Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3608_Библиотеки_им_академика_М_И_Перельмана
.pdf
peripheral edema, a finding occasionally mistaken for venous disease in these patients. With severe ischemia, any skin perturbation,
including bedclothes or blankets, may cause pain; in ischemic neuropathy, this causes a lancinating pain in the foot. Other symptoms
of CLI include hypesthesia, cold intolerance, muscular weakness,
and joint stiffness of the affected limb. Severity of CLI is categorized
in both the Fontaine and Rutherford classification schemes (see
Tables 18-1 and 18-2).
Differential Diagnosis of Critical Limb Ischemia
Differential diagnosis of CLI includes vascular and nonvascular
diseases (
when components of large-vessel atherosclerotic plaque embolize
to distal vessels (
rial is composed of fibroplatelet debris and cholesterol crystals.
A common cause of atheroembolism is iatrogenic disturbance
of the vessel, whether from catheterization or surgery. Several features may help in differentiating atheroembolism from traditional
CLI. Patients typically have pulses palpable down into the feet,
because the emboli require a patent pathway to distal portions
of the extremities. Other clinical clues include new renal insufficiency and blood eosinophilia. On examination, the patient will
have areas of cyanosis or violaceous discoloration of the toes or
portions of the feet and areas of livedo reticularis.
thromboemboli of large fibroplatelet accumulations that originate
in the heart or large arteries and occlude conduit arteries (see
Chapter 46). These patients have an accelerated course and may
present with the “five Ps” of acute ischemia: pain, pallor, poikilothermia, paresthesia, and paralysis. Other causes of limb ischemia
include vasospasm, TAO, other vasculitides, and connective tissue disorders (see Chapters 41, 44, and 48). Other causes of ulcers
include neuropathy, venous disease, and trauma (see Chapter 61).
such as gout, fasciitis, and trauma (see
Ischemia
Atherosclerosis
Atheroemboli
Acute arterial occlusion:
Vasculitis
TAO
Scleroderma
SLE
MCTD
Cryoglobulinemia
Vasospasm
Raynaud phenomenon
Acrocyanosis
Ulcers
Neuropathy
Venous insufficiency
Trauma
Pain
Neuropathy
Arthritis
Gout
Rheumatoid arthritis
Fasciitis
Trauma
MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus;
TAO, thromboangiitis obliterans.
Box 18-2). Atheroembolism, or blue toe syndrome, occurs
Fig. 18-2) (see Chapter 47). The embolized mate-
Acute limb ischemia may occur from thrombosis in situ or from
Nonvascular causes of foot pain include neuropathy, arthritides
Box 18-1).
Box 18-2 Differential Diagnosis of Critical Limb
Ischemia
In situ
thrombosis
Emboli
FIGURE 182 Atheroembolism after catheterization. Note areas of
cyanosis and surrounding livedo reticularis. This patient had a palpable dorsalis
pedis pulse.
Physical Examination
A comprehensive physical examination that includes general
appearance of the patient, integument, heart, lungs, abdomen, and
limbs should be performed during the initial patient encounter
to elucidate evidence of systemic disease and provide insight
into cause and manifestation of the patient's vascular disease.
The entire vascular system should be examined. Blood pressure
is measured in each arm. A blood pressure difference of 10 mmHg
or more may be indicative of innominate, subclavian, axillary, or
brachial artery stenosis. The carotid, brachial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibial pulses should
be palpated in every patient (Fig. 18-3). Several pulse-descriptive
schemes have been promulgated. One is to grade the pulses as
0 (absent), 1 (diminished), and 2 (normal). A very prominent
or forceful pulse may occur in patients with aortic regurgitation
or high cardiac output states. Absence of any pulse in the lower
extremity, except in the dorsalis pedis, increases the likelihood of
20
PAD.
The dorsalis pedis pulse is not palpable in approximately
8% of healthy patients.
cate a significant stenosis between the present and absent pulse.
Occasionally, pulses may be palpable below the level of a significant stenosis. This most commonly occurs in the setting of iliac
artery disease when there may be sufficient collateral vessels to
maintain perfusion to distal arteries.
The abdominal aorta should also be palpitated if permitted
by body habitus to elicit evidence of aortic aneurysm. A widened pulse in the abdomen or over a peripheral artery (e.g., the
popliteal artery) may be indicative of an aneurysm. Once palpated, the abdomen and several peripheral vessels also should
be auscultated. Palpation of an expansile or pulsatile periumbilical mass is indicative of an abdominal aortic aneurysm. Proper
auscultation of normal vessels with a stethoscope should reveal
no sound. Bruits should be sought over the carotid and subclavian arteries, in the abdomen, in the lower back, and over
the femoral arteries. Presence of a bruit, indicative of turbulent
blood flow, typically occurs as a result of arterial stenosis, but
may indicate extrinsic compression or arteriovenous malformation. Vessels with no flow, resulting from complete occlusion, do
not convey bruits.
A skin examination should be performed, looking for alterations in temperature, edema, signs of active or healed lesions,
or signs of chronic ischemia—including thin shiny skin, thickened yellow nails, and loss of hair. Foot or toe cyanosis or pallor
may be a forerunner of ulceration. Inspection of the skin may
reveal trophic signs of chronic ischemia, including sympathetic
denervation (impaired hair growth or impaired sweating) and
sensorimotor neuropathy (lack of vibratory sense). Critical limb
ischemia may cause muscle and subcutaneous tissue atrophy,
20
Absence of a peripheral pulse may indi-
233
CH
18
PERIPHERAL ARTERY DISEASE: CLINICAL EVALUATION
234
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
CH
18
AB
FIGURE 183 Palpation of pedal pulses. A, Palpation
of posterior tibial (PT) pulse. Examiner should place his/her
fingers in the curve below the malleolus with light pressure and
reposition as needed. Application of passive foot dorsiflexion
occasionally makes PT palpation easier. B, Dorsalis pedis pulse
is typically appreciated within 1 cm of the dorsum, most
prominent near navicular bone.
hair loss, petechiae, and thin or encrusted skin. In CLI, the toes
and foot are cool and pallor may be present when the foot is in
the neutral (or horizontal) position.
Changes in skin appearance with elevation and dependency
may provide a gauge for PAD severity. The leg should be elevated to 45 to 60 degrees for 1 minute. If pallor develops quickly
(within 10-15 seconds), severe PAD is likely. After 1 minute, the
patient sits up and the leg is placed in a dependent position.
The time to pedal vein refill should be recorded. Ischemicinduced arteriolar and venular dilation may lead to development of a violaceous appearance of the foot with dependency,
called dependent rubor (
Fig. 18-4). Normal refill occurs rapidly,
typically within 10 to 15 seconds. Prolongation of venous filling or the development of numbness beyond 1 minute suggests
severe PAD.
Arterial fissures most commonly develop in the heel, toes, in the
web space between the toes, or in segments subjected to pressure
(the ball of the foot). Arterial ulcers are circumscribed, tender, and
prone to infection. The base of the ulcer is usually pale. The ulcers,
in contrast to venous ulcers, are dry; however, the devitalized tissue
is prone to infection, which may generate a purulent exudate.
The ulcer may be covered by an eschar. In CLI, gangrene most
commonly occurs in the digits but may occur on the ball of the
foot or heel. In the absence of infection, gangrene tends to be dry,
and the skin is mummified.
Two classification schemes are used to categorize the clinical
assessment of patients with PAD: the Fontaine Stage Classification
of PAD and the Rutherford Categorical Classification of PAD. In
the system described by Fontaine, the severity of PAD is classified into 1 of 4 stages ranging from asymptomatic in stage 1,
intermittent claudication in stage 2, daily rest pain in stage 3, and
focal tissue necrosis in stage 4 (see Table 18-1). The Rutherford
system employs seven categories, dividing severity of claudication into three categories (mild, moderate, and severe) and CLI
into three categories (rest pain, minor tissue loss, and major tissue loss) (see
Table 18-2).
FIGURE 184 Dependent rubor. This
patient with severe peripheral artery disease
(PAD) (note previously amputated second
digit) develops a ruborous appearance of
the forefoot with dependent positioning as a
result of arteriolar and venular dilation.
Diagnostic Testing
Office-Based Ankle-Brachial Index
Measurement of the ABI is a simple method employed to corroborate the historical and physical findings of PAD. The ABI
is the ratio of the systolic blood pressure at the ankle and brachial artery. The latter is an estimate of central aortic pressure. Brachial artery systolic blood pressure is measured in
both arms and ankles using a handheld 5- or 10-MHz Doppler
ultrasound device and sphygmomanometric cuff. The cuffs are
placed on each arm above the antecubital fossa and above each
ankle. The cuffs are sequentially inflated above systolic pressure
and then are slowly depressurized. The Doppler probe, placed
over the brachial artery and the dorsalis pedis and posterior tibial arteries, monitors the pressure (
deflated, reappearance of a Doppler signal indicates the systolic
pressure at the level of the cuff.
Brachial artery pressures must be measured in both arms
because atherosclerosis may occur in subclavian and axillary
arteries. The higher of the two brachial systolic blood pressures
is used for reference in the ABI calculation. Hence, the ABI is the
Fig. 18-5). As the cuff is slowly
235
CH
18
PERIPHERAL ARTERY DISEASE: CLINICAL EVALUATION
A
C
B
FIGURE 185 Measurement of the ankle-brachial index (ABI). Brachial
artery systolic blood pressure is determined in both arms and both ankles using a
handheld 5- or 10-MHz Doppler ultrasound and sphygmomanometric cuff. Because
atherosclerosis may occur in subclavian and axillary arteries, brachial artery pressures
must be measured in both arms (A). The higher of the two brachial systolic blood
pressures is used as the reference pressure in ABI calculation. In each ankle, pressure
should be measured at dorsalis pedis (B) and posterior tibial pulse (C). ABI is the
quotient of the highest systolic pressure at each ankle divided by the highest pressure
of the two brachial artery pressures.
236
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
systolic pressure at each ankle divided by the higher pressure of
the two brachial artery pressures; an ABI may be generated for
each leg. When assessing foot perfusion, the ABI uses the highest
of the pedal pressures in each leg.
21
Both pedal pressures (dorsalis pedis and posterior tibial artery) are considered when seeking evidence of atherosclerosis. Some have suggested that ankle
CH
pressure used to calculate ABI should be an average of the two
18
pedal pressures.
22
Normal systolic pressure at the ankle should be at least the
same as in the arm, yielding an ABI of 1.0 or greater. As a result of
reflected arterial pressure waves, healthy persons tend to have an
ABI ranging from 1.0 to 1.43. Recognizing an intrinsic (up to 10%)
variability of blood pressure when measured sequentially, since
ankle pressures are not measured simultaneously, an abnormal
ABI consistent with the diagnosis of PAD is categorized as 0.9 or
less, whereas an ABI above 0.9 to 1.0 is borderline abnormal.
ABI is a reliable determinant of PAD, with a sensitivity for ABI 0.9
or less ranging from 79% to 95% and specificity of 96% to 100%.
An ABI of 0.4 or less is extremely abnormal and typically present
in patients with CLI. Arterial calcification may introduce a false
elevation in ABI, typically greater than 1.4, as a result of noncompressible vessels at the ankle. Arterial calcification occurs more
commonly in patients with diabetes or end-stage renal disease and
in the elderly.
25,26
The ABI provides prognostic information because it is a
barometer of the burden of systemic atherosclerosis. In the ABI
Collaboration, the incidence of adverse events rose as the ABI
dropped below 1.0, even in the absence of symptoms.
the ABI, the greater the cardiovascular morbidity and mortality.
An ABI of 0.8 or less is associated with twice the age-adjusted
10-year mortality, and an ABI of 0.4 or less, is associated with a fourfold increase in mortality.
21,27
Measuring the ABI provides an assess-
ment of both PAD and cardiovascular risk.
There are limitations to ABI measurement. The correlation
between ABI, functional capacity, and symptoms is weak. Resting
ABI is occasionally normal in patients with PAD; this may occur
in patients with aortoiliac stenoses and a well-collateralized arterial system that maintains perfusion pressure. In patients with a
normal ABI but a strong suspicion of significant PAD, office-based
exercise testing may be performed. Exercise accentuates arterial
gradients by increasing the turbulence across the flow-limiting
lesion and decreasing muscular arteriolar resistance to significantly attenuate lower-extremity perfusion pressure. In fact, arterial pressure at the ankle may reach zero in patients who develop
claudication and recover more than 10 minutes after exercise
cessation. In the office, stair climbing or active pedal plantar flex-
30
ion
may be used to elicit symptoms and document a decrease
in ankle pressure (and ABI) to confirm the diagnosis of intermittent claudication.
Noninvasive Laboratory Testing for Peripheral
Artery Disease
For patients in whom revascularization is considered, such as
those with CLI or disabling claudication, location and severity of
disease should be evaluated by additional noninvasive testing.
There are two general formats of noninvasive testing to discern
location and severity of PAD: physiological testing and anatomical imaging.
PHYSIOLOGICAL TESTING
Physiological or functional testing most commonly occurs in a
noninvasive vascular laboratory (see Chapter 12). Measurement
of limb segmental systolic pressures employs methods similar
to ABI measurement (
placed on the proximal thigh, distal thigh, calf, and ankle. The
cuffs are inflated sequentially to suprasystolic pressure and then
deflated to determine systolic pressure at each site. A Doppler
probe is placed on the posterior tibial or dorsalis pedis artery.
Fig. 18-6). Sphygmomanometric cuffs are
23
27
The lower
The
21,24
28,29
Arterial stenosis or occlusion will decrease the perfusion pressure. Arterial pressure gradients of more than 20 mmHg between
thigh cuffs and 10 mmHg between cuffs below the knee indicate
presence of a stenosis. As with the ABI, the most common source
of error for the test is vascular calcification. In the setting of vascular calcification, a toe brachial index may be obtained. Pressures
in the toe may be measured with strain gauge photoplethysmography. Pressure is measured in the toes and a ratio of toe pressure
to brachial artery pressure is generated; a value of 0.7 or less is
consistent with PAD.
Pulse volume recordings (PVRs) or segmental pneumatic plethysmography determines the relative change in limb volume with
each pulse and can be obtained along with segmental pressure
measurements. The pulse-volume waveform represents the product of pulse pressure and vascular wall compliance. In a healthy
person, the pulse-volume waveform is similar to a normal arterial
pressure waveform and includes rapid upstroke, dicrotic notch,
and downstroke (see
Fig. 18-6). The waveform changes when it is
recorded distal to a significant stenosis as perfusion pressure falls.
Initially, there is a loss of the dicrotic notch. As the stenosis worsens,
waveform upstroke (anacrotic slope) is delayed, amplitude is less,
and the downstroke (catacrotic slope) is slower. Combined use of
segmental pressure measurements and PVRs improves the accuracy of identifying significant stenosis.
Treadmill Testing
As described earlier, eliciting symptoms through exercise may
permit the diagnosis of PAD, despite a normal or near-normal ABI.
When a vessel has a significant stenosis, increasing flow through
the lesion decreases energy delivered beyond the area of stenosis. Treadmill exercise increases blood flow through a stenosed
vessel and can increase sensitivity of the ABI. In the vascular laboratory, a diagnosis of intermittent claudication and a quantification
of exercise tolerance may be obtained through treadmill exercise
testing. Many protocols exist to test walking ability, but each falls
into one of two types: constant or graded exercise. In constant
exercise protocols (e.g., Carter protocol), a specific speed (1.5-
2.0 mph) and treadmill grade (0%-12%) is chosen, whereas in the
graded exercise protocols (e.g., Hiatt or Gardner protocol), speed
and/or treadmill grade may increase.
31
In both protocols, the brachial and ankle pressures are determined pretest at rest, patients
exercise until they are unable to continue, and brachial and ankle
pressures are redetermined within 1 minute of exercise cessation. Patients with PAD as a cause of exercise limitation will have
an attenuated rise in ankle pressure compared to brachial artery
pressure or, more commonly, a fall in ankle pressure, thus lowering
the ABI. The fall in ankle pressure is directly related to severity of
arterial occlusive disease. Analogously, length of recovery is also
directly related to disease severity. Two parameters are recorded
in addition to the ABI: the time claudication begins (initial claudication time), and the time until exhaustion or cessation (absolute
claudication time). Variability of walking distance is greater in the
constant exercise protocols than the graded protocols, making the
latter more commonly used.
ANATOMICAL IMAGING OF THE PERIPHERAL
CIRCULATION
Defining arterial anatomy is not typically necessary to make the
diagnosis of PAD but is required for patients who will be undergoing revascularization. Following is a discussion of the major methods used to image peripheral arteries.
Duplex Ultrasonography
Duplex ultrasonography of the lower extremities is performed in
most vascular laboratories (see Chapter 12). The combination of
bright (B)-mode ultrasound, color Doppler imaging, and pulsedDoppler velocity analysis can accurately identify the location
and severity of atherosclerotic lesions in the legs. Normally, flow
through each arterial segment should be laminar, with a uniform
Pulse volume
recordings
Pulse volume
recordings
237
CH
18
PERIPHERAL ARTERY DISEASE: CLINICAL EVALUATION
124
124
116 78
86 76
FIGURE 186 Segmental pressure measurements. Sequential Doppler pressures are measured by placing sphygmomanometric cuffs on the proximal thigh,
distal thigh, calf, and ankle. Cuffs are inflated above systolic pressure and then slowly depressurized. Simultaneously, a Doppler probe placed over the dorsalis pedis or
posterior tibial artery monitors pressure. As the cuff is slowly deflated, reappearance of Doppler signal indicates systolic pressure at the level of the cuff which permits
blood flow. Arterial stenosis or occlusion will decrease perfusion pressure. Arterial pressure gradients between cuffs indicate presence of a stenosis. In this example,
arterial pressures (mmHg) are noted in the location of each sphygmomanometric cuff. Patient has evidence of a systolic gradient between both upper thigh cuffs,
suggestive of right iliac and/or common femoral arterial occlusive disease, and a gradient between right calf and ankle suggestive of arterial occlusive disease in
the infrapopliteal arteries. A significant gradient between the left lower thigh cuff and calf cuff is indicative of distal superficial femoral artery and/or popliteal artery
occlusive disease.
146
124
homogeneous color appearance. Blood flow becomes turbulent
and velocity increases at sites of sclerosis, creating areas of color
discordance. Pulsed Doppler measurements in the area of stenosis
demonstrate increased flow velocity and spectral broadening.
Applying the concepts of the Poiseuille law regarding movement of incompressible viscous fluids through a tube, the
ratio of peak systolic velocity in the area of a stenosis is compared with the normal area of artery proximal to the stenosis.
A ratio of 2 or greater is consistent with stenosis of 50% or more
(
Fig. 18-7). In one meta-analysis of seven studies, the sensitivity
and specificity of duplex ultrasound to detect 50% or greater
stenosis or occlusion were 88% and 96%, respectively, and to
detect complete occlusion were 90% and 99%, respectively.
32
In another meta-analysis of 14 studies, the sensitivity and specificity of duplex ultrasound with and without color-guided
Doppler analysis to detect 50% or greater stenosis or occlusion
was 93% and 95%, respectively.
33
Duplex ultrasonography is less
accurate at the site of calcified plaque because of the acoustic
shadowing caused by the dense calcium. Serial stenoses
are more difficult to diagnose because ultrasound diagnosis
relies on comparing peak arterial velocities between adjacent
segments, and there are altered hemodynamics between sequential stenoses. Single-center studies have found that ultrasound
may be used alone in planning both percutaneous and surgical peripheral revascularization.
34–37
Duplex ultrasonography is also used in the postoperative surveillance of arterial bypass grafts. A program of routine ultrasound surveillance is more likely to diagnose significant bypass
graft stenoses than history, physical examination, or ABI. Clinical
trials have evaluated the efficacy of ultrasound surveillance as a
strategy to identify graft stenosis and prompt repair before graft
occlusion occurs.
38
One study randomized 156 patients to serial
ultrasonography or ABI. Patients were referred for angiography
and then corrective revascularization if 50% or greater stenosis
was identified by ultrasound, or if the ABI decreased by 0.15 compared with the postoperative baseline.
39
Assisted primary cumulative vein graft patency in the ultrasound group was 78% compared
with 53% in the ABI group after 3 years. In other randomized studies, however, no benefit was found for ultrasound compared with
ABI 1 year after surgery.
bypass grafts
39,42,43
40,41
The data for surveillance for synthetic
and after angioplasty44 are less robust than for
vein grafts.
238
BC
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
CH
18
FIGURE 187 A, Poiseuille law defines
movement of an incompressible viscous fluid
A
through a tube. Fluid entry into tube must equal
its exit; thus, the ratio of peak-systolic velocity in
the area of stenosis is proportional to the segment
of normal vessel proximal to stenosis. When the
ratio is greater than 2, stenosis of more than
50% is diagnosed. Sensitivity and specificity of
duplex ultrasound evaluation in determination
of stenoses of 50% or greater range from 90% to
95%. Normal arterial flow velocity is approximately
100 cm/s. B, Doppler ultrasound is passed through
a recently placed superficial femoral artery (SFA)
stent, demonstrating normal flow velocity. This
is indicative of a patent stent without evidence
of restenosis. C, Doppler ultrasound is passed
through distal anastomosis of a femoral-popliteal
bypass graft, demonstrating a flow velocity of
4.4 m/s. This is consistent with greater than 75%
stenosis. Velocity in proximal normal segment is
1.3 m/s (not shown).
Magnetic Resonance Angiography
Magnetic resonance angiography (MRA) is an accurate imaging modality to diagnose PAD, visualize peripheral arteries, and
determine the location of stenoses (see Chapter 13). Techniques
used to image the arterial tree include black blood, phase contrast, time of flight ( TOF ), and contrast-enhanced MRA.
45
The
application of two magnetic pulses to suppress signal in the vessel lumen yields a dark appearance of flowing blood, with the
vessel wall remaining white. Selective removal of blood from the
image causes the lumen to appear black, and the technique is
therefore called black blood. When the phase shift of moving
electron spins in flowing blood is compared with surrounding
stable tissue, blood volume and velocity can be measured to
permit assessment of blood flow. Application of electrocardiographic gating while interrogating the flow-related enhancement
of spins into a partially saturated area provides a time of flight
angiogram.
lengthy acquisition types, turbulence, nonlinear vascular structures, and retrograde flow.
46,47
Limitations of a flow-based TOF MRA include
48
Most MRAs are performed using contrast, most commonly
gadolinium. Contrast-enhanced MRA provides a high-resolution
angiogram. Contrast-enhanced TOF MRA is useful as a noninvasive imaging test to define lower-extremity vascular anatomy. In a
meta-analysis comparing contrast-enhanced MRA with TOF MRA,
the contrast-enhanced study had a much greater diagnostic accu-
48
r a c y.
Use of contrast has improved scan quality and efficiency and
enhanced vessel visualization and identification, especially in distal
49
vessels
the presence of stenoses and reveal distal vessels suitable for bypass
not demonstrated by contrast angiography.
(Fig. 18-8). Magnetic resonance angiography can identify
50,51
In a meta-analysis of
32 studies of contrast-enhanced MRA and intraarterial digital subtraction angiography (DSA), the pooled sensitivity of MRA was 95%,
and specificity was 96%.
One potential limitation is a tendency for MRA to overestimate
lesion severity.
53
Similar benefits and limitations exist in the imag-
52
ing of bypass grafts. Magnetic resonance angiography has a sensitivity as high as 91% for identification of arterial bypass graft
stenoses
ses.
54
but overestimates lesion severity in up to 30% of steno-
55,56
A sound strategy may involve use of MRA initially because
FIGURE 188 Gadolinium-enhanced magnetic resonance angiogram
(MRA). This MRA was performed in a patient with Takayasu's arteritis. Several
findings are notable. Patient has an occluded left renal artery, and right internal
iliac artery has severe stenosis (thick arrow). At the thin arrow is an area of
dropout due to image interference by a previously placed stent. Curved arrow
indicates occluded left upper renal artery.
of the noninvasive nature of the test and its superior identification of bypass vessels, reserving DSA for cases requiring greater
definition.
57
Technological advancement is rapid in MRA, improving detection and identification of arterial occlusive disease. As
imaging protocols and techniques, such as three-dimensional
(3D) MRA imaging, gain acceptance and are made commonly
available, MRA may ultimately be used as a stand-alone evaluation prior to revascularization.
58–60
Computed Tomographic Angiography
Computed tomographic angiography (CTA) has recently undergone rapid improvements in technology and imaging, allowing
its entry into peripheral vascular imaging (see Chapter 14). Much
of this advance results from development of multidetector-row
CT scanners and improved resolution of arteries. Availability of
higher resolution to scanners is particularly relevant for smaller
and more distal arteries.
In meta-analyses of studies mostly using multidetector CT scanners, pooled sensitivity and specificity for detecting stenoses of
50% or greater in leg arteries were 91% to 92% and 91% to 93%,
respectively.
32,61
As scanner number increases, newer CT scanners
should have even greater accuracy.
Computed tomography angiography is commonly presented
using a maximal intensity projection (MIP) or with a volume
rendering technique (
Fig. 18-9). The MIP algorithm displays
only the pixel with the highest intensity along a ray perpendicular to the plane of projection. This algorithm creates a twodimensional (2D) projectional image similar in appearance to
MRA or contrast angiography. Volume rendering applies shades
of gray to pixels of varying density.
62
Fourier transfer functions
allow modification of the relative contribution of various pixel
values. Volume rendering considers pixels that are only partially filled with contrast material. Arterial calcification limits
imaging with both CT techniques. Optimal techniques used for
postprocessing are being developed.
63
As resolution improves,
239
CH
18
PERIPHERAL ARTERY DISEASE: CLINICAL EVALUATION
FIGURE 1810 Contrast abdominal angiogram demonstrating
significant aortic stenosis just proximal to bifurcation into iliac arteries
(arrow).
FIGURE 189 Volume-rendered computed tomographic (CT) angiogram
of the lower extremities. Note superficial femoral artery (SFA) occlusion and
collateral formation depicted by this study. (Image courtesy Dr. Joseph Schoepf.)
CTA may become a regular instrument in the diagnostic armamentarium because of its rapid study time (typically <1 minute) or because of the 75% reduction in ionizing radiation
compared with angiography.
Contrast Angiography
Contrast angiography is the most venerable and widely available method for imaging arterial anatomy (see Chapter 15).
Angiography commonly serves as the standard for determining the sensitivity and specificity of newer techniques and
is an excellent method to clarify arterial anatomical queries
(
Fig. 18-10). Technical improvements in equipment, includ-
ing smaller catheters, image resolution, and digital subtraction,
have enhanced the capability of angiography. Digital subtraction
eliminates bony and soft-tissue shadows from the angiographic
image, enhancing angiographic detail. Despite wide acceptance
of angiography as a reliable method for defining arterial anatomy,
its invasive nature, requirement for contrast, nephrotoxicity, risk
of atheroembolism, and risk of pseudoaneurysms or arteriovenous fistula (AVF) continue to foster development of alternative
angiographic methods.
Summary
An algorithm for evaluating the patient with PAD is depicted
in
Figure 18-11. Diagnosis and evaluation of PAD is required
in patients predisposed to develop PAD because of age or the
presence of atherosclerotic risk factors and in patients whose
history or examination are suggestive of PAD. An office evaluation should include measurement of ABI. An exercise test with
measurement of the ABI after exercise is appropriate if resting
ABI is normal, yet clinical suspicion remains high. Patients with
noncompressible ankle vessels should be referred to a vascular
laboratory for additional testing, including segmental pressure
measurements, pulse-volume recordings, and/or duplex ultrasonography. Symptomatic patients, particularly those with CLI
who are being treated for revascularization, should undergo
anatomical imaging with CT, MRA, or conventional carotid
angiography.
240
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
CH
18
Antiplatelet therapy
Low clinical
suspicion
Normal
exercise test
or low suspicion:
No PAD
Assess CV risk:
Smoking
Lipids
Blood pressure
Glycemia
Modify risk factors
Age 50 – 69 y DM or smoking
Age 70 y
Claudication symptoms
Abnormal vascular exam
Measure ABIABI 0.9 – 1.3
High clinical
ABI 0.9
suspicion
Exercise test
Abnormal result:
PAD diagnosed
Assess extremity risk
CLI
Disabling claudication
Rest pain
Non-healing ulcer
Gangrene
Imaging and revascularization
ABI 1.3
PVR
Toe pressures
imaging
Normal result:
No PAD
Asymptomatic
claudication
Medical therapy
or
Exercise
FIGURE 1811 Algorithm for peripheral artery disease
(PAD) evaluation. History, physical examination, and ankle-
brachial index (ABI) make the diagnosis of PAD in majority of
cases. Treadmill exercise testing is performed in conjunction
with measurement of ABI performed prior to and immediately
following exercise. Segmental pressure measurements, pulse
volume recordings (PVR), toe pressures, and arterial duplex
ultrasound imaging are noninvasive vascular tests used to
consider and assess severity of PAD. Anatomical imaging by
duplex ultrasonography, computed tomography angiography
(CTA), magnetic resonance angiography (MRA), or conventional
contrast angiography is used to assess symptomatic patients
who require revascularization. Patients with PAD require risk
factor assessment and treatment. The physician should more
aggressively inquire about leg symptoms and inspect feet for
evidence of critical limb ischemia (CLI). CV, cardiovascular; DM,
diabetes mellitus.
REFERENCES
1. Pande RL, Perlstein TS, Beckman JA, et al: Secondary prevention and mortality in peripheral
artery disease: National Health and Nutrition Examination Study, 1999 to 2004, Circulation
124:17–23, 2011.
2. Selvin E, Erlinger TP: Prevalence of and risk factors for peripheral arterial disease in the United
States: Results from the National Health and Nutrition Examination Survey, 1999-2000,
Circulation 110:738–743, 2004.
3. Diehm C, Schuster A, Allenberg JR, et al: High prevalence of peripheral arterial disease and
co-morbidity in 6880 primary care patients: cross-sectional study, Atherosclerosis 172:95–105,
2004.
4. Hirsch AT, Criqui MH, Treat-Jacobson D, et al: Peripheral arterial disease detection,
awareness, and treatment in primary care, JAMA 286:1317–1324, 2001.
5. McDermott MM, Greenland P, Liu K, et al: Leg symptoms in peripheral arterial disease:
associated clinical characteristics and functional impairment, JAMA 286:1599–1606, 2001.
6. Rose GA: The diagnosis of ischaemic heart pain and intermittent claudication in field
surveys, Bull World Health Organ 27:645–658, 1962.
7. Norgren L, Hiatt WR, Dormandy JA, et al: Inter-Society Consensus for the Management of
Peripheral Arterial Disease (TASC II), J Vasc Surg 45(Suppl S):S5–S67, 2007.
8. Regensteiner JG, Steiner JF, Panzer RJ, et al: Evaluation of walking impairment by
questionnaire in patients with peripheral arterial disease, J Vasc Med Biol 2:142, 1990.
9. McDermott MM, Mehta S, Greenland P: Exertional leg symptoms other than intermittent
claudication are common in peripheral arterial disease, Arch Intern Med 159:387–392,
1999.
10. McDermott MM, Ferrucci L, et al: The ankle-brachial index is associated with the magnitude
of impaired walking endurance among men and women with peripheral arterial disease,
Vasc Med 15:251–257, 2010.
11. McDermott MM, Mehta S, Liu K, et al: Leg symptoms, the ankle-brachial index, and walking
ability in patients with peripheral arterial disease, J Gen Intern Med 14:173–181, 1999.
12. Hirsch AT, Haskal ZJ, Hertzer NR, et al: ACC/AHA 2005 practice guidelines for the
management of patients with peripheral arterial disease (lower extremity, renal,
mesenteric, and abdominal aortic): a collaborative report from the American Association
for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography
and Interventions, Society for Vascular Medicine and Biology, Society of Interventional
Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to
Develop Guidelines for the Management of Patients with Peripheral Arterial Disease):
endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation;
National Heart, Lung, and Blood Institute; Society for Vascular Nursing; Transatlantic InterSociety Consensus; and Vascular Disease Foundation, Circulation 113:e463–e654, 2006.
13. Slovut DP, Olin JW: Fibromuscular dysplasia, N Engl J Med 350:1862–1871, 2004.
14. Epidemiology of lower extremity amputation in centres in Europe, North America and
East Asia. The Global Lower Extremity Amputation Study Group, Br J Surg 87:328–337, 2000.
15. Sigvant B, Wiberg-Hedman K, Bergqvist D, et al: A population-based study of peripheral
arterial disease prevalence with special focus on critical limb ischemia and sex differences,
J Vasc Surg 45:1185–1191, 2007.
16. Diabetes-related amputations of lower extremities in the Medicare population--Minnesota,
1993-1995, MMWR Morb Mortal Wkly Rep 47:649–652, 1998.
17. Jude EB, Oyibo SO, Chalmers N, et al: Peripheral arterial disease in diabetic and nondiabetic
patients: a comparison of severity and outcome, Diabetes Care 24:1433–1437, 2001.
18. Jonason T, Bergstrom R: Cessation of smoking in patients with intermittent claudication.
Effects on the risk of peripheral vascular complications, myocardial infarction and
mortality, Acta Med Scand 221:253–260, 1987.
19. Lassila R, Lepantalo M: Cigarette smoking and the outcome after lower limb arterial
surgery, Acta Chir Scand 154:635–640, 1988.
20. Khan NA, Rahim SA, Anand SS, et al: Does the clinical examination predict lower extremity
peripheral arterial disease? JAMA 295:536–546, 2006.
21. Aboyans V: ABI scientific statement, Circulation In press.
22. McDermott MM, Criqui MH, Liu K, et al: Lower ankle/brachial index, as calculated by
averaging the dorsalis pedis and posterior tibial arterial pressures, and association with leg
functioning in peripheral arterial disease, J Vasc Surg 32:1164–1171, 2000.
23. ACCF/AHA Focused Update of the Guideline for the Management of patients with
peripheral artery disease (Updating the 2005 Guideline): a report of the American College
of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
Circulation;124:2020–2045, 2011.
24. Lijmer JG, Hunink MG, van den Dungen JJ, et al: Roc analysis of noninvasive tests for
peripheral arterial disease, Ultrasound Med Biol 22:391–398, 1996.
25. Leskinen Y, Salenius JP, Lehtimaki T, et al: The prevalence of peripheral arterial disease
and medial arterial calcification in patients with chronic renal failure: requirements for
diagnostics, Am J Kidney Dis 40:472–479, 2002.
26. Ishimura E, Okuno S, Kitatani K, et al: Different risk factors for peripheral vascular
calcification between diabetic and non-diabetic haemodialysis patients–importance of
glycaemic control, Diabetologia 45:1446–1448, 2002.
27. Fowkes FG, Murray GD, Butcher I, et al: Ankle brachial index combined with Framingham
risk score to predict cardiovascular events and mortality: a meta-analysis, JAMA
300:197–208, 2008.
28. Vogt MT, McKenna M, Anderson SJ, et al: The relationship between ankle-arm index and
mortality in older men and women, J Am Geriatr Soc 41:523–530, 1993.
29. Sikkink CJ, van Asten WN, van't Hof MA, et al: Decreased ankle/brachial indices in relation
to morbidity and mortality in patients with peripheral arterial disease, Vasc Med 2:169–173,
1997.
30. McPhail IR, Spittell PC, Weston SA, et al: Intermittent claudication: an objective officebased assessment, J Am Coll Cardiol 37:1381–1385, 2001.
31. Hiatt WR, Hirsch AT, Regensteiner JG, et al: Clinical trials for claudication. Assessment of
exercise performance, functional status, and clinical end points. Vascular Clinical Trialists,
Circulation 92:614–621, 1995.
32. Collins R, Burch J, Cranny G, et al: Duplex ultrasonography, magnetic resonance angiography,
and computed tomography angiography for diagnosis and assessment of symptomatic,
lower limb peripheral arterial disease: systematic review, BMJ 334:1257, 2007.
33. de Vries SO, Hunink MG, Polak JF: Summary receiver operating characteristic curves as a
technique for meta-analysis of the diagnostic performance of duplex ultrasonography in
peripheral arterial disease, Acad Radiol 3:361–369, 1996.
34. Proia RR, Walsh DB, Nelson PR, et al: Early results of infragenicular revascularization based
solely on duplex arteriography, J Vasc Surg 33:1165–1170, 2001.
35. Ascher E, Mazzariol F, Hingorani A, et al: The use of duplex ultrasound arterial mapping
as an alternative to conventional arteriography for primary and secondary infrapopliteal
bypasses, Am J Surg 178:162–165, 1999.
36. Lofberg AM, Karacagil S, Hellberg A, et al: The role of duplex scanning in the selection
of patients with critical lower-limb ischemia for infrainguinal percutaneous transluminal
angioplasty, Cardiovasc Intervent Radiol 24:229–232, 2001.
37. Mandolfino T, Canciglia A, D'Alfonso M, et al: Infrainguinal revascularization based on
duplex ultrasound arterial mapping, Int Angiol 25:256–260, 2006.
38. Westerband A, Mills JL, Kistler S, et al: Prospective validation of threshold criteria for
intervention in infrainguinal vein grafts undergoing duplex surveillance, Ann Vasc Surg
11:44–48, 1997.
39. Lundell A, Lindblad B, Bergqvist D, et al: Femoropopliteal-crural graft patency is improved
by an intensive surveillance program: A prospective randomized study, J Vasc Surg 21:
26–33, discussion 33–24, 1995.
40. Ihlberg L, Luther M, Alback A, et al: Does a completely accomplished duplex-based
surveillance prevent vein-graft failure? Eur J Vasc Endovasc Surg 18:395–400, 1999.
41. Ihlberg L, Luther M, Tierala E, et al: The utility of duplex scanning in infrainguinal vein
graft surveillance: results from a randomised controlled study, Eur J Vasc Endovasc Surg 16:
19–27, 1998.
42. Tinder CN, Chavanpun JP, Bandyk DF, et al: Efficacy of duplex ultrasound surveillance after
infrainguinal vein bypass may be enhanced by identification of characteristics predictive
of graft stenosis development, J Vasc Surg 48:613–618, 2008.
43. Brumberg RS, Back MR, Armstrong PA, et al: The relative importance of graft surveillance and
warfarin therapy in infrainguinal prosthetic bypass failure, J Vasc Surg 46:1160–1166, 2007.
44. Connors G, Todoran TM, Engelson BA, et al: Percutaneous revascularization of long
femoral artery lesions for claudication: patency over 2.5 years and impact of systematic
surveillance, Catheter Cardiovasc Interv 77:1055–1062, 2011.
45. Tatli S, Lipton MJ, Davison BD, et al: From the RSNA refresher courses: MR imaging of aortic
and peripheral vascular disease, Radiographics 23 Spec No:S59–S78, 2003.
46. Steffens JC, Link J, Schwarzenberg H, et al: Lower extremity occlusive disease: diagnostic
imaging with a combination of cardiac-gated 2D phase-contrast and cardiac-gated 2D
time-of-flight MRA, J Comput Assist Tomogr 23:7–12, 1999.
47. Quinn SF, Sheley RC, Semonsen KG, et al: Aortic and lower-extremity arterial disease: evaluation
with MR angiography versus conventional angiography, Radiology 206:693–701, 1998.
48. Nelemans PJ, Leiner T, de Vet HC, et al: Peripheral arterial disease: meta-analysis of the
diagnostic performance of MR angiography, Radiology 217:105–114, 2000.
49. Dellegrottaglie S, Sanz J, Macaluso F, et al: Technology insight: magnetic resonance
angiography for the evaluation of patients with peripheral artery disease, Nat Clin Pract
Cardiovasc Med 4:677–687, 2007.
50. Dorweiler B, Neufang A, Kreitner KF, et al: Magnetic resonance angiography unmasks
reliable target vessels for pedal bypass grafting in patients with diabetes mellitus, J Vasc
Surg 35:766–772, 2002.
51. Kreitner KF, Kalden P, Neufang A, et al: Diabetes and peripheral arterial occlusive disease:
prospective comparison of contrast-enhanced three-dimensional MR angiography
with conventional digital subtraction angiography, AJR Am J Roentgenol 174:171–179,
2000.
52. Menke J, Larsen J: Meta-analysis: accuracy of contrast-enhanced magnetic resonance
angiography for assessing steno-occlusions in peripheral arterial disease, Ann Intern Med
153:325–334, 2010.
53. Winterer JT, Schaefer O, Uhrmeister P, et al: Contrast enhanced MR angiography in the
assessment of relevant stenoses in occlusive disease of the pelvic and lower limb arteries:
diagnostic value of a two-step examination protocol in comparison to conventional DSA,
Eur J Radiol 41:153–160, 2002.
54. Bendib K, Berthezene Y, Croisille P, et al: Assessment of complicated arterial bypass grafts:
value of contrast-enhanced subtraction magnetic resonance angiography, J Vasc Surg
26:1036–1042, 1997.
55. Dorenbeck U, Seitz J, Volk M, et al: Evaluation of arterial bypass grafts of the pelvic
and lower extremities with gadolinium-enhanced magnetic resonance angiography:
comparison with digital subtraction angiography, Invest Radiol 37:60–64, 2002.
56. Loewe C, Cejna M, Schoder M, et al: Contrast material-enhanced, moving-table MR
angiography versus digital subtraction angiography for surveillance of peripheral arterial
bypass grafts, J Vasc Interv Radiol 14:1129–1137, 2003.
57. Brillet PY, Vayssairat M, Tassart M, et al: Gadolinium-enhanced MR angiography as first-line
preoperative imaging in high-risk patients with lower limb ischemia, J Vasc Interv Radiol
14:1139–1145, 2003.
58. Cronberg CN, Sjoberg S, Albrechtsson U, et al: Peripheral arterial disease. Contrastenhanced 3D MR angiography of the lower leg and foot compared with conventional
angiography, Acta Radiol 44:59–66, 2003.
59. Bezooijen R, van den Bosch HC, Tielbeek AV, et al: Peripheral arterial disease: sensitivityencoded multiposition MR angiography compared with intraarterial angiography and
conventional multiposition MR angiography, Radiology 231:263–271, 2004.
60. Steffens JC, Schafer FK, Oberscheid B, et al: Bolus-chasing contrast-enhanced 3D MRA of
the lower extremity. Comparison with intraarterial DSA, Acta Radiol 44:185–192, 2003.
61. Heijenbrok-Kal MH, Kock MC, Hunink MG: Lower extremity arterial disease: multidetector
CT angiography meta-analysis, Radiology 245:433–439, 2007.
62. Lawler LP, Fishman EK: Multi-detector row CT of thoracic disease with emphasis on 3D
volume rendering and CT angiography, Radiographics 21:1257–1273, 2001.
63. Becker CR, Wintersperger B, Jakobs TF: Multi-detector-row CT angiography of peripheral
arteries, Semin Ultrasound CT MR 24:268–279, 2003.
241
CH
18
PERIPHERAL ARTERY DISEASE: CLINICAL EVALUATION
CHAPTER
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
19 Medical Treatment of Peripheral
Artery Disease
Heather L. Gornik, Mark A. Creager
Treatment of patients with peripheral artery disease (PAD)
must take into consideration the risk of adverse cardiovascular events related to systemic atherosclerosis (myocardial
infarction [MI], stroke, death) and limb-related symptoms and
prognosis (functional capacity, quality of life, limb viability).
The risk of MI, stroke, or death related to cardiovascular disease is increased three- to sixfold in patients with PAD (see
Chapter 16). Functional limitations imposed by PAD, including symptoms of limb claudication, impaired walking ability,
and critical limb ischemia (CLI), adversely affect quality of
life and restrict patients’ abilities to participate in many basic
vocational and recreational activities. In addition, patients
with PAD are at increased risk of lower-extremity ulceration
and amputation, and thus foot care represents an important
component of management of these patients. Medical management of the patient with PAD has three central goals: (1)
prevention of cardiovascular events, (2) improvement of quality of life and functional capacity, and (3) protection and care
of the limb (
to support aggressive risk factor modification and antiplatelet
therapy for patients with PAD to reduce adverse cardiovascular events. We also review the physical and medical therapies used to treat patients with intermittent claudication and
CLI to improve lower-extremity function and ameliorate symptoms. Foot care for PAD is briefly discussed. Catheter-based
revascularization for PAD is reviewed in Chapter 20, and surgical revascularization for PAD is reviewed in Chapter 21.
Multisocietal consensus guidelines for management of the
patient with PAD are available and may be helpful in clinical
practice.
Fig. 19-1). In this chapter, we review the evidence
1,2
Risk Factor Modification and Antiplatelet
Therapy for Prevention of Cardiovascular
Events
Smoking Cessation
Tobacco smoking is strongly associated with development and
progression of PAD, with the risk of PAD among smokers as high as
threefold that of nonsmokers (see Chapter 16). Smoking cessation
is a critical component of risk factor modification for patients with
PAD. Epidemiological studies have established that smoking cessation improves both cardiovascular and limb-related outcomes
among patients with PAD. Given the established hazards of cigarette smoking, it would be unethical to conduct a randomized clinical trial of smoking cessation.
Smoking cessation has salutary effects on claudication symptoms, exercise physiology, and limb-related outcomes in patients
with symptomatic PAD. Patients with intermittent claudication
who quit smoking have longer pain-free walking times and maximal walking times compared with patients who continue to
3
smoke.
In a prospective study of patients with intermittent claudication followed with serial noninvasive vascular testing over
a period of 10 months, patients who quit smoking had significant improvements in maximal treadmill walking distance and
postexercise ankle pressure, whereas ongoing smokers had no
changes in these parameters.
ated with improved clinical outcomes in patients with PAD. In a
Swedish study, patients with intermittent claudication who were
active smokers or who had quit within 6 months were followed
4
Smoking cessation is also associ-
prospectively for development of limb-related and cardiovascular outcomes.
was associated with development of CLI and was also an independent predictor of the need for surgical revascularization. Indeed,
only patients who continued to smoke developed rest pain during
the follow-up period. Ongoing smoking was also associated with
development of MI and a trend toward decreased overall survival
at 10 years of follow-up.
Continued cigarette smoking is associated with adverse outcome among patients with PAD referred for vascular surgery. In
a prospective study of patients referred for femoropopliteal arterial bypass grafting, ongoing tobacco use was associated with
a significant reduction in the 1-year cumulative patency rate of
both venous and prosthetic lower-extremity bypass grafts.
Australian study of patients who underwent lumbar sympathectomy or lower-extremity bypass grafting for symptomatic PAD,
patients who quit smoking following surgery had dramatically
improved 5-year survival rates compared to patients who continued to smoke.
operative patients were due to a major vascular event, whereas
the remaining deaths were due to other smoking-related illnesses,
principally chronic obstructive pulmonary disease (COPD) and
lung cancer.
Degree of ongoing tobacco use following revascularization may
also be predictive of adverse events. In a registry study of patients
who underwent their first arterial revascularization procedure,
patients categorized as heavy smokers (>15 cigarettes/day) had
significantly reduced overall survival compared to moderate smokers (<15 cigarettes/day).
amputation rate among heavy smokers compared with moderate
smokers at 3 years’ follow-up.
Despite the multiple benefits of smoking cessation in patients
with PAD, it is an extremely difficult goal to accomplish, and
initial success rates are low. The efficacy of physician advice in
achieving smoking cessation is less than 5%.
is at least 10-fold higher when smoking cessation advice and
encouragement are given to patients at risk for MI, or patients
who have survived an MI. Intensive counseling customized to
PAD patients who continue to smoke is associated with a significant improvement in confirmed tobacco abstinence at
6 months of follow-up, compared to standard clinical smoking
cessation advice.10 Smoking cessation programs may be more
successful when coupled with pharmacological therapy, including both nicotine and non-nicotine agents. The antidepressant
bupropion has been demonstrated to improve tobacco abstinence rates at 12 months relative to placebo when used alone or
in combination with the nicotine patch.11 Recently, varenicline,
a novel partial agonist of the nicotinic acetylcholine receptor
(nAchR) α4β, has been shown to improve tobacco abstinence
rates among subjects both with and without cardiovascular disease, including patients with PAD.
vascular disease, varenicline was associated with a threefold
likelihood of abstinence at 1-year follow-up compared with placebo, although the absolute abstinence rate was only 19.2%.
Side effects of varenicline include sleep abnormalities, nausea,
and flatulence.
ciated with an increased risk of neuropsychiatric side effects.
Package labeling for both agents includes a black box warning
recommending observation for changes in behavior or mood or
development of suicidal ideation while receiving these agents
for smoking cessation treatment.
5
At 7 years of follow-up, ongoing tobacco smoking
6
In an
7
The majority of deaths that occurred in the post-
8
In addition, there was a 10-fold higher
9
The success rate
12,13
Among those with cardio-
13,14
Both varenicline and bupropion are asso-
14,15
13
242
Соседние файлы в папке Библиотека им академика М.И. Перельмана