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vascular system

ACUTE LIMB ISCHEMIA


Jovan N. Markovic, MD, and Cynthia K. Shortell, MD, FACS*
Acute limb ischemia (ALI) is one of the most challenging
conditions in vascular surgery and carries a high risk of
amputation and mortality when treatment is delayed. To
emphasize this, the Trans-Atlantic Inter-Society Consensus
(TASC II) Working Group defined ALI as any sudden
decrease in limb perfusion causing a potential threat to limb
viability.1 The incidence of ALI in the general population is
approximately 1.7 in 10,000 per year.2 Limb ischemia occurs
when there is abrupt interruption of blood supply to an
extremity because of either embolic or in situ thrombotic
arterial or bypass graft occlusion. The severity of symptoms
is directly related to the duration of the hypoperfusion and
the abundance of preexisting collateral circulation; the clinical presentation is often complicated by various comorbid
conditions typically seen in patients with vascular diseases
[see Table 1]. The goals of management include limb salvage,
minimization of morbidity, and prevention of death.
However, given that no objective markers of limb viability
are currently available, the initial determination of whether
a limb is likely to be viable must be made on clinical grounds
by an experienced practitioner with knowledge of the
patients underlying pathophysiology, coexisting comorbidities, and the availability of treatment options.

Table 1 Incidence of Medical Comorbidities in


Patients Presenting with Acute Limb Ischemia155
Incidence (%)

Comorbidity
Cerebrovascular disease

Roches- TOPAS- TOPASter Trial 1 Trial


2 Trial
(N =
(N =
(N =
Total (N
114)
213)
544)
= 871)
NR

15.4

11.5

11.6

Congestive heart failure

NR

15.5

12.5

13.3

Coronary artery disease

56.1

47.1

42.5

45.4

Diabetes mellitus

28.1

36.7

29.0

30.8

Hypercholesterolemia

31.6

29.6

23.5

26.0

Hypertension

63.2

60.9

69.6

60.3

Malignancy

NR

11.9

11.5

11.6

Tobacco history

51.8

79.3

77.5

74.6

NR = not reported; TOPAS = Thrombolysis Or Peripheral Arterial Surgery.

* The authors and editors gratefully acknowledge the contributions of the previous author, Sonny Tucker, MD, and Vicken
N. Pamoukian, MD, FACS, to the development and writing
of this chapter.
Financial disclosure information is located at the end of this chapter
before the references.

2012 Decker Intellectual Properties

A study from the 1970s that comprised more than 3,000


patients with ALI from 35 centers documented a mortality
of 26% and an amputation rate of 37%.3 A decade later,
a Swedish study showed a mortality rate of 20% in 201
patients with acute arterial embolism or thrombosis
treated with thromboembolectomy.4 Since then, substantial
progress in surgical management has been made and major
technological advances have occurred, but morbidity and
mortality remain high, with death rates approximating 15%
and amputation rates ranging from 10 to 30%.5
Given the general frailty of ALI patients and the multiplicity of available therapeutic options, it is prudent to take a
methodical approach to the management of ALI. Making
use of algorithms, decision trees, or clinical pathways can
help the clinician visualize and evaluate multiple potential
options, which then serve as the basis for selecting the path
likely to yield the best outcome.
clinical evaluation

History
An early clinical evaluation is crucial for the diagnosis
and identification of the underlying etiology of the ALI.
A delay in treatment can result in limb loss, significant
morbidity, or death. Because ALI is a clinical diagnosis, a
complete history is essential (unless it is unobtainable
for some reason). Generally, the dominant symptoms are
related to pain (usually the first manifestation) or to loss
of motor or sensory function of the affected extremity. The
onset and duration of symptoms should be determined,
and the location and intensity of any changes should be
established. The pain of ALI is often not well localized and
is unaffected by gravity. An effort should be made to determine whether the likely cause is embolic or thrombotic: pain
of sudden onset suggests an embolic cause, whereas longstanding pain before the acute event suggests a thrombotic
cause [see Etiology of ALI, below].
It is imperative to ask whether the patient experienced
pain before the current ischemic episode and whether the
current episode is the first. The history should elicit the functional status of the affected extremity prior to the ischemic
event. It is also important to ask about previous vascular
procedures (including bypass or endovascular interventions), as well as previous or current cardiac disease (e.g.,
myocardial infarction [MI], atrial fibrillation, or valvular
disease), aneurysmal disease, or vasculitis. Finally, inquiries
should be made about previous atherosclerotic disease,
symptoms of claudication, rest pain, nonhealing ulcers,
current risk factors for atherosclerosis (e.g., hypertension,
smoking, diabetes, tobacco abuse, hyperlipidemia, and
stroke), and previous clotting episodes. The presence of
motor or sensory changes in the affected limb is very important in determining the urgency for revascularization.
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acute limb ischemia 2

The characteristic signs of ALI may be summarized as


the six ps: pulselessness, pain, pallor, poikilothermia,
paresthesia, and paralysis:
1. Pulses should be palpated and documented. Any previous documentation should be noted and used for comparison. The level at which pulses become absent can
predict the site of arterial occlusion. However, fresh clot
has a soft, semiliquid consistency that may allow the
pulse to be transmitted at the level of obstruction. Only
when the thrombus becomes organized and densely
compacted is the pulse lost at the site of occlusion. As an
example, in a patient with obstruction at the popliteal
artery, popliteal pulses remain palpable in the earlier
stages of the process, but distal pulses are lost [see
Table 2]. Intact pulses in the contralateral extremity indicate that an embolic etiology is most likely. Absent pulses
in the contralateral extremity suggest underlying peripheral arterial disease and point to in situ thrombosis.
2. Pain is the most common symptom in an ischemic limb,
and it progresses along with the ischemia. It must be
noted that as ischemia continues to progress, severe pain
can be replaced by anesthesia of the limb, which can confound the examiner. Thus, pain should be documented
with regard to severity, localization, and progression. In
contrast to the rest pain that is limited to the forefoot
(pathognomonic for critical limb ischemia), pain associated with ALI is diffuse throughout the entire affected
extremity. Pain is usually the first symptom of ALI, with
one exception. In acute aortic thrombosis, the first symptom is usually paralysis of the affected extremities rather
than pain. Data from a study that evaluated 31 patients
who underwent embolectomy for acute embolism of the
aortic bifurcation showed that 84% and 14% of patients
with acute aortic occlusion presented with paralysis and
pain, respectively.6 The authors of this study emphasized
that 55% of patients were referred incorrectly to a neurologist to evaluate paresthesia rather than to a vascular
surgeon to treat underlying ALI.
3. Pallor may be seen in the early stages, followed by cyanosis. Pallor develops due to complete empting and/or
vasospasm of arteries. As ischemia progresses, the limb
will appear mottled, and in early stages, mottling blanches
under pressure. Capillary refill on blanching the skin
indicates that the affected limb is still retrievable. In
patients with thrombosis, initial pallor may be followed
by gradual return of skin perfusion and capillary refill
over 6 to 12 hours if collaterals are developed.
4. Poikilothermia may propagate the ischemic cascade
through its vasoconstrictive effects. The level of coolness

Table 2

and pallor is typically one level below the point of occlusion on the arterial tree and should correlate with the
pulses or signals found. As always, baseline documentation should be done so that the progression or resolution
of the process can be tracked.
5. Paresthesia is an essential finding. The earliest sign of
tissue loss is the loss of light touch, two-point discrimination, vibratory perception, and proprioception, especially
in the first dorsal web space of the foot. Proprioception
and light touch sensation are lost early in ALI because
they are conducted by small myelinated neuron fibers,
whereas larger sensory nerves responsible for temperature, pain, and pressure are maintained unless ischemia
is prolonged.
6. Paralysis, if present, is an indication of advanced limbthreatening ischemia. The extent of paralysis must be
determined. The intrinsic muscles of the foot are affected
by ischemia of the vessels around the ankle. Dorsiflexion
and plantar flexion of the foot are functions of muscles
that rely on blood supplied by the popliteal and superficial femoral arteries. Loss of dorsiflexion and plantar
flexion indicates that blood flow is interrupted at a higher
level and signals that more tissue may be at risk. Once
motor function is lost, limb salvage is more challenging.
At this stage, skin mottling is more prominent and nonblanching, representing nonreversible ischemic changes.

Staging of Limb Ischemia


The primary goal of the clinical evaluation is to determine
the severity of the disease process so that appropriate
management can be rapidly instituted. To this end, the key
question that must be answered is whether the limb is
viable. Based on a classification system initially proposed
by Rutherford and colleagues7 in 1997 the Joint Council of
the Society for Vascular Surgery and the North American
Chapter of the International Society for Cardiovascular
Surgery developed reporting standards for ALI and stratified it into three distinct categories on the basis of the severity of the disease process: category I (viable), category II
(threatened: marginally and immediately), and category III
(irreversible) [see Table 3].8 This staging strategy was also
featured in both the TASC I and TASC II documents on
peripheral arterial disease.1,9
Staging of ALI is based on the clinical assessment of motor
and sensory function of the affected limb combined with
interrogation of ankle arterial flow velocity signals (as well
as venous sounds for category III) using a handheld Doppler
ultrasound unit. Terminology in this classification system
was used not only to characterize the degree of ischemia but

Localization of Arterial Obstruction through Palpation of Peripheral Pulses164

Palpable Pulses
Femoral

Popliteal

Pedal

Aortoiliac segment

Location of Obstruction

Femoral segment

Thrombosis, femoral atherosclerosis; common femoral embolus

++

Distal popliteal tibials

Popliteal aneurysm with embolization

Distal popliteal tibials

Popliteal embolus; popliteal/tibial atherosclerosis, diabetes

= no palpable pulse; + = detectable pulse; ++ = bounding pulse.

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Possible Causes
Aortoiliac atherosclerosis; embolus to common iliac bifurcation

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acute limb ischemia 3

Table 3 Clinical Categorization of Acute Limb Ischemia8


Findings
Category

Description/Prognosis

Doppler Signals

Sensory Loss

Muscle Weakness

Arterial

Venous

I. Viable

Not immediately threatened

None

None

Audible

Audible

IIa. Marginally
threatened

Salvageable if promptly treated

Minimal (toes) or none

None

(Often) inaudible

Audible

IIb. Immediately
threatened

Salvageable with immediate


revascularization

More than toes,


associated with rest
pain

Mild, moderate

(Usually) inaudible

Audible

III. Irreversible*

Major tissue loss or permanent


nerve damage inevitable

Profound, anesthetic

Profound, paralysis
(rigor)

Inaudible

Inaudible

*When presenting early, category IIb and category III may be difficult to differentiate.

also to predict the need for intervention. In category I


(viable), patients present with acute occlusion of an artery
that is chronically narrowed. Therefore, abundant collaterals
can be found, the limb is viable, and there is no immediate
limb threat. In category II ALI, the ischemic limb is threatened but may be salvaged without the need for an amputation if timely revascularization can be achieved. Category II
is further subdivided into categories IIa and IIb. Category IIa
is named marginally threatened, which implies a mild
to moderate threat to limb viability over time that allows
limb salvage if revascularization is performed soon. Thus,
category IIa includes patients with mild forefoot numbness
or any lesion for which prompt revascularization of the limb
achieves a good result. Category IIb (immediately threatened) includes patients with diminished sensation of the
entire foot and weakness of calf muscles whose limb is still
salvageable but who require immediate revascularization.
In category III (irreversible), ischemia is irreversible, and
amputation is required. Clinical features include permanent
tissue loss, anesthesia, and paralysis of the limb.
In general, in category I, there is no sensory loss and
Doppler signals from ankle arteries are audible. If Doppler
signals from ankle arteries are not audible (and sensory
functions is preserved), ALI is categorized as IIa. In some
patients with IIa stage of the disease, mild sensory loss can
be detected that is limited in extent to the toes. Both categories (I and IIa) have preserved motor function. Category IIb
is characterized by loss of motor function, prompting
immediate revascularization of the affected extremity.
Category III represents a nonviable extremity. In these
patients, major tissue loss and/or permanent neuromuscular damage are inevitable regardless of revascularization
efforts.
investigative studies
Additional diagnostic tests should be performed to
support the clinical evaluation. An electrocardiogram (ECG)
should be obtained, and if a cardiac source is suspected, a
transesophageal echocardiogram should be obtained as well.
A full set of laboratory tests, including a complete blood
count and a platelet count, blood chemistries, and coagulation profiles, should be ordered. In addition, chest and
abdominal x-rays should be done to look for obvious calcifications. If it appears that a hypercoagulable state may be
causing thrombosis, a hypercoagulability profile should

be ordered. As recommended in the TASC II report, a


thrombophilia screen, which includes anticardiolipin and
antiplatelet factor IV antibodies, as well as measurement of
homocysteine levels, should be performed, especially in
young patients with acute thrombosis or in patients with a
significant family history of thrombotic events.1 If, however,
a limb is acutely ischemic and exhibits clear motor or
sensory deficits, diagnostic tests other than an ECG and
basic hematologic and blood chemistry studies should not
be allowed to delay treatment.

Evaluation of Arterial Tree


An objective evaluation of the arterial tree should be
performed when feasible. If ischemia is particularly severe
and long-lasting, a full angiographic evaluation may not be
possible; however, noninvasive duplex studies and, if time
permits, angiography should be considered strongly in this
setting.
Doppler segmental pressures and ankle-brachial index
Evaluation of Doppler segmental pressures should begin
at the level of the ankle and should include assessment of
arterial signals and venous hums. When arterial signals are
found, the ankle-brachial index (ABI) should be measured.
The ABI is derived from the ankle systolic pressure and the
brachial systolic pressure and is determined as follows. The
systolic pressure is measured in each arm, and the higher of
the two measurements is taken to be the brachial systolic
pressure. A cuff is then placed on each calf, and the examiner listens to signals in the dorsalis pedis and posterior
tibial arteries. The cuff is inflated until the signal is no longer
heard. At this point, the cuff is slowly released, and the
systolic pressure is recorded at the point where the signal is
once again audible. Again, the higher of the two systolic
measurements is taken to be the ankle systolic pressure. The
systolic ankle pressure is then divided by the brachial systolic pressure to yield the ABI. Normally, the ABI is greater
than 1.0 because ankle pressures are slightly higher than
arm pressures due to gravity.
However, a normal ABI value does not rule out the presence of arterial occlusion. The ABI can be falsely elevated if
the distal arteries are not compressible. Falsely elevated ABI
can be recorded in diabetic patients, elderly patients, and
patients with renal disease due to incompressible calcified
lower extremity arteries. When the ABI falls below 0.6, there

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is a significant difference in blood pressure between the
proximal arterial tree and the distal extremity, which usually denotes an occlusive process. An ABI lower than 0.5
is seen in patients with critical ischemia. In these patients,
inspection of flow velocity waveform recording the pedal
arteries in conjunction with toe pressure measurement can
be used to determine the presence and degree of ischemia
if the severity of the ischemia is not limb threatening and
allows investigative studies. Next, segmental pressures are
obtained by placing cuffs at the ankle, below the knee, above
the knee, and on the thigh. Systolic blood pressures are
measured at each location, and any pressure drop greater
than 15 mm Hg is considered significant. When the venous
Doppler signal or hum is lost in addition to the arterial
Doppler signal, the ischemia is severe. However, the absence
of signals does not always signify an irreversibly threatened
limb.
Duplex ultrasonography Duplex scanning is a noninvasive imaging modality that can be valuable for localizing
the site of occlusion, especially in bypass grafts. In addition,
duplex ultrasonography has been useful in assessing the
patency of a single arterial segment (i.e., bypass graft or
stented superficial femoral artery). Unfortunately, it is not
always a practical option in acute circumstances, both
because the machine is often unavailable in the emergency
setting and because the results of scanning are highly
operator dependent. However, in specialized centers where
a duplex ultrasound machine is readily available and
personnel are experienced in its use, a quick look at the
suspected site may yield helpful information.10 In stenotic
regions, the velocities measured across the lesion are greatly
increased.11,12 Duplex ultrasonography can also be used to
assess plaque morphology, stenoses, dissections, and thrombi. In some centers, duplex ultrasound technology has obviated the need for lengthy arteriograms and has benefited
patients by reducing ischemia time.
Arteriography Arteriography remains the gold standard for diagnosis of ALI and may even be a primary tool
in its management. An important consideration is whether
the delay in performing arteriography can be tolerated in
patients with limb-threatening ischemia. In general, in
highly specialized centers, patients who require urgent
revascularization are evaluated with catheter-based arteriography in operating room angiosuites because it provides
detailed and accurate information regarding the etiology,
localization, and extent of the lesion as well as adequate
visualization of the distal arterial vascular tree without a
delay in therapy. In contrast, arteriography in formal
angiography suites should be reserved for patients with
viable limbs who can tolerate the additional delay before
revascularization and should not be performed if doing so
would keep a critically ischemic limb from receiving prompt
revascularization.
Arteriography should be performed from a site remote
from the point of concern. Thus, if lytic therapy is to be
administered, entry-site bleeding will be minimized. A
complete angiogram that includes the runoff vessels in the
foot should be performed to establish the baseline degree of
arterial disease and delineate the anatomy of the inflow and

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acute limb ischemia 4


outflow vessels. This information facilitates subsequent
planning for revascularization should this step prove necessary. Although arteriography is considered to be the gold
standard in the management of patients with ALI, this
imaging modality is invasive and exposes patients to both
radiation and potentially nephrotoxic contrast material.
Digital subtraction angiography is preferred in that it
allows a reduced contrast load and lowers the incidence of
contrast-associated renal injury.13,14 If the patient is allergic
to the contrast agent or has renal insufficiency, CO2 or
gadolinium-based angiography may be performed instead.
These two modalities have the advantage of minimizing
nephrotoxicity but yield poorer suprainguinal arterial visualization compared with standard contrast angiography.15,16
Arteriography may help differentiate embolic from
thrombotic arterial occlusion and direct proper surgical
intervention. Typical arteriographic findings in a patient
with arterial embolism include an identifiable source, sharp
cutoff, minimal atherosclerosis, a few collateral vessels, and
a discrete clot that is clearly visible on contrast studies. If the
arteriogram is obtained early following the ALI, acute
emboli will appear as a crescent-shaped occlusion at the
proximal side of the clot (meniscus sign). Distal to the clot,
the artery may appear narrowed secondary to vasospasm.
The remaining arteries are typically normal in ALI caused
by embolism. In contrast, in a patient with arterial thrombosis, the thrombus has no identifiable source, diffuse atherosclerotic vessel wall disease is present, cutoff is tapered and
irregular, and there is ample collateral circulation. Extensive
collateralization is pathognomonic because patients with
long-standing peripheral arterial disease develop collateral
arteries over time to bring blood flow distal to a stenosis of
the affected artery. The location of the clot is another feature
that can be useful to differentiate embolic versus thrombotic
ALI. Emboli frequently lodge at arterial bifurcations,
whereas thrombotic clot is usually seen at sites of chronic
atherosclerotic disease.
Other modalities Depending on availability within a
given institution and the level of quality achievable within
the institution, either computed tomographic angiography
(CTA) or magnetic resonance angiography (MRA) may be
employed as alternative means of evaluating the vasculature
of the limb. These two modalities are less invasive than
conventional angiography but, depending on the particular
information being sought, may yield images of lower resolution than a standard angiogram and may be less diagnostically accurate. Today, MRA is most commonly employed in
patients with renal insufficiency to limit the dye load and
nephrotoxicity. CTA is characterized by the ability to obtain
cross-sectional imaging of the affected artery, speed, and
convenience. However, CTA depends on contrast media,
preventing its use in patients who require catheter angiography and intervention because this additional load of contrast increases the risk of renal injury. In addition, CTA may
fail to demonstrate a target vessel for revascularization
distal to an occlusion. Nevertheless, as scanning technology
continues to advance, the role of CTA and MRA in the
evaluation of limb ischemia will continue to evolve.

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management
The major goal of therapy is reperfusion of the affected
extremity irrespective of underlying etiology. Until the middle of the 20th century, when revascularization techniques
were developed, amputation was the only treatment for
acute lower extremity ischemia. In the 1960s, the rates of
amputation and mortality flowing management of ALI were
as high as 50%.17 Today, however, the vascular surgeon
possesses an immense armamentarium for the treatment of
this condition, ranging from emergency bypass to embolectomy or thrombectomy to thrombolytic therapy. Clinical
outcome of the treatment is determined by the severity
of the presenting ischemia, the timing of its recognition,
and the treatment methods undertaken to reperfuse affected
extremity and to treat local and/or distal (systemic) reperfusion injury.
ALI constitutes a clinical emergency, and only a few emergency conditions carry the same potential for amputation,
morbidity, and mortality as ALI. Rapid restoration of flow
to the extremity substantially reduces morbidity and mortality. Accordingly, the clinician must be thoroughly familiar
with the therapeutic modalities available and capable of
making an appropriate choice among them without undue
delay. Whichever therapeutic modality is chosen for a given
patient, several primary measures should be undertaken
to protect and optimize the status of the extremity. Full,
systemic anticoagulation (usually with heparin unless contraindicated) should not be delayed. The extremity should
be placed in a dependent position, with care taken to avoid
extrinsic pressure on the limb. Temperature fluxes should
be minimized: cold induces vasoconstriction, and heat
increases tissue demand and metabolic and circulatory
demands. Finally, tissue oxygenation should be maximized
via transfusion, improvement in cardiac function, and restoration of intravascular volume. Dehydration is commonly
seen in these patients and is best treated with intravenous
administration of isotonic fluids (e.g., 0.9% NaCl). In a 1989
study, Berridge and colleagues demonstrated that the use of
continuous O2 inhalation during ALI may improve tissue
oxygenation before, during, and after definite treatment.18
Thus, patients with ALI should be given at least 24% O2 by
face mask to promote tissue oxygenation.
Proper and timely preoperative preparation is crucial for
preventing rapid deterioration of the patients condition.
As noted above, laboratory tests and radiologic studies are
necessary, and a cardiology evaluation is often helpful.
A central venous line should be inserted in patients with
cardiac impairment, and appropriate treatment of cardiac
arrhythmia and cardiac failure (or both) with antiarrhythmics and/or diuretics should not be delayed. Administration of fluids is beneficial to prevent nephrotoxicity due to
contrast administration. Special attention with fluid administration should be paid to patients with cardiac failure to
avoid volume overload. The ABI should be documented.
Abnormalities in blood counts, electrolyte concentrations,
and coagulation profiles should be corrected. The duration
of ischemia should be noted and any comorbid conditions
identified so that the examiner can determine the appropriate degree of monitoring required (e.g., arterial line or
pulmonary arterial catheter).

acute limb ischemia 5

Anticoagulation
Heparin administration should be started as soon as the
diagnosis of ALI is entertained. Numerous studies have
shown that this measure decreases the morbidity and mortality associated with ALI and increases the limb salvage
rate. Heparin impedes the propagation of thrombus and,
in the instance of embolism, may help prevent additional
embolic events. Unfractionated heparin (5,000 IU) should
be administered intravenously immediately followed by
continuous heparin drip to maintain an activated partial
thromboplastin time (aPTT) ratio of more than 2.
Heparin acts at multiple sites in the normal coagulation
system, inhibiting reactions that lead to the clotting of blood
and the formation of fibrin clots both in vitro and in vivo.
Small amounts of heparin bind to the antithrombin III (AT),
causing conformational changes that result in profound AT
activation. The activated AT inhibits thrombosis by inactivating thrombin and several other proteins in the coagulation cascade, especially factor Xa.19 Once active thrombosis
has developed, heparin can inhibit further coagulation by
inactivating thrombin and preventing the conversion of
fibrinogen to fibrin. Heparin also prevents the formation
of a stable fibrin clot by inhibiting the activation of fibrinstabilizing factor.1921
Heparin does not have fibrinolytic activity and therefore
does not lyse existing clots. Heparin therapy can be complicated by heparin-induced thrombocytopenia (HIT), which
has a reported incidence of 0 to 30%.22 In HIT, the immune
system develops antibodies (mostly of IgG class) against
molecular complex heparin-platelet factor 4 (PF4).23 PF4 is
a cytokine released from activated platelets during platelet
aggregation phase of the coagulation process. Binding of
heparin to PF4 is required to trigger immune reaction and
subsequently induce HIT because heparin molecules alone
are not immunogenic. If the thrombocyte count falls below
100,000/L or if recurrent thrombosis develops, heparin
should be discontinued.24,25 Patients receiving heparin may
experience new thrombus formation, either early or late, in
association with this thrombocytopenic phenomenon as a
consequence of irreversible heparin-induced platelet aggregation (the so-called white clot syndrome). This process may
lead to severe thromboembolic complications, including
skin necrosis, gangrene of the extremities, MI, pulmonary
embolism, stroke, and, possibly, death.24,26,27 Accordingly,
if new thrombosis develops in association with thrombocytopenia, heparin should be promptly discontinued and a
suitable alternative (e.g., a direct thrombin inhibitor) used
instead. Periodic platelet counts, hematocrits, and tests for
fecal occult blood are recommended during the entire course
of heparin therapy, regardless of the route of administration.
As noted above, the anticoagulation effect should be monitored with the aPTT. Bleeding time is usually unaffected by
heparin. Clotting time is prolonged by full therapeutic doses
of heparin but, in most cases, is not measurably affected by
low doses.

Thrombolytic Therapy
The use of thrombolytic agents to treat chronic and
acute arterial insufficiency dates back to the 1970s, when
it was popularized by Dotter.28 All currently available
thrombolytic agents are plasminogen activators. They are

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characterized by different degrees of specificity directed at
the cleavage of a peptide bond in the plasminogen, converting it to plasmin. Plasmin subsequently cleaves fibrin
polymer, leading to thrombus dissolution. Thrombolytic
agents that are most frequently indicated for the treatment
of ALI include streptokinase (SK), urokinase (UK), and
tissue plasminogen activator (t-PA).
SK is derived from Streptococcus bacteria and was the first
thrombolytic agent to be described in 1933 by Tillett and
Garner.29 SK differs from other thrombolytic agents with
respect to the plasminogen-binding mechanism. To convert
plasminogen to plasmin, SK first needs to form a molecular
complex with plasminogen. This SK-plasminogen macromolecular complex activates a second plasminogen molecule to
form an active plasmin that will initiate subsequent dissolution of thrombus. It must be noted that SK is characterized
with a significant immunogenic potential. Patients with
exposure to SK have preformed SK antibodies that inactivate newly administered SK, making dosing of the SK a
challenge. Some authors suggest measurement of SK antibody titer prior to beginning SK therapy and titer-based
dosing of the SK.30
UK directly activates plasminogen to plasmin. The fibrinolytic potential of urine was first recognized and described
by Macfarlane and Pinot in 1947,31 but the active fibrinolytic
molecule was not extracted and named urokinase until
1952.32 Today, most UK is extracted from human neonatal
kidney cells or derived from recombinant techniques using
the murine hybridoma cell line (recombinant urokinase
[r-UK]).
t-PA is a fibrinolytic agent produced by endothelial cells.
It exhibits very high fibrin specificity and in plasma is
associated with little plasminogen activation. t-PA and plasminogen bind to fibrin at the site of the thrombus, leading
to a conformational change in both molecules that induces
the conversion of plasminogen to plasmin and dissolution
of the thrombus. Alteplase and duteplase are single- and
double-chain recombinant tissue plasminogen activator
(rt-PA), respectively. As mentioned above, they are clot
selective because they are more active on fibrin-bound
plasminogen than on free plasma fibrinogen. Tenecteplase
is a relatively novel molecule that is characterized with a
longer half-life and greater fibrin specificity and thus can
be administered as a single bolus rather than as continuous
infusion.
Systemic fibrinolytic therapy has not proved effective and
consequently has been supplanted by intra-arterial (catheterdirected) thrombolysis, which yields significantly better
results. The superiority of catheter-directed thrombolytic
therapy over systemic therapy was objectively established
by Berridge and colleagues in a randomized trial that
included 60 patients with acute or subacute arterial thrombosis treated with three different thrombolytic regimens:
intravenous rt-PA, intra-arterial rt-PA, or intra-arterial SK.33
Limb salvage at the 1-month follow-up was documented
in 80%, 60%, and 45% of patients treated with intra-arterial
rt-PA, SK, and intravenous rt-PA, respectively. Hemorrhagic
complications were documented in only one patient who
received intra-arterial rt-PA following catheter perforation.
This was significantly lower when compared with six and
13 patients with hemorrhagic complications in patients

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acute limb ischemia 6


randomized to SK and intravenous rt-PA, respectively. Still,
the role of thrombolytic therapy for ALI is somewhat
controversial. In addition, such therapy requires a skilled
team with considerable clinical expertise, typically including
a vascular surgeon, an interventional radiologist, and
well-trained ancillary staff. The benefits of pharmacologic
clot lysis must always be weighed against those of surgical
intervention and the risk of bleeding associated with
fibrinolysis.
Despite the use of fibrin-specific agents and catheterdirected infusion, thrombolytic agents still exert systemic
effects, most of which are dose related. About 10% of
patients receiving thrombolytic therapy experience significant bleeding, including bleeding from both puncture and
remote sites. Absolute contraindications to the use of lytic
agents include recent surgery, recent stroke or brain tumor,
pregnancy, a bleeding diathesis, recent trauma, and active
bleeding [see Table 4].
Thrombolysis versus surgical treatment Three prospective, randomized trialsthe University of Rochester trial,
the Surgery versus Thrombolysis for Ischemia of the Lower
Extremity (STILE) trial, and the Thrombolysis Or Peripheral
Arterial Surgery (TOPAS) trialaddressed the differences
between thrombolytic therapy and traditional surgery.3437
Rochester trial This randomized, controlled, single-center
trial compared catheter-directed UK thrombolysis with
surgery in 114 patients with ischemia of less than 7 days
duration.34 All patients had severely threatened limbs (Rutherford class IIb) with a mean symptom duration of approximately 2 days. At the end of 1 year, the cumulative survival
rate was significantly higher in patients randomized to
receive thrombolytic therapy than in patients randomized
to open surgery (84% versus 58%; p = .01). The defining
variable for mortality differences in this study was the
higher incidence of cardiopulmonary complications during
the periprocedural period in patients randomized to open
surgical revascularization. The rate of long-term mortality

Table 4

Contraindications to Thrombolytic
Therapy165

Absolute contraindications
Established cerebrovascular event (including TIAs) within past
2 mo
Active bleeding diathesis
GI bleeding within past 10 days
Neurosurgery (intracranial, spinal) within past 3 mo
Intracranial trauma within past 3 mo
Major relative contraindications
Cardiopulmonary resuscitation within past 10 days
Major nonvascular surgery or trauma within past 10 days
Uncontrolled hypertension: systolic BP > 180 mm Hg, diastolic
BP 110 mm Hg
Puncture of noncompressible vessel
Intracranial tumor
Recent eye surgery
Minor relative contraindications
Hepatic failure, particularly in patients with coagulopathy
Bacterial endocarditis
Pregnancy
Diabetic hemorrhagic retinopathy
BP = blood pressure; GI = gastrointestinal; TIA = transient ischemic attack.

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was relatively low when cardiopulmonary complications
did not occur. The cumulative limb salvage rate was similar
in the two groups (82% at 12 months). Total hospital charges
were comparable as well, which suggests that at the initial
treatment, thrombolytic therapy is as costly as surgery. The
median in-hospital cost of treatment in the thrombolytic and
open surgery groups was $15,672 and $12,253, respectively.
Major bleeding was encountered in 11% of patients.
STILE (Surgery versus Thrombolysis for the Ischemic Lower
Extremity) trial This randomized, controlled, multicenter
trial was designed to evaluate catheter-directed thrombolysis versus surgery and to determine differences in outcomes
between rt-PA and UK in 393 patients.35 In this study, both
patients with chronic limb ischemia and patients with
ALI were included. Patients were not stratified based on the
duration of ischemia during randomization. The Data and
Safety Monitoring Committee stopped the trial early
because of an increase in the number of patients with ongoing ischemia in the thrombolysis groups. An ad hoc committee later determined that the reason for this increase was the
inclusion of chronically symptomatic patients in the study.
In any case, the study clearly demonstrated that patients
with less than 14 days of ischemia had a lower amputation
rate when treated with thrombolysis (11% versus 30%) but
that patients with more than 14 days of ischemia had a
lower amputation rate when treated with surgery. A subgroup analysis showed a significantly shorter time of lysis
in patients randomized to rt-PA when compared with
patients randomized to UK (8 hours versus 16 hours;
p = .01). Additional analysis did not show any difference in
safety and efficacy between rt-PA and UK.
TOPAS (Thrombolysis Or Peripheral Arterial Surgery) trial
The preliminary dose-ranging TOPAS trial compared surgery with r-UK thrombolysis in 213 patients with ischemic
symptoms of less than 14 days duration.36 At the end of 1
year, the amputation rates in the two groups were similar.
Bleeding complications were seen only in patients undergoing thrombolysis, four of whom (2.1%) had intracranial
hemorrhage. When additional end points were considered,
the thrombolysis group was found to require significantly
fewer major interventions at the time of discharge and at
12 months. Patients randomized to catheter-directed r-UK
received three different dosage regimens (2,000, 4,000,
or 6,000 IU/min for 4 hours followed by an infusion of
2,000 IU/min for additional 44 hours, for a maximum of
48 hours). The regimen of 4,000 IU/min seemed to be the
most effective when efficacy and safety were considered.
Complete lysis (defined as > 95% thrombus extraction) was
documented in 71% of patients randomized to a 4,000 IU/min
dosage regimen (mean infusion time 23 hours). In contrast,
complete lysis was achieved in 67% of patients who received
the 2,000 IU/min and 60% of patients who received the
6,000 IU/min dosage regimen. Hemorrhagic complications
were documented in 2%, 13%, and 16% of patients who
received the 4,000, 2,000, and 6,000 IU/min regimen, respectively. The 1-year mortality rates were not significantly
different between the surgical group and the 4,000 IU/min
r-UK group (14% versus 16%). Similarly, there was no significant difference in amputation-free survival rates between
these two groups (75% versus 65%).

acute limb ischemia 7


The preliminary dose-ranging TOPAS trial led to a larger
trial that compared r-UK with surgical revascularization
as initial treatment for acute arterial occlusion of lower
extremities. This randomized, multicenter trial conducted
at 113 North American and European sites randomized
544 patients into two equal cohorts that underwent either
catheter-directed intra-arterial r-UK treatment or surgical
revascularization.37 Both groups of patients had acute arterial obstruction of 14 days or less. In the r-UK group,
amputation-free survival rates were 71.8% at 6 months and
65.0% at 1 year compared with respective rates of 74.8% and
69.9% in the group that underwent surgical revascularization. Major hemorrhage was documented in 32 patients
(12.5%) in the r-UK group and 14 patients (5.5%) in the surgery group. The authors also documented four episodes
(1.4%) of intracranial hemorrhage in the r-UK group (one of
which was fatal). There were no episodes of intracranial
hemorrhage in the group of patients randomized to the surgical revascularization. Although it was associated with a
higher incidence of hemorrhagic complications, r-UK treatment lowered the need for open surgical procedure without
a significantly increased risk of amputation and mortality.
Recombinant tissue plasminogen activator versus urokinase A
prospective, randomized, multicenter trial evaluated local
thrombolysis with either rt-PA or UK in 234 patients with
thrombotic femoropopliteal occlusions (223 [95%] native
femoral or popliteal arteries, 11 [5%] bypass grafts).38 Complete reperfusion occurred in 62% of the patients treated
with rt-PA and in 50% of the patients treated with UK.
However, bleeding was observed in 12.8% of rt-PA-treated
patients (including one instance of cerebral hemorrhage)
and in 9.1% of UK-treated patients (none of whom experienced cerebral bleeding).
Three additional trials compared UK versus rt-PA for the
management of patients with lower extremity arterial occlusion or graft occlusion.35,39,40 As mentioned above, the STILE
trial showed no differences in efficacy or bleeding complications between rt-PA and UK. Data from this study demonstrated a significant difference (p < .02) in the speed of lysis
favoring rt-PA.35 In another study that randomized 120
patients with acute or subacute infrainguinal arterial thrombosis (femoral [n = 21], femoropopliteal [n = 33], popliteal
[n = 13], and popliteocrural [n = 53] artery) to local lysis
using UK or rt-PA, Schweizer and colleagues found that
patients receiving rt-PA had better lytic success and more
rapid lysis with less severe ischemia at 6 months.40 No major
hemorrhages were encountered in either group. Large local
hematomas occurred in 8% and 15% of patients treated with
UK and rt-PA, respectively. It must be emphasized that the
authors of this study compared high doses of rt-PA (5 mg
bolus followed by 5 mg/h infusion) with moderate or low
doses of UK (60,000 IU/h with no bolus). Both groups
of patients were anticoagulated with intravenous heparin
(500 IU bolus followed by an infusion of 700 to 750 IU/h)
during the treatment.
In another study, from Brigham and Womens Hospital,
Myerovitz and colleagues equally randomized 32 patients
with peripheral arterial or bypass occlusion to either rt-PA
or UK treatment.39 The cumulative number of patients with
successful thrombolysis was eight in the rt-PA group versus
six in the UK group at 24 hours. Data from this study showed

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no apparent differences in 30-day clinical success, save that
the end point of 95% clot lysis occurred more rapidly in the
rt-PA group (p = .04). The authors also documented major
bleeding complications in five rt-PA patients and two UK
patients. As in the previous study, the authors of this trial
compared high doses of rt-PA (10 mg bolus followed by
5 mg/h for 24 hours) with relatively low doses of UK
(60,000 IU bolus followed by 240,000 IU/h for 2 hours, followed by 120,000 IU/h for 2 hours, followed by 60,000 IU/h
for 20 hours). Given widely disparate dosing regimens
between rt-PA and UK, the data from these trials must be
interpreted with caution because the data from several other
studies showed that bolus followed with high-dose infusion
of rt-PA reduced lysis time and increased the incidence of
hemorrhage compared with lower doses.41,42
Current recommendations Current data suggest, but do
not prove, that thrombolytic therapy is effective as initial
therapy for patients with acute arterial and graft occlusions
and no sensorimotor deficits. Such an approach, however,
is not suitable for patients with common femoral artery
emboli, which should be treated surgically, and there are
certain patients with sensorimotor deficits (e.g., those
without any runoff) for whom the potential benefits of
thrombolysis outweigh the risks of delay.
At present, acute thrombotic arterial occlusion in an
occluded bypass graft is the area where intra-arterial fibrinolysis may be most useful, permitting better planning of
the subsequent operation and resulting in a less extensive
procedure. Such therapy, however, does not necessarily
yield improvements in major long-term end points. It is
important to remember that thrombosis of femoropopliteal
or similar bypasses is related to early or late surgical stenosis
and atherosclerosis and that restoring flow usually does not
suffice to ensure continued patency.
Logistics of thrombolysis In patients with mild or no
sensory deficits, angiography is performed first. Depending
on the location of the obstruction, the type of clot present,
and the level of patient risk, the patient may be offered
thrombolysis as initial therapy.
In our practice, the patient is taken from the emergency
department to the angiography suite. Informed consent
is obtained for diagnostic and therapeutic angiography
(including the use of stents, balloon angioplasty, stent grafts,
and thrombolysis) and for the performance of an emergency
surgical procedure. A discussion is undertaken with the
patient to outline the course of treatment and to explain that
indwelling catheters may have to be placed and that a stay
in the intensive care unit may be required.
Access to the arterial system is gained via a single-wall
puncture technique; the risk of posterior wall bleeding
associated with a double-wall technique is thereby avoided.
Access should be obtained from a site as remote from the
intervention site as possible. Generally, this is accomplished
by starting from the contralateral groin of the target artery
and going up and over the aortic bifurcation and then back
to the ipsilateral artery. By removing the puncture site from
the side of catheter-directed thrombolysis, the incidence of
bleeding and formation of hematomas or pseudoaneurysms
is reduced.

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acute limb ischemia 8


After completion of the angiogram and delineation of the
pathology, a guide wire is passed into the occluded area. We
use a 0.035 in. hydrophilic guide wire, which has a slippery,
wet coating that enables it to cross nonhydrophilic lesions.
Once in place, the wire is guided through the clot. A multiplesidehole catheter is placed through the clot, and a handinjection angiogram is performed to confirm that the catheter
tip is in the true lumen. The guide wire is then left within
the catheter to occlude the tip so that the lytic agent is
preferentially infused through the sideholes. This graded
coaxial infusion technique allows the agent to reach the
greatest possible surface area, maximizes the length of infusion, and enables the surgeon to treat some of the longest
bypass grafts. If the guide wirecatheter system cannot be
advanced into the clot, it is highly unlikely that thrombolysis will be successful. In a study that included 103 patients
with limb-threatening arterial occlusion lasting 14 days or
less treated at University of Rochester Medical Center with
catheter-directed UK thrombolysis, Ouriel and colleagues
demonstrated that the ability to traverse a guide wire
through the length of the thrombus within the occluded
artery can be used to predict a successful outcome.43 In 84
(81.6%) patients with successful guide wire traversal, successful lysis was achieved in 89% of cases. In the remaining
19 (18.4%) patients in whom traversal of the thrombus with
a guide wire was not possible, clot lysis was achieved in
only 16% of cases (p = .003). Another important aspect of
thrombolytic procedures that can help predict the success of
the intervention determined by the same authors was successful positioning of infusion catheter within the thrombus
(p = .001). Successful catheter placement was documented in
89 (86.4%) patients. In this subgroup of patients, successful
catheter placement was associated with clot lysis in 88% of
cases. In the remaining 14 (13.6%) patients in whom the
catheter could not be positioned within the thrombus, lysis
was never achieved.
In many cases, mechanical thrombus removal, with or
without pulse spray, is employed initially, followed by continuous infusion of a thrombolytic agent. In addition to lytic
therapy, administration of heparin is started (200 to 400 IU
IV or via sheath) to prevent pericatheter thrombosis. Serial
laboratory evaluation is carried out to verify that the patient
is not bleeding and that the fibrinogen level is higher than
100 mg/dL. Serial follow-up arteriograms are obtained to
monitor progress. It is critically important that successful
thrombolysis be followed by treatment, whether endovascular or open, of any lesions uncovered during thrombolysis;
if it is not, reocclusion is inevitable. At the conclusion of
thrombolysis and before intervention, the patient must be
maintained on a heparin drip (or on another anticoagulant)
to prevent the formation of a new thrombus. The rate of
successful reperfusion is approximately 90 to 95% in most
studies.
An important advantage of this selective approach is that
it allows simultaneous angiographic definition of the nature
of the occlusion (i.e., embolic or thrombotic) and of any
vessel wall abnormalities that would lead to rethrombosis
if not corrected by means of surgery or balloon angioplasty.
A major drawback to this approach is that arterial catheterization is required for prolonged periods (20 hours, on
average), leading to major bleeding and thromboembolic

vasc
complications in 6 to 20% of patients. Therefore, the end
points of thrombolytic therapy are (1) resolution and
reconstitution of flow through the obstruction, (2) absence
of change in the occlusion of the vessel on angiography,
and (3) bleeding complications. If it is determined that
thrombolysis is not progressing, it should be abandoned and
surgical intervention undertaken.

Thrombectomy
Percutaneous aspiration thrombectomy This technique
uses a large-lumen, thin-walled catheter and a large syringe
(50 mL) to remove an embolus or thrombus from a vascular
conduit, whether native vessel or graft. The catheter is
placed as previously described [see Logistics of Thrombolysis, above] and is parked immediately adjacent to the clot.
Aspiration of the clot with the syringe is then attempted.
If the clot is new, success is likely, but an old clot that is
organized will not be as amenable to removal. Percutaneous
aspiration thrombectomy can be used as a stand-alone
procedure or together with thrombolysis (to reduce time of
procedure and to reduce dosage of the fibrinolytic agent).
However, it is most effective as an adjunct to catheterdirected thrombolysis.44,45
Percutaneous mechanical thrombectomy Based on their
mechanism of action, percutaneous thrombectomy devices
can be classified in several groups. Hydrodynamic (rheolytic) percutaneous mechanical thrombectomy (PMT) functions on the basis of a hydrodynamic circulation. The basic
concept is that a hydrodynamic vortex is created around the
tip of the PMT catheter. Thrombectomy is accomplished
with the introduction of a pressurized saline jet stream
through the directed orifices in the distal tip of the catheter.
The jets generate a localized low-pressure zone via the
Bernoulli effect, which fragments thrombus via a negative
pressure zone. The saline and the fragmented thrombus are
then sucked back into the exhaust lumen of the catheter
and out of the body for disposal. This technique has proved
beneficial when used in appropriate settings and properly
selected patients. Its efficacy depends on the age of the clot.
Fresh thrombus is readily treated with PMT, but older clots
are much less amenable to this technique and may have to
be treated with an adjunctive catheter-based modality (e.g.,
angioplasty, intra-arterial thrombolysis, or atherectomy).4649
Several clinical trials have validated the efficacy and safety
of PMT devices. Data from a multicenter trial involving 21
patients demonstrated that hydrodynamic PMT (AngioJet,
Possis Medical, Minneapolis, MN) can be effective, especially in high-risk patients who are unfit for open surgery
and in patients with a contraindication to thrombolytic therapy: 57% of patients in this trial had severe comorbidities
and 52% of patients had contraindication to thrombolytic
therapy.50 All patients presented to the hospital within 2
weeks of the development of limb-threatening ischemia.
Limb salvage was achieved in 95% of cases, and 6-month
limb salvage was documented in 89% of cases. Data from
several other studies showed that PMT treatment required
adjunctive thrombolytic therapy for complete thrombus
removal.5154 Dr. Ouriels group reported experience with
hydrodynamic PMT and adjunctive pharmacologic thrombolysis in 86 patients with acute (n = 65) and subacute

acute limb ischemia 9


(n = 21) peripheral arterial occlusions.51 Adjunctive thrombolytic therapy was used in 58% of patients. Near-complete
thrombus dissolution (defined as > 95% thrombus extraction
on the completion angiogram) was documented in 61.4% of
patients, and partial success of treatment (defined as 50 to
95% luminal restoration) was seen in 22.9% of patients. The
median increase in ABI was 0.64 (95% CI 0.43 to 0.81). The
limb salvage rate and mortality at the 1-month follow-up
were 88.4% and 9.3%, respectively. The major concern with
PMT treatment is the formation of thromboembolic debris,
which can lead to distal embolic events than can occur with
all PMT devices.55
Ultrasound-based devices use pulsed-wave, low-power
(2.1 W), high-frequency (2.2 MHz) ultrasound energy (to
alter thrombus fibrin composition and subsequently increase
thrombus permeability for thrombolytic agent) followed by
local, catheter-directed thrombolysis. Data from a retrospective, nonrandomized trial that evaluated 25 patients with
acute or subacute arterial (60%) and bypass graft (40%)
occlusion, treated with ultrasound-accelerated thrombolysis
(Lysus Peripheral Catheter System, EKOS Corporation,
Bothell, WA), demonstrated complete thrombus lysis
(defined as > 95% thrombus removal and < 30% residual
stenosis on the completion angiogram) in 22 patients (88%).56
At the 30-day followup, the authors documented an 80%
patency rate. Two reocclusions occurred 2 and 18 days postthrombolysis. A severe groin hematoma, which occurred
2.25 hours after starting the treatment, was the only complication documented, in a patient with dislocated sheath.
Interestingly, the authors of this study matched the inclusion and exclusion criteria to the above-mentioned TOPAS
trial.37 In this study, the rates of complete lysis were 33%
after 6 hours (from the initiation of the treatment) and 92%
at the final arteriography compared with respective rates of
22.4% and 68% in the TOPAS trial. Data from this study also
showed that the average thrombolytic infusion times and
length of hospitalization were shorter (16.9 hours versus
24.4 hours and 4 days versus 10 days) when compared with
the TOPAS trial. It must be noted that the mean occlusion
length was longer in the TOPAS trial (32.4 cm versus
25.1 cm). Several other studies also demonstrated the safety
and efficacy of ultrasound-accelerated thrombolysis in ALI
patients, as well as in patients with deep vein thrombosis
(DVT) and chronic peripheral arterial occlusive disease.5759
Pharmacomechanical devices incorporate the use of
mechanical thrombectomy and pharmacologic thrombolysis
combined with balloon containment of a thrombus. Following the infusion of a thrombolytic agent, through multisided
holes on the catheter (placed between proximally and distally inflated balloons), mechanical dissolution of a thrombus is initiated via oscillation (3,000 rpm) of a sinusoidal
dispersion wire. To prevent distal embolization, thrombus
microparticles are aspirated through the sheath prior to the
distal balloon deflation.
The use of pharmacomechanical devices has been
described in the treatment of DVT, thrombosis secondary to
subintimal angioplasty and trauma, and cardioembolic and
atherosclerotic ALI.6062 Kasirajan and colleagues used the
Trellis Thrombectomy System (Trellis, Bacchus Vascular
Inc., Santa Clara, CA) to treat ALI (class IIa) in patients with
femoropopliteal and femorofemoral synthetic bypass graft

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occlusion.63 The mean length of the occlusion was 36.0
7.5 cm and was treated with mechanical thrombus fragmentation for 24.0 10.7 minutes. Data from this study showed
an average thrombus removal rate of 95% and no side
effects. In 2012, Daly and colleagues suggested that placing
a filter basket distal to the Trellis catheter should be considered in patients with a large clot burden and subsequently
anticipated incomplete thrombus dissolution to prevent
distal embolization after distal balloon deflation.64
In summary, the development and technical refinements
of percutaneous thrombectomy devices have provided several promising treatment modalities that have the potential
to reduce the morbidity and mortality associated with ALI.
Due to the lack of level 1 data from randomized, prospective, controlled clinical trials, regarding the superiority of
one currently available percutaneous thrombectomy device
over another, the decision regarding which treatment
modality is most appropriate is based on the individual
patients characteristics and on the judgment of an experienced vascular surgeon.

Surgical Embolectomy and Revascularization


When a patient has significant sensory and motor deficits
related to a profoundly ischemic limb, immediate surgical
revascularization is indicated. The decision whether to
accomplish this percutaneously or surgically should be
made expeditiously. Operating room availability should be
determined, the method of anesthesia should be chosen, and
the technical details of the procedure should be planned.
Heparin administration should be started before the patient
enters the operating room. General anesthesia is the preferred method of anesthesia. Operation under local anesthesia may be performed in a thin patient with significant
comorbidities (including severe cardiac risk) and clear-cut
embolus. However, local anesthesia may not be sufficient. A
local anesthetic can achieve analgesia of the wound but does
not provide analgesia during embolectomy and arteriography. Some surgeons administer a small volume of 1% intraarterial lidocaine to abolish pain during embolectomy.65
Even if the procedure is started under local anesthesia, an
anesthesiology team should always be present to monitor
the patient and, if required, convert the patient to general
anesthesia.
For lower extremity emboli, access to the femoral vessels
should be obtained first. The patient is placed in the supine
position, and the lower abdomen, groin, and entire lower
extremity should be prepared and draped. A longitudinal
groin incision is used to expose the bifurcation of the common femoral artery. The common, deep, and superficial
femoral arteries are controlled proximally and distally with
vessel loops, and the common femoral artery is opened
transversely proximal to the bifurcation. A transverse arteriotomy is used for two reasons: it is easier to close the common femoral arteriotomy without narrowing the arterial
lumen, and it is technically feasible to convert it to the
diamond-shaped side part of the proximal end-to-side
anastomosis if a bypass is required. Any visible thrombus
at the bifurcation is removed by suction and/or careful
upward traction with forceps.
Balloon embolectomy of the superficial femoral, deep
femoral, common femoral, and external iliac arteries is then

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acute limb ischemia 10


performed. Differently sized embolectomy catheters are
used, depending on the size of each artery. In our experience, a 3 French catheter is usually suitable for the deep
femoral artery, a 4 French catheter for the superficial femoral
artery, and a 5 French catheter for the common femoral and
external iliac arteries. The catheter should be passed as
distally as possible, and the balloon should be inflated only
as the catheter is withdrawn. This maneuver is repeated
until no more thrombotic material can be retrieved. The
extracted clot is sent for pathologic evaluation. As recommended in the TASC II Inter-Society Consensus guidelines,
completion angiography should be performed to identify
residual occlusion or critical arterial lesions requiring
further treatment, such as bypass.1 If no residual occlusion
or critical lesions are identified, the transverse arteriotomy is
closed with a running 5-0 polypropylene suture from each
end.
When the clot is localized to the distal vessels of the lower
extremity, control of the popliteal artery and its branches is
obtained via a popliteal incision. A skin incision is made on
the medial aspect of the knee and carried down from the
femoral condyle. Attention should be paid to preserve the
great saphenous vein as it crosses at the knee level where
the skin incision is made. The incision is deepened by incising the muscular fascia anterior to the medial head of the
gastrocnemius muscle. To achieve complete exposure of the
popliteal artery and branches, the proximal attachment of
the soleus muscle to the posterior tibia should be divided.
The paired anterior tibial veins should also be divided where
they cross the tibioperoneal trunk. A longitudinal arteriotomy of the popliteal artery should be extended distally to
cross the origin of the anterior tibial artery to permit adequate exposure of the tibial vasculature. A 3 French catheter
should be adequate for selective embolectomy of each tibial
artery. As discussed above, completion arteriography is performed to assess patency of the tibial arteries after thrombectomy. Residual clot can be treated with intra-arterial
thrombolysis. Persistent occlusion of popliteal artery
requires a bypass around the occluded arterial segments.
If embolectomy is successful, the longitudinal popliteal
arteriotomy is closed with a vein patch. The fascial layer of
the wound should not be closed to prevent compartment
syndrome in patients who develop reperfusion-associated
muscle edema.
If distal clot is still present after popliteal embolectomy
and intraoperative thrombolysis, direct tibial embolectomy
should be considered. Short, longitudinal incisions at the
ankle level are used to expose the anterior and posterior
tibial arteries. A small transverse arteriotomy is performed
to pass a 2 French catheter proximally (toward poplital fossa)
and distally (into the foot). Residual clot can be treated with
intra-arterial thrombolysis. In a study that included 126
patients (143 acutely ischemic limbs) treated with anklelevel tibioperoneal artery thromboembolectomy and adjuvant UK thrombolysis, Wyffels and colleagues documented
a limb salvage rate of 98%.66
For upper extremity emboli, the patient is placed in the
supine position followed by application of a topical antiseptic agent to the entire arm, axilla, and supraclavicular
fossa. The affected upper extremity is abducted laterally and
placed on a board. The brachial artery is exposed first, and

vasc
this is most easily accomplished in the antecubital fossa.
A curvilinear (lazy S) incision is made that starts on the
medial aspect of the upper arm, extends transversely across
the antecubital fossa, and ends halfway down the middle of
the lower arm. The brachial artery is exposed deep to the
bicipital aponeurosis, and a transverse arteriotomy is made
proximal to the bifurcation. This incision allows control
of the brachial, radial, and ulnar arteries. A 3 French embolectomy catheter is typically used here. If the pulse is not
present, the catheter should be passed proximally into the
brachial artery first. This is followed by selective embolectomy down the radial and ulnar arteries. Regardless of the
clot location, several passes of the balloon catheter are made
in each vessel until no more clot can be retrieved and there
is brisk back-bleeding from the vessel. A completion angiogram is obtained to visualize the distal vessels and elucidate
any anatomic pathology in the native vessels. If distal clot is
still present after the completion angiogram, intra-arterial
thrombolysis can be employed for a brief period to soften
the clot. The multiple sidehole catheter is advanced distally
to the location of the clot, the guide wire is passed through
the lesion, and the catheter is passed over the wire into
the substance of the clot. Infusion of the lytic agent is then
started. Repeat angiograms indicate whether the clot has
dissolved or is still present. If the clot is still apparent, repeat
embolectomy is attempted. If completion arteriography
shows successful embolectomy, the arteriotomy is closed
using interrupted 6-0 polypropylene suture.
If thrombosis rather than embolism is suspected, an
underlying lesion must be sought. Failure to establish inflow
via brachial embolectomy should prompt angiographic
evaluation of the axillary and subclavian arteries for aneurysm or occlusion. A proximal occlusion of the subclavian
artery is most expeditiously treated by stenting via the
exposed brachial artery when possible. However, axillary
and subclavian aneurysms are often associated with chronic
compression by a cervical rib in the thoracic outlet and
should be repaired through a separate incision.
Several technical points of balloon embolectomy deserve
emphasis. In performing the embolectomy, attention should
be paid to the tactile sensations felt as the inflated balloon is
withdrawn. Such sensations give the operator a sense of the
disease process. When several deflations are needed and the
withdrawal path of the balloon feels rough, a long-standing
process (e.g., an atherosclerotic calcified vessel with anatomic discrepancies) is likely. If there appears to be no
residual clot after embolectomy, then a completion angiogram is sufficient and the artery can be closed primarily. In
cases where the source of embolus is not identified or the
source cannot be corrected, the patient should be considered
for long-term anticoagulation. Heparin is continued into the
postoperative period, and the patient is eventually switched
to warfarin, which is continued for at least 6 months postoperatively. Data from several studies have demonstrated that
postoperative anticoagulation treatment reduces the risk of
recurrent thromboembolic events, especially in patients with
atrial fibrillation.6769 In a study that included 287 patients
with acute thromboembolic lower extremity ischemia,
Campbell and colleagues demonstrated that recurrent limb
ischemia and amputation were less common in patients who
received warfarin anticoagulation initially than in patients

acute limb ischemia 11


who were not anticoagulated with warfarin (7% versus 17%
and 5% versus 21%, respectively).70
The location from which the embolus originated should
always be sought and appropriately treated. When an
underlying lesion is identified, a decision must be made as
to whether it can be treated with angioplasty or stenting or
whether a formal bypass is required to correct the problem
and salvage the limb. Key to the final management of these
patients is assessment of the lower extremities, especially
the calves, for compartment syndrome. To minimize the
chances that an otherwise successful surgical operation may
fail as a consequence of this syndrome, we typically perform
prophylactic fasciotomies on the extremity if profound
ischemia has been present for several hours.

Cost Considerations
A retrospective study published in 1995 compared thrombolysis with surgical thrombectomy as first-line therapy for
ALI.71 Only the costs of the initial admission were documented. The average charge for the two treatments ranged
from $20,000 to $26,000. Economic analysis confirmed that
the total economic impact of thrombolysis approximated
that of initial operative therapy. The conclusion of the study
was that there was no difference between an endovascular
approach and an operative approach with respect to cost. A
more recent study by Korn and colleagues retrospectively
analyzed 100 consecutive cases of acute and subacute lower
extremity ischemia in 85 patients treated with UK thrombolysis.72 The authors documented that the cost of initial
hospitalization for thrombolysis approximated $18,500 per
patient and concluded that thrombolysis can be as or more
costly than traditional surgery. These data show that when
acute treatment of ALI is being considered, cost should not
be factored into the decision-making process. The choice of
treatment strategy should be based on the availability of the
equipment, the experience of the surgeon, and the evidence
regarding the safety and efficacy of the procedure for each
case.
Atheromatous Embolization
Atheroembolism is a condition in which microscopic
cholesterol-laden debris travels from proximal arteries to
reach the most distal arterial segments, typically in the skin
of the lower extremities.7376 This debris usually originates
from unstable plaque found at inflection points in the
arterial tree, especially in the aorta.77,78 It may also originate
from aneurysmal sacs either in the aorta or in the peripheral
arteries. The atheromatous embolization can also be a manifestation of a multisystem disorder associated with high
mortality and morbidity rates. Although it was first reported
more than a century ago (in 1862) by German pathologist
Panum,79 this disorder still remains poorly recognized
and underdiagnosed by many practitioners. Much of the
confusion can be attributed to the numerous clinical manifestations that are apparent across many different medical
specialties, making the differential diagnosis broad and the
diagnosis challenging. The confusion has been compounded
by the inexact nomenclature that permeates the medical
literature. Unfortunately, archaic terms such as blue toe
syndrome, purple toe syndrome, cholesterol embolism,

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cholesterol crystal embolization, multiple cholesterol
emboli syndrome, or the pseudovasculitic syndrome are
still frequently used by some specialists.8085 Based on data
from autopsy studies, the estimated incidence of atheromatous embolization is relatively low and ranges from 0.15
to 3.4%.8688 However, data from several clinical studies
demonstrated that the incidence is much higher in older
patients with atherosclerosis, especially in patients with
known atherosclerosis who underwent arteriography or
cardiac and/or vascular surgical procedures.8993 Thurlbeck
and Castleman found that 17 of 22 patients (77.3%) who died
after open abdominal aortic aneurysm repair had evidence
of atheromatous embolization on a postmortem examination.93
clinical evaluation
A high index of suspicion for atheromatous embolization
should be present in all patients with unexplained MI,
stroke, acute renal failure, mesenteric ischemia, cutaneous
ischemic manifestations, or limb ischemia, especially following vascular or cardiac surgery, as well as angiographic or
endovascular procedures. Patients with atheroembolism of
the extremity usually present with focal toe ischemia, the
so-called blue toe syndrome, in conjunction with palpable
pulses in the distal extremity [see Figure 1]. Acute pain of
sudden onset is typically noted in the affected area. The pain
can often establish the exact timing of embolization. Cyanosis is present either on the toe or over a more extensive area
if the atheroemboli were circulated throughout the extremity.94 When both lower extremities are involved, the source
of the microemboli is commonly found above the aortic
bifurcation. Unilateral manifestation implies that atheroemboli most likely originated distal to the bifurcation. The
descending thoracic, suprarenal, and infrarenal aortas are
common sources of atheromatous embolization to the lower
extremities and to the visceral and renal arteries.
A complete vascular examination should be performed
and pulses documented. Although a patent arterial tree is
the rule, emboli that are sufficiently small may travel through
collateral channels. Palpation should be done to detect
any aneurysmal disease. A massive proximal atheroembolic
event may affect the entire abdominal wall and both extremities, giving the appearance of livedo reticularis.
Livedo reticularis is the most common (present in > 50%
of all patients) cutaneous manifestation of atheromatous
embolization.95 It must be noted that livedo reticularis is
not pathognomonic for atheromatous embolization as it can
be seen in patients with several other disorders, including
antiphospholipid antibody syndrome, systemic lupus
erythematosus, cryoglobulinemia, and macroglobulinemia.
It can also be seen in healthy young women96 and in patients
taking steroids. Livedo reticularis results from delayed
venous drainage of the skin secondary to embolic obstruction of capillaries, venules, and small arteries. It frequently
involves the lateral aspect of the toes, feet, soles, and
calves.97.98 Less frequently, it is seen on the buttocks or trunk.
As the source of the atheroemboli ascends in the arterial
tree, more vital organs (e.g., the kidneys and the gastrointestinal tract) may be damaged. Manipulation of an intraarterial catheter, surgical manipulation of the arterial tree,
or clamping in an area of disease can also result in plaque

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acute limb ischemia 12


disruption. In these cases, the adverse effects are usually
apparent immediately after the procedure.
investigative studies
A number of noninvasive tests may be used to localize the
source of atheroembolization. Doppler segmental pressures
may be used to localize the responsible lesion by documenting a significant drop in pressure between measured levels.
Duplex ultrasonography can detect aneurysms in the
abdominal aorta and femoral or popliteal arteries. It can also
be used to define calcified plaques and high-grade stenotic
lesions in the lower extremity arteries. B-mode imaging can
also provide clues to the morphology of a plaque, such as
intraplaque hemorrhage and irregular surfaces. However,
as mentioned earlier in the text, the accuracy of duplex
ultrasonography is highly operator dependent.
When the aorta is the suspected source of emboli, CTA,
magnetic resonance imaging, or MRA should be performed;
these modalities provide better visualization of intraluminal
disease. In addition to detecting thoracic and abdominal
aneurysms, CTA is useful for the detection of iliac artery
aneurysms and for identifying concomitant occlusive
disease. In patients with atheromatous embolization and
nonlimb-threatening ischemia, CTA of the thoracic and
abdominal aorta should be obtained to evaluate for the
underlying source of atheroembolic events. Although more
invasive, catheter arteriography also plays a useful role in
identifying intraluminal pathology along the entire vascular
tree. However, it should be stressed that catheter arteriography can increase the risk of atheroembolic showers; this
modality should be used if alternative imaging modalities
are not available. Another invasive modality, intravascular
ultrasonography, may be performed in the operating room
or interventional suite with a guide wire in place to help
delineate the extent of the underlying disease.
management
The two major goals of the management of atheromatous
embolization are to treat the end-organ that is affected
and to prevent further embolization from occurring. If the
atheroembolic events are minor and solitary, conservative
medical management is recommended. If, however, the
emboli are recurrent or massive, a thorough evaluation
should be initiated, followed by urgent treatment.
Medical management of atheroembolism consists primarily of antiplatelet agents and HMG-CoA reductase inhibitors
(statins). Given that most patients with atheroemboli are
already receiving aspirin, the addition of clopidogrel or
ticlopidine is appropriate. In a series of 35 patients, complete
recovery of leg ischemia and symptom relief occurred in
more than 50% of patients who received antiplatelet
therapy.99 The optimal agents for preventing recurrence
of atheroembolism may prove to be lipid-lowering drugs,
particularly statins. Cabili and colleagues reported a study
that demonstrated improvement in overall lower extremity
ischemia caused by atheromatous embolization and no
recurrence for 30 months after the initiation of statin therapy.100 A multivariate analysis from a retrospective study that
involved 519 patients with severe thoracic aortic plaque
demonstrated that statin therapy was independently protective (p = .0001) against recurrent embolic events.101 Furthermore, given the goal of preventing recurrence, lifestyle

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acute limb ischemia 13

Patient presents with apparent blue toe syndrome

Signs and symptoms are not consistent


with atheroembolism

Signs and symptoms are consistent


with atheroembolism

Consider other diagnoses: vasculitis


frostbite chilblains recreational drugs.

Assess degree and extent of disease.


Identify source of atheroemboli.

Emboli are unilateral

Emboli are bilateral

Obtain duplex scan and angiogram.

Perform CT or MRI. Obtain angiogram


and intravascular sonogram.

Patient has diffuse atherosclerotic disease

Patient has discrete source lesion


Place endovascular covered stent at
lesion site.

Disease is mild

Disease is severe
Assess level of operative risk.

Patient is not good


operative candidate

Patient is good
operative candidate

Give antiplatelet therapy:


aspirin clopidogrel
Treat ischemic injury.

Atheroemboli do not recur

Atheroemboli recur

Perform surgical bypass or exclusion of target area.


Figure 1 Algorithm outlining workup of a patient with blue toe syndrome as a result of atheroembolism. CT = computed tomography; MRI =
magnetic resonance imaging.
modification should be initiated to minimize preventable
risk factors for atheromatous embolization as well as coronary and peripheral arterial disease. All patients should
be counseled to stop smoking. Aggressive treatment of
diabetes is also warranted. Strict glycemic control should be
initiated to achieve recommended hemoglobin A1c levels of
less than 6.5 to 7.0%. Tight control of blood pressure is very
important as well. The blood pressure goal for nondiabetic
and diabetic patients is less than 140/90 mm Hg and less
than 130/80 mm Hg, respectively.102
The role of warfarin therapy in treating atheroembolic
disease has not been established with certainty. Such
therapy may even aggravate the disease process by causing
intraplaque hemorrhage and increased embolization. The

Warfarin Aspirin Recurrent Stroke Study (WARSS), a


randomized multicenter study that included 2,206 patients
who had recently experienced an ischemic stroke, found no
evidence that warfarin is superior to aspirin for preventing
recurrent ischemic stroke or death within 2 years.103 The
WARSS also found that there was a significant difference in
bleeding risk between warfarin-treated patients and aspirintreated patients. For patients with diffuse atherosclerotic
disease, the mainstay of therapy is an antiplatelet regimen.
Traditionally, an atheroembolic source has been treated by
surgical excision or by exclusion of the disease process with
a bypass graft, either of which provides a good degree
of safety from further embolization.104 With the advent of
endovascular surgery, however, the use of covered stents,

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acute limb ischemia 14

placed securely and precisely at the site of the offending


lesion, appears to be an increasingly effective and popular
option [see Table 5].105,106 Dougherty and Calligaro demonstrated successfully treated ulcerated aortic plaques with
covered stents in a small series of patients with lower
extremity ischemia.105 In another small series, 19 patients
with embolizing abdominal aortic aneurysms were treated
with aortic stent grafts. Eight of nine patients (88.9%) with
follow-up of 1 year had complete resolution of their ischemic symptoms, with no recurrent manifestations of atheromatous embolization.107 Despite successful abdominal aortic
aneurysm exclusion, one patient in the series had persistent
foot ischemia at 1 year of follow-up, but the source of persisting atheromatous embolization was believed to be severe
coexisting thoracic aortic disease. Although endovascular
treatment for atheromatous embolization is becoming
increasingly promising, randomized, controlled trials are
needed to accurately assess the safety and efficacy of the
different endovascular treatment modalities and compare
them with traditional surgery.
Our current approach to treating atheroembolism may be
summarized as follows. The source lesion is first identified
by means of the modalities already discussed. If embolization is minor, aspirin, clopidogrel, and a statin are started.
If embolization is recurrent or massive, an endovascular
approach is attempted, involving the placement of a covered
stent over the lesion. This approach is indicated for segments of the arterial tree where there are no collaterals so
that vital blood flow to organs is not hindered. If aneurysmal disease is present, either conventional or endovascular
therapeutic approaches may be applied to exclude any
source of emboli. In the case of thoracic aortic disease,
covered stents may be placed to push the plaque against the
wall and prevent further embolization. If suprarenal plaque
cannot be treated with a stented graft, aortic ligation with an
axillobifemoral bypass may be performed. Such treatment
does not, however, protect the renal and visceral vessels,
and these patients require lifelong strict antiplatelet therapy.
Pathophysiology, Etiology, and Complications
pathophysiology of ali
As mentioned above, ALI begins when arterial embolization, local thrombosis, or arterial trauma results in occlusion
of a peripheral artery or bypass graft. The ischemic process
may then develop slowly, over an extended period, or
quickly, over a few hours. A protracted course leading to

Table 5 Surgical Management of


Atheroembolism
Source of Emboli

Treatment

Upper extremity

Bypass of subclavian or axillary artery


First rib or cervical rib resection

Aorta

Focal disease: covered aortic stent


Diffuse disease: aortobifemoral bypass

Iliac artery

Covered iliac stent

Popliteal artery

Ligation and bypass of popliteal artery

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thrombosis allows collateral vessels to form, resulting in the


gradual onset of symptoms. When occlusion is acute, however, as in trauma, embolization, or acute thrombosis of a
vessel or a bypass graft, signs and symptoms of acute ischemia may become rapidly apparent, including excruciating
pain, mottling, cyanosis, and, commonly, sensory and motor
changes. The magnitude of the ischemic injury is directly
proportional to the duration of ischemia and the amount of
tissue affected.
The pathophysiology of limb ischemia is related to the
progression of tissue infarction and irreversible cell death.
Compared with other organs and tissues (e.g., the brain and
the heart), the extremities are relatively resistant to ischemia.
However, the various tissue types of which an extremity is
composed have different metabolic rates. The extent to
which each cell type can tolerate ischemia depends on its
metabolic rate. Bone and skin are the most resistant to
ischemia, nervous tissue is the least resistant, and muscle is
somewhere in between. Although nerve tissue is the type
that is most sensitive to ischemia, skeletal muscle, the major
structural component of an extremity, plays the largest
pathophysiologic role in the local and systemic effects of
ALI. Initial ischemia leads to a conversion of muscle
metabolism from aerobic to anaerobic. This ultimately leads
to increased production of lactates and subsequent disruption of acid-base balance characterized by profound metabolic acidosis.108 In the setting of hypoxia, dysfunction of the
calcium-sodium exchanger occurs, resulting in the elevated
levels of free calcium within the myocytes. Elevated levels
of free calcium interact with muscle fibers, resulting in
skeletal muscle fiber necrosis.109 Cell lysis leads to release
of intracellular potassium and free myoglobin, with toxic
systemic effects. For muscle tissue, 6 hours is the approximate upper limit of ischemic tolerance; nervous tissue is
affected well before this point.110 Knowledge of the varying
degrees of ischemic tolerance helps in determining the
viability of the limb.

Hypoperfusion-Reperfusion State
The severity of ALI symptoms is directly related to
the duration of ischemia and the effects of reperfusion.
Hypoperfusion (ischemia)-reperfusion injury occurs in the
settings of reversible diminished or absent blood supply to
a tissue followed by the return of oxygenated blood flow.
Regardless of the cause of the ischemia, hypoperfusion leads
to ischemic infarcts via various mechanisms. In addition to
diminished delivery of O2 to tissues during the hypoperfusion state, three major physiologic events occur. First, movement of blood through the vessels is slowed. As a result,
the thrombus is able to grow and propagate, occluding
collateral vessels and further decreasing blood flow. Second,
ischemic cells swell and accumulate water. The resulting
increase in pressure within a fixed space between fascial
structures creates an elevation of pressure within the
compartment that further decreases flow and exacerbates
the injury. Third, the precapillary arteriolar cells swell,
narrowing the lumina of distal arterioles, capillaries, and
venules and again reducing blood flow. As a result, biotoxic
products of anaerobic metabolism accumulate within the
ischemic tissues distal to the occlusion with resultant
tissue edema, which, if left uncorrected, may progress to
compartment syndrome.

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acute limb ischemia 15

The reperfusion state that results when flow is restored


can be as detrimental to the ischemic extremity as the hypoperfusion state. In addition to local symptoms in the affected
extremity, metabolic consequences of reperfusion can have
severe systemic effects that are associated with significant
morbidity and mortality. In severe cases, systematic involvement may result in systematic inflammatory response syndrome or even in multiple organ dysfunction syndrome,
which is often associated with high rates of mortality.111
During abrupt reperfusion, highly active O2 metabolites are
produced by neutrophils.112 These free radicals destroy cells
by attacking the unsaturated bonds of fatty acids within the
phospholipid membrane, thereby disrupting the cell membrane, allowing water to enter the cell, and eventually causing cell lysis. Volume repletion and urinary alkalinization as
well as free radical scavengers have been recommended as
initial supportive treatment. Free radical scavengers (e.g.,
mannitol and superoxide dismutase) have a slight protective
effect against reperfusion injury when given before largescale release of these radicals.113,114 In addition, myoglobin
from injured muscle cells is released into the circulation and
is cleared via the renal system. Myoglobin may cause renal
failure through its direct toxic effect on the renal tubules and
through the accumulation of casts in the tubules. Creatine
phosphokinase levels may also increase to dramatic levels
once perfusion is reestablished. High concentrations of lactic
acid, potassium, thromboxane, and cellular enzymes are
secreted as a consequence of the rhabdomyolysis; these
substances accumulate in the ischemic limb and are released
into the systemic circulation on reperfusion.115 In one
study that measured the venous effluent from a series of
patients with limb ischemia, the pH was 7.07 and the
mean potassium level was 5.7 mEq/L 5 min after surgical
embolectomy.116
Detrimental physiologic changes are seen when toxic
O2 metabolites are released systemically. Profound acidosis,
hyperkalemia, myoglobinuria, renal failure, depression of
myocardial function, an increase in cardiac dysrhythmias,
and loss of vascular tone may induce shock and even lead
to death.117
etiology of ali
The etiology of ALI can be divided into two distinct categories: thrombosis and embolism. A thorough evaluation
must be performed to elucidate the precise cause of ischemia
in each patient. The two categories are each associated with
specific symptoms and signs [see Table 6]. Knowledge of
these associations helps direct the clinician toward the most
appropriate means of accomplishing limb salvage in a given
situation.

Thrombosis of a native vessel or bypass graft almost


always develops in conjunction with an underlying occlusive lesion in the vessel or graft. The lesion usually has been
present for some time, and the thrombosis occurs due to
reduced blood flow. In contrast, embolic events occur in
smaller-caliber vessels that are not diseased, with emboli
commonly resting at or immediately distal to branch
points.

Thrombosis
Native artery thrombosis Native artery thrombosis
represents the end stage of a long-standing disease process
of atheromatous plaque formation at specific sites in the
arterial tree. Atherosclerotic plaque begins with the slow
deposition of lipids in the intima of the vessel and continues
with the deposition of calcium, resulting in an atherosclerotic core.118 This core has a highly thrombogenic surface
that encourages platelet aggregation, which results in disturbances of blood flow.119 The flow disturbances create
a zone of separation, stagnation, turbulence, and distorted
velocity vectors. These factors cause low shear rates at
inflection points in the arterial tree, and endothelial damage
ensues. The endothelial damage activates a repair process
that results in intimal hyperplasia, which induces further
attraction of platelets and eventual thrombus formation. The
process by which occlusion develops from an atheromatous
plaque may be more important than the degree of stenosis
within the lumen. This would explain why acute occlusion
occurs in vessels with minimal (< 50%) stenosis: atheromatous plaque not only reduces blood flow but also represents
an irregular surface within the arterial lumen that is prone
to thrombus formation. The contact between the atherosclerotic core and the bloodstream leads to platelet aggregation
and hence to eventual thrombosis. Occasionally, thrombosis
of a native artery occurs without any obvious underlying
pathologic condition. In such cases, a thorough investigation
should be initiated into other causes of thrombosis (e.g.,
hypovolemia, malignancy, hypercoagulable states, and
blood dyscrasias).
Bypass graft thrombosis Aggressive management of
patients with peripheral arterial disease has led to an
increase in bypass graft procedures. As a result, graft
thrombosis has now become the leading cause of acute
lower extremity ischemia. Some patients have graft occlusions without any definable underlying lesion, but most
have a definable lesion. In patients with native conduits,
intimal hyperplasia leading to the narrowing of the vein
graft and valvular hyperplasia are the two leading causes of
graft failure.120 The situation is different in the prosthetic

Table 6 Differentiation of Embolism from Thrombosis


Variable

Embolism

Thrombosis

Identifiable source

Frequently detected

None

Claudication

Rare

Frequent

Physical findings

Proximal and contralateral pulses normal

Evidence of ipsilateral and contralateral peripheral vascular


disease

Angiographic findings

Minimal atherosclerosis; sharp cutoff; few


collaterals; multiple occlusions

Diffuse atherosclerotic disease; tapered and irregular cutoff;


well-developed collateral circulation

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graft population where the graft failure is attributed to
one of the following: thrombogenicity of the graft material,
kinking of the graft from crossing joints, anastomotic intimal
hyperplasia, and progression of atherosclerotic disease
proximal or distal to the graft. Among these, anastomotic
irregularities probably represent the most common cause
of graft thrombosis.111 Data from the most recent studies
suggest that geometric remodeling of the native conduits
and decreased vein graft adaptation to the arterial environment are caused by mediators of inflammation.121 Fortunately,
diminished blood flow in the graft can be detected before
graft thrombosis occurs. Establishing a policy of routine
ultrasound surveillance after bypass procedure and prompt
revision of an identified vein graft stenosis is important; if
an advanced lesion is not corrected, graft thrombosis leads
to acute ischemic events with the possibility of limb loss.
Advanced vein graft stenosis should be repaired using open
surgical or endovascular techniques prior to occlusion.
Most short lesions (< 2 cm in length) can be corrected by
percutaneous transluminal angioplasty (PTA). Longer or
more complex lesions should be treated with vein patch
angioplasty or a short bypass.

Embolism
Peripheral arterial embolization results in the sudden
onset of severe ischemia as the absence of collateral vessels
compounds the reduction in flow to the extremity. The heart
is by far the most common source of spontaneous arterial
emboli, accounting for about 90% of cases. The incidence of
embolic phenomena has increased as the population has
aged, with a corresponding increase in the number of
patients with significant cardiac disease. Over the past
25 years, the incidence of embolization has doubled, from 23
to 51 per 100,000 admissions. Atherosclerotic heart disease
currently accounts for as many as 60 to 70% of all cases of
arterial embolism.122,123 Atrial fibrillation and rheumatic valvular disease account for the remaining 30 to 40%.113,124 With
respect to peripheral emboli in particular, atrial fibrillation
is currently responsible for 65 to 75% of cases. Transthoracic
echocardiography is insensitive in visualizing atrial clots,
especially in the left atrial appendage, which is the most
common cardiac source of emboli.125,126 Transesophageal
echocardiography, however, offers significantly better imaging of all four chambers and thus is considered the superior
diagnostic test for suspected cardiac embolic sources.127130
MI is the next most important cause of peripheral emboli.
One study from 1986 evaluated 400 patients and found that
MI was a causative factor in 20%.115 A left ventricular wall
thrombus is often seen after an acute MI, with or without a
left ventricular wall aneurysm; however, only 5% ultimately
embolize and result in peripheral ischemia.131134 Other
studies suggest that day 3 to day 28 is the period during
which the risk of embolization is highest for an intracardiac
thrombus.135
Other cardiac sources of peripheral emboli include the
ring portions of prosthetic cardiac valves and biologic
xenovalves. Chronic anticoagulation is recommended for
prosthetic valves, but the biologic xenovalves do not require
anticoagulation.136,137 Cardiac tumors (e.g., atrial myxomas)
are rare sources of peripheral emboli.126 Cardiac vegetations
from bacterial or fungal endocarditis should be considered

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acute limb ischemia 16


possible sources of peripheral emboli when intravenous
drug abuse is suspected in a patient with no previous
history of cardiac disease.138,139
Noncardiac sources account for 5 to 10% of peripheral emboli. The majority of these involve upstream atherosclerotic
arterial disease (e.g., aneurysms or unstable plaques).140143
Unstable plaque is prone to ulceration and rupture, creating
a highly thrombogenic surface that promotes platelet aggregation and creates thromboembolic debris that leads to
distal arterial embolization. Foreign objects (e.g., missiles)
and tumors (e.g., melanoma) can also embolize if they gain
access to the arterial tree.144147 Paradoxical embolization
occurs when a venous thrombus crosses from the right heart
circulation to the left, via an atrial or ventricular route such
as an atrioseptal defect, a ventricular septal defect, or patent
foramen ovale. Once the embolus gains access to the left
ventricle, it becomes an arterial embolus.148150 About 5 to
10% of emboli remain unidentified despite a thorough
diagnostic evaluation151,152; some of these are now being
attributed to hypercoagulable states and are considered
indications for chronic anticoagulation.153
Incidence The increase in the number of endovascular
interventions has affected the etiology of arterial embolism,
with a greater number of embolic episodes now arising from
endovascular procedures. A 1996 study found that 45% of
all atheroemboli were iatrogenic and that the majority of
these (83%) originated during manipulation of the abdominal aorta and the proximal arteries, including the iliac artery
and the femoropopliteal artery, with the remainder originating during surgery.154 Emboli usually lodge at arterial
bifurcations and thus cause hypoperfusion of more than one
vessel. Axial limb vessels account for 60 to 80% of clinically
significant embolic events, with the remainder divided
between cerebral vessels (20%) and upper extremity vessels
(10 to 20%).115,126,155 The most common site for embolic lodgment is the common femoral bifurcation [see Figure 2]. The
aortoiliac region is the next most common site, followed
closely by the popliteal artery.108,114,115,126,156 The presence of
normal pulses in the contralateral leg in a patient with an
ischemic leg should elicit an aggressive workup to rule
out a cardiac embolic source and, as mentioned above, may
be a clue that the occlusive event is embolic rather than
thrombotic.
Upper extremity emboli Acute ischemia of the upper
extremity is usually caused by embolism, usually from a cardiac source. Subclavian aneurysms, arteriovenous fistulas,
upper extremity arterial bypasses, and iatrogenic manipulation of the arteries (including axillary bypass procedures
and arteriovenous hemodialysis fistulas) are rare causes.157
As noted above, emboli lodge at bifurcations within the
arterial tree. In the upper extremity, the bifurcation of the
brachial artery into the radial and ulnar arteries is the most
common lodgment site, followed by the takeoff of the deep
brachial artery. Adequate exposure of all three arteries can
be obtained via an elongated S-shaped incision that runs
medially to laterally across the elbow joint. Given that the
antecubital region is characterized by an abundant collateral
circulation, acute occlusion of the brachial artery is usually
well tolerated in regard to limb-threatening distal ischemia

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acute limb ischemia 17

Axillary
(4.5%)
Aorta
(9.1%)
Common
lliac
(13.6%)
Brachial
(9.1%)

External
lliac
(3.0%)

Radial
(1.2%)
Ulnar
(1.2%)

Common
Femoral
(34.0%)

Superficial
Femoral
(4.5%)
Popliteal
(14.2%)

Anterior
Tibial
(2.8%)

Figure 2

Posterior
Tibial
(2.8%)

The most common sites of arterial embolic occlusions.

and carries a better prognosis than acute occlusion of the


popliteal artery. In a study that analyzed 61 patients with
acute upper extremity ischemia compared with patients
treated for lower extremity ischemia over the same 5-year
period, amputation and mortality rates in patients with
upper extremity ischemia were reported as 0 and 5% compared with respective rates of 5 and 30% in the patients
treated for lower extremity ischemia.158 Similar to data from
the University of Rochester trial,34 this study demonstrated
that the group with the higher mortality rate had the higher
incidence of cardiopulmonary complications.
Other causes Sepsis and cardiogenic shock can result in
low-flow states that place patients at high risk for thrombosis. Certain vasoconstrictors and recreational drugs are also
associated with lower extremity thrombosis.159.160 Patients
with these conditions usually present with bilateral extremity ischemia. Vasculitides (e.g., Takayasu disease) may
also cause extremity ischemia.161 The hypercoagulable states
(e.g., AT deficiency, antiphospholipid syndrome, protein C

and S deficiencies, activated protein C resistance, and


hyperprothrombinemia), usually associated with venous
thrombosis, may also be associated with acute arterial
thrombosis.162 The contribution of these states to ALI, with
usually devastating consequences, is increasingly being
recognized. Another rare but important etiology for ALI is
vascular trauma. Although improvements in the management of ALI associated with vascular trauma have reduced
the amputation rate to less than 5%, management of these
patients is still characterized by long-term disability, which
remains a persistent problem for 20 to 50% of patients.163
Financial Disclosures: None Reported
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