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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3925_Библиотеки_им_академика_М_И_Перельмана
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232 Sanz et al.
also decrease wall strength, thus favoring rupture (16–18). Reductions in the
number of smooth muscle cells appear to favor aortic dilatation due to loss of their
metabolic function rather than because of diminished contractile capacity (7).
Collagen abnormalities, such as those seen in Ehlers–Danlos syndrome, are
similarly associated with increased risk of arterial dilatation and dissection (19).
Although conflicting results have been reported, collagen amount seems to be
increased in pathologic aortas, perhaps in an attempt to repair or maintain struc-
tural integrity, although newly synthesized collagen may be defective (20–23).
Elastin and collagen crosslinks, which play a role in filament stabilization, are
also abnormally reduced in aneurysms (23,24).
Other structural proteins may also be involved in aneurysm formation and
predisposition for dissection (7). Fibrillin, abnormal in Marfans’s syndrome, con-
tributes to the extracellular microfibrillar ultrastructure that serves as the support for
elastin deposition and plays a role in the distribution of shear stress (7,25) Fibulin-5
participates in the regulation of elastic fiber assembly. Its expression is reduced in
subjects with proximal aortic dissection and correlates with the degree of elastin
degeneration (26). Also, peptidases, such as matrix metalloproteinases and elastase,
play a role in elastin and collagen degeneration and aneurysm formation (27–29).
Mural ischemia is probably a significant contributor to the development of
aortic dissection. Whereas the intima and inner media nourish mainly by passive
diffusion from the lumen, the outer layers of large arteries receive their nutrients
through the vasa vasorum (30). Interestingly, the common plane of dissection of
the vessel wall is the outer third of the media, the limit between the two zones
(30,31). Intimal thickening characteristic of atherosclerotic disease may compro-
mise the nourishment of the inner media. Similarly, a decrease in number or func-
tion of the vasa vasorum results in ischemic medial necrosis, morphologic changes
in collagen and elastin fibers of the outer media, increases in collagen content, and
enhanced aortic stiffness at various levels of mechanical stress (32,33). Ischemia
promotes inhomogeneity in the transmural mechanical properties, resulting in
increased interlayer shear stress that may favor dissection (33). Alterations in vasa
vasorum functionality take place, for example, in arterial hypertension (34).
Hemodynamic Factors
In a cylindrical tube, circumferential stress is determined by Laplace’s law (35):
T ≈ P
t
× R/μ,
where T is the circumferential wall tension, P
t
the transmural wall pressure (intra-
vascular minus extravascular wall pressure), R the radius of the vessel, and
μ
the
wall thickness. Although there are ethnic and interindividual differences in aortic
wall thickness that may influence wall tension (36), transmural pressure and the
vessel diameter are considered the most important determinants. It is clear from
Laplace’s law that stress will increase proportionally to the arterial diameter,
which explains why aneurysms rupture more frequently than nondilated segments.
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Acute Aortic Dissection 233
P
t
is usually simplified to the intravascular distending force, that is, the arterial
pressure. Indeed, arterial hypertension has been often associated with the propen-
sity to develop aortic dissection and aneurysms, and constitutes a common clinical
finding in acute aortic syndromes (3,37–39). An increment in systolic blood pres-
sure of 26 mmHg has been found equivalent to an increase in aortic diameter of
1 cm in terms of generated wall stress (16).
However, wall stress prediction is actually much more complex, particularly
in the presence of aneurismal dilatations where the assumption of a cylindrical
shape of Laplace’s law does not hold. Stress distribution in aneurysms is in fact
largely heterogeneous—depending on the shape of the dilatation, local differences
in the wall characteristics, or presence of mural thrombosis (17). Apart from
circumferential stress (perpendicular to the arterial wall), there is probably con-
siderable shear stress among lamellae, as there is slight motion of the different
layers of the media along the plane of the vessel wall. This shear stress also
increases significantly in the presence of aortic dilatation (31). As mentioned
earlier, uniformity in stress distribution is an important protective characteristic
of the arterial wall. Homogeneity of the media is lost in the presence of focal
fibrosis, calcification, islets of mucoid material, or intramural hemorrhage that can
occur with conditions associated with medial degeneration (13,31,40). This results
in nonuniform distribution of stress that can trigger dissection (31).
Although it is clear that wall stress is directly proportional to blood pressure,
observations made in the 1960s suggested that pressure itself is not the main
determinant of aortic disruption. Interestingly, both normal and diseased aortas were
found to be highly resistant to rupture from static forces, indicating the impor-
tance of pulsatility as a contributor to wall rupture (41). This led to the hypothesis
that the morphology of the arterial pulse wave might have a stronger influence
than the actual pressure level (42,43).
In this regard, the contractile status of the myocardium plays an important
pathophysiological role. Impulse is defined as the product of force and time.
The term cardiac impulse has been employed to define the net force exerted by
the contracting myocardium during ejection. During systole, the maximum rate
of myocardial shortening occurs at the beginning of contraction, when load is
minimal, and the velocity of shortening decreases as load grows. This results in
maximal velocity of ejected blood early in systole, which coincides with the
maximal rate of pressure change within the ventricle (or dp/dt
max
). Information
regarding ventricular impulse and dp/dt
max
can be derived from the upslope of the
initial portion of the aortic pressure curve (Fig. 2) (44,45).
Sympathetic stimulation results in increases in cardiac impulse, whereas
reductions in sympathetic tone lead to diminished force of contraction and
decreased dp/dt
max
(44). The impact of dp/dt
max
and pulsatility is most prominent
in the ascending aorta and the aortic isthmus—areas where intimal tears often
develop (46). The maximal rate of pressure rise (dp/dt
max
) appears to be the most
important determinant of aortic rupture and the progression of dissection. It is
important to realize that regardless of the initial mechanism leading to wall
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234 Sanz et al.
disruption (intimal tear or intramural bleeding), it is the progression of the dissec-
tion that leads to clinical complications (47).
In an important experiment, Prokop et al. (48) evaluated the effects of step-
wise increases in flow, pressure, or dp/dt
max
on the rate of dissection progression
using prosthetic as well as explanted dog aortas in which an artificial tear was
produced. Neither high nonpulsatile flows nor elevated intra-aortic pressures
caused dissection extension. However, pulsatile flow led to progression of dissec-
tion both proximal and especially distal to the intimal tear. Importantly, the rate
of dissection was not dependent on the mean or peak pressure. When dp/dt
max
was
gradually increased, the rate of dissection progressed in parallel. Moreover,
a threshold value of dp/dt
max
was identified below which no progression of dissec-
tion occurred (Fig. 3). In the animal aortas, some of the dissections progressed to
complete wall rupture, whereas, in others, the false cavity recanalized into the true
lumen, a behavior similar to that observed in spontaneous human dissections.
Figure 2 In the aortic pressure curve, the tangent (dashed line) of the steepest point in the
ascending portion indicates the maximum pressure change (dp/dt
max
).
Figure 3 Enhanced progression of aortic dissection in relation with increasing levels of
dp/dt
max
. It can be noted that, at least in the experimental setting, no progression occurs below
a threshold of dp/dt
max
. Source: From Ref. 48.
10
9
8
7
6
5
4
3
2
1
0
Dissection progression/100 pulses (mm)
dp/dtmax
600
800
900
1000
1200
1400
1600
1800
2000
2200
2400
(mmHg/s)
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Acute Aortic Dissection 235
From these experiments, it was shown that static forces and/or laminar flow do not
appear to promote extension of the dissection, as there is no pressure gradient
between the torn intima and the adjacent tissue. However, in the presence of pul-
satile flow, such a gradient, proportional to dp/dt
max
, develops and leads to rapid
progression of the dissection. Elastic pulsation of the wall with each heartbeat or
shear stress caused by flowing blood could additionally contribute to the evolution
of the dissection, although these forces appear to play minor roles (48).
Anti-impulse Therapy and Blood Pressure Control
for Acute Aortic Dissection
The pathophysiological considerations we have described provide the rationale
for using drugs with anti-impulse properties as the cornerstone of medical therapy
in acute aortic dissection. Although blood pressure control is also fundamental,
it is crucial to realize that drugs with arterial vasodilator properties, very effective
in decreasing arterial pressure, often result in increments in dp/dt
max
and may
paradoxically increase the risk of wall rupture (Fig.4) (46,49). This is due to reflex
sympathetic responses mediated by arterial baroreceptors when blood pressure
drops, leading to increased cardiac chronotropy and inotropy.
Additional evidence supporting the use of anti-impulse therapy came from
experimental studies evaluating the effects of chronic administration of various
drugs on the risk of aortic ruptures. These studies were performed in turkeys with
medial degeneration induced by
β
-aminopropionitrile, an inhibitor of lysyl oxi-
dase, which interferes with the formation of elastin and collagen crosslinks (50).
Figure 4 Diagram of aortic pressure curves under various conditions. The continuous
line (b) represents the baseline state. Administration of a vasodilator agent such as nitro-
prusside is represented by the dashed curve (a). There is significant decrease in pressure
levels and acceleration in heart rate, but this is accompanied by a steepest slope of the
ascending portion of the curve (increased dp/dt
max
). Beta blockade administration is repre-
sented by the dotted line (c). Although the degree of pressure lowering is usually smaller,
the drug negative inotropic and chronotropic effects result in decreased impulse and dp/dt
max
.
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236 Sanz et al.
Hydralazin, a direct arterial vasodilator, increased the risk of aortic rupture due to
its inability to reduce dp/dt
max
and also probably because of direct toxic effects on
elastin ultrastructure (50,51). Drugs with sympathicomimetic activity also favored
rupture (52). On the other hand, propranolol, a nonselective
β
-1 and
β
-2 receptor
blocker, increased aortic tensile strength and reduced contractility and dp/dt
max
,
conferring the greatest protection (50,53). The cardioselective
β
-1 receptor anta-
gonists sotalol and practolol also lowered dp/dt
max
with little change in the aortic
tensile strength, resulting in partial protection from aortic rupture (50,53). Similar
partial protection was observed with reserpine, a drug that depletes catecholamine
stores and causes increases in aortic tensile strength, but increments in dp/dt
max
(50,52). Interestingly, propranolol demonstrated protective actions at doses with-
out significant hemodynamic effects, suggesting direct effects on the arterial wall.
Subsequently, it was shown that propranolol enhances the formation and maturation
elastin crosslinks in the aorta, probably by stimulating of lysil-oxidase (54).
In one study, in patients with Marfan’s syndrome, intravenous propranolol failed
acutely to reduce dp/dt
max
, suggesting that it might be less effective in the presence
of a dilated aortic root (55).
Despite the important beneficial effects derived from decreasing dp/dt
max
,
the role of arterial pressure must not be underestimated. In a study involving dogs
with surgically produced dissection, progression in one hour was evaluated under
different pharmacological treatments. In agreement with prior considerations,
nitroprusside was effective in controlling arterial hypertension but not dissection
progression. However, the control of dp/dt
max
with propranolol alone was also
insufficient. The best results were reached with the combination of nitroprusside
and propranolol or with trimethaphan, an autonomic ganglion blocker with effects
in contractility and vascular resistance (56). Therefore, both aggressive reductions
in both blood pressure and dp/dt
max
constitute the basis for contemporary medical
therapy of acute aortic syndromes.
MEDICAL TREATMENT OF ACUTE AORTIC DISSECTION
General Considerations
An overview of the management of acute aortic dissection is shown in Figure 5.
Current recommendations, particularly with respect to medical treatment, are
largely based on noncontrolled experience and studies with limited numbers
of patients. As pointed out elsewhere, evidence-based medicine principles are
difficult to apply in a relatively uncommon and life-threatening condition (57).
Initial series suggested that medical therapy was a potential alternative to surgical
intervention in aortic dissection and that untreated patients fared worse than those
treated either medically or surgically (58–62).
In uncomplicated type B dissection, surgery does not improve survival
(63,64) and therefore these patients are managed medically in most instances.
Surgery (or percutaneous intervention) is usually reserved for those cases with
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Acute Aortic Dissection 237
ischemic complications, impending rupture, severe aortic dilatation, or intractable
pain (37,65). However, due to the reductions in surgical morbidity-mortality
achieved during the last decades, early operation may be considered in good sur-
gical candidates (i.e., younger subjects) or in cases of estimated higher risk (such
as Marfan’s syndrome, residual patency of the false lumen, or poor response to
drug therapy) (46,66,67). Recently, the absence of pain has also been associated
with higher mortality in type B dissection (68).
In type A dissection, immediate surgery is the treatment of choice, because
survival is largely improved when compared with the dismal natural history of the
disease (37,65,69–71). However, if surgery is not possible due to significant comor-
bidities or patient’s refusal, intensive medical therapy may be associated with accept-
able short-term survival, particularly in those diagnosed after the initial phase (72).
The patient in whom acute aortic dissection/rupture is suspected requires early
and aggressive medical management (Fig. 6), while urgent imaging and surgical
Figure 5 Flow diagram of the global approach to the patient with suspected acute dissec-
tion of the aorta. The dashed line indicates a less well-accepted alternative.
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238 Sanz et al.
evaluation occur. Whereas the decision to proceed with surgery is individualized
(depending on the aforementioned considerations and institutional expertise and
approach), all patients should be managed medically in the meantime. The goals
of medical therapy are both clinical and hemodynamic stabilization.
The patient should be admitted to an intensive care unit, where vital signs,
cardiac rhythm, urine output, and neurologic status can be closely monitored for
any change due to aortic complications (73). Blood pressure should initially be
quantified in both arms, as there may be involvement of the arch vessels by the
dissection with falsely low measurements unilaterally. Subsequently, it is prefer-
able to monitor blood pressure with an arterial line, enabling optimal choice and
titration of medical therapy, especially in the presence of hemodynamic instability.
The arterial line should typically be placed in the right radial artery, because
the right brachiocephalic artery is less often affected by the dissection. If there is
Figure 6 Schematic diagram of the medical management of patients with suspected or
confirmed acute dissection of the aorta. Subjects with normal blood pressure may still require
medication to reach the desired hemodynamic goals. Abbreviations: CHF, congestive heart
failure; IV, intravenous; MAP, mean arterial pressure; SAP, systolic arterial pressure.
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Acute Aortic Dissection 239
concern about involvement of the brachiocephalic trunk, or significantly higher
blood pressure measurements from the left arm, then a left radial arterial line
should be placed (37). Because hemodynamic deterioration may occur abruptly,
an intravenous access different from that used for drug infusions should be
readily available. Antithrombotic medications (e.g., heparin and fibrinolytics),
commonly used in other chest pain syndromes, should be withheld until the
diagnosis of dissection is ruled out, as their administration may have catastrophic
consequences. Pain contributes to a hyperadrenergic state with worsening of
tachycardia and hypertension, and should be eliminated promptly by the intra-
venous administration of morphine sulfate, a drug with additional blood pressure
lowering effects.
Medical management largely varies depending on the patient’s hemo-
dynamic status (Fig. 6). A normotensive or hypotensive patient requires close
evaluation for heart failure (due to concomitant aortic insufficiency or myocardial
ischemia), blood loss, and pericardial tamponade, prior to the administration of
volume. Hypotension or shock constitute signs of ominous prognosis (74) and
should usually be treated with volume resuscitation. A patient with significant
hemodynamic instability may require intubation and mechanical ventilation. In the
case of tamponade, pericardiocentesis appears to be contraindicated, based on a
small series in which three of four patients completing the procedure successfully
subsequently developed electromechanical dissociation and death within 40 min-
utes (75). This may be due to acute rebound of arterial pressure or increase in the
pressure gradient between the false lumen and the intrapericardial space, favoring
new bleeding, after correction of the tamponade. Immediate bedside sternotomy for
surgical access to the ascending aorta has been suggested in some cases of tampon-
ade, but remains controversial (65). Cornerstones in the medical management of
hypertensive and most normotensive patients with suspected acute aortic dissection
are anti-impulse therapy and blood pressure control, with a target systolic blood
pressure of 100–120 mmHg or mean arterial pressure of 60–75 mmHg (37,46).
Pharmacological Therapy
Short-acting intravenous agents are preferred to facilitate titration to blood
pressure goals, both in the intensive care unit and the operating room. In patients
who are normotensive and clinically stable (at presentation or after intravenous
therapy) and who are not undergoing intervention, oral drugs can be started as a
preliminary step before discharge. Table 1 summarizes pharmacologic properties
of intravenous drugs commonly used in the management of acute aortic dissection
and Table 2 is a summary of advantages and disadvantages of the different drugs.
Beta Blockers
The initial agent of choice in most cases should be an intravenous beta blocker.
Beta blockers have the dual advantage of decreasing dp/dt
max
as well as lowering
blood pressure. They are contraindicated in patients with significant bradycardia
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240 Sanz et al.
Table 1 Pharmacologic Properties of Intravenous Agents for the Management of Acute Aortic Dissection
Initial maintenance Mechanism Onset of Duration of
Drug Initial bolus dose Maximum dose of action action effect
Anti-impulse agents
Beta blockers
Esmolol 500 μg/kg 10–50 μg/kg/min 300 μg/kg/min β1-antagonist 2 min 20 min
Metoprolol 5 mg q5min × 3 5 mg q2–3hr 5 mg q2–3h β1-antagonist 2 min 3–6 hr
Propranolol 1–2 mg 1 mg/hr gtt or 2 mg/hr gtt or β1-, β2-antagonist 5 min 3–6 hr
2 mg q3–4hr 4 mg q3–4hr
Labetalol 20 mg 2 mg/min gtt or 300 mg in 24 hr β1-, β2-, β1-antagonist 2–5 min 2–4 hr
20–80 mg boluses
Calcium blockers
Verapamil 5–10 mg 5 mg/hr 5 mg/hr Negative inotrope/ 3–5 min not available
chronotrope
Ganglionic blocker
Trimethaphan 0.5 mg/min 15 mg/min Ganglionic blocker 1–5 min 10 min
Vasodilator agents
Nitroprusside 0.25 μg/kg/min 2 μg/kg/min Arterial and venous dilator seconds 3 min
Enalaprilat 0.625–1.25 mg 0.625–1.25 mg q6hr 5 mg q6hr ACE inhibitor 15 min 12–24 hr
Fenoldopam 0.1 μg/kg/min 1.6 μg/kg/min Dopamine1-agonist 15 min 15 min
Calcium blockers
Nicardipine 5 mg/hr 15 mg/hr Vasodilator 5–15 min 4–6 hr
Diltiazem 5 mg q5min × 3 5 mg/hr 15 mg/hr Vasodilator, negative 2–7 min not available
chronotrope
Note: Table and doses are for reference only and should be individualized for the management of actual patients.
Abbreviations: ACE, angiotensin converting enzyme; gtt, drip.
Source: From Refs. 37, 73, 81, and 94.
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Acute Aortic Dissection 241
or high-grade heart block, and should be used with caution if there is a history of
congestive heart failure or bronchospasm.
Esmolol hydrochloride has the advantages of rapid onset on action, short
half-life of distribution (two minutes) and elimination (nine minutes), and brief
duration of action. Serum drug levels are undetectable 20 to 30 minutes after
cessation of infusion. Esmolol is hydrolyzed by erythrocyte cytosol esterases into
methanol and an acid metabolite with a low affinity for beta receptors. Therefore,
its pharmacokinetic properties are not significantly altered in the setting of renal
insufficiency or liver disease (76).
Esmolol interacts with several commonly used drugs, including those
that play a role in the medical and surgical management of patients with aortic
Table 2 Advantages and Disadvantages of Intravenous Agents for the Management
of Acute Aortic Dissection
Drug Advantages Disadvantages
Anti-impulse agents
Beta blockers Decrease dp/dt
max
Contraindicated in bradycardia,
and blood pressure bronchospasm
Esmolol Rapid onset, short duration High fluid volume, drug levels
increased by morphine
Metoprolol Inexpensive, widely available Longer duration of action
Labetalol Alpha and beta blockade, Longer duration of action
maintains cardiac output
Propranolol Inexpensive, widely available Longer duration of action
Calcium Decrease blood pressure and Contraindicated in bradycardia
blockers maybe dp/dt
max
Verapamil Can be used in setting of Constipation, limited evidence
bronchospasm
Ganglionic
blocker
Trimethaphan Can be used when beta Unpredictable hemodynamics,
blockers contraindicated anticholinergic, tachyphylaxis
Vasodilator Decrease blood pressure Increase force of left ventricular
agents ejection, reflex tachycardia
Nitroprusside Most rapid onset and Thiocyanate toxicity
shortest duration
Enalaprilat Useful in high renin states Very long duration of action
Fenoldopam Intermediate onset and Tachyphylaxis, contraindicated
duration in glaucoma
Calcium blockers
Nicardipine Can be used in the setting Long elimination half life;
of bronchospasm interaction with anesthetic agents
Diltiazem Can use in bronchospasm, Peripheral edema, gastrointestinal
some negative inotropic side effects, limited evidence
effect
Source: From Refs. 37, 73, 81, and 94.
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