++
Interruption of the lumbar sympathetic chain has a time-honored
place in the treatment of peripheral ischemia. Before the advent
of arterial reconstruction, it was the only surgical measure that produced
pain relief. The indications for sympathectomy have diminished considerably
over the last 40 years. Currently, this is a treatment with a limited
role.23,24 Successful reports for the procedure
performed by laparoscopy and with chemical sympathectomy continue
to appear in the literature.25,26 Sympathectomy
may improve blood flow to the foot and may improve rest pain, heal
ulceration, and prevent skin necrosis.
++
If the affected foot is warmer than the unaffected foot, this
suggests that autosympathectomy has occurred (especially in diabetic
patients), and that the procedure will not be beneficial. However, there
are patients who do not respond despite favorable characteristics.
If the popliteal inflow index (Doppler inflow pressure in a popliteal
artery versus arm pressure) is ≥0.7, a
good response can be predicted. It is unlikely that a favorable
response will be obtained if the ankle-to-arm ratio is <0.35.27
++
Lumbar sympathectomy can be achieved by injection or surgery.
The technique of lumbar sympathetic block is well described in the
references.28 An accurate block of the sympathetic
chain at L3 may be adequate and it may not be necessary to use multiple
needles (See Appendix A, II). However, the use of radiographic control
will make the procedure easier and safer. If repeated blocks with
dilute local anesthetic solution produce appreciable circulatory
improvement, a neurolytic block with 5 mL aqueous phenol 5% solution
can be considered as an alternative to surgical sympathectomy.29
++
Operative sympathectomy may be completed by a relatively atraumatic
extraperitoneal approach under general anesthesia in which lumbar
ganglia 2, 3, and 4 are excised together with the chain connecting
them. Post-sympathectomy neuralgia, an aching pain in the femoral
nerve distribution, is a complication that may resolve in 6 to 8
weeks. This is also a complication of chemical sympathectomy if
the agent spreads through the prevertebral fascia to the level of
the L1 nerve root or through the psoas fascia to reach its major
peripheral nerve.
+++
Other Methods
of Improving the Peripheral Circulation
+++
Regional Sympathetic
Block (See Appendix A)
++
An effective
alternative means of producing sympathetic block in a limb is to
administer intravenous agents affecting postganglionic neurons to
produce noradrenergic block using an intravenous regional anesthesia
(IVRA) technique. Before its manufacture was discontinued,
guanethidine was used in the last decade with some success in complex
regional pain syndrome and peripheral vascular disease.30,31 By
acting on postganglionic neurons, guanethidine first released norepinephrine
and then caused noradrenergic block by preventing the reuptake of
norepinephrine by the neurons. Other drugs, such as clonidine,32 phentolamine,33 bretylium,34 ketorolac, and corticosteroid,
reported effective in management of pain due to complex
regional pain syndrome and administered by IVRA technique
may also find application in management of pain due to peripheral
vascular disease. In the IVRA technique, a tourniquet is placed
around the proximal part of the limb and inflated. The limb may
be elevated for several minutes to enhance venous drainage prior
to inflating the tourniquet. The drug diluted in 50 mL of normal
saline may be injected into an indwelling intravenous catheter in
the affected leg or arm after tourniquet inflation. Lidocaine can be
added to help the patient tolerate the tourniquet. The tourniquet is
kept inflated for 15 minutes. This method may be valuable in patients
who are receiving anticoagulant therapy in whom paravertebral
lumbar sympathetic block could potentially cause significant
hemorrhage. IVRA can also be considered in cases in which the
effects of operative lumbar sympathectomy are receding.
+++
Spinal Cord
Stimulation
++
Initial reports of the value of large fiber nerve stimulation
suggested that patients with pain from peripheral arteriosclerotic
disease that had not responded to arterial bypass surgery and/or
sympathectomy might respond to stimulation of posterior spinal roots
using implanted electrodes. Plethysmographic blood flow and skin
temperature were also noted to increase. More recently, it has been
suggested that the primary effect may be occurring within the lamina
of the dorsal horn of the spinal cord. Pain transmission in this
layer is controlled by wide dynamic range neurons. Substance P was
one of the first neuropeptides identified as modulating pain transmission,
and may be particularly affected by descending traffic modulating
pain transmission. It is likely that there are multiple mechanisms
involved. The stimulating electrodes may be introduced into the epidural
space under direct surgical visualization or by means of a 15-gauge
Tuohy needle with the electrodes placed between T 9 and T11.35 This
area of the spinal cord corresponds to lumbar segmental level output.
Spinal cord stimulation at this level is associated with increased
skin temperature, blood flow, decreased edema, and prolonged pain
relief. The stimulating electrodes may be adjusted until stimulation
of large fiber afferents produce a tingling paresthesia that overlies the
painful region.36 According to Augustinsson and
coworkers,37 these vasodilating effects of spinal
stimulation could be explained by (1) segmental inhibition of vasoconstrictor
fibers, (2) antidromic activation of posterior root fibers, and
(3) activation of ascending pathways to supraspinal autonomic centers.
Interestingly, stimulation over lumbar spines or peripheral nerves
was ineffective in these patients.37,38 The long-term
efficacy is reported to be excellent at 70% to 90% when
compared with results of 50% to 70% for neuropathic
pain.39,40
++
The search for a noninvasive treatment of peripheral ischemia
has highlighted many drugs that, after a brief popularity, have
vanished from our treatment armamentarium. The following discussion
of drug therapy approaches includes vasodilators, antithrombotic
measures, fibrinolysis, antiplatelet drugs, attempts to modify tissue
response to anoxia, prostacyclin, and gene therapy.
++
Because the regulation of blood flow in the normal foot is affected
simply by decreasing or increasing sympathetic tone, alpha-adrenergic
blocking agents have been used, including thymoxamine, phentolamine,
phenoxybenzamine, and clonidine. Other drugs have a local effect
on vascular smooth muscle. These include papaverine and derivatives
of nicotinic acid. Priscoline is an alpha-receptor blocker that
also has a direct effect.
++
Systemic use of vasodilators actually may reduce blood flow in
the worst affected limb by shunting blood to healthier areas (the
vasodilator paradox).41 A local effect may be obtained
by direct intraarterial injection or by retrograde intravenous infusion
(Bier technique). Ketanserin, a serotonin2-receptor antagonist,
and nifedipine may play a role in therapy,42 although
lowered systemic blood pressure and hence perfusion pressure to
the ischemic tissue, and the presence of maximal dilation of local
vessels in the ischemic region, suggest vasodilator treatment might
not be effective.
+++
Antithrombotic
Measures
++
Anticoagulant treatment has not been shown to be helpful in peripheral
vascular disease because thrombosis, when it occurs, is only the
final episode in the generation of the ischemic limb.
++
Fibrinogen is the substrate for thrombin that converts it to
fibrin. Dissolution of fibrin can be achieved using streptokinase,
urokinase, and tissue-plasminogen activator. Although it would not affect
the atheroma, and restenosis may follow cessation of therapy, it
may delay progression and be useful therapy in acute occlusion.
Its use should be followed by arteriography to assess the need for
reconstruction.
+++
Phosphodiesterase
Inhibitors
++
Currently, the only two drugs approved by the FDA for use in
intermittent claudication are Cilostazol and pentoxifylline. Both
drugs show phosphodiesterase inhibition that can increase the concentration
of cyclic AMP, leading to inhibition of platelet aggregation, thromboxane
release, and increase in prostacyclin release. Unlike milrinone,
which has similar effects on vessels and platelets, Cilostazol does
not display significant inotropic effect.43 Pentoxifylline
also affects blood rheology and specifically increases flexibility
of red blood cells.
++
Drugs such as aspirin, dipyridamole, ticlopidine, and prostacyclin
inhibit release of thromboxane A and prevent platelet aggregation.
Because the latter occurs in turbulent flow proximal or distal to
atheromatous stenosis or occlusion, such treatment is only of secondary
importance in peripheral arterial disease. However, along with lipid-lowering
drugs, antiplatelet therapy is the mainstay of secondary prevention
to prevent MI and stroke in all patients with peripheral artery disease,
even those who do not have signs or symptoms of coronary or carotid
disease. Low-dose aspirin, between 81 and 325 mg per day, is the
mainstay of preventive treatment for these patients.
++
Naftidrofuryl was marketed first as a vasodilator, but it is
purported to influence muscle metabolism beneficially through the
Krebs cycle. Although a meta-analysis of seven randomized controlled
trials involving 229 patients showed reduction in pain and analgesic
consumption, these results were not statistically significant and
the drug was withdrawn in the United States for treatment of peripheral
arterial disease in 1995.44 Levocarnitine and propionyl
levocarnitine are two drugs that may provide benefit by lessening the
acylcarnitine metabolite buildup resulting from an impaired mitochondrial
electron transport in ischemic muscle, though propionyl levocarnitine
is not yet FDA approved.45
+++
Arachidonic
Acid Derivatives
++
The term prostaglandin was coined by Von Euler,46 who
discovered some of the pharmacologic effects of semen. Endoperoxides
derived from cell membrane arachidonic acid are converted to thromboxane
A2 in platelets (vasoconstrictor and platelet aggregator)
or to prostacyclin in blood vessel endothelium (vasodilator and
inhibitor of platelet aggregation). The balance between these two
classes of compounds maintains intravascular hemostasis.
++
The earliest report of the use of prostacyclin for treating ischemic
feet used prostaglandin E1 by intraarterial infusion; the
same team later administered the drug by the intravenous route.
In both instances, they reported dramatic relief of rest pain in
small patient groups and healing of some ulcers.47,48 More
recently, prostaglandin I2, also a platelet inhibitor and
vasodilator, was administered daily as an intravenous infusion (iloprost),
or given orally (beraprost) with encouraging results.49
++
Gene therapy may be helpful in restoring blood flow to ischemic
extremities. A Boston group reported results in a small phase I
study. Human DNA coded to make vascular endothelial growth factor
(VEGF) was introduced into Escherichia coli plasmid, which was grown
in culture, purified, and administered by intramuscular injection
into ischemic muscles of patients with critical limb ischemia defined
as rest pain with nonhealing ischemic ulcers in human volunteers
felt to be poor candidates for revascularization surgery. VEGF,
secreted by endothelial cells, is the same protein as vascular permeability
factor. It has binding sites limited to endothelial cells and so
is site-specific. Injection of plasmid VEGF DNA manufactured by
E. coli produced significant transient edema in the limbs where
it was injected. ELISA measured VEGF concentration also increased
transiently and was associated in time with increased small blood
vessel formation that persisted after VEGF levels returned to baseline,
increased ankle-brachial index, healing of ulcers, increased exercise
tolerance, and resolved the problem of rest pain. The authors cautiously interpreted
their data as supportive for the strategy of intramuscular gene
therapy for therapeutic angiogenesis in patients with critical limb
ischemia.50