Review Article

Raynauds Phenomenon
Renu Saigal**, Amit Kansal*, Manoop Mittal*, Yadvinder Singh*, Hari Ram*
Abstract
Raynauds phenomena (RP) is a commonly encountered clinical manifestation which may be primary or
secondary to underlying disease. There is imbalance between vasoconstricting and vasodilating factors. Physical
examination, nailfold capillaroscopy and immunological tests can differentiate primary from secondary RP.
Treatment involves prevention of RP so that permanent ischemic damage i.e. gangrene can be avoided. Avoidance
of exposure to cold, emotional stress and certain drugs is mandatory and if attacks are occurring then vasodilators,
prostaglandin analogues, anticoagulants and antiplatelet drugs may be added.
An attempt has been made to guide the clinician to diagnose and treat a patient of RP through this article.

Definition disease (also known as secondary Raynauds).

R aynauds phenomenon (RP) refers to reversible spasm of The prevalence of primary Raynauds varies among different
peripheral arterioles in response to cold or stress. populations; from 4.9-20.1% in women to 3.8-13.5% in men. The
frequency of secondary Raynauds depends on the underlying
RP is usually seen in distal digits but may also involve nose,
disorder. The differences between primary and secondary
ears and tongue. RP is characterized by triphasic response
Raynauds phenomenon are summarized in Table 1.
(Fig. 1).
Raynauds phenomenon should also be distinguished from
Phase 1 Pallor due to vasoconstriction of
acrocyanosis, a condition characterized by persistent, symmetric
precapillary muscular arterioles
cyanosis of the hands, less commonly of feet that is aggravated
Phase 2 Cyanosis due to venous pooling by cold temperatures; it is due to vasospasm of small vessels
and deoxygenation of venous blood. Ischemic Phase of the skin.
Phase 3 Erythema because of reactive
hyperemia. It is associated with throbbing Physiology of Vascular Tone
pain. Vascular tone is maintained by (A) endothelium of vessel wall
Critical ischemia is characterized by severe pain, downward (B) neural factors. Lumen patency is maintained by inhibition
positioning of hand and if not relieved, may lead to ulceration of platelets, fibrinolysis and maintenance of viscosity of blood.
or gangrene. Endothelium of vessel wall forms vasodilators e.g. endothelium
Raynauds phenomenon should be distinguished from dependent relaxing factor (EDRF) which is nitric oxide (NO). NO
Raynauds disease. They are distinct disorders that share generates cGMP, a potent vasodilator and inhibitor of platelet
a similar name. Raynauds disease is the occurrence of the function. Endothelial dependent relaxation may be lost in the
vasospasm alone, with no association with another illness Table 1 : Differences between Primary and Secondary RP5
(also known as Primary Raynauds). Raynauds phenomenon is
secondary to other conditions, most commonly an autoimmune Primary RP Secondary RP
Exaggerated physiological Secondary to serious underlying
Raynauds Phenomenon response to cold or stress. disease.
No arterial structural abnormality, Abnormal nail fold capillaries are
Raynauds normal nail fold capillaries. present3
Phenomenon Symmetric attacks Asymmetric intense painful
attacks
1. 3. Tissue necrosis, ulceration or Ischemic skin lesions viz ulcers
gangrene is absent and pulp pitting present
Median age of onset is 14 years. Age at onset is > 30.
Only 27% begin at 40 years or
later.1
Clinical features of Connective Clinical features of CTD like
tissue diseases (CTD) are absent. arthritis, myalgia, sclerodactyly,
Fingers become 2. fever, sicca symptoms, rash,
white due to lack of weight loss, and cardiopulmonary
blood ow, then blue abnormality are present
as vessels dilate to
ESR normal, CRP negative ESR Raised, CRP positive
keep blood in tissues,
nally red as blood ANA and other autoantibodies ANA and other autoantibodies
ow returns absent may be present.4
Fig 1 : Triphasic response in RP Increased frequency of migraine May not be present
and Prinzmetal Angina
**
Professor and Unit Head, Department of Medicine, *Resident, (Vasospatic disorders) may be
Department of Medicine, Sawai Man Singh Medical College and present. 25% may have family
Hospital, Jaipur, India. history of RP in first degree
Received: 30.01.2009; Revised: 18.06.2009; Accepted: 20.06.2009 relative2

JAPI may 2010 VOL. 58 309

 VASOCONSTRICTION VASODILATION
Reactivity of
smooth muscle
Vasodilatory
neuropeptides e.g. CGRP
2-adrenoceptors from sensory aerents
Smooth muscle cell
Endothelial cell
Endothelin-1 NO
from endothelial cells from endothelial cells
Platelet activation
/aggregatin
Oxidative stress Fibrinolysis
Red blood cell
deformability
Viscosity
ENDOTHELIAL
REDUCED BLOOD FLOW /
DAMAGE PROCOAGULANT TENDENCY
Fig. 2 : Pathogenesis of RP
On left : Increased vasoconstrictor impulses Increased activity of -2
adrenoreceptors, increased endothelin -1 from injured endothelial cells
because of ischemia
On right : Decreased vasodilatation: Decreased vasodilatory
neuropeptides CGRP (Calcitonin gene related peptides), decreased
nitric oxide from endothelial cells. Increased procoagulant activity :
increased platelet activity, decreased fibrinolysis & RBC deformability
& increased viscosity
presence of reactive oxygen species, leading to vasoconstriction
and vascular injury. Endothelial cells also produce prostacyclin
(PGI2), prostaglandin E1 and E2 and leukotienes which like NO
are potent vasodilators and antiplatelet agents.
Besides vasodilators, endothelial cells also express
vasoconstrictor substances like endothelin -1 and angiotensin
II and thromboxane A2. Endothelin-1 is released in response to
epinephrine, thrombin, shear stress and oxidized lipoproteins.
Endothelin-1 exerts its biological function by G protein
coupled cellular receptors, ET A and ET B. ET A is expressed
predominantly on vascular smooth muscle and mediates the
vasoconstrictor effect of ET-1. Binding of ET-1 to ET B, which is
expressed by endothelial cells, causes vasorelaxation in addition
to ET -1 clearance.
Peripheral nerve endings also releases vasodilating factors
like substance P, vasoactive intestinal peptide and calcitonin
gene related peptides (CGRP). The latter, released from sensory
afferents acts through CGRP receptors, widely distributed in
body, are the most potent endogenous vasodilatory peptides.
Neuropeptide Y (NPY) is present in central and peripheral
nervous system and is co-localised with noradrenergic
transmitters in postganglionic sympathetic fibers. It is released
in response to nerve stimulation and ischemia. NPY acts with
norepinephrine and is released in response to cold or stress,
from sympathetic nerve endings, stimulates 2 adrenoreceptors
and causes vasoconstriction besides NPY is a strong inducer of
smooth muscle cell proliferation.
Platelets, mast cells, and fibroblasts participate in the
regulation of vascular tone through release of platelet- derived
growth factor, epidermal growth factor, histamine and cytokines.
Pathogenesis (Fig. 2)
There is imbalance between vasoconstricting and vasodilating
factors.
ET-1 levels are increased, and there is a diminution of
CGRP-containing perivascular nerves in finger skin and there is
upregulation of normally silent 2 adrenoreceptors.
310 JAPI may 2010 VOL. 58
Intravascular abnormalities include platelet activation,
impaired fibrinolysis, increased viscosity and probably oxidant
stress.
Various mechanisms are:
A. Increased Vasoconstriction:
Increased reactivity of vascular smooth muscles
supplied by 2 adrenoreceptor which are prominent
on cutaneous blood vessels of digits.
Increased endothelin 1(vasoconstrictor) secreted by
endothelial cells in response to ischemic injury.
B. O2 free radical injury to endothelial cells and tissues because
of ischemia and subsequent reperfusion
C. Decreased vasodilatation:
Decreased vasodilatory neuropeptides e.g. calcitonin
gene related peptides (CGRP) from sensory afferents
leads to RP. In primary RP, in RP secondary to systemic
sclerosis, and in patients who use vibrating tools, a
significant reduction of CGRP fibres is detected.
Decreased NO (nitric oxide) and prostacyclin from
injured endothelial cells.
D. I n c r e a s e d p l a t e l e t a c t i v a t i o n /
aggregation: Thromboxane A 2 and
serotonin (potent vasoconstrictors) are
(D, E, F, G -
produced. decrease blood
E. Decreased fibrinolysis. flow)
F. Decreased red cell deformability.
G. Increased viscosity
The decreased blood flow may be the result of increased
blood viscosity as in cryoglobulinemia or Waldenstrom
macroglobulinemia, abnormalities of the vasculature (specifically
the endothelium), structural disease of vessel with intimal
proliferation and lumen narrowing or vessel occlusion due to
thrombus or entrapment of vessels in excess extracellular matrix
as in scleroderma or unusually intense vasoconstriction.
Release of von Willebrand factor (a measure of endothelial
injury), decreased nitric oxide synthesis, and local inflammation
and increased circulating levels of interleukin-13 (a cytokine that
promotes fibrosis and inflammation) have all been implicated
in patients of systemic sclerosis.
In patients with scleroderma, secondary Reynauds is
associated with narrowing of the blood vessels from intimal
proliferation, this leads to baseline ischemia and hypoxia.
Vasospasm occurs on the background hypoxia. It has also been
associated with an increase in endothelin-1, a vasoconstrictor
substance. Endothelin-1 levels are increased in RP associated
with scleroderma and marked increase in its level occurs in
response to cooling as compared to normal individuals. It is
believed to be a product of abnormal endothelial cells that are
present in the skin of these patients.
In primary RP, reduction in CGRP and high -2 adrenergic
activity stand out as two prominent factors. While endothelial
dependent processes are believed to be more important in the
exacerbation than initiation of RP, especially secondary RP.
Various diseases associated with Reynauds phenomenon
include the following:
Autoimmune Diseases
(Figures in parenthesis indicates patients with RP)
Systemic sclerosis (90%) (both diffuse (dc SSc) and limited
 (Lc SSc) i.e. CREST syndrome- calcinosis, raynauds
phenomenon, esophageal dysmotility, sclerodactyly,
telangectasia)
Mixed connective tissue disease (MCTD) (85%)
Sjogren syndrome (33%)
Systemic lupus erythematosus (SLE) (10-44%)
Polymyositis (PM) (29%) and dermatomyositis (DM) (25%)
Rheumatoid arthritis (RA) (10-15%)
Cryoglobulinemia, cryofibrinogemia (10%)
Antiphospholipid syndrome (APLA)
Primary biliary cirrhosis
Primary pulmonary hypertension
Drugs
Ergotamines Cyclosporine A
Interferon and Cytotoxic drugs:
Oestrogens bleomycin, cisplatin, vin
Nicotine cristine,vinblastine,carb
oplatin
B blockers
Bromocriptine
Cocaine
Sulfasalazine
Clonidine
Sympathomimetics
Environmental Agents and Injury
Frostbite
Repetitive occupational stress:
Hand arm vibration syndrome (HAVS) - In rock drillers,
grinders, lumberjacks, jackhammerers and sanders
Hypothenar hammer syndrome (HHS) Ulnar artery aneurysm
has been seen in persons who use ulnar border of palm as
hammer and thrombosis of ulnar artery leads to localized
RP in medial two fingers.
Neuropathy:
Carpal tunnel syndrome
Other Systemic Diseases
Hypothyroidism, Cancer, Cold agglutinin syndrome
POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy, M protein and skin changes)
Medications have been associated with exacerbations of
primary or secondary Raynauds. Most of these medications
promote vasoconstriction e.g. ergot alkaloids, nonspecific
beta-adrenergic antagonists, and oral contraceptives. Some
chemotherapeutic agents e.g. bleomycin and the vinca alkaloids
are associated with fibrosis and may decrease blood flow with
subsequent development of secondary Raynauds.
U1-RNP antibodies may represent a marker for the vascular
process that causes Raynauds phenomenon. It can also be
considered a marker for associated structural vasculopathy.6
Physical Examination
Digits should be examined if either primary or secondary
Raynauds is suspected for:
- Sclerodactyly, calcinosis, arthritis or digital ulcers.
- Nailfold capillaries under magnification from a
dissecting microscope or ophthalmoscope (vide infra)
Any signs or symptoms of other syndromes associated with
secondary Raynauds phenomenon should be looked for e.g.
JAPI may 2010 VOL. 58 311
- Bone pain may suggest a paraneoplastic syndrome
associated with a hyperviscosity syndrome.
- The presence of nephritis, malar erythema, and arthritis
suggests systemic lupus erythematosus.
Persistent cyanosis or necrotic distal tissue suggests an
underlying disorder, like scleroderma or permanent
ischemia. Livedo reticularis suggests an autoimmune
disorder or coagulation abnormality (Antiphospholipid
syndrome).
Carpal tunnel syndrome has been associated with Raynauds
phenomenon.
In older patients with new-onset Raynauds and no obvious
underlying cause, malignancy must be suspected.
Laboratory Investigations in RP
Complete blood counts, ESR
Urinalysis
General blood chemical analyses
Antinuclear antibody (immunofluorescent assay IFA)
Disease specific autoantibodies
C3 and C4 complement levels
If all the above tests are normal then following tests should
be performed
Thyroid function tests
Serum protein electrophoresis
Tests for cryoglobulins
Anti-topoisomerase antibodies and anticentromere
antibodies
Serum viscosity
Serum creatine kinase
Rheumatoid factor
Hepatitis panel
Cold agglutinins
Antiphospholipid antibodies studies
Cryoglobulins
X-ray hands Subcutaneous calcification is present in
CREST syndrome
Specific Tests
Digital perfusion: Measured by digital plethysmography,
digital blood pressure, laser Doppler and flowmetry are
mainly used for research purpose.
Nail-fold vasculature by capillaroscopy
3 rd or 4 th finger at room temperature is examined
by ophthalmoscope, using + 40 D lens or hand held
illuminating microscope giving 10-40X magnification. Place
a drop of grade B immersion oil or KY lubricant jelly on the
digit proximal to cuticle and capillary loops are looked for.
Normal capillary loops are evenly arranged hairpin like
thin, uniform and symmetric vessels. (Fig. 3a)
In SSc these vessels are irregular, dilated, elongated and
tortuous. These are bushy, engorged or corkscrew on
appearance. (Fig. 3b)
In Limited cutaneous systemic sclerosis (Lc SSc) there is
only dilatation without dropout of vessels while in diffuse
cutaneous systemic sclerosis (dc SSc), MCTD and DM there
is dropout of capillaries i.e. areas of avascularity as well.
(Fig. 3b).

Fig. 3a : Normal nail fold capillaries
Fig. 3b : Dilated and dropout capillaries in systemic sclerosis
Doppler arterial ultrasound: Digital plethysmography or
angiography:
Patients with asymmetric attacks, absent pulses, single digit
involvement, and asymmetry of blood pressure or evidence
of critical ischemia should undergo to rule out large artery
disease such as:
Atherosclerosis
Thromboangiitis obliterans
Vasculitis
Thromboembolic disease
Thoracic outlet syndrome
Treatment
General Measures
A. Avoidance of exposure to cold, vibrating tools and stress.
Patient is asked to keep body warm by wearing gloves,
mittens, stocking and woolens.
Relaxation techniques and biofeedback to decrease
emotional stress so that there is least sympathomimetic
stimulation.
B. Avoid drugs:
Oestrogens
Sympathomimetics (decongestants in cold remedies)
Clonidine
Ergotamine
Serotonin receptor agonists sumatriptan
C. Smoking should be stopped
D. Calcium channel blockers (CCB):
CCB are arterial vasodilators. They also have
antiplatelet effect and reduce oxidative stress.
Nifedipine: 10-30 mg tid per oral (PO)
Amlodepine: 5 20 mg daily PO
Diltiazem can also be used but it is not as effective as
the dihydropyridine class of CCB.
E. Sympatholytic:
Prazosin: 1-5 mg/d PO ( 1 Adrenergic Blocker as 2
Adrenoreceptor blocker are not available). It was found
312 JAPI may 2010 VOL. 58
more effective than placebo (7). with long term use tolerance
may develop.
F. Angiotensin II receptor antagonist:
Losartan 25 100 mg/d
In addition to vasodilatation, it is also anti-inflammatory
and blocks the fibrogenic effect of angiotensin II.8
G. Selective serotonin re-uptake inhibitor:
Fluoxetine: 10 mg PO upon waking; can be increased
q2wk; not to exceed 60 mg/d
A better response was seen in patients with Raynauds
disease versus patients with Raynauds phenomenon.9
H. Selective serotonin antagonist:
Ketanserin : 40 mg tid (PO)
I. Statins:
Improve endothelial cell dysfunction and decrease platelet
aggregation and vascular smooth cell proliferation is also
decreased.
J. Anti-oxidants:
Vitamin E 400 mg /d
Probucol10
K. Treatment of infection:
Avascular areas are prone to develop infections so antibiotics
and proper dressing of infected areas is required. If
ulcerations develop, patients need to keep them sterile and
to treat any infections aggressively that may intercede. All
of this should be done under the supervision of a physician.
L. Fish oils: containing omega-3-fatty acids may be beneficial
to some patients with primary Raynauds.11
They reduce plasma viscosity and act as a substrate for
production of prostacyclin.
For Critical Ischemia
Prostaglandin
Iloprost 0.5-2.0 ng/kg/min IV Infusion for 6-24 hours for
2-5 days (Vasodilator and Inhibits platelet aggregation).
Synthetic analogue of prostacyclin PGI2 that dilates systemic
and pulmonary arterial vasculature.
Adverse events: Chest Pain, headache, nausea & jaw pain.
Epoprostenol 0.5- 6 ng / kg / min Infusion for 1- 3 days.
Analogue of PGI2 has potent vasodilatory properties,
immediate onset of action, and half-life of approximately 5
min. In addition to vasodilator properties, also contributes to
inhibition of platelet aggregation and plays role in inhibition
of smooth muscle proliferation. Continuous chronic infusion
should be administered through central venous catheter.12
Acute dose: 2 ng/kg/min continuous IV; increase by 2 ng/kg/
min q15min or longer until dose-limiting effects are elicited (eg,
chest pain, anxiety, dizziness, changes in heart rate, dyspnea,
nausea, vomiting, headache, hypotension, flushing).
Areas of uncertainities
1. Nitroglycerin patch: 1/4- 1/2 inch 2 % ointment. It is a NO
donor. Effective for short term use but may cause headache.
Used on those digits which are most severely affected,
applied in the morning and then 6 hours later.
2. Phosphodiesterase inhibitors: These drugs enhance the
effect of NO through inhibiting degradation of cyclic
guanosine monophosphate.
Cilostazol : A synthetic phosphodiesterase III inhibitor
 that reversibly inhibits platelet aggregation and produced
beneficial effect in primary and secondary Raynauds
phenomenon in 6 week double blind placebo controlled
trial.13
Sildenafil and Tadalafil : There are no formal clinical trials
reports. Beneficial role shown in case reports.
3. NO donor (L-arginine): In body NO is derived from
L-arginine with the help of enzyme NO synthetase. Reversal
of digital necrosis was seen with oral L-arginine in few case
reports.
4. Endothelin receptors inhibitors:
Bosentan- Inhibits vessel constriction and elevation of blood
pressure by competitively binding to endothelin-1 (ET-1)
receptors ETA and ETB in endothelium and vascular smooth
muscle. Prevents development of new digital ulcers in
systemic sclerosis.14
Dose: <40 kg: 62.5 mg PO bid; not to exceed 125 mg/d
>40 kg: 62.5 mg PO bid for 4 wk initially, then increase to
125 mg PO bid
5. Beraprost: Oral administration to patients with scleroderma
and digital ulcers resulted in fewer patients developing new
digital ulcers.(15)
6. Botulinum toxin A: Perivascular injection of botulinum
toxin A has been shown to be effective treatment for RP.16
7. Localized Microsurgical Sympathectomy: For isolated
ischemia of one or two digits.
8. Sympathectomy: < 20 % benefitted. Its role is controversial
and benefit is temporary.
Acute Ischemic Crisis
I. Short acting CCB: Nifedipine has antiplatelet effect alsoj.17
II. Antiplatelet drugs: Aspirin has been found to be effective
in ischemic crisis. 18 Activated platelets are source of
vasospastic substances, such as serotonin and thromboxane
A2.
III. Chemical sympathectomy: Digital or wrist block with
lidocaine or bupivacaine at the base of the involved digits
decreases sympathomimetic input, reduces ischemic pain,
and improves blood flow.
IV. Iloprost or epoprostenol
V. Anti-coagulation: with heparin for 24- 72 hours if there is
persistent ischemia as microthrombi likely to contribute to
vaso-occlusion. Low molecular weight heparin may be used.
VI. Localized digital sympathectomy : Adventitia of digital
arteries is divided to interrupt sympathetic nerve fibres
especially in those with severe digital ischemia which is
not responsive to medical treatment.18,19
VII. Plasmapheresis : Patients with hyperviscosity syndromes
and cryoglobulinemia improve with treatments that
decrease the viscosity and improve the rheologic properties
of their blood.
VIII. Further workup for vasculitis, thrombosis, arthrosclerosis,
among other conditions, must be performed while treatment
is in place if critical digital ischemia persists.
Prognosis
Prognosis of primary Raynauds is usually very good, with
no mortality and little morbidity.
JAPI may 2010 VOL. 58 313
Prognosis of secondary Raynauds is related to the underlying
disease. Prognosis for the involved digit in these patients is
related to the severity of the ischemia and the effectiveness of
maneuvers to restore blood flow.
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