15
Metabolic and Systemic
Consequences of Acute
Limb Ischemia
Frank Padberg Jr., MD  •  Walter N Durán, PhD
Key Points
• The severe consequences of acute limb
ischemia are considered in three broad
categories: ischemia, reperfusion, and local
effects (compartment syndrome).
Ischemia
• Tissue and organ tolerance for ischemia is
highly variable. The duration and extent
of ischemia are major factors affecting
outcome.
• Prompt restoration of blood flow remains
the most effective intervention to minimize
the deleterious effects of ischemia–
reperfusion injury.
• Innovative experimental approaches
developed to ameliorate the adverse effects
of reperfusion have yet to translate into
clinical practice.
Reperfusion
• Revascularization produces both local
and systemic effects from release of
toxic metabolites and stimulation of
inflammatory mediators.
Acute limb ischemia may result from
arterial trauma, arterial occlusion, throm-
bosis of a previous reconstruction, or
thromboemboli. The magnitude of acute
ischemic injury increases proportionally
with the duration of ischemia and the
mass of tissue affected. The mechanism
of injury in reperfusion involves a series
of events including inadequate oxygen delivery, reduction
in cellular energy stores, accumulation of noxious metabo-
lites, and oxygen-derived free radical injury.1 The release of
toxic metabolic products into the systemic circulation causes
278
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• Continued research into the mechanisms
of microvascular dysfunction may enable
the development of new therapeutic
interventions, which could be administered
at the time of reperfusion. These
investigations focus on the structural
basis of hyperpermeability, knowledge of
endothelial cell function, enhancement of
barrier function in the vascular wall, and
leukocyte interactions.
Local Effects
• A diffuse increase in microvascular
permeability produces the clinical
finding of tissue edema. Reperfusion
edema constrained by a restrictive fascial
envelope results in compartmental
hypertension.
• Compartment syndrome remains primarily
a clinical diagnosis; however, measurement
of compartment pressures may resolve an
indistinct clinical presentation.
• Prompt, thorough fasciotomy decompresses
compartmental hypertension.
remote organ cellular dysfunction, increases in microvascular
permeability, and produces tissue edema. Increased perme-
ability to macromolecules is one of the earliest signs of dys-
function in skeletal muscle. Intravital microscopy techniques
indicate that a significant increase in macromolecular trans-
port occurs during the reperfusion phase.2 The cellular altera-
tions produced by ischemia are exaggerated by reperfusion.
In addition, reperfusion causes new injury due to complex
interactions between the newly reintroduced molecular oxy-
gen and the cellular metabolic state set up by ischemia.
Significant secondary complications such as tissue necrosis,
neuromuscular dysfunction, amputation, sepsis, multisystem
 Chapter 15  Metabolic and Systemic Consequences of Acute Limb Ischemia 279

Table 15-1
SVS/ISCVS Criteria for Limb Viability. Clinical Categories of Acute Limb Ischemia
(Based on SVS/ISCVS Classifcation)
Category Description/Prognosis Sensory Loss Muscle Weakness Arterial Venous

I. Viable Not immediately threatened None None Audible Audible

II.    Threatened
a. Marginally Salvageable if promptly Minimal or none None (Often) inaudible Audible
treated
b. Immediately Salvageable with immediate More than toes; often Mild, moderate (Usually) inaudible Audible
revascularization associated with rest
pain
III. Irreversible Major tissue loss or ­ Profound, anesthetic Profound, paralysis Inaudible Inaudible
permanent nerve damage (rigor)
inevitable

organ failure, and death may follow acute arterial ischemia– is often less clear after an episode of arterial thromboem-
reperfusion (IR) of skeletal muscle.3-5 When the increase in bolism.4,8 Combined arteriovenous injuries are more likely
permeability occurs within a restricted space, progressive to result in tissue edema, especially when associated with
swelling may obstruct venous return, capillary perfusion, and venous occlusion. Coexistent hypotension exacerbates the IR
finally arterial flow. The combined effect produces ischemic injury.
injury to the tissues within that space. This condition, known Edema due to reperfusion of an ischemic extremity may
as compartment syndrome, may be amenable to interventions develop several hours following revascularization; therefore,
including mechanical decompression by fasciotomy or phar- monitoring for compartmental hypertension should be a rou-
macotherapy designed to prevent or reduce tissue edema. tine part of the careful postoperative evaluation.
It may be difficult to distinguish isolated compartment
syndrome from acute limb ischemia. Clinical situations in
CLINICAL SIGNIFICANCE which acute compartmental hypertension may mimic acute
The morbidity and mortality associated with acute limb isch- arterial ischemia are noted in Table 15-2. The most common
emia are significant. The mortality rate for acute limb ischemia nonarterial cause is fracture with secondary hemorrhage
is 9% to 25%.5,6 The major amputation rate is 13% to 25%. within a compartment. Other examples include prolonged
Factors reported to be associated with reduced risk of mortal- compression of a muscular part, which may result from posi-
ity are patient age less than 63 years, heparin administration, tioning for protracted surgery or prolonged immobilization
and percutaneous transluminal angioplasty. Increased risk of
mortality has been associated with embolectomy, amputation,
and fasciotomy.6 In one large review, approximately 10% of
the amputations were performed as the primary procedure for Table 15-2
limbs deemed nonsalvagable. In one small series of patients Causes of Compartment Syndromes
with severe, bilateral limb ischemia and paralysis from acute
aortic occlusion, mortality was 63% with amputation and Decreased compartment Closure of fascial defects
paraplegia present in two of the three survivors.4 volume Application of excessive traction
Patients presenting with acute limb ischemia are classified Increased compartment Bleeding
content Major vascular
into three basic categories corresponding to recommendations coagulation disorder
for management.5,7 The three categories of ischemia—viable, Increased capillary filtration
threatened, and irreversible—are in turn based on the clinical Bites–Reptiles or insects
findings of sensory loss (none to extensive), muscle weakness Ischemia–reperfusion
(none to paralysis, rigor), and presence (or absence) of a pedal Trauma
Intraarterial drug injection
Doppler signal (Table 15-1).5,7 Cold
Effective management of acute limb ischemia and its sequelae Orthopedic injury
may require fasciotomy. A contemporary study based on the Increased capillary pressure
U.S. National Inpatient Sample reported fasciotomy in 4.3% of Acute venous obstruction
limbs coded for acute embolism and thrombosis of the lower Diminished serum osmolarity
Nephrotic syndrome
extremities. Fasciotomy was more common (25%) in a concom- Other causes
itant, retrospective experience at an academic institution. Those Infusion infiltration
requiring fasciotomy were also at greater risk of amputation and Pressure transfusion
death, presumably reflecting more advanced ischemia.6 Muscular hypertrophy
Popliteal cyst
Externally applied Tight casts, dressings, or splints
ETIOLOGY pressure Increased pressure on the
limb due to prolonged
Ischemia followed by restoration of blood flow precipitates immobilization during long
increases in permeability and local edema. The duration of surgical ­procedures or after
­recreational drug use
ischemia can often be assessed accurately after trauma but

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280 SECTION III  Acute Limb Ischemia
after recreational drug use.8-12 A dressing or a cast that is too
tight can cause external pressure. Crush injury and constric-
tion from a circumferential burn eschar can be ­devastating.3
Less common causes of compartment syndrome include
massive soft-tissue swelling following the bite of a poison-
ous snake or insect due to release of toxins, unintentional
extravascular infusion of intravenous fluids or medications,
and iatrogenic compartment syndrome resulting from pro-
longed application of an extremity tourniquet or military
antishock trousers.13 Other unusual causes include phleg-
masia cerulea dolens, malfunctioning pneumatic venous
compression boots, and intraaortic balloon counterpulsa-
tion devices.14-16 Complications related to intraarterial drug
injections include diffuse arterial injury and acute ischemia
from ligation of the infected arterial pseudoaneurysm.10
Common clinical situations involving arterial compro-
mise and associated compartmental hypertension include
thromboembolism, occlusion of arterial reconstructions,
primary arterial thrombosis, thrombosis of an aneurysm,
arterial injuries, and high-velocity injuries with extensive
soft-­tissue damage.4,6,8,17-19
PATHOPHYSIOLOGY
The clinical components of acute limb ischemia may be con-
sidered in three broad categories: ischemia, reperfusion with
its potential systemic effects, and local tissue hypertension.
Some tissues are more susceptible than are others.
Ischemia
The magnitude of the ischemic insult is directly related to
the duration and mass of ischemic tissue, as well as the
severity of hypoperfusion. Skeletal muscle can tolerate
complete ischemia for 4 to 6 hours, after which the injury
becomes irreversible. Studies performed in our labora-
tory using canine models demonstrated that 6 hours of
complete ischemia consistently produced skeletal muscle
necrosis. This was verified in whole-limb preparations
with both tourniquet and multiple ligation–induced isch-
emia and with isolated gracilis muscle preparations.20,21
Following clinical episodes of arterial embolization in
humans, mortality and amputation rates increase when
the ischemia is prolonged for greater than 6 hours.22 When
ischemia is prolonged, the microvasculature loses its integ-
rity and massive increases in permeability may accompany
restoration of arterial perfusion. Systemic hypotension in
the presence of acute limb ischemia amplifies the ischemia
reperfusion injury response in the affected tissues. Isch-
emia, along with reperfusion injury to these tissues, may
result in permanent impairment of function, amputation,
or death.
Reperfusion
The reperfusion phase following ischemia is complex and
may produce both local metabolic abnormalities and a sys-
temic inflammatory response due to the release and acti-
vation of toxic metabolic products. Hemodynamically,
reperfusion is characterized by diffuse hyperemic flow to
the entire extremity.21 Clinically important consequences
include the development of acidosis, hyperkalemia, renal
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failure, acute respiratory insufficiency, arrhythmias, and neu­
romotor dysfunction. Acidosis and hyperkalemia result
from the washout of accumulated byproducts of anaerobic
metabolism. The factors responsible for the development of
IR injury are the toxic metabolites of molecular oxygen such
as superoxide radicals and hydroxyl radicals. The electronic
configurations of these free radicals are highly unstable, and
they react with other molecules to stabilize rapidly; however,
in so doing, they cause structural and functional changes in
cell membranes and organelles, resulting in their disruption.
Many of these reactions result in the further release of free
radicals, which, by themselves, are capable of propagating
this process.23
Specific Tissues: Organs
Studies suggest that the fundamental mechanisms of reperfu-
sion injury are similar in many organs, including the gastro-
intestinal tract, skin, heart, kidneys, and brain. Remote organ
injury, including lungs, kidneys, heart, gastrointestinal tract,
and brain, as a consequence of IR is a major cause of morbid-
ity and even death from multiorgan failure.
Vulnerability to ischemia and reperfusion injury is vari-
able and depends on the organ, the tissue, and the clinical
situation. The brain, kidneys, and bowel are more susceptible
to ischemia reperfusion injury than are the extremities. The
duration of ischemia that can be tolerated by an organ is also
variable; it is as short as 3 to 4 minutes for the brain and as
much as 40 to 60 minutes for the kidneys.
With respect to the extremities, the most sensitive tissues
are the sensory and motor nerves, followed by skeletal muscle,
skin, and bone, which is why a neurosensory deficit is often
the earliest clinical finding, preceding muscular dysfunction.
Bourne and Rorabeck have shown that muscle blood flow
and peroneal nerve conduction velocities decreased propor-
tionately to the duration and magnitude of tissue hyperten-
sion.24 Peroneal nerve conduction was lost with 30 minutes of
complete arterial ischemia.
Local Tissue Hypertension
Increased microvascular permeability promotes local
edema. Arteriolar and capillary flows are the most sensitive
to changes in compartment pressures. Subcutaneous tissues
tolerate uncontrolled edema reasonably well, but when the
edema is contained within a fascial compartment, the pres-
sure soon exceeds the intraluminal pressure of the venules,
resulting in regional venous obstruction. Compartment syn-
drome has been described as a clinical condition in which
increased pressure within a fascial compartment compro-
mises the circulation and function of the tissues within that
space.11
Ashton measured critical, closing pressures in the capil-
laries and found they were 21 and 33 mm Hg in the leg and
the arm, respectively.25 Depending on the situation, com-
partmental pressures as low as 20 to 40 mm Hg may result
in compromised arterial inflow and tissue ischemia. Signifi-
cant nerve damage has been reported when pressures of 30 to
40 mm Hg were present for 6 to 12 hours.12 Early mechani-
cal decompression by fasciotomy is believed to be effective in
minimizing the secondary local complications of compart-
ment syndrome.
 Chapter 15  Metabolic and Systemic Consequences of Acute Limb Ischemia
DIAGNOSIS AND MANAGEMENT
Ischemia
Clinical recognition of the severity of acute limb ischemia
is critical to successful management since timely revascu-
larization is the most effective means of minimizing the
­deleterious effects of injury. Immediate limb viability is not
usually in question when ankle brachial indices or absolute
ankle pressures can be obtained (Society for Vascular Surgery/
International Society for Cardiovascular Surgery category I);
these measurements quantitate the degree of arterial insuffi-
ciency and can be repeated as needed. The threatened limb,
characterized by minimal sensory loss and absence of muscle
weakness (category IIA), is salvageable with prompt revas-
cularization. Associated ischemic pain at rest with mild to
moderate muscle weakness (category IIB) requires immediate
intervention. An anesthetic extremity with muscular paralysis
and absence of a pedal Doppler signal is indicative of profound
ischemia.5,7,10 Depending on the severity of these findings and
the duration of ischemia, such limbs may have sustained irre-
versible ischemia5; the presence of profound limb anesthesia
and muscle rigor suggests irreversible ischemia (category III),
and such patients should not be revascularized. The morbid-
ity and mortality of acute limb ischemia are increased when
ischemia has persisted for more than 6 hours, fasciotomy is
required, or amputation is performed.5,6,22
Early recognition of the extent of ischemia is the first step,
followed by expeditious revascularization. Immediate admin-
istration of heparin is beneficial, but thrombolysis has not
been proven superior to surgical intervention.5,8 Diagnostic
arteriography is advantageous when the clinical evaluation
suggests a problem proximal to the inguinal ligament or the
clavicle but is often unnecessary in traumatic extremity inju-
ries. When time is short or prolonged transport is needed,
temporary bypass using an appropriately sized carotid shunt
is a valuable tool for diminishing the ischemia. This is most
useful in battlefield or trauma surgery.
Reperfusion
Reperfusion after successful revascularization releases toxic
metabolites that have accumulated during the ischemia. The
reperfusion syndrome is characterized by acidosis, hyperka-
lemia, myoglobinuria, renal failure, and refractory dysrhyth-
mias.26,27 The presence of myoglobin in the urine is signaled by
a dark, reddish color; the urine is dipstick positive for hemoglo-
bin, but no red cells are present on microscopy or pigmented
granular casts are noted in the sediment. Urine myoglobin of
more than 20 mg/dl is predictive of acute renal failure.5 Cre-
atinine phosphokinase is a marker of ischemic muscle injury;
half of those patients with creatinine phosphokinase greater
than 5000 U/L also develop acute renal failure.5 Replacement
of intravascular volume helps avoid renal hypoperfusion and
increases parenchymal and tubular flow; in addition, adminis-
tration of intravenous mannitol and alkalinization of the urine
can minimize precipitation of myoglobin in the renal tubules.3
Acidosis and hyperkalemia contribute to myocardial irritability;
specific antiarrhythmic therapy to reduce these sequelae may
be supplemented by infusion of dextrose, insulin, and ­fluids.
Pharmacotherapy aimed at prevention and ­treatment of reper-
fusion-induced injury continues to be actively investigated.
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281
Additional management options include restricted flow resto-
ration, outflow washout, preperfusion agents, and leukocyte
depletion.28-32 However, none of these modalities has yet been
shown to have clinical utility.
Local Tissue Hypertension
The clinical diagnosis of compartmental hypertension may be
quite subtle, since it is normally suggested by various nonspe-
cific clinical findings. As a result, heightened suspicion and
good clinical judgment play large roles in formulating therapy;
objective measurement of intracompartmental pressures may
help determine the need for surgical intervention in patients
with inconclusive findings. The clinical findings of compart-
mental hypertension are often subtle and delayed in onset.
Pain is an early complaint and is often remarkable because it
seems to be out of proportion with the physical findings; how-
ever, its absence may be falsely reassuring in a patient with
spinal cord injury or an altered level of consciousness. Severe
tenderness, paresthesia, paresis, and pain on passive stretch
are signs of compartment syndrome. Unfortunately, all of
these findings are nonspecific. On palpation, the compartment
may feel tense and sometimes even boardlike. Neurological
findings such as hypoesthesia, paresthesia, decreased motor
function, or a combination of these, especially if progressive,
are strongly suggestive of compartment syndrome. The ear-
liest abnormality is often numbness in the dorsal web space
between the first and the second toes; sensory innervation of
this anatomical site is distributed through the lateral anterior
tibial nerve, a branch of the deep peroneal nerve that exits the
anterior compartment. However, in the trauma setting, these
deficits must be differentiated from those due to direct nerve
injury, highlighting the importance of an adequate baseline
neurological examination. Loss of pulses or diminution of
arterial Doppler signals constitutes a late sign of compartmen-
tal hypertension and indicates pathological elevation of com-
partmental pressures in the absence of arterial injury. Changes
in venous Doppler signals in the affected extremity have been
suggested as an early marker since normal venous pressure is
rapidly exceeded as compartmental hypertension progresses;
however, this observation requires further clinical corrobora-
tion and the technique has not been widely adopted.
Ulmer applied probability theory to articles on compart-
ment syndrome to evaluate the reliability of clinical diagnosis.
The four findings evaluated were pain, paresthesias, paresis,
and pain on passive stretch. In general, the sensitivity of clini-
cal findings for the diagnosis of compartment syndrome of
the leg is low (13% to 19%).33 The positive predictive value of
the clinical examination was 11% to 15%, and the specificity
and negative predictive value were both 97% to 98%. These
findings suggest that the clinical features of compartment syn-
drome of the lower leg are more useful by their absence in
excluding the diagnosis than by their presence in confirming
the diagnosis. The probability of compartment syndrome with
one clinical finding was approximately 25% but increased to
93% in the presence of three clinical findings.33
When an at-risk patient complains of pain that is clinically
suspicious of compartment syndrome, the first step should
be to remove all circumferential dressings. If a plaster cast is
­present, it may be split and removed or a window may be cut
for additional evaluation. If the clinical findings are convinc-
ing, complete fasciotomy should be considered. However, if
282 SECTION III  Acute Limb Ischemia

Measurement of compartment pressures: Wick technique Measurement of compartment pressures:

Stryker needle measurement

Heparinized saline

Saline
Transducer
Transducer Pressure
reading

EKG A
CP
Measurement of compartment pressures:
Standard intra-vascular transducer system
Figure 15-1.  Measurement of compartment pressures: wick technique.
Continuous monitoring of tissue pressures can be maintained for as long
as necessary. This may be helpful in the patient who has an evolving OR/ICU monitor
clinical course and whose examination is equivocal.
HR
BP Critical care environment
the diagnosis remains uncertain, determination of compart- CVP
ment pressures may be of value. CP

COMPARTMENTAL DECOMPRESSION
Measurement of Compartment Pressures
Whenever it is impossible to assess sensorimotor function (i.e.,
in patients with altered level of consciousness or spinal cord
injury and in children), measurement of compartment pres-
sures is one of the few methods available to establish or exclude
the diagnosis of compartment syndrome. Feliciano et al.
recommended that compartment pressure measurements be
considered routinely in the susceptible patient.34 Reperfusion
edema may develop insidiously and may not be evident imme-
diately. Continuous or repeated pressure measurements may
be required, in conjunction with repeated clinical evaluations,
when fasciotomy is not performed at the initial procedure.
Several catheters have been used for measurement of intra-
compartmental pressures. Wick or slit catheters (Figure 15-1)
are equally efficacious for continuous monitoring of com-
partment pressures. The Stryker needle (intracompartmental
pressure monitoring system, Stryker Surgical, Kalamazoo,
Michigan; Figure 15-2A) is a portable instrument that allows
single-puncture measurement of compartment pressure at
the bedside and is currently the most popular method in the
North America. However, no special instrument is required
for measuring compartment pressure in the operative or criti-
cal care setting. A standard intravascular transducer system
can be used for one-time determination of tissue pressure;
when flushed between measurements, the same needle and
transducer may be used to probe multiple fascial compart-
ments (Figure 15-2B). A decrease in tissue pressure following
decompression may also be documented.
Indications for Fasciotomy
Fasciotomy should be performed whenever firm clinical
evidence exists of compartment syndrome. However, since
the clinical findings are often nonspecific, compartment
Transducer
18G
needle
IV
tubing
3-way
B stopcock
Figure 15-2.  Measurement of compartment pressures. A, The Stryker
is a portable instrument that allows single-puncture measurement of
compartment pressures at the bedside. B, The standard intravascu-
lar transducer system may be used to determine tissue pressures at a
given time, and the same needle may be used to probe multiple fascial
­compartments.
pressure measurements should be considered in equivo-
cal cases to aid in clinical decision making. In the final
analysis, the decision to proceed with fasciotomy remains
controversial and must be based on clinical judgment and
experience.
Based on experimental work, decompressive fasciotomy
is recommended when intracompartmental pressure exceeds
30 to 45 mm Hg. Unfortunately, no specific threshold pres-
sure exists at which compartment syndrome occurs. Matsen
et al. demonstrated uniform damage when tissue pressures
have exceeded these values,35 but compartment syndrome can
occur at pressures as low as 20 to 30 mm Hg. The duration of
the compartmental hypertension, the systemic hemodynam-
ics of the patient, and the presence or absence of coexisting

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 Chapter 15  Metabolic and Systemic Consequences of Acute Limb Ischemia 283

peripheral vascular disease are among the factors that may

lower the threshold for performing decompressive fasciotomy. Anterior compartmental syndrome of the leg
Heppenstall et al. emphasized the concept of compartmen-
tal perfusion pressure (CPP), defined as the mean systemic Tibialis anterior Deep peroneal Extensor hallucis
arterial pressure minus the compartmental pressure.36 An muscle nerve longus muscle
increasing compartmental pressure with coexistent systemic
hypotension can rapidly reduce the CPP to zero. Compart-
ment syndrome is seen often when the difference between the Extensor
mean arterial pressure and the pressure in the involved com- digitorum
partment is less than 40 mm Hg; blood flow ceases when the longus
CPP is 25 mm Hg or less.37 muscle

COMMON LOCATIONS
AND MANAGEMENT
The forearm and the lower leg are the usual locations for com-
partment syndrome. However, the alert clinician is aware of its
occurrence at less common sites such as the hand or the foot or
even less commonly the shoulder, the upper arm, the buttock,
Symptoms and signs
or the thigh. These unusual sites are more typically involved
• Weakness of toe extension and foot dorsiflexion
when there has been prolonged inadvertent compression of
• Pain on passive toe flexion and foot plantar flexion
muscle groups, such as when an unattended subject remains
• Hypesthesia in the dorsal first web space
collapsed after a stroke or drug overdose. The compression is
• Tenseness of the anterior compartmental fascia
relieved when the affected extremity is moved and reperfusion A
commences. Compartment syndrome may be more common
in the forearm and leg because the musculature is constrained Deep posterior compartmental syndrome of the leg
by firm, well-defined fascial boundaries in a relatively limited
anatomical space. Posterior tibial Flexor digitorum Tibialis posterior
nerve longus muscle muscle

Operative Treatment Flexor hallucis

longus muscle
Mechanical decompression of established compartmental
hypertension is achieved by the release of skin and fascia by
incision. When a tense firm fascia is incised in the limb with
compartmental hypertension, muscles bulge into the opera-
tive field, change color from pale to dusky to bright red, and
become soft and pliable.

LOWER EXTREMITY
Compartment syndrome may involve all four compartments
of the leg. The anterior tibial compartment is most likely to be
involved (Figure 15-3A) but significant damage is most common
in the deep posterior compartment (Figure 15-3B).12 The likeli-
hood of compartment syndrome is increased after combined Symptoms and signs
arterial and venous injury, as opposed to isolated arterial or • Weakness of toe flexion and foot inversion
venous injury. Once recognized, immediate fasciotomy is indi- • Pain on passive toe extension and foot eversion
cated for decompression of the muscle compartment to prevent • Hypesthesia of the plantar aspect of the foot and toes
tissue necrosis and irreversible loss of neuromuscular function. • Tenseness of the deep posterior compartmental fascia
B (between the tibia and Achilles tendon)

Anatomical Considerations
A major nerve traverses each of the four compartments of the
leg (Figure 15-4), the identification of which is important in
localizing symptoms. Knowledge of their anatomical course is
useful in performing successful uncomplicated fasciotomy. The
deep peroneal nerve arises from the common peroneal nerve
and traverses the anterior compartment to exit as the anterior
tibial nerve. It carries sensory innervation to the ­ dorsum of
the foot in the first web space and motor fibers to the fore-
foot extensors. The superficial peroneal nerve also arises from
Figure 15-3.  Compartmental syndromes of the leg. A, Anterior compart-
mental syndrome of the leg. The anterior compartment contains the deep
peroneal nerve (DPN), along with three muscles: tibialis anterior (TA),
extensor hallucis longus (EHL), and extensor digitorum longus (EDL).
B, Deep posterior compartmental syndrome of the leg. The deep pos-
terior compartment contains the posterior tibial nerve (PTN), as well as
three muscles: tibialis posterior (TP), flexor hallucis longus (FHL), and
flexor digitorum longus (FDL).

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284 SECTION III  Acute Limb Ischemia
The four compartments of the leg
Sural Posterior
nerve tibial nerve
SPC DPC
LC AC
Superficial Deep
peroneal peroneal
nerve nerve
Figure 15-4.  The four compartments of the leg. Anterior compartment
(AC), lateral compartment (LC), superficial posterior compartment (SPC),
and deep posterior compartment (DPC).
the common peroneal nerve and exits the lateral compartment
midleg; it provides sensory innervation to the medial great toe
and the second, third, and fourth dorsal web spaces. This nerve
is identified during fasciotomy to prevent injury. The posterior
tibial nerve forms the nerve of the deep posterior compartment
and is responsible for plantar sensation and toe flexion. The
superficial posterior compartment contains the gastrocnemius
and soleus muscles and is traversed by the sural nerve that pro-
vides sensory input to the lateral aspect of the foot.
Fasciotomy of the Leg
Three techniques of four-compartment fasciotomy are com-
monly discussed for decompression of the leg:
• Dual-incision fasciotomy
• Single-incision fasciotomy
• Lateral or fibulectomy fasciotomy
Dual-Incision Fasciotomy
We prefer dual-incision, four-compartment fasciotomy to
ensure complete skin and fascial decompression of all com-
partments (Figure 15-5). The temptation is to spare the length
of the skin incision in the hope of avoiding the need for sub-
sequent skin grafting; however, inadequate fasciotomy is most
often the result of inadequate skin or fascial incisions. The ini-
tial incision includes skin and subcutaneous tissue down to
the fascia. The lateral and anterior fasciotomy is then started
in the midportion of the leg over the junction of the anterior
and lateral compartments, with particular attention paid to
the identification and preservation of the superficial pero-
neal nerve that exits the fascia at the level of the midleg. The
­fascia is incised from the extensor retinaculum at the ankle
to just below the fibular head using a long, blunt-tipped scis-
sor. The medial fasciotomy begins in the middle third of the
leg. The saphenous vein is retracted anteriorly, and the super-
ficial posterior compartment is incised. The deep posterior
­compartment is opened posteromedially, where the superficial
posterior muscles form the Achilles’ tendon and the avascular
plane of the posterior intermuscular septum is incised.
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Single-Incision Fasciotomy
Single-incision four-compartment fasciotomy begins laterally
over the posterior fibular border from just below the fibular
head to 4 cm above the malleolus (Figure 15-6). Anterior and
posterior skin flaps are raised, and longitudinal incisions are
made in the anterior, lateral, and superficial posterior com-
partments. Retracting the muscles of the lateral compartment
anteriorly, the attachment of the soleus to the posterior fibula
aids identification and incision of the deep posterior compart-
ment. Care must be taken to avoid injury to the peroneal and
posterior tibial neurovascular bundles, which are located adja-
cent and medial to the fibula. Some authors have expressed
difficulty with this approach when severe disruption of tis-
sue planes occurs. In addition, tibial fracture management is
difficult through this incision.
Fibulectomy Fasciotomy
Fibulectomy fasciotomy achieves decompression of the pos-
terior and anterior compartments through fibulectomy via
the periosteal bed. Fibulectomy must not include the fibular
head or the distal 8 cm of the fibula to minimize deformity
and to maintain stability of the ankle. Removal of the fibula
requires considerably more dissection than the other methods
and destabilizes the limb if the tibia is fractured. In addition,
free tissue transfer techniques based on the fibula are no lon-
ger available after its excision. Since equivalent decompression
is achieved with the single- and dual-incision techniques, this
procedure has not gained widespread acceptance.
Fasciotomy of the Thigh and Buttock
Thigh and gluteal compartment syndromes are rare and sel-
dom recognized. They occur most commonly in individuals
with altered mental status who remain in one position for an
extended period following drug or alcohol use. The physiology
and manifestations are similar to those seen in the more com-
mon and readily recognized compartment syndromes of the
lower leg. Diagnosis is often delayed, resulting in significant
morbidity and possible mortality. The mainstay of treatment
consists of fasciotomy and debridement.
Decompression of the anterior and posterior compart-
ments of the thigh may be accomplished with full-length inci-
sions. The gluteus is easily decompressed through longitudinal
cutaneous incisions. Individual epimysial envelopes may also
require separate incisions for decompression.
upper extremity
Fasciotomy of the Upper Extremity
Compartment syndromes in the upper extremity are uncom-
mon and difficult to diagnose. Intracompartmental pressure
measurements may help confirm the diagnosis. In addition to
acute disruption of arterial flow, compartment syndrome in the
upper extremities should be suspected in patients with supracon-
dylar fracture, fractures of the forearm, brachial artery puncture,
­subfascial intravenous infiltrations, crush injuries, extremity
replantations, and gunshot wounds. The deep volar compartment
of the forearm is most vulnerable as it is supplied by the anterior
interosseous artery, which has no significant collateral flow.
 Chapter 15  Metabolic and Systemic Consequences of Acute Limb Ischemia 285

Dual-incision fasciotomy

Patella
Great
Patella saphenous
Fibula head
vein
Common peroneal
nerve

Soleus
muscle
Superficial
peroneal
nerve
Fasciotomy
incisions
Fasciotomy
incisions
Lateral
malleolus Medial malleolus

A Lateral fasciotomy C Medial fasciotomy

Interosseous
Fasciotomy membrane Superficial
Anterior incisions peroneal
compartment Saphenous nerve
vein and nerve
Anterior tibial
artery, vein
and deep Superficial
Fasciotomy
peroneal nerve peroneal
incisions
nerve
Saphenous
vein and nerve Lateral
compartment
Posterior tibial Deep posterior
artery, vein compartment
and nerve Fibula Fibula
Superficial
posterior
Peroneal Interosseous compartment Peroneal
artery membrane artery
Posterior tibial artery,
B D vein, and nerve

Figure 15-5.  Dual-incision fasciotomy. The longitudinal incisions are illustrated in the top figures (A, C); the level of the cross-sections (B, D) are indi­
cated with a dotted horizontal line. A, B, The anterior and lateral compartments are decompressed by longitudinal fascial incisions beneath a lateral skin
incision. The superficial peroneal nerve exits the fascia close to the skin incision. C, D, The superficial and deep posterior compartments are decom-
pressed through longitudinal incisions on the medial aspect of the leg. The greater saphenous vein and nerve are preserved and retracted anteriorly.

Technique of Fasciotomy predominantly located on the volar aspect. Decompressive

Fasciotomy is performed through the incisions outlined in
Figure 15-7. Typically, a dorsal incision and a volar incision
are required to decompress the forearm. A curvilinear volar
incision allows release of the flexor compartment. The course
of the incision may be altered to accommodate preexisting
traumatic wounds. In the forearm, the muscles at risk are
fasciotomy should relieve the median ulnar and radial nerves
and the thumb and finger muscles (Figure 15-8). Although
volar release is usually sufficient, dorsal incisions may also be
needed. Intraoperative compartmental pressure measurement
may be valuable in determining the need for a dorsal inci-
sion. A longitudinal incision provides release to the extensor
compartment. In severe cases, the deep intramuscular fascia

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286 SECTION III  Acute Limb Ischemia

Parafibular fasciotomy (single incision fasciotomy) Incisions for forearm fasciotomy

LC

LC AC

Superficial
C peroneal nerve Figure 15-7.  Incisions for forearm fasciotomy.

Cross-section of the forearm

Superficial Radial Median Ulnar Ulnar

branch of artery nerve artery nerve
radial nerve

D SPC

E DPC

Figure 15-6.  Parafibular fasciotomy (single-incision fasciotomy). A, The

skin incision runs along the fibula. B, The lateral compartment (LC) lies
just under the skin. C, The anterior compartment (AC) is exposed by
retracting the anterior skin flap. D, The superficial posterior compart- Anterior interosseous Interosseous Posterior interosseous
ment (SPC) is exposed by retracting the posterior skin flap. E, The deep artery and nerve membrane nerve (deep branch
posterior compartment (DPC) is exposed by retracting the lateral com- of radial)
partment anteriorly and the superficial posterior compartment posteri-
orly and then dividing the fibular attachments of the soleus. Figure 15-8.  Cross-section of the forearm.

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 Chapter 15  Metabolic and Systemic Consequences of Acute Limb Ischemia
enveloping the flexor digitorum superficialis, the flexor digi-
torum profundus, and the flexor pollicis longus may have to
be opened as well. The thick transcarpal ligament is divided
distally to perform a carpal tunnel release. The proximal inci-
sion should release the lacertus fibrosus to decompress the
median nerve at the elbow.
CONTRAINDICATIONS
TO REVASCULARIZATION
AND COMPLICATIONS
In cases of prolonged and advanced ischemia, tissue necro-
sis may have already occurred and revascularization may be
contraindicated. Ascertaining the extent of preexisting tissue
damage is one of the most difficult decisions for the surgeon,
especially in moribund patients with acute ischemia, who can
neither provide a history nor cooperate with the clinical exam-
ination. For the patient with a painful, immobile, insensate
extremity, functional recovery may be limited by neuropathic
pain, weakness, contracture, and loss of protective sensation.
Reperfusion following reconstruction, fasciotomy, or both
may result in the release of toxic metabolites into the systemic
circulation, resulting in myoglobinuric renal failure, systemic
inflammatory response syndrome, sepsis, shock, multisystem
organ failure, and death. All of these effects are exaggerated in
a patient with concomitant hypotension.
The decision to proceed with revascularization and fasciot-
omy rather than primary amputation is based primarily on the
severity of the clinical findings, the duration of ischemia, and
the muscle mass involved in the ischemic insult. If the dura-
tion of profound limb ischemia is more than 6 to 12 hours, the
likelihood of tissue salvage becomes small and the risk of com-
plications following revascularization increases significantly.
However, systemic effects of IR are less pronounced when less
tissue has been subjected to the ischemic insult. Thus, time is
not the sole determinant in the decision-making process. The
experienced clinician must individualize therapy according to
the specific circumstances of each patient.
Fasciotomy incisions may create new issues related to
wound healing in a patient with preexisting chronic peripheral
vascular disease. Thus, comorbidies predispose the patient to
additional complications such as conversion of closed to open
fractures, osteomyelitis, delayed wound closure, wound sepsis,
bleeding, and cosmetic deformity. Reasons for perceived fail-
ure of fasciotomy may relate to associated profound ischemia,
delay in fascial decompression, incomplete fasciotomy, and
errors in technique. Following successful revascularization,
most patients experience few problems with wound healing;
however, additional operations for split thickness skin grafts
or closure by direct suture may be required.
MECHANISMS OF MICROVASCULAR
DYSFUNCTION AFTER IR
Increased Microvascular Permeability
The microcirculation represents the first barrier in IR injury
in all tissues and may be a useful target for therapeutic
interventions. Increased permeability to macromolecules,
stimulated adhesion and emigration of leukocytes, and no-
reflow ­phenomenon are characteristic responses of ischemic
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287
microvessels. One of the key concepts of the structural basis
of increased microvascular permeability relates to widening of
the intercellular gap junctions due to endothelial cell contrac-
tion.38 The postcapillary venules are the main site of hyperper-
meability induced by inflammatory mediators as studied by
electron and fluorescence microscopy.39 These microvessels
are also responsible for the permeability alterations in IR.
The signaling pathways for inflammatory agents that cause
hyperpermeability involve the activation of protein kinase C,
activation of nitric oxide (NO) synthetase, and synthesis of
NO.40-45 Reports are consistent with the hypothesis that endo-
thelial NO synthetase activity and release of NO result in acti-
vation of soluble guanyl cyclase and synthesis of guanosine
3′,5′-cyclic monophosphate.46 Guanosine 3′,5′-cyclic mono-
phosphate activates the mitogen-activated protein kinases
p42/44, which are important in the regulation of baseline,
as well as agonist-induced, permeability.47 The final step in
the sequence of molecular modifications appears to involve
proteins located at the cell junctional–cytoskeletal complex.
Studies performed mainly in tissue culture have identified
vascular endothelial–cadherin and β-catenins as possible key
molecules. Phosphorylation induced by mitogen-activated
protein kinase and disorganization of the vascular endothelial–
cadherin may result in structural changes in the cellular
cytoskeleton and hyperpermeability.48
Hyperpermeability, a hallmark of inflammation, is among
the important initial events in the microvascular response to
IR. Knowledge of the dynamics of this fundamental process
and the development of adequate therapies has focused on
investigating how to prevent the onset and the maintenance of
the elevated permeability. Thus, we have learned much about
how to counteract or inhibit the action of specific agents that
elevate permeability. Less effort has been devoted to under-
standing the mechanisms that normally enhance the barrier
properties of the microvascular wall, knowledge that once
acquired might be applied to prevent or terminate excessive
increases in microvascular permeability.
Endothelial Cell and Vascular Wall
Interactions
The xanthine oxidase–containing microvascular endothe-
lial cells, along with the neutrophils, are the most probable
sources of oxygen-derived free radicals. Ischemia activates a
calcium-dependent protease that catalyzes the conversion of
xanthine dehydrogenase to its oxidase form. As ischemia con-
tinues, adenosine triphosphate is degraded to hypoxanthine,
which is then converted to uric acid by xanthine oxidase with
the production of superoxide anion. Superoxide dismutase
converts superoxide anion to hydrogen peroxide, which in the
presence of ferric ion produces the hydroxyl radical, a highly
toxic oxidant. Support for the role of oxygen-derived free rad-
icals in the microvascular dysfunction associated with IR1,29
comes from the observed efficacy of free radical scavengers
in the reduction of the indices of IR-induced microvascular
dysfunction to about half of their unopposed values.
NO, derived from L-arginine, is produced by vascular
and perivascular cells and has been implicated in IR-induced
microvascular dysfunction. It may serve as an antiadhe-
sive substance to protect the endothelium against leukocyte
­adherence.49 In addition, the uncoupling of NO and forma-
tion of peroxynitrite (ONOO−), a powerful reactive oxygen
288 SECTION III  Acute Limb Ischemia
metabolite, leads to formation of hydroxyl radicals.50 Per-
oxynitrite, the reaction product of superoxide and NO, is
potentially more harmful than either superoxide or hydroxyl
radical due to its longer half-life.
Endothelial cells are involved in the control of blood flow,
microvascular permeability, vessel contractility, angiogenesis,
coagulation, leukocyte traffic, and immunity. These endo-
thelial functions are exquisitely modulated by endogenous
and exogenous factors. Deviations from the normal balance
because of a deficiency or an excess of the regulatory factors
may lead to pathological states. Thus, a better understanding
of the endothelial pathophysiological mechanisms involved in
IR may provide opportunities for successful clinical interven-
tions. Most research on IR and inflammation has focused on
prevention of hyperpermeability and on modulation or control
of proinflammatory agents that increase basal permeability.
Much less attention has been given to elements that would
normally contribute to the maintenance of the integrity of the
microvascular wall and that would enhance its barrier proper-
ties. Based on the premise that knowing how hyperpermeabil-
ity signals are terminated is just as important as understanding
how they are generated, it seems important to foster advances
in signaling processes that are aimed at maintaining the barrier
properties of the microvascular wall and should contribute to
inactivation of the inflammatory increase in permeability and
return the barrier properties of the microvascular wall to base-
line levels after IR.
Recent advances in cell research have provided a solid
framework to consider cyclic adenosine monophosphate
(cAMP) as an important second messenger in regulating and
promoting cell adhesion and, by extension, the integrity of the
microvascular barrier. cAMP is produced by adenyl cyclases
and is a pleiotropic-signaling second messenger. The classical
view has been that most, if not all, actions of cAMP proceed by
activation of protein kinase A and are terminated by phospho-
diesterase 4–catalyzed degradation. This view has been signifi-
cantly changed since the recent discovery of Epac, an exchange
protein activated by cAMP,51 which is a guanine nucleotide
exchange factor and responds with specificity to activation by
cAMP.52
Specific stimulation of Epac–Rap1 enhances the endothe-
lial barrier properties in human umbilical vein endothelial
cells,53,54 a process involving formation and tightening of cell
junctions through vascular endothelial–cadherin.55 Prostacy-
clin and forskolin, which enhance cAMP production, induced
cortical actin rearrangement in a Rap1-dependent manner
and decreased permeability in human umbilical vein endo-
thelial cells.54 These findings provide a subcellular explanation
for a report that iloprost, a prostacyclin analogue, reduced the
impact of IR on hyperpermeability in striated muscle.56,57
Current management of acute limb ischemia is based on
the restoration of blood flow to the ischemic extremity as
rapidly as possible to reduce the degree of ischemic injury.
Superimposed on this algorithm is the use of pharmacologi-
cal agents and nonpharmacological methods for reducing IR
injury. These algorithms respond to the double jeopardy fac-
ing the vascular surgeon—namely, that unattended ischemia
leads to necrosis, making prompt restoration of blood flow a
must, but reperfusion compounds the problem, and its con-
sequences (including compartment syndrome) may interfere
significantly with survival of the organ and the patient. Stud-
ies advancing knowledge of the mechanisms that maintain
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the vascular wall barrier properties will be clinically relevant
as they contribute an approach that will allow vascular sur-
geons to implement a directed and timed enhancement of the
barrier properties of the microvascular wall.
LEUKOCYTES
After a period of controversial reports, it now seems estab-
lished that hyperpermeability in response to an inflammatory
challenge is regulated by endothelial cells, mainly through
endothelial NO synthase.41,44,58 Endothelial NO synthetase–
modulated processes are orchestrated in synchrony with cell
contraction and junctional reorganization induced by poly-
morphonuclear leukocytes.59-61 Support for the involvement
of leukocytes in IR comes from experiments in which either
the animal or the experimental muscle has been rendered leu-
kopenic by radiation, chemical, or physical means.62,63 Leuko-
penia decreases the impact of IR on changes in microvascular
permeability by reducing the increase in transport of macro-
molecules from a sevenfold down to a twofold increase com-
pared to that obtained in the untreated ischemic muscle.62,64
nicotinamide adenine dinucleotide phosphate (reduced form)
oxidase (NADPH oxidase), within the leukocytes, converts
cytoplasmic NADPH to nicotinamide adenine dinucleotide
phosphate (oxidized form), resulting in the formation of
superoxide anion and hydrogen peroxide, with subsequent
release of hydroxyl radicals. Leukocytes also possess myelo-
peroxidase, an enzyme that catalyzes a reaction between
hydrogen peroxide and chloride to form hypochlorous acid,
a powerful oxidant. Levels of myeloperoxidase have been
found to remain constant during ischemia and to increase at
15 minutes and 1 hour of reperfusion.65 In addition, activated
neutrophils release elastase, collagenase, and cathepsin G,
substances that are able to degrade microvascular basement
membrane and lead to increases in permeability and cellular
dysfunction.
OTHER CHEMICAL MEDIATORS
AND SIGNALING MOLECULES
Calcium ions modulate the activity of leukocytes, as well as the
contractile properties of endothelial cells, and play an impor-
tant role in the pathophysiology of skeletal muscle IR injury
and associated microvascular injury.65 Thromboxane A2 has
been implicated in causing microvascular alterations in the
lung following reperfusion of ischemic canine hindleg.63
Platelet-activating factor is a vasoconstrictor, a strong pro-
moter of microvascular permeability, and a powerful neutro-
phil chemoattractant.66 The possibility that hydrogen peroxide
may be the stimulus for platelet-activating factor synthesis in
IR is indirectly supported by experiments in which human
recombinant superoxide dismutase administered intrave-
nously caused a 30% decrease in neutrophil adherence.67
PREVENTIVE STRATEGIES
What can be done to protect organs and tissues from the
effects of ischemia and reperfusion injury? Early operation
and revascularization decrease ischemic time, temporary
bypass shunts maintain tissue perfusion, and oxygenation and
tissue cooling may be used to decrease metabolic demands.
 Chapter 15  Metabolic and Systemic Consequences of Acute Limb Ischemia
In elective ischemic events such as transplantation, tissue pres-
ervation can be enhanced by preischemic interventions. How-
ever, with acute limb ischemia, additional opportunities only
present themselves during management of the reperfusion
phase. Hypothermic and controlled reperfusion can reduce
edema and necrosis.68 The clinical applicability of biochemical
interventions designed to reduce reperfusion-induced injury
in end organs remains unproven. Much experimental work
has been done to study pharmacological intervention for the
prevention and treatment of reperfusion-induced injury. The
potential beneficial effects of substances such as verapamil,
mannitol, prostacyclin, monoclonal antibodies, superoxide
dismutase, hetastarch high-molecular-weight carbohydrates,
and heparin continue to be investigated. Many of these agents
have demonstrated benefit in experimental studies that have
not translated into clinical advantages.
Because leukocyte–endothelium interactions play an
important role in bringing about IR damage,63,69 these cells
and their biochemical processes are considered possible tar-
gets for therapeutic interventions. A major aim is to minimize
adhesion of leukocytes to microvascular endothelium.70 Simi-
larly, receptor antagonists to platelet-activating factor, admin-
istered just before reperfusion, effectively inhibit the ability of
the phospholipid to recruit leukocytes to the injured area and
abrogate their adhesion to the microvascular wall.70 Reduc-
tion or elimination of leukocyte adhesion to endothelium
may inhibit the oxidative stress that leads to parenchymal and
cellular dysfunction.
Restriction of calcium in reperfusion, either by using
entry blockers (such as verapamil)64 or by administration of
low calcium–modified solutions, may also be a useful way to
decrease damage in reperfused muscle and to restore contrac-
tile ­function.68
Monoclonal antibodies directed against adhesion molecules
on endothelium, leukocytes, or both also provide effective pro-
tection against immediate IR damage.69 Clinical application
of monoclonal antibodies awaits improvement in their design
that will avoid rendering these critically ill patients immu-
nodeficient for a significant interval after treatment. These
monoclonal antibodies, and specific receptor-blocking agents,
work effectively when administered immediately before reper-
fusion and offer the possibility for development of therapeutic
approaches applicable at the time of revascularization.
SUMMARY
Ischemic tissue injury is the primary cause of morbidity and
mortality from acute interruption of arterial blood flow.
However, the main component of this injury occurs during
reperfusion. Early recognition of the severity of limb ischemia
with prompt restoration of blood flow is an obvious method
for reducing the duration of ischemia. However, intervention
at the time of reperfusion offers a broad additional oppor-
tunity since treatment is initiated when tissue perfusion is
restored. The cascade of events that occurs after successful
revascularization of an ischemic limb may be amenable to
innovative interventions. Current investigations are targeted
at understanding these cellular mechanisms and interactions
to develop new therapeutic measures to diminish the detri-
mental metabolic and systemic consequences of ischemia and
reperfusion. Research directed toward alteration of endo-
thelial function includes reducing permeability, enhancing
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289
­ arrier properties, and discouraging leukocyte adherence to
b
the endothelium.
Since IR injury cannot be well controlled, the alert phy-
sician must remain ever vigilant when faced with the com-
mon clinical settings in which compartmental hypertension
is known to occur. The incidence may be much higher than
reported because some of its late sequelae, including joint
stiffness, claw toes, and equinus deformities, may be quite
subtle. The diagnosis of compartment syndrome is not always
straightforward. However, in clinical practice, its recogni-
tion is often delayed and fasciotomy is performed too late.
Clinicians are advised to err on the side of early fasciotomy to
avoid significant and permanent morbidity. Measurement of
compartment pressures may be useful in equivocal cases or
in sedated or neurologically impaired patients who are diffi-
cult to assess clinically. No substitutes exist for experience and
sound clinical judgment.
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