treatment algorithm (not prospectively validated)
• Serum Ck level >20 000 U/L threshold for Tx
• Primary goal to prevent ARF
• U/O goal 200 mL/hour
• Maintain urine pH 6-7
• Keep serum pH <7.5
• Hemodynamic stability and avoid overload
• Bolus of 1 L D5 0.22% NaCl + 100 mEq NaHCO3 over 30
minutes
• Then 2-5 mL/kg per hour
• Bolus 0.5 gm/kg 20% mannitol over 15 minutes
• Then 0.1 gm/kg per hour
• Titrate infusions to u/o of >200mL per hour
• Acetazolamide aids bicarb excretion in urine
• If urine pH <6.0 or serum pH >7.5
RHABDO
RHABDO
RHABDO
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Crush injuries and compartment syndrome are important
causes of acute renal failure
Ischemia-reperfusion is main mechanism of muscle injury
Infusion of fluid before extrication or soon after injury
may lessen the severity of the crush syndrome
Serum CK can be use to screen pts with crush to
determine severity
Restore intra-vascular volume and u/o
Begin forced mannitol-alkaline diuresis
Low threshold for checking compartment pressures
Err on side of early fasciotomy