Ischemic Pain in The Extremities and Raynaud's Phenomenon

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EVIDENCE-BASED MEDICINE

Evidence-Based Interventional Pain Medicine


According to Clinical Diagnoses

25. Ischemic Pain in the Extremities and


Raynaud’s Phenomenon

Jacques Devulder, MD, PhD*; Hans van Suijlekom, MD, PhD ; Robert van Dongen,
‡ § ¶
MD, PhD, FIPP ; Sudhir Diwan, MD, FIPP ; Nagy Mekhail, MD, PhD, FIPP ;
††
Maarten van Kleef, MD, PhD, FIPP**; Frank Huygen, MD, PhD, FIPP
*Department of Anesthesiology and Multidisciplinary Pain Centre, University Hospital Ghent,

Ghent, Belgium; Department of Anesthesiology and Pain Management, Catharina Ziekenhuis,

Eindhoven, The Netherlands; Department of Anesthesiology, Pain and Palliative
Medicine, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands;
§
Department of Anesthesiology and Pain Medicine, Weill Cornell Medical College, Cornell

University, New York, New York, U.S.A.; Department of Pain Management,
The Cleveland Clinic, Cleveland, Ohio, U.S.A.; **Department of Anesthesiology and Pain
Management, Maastricht University Medical Centre, Maastricht, The Netherlands;
††
Department of Anesthesiology and Pain Management, Erasmus Medical Centre,
Rotterdam, The Netherlands

n Abstract: Two important groups of disorders result from an establish a diagnosis as soon as possible in order to influ-ence
the evolution of the disease.
insufficient blood supply to the extremities: critical vascular
disease and the Raynaud’s phenomenon. The latter can be A sympathetic nerve block can be considered in patients with
subdivided into a primary and a secondary type. Crit-ical critical ischemic vascular disease after extensive conser-vative
ischemic disease is often caused by arteriosclerosis due to treatment, preferably in the context of a study (2B±). If this has
hypertension or diabetes. Primary Raynaud’s is idiopathic and insufficient effect, spinal cord stimulation can be considered in
will be diagnosed as such if underlying systemic pathol-ogy has a selected patient group (2B±). In view of the degree of
been excluded. Secondary Raynaud’s is often a manifestation invasiveness and the costs involved, this treat-ment should
of a systemic disease. It is essential to try to preferably be applied in the context of a study and with the use
of transcutaneous pO2 measurements.
In case of primary Raynaud’s, life style changes are the first
Address correspondence and reprint requests to: Maarten van Kleef, step. Sympathectomy can be considered as a treatment of
MD, PhD, FIPP, Department of Anesthesiology and Pain Management, Raynaud’s phenomenon (2C+), but only after multidisciplin-ary
Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht,
The Netherlands. E-mail: maarten.van.kleef@mumc.nl.
evaluation of the patient and in close consultation with the
DOI. 10.1111/j.1533-2500.2011.00460.x patient’s rheumatologist, vascular surgeon or inter-nist. n

2011 The Authors


Pain Practice 2011 World Institute of Pain, 1530-7085/11/$15.00 Key Words: evidence-based medicine, ischemic pain,
Pain Practice, Volume 11, Issue 5, 2011 483–491 Raynaud’s phenomenon
484 • DEVULDER ET AL.

Critical ischemic vascular disease is most common


INTRODUCTION
in patients over 55 years old as a result of arterial vascular
This review on ischemic pain in the extremities and disease. The annual incidence is 0.25 to 0.45 patients per
Raynaud’s phenomenon is part of the series ‘‘Evi-dence- 1,000 population. The disease initially presents as vague
based Interventional Pain Medicine according to clinical pain in the extremities, but ends in necrosis and amputation
diagnoses.’’ Recommendations formulated in this chapter of the extremity in the course of 5 years.
are based on ‘‘Grading strength of recom-mendations and Raynaud’s phenomenon occurs frequently in our
quality of evidence in clinical guide-lines’’ described by society with an incidence of 3% to 21%.
1
Guyatt et al., and adapted by van Kleef et al. in the There is a primary form, also termed Raynaud’s dis-
2
editorial accompanying the first arti-cle of this series ease, in which no underlying cause for the symptoms can
(Table 1). The latest literature update was performed in be found. The secondary form, indicated with the general
September 2010. term Raynaud’s syndrome, does have an underlying cause.
Pain takes a central position in a varied group of It is usually associated with systemic pathology, in
disorders, due to insufficient blood supply to the particular rheumatic pathology.
extremities. It results in ischemia of the peripheral tis-sues, The main pathophysiology is impaired perfusion of the
which causes pain and often functional limitation in the peripheral parts of the extremities. Initially, it man-ifests
patient. Pain is a signal indicating a serious problem. Two itself as white discoloration of the fingers or toes and later
important groups of disorders can be distinguished: critical as blue discoloration leading to ulcers. The most important
3 4–6
vascular disease and the Ray-naud’s phenomenon. The diseases to consider include systemic diseases such as
latter can be subdivided into a primary and a secondary generalized sclerosis and scleroderma. In 90% of the cases
4,5 with these diseases, Raynaud’s phenomenon is the first
type. The context and the cause of each of these three
7
groups is different, which means that good diagnostics are symptom. Thromboangiitis obliterans or Buerger’s disease
essential to identify and influence the prognosis. can also be classified under secondary Raynaud’s. The age
at onset is usually under 45 years. It is an immune-
mediated arteritis of which the pathology is not fully
known, but smoking or smoke cessation can seriously
EPIDEMIOLOGY
affect the symptom-atology. The incidence of the diseases
Since there are two subgroups, the incidence and epi- varies consider-ably throughout the world. In the U.S. and
demiology of these groups is also different. Europe, the

Table 1. Summary of Evidence Scores and Implications for Recommendation

Score Description Implication

1A+ Effectiveness demonstrated in various RCTs of good quality. The benefits


clearly outweigh risk and burdens 9
1B+ One RCT or more RCTs with methodological weaknesses, demonstrate effectiveness. > Positive recommendation
The benefits clearly outweigh risk and burdens =

;
One or more RCTs with methodological weaknesses, demonstrate effectiveness.
2B+ Benefits closely balanced with risk and burdens >
9
2B± Multiple RCTs, with methodological weaknesses, yield contradictory results
better or worse than the control treatment. Benefits closely balanced with risk and =
burdens, or uncertainty in the estimates of benefits, risk and burdens Considered, preferably
study-related
2C+ Effectiveness only demonstrated in observational studies. Given that there is ;
no conclusive evidence of the effect, benefits closely balanced with risk and burdens

0 There is no literature or there are case reports available, but these are insufficient to prove
Only study-related
effectiveness and/or safety. These treatments should only be applied in relation to studies

2C) Observational studies indicate no or too short-lived effectiveness. Given that


there is no positive clinical effect, risk and burdens outweigh the benefit >
2B)
One or more RCTs with methodological weaknesses, or large observational 9 Negative
studies that do not indicate any superiority to the control treatment. Given > recommendation
that there is no positive clinical effect, risk and burdens outweigh the benefit =
>
;

RCT of a good quality which does not exhibit any clinical effect. Given that there is
2A)
no positive clinical effect, risk and burdens outweigh the benefit >

RCT, randomized controlled trial.


25. Ischemic Pain in the Extremities and Raynaud’s Phenomenon • 485

incidence is 0.5% to 15%, whereas the incidence mounts to PATHOPHYSIOLOGY


60% in some Asian countries. It is not clear how this large
The exact pathophysiological mechanism remains as yet
difference can be explained; it may be related to smoking
largely unclear. However, it has been shown that the
and the type of tobacco used.
physiological vasoconstriction on noradrenaline is
enhanced by cold and that there is an increased sensitivity
ETIOLOGY to a2-agonists and serotonin. The vaso-constrictive
endothelin-1 would also be involved, and the Calcitonin
As indicated above, the etiology of the diseases is dif- Gene Related Peptide (CGRP) and Cyclooxygenase
ferent. 10
supposedly play a (modulating) role.
Critical ischemic disease is often caused by arterio-
sclerosis due to hypertension or diabetes. Prevention by
The primary or idiopathic form (Raynaud’s disease)
means of proper health hygiene is important and can
often presents without an apparent cause and has a
influence the incidence and severity as well as the
prognosis. favorable course over time. In case of the secondary form
(Raynaud’s syndrome), there is often a disorder of the
Primary Raynaud’s is idiopathic and will be diag-
connective tissue, collagen or a rheumatic dis-ease, often
nosed as such if underlying systemic pathology has been
with autoimmune features (scleroderma, Sjo¨gren’s
excluded.
disease, rheumatoid arthritis, systemic lupus
Secondary Raynaud’s is often a manifestation of a
erythematosus, polymyositis) or a peripheral vascular
systemic disease. It is essential to try to establish a diag-
disease (thromboangiitis obliterans or Buerger’s dis-ease).
nosis as soon as possible in order to influence the evolu-
In rare cases, it occurs in combination with a malignancy
tion of the disease. A sclerotic disease can indeed have a
or chemotherapy (cisplatinum, bleomycin, and vincristine).
large impact on the functioning of vital organs such as the
lungs, liver, or kidneys. Because secondary Ray-naud’s
also occurs in other disorders such as Buerger’s disease or
even as an expression of a paraneoplastic phe-nomenon,
these should always be considered. In some cases, it can be I. DIAGNOSIS
8
an adverse effect of chemotherapeutics. I.A HISTORY
Buerger’s disease appears to be an immune-medi-ated
The clinical history will mainly include pain in the
pathology, occurring both in men and in women. The
extremities. In case of critical ischemic disease due to
symptoms already present at an early age, but are
arteriosclerosis, patients often indicate evolution of
predominantly determined by smoking behavior. The first
nonspecific pain in the extremities while walking that
step in the treatment is therefore to refrain from tobacco
disappears at rest. The first symptom is usually intermittent
use.
claudication followed by an increasingly serious
Table 2 gives an overview of the differences between
symptomatology over the years. Eventually, slow-healing
primary and secondary Raynaud’s phenome-non, based on
9 ulcers will develop.
a recent publication by Pope.
Critical ischemic disease predominantly occurs in the
older population. This is in contrast to Buerger’s disease in
which the first symptoms are also atypical pain with
Table 2. Differences between Primary and Secondary eventual discoloration and ulceration. Patients with
Raynaud’s Phenomenon
Raynaud’s phenomenon mostly complain of pain in the
Primary Secondary distal parts of extremities, often accom-panied by white
Incidence 3% to 5% 0.2% discoloration of the extremities. At a later stage, the
In combination with other diseases No Yes
discoloration darkens and ulcers may eventually develop.
Associated with antibodies No Often
Dilated capillaries in nail bed No Often
Familial predisposition Yes Yes
Connective tissue disorders in family Yes Yes
Medicinal treatment necessary Rarely Often
Complications No, rarely Yes
I.B PHYSICAL EXAMINATION
Improves after some time Yes, often Sometimes
Ischemic pain is usually accompanied by a dis-coloration
From Pope JE9 Reprinted by permission of the publisher. of the extremities. This is mostly a white
486 • DEVULDER ET AL.

discoloration of the distal parts of extremities, but it may II. TREATMENT OPTIONS
change to a dark blue, color. Also important is that there
are no arterial pulsations in the affected area. The A. II.A CONSERVATIVE MANAGEMENT FOR
extremity will feel colder and may show skin lesions that ISCHEMIC VASCULAR DISEASE
heal very poorly in a later stage. The distal peripheral parts Patients with pain due to a vascular disease initially receive
may show a tendency to necrosis. conservative and pharmacological therapy that aims at
General examination to evaluate the patient’s health treating the underlying cause. If the symptoms persist, it
(weight loss, malignancy) is relevant. The blood pressure may be decided to perform vascular surgery. The patient
should be measured and examination focusing on disorders group discussed in this chapter concerns inoperable,
of the connective tissues or on peripheral vascular disease vascular patients with pain at rest and/or ulcers (Fontaine
should be carried out. The hands and feet should be 11
III en IV) (Table 3).
inspected (wounds, ulcers); presence of dilated capillaries
in the nail bed is also important.
A. II.B INTERVENTIONAL MANAGEMENT FOR
ISCHEMIC VASCULAR DISEASE

I.C ADDITIONAL TESTS The treatment of these patients is aimed at pain reduc-tion
and cure of the ulcers in order to prevent amputa-tion. The
Additional laboratory testing (sedimentation, anti-bodies, literature mentions two methods:
renal function) focusing on autoimmune dis-orders can
1. Sympathectomy
best be performed by an internist/ rheumatologist.
2. Spinal cord stimulation
In case of critical ischemic vascular disease, the
imaging of the coronary arteries will be important, because Sympathectomy
it provides information about the prognosis and about
whether surgical intervention could be use-ful. Imaging is Sympathectomy primarily has a vasodilatatory effect on
less relevant in cases of Buerger’s dis-ease and Raynaud’s the collateral circulation resulting from a reduced
phenomenon; clinical and laboratory examination will sympathetic tone. Improved oxygenation of the tissues
provide sufficient infor-mation to make the diagnosis. leads to less tissue damage, which results in decreased pain
and increased healing of the ulcers. Pain reduction also
occurs due to the interruption of sympathetic nociceptive
Once the diagnosis has been established, the evo-lution
interaction.
can be followed by means of capillaroscopy, which
determines both the number of capillaries and the rate of Three randomized studies were reported in the litera-
12
red blood cell circulation. The determina- ture. Only Cross and Cotton found significant pain
tion of the transcutaneous oxygen saturation is also reduction in the group treated with chemical lumbar sym-
a parameter indicating the severity of the disease; pathectomy compared to the control group (bupivacaine
it can also be used to demonstrate improvement injection) (66.7% vs. 23.5%), but no changes in the ankle-
brachial index. The two other randomized controlled trials
in the microcirculation resulting from particular 13,14
treatments. (RCTs) did not show any objective advantages.
Over the years, however, several cohort studies have
been conducted examining the effect of sympathectomy,
I.D DIFFERENTIAL DIAGNOSIS
In cases of secondary Raynaud’s especially, it is impor- Table 3. Classification of Perfusion Disorders in Peri-pheral
Arterial Vascular Disease according to Fontaine
tant to demonstrate or exclude concomitant disorders.
Severe vascular disease may lead to organ damage.
Medicinal therapy is often indicated. The primary form
may resemble acrocyanosis (blue discoloration of the
nails) and primary livedo reticularis (red-blue dis-colored
skin in a reticular pattern); both are caused by reduced
perfusion of the skin and are enhanced by cold exposure
and emotional stress.
Stage I No symptoms (sufficient peripheral circulation)
Stage II Pain upon exertion, intermittent claudication
IIa ability to walk > 100 m
IIb ability to walk < 100 m
Stage III Pain at rest in the extremity concerned and
in the supine position due to a poor muscle
perfusion. The pain often temporarily
decreases if the leg is dependent
Stage IV Trophic disorders such as necrosis/gangrene
25. Ischemic Pain in the Extremities and Raynaud’s Phenomenon • 487

15 ous pO2 between a lying and a sitting position was


either surgical or chemical. Sanni et al. concluded in their
review that although the RCTs did not support its use, > 15 mm Hg, and who showed a significant amputa-tion
23
many cohort studies have shown a positive effect of reduction. Several nonrandomized studies have
sympathectomy in patients with critical ische-mic vascular demonstrated a significantly lower amputation per-centage
disease. A retrospective study by Repealer van Driel et 3,24–26
in SCS groups.
16
al., including 60 successive surgical lum-bar A Cochrane Review of 2005 concluded that SCS in
sympathectomies, showed good results (no rest pain, critical ischemic vascular disease: (1) leads to fewer
healing of ulcers and no major amputations) in 48% of the amputations; (2) provides better pain relief; and (3) restores
patients after 6 months. 3
more patients to Fontaine stage II. Patients receiving
17
Keane performed lumbar chemical sympathectomy conservative treatment exhibited more adverse effects due
using phenol 6% under X-ray guidance in 132 patients with to medication, including: (1) gas-trointestinal hemorrhage;
critical ischemic vascular disease. Favorable results (no (2) nausea; and (3) dizziness. It should be noted that SCS
rest pain, warm extremity, and no amputa-tion) were also is associated with complications including
obtained in 52% of the patients after a fol-low-up of 16 implantation problems, as well as additional intervention
18
months. Mashiah studied 373 patients with critical due to lead migration and infection. SCS is more
ischemic vascular disease who were treated with lumbar expensive: 36,500 Euros (SCS) vs. 28,600 Euros
chemical sympathectomy. Success (no pain, healing of (conservative).
ulcers after 6 to 12 months and no amputation) was Spinal cord stimulation may reduce amputation rate and
achieved in 58.7% of the patients. The amputation ratio pain in selected patients with critical ischemic vas-cular
was 20% and the mortality was 9%. Although the effect of disease that is refractory to conservative and minimally
sympathectomy in critical ischemic vascular disease is not invasive pain treatment.
consistent, several stud-ies have shown a trend toward
better pain reduction and ulcer healing, which justifies its
consideration.
A. II.C COMPLICATIONS OF INTERVENTIONAL
MANAGEMENT FOR ISCHEMIC VASCULAR
DISEASE
Spinal Cord Stimulation
Complications of sympathectomy and SCS are described in
Spinal cord stimulation (SCS) has been used to treat a another article in this series, ‘‘Complex Regional Pain
27
variety of chronic pain syndromes since 1967. The effect of Syndrome (CRPS).’’
19
SCS is probably based on several mechanism of action.
20
In 1996, Jivegard et al. published a ran-domized study on A. II.D EVIDENCE FOR INTERVENTIONAL
the effect of SCS in 51 patients with critical ischemic MANAGEMENT FOR ISCHEMIC VASCULAR
vascular disease with a follow-up of 18 months. He DISEASE
concluded that SCS resulted in better pain reduction than
treatment with analgesics, but there was no significant The summary of the evidence for the interventional
difference in amputation rates between both groups. A management of extremity pain due to vascular disease is
subgroup analysis in patients without arterial hypertension given in Table 4.
did show a significant difference in amputation
percentages.
21 A. III RECOMMENDATIONS FOR ISCHEMIC
A Belgian national study by Suy et al. showed no VASCULAR DISEASE
significant difference in amputation percentages, although
there was a tendency favoring fewer amputa-tions in the A sympathetic nerve block can be considered in patients
group receiving SCS. A randomized study by Klomp et with critical ischemic vascular disease after extensive
22
al. including 120 patients with critical ischemic vascular
disease showed that SCS with phar-macological treatment Table 4. Summary of the Evidence for Interventional
was not significantly better with respect to amputation Management for Ischemic Vascular Disease
scores at 2-year follow-up than the group receiving
pharmacological treatment alone. In 2001, the same
research group published the results of a subgroup in
whom the difference in transcutane-
Technique Evaluation

Sympathectomy 2B±
Spinal cord stimulation 2B±
488 • DEVULDER ET AL.

conservative treatment, preferably in the context of a ing vasoconstrictive medication. If pharmacological


+
study. If this has insufficient effect, SCS can be consid- treatment is required, the vasodilators nifedipine (Ca -
ered in a selected patient group. In view of the degree of antagonist) and prazosin (a1-blocker) have been stud-
4,5
invasiveness and the costs involved, this treatment ied most, but their effects have been disappointing. should preferably
be applied in the context of a study, The main problems encountered with these drugs are with transcutaneous pO 2
measurements recommended. the adverse effects and the loss of efficacy long-term.
The treatment of secondary Raynaud’s is initially aimed
at the underlying disease. Figure 2 presents an algorithm
A. III.A CLINICAL PRACTICE ALGORITHM FOR
for the conventional treatment of Raynaud’s disease.
ISCHEMIC VASCULAR DISEASE
Figure 1 represents the treatment algorithm for ische-mic
vascular disease.
B. II.B INTERVENTIONAL MANAGEMENT FOR
RAYNAUD’S PHENOMENON
Sympathectomy
A. III.B TECHNIQUE(S)
Sympathectomy is not often performed in patients with
We refer to the paper in this series on ‘‘CRPS’’ for the
27 Raynaud’s. However, it can be considered in patients with
techniques. dystrophic changes leading to ulceration. The liter-ature
does not include any RCTs. In their retrospective study (n
28
B. II.A CONSERVATIVE MANAGEMENT FOR = 28), Matsumoto et al. found an initially favorable result
RAYNAUD’S PHENOMENON in 92.9% after endoscopic thoracic sympathectomy (ETS);
however, recurrent symptoms were subsequently noted in
The treatment of the primary form of Raynaud’s phe- 82.1%. Despite recurrent symptoms, these patients did not
nomenon is usually conservative and not pharmacolog- 29
exhibit ulcerations during the study period. Maga et al.
ical. In case of primary Raynaud’s, it is generally sufficient
showed a long-lasting positive effect (follow-up 5 years)
to inform the patient well and advise them to avoid
on microcir-culation after ETS (Th2-Th4). Although
provoking factors by wearing warm clothes, stopping
symptoms returned in 28% of patients, no ulcerations were
smoking, taking sufficient exercise and avoid- seen. A recent retrospective (n = 34) study by Thune et
30
al. demonstrated that most patients (83%) experience an
immediate positive effect after thoracoscopic sympa-
thectomy. In their study, this effect persisted in 33% of
patients after a mean follow-up of 40 months.

B. II.C OTHER TREATMENTS


Botulinum Toxin A Injections
31
A study by Van Beek et al. describes 11 patients with rest
pain and finger ulcers who received perivascular injections
with botulinum toxin A. There was an immediate favorable
effect on the pain in 100% of the patients. In nine patients
(82%), the ulcers healed spontaneously and this effect was
still present in these patients after follow-up of as long as
30 months.

B. II.D COMPLICATIONS OF INTERVENTIONAL


MANAGEMENT FOR RAYNAUD’S PHENOMENON
Complications of sympathectomy are described in the
Figure 1. Algorithm for the treatment of critical ischemic vascu-
27
lar disease. article ‘‘CRPS.’’
25. Ischemic Pain in the Extremities and Raynaud’s Phenomenon • 489

Table 5. Summary of the Evidence for Interventional


Management for Raynaud’s Phenomenon

Technique Evaluation

Sympathectomy 2C+

Figure 3. Algorithm for the treatment of Raynaud’s phenome-non.

Figure 2. Algorithm for the conservative treatment of Ray-naud’s B. III.B TECHNIQUE


disease.
Both, the technique of SCS and of sympathetic nerve
27
blocks are described in the article on CRPS.
B. II.E EVIDENCE FOR INTERVENTIONAL
MANAGEMENT FOR RAYNAUD’S PHENOMENON
IV. SUMMARY
The summary of the evidence for the interventional
Patients with pain due to critical ischemic vascular dis-
management of extremity pain due to vascular disease is
ease should first receive conservative and medicinal
given in Table 5.
treatment directed at the underlying cause.
A sympathetic nerve block can be considered in
B. III RECOMMENDATIONS RAYNAUD’S inoperable vascular patients with refractory rest pain and/or
PHENOMENON ulcers.
Considering the degree of invasiveness and the costs of
Sympathectomy can be considered in the treatment of
the disease, SCS can be applied, preferably in the context
Raynaud’s phenomenon, but only after multidisciplin-ary
of a study.
evaluation of the patient and in close consultation with the
Treatment of the primary form of Raynaud’s is gen-
patient’s rheumatologist, vascular surgeon or internist.
erally conservative and nonmedicinal.
Treatment of secondary Raynaud’s phenomenon is
initially aimed at the underlying cause.
B. III.A CLINICAL PRACTICAL ALGORITHM OF Sympathectomy can be considered in patients with
RAYNAUD’S PHENOMENON refractory pain after extensive multidisciplinary evalu-ation
and in consultation with the patient’s rheumatol-ogist,
The algorithm for the interventional management of
vascular surgeon or internist.
Raynaud’s phenomenon is illustrated in Figure 3.
490 • DEVULDER ET AL.

ACKNOWLEDGEMENTS 14. Fyfe T, Quin RO. Phenol sympathectomy in the treat-


ment of intermittent claudication: a controlled clinical trail. Br J
This review was initially based on practice guidelines Surg. 1975;62:68–71.
written by Dutch and Flemish (Belgian) experts that are 15. Sanni A, Hamid A, Dunning J. Is sympathectomy of
assembled in a handbook for the Dutch-speaking pain benefit in critical leg ischaemia not amenable to revascu-
larisation? Interact Cardiovasc Thorac Surg. 2005;4:478– 483.
physicians. After translation, the manuscript was updated
and edited in cooperation with U.S./Inter-national pain
16. Repealer van Driel O, Van Bockel J, Van Schilfgarde R.
specialists. The authors thank Arno Lata-ster for review Lumbar sympathectomy for severe lower limb ischaemia: results
and control of anatomical terminology, Jose´ Geurts and and analysis of factors influencing outcome. J Cardio-vasc
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regarding the manuscript. 17. Keane FB. Phenol lumbar sympathectomy for severe
arterial occlusive disease in the elderly. Br J Surg. 1977; 64:519–
521.
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