NEJM CARDIOVASCULAR DISEASE ARTICLES - Part 3 pot

editorials
n engl j med 356;17 www.nejm.org april 26, 2007
1775
haps more effort should be spent assisting our
patients with smoking cessation and the preven-
tion of diabetes, rather than our focusing so in-
tently on the dyslipidemic effects of antiretroviral
therapy, especially since uncontrolled viremia is
a greater risk factor for death from cardiovascu-
lar causes than are the metabolic changes asso-
ciated with such therapy.
Aggressive treatment of HIV clearly is the
main clinical priority, and such therapy appears
to reduce cardiovascular risk, at least in the short
term. With increased exposure to antiretroviral
therapy, there is increased exposure to cardiovas-
cular risk factors. Being treated with a protease
inhibitor may increase cardiovascular risk mod-
estly; however, longer-term studies are needed to
understand the significance of this observation
and to determine which drugs within the classes
of protease inhibitors and nonnucleoside reverse-
transcriptase inhibitors may contribute to the
problem. Patients with HIV infection are living
longer — that’s the good news. But the longer
you live, the more likely it is that heart disease
will develop, so the treatment of modifiable risk
factors is prudent.
Dr. Stein reports receiving consulting fees from Abbott and Bristol-
Myers Squibb and grant support from Bristol-Myers Squibb. No other
potential conflict of interest relevant to this article was reported.

From the University of Wisconsin School of Medicine and Public
Health, Madison.
Passalaris JD, Sepkowitz KA, Glesby MJ. Coronary artery
disease and human immunodeficiency virus infection. Clin Infect
Dis 2000;31:787-97.
Maggi P, Fiorentino G, Epifani G, et al. Premature vascular
lesions in HIV-positive patients: a clockwork bomb that will ex-
plode? AIDS 2002;16:947-8.
Stein JH. Managing cardiovascular risk in patients with HIV
infection. J Acquir Immune Defic Syndr 2005;38:115-23.
Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardio-
vascular and cerebrovascular events in patients treated for hu-
man immunodeficiency virus infection. N Engl J Med 2003;348:
702-10.
The Strategies for Management of Antiretroviral Therapy
(SMART) Study Group. CD4+ count–guided interruption of anti-
retroviral treatment. N Engl J Med 2006;355:2283-96.
Stein JH, Cotter BR, Parker RA, et al. Antiretroviral therapy
improves endothelial function in individuals with human immu-
nodeficiency virus infection: a prospective, randomized multi-
center trial (Adult AIDS Clinical Trials Group Study A5152s).
Circulation 2005;112:II-237. abstract.
The DAD Study Group. Class of antiretroviral drugs and
the risk of myocardial infarction. N Engl J Med 2007;356:1723-
35.
Currier J, Kendall M, Henry K, et al. 3-Year follow-up of ca-
rotid intima-media thickness in HIV-infected and uninfected
adults: ACTG 5078. Presented at the 13th Conference on Retro-
viruses and Opportunistic Infections, Denver, February 5–8, 2006.
abstract.

Grundy SM, Cleeman JI, Merz CN, et al. Implications of
recent clinical trials for the National Cholesterol Education Pro-
gram Adult Treatment Panel III guidelines. Circulation 2004;
110:227-39. [Erratum, Circulation 2004;110:763.]
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review article
The
new england journal of medicine
n engl j med 355;5 www.nejm.org august 3, 2006
488
Mechanisms of Disease
Chronic Venous Disease
John J. Bergan, M.D., Geert W. Schmid-Schönbein, Ph.D.,
Philip D. Coleridge Smith, D.M., Andrew N. Nicolaides, M.S.,
Michel R. Boisseau, M.D., and Bo Eklof, M.D., Ph.D.
From the Departments of Surgery (J.J.B.)
and Bioengineering (G.W.S S.), Whitaker
Institute of Biomedical Engineering, Uni-
versity of California, San Diego, La Jolla;
the Department of Vascular Surgery, Royal
Free and University College Medical School,
Middlesex Hospital, London (P.D.C.S.); the
Department of Surgery, Imperial College
London, University of Cyprus, and Vascu-
lar Screening and Diagnostic Centre, Nic-
osia, Cyprus (A.N.N.); the Department of

Vascular Biology and Pharmacology, Uni-
versity of Bordeaux 2, Bordeaux, France
(M.R.B.); and the Department of Surgery,
University of Lund, Lund, Sweden (B.E.).
Address reprint requests to Dr. Bergan
at 9850 Genesee, Suite 410, La Jolla, CA
92037, or at
N Engl J Med 2006;355:488-98.
Copyright © 2006 Massachusetts Medical Society.
C
hronic venous disease of the lower limbs is manifested by a
range of signs, the most obvious of which are varicose veins and venous ul-
cers. However, the signs also include edema, venous eczema, hyperpigmen-
tation of skin of the ankle, atrophie blanche (white scar tissue), and lipodermato-
sclerosis (induration caused by fibrosis of the subcutaneous fat) (Fig. 1). Considerable
progress has been made in understanding the mechanisms that underlie these di-
verse manifestations, in particular the role of inflammation. This article reviews
these advances and places them in a clinical context.
Chronic venous disease can be graded according to the descriptive clinical,
etiologic, anatomical, and pathophysiological (CEAP) classification, which provides
an orderly framework for communication and decision making.
1,2
The clinical signs
in the affected legs are categorized into seven classes designated C
0
to C
6
(
Table 1
).

Leg symptoms associated with chronic venous disease include aching, heaviness,
a sensation of swelling, and skin irritation; limbs categorized in any clinical class
may be symptomatic (S) or asymptomatic (A). Chronic venous disease encom-
passes the full spectrum of signs and symptoms associated with classes C
0,s
to C
6
,
whereas the term “chronic venous insufficiency” is generally restricted to disease
of greater severity (i.e., classes C
4
to C
6
). Thus, varicose veins in the absence of skin
changes are not indicative of chronic venous insufficiency.
THE SCALE OF THE PROBLEM
Prevalence
Chronic venous disease is extremely common, although the prevalence estimates
vary. A cross-sectional study of a random sample of 1566 subjects 18 to 64 years of
age from the general population in Edinburgh, Scotland,
3
found that telangiectases
and reticular veins were each present in approximately 80 percent of men and 85
percent of women. Varicose veins were present in 40 percent of men and 16 percent
of women, whereas ankle edema was present in 7 percent of men and 16 percent of
women.
3
Active or healed venous leg ulcers occur in approximately 1 percent of the
general population.
3,4

Although not restricted to the elderly, the prevalence of chronic venous disease,
especially leg ulcers, increases with age.
3-5
Most studies have shown that chronic
venous disease is more prevalent among women, although in a recent study, the
difference between sexes was small.
6
In the Framingham Study, the annual inci-
dence of varicose veins was 2.6 percent among women and 1.9 percent among
men,
7
and in contrast to the Edinburgh Vein Study, the prevalence of varicose veins
was higher in men.
3,8
In the San Diego Population Study, chronic venous disease
was more prevalent in populations of European origin than in blacks or Asians.
9

Risk factors for chronic venous disease include heredity, age, female sex, obesity
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mechanisms of disease
n engl j med 355;5 www.nejm.org august 3, 2006
489
A
C
DB
Figure 1. Clinical Manifestations of Chronic Venous Disease.
Telangiectases (clinical, etiologic, anatomical, and pathophysiological [CEAP] class C
1
) are shown in Panel A, varicose

veins (CEAP class C
2
) in Panel B, pigmentation (CEAP class C
4
) in Panel C, and active ulceration (CEAP class C
6
) in
Panel D.
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The new england journal of medicine
n engl j med 355;5 www.nejm.org august 3, 2006
490
(especially in women), pregnancy, prolonged
standing, and greater height.
4,8,10-12
Economic Impact
The high prevalence of varicose veins and the
chronicity of leg ulcers mean that chronic venous
disease has a considerable impact on health care
resources. In a population study in the United
Kingdom, the median duration of ulceration was
nine months, 20 percent of ulcers had not healed
within two years, and 66 percent of patients had
episodes of ulceration lasting longer than five
years.
13
It has been estimated that venous ulcers
cause the loss of approximately 2 million working
days and incur treatment costs of approximately
$3 billion per year in the United States.

14
Overall,
chronic venous disease has been estimated to ac-
count for 1 to 3 percent of the total health care
budgets in countries with developed health care
systems.
4,15,16
SYMPTOMS AND QUALITY OF LIFE
Symptoms traditionally ascribed to chronic ve-
nous disease include aching, heaviness, a feeling
of swelling, cramps, itching, tingling, and rest-
less legs. The proportion of patients presenting
with any venous symptom increases with increas-
ing CEAP class.
17
In an international study of 1422
patients with chronic venous disease, the overall
score for symptom severity was significantly cor-
related with the CEAP clinical class, after con-
trolling for age, sex, body-mass index, coexisting
conditions, and the duration of chronic venous dis-
ease.
18
Chronic venous disease is associated with a
reduced quality of life, particularly in relation to
pain, physical function, and mobility. It is also
associated with depression and social isolation.
19

Venous leg ulcers, the most severe manifestation

of chronic venous disease, are usually painful
20

and affect the quality of life.
21
A large-scale study
of 2404 patients using the generic Medical Out-
comes Study 36-item Short-Form General Health
Survey questionnaire found a significant associa-
tion between the quality of life and the severity
of venous disease.
22
Similarly, a correlation be-
tween the CEAP class and the quality of life has
been found with the use of a disease-specific
questionnaire.
18
The impairment associated with
CEAP classes C
5
and C
6
has been likened to the
impairment associated with heart failure.
23
VENOUS HYPERTENSION
Despite the diversity of signs and symptoms as-
sociated with chronic venous disease, it seems
likely that all are related to venous hypertension.
In most cases, venous hypertension is caused by

reflux through incompetent valves,
6,24
but other
causes include venous outflow obstruction and
failure of the calf-muscle pump owing to obesity
or leg immobility. Reflux may occur in the super-
ficial or deep venous system or in both. A review
of 1153 cases of ulcerated legs with reflux found
superficial reflux alone in 45 percent, deep reflux
Table 1. Revised Clinical Classification of Chronic Venous Disease of the Leg.*
Class Definition Comments
C
0
No visible or palpable signs of venous disease
C
1
Telangiectases, reticular veins, malleolar flare Telangiectases defined by dilated intradermal venules
<1 mm diameter
Reticular veins defined by dilated, nonpalpable, sub-
dermal veins ≤3 mm in diameter
C
2
Varicose veins Dilated, palpable, subcutaneous veins generally
>3 mm in diameter
C
3
Edema without skin changes
C
4
C

4a
C
4b
Skin changes ascribed to venous disease
Pigmentation, venous eczema, or both
Lipodermatosclerosis, atrophie blanche, or both
C
5
Skin changes with healed ulceration
C
6
Skin changes with active ulceration
* Adapted from Porter and Moneta
1
and Eklof et al.
2
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mechanisms of disease
n engl j med 355;5 www.nejm.org august 3, 2006
491
alone in 12 percent, and both forms in 43 per-
cent.
25
An analysis of cases of chronic venous
disease indicated that primary valvular incompe-
tence was present in 70 to 80 percent and a con-
genital anomaly in 1 to 3 percent; valvular in-
competence was due to trauma or deep-vein
thrombosis in 18 to 25 percent.
6,24

Pressure in the veins of the leg is determined
by two components: a hydrostatic component re-
lated to the weight of the column of blood from
the right atrium to the foot and a hydrodynamic
component related to pressures generated by con-
tractions of the skeletal muscles of the leg and
the pressure in the capillary network. Both com-
ponents are profoundly influenced by the action
of the venous valves. During standing without
skeletal-muscle activity, venous pressures in the
legs are determined by the hydrostatic compo-
nent and capillary flow, and they may reach 80 to
90 mm Hg. Skeletal-muscle contractions, as dur-
ing ambulation, transiently increase pressure with-
in the deep leg veins. Competent venous valves
ensure that venous blood flows toward the heart,
thereby emptying the deep and superficial ve-
nous systems and reducing venous pressure, usu-
ally to less than 30 mm Hg (Fig. 2). Even very
small leg movements can provide important
pumping action. In the absence of competent
valves, however, the decrease in venous pressure
with leg movements is attenuated. If valves in
the perforator veins are incompetent, the high
pressures generated in the deep veins by calf-
muscle contraction can be transmitted to the
superficial system and to the microcirculation in
skin. It seems likely, therefore, that the clinical
signs of chronic venous disease stem from venous
pressures in the leg that reach higher-than-normal

levels and remain elevated for prolonged periods.
VALVE AND VEIN-WALL CHANGES
IN CHRONIC VENOUS DISEASE
Changes in Venous Valves
Venous valve incompetence is central to the ve-
nous hypertension that appears to underlie most
or all signs of chronic venous disease. Alterations
in and damage to valves have been noted on ex-
amination with an angioscope, a fiberoptic cath-
eter that allows clinicians to view the interior of
a blood vessel. These changes include stretching,
splitting, tearing, thinning, and adhesion of valve
leaflets.
27
A reduction in the number of valves
per unit length has been obser ved in segments of
saphenous veins from patients with chronic ve-
nous insufficiency.
28
An important step forward
came when Ono et a l.
29
found infiltration of valve
leaflets and the venous wall by monocytes and
macrophages in all vein specimens from patients
with chronic venous disease and in no specimens
from controls. Infiltration was associated with
areas of endothelium that expressed intercellular
adhesion molecule 1 (ICAM-1).
30

Structural Changes in the Vein Wall
Histologic and ultrastructural studies of varicose
saphenous veins have found hypertrophy of the
vein wall with increased collagen content,
31
to-
gether with disruption of the orderly arrangements
of smooth-muscle cells and elastin fibers.
32,33
Cul-
tures of smooth-muscle cells from varicose sa-
phenous veins have disturbed collagen synthesis,
resulting in overproduction of collagen type I and
reduced synthesis of collagen type III.
34
Because
collagen type I is thought to confer rigidity and
collagen type III to confer distensibility to tissues,
such changes could contribute to the weakness
and reduced elasticity of varicose veins.
A complicating factor is the heterogeneity of
the varicose-vein wall; hypertrophic segments can
alternate with thinner atrophic segments with
fewer smooth-muscle cells and reduced extracel-
lular matrix. Degradation of extracellular matrix
Foot-Vein Pressure (mm Hg)
80
90
70
60

40
30
10
50
20
0
010203040
Seconds
Limb with incompetent venous valves
Normal limb
100
Walking
Standing
Figure 2. Action of the Musculovenous Pump in Lowering Venous Pressure
in the Leg.
After prolonged standing, venous pressure in the foot is approximately
90 mm Hg in both a patient with incompetent venous valves and a person
with a normal leg. During walking, the musculovenous pump rapidly lowers
the venous pressure in the normal leg but is ineffective in the leg with valvu-
lar incompetence. (Reproduced from Coleridge Smith
26
with the permission
of the publisher.)
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The new england journal of medicine
n engl j med 355;5 www.nejm.org august 3, 2006
492
proteins is caused by an array of proteolytic
enzymes, including matrix metalloproteinases
(MMPs) and serine proteinases, which are pro-

duced by vascular cells and inflammatory cells
such as macrophages.
35
MMPs are released as in-
active proenzymes that are activated by other
proteinases, including those produced by mast
cells,
36,37
whereas tissue inhibitors of MMPs
(TIMPs) reduce MMP activity. In varicose veins,
ratios of TIMP-1 to MMP-2 and TIMP-2 to MMP-2
have been found to be 3.6 times and 2.1 times,
respectively, those in veins of control subjects.
38

These altered ratios could favor the accumulation
of extracellular matrix material in varicose veins.
Elevated levels of the cytokines transforming
growth factor β
1
(TGF-β
1
) and fibroblast growth
factor β (FGF-β, also referred to as basic fibro-
blast growth factor) have also been found in the
walls of varicose veins.
39
TGF-β
1
stimulates col-

lagen and elastin synthesis and increases the ex-
pression of TIMPs,
40
whereas FGF-β is chemotac-
tic and mitogenic for smooth-muscle cells.
41
These
findings of changes in proteolytic enzymes and
their inhibitors and cytokines could signal the
beginning of an understanding of the mecha-
nisms that cause hypertrophic changes in the vein
wall.
42
Other changes have been found in vari-
cose regions of saphenous veins, which contain
increased numbers of mast cells.
43
Proteinases
from mast cells can activate MMPs, which de-
grade extracellular matrix. With time, local differ-
ences in the balance of opposing synthetic and
degradative processes could lead to hypertrophic
and atrophic segments of the same vein.
Role of Pressure and Shear Stress
The Role of Elevated Pressure
The acute effects of increased venous pressure
have been studied in animal models. In rats, pro-
duction of an arteriovenous fistula between the
femoral artery and vein abruptly increased the
pressure in the femoral vein to approximately

90 mm Hg.
43-45
Although the valves were stretched
immediately by the increased pressure, reflux did
not occur until at least two days later and then
increased with time. After three weeks, the num-
bers of granulocytes, monocytes, macrophages,
and lymphocytes were increased in the pressurized
valves, and MMP-2 and MMP-9 levels were raised.
Morphologic changes in the valves also occurred;
there were reductions in leaflet height and width,
and some valves disappeared. These studies sug-
gest that valves can tolerate high pressures for
limited periods, but when there is prolonged
pressure-induced inflammation, valve remodel-
ing and loss and reflux occur.
When a rat mesenteric venule was experimen-
tally occluded, the effects of increased pressure
could be separated from the effects of reduced
flow by comparing regions on either side of the
occlusion; flow was essentially zero at both sites,
but only the upstream site had high pressure.
46,47

Leukocyte rolling, adhesion, and migration, as
well as microhemorrhage and parenchymal-cell
death, were all increased at the high-pressure site.
The Role of Shear Stress
Before considering the molecular mechanisms by
which shear stress modulates endothelial and leu-

kocyte behavior, we will summarize recent work
on blood flow through venous valves. Venous
valves are operated by pressure rather than by
flow-driven devices, so that little or no reflux is
needed to bring about complete closure of the
valve.
48
The recently introduced technique of
B-flow ultrasonography has allowed detailed in-
vestigation of patterns of blood flow and valve
operation in situ.
49
Venous flow is normally pul-
satile; venous valves open and close approximate-
ly 20 times per minute while a person is standing.
When the valve leaflets are fully open, they do
not touch the sinus wall (Fig. 3). Flow through
the valve separates into a proximally directed jet
and a vortical flow into the sinus pocket behind
the valve cusp; the vortical flow prevents stasis in
the pocket and ensures that all surfaces of the
valve are exposed to shear stress. Valve closure
occurs when the pressure caused by the vortical
flow exceeds the pressure on the luminal side of
the valve leaflet because of the proximally directed
jet. Interestingly, foot movements, which increase
the velocity of the jet, reduce the pressure on the
luminal side of the valve leaflets and cause closure
of the valve. Thus, minimal reflux occurs and
endothelial surfaces are not generally exposed to

reverse blood flow.
Shear stress is transduced in endothelial cells
by several possible mechanisms and mediated by
a complex network of signaling pathways
50,51
that
can modify the expression of numerous genes.
52

An important theme of current research on the
effects of shear stress is that pulsatile, laminar
shear stress can promote the release of factors
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mechanisms of disease
n engl j med 355;5 www.nejm.org august 3, 2006
493
that reduce inflammation and the formation of
reactive free radicals. By contrast, low or zero
shear stress, disturbed or even turbulent flow,
and especially reversal of the direction of flow
all promote an inflammatory and thrombotic
phenotype (Fig. 4).
50,53-55
These processes oper-
ate in the venous and arterial systems, where they
may underlie the observation that atherosclerotic
lesions occur preferentially in regions of low or
reversing shear stress.
56,57
Leukocytes respond to fluid shear stress by the

rapid retraction of pseudopods and the shedding
of CD18 adhesion molecules; neutrophils attached
to a glass surface round up and detach when
exposed to shear stress.
58,59
The response to shear
stress is suppressed by inflammatory mediators
and enhanced by donors of nitric oxide.
60
Several aspects of the inflammatory process
include elements of positive feedback or ampli-
fication. For example, the endothelial glycocalyx
is likely to have a profound influence on the
transduction of shear stress by endothelial cells.
61

Nearly all of the mechanical stress caused by lu-
minal flow is transferred to the glycocalyx; shear
stress at the endothelial-cell surface itself is ex-
tremely small.
61
The glycocalyx may also mask
cell adhesion molecules and prevent leukocyte
adhesion.
62,63
However, inflammation can cause
disruption or shedding of the glycocalyx,
64
which
will alter shear stress responses and may promote

further leukocyte adhesion.
63
It is not known what initiates the inflamma-
tory events in venous valves and walls. Altered
shear stress may be important in several ways.
Prolonged pooling of blood causes distention of
lower limb veins and distortion of venous valves.
Leakage through such valves exposes endothelial
cells to flow reversal. Venous stasis, even in the
absence of reflux, produces regions of low or zero
shear stress, whereas subsequent structural chang-
es and irregularities in vessel walls may induce
regions of disturbed and even turbulent flow. All
of these events can initiate and maintain inflam-
matory reactions. Overall, it appears that inflam-
matory processes involving leukocyte–endothelial
interactions and triggered largely in response to
abnormal venous flow are important in causing
the adverse changes in venous valves and vein
walls. The extent and rate of progression of the
different changes will depend on the interplay of
many factors, producing wide variation among
patients.
SKIN CHANGES
Venous hypertension seems central to the skin
changes in chronic venous disease. In a sample
of 360 lower limbs of patients with a wide spec-
trum of venous disease, there was a linear trend
toward more severe skin damage with increasing
postexercise venous pressure.

65
An increase in the
occurrence of leg ulceration with increasing post-
exercise venous pressure was also observed in pa-
tients with chronic venous disease; the changes
ranged from 0 percent venous ulceration in pa-
tients with postexercise venous pressures of less
than 30 mm Hg up to 100 percent in patients
with postexercise venous pressures of more than
90 mm Hg.
66
The proposal that cuffs of fibrin
around dermal capillaries caused by filtration of
fibrinogen could impede the diffusion of oxygen
and lead to degenerative skin changes
67
has been
superseded by the theory that chronic inflamma-
tion has a key role in skin changes of chronic
venous disease.
7 cm/sec
A
B
18 cm/sec 10 cm/sec
13 cm/sec
V
axial
V
vortical
P

o
P
i
Figure 3. Velocity of Blood Flow through a Venous Valve (Panel A) and Forces
Acting on a Venous Valve Leaflet (Panel B).
In Panel A, the reduced cross-sectional area between the valve leaflets pro-
duces a proximally directed jet of increased axial velocity. In Panel B, axial
flow between the leaflets generates a pressure (P
o
) that tends to keep the
leaflet in the open position, and vortical flow in the valve pocket generates
a pressure (P
i
) that tends to close the leaflet. These pressures depend on the
respective flow velocities (V
vortical
and V
axial
); pressure is inversely related to
velocity. (Adapted from Lurie et al.
49
with the permission of the publisher.)
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The new england journal of medicine
n engl j med 355;5 www.nejm.org august 3, 2006
494
Chronic Inflammation
Current thinking about the basis of the skin
changes in chronic venous disease can be traced
back to the observation that the blood returning

from feet that have been passively dependent for
40 to 60 minutes is depleted of leukocytes, espe-
ci ally i n pat ients with chron ic venous d ise ase.
68,69

This finding suggests that leukocytes accumulate
in the leg under conditions of high venous pres-
sure. It is likely that the accumulation is largely
due to leukocyte adhesion to, as well as migration
through, the endothelium of small vessels, especial-
ly postcapillary venules. Another observation is
that plasminogen activator is released into the con-
gested vasculature, indicating that the accumulat-
ed leukocytes become activated. All this suggests
that an inflammatory reaction is important in pro-
voking skin changes in chronic venous disease.
Support for what has come to be known as
the microvascular leukocyte-trapping hypothesis
has come from immunocytochemical and ultra-
structural studies that showed elevated numbers
of macrophages, T lymphocytes, and mast cells in
skin-biopsy specimens from lower limbs affected
by chronic venous disease.
70,71
In rat models of
both acute
72
and chronic
73
venous hypertension,

elevated levels of tissue leukocytes were found in
skin samples from affected legs, but not in those
from sham-operated controls.
Mechanisms of Inflammation
Circulating leukocytes and vascular endothelial
cells express several types of membrane adhesion
molecules. The transient binding of L-selectin on
the leukocyte surface to E-selectin on endothelial
cells underlies leukocyte rolling along the endo-
thelial surface. When leukocytes are activated,
they shed L-selectin into the plasma and express
members of the integrin family, including CD11b,
which binds to ICAM-1. Integrin binding promotes
firm adhesion of leukocytes, the starting point
for their migration out of the vasculature and de-
granulation.
74
After venous hypertension was induced in pa-
tients with chronic venous disease by their stand-
ing for 30 minutes, levels of L-selectin and the
integrin CD11b on circulating neutrophils and
monocytes decreased, reflecting the trapping of
these cells in the microcirculation. Simultaneous-
ly, plasma levels of soluble L-selectin increased,
reflecting the shedding of these molecules from
leukocyte surfaces during leukocyte–endothelial
adhesion.
75
Basal plasma levels of the adhesion
molecules ICAM-1, endothelial leukocyte-adhesion

molecule 1, and vascular-cell adhesion molecule 1
were higher in patients with chronic venous dis-
ease than in control subjects, and increased sig-
nificantly in response to venous hypertension pro-
voked by standing.
76
In addition to having local factors operating
in relation to venous hypertension, patients with
chronic venous disease tend to have a systemic
increase in leukocyte adhesion. For example, plas-
ma from patients with chronic venous disease in-
duces more activation of normal, quiescent leuko-
cytes (assessed by oxygen free radical production
and pseudopod formation) than does plasma from
control subjects.
77
The plasma factor responsible
for this effect is unknown.
The Link between Inflammation
and Skin Changes
The chronic inflammatory state in patients with
chronic venous disease is related to the skin chang-
es that are typical of the condition. Increased ex-
Steady laminar blood flow
Shear stress
Low mean shear stress
Antithrombotic agents
NO
Prostacyclin
Tissue plasminogen

activator
Thrombomodulin
Growth-
inhibiting
agents
Growth-
promoting
agents
Vein-wall damage
NO
TGF-b
Angiotensin II
Endothelin-1
Platelet-derived growth factor
NO
Antimigration agents
Prosurvival
Prothrombotic agents
MCP-1
VCAM-1
Promotion
of migration
Promotion
of apoptosis
A
Flow reversal
B
Tunica externa
Tunica media
Tunica intima

Smooth-muscle cells
Endothelium
Figure 4. Contrasting Effects of Steady, Laminar Shear Stress (Panel A)
and Turbulent or Reversing Shear Stress (Panel B) on Vessel Walls.
NO denotes nitric oxide, MCP-1 monocyte chemoattractant protein 1,
and VCAM-1 vascular-cell adhesion molecule. (Reproduced from Traub
and Berk
50
with the permission of the publisher.)
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mechanisms of disease
n engl j med 355;5 www.nejm.org august 3, 2006
495
pression and activity of MMP (especially MMP-2)
have been reported in lipodermatosclerosis,
78
in
venous leg ulcers,
79
and in wound fluid from
nonhealing venous ulcers.
80
In addition, levels of
TIMP-2 are lower in lipodermatosclerotic skin and
ulcers.
78,80
Unrestrained MMP activity may con-
tribute to the breakdown of the extracellular ma-
trix, which promotes the formation of ulcers and
impairs healing.

In lipodermatosclerosis, the skin capillaries
are elongated and tortuous,
81
and they may take
on a glomerular appearance, with proliferation
of the capillary endothelium in more advanced
cases.
82
Vascular endothelial growth factor (VEGF),
which is likely to be involved in these changes,
has been shown to increase microvascular per-
meability.
83
Plasma levels of VEGF increased dur-
ing the venous hypertension that was induced by
30 minutes of standing in control subjects and
in patients with chronic venous disease, and the
levels were higher in patients than in control sub-
jects.
84
Furthermore, plasma VEGF levels were
higher in patients with chronic venous disease
with skin changes than in such patients with
normal skin.
85
Another feature of the skin changes associated
with chronic venous disease is dermal tissue fi-
brosis. TGF-β
1
is a fibrogenic cytokine. In one

study, skin from the lower calf of patients with
chronic venous disease contained significantly
elevated levels of active TGF-β
1
as compared with
normal skin or skin from the thigh region of the
same patients.
86
The TGF-β
1
was located in leu-
kocytes and fibroblasts and on collagen fibrils.
Pappas et al.
86
have proposed that activated leuko-
cytes migrate out of the vasculature and release
TGF-β
1
, stimulating collagen production by der-
mal fibroblasts, which culminates in dermal fi-
brosis. Altered collagen synthesis by dermal fibro-
blasts in apparently healthy areas of skin in
patients with varicose veins has also been re-
ported.
87
The hyperpigmentation of skin in lipodermato-
sclerosis may not be just an innocent by-product
of capillary hyperpermeability. The extravasation
of red cells leads to elevated levels of ferritin and
ferric iron in affected skin.

88,89
These increases
may cause oxidative stress, MMP activation, and
the development of a microenvironment that ex-
acerbates tissue damage and delays healing.
90

Consistent with this view, the hemochromatosis
C282Y mutation (a common genetic defect of iron
metabolism) is associated with an increase in
the risk of ulceration by a factor of nearly seven
in patients with chronic venous disease.
91
IMPLICATIONS FOR TREATMENT
Although the causal and temporal sequences of
events that occur during the development and
progression of chronic venous disease have not
been ascertained, the emerging twin themes of
disturbed venous-flow patterns and chronic in-
flammation may underlie all the clinical manifes-
tations of the disease (Fig. 5). Early treatment
aimed at preventing venous hypertension, reflux,
and inflammation could alleviate symptoms of
chronic venous disease and reduce the risk of ul-
cers, both of which reduce the quality of life and
are expensive to treat. Compression stockings im-
prove venous hemodynamics,
92
reduce edema and
skin discoloration,

93
and improve the quality of
Risk factors for chronic venous disease
Genetic factors
Female sex (progesterone)
Pregnancy
Age
Greater height
Prolonged standing
Obesity
Venous dilation
Inflammation
Valve distortion,
leakage
Altered shear
stress
Valve and vein-
wall changes
Capillary
hypertension
Capillary leakage
Inflammation
Edema
Venous
hypertension
Chronic
reflux
Venous ulcer Skin changes
Figure 5. Venous Hypertension as the Hypothetical Cause of the Clinical
Manifestations of Chronic Venous Disease, Emphasizing the Importance

of Inflammation.
Some steps are speculative, and to enhance clarity, not all possible inter-
connections are shown.
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The new england journal of medicine
n engl j med 355;5 www.nejm.org august 3, 2006
496
life
94
in patients with chronic venous disease.
Evidence is accumulating that surgery aimed at
preventing venous reflux can aid healing and
prevent the recurrence of ulcers
95,96
; it therefore
seems reasonable to speculate that such treat-
ment could reduce the risk of ulcers if performed
early in the course of chronic venous disease.
Treatment to inhibit inflammation may offer the
greatest opportunity to prevent disease-related
complications. Currently available drugs can at-
tenuate various elements of the inflammatory cas-
cade,
97,98
particularly the leukocyte–endothelium
interactions that are important in many aspects
of the disease.
46,99,100
These agents deserve de-
tailed study. Overall, a determined and proactive

approach to the treatment of the early stages of
chronic venous disease could reduce the number
of patients needing treatment for intractable ul-
cers. In the long term, improved understanding of
the cellular and molecular mechanisms involved
may allow the identification of additional targets
for pharmacologic intervention.
Dr. Bergan reports having served as a consultant to VNUS
Technologies. Dr. Schmid-Schönbein reports being a member of
the editorial board of Phlebolymphology, a journal sponsored by
Servier. Dr. Coleridge Smith reports having received consulting
fees from Servier and lecture fees from Medi Stockings, Servier,
and Saltzmann. No other potential conflict of interest relevant
to this article was reported.
References
Porter JM, Moneta GL. Reporting stan-
dards in venous disease: an update. J Vasc
Surg 1995;21:635-45.
Eklof B, Rutherford RB, Bergan JJ, et
al. Revision of the CEAP classification for
chronic venous disorders: consensus state-
ment. J Vasc Surg 2004;40:1248-52.
Evans CJ, Fowkes FGR, Ruckley CV,
Lee AJ. Prevalence of varicose veins and
chronic venous insufficiency in men and
women in the general population: Edin-
burgh Vein Study. J Epidemiol Community
Health 1999;53:149-53.
Kurz X, Kahn SR, Abenhaim L, et al.
Chronic venous disorders of the leg: epi-

demiology, outcomes, diagnosis and man-
agement: summary of an evidence-based
report of the VEINES task force. Int Angiol
1999;18:83-102.
Moffatt CJ, Franks PJ, Doherty DC,
Martin R, Blewett R, Ross F. Prevalence
of leg ulceration in a London population.
QJM 2004;97:431-7.
Labropoulos N. Hemodynamic chang-
es according to the CEAP classification.
Phlebolymphology 2003;40:130-6.
Brand FN, Dannenberg AL, Abbott RD,
Kannel WB. The epidemiology of varicose
veins: the Framingham Study. Am J Prev
Med 1988;4:96-101.
Lee AJ, Evans CJ, Allan PL, Ruckley CV,
Fowkes FG. Lifestyle factors and the risk
of varicose veins: Edinburgh Vein Study.
J Clin Epidemiol 2003;56:171-9.
Criqui MH, Jamosmos M, Fronek A, et
al. Chronic venous disease in an ethnically
diverse population: the San Diego Popula-
tion Study. Am J Epidemiol 2003;158:448-
56.
Fowkes FG, Lee AJ, Evans CJ, Allan PL,
Bradbury AW, Ruckley CV. Lifestyle risk
factors for lower limb venous reflux in the
general population: Edinburgh Vein Study.
Int J Epidemiol 2001;30:846-52.
Laurikka JO, Sisto T, Tarkka MR,

Auvinen O, Hakama M. Risk indicators
for varicose veins in forty- to sixty-year-
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
olds in the Tampere varicose vein study.
World J Surg 2002;26:648-51.
Chiesa R, Marone EM, Limoni C,
Volonte M, Schaefer E, Petrini O. Demo-
graphic factors and their relationship with
the presence of CVI signs in Italy: the 24-
cities cohort study. Eur J Vasc Endovasc
Surg 2005;30:674-80.
Callam MJ, Harper DR, Dale JJ, Ruck-
ley CV. Chronic ulcer of the leg: clinical
history. Br Med J (Clin Res Ed) 1987;294:
1389-91.
McGuckin M, Waterman R, Brooks J,
et al. Validation of venous leg ulcer guide-
lines in the United States and United
Kingdom. Am J Surg 2002;183:132-7.
Ruckley CV. Socioeconomic impact of

chronic venous insufficiency and leg ulcers.
Angiology 1997;48:67-9.
Van den Oever R, Hepp B, Debbaut B,
Simon I. Socio-economic impact of chron-
ic venous insufficiency: an underestimat-
ed public health problem. Int Angiol 1998;
17:161-7.
Carpentier PH, Cornu-Thénard A, Uhl
J-F, Partsch H, Antignani PL. Appraisal of
the information content of the C classes
of CEAP clinical classification of chronic
venous disorders: a multicenter evaluation
of 872 patients. J Vasc Surg 2003;37:827-
33.
Kahn SR, M’lan CE, Lamping DL,
Kurz X, Bérard A, Abenhaim LA. Relation-
ship between clinical classification of
chronic venous disease and patient-report-
ed quality of life: results from an interna-
tional cohort study. J Vasc Surg 2004;39:
823-8.
van Korlaar I, Vossen C, Rosendaal F,
Cameron L, Bovill E, Kaptein A. Quality of
life in venous disease. Thromb Haemost
2003;90:27-35.
Nemeth KA, Harrison MB, Graham
ID, Burke S. Understanding venous leg
ulcer pain: results of a longitudinal study.
Ostomy Wound Manage 2004;50:34-46.
Franks PJ, Moffatt CJ. Health related

12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
quality of life in patients with venous ul-
ceration: use of the Nottingham health
profile. Qual Life Res 2001;10:693-700.
Kaplan RM, Criqui MH, Denenberg JO,
Bergan J, Fronek A. Quality of life in pa-
tients with chronic venous disease: San
Diego Population Study. J Vasc Surg 2003;
37:1047-53.
Andreozzi GM, Cordova RM, Scom-
parin A, Martini R, D’Eri A, Andreozzi F.
Quality of life in chronic venous insuffi-
ciency: an Italian pilot study of the Tri-
veneto Region. Int Angiol 2005;24:272-7.
Kistner RL, Eklof B, Masuda EM. Di-
agnosis of chronic venous disease of the
lower extremities: the “CEAP” classifica-
tion. Mayo Clin Proc 1996;71:338-45.
Tassiopoulos AK, Golts E, Oh DS, Lab-
ropoulos N. Current concepts in chronic
venous ulceration. Eur J Vasc Endovasc

Surg 2000;20:227-32.
Coleridge Smith PD. The microcircu-
lation in venous hypertension. Vasc Med
1997;2:203-13.
Van Cleef JF, Hugentobler JP, Desvaux
P, Griton P, Cloarec M. Étude endos co-
pique des reflux valvulaires saphéniens.
J Mal Vasc 1992;17:Suppl B:113-6.
Sales CM, Rosenthal D, Petrillo KA, et
al. The valvular apparatus in venous in-
sufficiency: a problem of quantity? Ann
Vasc Surg 1998;12:153-5.
Ono T, Bergan JJ, Schmid-Schönbein
GW, Takase S. Monocyte infiltration into
venous valves. J Vasc Surg 1998;27:158-66.
Takase S, Bergan JJ, Schmid-Schön-
bein GW. Expression of adhesion mole-
cules and cytokines on saphenous veins
in chronic venous insufficiency. Ann Vasc
Surg 2000;14:427-35.
Travers JP, Brookes CE, Evans J, et al.
Assessment of wall structure and compo-
sition of varicose veins with reference to
collagen, elastin and smooth muscle con-
tent. Eur J Vasc Endovasc Surg 1996;11:
230-7.
Porto LC, Ferreira MA, Costa AM, da
22.
23.
24.

25.
26.
27.
28.
29.
30.
31.
32.
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
mechanisms of disease
n engl j med 355;5 www.nejm.org august 3, 2006
497
Silveira PR. Immunolabeling of type IV
collagen, laminin, and alpha-smooth mus-
cle actin cells in the intima of normal and
varicose saphenous veins. Angiology 1998;
49:391-8.
Wali MA, Eid RA. Changes of elastic
and collagen fibers in varicose veins. Int
Angiol 2002;21:337-43.
Sansilvestri-Morel P, Rupin A, Badier-
Commander C, et al. Imbalance in the
synthesis of collagen type I and collagen
type III in smooth muscle cells derived
from human varicose veins. J Vasc Res
2001;38:560-8.
Jacob MP, Badier-Commander C, Fon-
taine V, Benazzoug Y, Feldman L, Michel
JB. Extracellular matrix remodeling in the
vascular wall. Pathol Biol (Paris) 2001;49:

326-32.
Lees M, Taylor DJ, Woolley DE. Mast
cell proteinases activate precursor forms
of collagenase and stromelysin, but not of
gelatinases A and B. Eur J Biochem 1994;
223:171-7.
Johnson JL, Jackson CL, Angelini GD,
George SJ. Activation of matrix-degrading
metalloproteinases by mast cell proteases
in atherosclerotic plaques. Arterioscler
Thromb Vasc Biol 1998;18:1707-15.
Badier-Commander C, Verbeuren T,
Lebard C, Michel J-B, Jacob M-P. Increased
TIMP/MMP ratio in varicose veins: a pos-
sible explanation for extracellular matrix
accumulation. J Pathol 2000;192:105-12.
Badier-Commander C, Couvelard A,
Henin D, Verbeuren T, Michel J-B, Jacob
M-P. Smooth muscle cell modulation and
cytokine overproduction in varicose veins:
an in situ study. J Pathol 2001;193:398-407.
Overall CM, Wrana JL, Sodek J. Tran-
scriptional and post-transcriptional regu-
lation of 72-kD gelatinase/type IV collage-
nase by transforming growth factor-β1 in
human fibroblasts: comparisons with col-
lagenase and tissue inhibitor of matrix
metalloproteinase gene expression. J Biol
Chem 1991;266:14064-71.
Lindner V, Reidy MA. Proliferation of

smooth muscle cells after vascular injury
is inhibited by an antibody against basic
fibroblast growth factor. Proc Natl Acad
Sci U S A 1991;88:3739-43.
Morozov KM, Abalmasov KG, Serov
RA, Krylova RG. Morphological changes
in femoral vein wall structure in presence
of persistent vertical reflux. Vestn Ross
Akad Med Nauk 2005;4:81-5. (In Russian.)
Takase S, Pascarella L, Bergan JJ,
Schmid-Schönbein GW. Hypertension-
induced venous valve remodeling. J Vasc
Surg 2004;39:1329-34.
Takase S, Pascarella L, Lerond L, Ber-
gan JJ, Schmid-Schönbein GW. Venous
hypertension, inflammation and valve re-
modeling. Eur J Vasc Endovasc Surg 2004;
28:484-93.
Pascarella L, Schmid-Schönbein GW,
Bergan J. An animal model of venous hy-
pertension: the role of inflammation in
33.
34.
35.
36.
37.
38.
39.
40.
41.

42.
43.
44.
45.
venous valve failure. J Vasc Surg 2005;41:
303-11.
Ta ka s e S, L er on d L , B e rg an J J, Sc h mi d -
Schönbein GW. The inflammatory reac-
tion during venous hypertension in the
rat. Microcirculation 2000;7:41-52.
Idem. Enhancement of reperfusion in-
jury by elevation of microvascular pres-
sures. Am J Physiol Heart Circ Physiol
2002;282:H1387-H1394.
Qui Y, Quijano RC, Wang SK, Hwang
NH. Fluid dynamics of venous valve clo-
sure. Ann Biomed Eng 1995;23:750-9.
Lurie F, Kistner RL, Eklof B, Kessler D.
Mechanism of venous valve closure and
role of the valve in circulation: a new con-
cept. J Vasc Surg 2003;38:955-61.
Traub O, Berk BC. Laminar shear
stress: mechanisms by which endothelial
cells transduce an atheroprotective force.
Arterioscler Thromb Vasc Biol 1998;18:
677-85.
Yoshizumi M, Abe J, Tsuchiya K, Berk
BC, Tamaki T. Stress and vascular respons-
es: atheroprotective effect of laminar fluid
shear stress in endothelial cells: possible

role of mitogen-activated protein kinases.
J Pharmacol Sci 2003;91:172-6.
Ohura N, Yamamoto K, Ichioka S, et al.
Global analysis of shear stress-responsive
genes in vascular endothelial cells. J Ath-
eroscler Thromb 2003;10:304-13.
Berk BC, Abe JI, Min W, Surapisitchat
J, Yan C. Endothelial atheroprotective and
anti-inflammatory mechanisms. Ann N Y
Acad Sci 2001;947:93-109.
Passerini AG, Milsted A, Rittgers SE.
Shear stress magnitude and directionality
modulate growth factor gene expression
in preconditioned vascular endothelial cells.
J Vasc Surg 2003;37:182-90.
Sorescu GP, Sykes M, Weiss D, et al.
Bone morphogenic protein 4 produced in
endothelial cells by oscillatory shear stress
stimulates an inflammatory response.
J Biol Chem 2003;278:31128-35.
Asakura T, Karino T. Flow patterns
and spatial distribution of atherosclerotic
lesions in human coronary arteries. Circ
Res 1990;66:1045-66.
Moore JE Jr, Xu C, Glagov S, Zarins
CK, Ku DN. Fluid wall shear stress mea-
surements in a model of the human ab-
dominal aorta: oscillatory behavior and
relationship to atherosclerosis. Atheroscle-
rosis 1994;110:225-40.

Moazzam F, DeLano FA, Zweifach BW,
Schmid-Schönbein GW. The leukocyte re-
sponse to fluid stress. Proc Natl Acad Sci
U S A 1997;94:5338-43.
Fukuda S, Schmid-Schönbein GW.
Regulation of CD18 expression on neutro-
phils in response to fluid shear stress.
Proc Natl Acad Sci U S A 2003;100:13152-7.
Fukuda S, Yasu T, Predescu DN,
Schmid-Schönbein GW. Mechanisms for
regulation of fluid shear stress response
in circulating leukocytes. Circ Res 2000;
86:E13-E18.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
Secomb TW, Hsu R, Pries AR. Effect
of the endothelial surface layer on trans-

mission of fluid shear stress to endothe-
lial cells. Biorheology 2001;38:143-50.
Zhao Y, Chien S, Weinbaum S. Dynam-
ic contact forces on leukocyte microvilli
and their penetration of the endothelial
glycocalyx. Biophys J 2001;80:1124-40.
Mulivor AW, Lipowsky HH. Role of
the glycocalyx in leukocyte-endothelial cell
adhesion. Am J Physiol Heart Circ Physiol
2002;283:H1282-H1291.
Idem. Inflammation- and ischemia-
induced shedding of venular glycocalyx.
Am J Physiol Heart Circ Physiol 2004;286:
H1672-H1680.
Payne SP, London NJ, Newland CJ,
Thrush AJ, Barrie WW, Bell PR. Ambula-
tory venous pressure: correlation with skin
condition and role in identifying surgi-
cally correctible disease. Eur J Vasc Endo-
vasc Surg 1996;11:195-200.
Nicolaides AN, Hussein MK, Szendro
G, Christopoulos D, Vasdekis S, Clarke H.
The relation of venous ulceration with am-
bulatory venous pressure measurements.
J Vasc Surg 1993;17:414-9.
Burnand KG, Whimster I, Naidoo A,
Browse NL. Pericapillary fibrin in the ulcer-
bearing skin of the leg: the cause of lipo-
dermatosclerosis and venous ulceration.
Br Med J (Clin Res Ed) 1982;285:1071-2.

Moyses C, Cederholm-Williams SA,
Michel CC. Haemoconcentration and ac-
cumulation of white cells in the feet dur-
ing venous stasis. Int J Microcirc Clin Exp
1987;5:311-20.
Thomas PR, Nash GB, Dormandy JA.
White cell accumulation in dependent legs
of patients with venous hypertension: a
possible mechanism for trophic changes
in the skin. Br Med J (Clin Res Ed) 1988;
296: 1693-5.
Wilkinson LS, Bunker C, Edwards JC,
Scurr JH, Smith PD. Leukocytes: their role
in the etiopathogenesis of skin damage in
venous disease. J Vasc Surg 1993;17:669-75.
Pappas PJ, DeFouw DO, Venezio LM,
et al. Morphometric assessment of the
dermal microcirculation in patients with
chronic venous insufficiency. J Vasc Surg
1997;26:784-95.
Lalka SG, Unthank JL, Nixon JC. Ele-
vated cutaneous leukocyte concentration
in a rodent model of acute venous hyper-
tension. J Surg Res 1998;74:59-63.
Hahn TL, Unthank JL, Lalka SG. In-
creased hindlimb leukocyte concentration
in a chronic rodent model of venous hyper-
tension. J Surg Res 1999;81:38-41.
Yong K, Khwaja A. Leukocyte cellular
adhesion molecules. Blood Rev 1990;4:211-

25.
Saharay M, Shields DA, Porter JB,
Scurr JH, Coleridge Smith PD. Leukocyte
activity in the microcirculation of the leg
in patients with chronic venous disease.
J Vasc Surg 1997;26:265-73.
Saharay M, Shields DA, Georgiannos
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
n engl j med 355;5 www.nejm.org august 3, 2006
498
mechanisms of disease
SN, Porter JB, Scurr JH, Coleridge Smith
PD. Endothelial activation in patients with
chronic venous disease. Eur J Vasc Endo-

vasc Surg 1998;15:342-9.
Takase S, Schmid-Schönbein G, Ber-
gan JJ. Leukocyte activation in patients
with venous insufficiency. J Vasc Surg
1999;30:148-56.
Herouy Y, May AE, Pornschlegel G, et
al. Lipodermatosclerosis is characterized
by elevated expression and activation of
matrix metalloproteinases: implications
for venous ulcer formation. J Invest Der-
matol 1998;111:822-7.
Norgauer J, Hildenbrand T, Idzko M,
et al. Elevated expression of extracellular
matrix metalloproteinase inducer (CD147)
and membrane-type matrix metallopro-
teinases in venous leg ulcers. Br J Derma-
tol 2002;147:1180-6.
Mwaura B, Mahendran B, Hynes N, et
al. The impact of differential expression of
extracellular matrix metalloproteinase in-
ducer, matrix metalloproteinase-2, tissue
inhibitor of matrix metalloproteinase-2
and PDGF-AA on the chronicity of venous
leg ulcers. Eur J Vasc Endovasc Surg 2006;
31:306-10.
Burnand KG, Whimster I, Clemenson
G, Thomas ML, Browse NL. The relation-
ship between the number of capillaries in
the skin of the venous ulcer-bearing area
of the lower leg and the fall in foot vein

pressure during exercise. Br J Surg 1981;
68:297-300.
Junger M, Hahn U, Bort S, Klyscz T,
Hahn M, Rassner G. Significance of cuta-
neous microangiopathy for the pathogen-
esis of dermatitis in venous congest ion due
to chronic venous insufficiency. Wien Med
Wochenschr 1994;144:206-10. (In German.)
Bates DO, Curry FE. Vascular endothe-
lial growth factor increases hydraulic con-
ductivity of isolated perfused micro vessels.
Am J Physiol 1996;271:H2520-H2528.
77.
78.
79.
80.
81.
82.
83.
Shoab SS, Scurr JH, Coleridge-Smith
PD. Increased plasma vascular endothelial
growth factor among patients with chron-
ic venou s d i se as e. J Va s c S u rg 19 9 8;2 8:535-
40.
Idem. Plasma VEGF as a marker of
therapy in patients with chronic venous
disease treated with oral micronised fla-
vonoid fraction — a pilot study. Eur J Vasc
Endovasc Surg 1999;18:334-8.
Pappas PJ, You R, Rameshwar P, et al.

Dermal tissue fibrosis in patients with
chronic venous insufficiency is associated
with increased transforming growth fac-
tor-β
1
gene expression and protein pro-
duction. J Vasc Surg 1999;30:1129-45.
Sansilvestri-Morel P, Rupin A, Jaisson
S, Fabiani J-N, Verbeuren TJ, Vanhoutte PM.
Synthesis of collagen is dysregulated in
cultured fibroblasts derived from skin of
subjects with varicose veins as it is in ve-
nous smooth muscle cells. Circulation
2002;106:479-83.
Ackerman Z, Seidenbaum M, Loewen-
thal E, Rubinow A. Overload of iron in t he
skin of patients with varicose ulcers: pos-
sible contributing role of iron accumula-
tion in progression of the disease. Arch
Dermatol 1988;124:1376-8.
Yeoh-Ellerton S, Stacey MC. Iron and
8-isoprostane levels in acute and chronic
wounds. J Invest Dermatol 2003;121:918-
25.
Wenk J, Foitzik A, Achterberg V, et al.
Selective pick-up of increased iron by defe-
roxamine-coupled cellulose abrogates the
iron-driven induction of matrix-degrad-
ing metalloproteinase-1 and lipid peroxi-
dation in human dermal fibroblasts in

vitro: a new dressing concept. J Invest
Dermatol 2001;116:833-9.
Zamboni P, Tognazzo S, Izzo M, et al.
Hemochromatosis C282Y gene mutation
increases the risk of venous leg ulceration.
J Vasc Surg 2005;42:309-14.
84.
85.
86.
87.
88.
89.
90.
91.
Ibegbuna V, Delis KT, Nicolaides AN,
Aina O. Effect of elastic compression stock-
ings on venous hemodynamics during
walking. J Vasc Surg 2003;37:420-5.
Motykie GD, Caprini JA, Arcelus JI,
Reyna JJ, Overom E, Mokhtee D. Evalua-
tion of therapeutic compression stock-
ings in the treatment of chronic venous
insufficiency. Dermatol Surg 1999;25:
116-20.
Andreozzi GM, Cordova R, Scomparin
MA, Martini R, D’Eri A, Andreozzi F. Ef-
fects of elastic stocking on quality of life
of patients with chronic venous insuffi-
ciency: an Italian pilot study on Triveneto
Region. Int Angiol 2005;24:325-9.

Barwell JR, Davies CE, Deacon J, et al.
Comparison of surgery and compression
with compression alone in chronic venous
ulceration (ESCHAR study): randomised
controlled trial. Lancet 2004;363:1854-
9.
Tenbrook JA Jr, Iafrati MD, O’Donnell
TF Jr, et al. Systematic review of outcomes
after surgical management of venous dis-
ease incorporating subfascial endoscopic
perforator surgery. J Vasc Surg 2004;39:
583-9.
Boisseau MR. Pharmacologie des médi-
caments veinotoniques: données actuelles
sur leur mode d’action et les cibles théra-
peutiques. Angeiologie 2000;52:71-7.
Eberhardt RT, Raffetto JD. Chronic ve-
nous insufficiency. Circulation 2005;111:
2398-409.
Takase S, Delano FA, Lerond L, Bergan
JJ, Schmid-Schönbein GW. Inflammation
in chronic venous insufficiency: is the
problem insurmountable? J Vasc Res 1999;
36:Suppl 1:3-10.
Nicolaides AN. From symptoms to leg
edema: efficacy of Daflon 500 mg. Angi-
ology 2003;54:Suppl 1:S33-S44.
Copyright © 2006 Massachusetts Medical Society.
92.
93.

94.
95.
96.
97.
98.
99.
100.
CLINICAL

TRIAL

REGISTRATION
The Journal encourages investigators to register their clinical trials
in a public trials registry. The members of the International Committee
of Medical Journal Editors plan to consider clinical trials for publication
only if they have been registered (see N Engl J Med 2004;351:1250-1).
The National Library of Medicine’s www.clinicaltrials.gov is a free registry,
open to all investigators, that meets the committee’s requirements.
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editorials
n engl j med 357;19 www.nejm.org november 8, 2007
1971
and reduction of radiation dose in early unfavorable stage Hodg-
kin’s lymphoma. Blood 2005;106:816a. abstract.
Meyer RM, Gospodarowicz MK, Connors JM, et al. Random-
ized comparison of ABVD chemotherapy with a strategy that
includes radiation therapy in patients with limited-stage Hodg-
12.
kin’s lymphoma: National Cancer Institute of Canada Clinical
Trials Group and the Eastern Cooperative Oncology Group. J Clin

Oncol 2005;23:4634-42.
Copyright © 2007 Massachusetts Medical Society.
Congenital Heart Disease and Brain Injury
Michael V. Johnston, M.D.
During the past 25 years, remarkable progress
has been made in the surgical treatment and sur-
vival of infants with congenital heart disease.
1

Recent data have shown that in-hospital death
rates for neonates were less than 10% for the
treatment of transposition of the great arteries
with the arterial-switch procedure and less than
20% for the treatment of hypoplastic left heart
syndrome with aortic arch reconstruction using
the Norwood procedure.
2
Before the development
of the Norwood procedure in 1980, the vast ma-
jority of infants with hypoplastic left heart syn-
drome died.
3
On the other hand, several studies have shown
that many children with congenital heart disease
survive with motor, visuospatial, behavioral, so-
cial, and academic problems that impair their
progress in school.
4,5
In a prospective study of
children with complex lesions who underwent sur-

gery before the age of 2 years, Majnemer et al.
found that half the group had substantial neuro-
logic impairment or motor delay persisting to
school age.
6
Although these disabilities have often
been attributed to brain injury from surgery or
support procedures, such as hypothermic circu-
latory arrest and cardiopulmonary bypass, more
than half of infants with congenital heart disease
also have neurobehavioral abnormalities in the
neonatal period when they are examined before
surgery.
7
This finding suggests that the patho-
genesis of brain disorders in these children may
be multifactorial and include antenatal, postna-
tal, and surgical components.
Several clinical trials have assessed the influ-
ence of the timing of surgery, as well as the sur-
gical support technique used, on later outcome.
In 1984, Newburger et al. reported that delaying
surgery for several months in children with cyano-
sis and transposition of the great arteries resulted
in a time-dependent reduction in intelligence as
well as a decline in visual-association and audi-
tory-association function; however, a similar de-
lay in children with acyanotic congenital heart
defects had no effect.
8

In the 1990s, the Boston Circulatory Arrest
Trial (BCAT) compared hypothermic circulatory
arrest with low-flow bypass and hypothermia as
a support for surgery in infants with dextrotrans-
position of the great arteries who underwent an
arterial-switch procedure.
9
Assessment at 1 year
showed that the group that underwent hypo-
thermic circulatory arrest had lower scores in
psychomotor development on the Bayley Scales of
Infant Development and a higher risk of neuro-
logic abnormalities than the group that under-
went hypothermic low-flow bypass. Perioperative
seizure activity was associated with lower psycho-
motor scores as well as a greater likelihood of
abnormalities on magnetic resonance imaging
(MRI).
10
However, follow-up at 8 years after sur-
gery showed that children in the group that un-
derwent hypothermic circulatory arrest did not
differ from children in the group that underwent
low-flow bypass in most of the end points mea-
sured. Psychomotor performance was below ex-
pectation in both groups in terms of academic
achievement, visuospatial skills, memory, and oth-
er abilities.
9
The group that underwent hypother-

mic circulatory arrest scored lower in motor skills,
clarity of speech, visual–motor tracking, and pho-
nologic awareness, but the group that under-
went low-flow bypass scored lower on behavior
in the classroom and continuous performance.
The BCAT study group concluded that factors
other than total circulatory arrest (e.g., genetic
polymorphisms and mutations, preoperative fac-
tors, and postnatal events) were also important
in determining the prognoses of these children.
The group recommended close developmental
follow-up for all children who undergo surgery
to repair congenital heart defects.
9
These results provide the background for the
important new study by Miller et al. in this issue
of the Journal.
11
The authors used MRI and three-
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
T h e n e w eng l a nd jo ur na l o f m edi c in e
n engl j med 357;19 www.nejm.org november 8, 2007
1972
dimensional magnetic resonance spectroscopic
techniques to examine the brains of term new-
borns (>36 weeks’ gestation) who had either trans-
position of the great arteries or single-ventricle
physiology in the neonatal period before surgery.
These infants were compared with age-matched
term infants who were enrolled in a study of nor-

mal brain development. In agreement with earlier
MRI findings in infants with congenital heart
disease,
12
Miller et al. found a high incidence of
injury to white matter that resembled periventric-
ular leukomalacia, as seen in premature infants.
However, they did not find lesions that are char-
acteristic of injury in term infants, such as dam-
age to the basal ganglia or the cerebral cortex in
a watershed pattern.
The results of spectroscopic and diffusion ten-
sor imaging (DTI) also suggested that the brain
tissue of these infants resembled that of prema-
ture infants. N-acetylaspartate, a marker that in-
creases in neurons with maturation and is reduced
by brain injury,
13
was found to be lower in infants
with congenital heart disease than in control in-
fants. In contrast, the average diffusivity of water
in the brain measured with DTI was higher in in-
fants with congenital heart disease than in con-
trol infants. Average diffusivity decreases with
increasing maturity, possibly because of reduced
water content and restriction of water movement
by the increasing complexity of neurons and glia.
Fractional anisotropy of white matter is another
measure provided by DTI that reflects greater re-
striction of water along the direction of a straight

line as opposed to a sphere. Fractional anisotropy
increases with the maturation of white matter;
the maturation reduction in the brains of infants
with congenital heart disease that was observed
by Miller et al. was also consistent with relative
immaturity.
Taken together, these results show that brain
injury is commonly seen in infants with severe
congenital heart disease at birth before surgery
and that it resembles white-matter injury seen in
premature infants because brain maturation is de-
layed. The results are consistent with data from
the earlier BCAT study in showing that infants
with congenital heart disease are at risk for devel-
opmental problems well before the time of sur-
gical intervention.
These observations add to the evidence that
newborns with congenital heart disease are at
risk for impaired brain development in utero.
This finding could be related to impaired deliv-
ery of oxygen and other substrates to the fetal
brain secondary to disordered fetal circulation
associated with the congenital heart lesion.
11

However, other developmental and genetic influ-
ences may also be important. For example, exten-
sive white-matter anomalies have been identified
in infants with the velocardiofacial syndrome
(a 22q11.2 deletion), which includes congenital

heart disease and cognitive and behavioral dis-
abilities.
14
Children with acyanotic congenital
heart disease, such as a ventricular septal defect,
have more preoperative neurobehavioral abnor-
malities than do infants with cyanosis,
7
and in-
fants with a ventricular septal defect are also
more likely than children with other types of
congenital heart disease to have periventricular
echodensities on preoperative cranial ultrasonog-
raphy.
15
The new information provided by ad-
vanced brain imaging and spectroscopy makes it
essential to learn more about fetal brain develop-
ment in children with congenital heart disease to
develop better neuroprotective strategies and im-
prove outcome.
No potential conflict of interest relevant to this article was
reported.
From the Kennedy Krieger Institute and Johns Hopkins University
School of Medicine — both in Baltimore.
Stasik CN, Gelehrter S, Goldberg CS, Bove EL, Devaney EJ,
Ohye RG. Current outcomes and risk factors for the Norwood
procedure. J Thorac Cardiovasc Surg 2006;131:412-7. [Erratum,
J Thorac Cardiovasc Surg 2007;133:602.]
Welke KF, Shen I, Ungerleider RM. Current assessment of

mortality rates in congenital cardiac surgery. Ann Thorac Surg
2006;82:164-70.
Goldberg CS, Gomez CA. Hypoplastic left heart syndrome:
new developments and current controversies. Semin Neonatol
2003;8:461-8.
Miatton M, De Wolf D, Francois K, Thiery E, Vingerhoets G.
Neurocognitive consequences of surgically corrected congenital
heart defects: a review. Neuropsychol Rev 2006;16:65-85.
Bellinger DC, Bernstein JH, Kirkwood MW, Rappaport LA,
Newburger JW. Visual-spatial skills in children after open-heart
surgery. J Dev Behav Pediatr 2003;24:169-79.
Majnemer A, Limperopoulos C, Shevell M, Rosenblatt B,
Rohlicek C, Tchervenkov C. Long-term neuromotor outcome at
school entry of infants with congenital heart defects requiring
open-heart surgery. J Pediatr 2006;148:72-7.
Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B,
Rohlicek C, Tchervenkov C. Neurologic status of newborns with
congenital heart defects before open heart surgery. Pediatrics
1999;103:402-8.
Newburger JW, Silbert AR, Buckley LP, Fyler DC. Cognitive
function and age at repair of transposition of the great arteries
in children. N Engl J Med 1984;310:1495-9.
Bellinger DC, Wypij D, duPlessis AJ, et al. Neurodevelop-
mental status at eight years in children with dextro-transposi-
tion of the great arteries: the Boston Circulatory Arrest Trial.
J Thorac Cardiovasc Surg 2003;126:1385-96.
1.
2.
3.
4.

5.
6.
7.
8.
9.
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
n engl j med 357;19 www.nejm.org november 8, 2007
1973
Rappaport LA, Wypij D, Bellinger DC, et al. Relation of sei-
zures after cardiac surgery in early infancy to neurodevelopmen-
tal outcome. Circulation 1998;97:773-9.
Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain
development in newborns with congenital heart disease. N Engl
J Med 2007;357:1928-38.
Galli KK, Zimmerman RA, Jarvik GP, et al. Periventricular
leukomalacia is common after neonatal cardiac surgery. J Thorac
Cardiovasc Surg 2004;127:692-704.
Barreiro CJ, Williams JA, Fitton TP, et al. Noninvasive assess-
10.
11.
12.
13.
ment of brain injury in a canine model of hypothermic circula-
tory arrest using magnetic resonance spectroscopy. Ann Thorac
Surg 2006;81:1593-8.
Campbell LE, Daly E, Toal F, et al. Brain and behaviour in
children with 22q11.2 deletion syndrome: a volumetric and voxel-
based morphometry MRI study. Brain 2006;129:1218-28.
van Houten JP, Rothman A, Bejar R. High incidence of cranial
ultrasound abnormalities in full-term infants with congenital

heart disease. Am J Perinatol 1996;13:47-53.
Copyright © 2007 Massachusetts Medical Society.
14.
15.
editorials
collections

of

articles

on

the

journal
’
s

web

site
The Journal’s Web site (www.nejm.org) sorts published articles into
more than 50 distinct clinical collections, which can be used as convenient
entry points to clinical content. In each collection, articles are cited in reverse
chronologic order, with the most recent first.
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
n engl j med 358;1 www.nejm.org january 3, 2008
9
The new england

journal of medicine
established in 1812 january 3, 2008 vol. 358 no. 1
Delayed Time to Defibrillation after In-Hospital Cardiac Arrest
Paul S. Chan, M.D., Harlan M. Krumholz, M.D., Graham Nichol, M.D., M.P.H.,
Brahmajee K. Nallamothu, M.D., M.P.H., and the American Heart Association
National Registry of Cardiopulmonary Resuscitation Investigators*
A bs t r ac t
From Saint Luke’s Mid-America Heart In-
stitute, Kansas City, MO (P.S.C.); the Uni-
versity of Michigan Division of Cardiovas-
cular Medicine, Ann Arbor (P.S.C., B.K.N.);
the Section of Cardiovascular Medicine
and the Robert Wood Johnson Clinical
Scholars Program, Department of Medi-
cine, and the Section of Health Policy and
Administration, Department of Epidemi-
ology and Public Health, Yale University
School of Medicine, and the Center for
Outcomes Research and Evaluation, Yale–
New Haven Hospital — all in New Haven,
CT (H.M.K.); the University of Washing-
ton–Harborview Center for Prehospital
Emergency Care, Seattle (G.N.); and the
Veterans Affairs Ann Arbor Health Services
Research and Development Center of Ex-
cellence, Ann Arbor, MI (B.K.N.). Address
reprint requests to Dr. Chan at the Mid-
America Heart Institute, 5th Fl., 4401
Wornall Rd., Kansas City, MO 64111, or at

*The American Heart Association Nation-
al Registry of Cardiopulmonary Resusci-
tation Investigators are listed in the Ap-
pendix.
N Engl J Med 2008;358:9-17.
Copyright © 2008 Massachusetts Medical Society.
Background
Expert guidelines advocate defibrillation within 2 minutes after an in-hospital cardiac
arrest caused by ventricular arrhythmia. However, empirical data on the prevalence
of delayed defibrillation in the United States and its effect on survival are limited.
Methods
We identified 6789 patients who had cardiac arrest due to ventricular fibrillation or
pulseless ventricular tachycardia at 369 hospitals participating in the National Reg-
istry of Cardiopulmonary Resuscitation. Using multivariable logistic regression, we
identified characteristics associated with delayed defibrillation. We then examined
the association between delayed defibrillation (more than 2 minutes) and survival to
discharge after adjusting for differences in patient and hospital characteristics.
Results
The overall median time to defibrillation was 1 minute (interquartile range, <1 to
3 minutes); delayed defibrillation occurred in 2045 patients (30.1%). Characteristics
associated with delayed defibrillation included black race, noncardiac admitting di-
agnosis, and occurrence of cardiac arrest at a hospital with fewer than 250 beds, in
an unmonitored hospital unit, and during after-hours periods (5 p.m. to 8 a.m. or
weekends). Delayed defibrillation was associated with a significantly lower probabil-
ity of surviving to hospital discharge (22.2%, vs. 39.3% when defibrillation was not
delayed; adjusted odds ratio, 0.48; 95% confidence interval, 0.42 to 0.54; P<0.001).
In addition, a graded association was seen between increasing time to defibrilla-
tion and lower rates of survival to hospital discharge for each minute of delay (P for
trend <0.001).
Conclusions

Delayed defibrillation is common and is associated with lower rates of survival after
in-hospital cardiac arrest.
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T h e n e w eng l a nd jo ur na l o f m edi c in e
n engl j med 358;1 www.nejm.org january 3, 2008
10
B
etween 370,000 and 750,000 hospital-
ized patients have a cardiac arrest and un-
dergo cardiopulmonary resuscitation each
year in the United States, with less than 30% ex-
pected to survive to discharge.
1
Among the lead-
ing causes of cardiac arrest among adults during
a hospitalization are ventricular fibrillation and
pulseless ventricular tachycardia from primary
electrical disturbances or cardiac ischemia.
2-4
In
contrast to cardiac arrests due to asystole or pulse-
less mechanical activity, survival from cardiac ar-
rests due to ventricular fibrillation or pulseless ven-
tricular tachycardia is improved if defibrillation
therapy is administered rapidly.
1,2,4
Current recommendations are that hospitalized
patients with ventricular fibrillation or pulseless
ventricular tachycardia should receive defibrilla-
tion therapy within 2 minutes after recognition of

cardiac arrest.
5,6
Previous studies have suggested
an association between time to defibrillation and
survival, but the inclusion of cardiac arrests not
amenable to defibrillation in most studies remains
a potential confounder of this association.
7-10

Moreover, the extent to which delayed defibrilla-
tion occurs in U.S. hospitals and its potential ef-
fect on survival are unclear.
Accordingly, we examined how often delayed
defibrillation occurred during in-hospital cardiac
arrests caused by ventricular arrhythmias and in-
vestigated the relationship between delayed defi-
brillation and survival, using data from the Na-
tional Registry of Cardiopulmonary Resuscitation
(NRCPR). The NRCPR is a large registry of U.S.
hospitals that uses standardized Utstein defini-
tions (a template of uniform reporting guidelines
developed by international experts) to assess both
processes of care and outcomes during in-hospi-
tal cardiac arrests.
6,11-15
It provides a unique re-
source for exploring these questions as well as
identifying key patient and hospital characteris-
tics associated with delayed defibrillation.
Me t h od s

Study Design
The study design of the NRCPR has been described
in detail.
4
Briefly, the NRCPR is a prospective, mul-
ticenter registry of in-hospital cardiac arrests that
collects data according to standardized Utstein
definitions.
6,11-15
Cardiac arrest is defined as ces-
sation of cardiac mechanical activity as determined
by the absence of a palpable central pulse, apnea,
and unresponsiveness. The NRCPR protocol spec-
ifies that all consecutive patients with cardiac ar-
rests and without do-not-resuscitate orders be
screened by dedicated staff at participating hospi-
tals. Cases are identified by centralized collection
of cardiac-arrest flow sheets, reviews of hospital
paging-system logs, routine checks for use of code
carts (carts stocked with emergency equipment),
and screening for code-cart charges from hospi-
tal billing offices.
Accuracy of data in the NRCPR is ensured by
certification of research staff, use of case-study
methods for newly enrolled hospitals before sub-
mission of data, and a periodic reabstraction pro-
cess, which has been demonstrated to have a mean
error rate of 2.4% for all data.
4
All patients are

assigned a unique code during a single hospital-
ization, and data are transmitted to a central re-
pository (Digital Innovation) without identifica-
tion of the patient. Oversight of data collection
and analysis, integrity of the data, and research
is provided by the American Heart Association.
The institutional review board of the University
of Michigan Medical School approved this study
and waived the requirement for written informed
consent.
Patient population
Our analysis included 369 acute care hospitals that
provided data for at least 6 months between Janu-
ary 1, 2000, and July 31, 2005. In patients 18 years
of age or older, we identified 14,190 cases of in-
hospital cardiac arrest in which the first identifi-
able rhythm was ventricular fibrillation or pulse-
less ventricular tachycardia (
Fig. 1
). If a patient had
multiple cardiac arrests during the same hospital-
ization, we excluded data from subsequent episodes
(involving 1587 recurrent arrests) to focus on the
index event. We also limited our study population
to patients whose cardiac arrests occurred while
they were in intensive care units (ICUs) or inpa-
tient beds. Because of the distinctive clinical cir-
cumstances associated with other hospital environ-
ments, we excluded a total of 3291 patients who
were in emergency departments, operating rooms,

procedure areas (cardiac catheterization, electro-
physiology, and angiography suites), and postpro-
cedural areas at the time of their cardiac arrest.
Finally, we excluded patients with implantable car-
dioverter–defibrillators (170 patients), those who
were receiving intravenous infusions of acute car-
diac life support protocol medications for pulse-
less ventricular tachycardia or ventricular fibril-
lation (epinephrine, amiodarone, lidocaine, or
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Del ayed Time to Defibrill ation After In-Hospital Car diac Ar rest
n engl j med 358;1 www.nejm.org january 3, 2008
11
procainamide) at the time of cardiac arrest (1565
patients), and patients for whom data on the time
of the cardiac arrest or defibrillation were missing
(766 patients) or inconsistent (22 patients). The pa-
tients who were excluded because of missing or in-
consistent time data had baseline characteristics
that were similar to those of patients in the final
study cohort, except that the excluded patients
had lower rates of previous myocardial infarction
(21.2% vs. 27.5%, P<0.001) and higher rates of sep-
ticemia (13.6% vs. 11.2%, P = 0.05). The final study
sample consisted of 6789 patients (
Fig. 1
).
Time to Defibrillation
The time to defibrillation was calculated as the in-
terval from the reported time of initial recogni-

tion of the cardiac arrest to the reported time of
the first attempted defibrillation. Both reported
times were determined from cardiac-arrest docu-
mentation in the patient’s medical records and re-
corded in minutes. In our primary analysis, we
used these data to determine the proportion of
study subjects with delayed defibrillation, which
was defined as a time to defibrillation greater than
2 minutes. In addition, we classified the study
subjects according to whether their defibrillation
time was 1 minute or less, 2 minutes, 3 minutes,
4 minutes, 5 minutes, 6 minutes, or more than
6 minutes.
End points
The primary outcome for our analysis was survival
to hospital discharge. We also evaluated three sec-
ondary outcomes: return of spontaneous circu-
lation for at least 20 minutes after onset of the
cardiac arrest, survival at 24 hours after the car-
diac arrest, and neurologic and functional status
at discharge. Neurologic and functional status were
assessed among survivors to discharge according
to previously developed performance categories.
16

For both neurologic and functional status, out-
comes were categorized as no major disability,
moderate disability, severe disability, or coma or
vegetative state; data on these outcomes were avail-
able for 84% of survivors to hospital discharge.

Patients whose data were missing did not differ sig-
nificantly from those without missing data with
regard to likelihood of delayed defibrillation (19.5%
vs. 19.1%, P = 0.85).
Statistical Analysis
Unadjusted analyses evaluated baseline differences
between patients with and without delayed defi-
brillation using Student’s t-test for continuous vari-
ables and the chi-square test for categorical vari-
ables. Multivariable logistic-regression models were
used to examine the relationship between indi-
vidual baseline characteristics and delayed defi-
brillation.
Multivariable models were then created to in-
vestigate the relationship between delayed defi-
brillation and outcomes. All models included age,
sex, race (white, black, Hispanic, Asian or Pacific
Islander, or Native American), and time to defibril-
lation (delayed or not delayed) as covariates. Addi-
tional candidate variables were selected from the
following list after they had been determined to
have a significant univariate association (P<0.05)
with survival: initial cardiac rhythm (ventricular
fibrillation or pulseless ventricular tachycardia),
22p3
12,603 Patients had an initial arrest
14,190 Cardiac arrests with pulseless ventricular
tachycardia or ventricular fibrillation occurred
1587 Recurrent arrests occurred
3291 Had an arrest in the emergency room,

the operating room, or a procedure area
1565 Were receiving intravenous anti-
arrhythmic drugs or epinephrine
170 Had an implantable cardioverter–
defibrillator
766 Had missing data on arrest or defibril-
lation times
22 Were recorded as having inconsistent
(negative) times to defibrillation
9312 Had an arrest in an intensive care unit
or in a general inpatient bed
7577 Were eligible for the cohort
6789 Constituted the final study population cohort
AUTHOR:
FIGURE:
JOB: ISSUE:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.

REG F
Enon
1st
2nd
3rd
Chan
1 of 2
01-03-08
ARTIST: ts
35801
Figure 1. Study Cohort.
Of the initial 14,190 cases of in-hospital cardiac arrest due to pulseless ven-
tricular tachycardia or ventricular fibrillation listed in the National Registry
of Cardiopulmonary Resuscitation, 6789 eligible patients were included in
the final study population.
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T h e n e w eng l a nd jo ur na l o f m edi c in e
n engl j med 358;1 www.nejm.org january 3, 2008
12
admitting diagnosis (medical, cardiac; medical,
noncardiac; surgical, cardiac; or surgical, noncar-
diac), presence or absence of congestive heart
failure or myocardial infarction at the time of ad-
mission, presence or absence of previous conges-
tive heart failure or myocardial infarction, pres-
ence or absence of coexisting medical conditions
at the time of cardiac arrest (respiratory, renal, or
hepatic insufficiency; metabolic or electrolyte de-
rangements; diabetes mellitus; baseline evidence
of motor, cognitive, or functional deficits; acute

stroke; acute nonstroke neurologic disorder; pneu-
monia; sepsis; major trauma; or cancer), the use or
nonuse of therapeutic interventions at the time
of cardiac arrest (intraaortic balloon pump, pul-
monary-artery catheter, or hemodialysis), time of
cardiac arrest (during work hours or during after-
hours periods [i.e., 5 p.m. to 8 a.m. or weekend]),
the use or nonuse of a hospital-wide cardiopulmo-
nary-arrest (code blue) alert, type of hospital bed
where the cardiac arrest occurred (ICU, inpatient
bed monitored by telemetry, or unmonitored in-
patient bed), and hospital size (<250, 250 to 499,
or ≥500 inpatient beds). We also performed analy-
ses to explore the relationship between time to
defibrillation and survival to hospital discharge
across a range of times.
All models used generalized estimating equa-
tions with an unstructured correlation matrix to
account for the potential effects of clustering of
Table 1. Baseline Characteristics According to Time to Defibrillation.*
Characteristic
≤2 Minutes
to Defibrillation
(N = 4744)
>2 Minutes
to Defibrillation
(N = 2045) P Value
Age — yr 67.9±13.9 67.6±14.8 0.49
Male sex — no. (%) 2876 (60.6) 1207 (59.0) 0.15
White race — no. (%)† 3608 (76.1) 1457 (71.2) <0.001

Ventricular fibrillation — no. (%) 3276 (69.1) 1454 (71.1) 0.08
Hospital-wide code blue —no. (%) 4141 (87.3) 1889 (92.4) <0.001
Type of hospital bed — no. (%) <0.001
Intensive care 2910 (61.3) 816 (39.9)
Inpatient, monitored by telemetry 1368 (28.8) 816 (39.9)
Inpatient, unmonitored 466 (9.8) 413 (20.2)
Hospital size — no. (%) <0.001
<250 beds 1124 (23.7) 576 (28.2)
250–499 beds 2178 (45.9) 886 (43.3)
≥500 beds 1387 (29.2) 565 (27.6)
Unknown 55 (1.2) 18 (0.9)
Geographic region — no. (%) 0.38
Northeast 502 (10.6) 233 (11.4)
Midwest 1352 (28.5) 550 (26.9)
South 2135 (45.0) 920 (45.0)
West 755 (15.9) 342 (16.7)
Admitting diagnosis — no. (%) <0.001
Medical, cardiac 2377 (50.1) 799 (39.1)
Medical, noncardiac 1427 (30.1) 861 (42.1)
Surgical, cardiac 508 (10.7) 145 (7.1)
Surgical, noncardiac 432 (9.1) 240 (11.7)
Time of cardiac arrest — no. (%)
After hours‡ 2650 (55.9) 1209 (59.1) 0.01
Weekend 1252 (26.4) 576 (28.2) 0.14

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Del ayed Time to Defibrill ation After In-Hospital Car diac Ar rest
n engl j med 358;1 www.nejm.org january 3, 2008
13
patients within hospitals. For all analyses, the null

hypothesis was evaluated at a two-sided signifi-
cance level of 0.05, with calculation of 95% con-
fidence intervals. All analyses were performed
with SAS software, version 9.1.
R e s ul t s
We identified 6789 patients from 369 hospitals who
had in-hospital cardiac arrests due to ventricular
fibrillation (69.7%) or pulseless ventricular tachy-
cardia (30.3%). Overall, the median time to defi-
brillation was 1 minute (interquartile range, <1 to
3 minutes), with 2045 patients (30.1%) noted as
having had delayed defibrillation according to our
definition (a time to defibrillation greater than
2 minutes).
Table 1
displays baseline characteris-
tics of patients with and of those without delayed
defibrillation.
Table 2
lists characteristics significantly asso-
ciated with delayed defibrillation in multivariate
analysis. Patient factors associated with delayed
defibrillation included black race and a noncardiac
admitting diagnosis. Significant hospital-related
factors included small hospital size (<250 beds),
occurrence of cardiac arrest in an unmonitored
inpatient bed, and occurrence of cardiac arrest af-
ter hours.
Return of spontaneous circulation occurred in
4168 patients (61.4%), 3372 patients (49.7%) sur-

vived to 24 hours after their cardiac arrest, and
2318 (34.1%) survived to hospital discharge. The
unadjusted survival outcomes were significant-
ly lower for patients with delayed defibrillation
Table 1. (Continued.)
Characteristic
≤2 Minutes
to Defibrillation
(N = 4744)
>2 Minutes
to Defibrillation
(N = 2045) P Value
Cardiac diagnosis — no. (%)
Congestive heart failure at admission 1295 (27.3) 470 (23.0) <0.001
Previous congestive heart failure 1404 (29.6) 623 (30.5) 0.44
Myocardial infarction at admission 1418 (29.9) 442 (21.6) <0.001
Previous myocardial infarction 1252 (26.4) 503 (24.6) 0.16
Coexisting medical conditions — no. (%)
Respiratory insufficiency 1703 (35.9) 712 (34.8) 0.39
Renal insufficiency 1542 (32.5) 679 (33.2) 0.69
Hepatic insufficiency 285 (6.0) 143 (7.0) 0.15
Metabolic or electrolyte derangement 792 (16.7) 346 (16.9) 0.95
Diabetes mellitus 1542 (32.5) 695 (34.0) 0.25
Baseline central nervous system deficits§ 526 (11.1) 237 (11.6) 0.55
Acute stroke 176 (3.7) 90 (4.4) 0.21
Acute nonstroke neurologic disorder 318 (6.7) 131 (6.4) 0.51
Pneumonia 569 (12.0) 270 (13.2) 0.21
Sepsis 512 (10.8) 258 (12.6) 0.08
Major trauma 38 (0.8) 23 (1.1) 0.16
Cancer 432 (9.1) 219 (10.7) 0.05

Therapeutic interventions — no. (%)
Intraaortic balloon pump 90 (1.9) 12 (0.6) <0.001
Pulmonary-artery catheter 247 (5.2) 66 (3.2) <0.001
Hemodialysis 161 (3.4) 72 (3.5) 0.83
* Plus–minus values are means ±SD.
† Race was determined by the hospital investigators.
‡ After hours was defined as before 8 a.m., after 5 p.m., or on weekends.
§ Central nervous system deficits included motor, cognitive, and functional deficits.
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T h e n e w eng l a nd jo ur na l o f m edi c in e
n engl j med 358;1 www.nejm.org january 3, 2008
14
(49.0% vs. 66.7% for return of spontaneous circu-
lation, 37.4% vs. 55.0% for survival to 24 hours,
and 22.2% vs. 39.3% for survival to hospital dis-
charge) (
Table 3
). A graded inverse association was
found between time to defibrillation and unad-
justed survival across a broad range of time thresh-
olds (
Fig. 2
).
After adjustment for patient- and hospital-
related characteristics, delayed defibrillation was
found to be associated with a significantly lower
likelihood of survival to hospital discharge (ad-
justed odds ratio, 0.48; 95% confidence interval
[CI], 0.42 to 0.54; P<0.001) (
Table 3

). When time
to defibrillation was evaluated in discrete intervals,
a graded inverse association was found between
longer delays and survival, with a significantly
lower likelihood of survival to hospital discharge
with increased time to defibrillation (
Fig. 2
).
Delayed defibrillation was also associated with
a significantly lower likelihood of return of spon-
taneous circulation (adjusted odds ratio, 0.55; 95%
CI, 0.49 to 0.62; P<0.001) and survival at 24 hours
after the cardiac arrest (adjusted odds ratio, 0.52;
95% CI, 0.46 to 0.58; P<0.001) (
Table 3
). These
results remained robust when examined separately
according to type of hospital bed (ICU, monitored
inpatient, or unmonitored inpatient) (see the Sup-
plementary Appendix, available with the full text of
this article at www.nejm.org). Finally, among those
surviving to discharge, delayed defibrillation was
associated with a significantly lower likelihood of
having no major disabilities in neurologic status
(adjusted odds ratio, 0.74; 95% CI, 0.57 to 0.95;
P = 0.02) or functional status (adjusted odds ratio,
0.74; 95% CI, 0.56 to 0.96; P = 0.02) (
Table 3
).
Di s c u s sion

We found that 30.1% of patients with cardiac ar-
rests due to ventricular arrhythmia underwent de-
fibrillation more than 2 minutes after initial rec-
ognition of their cardiac arrest, a delay that exceeds
guidelines-based recommendations.
5,6
Patients
with delayed defibrillation were significantly less
likely to survive to hospital discharge. Among sur-
vivors, patients with delayed defibrillation were less
likely to have no major disabilities in neurologic
or functional status. These findings support the
conclusion that rapid defibrillation is associated
with sizable survival gains in these high-risk pa-
tients. Furthermore, we found a graded association
between poorer survival and longer times to defi-
brillation, even for times beyond 2 minutes. These
observations reinforce the rationale for efforts to
shorten the time to defibrillation as much as pos-
sible to maximize the effectiveness of resuscita-
tion of patients with ventricular fibrillation or
pulseless ventricular tachycardia.
Our work confirms and extends the findings
of other investigations that have shown a relation-
ship between defibrillation time and survival. Al-
though earlier studies linked delayed defibrilla-
tion to poorer survival in hospitalized patients,
most of these reports included heterogeneous
study populations (i.e., both patients with “shock-
able” and those with “unshockable” rhythms, such

as asystole, at the time of cardiac arrest).
7,9,10
More-
over, these studies were generally small and in-
volved a limited number of hospitals. In contrast,
our analysis focused only on patients with cardiac
Table 2. Factors Associated with Delayed Time to Defibrillation in
Multivariable Analysis.*
Variable
Adjusted Odds Ratio
(95% CI) P Value†
Race or ethnic group‡
White Reference Reference
Black 1.23 (1.05–1.43) 0.009
Hispanic 1.09 (0.83–1.43) 0.56
Asian or Pacific Islander 0.99 (0.83–1.43) 0.98
Native American 1.25 (0.61–2.57) 0.54
Unknown 1.02 (0.78–1.34) 0.11
After-hours cardiac arrest§ 1.18 (1.05–1.33) 0.005
Type of hospital bed
Intensive care unit 0.39 (0.33–0.46) <0.001
Inpatient, monitored by telemetry 0.47 (0.41–0.53) <0.001
Inpatient, unmonitored Reference Reference
Hospital size
<250 beds 1.27 (1.08–1.47) 0.001
250–499 beds 1.02 (0.90–1.17) 0.72
≥500 beds Reference Reference
Admitting diagnosis
Medical, cardiac 0.67 (0.55–0.82) <0.001
Surgical, cardiac 0.67 (0.51–0.86) 0.002

Noncardiac Reference Reference
* Patient- and hospital-level variables that independently predicted a time to de
-
fibrillation of more than 2 minutes are shown. CI denotes confidence interval.
† P<0.01 for inclusion in the model.
‡ Race and ethnic group were determined by the hospital investigators.
§ After hours was defined as before 8 a.m., after 5 p.m., or on weekends.
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Del ayed Time to Defibrill ation After In-Hospital Car diac Ar rest
n engl j med 358;1 www.nejm.org january 3, 2008
15
arrest due to ventricular fibrillation or pulseless
ventricular tachycardia and excluded other poten-
tially inappropriate patients, such as those receiv-
ing concomitant treatment with intravenous anti-
arrhythmic or vasoactive infusions or those with
preexisting implantable cardioverter–defibrilla-
tors. The large size of the NRCPR and its use of
standardized definitions were instrumental in this
regard.
Several factors related to the hospital setting
were associated with delayed defibrillation, includ-
ing the occurrence of a cardiac arrest after hours
or in an unmonitored inpatient bed. These find-
ings imply that response times may be related,
in part, to the emergent availability of trained
medical personnel, access to defibrillation equip-
ment, and delays in recognition of a ventricular
arrhythmia.
In addition to hospital-related factors, certain

patient characteristics were found to be associat-
ed with a greater likelihood of delayed defibril-
lation. The relationship between a cardiac admit-
ting diagnosis and shorter time to defibrillation
is probably due to earlier recognition of the ven-
tricular arrhythmia. However, the association of
black race with delayed defibrillation is not intui-
tively obvious and raises potential issues of dis-
parities in care. Further studies are warranted to
determine whether such variations are due to geo-
graphic differences in access to hospitals with
more resources (such as more monitored beds) or
whether they reflect actual differences in practice
patterns according to race.
Our study should be interpreted in the context
of the following limitations. First, although data
available in the NRCPR allowed us to adjust for key
variables that have been linked to survival after
cardiac arrest, our study used an observational
design, and there are variables that we did not or
could not capture (for example, a physician’s a
priori assessment of the likelihood of survival or
good neurologic outcome in an arrest). These ad-
ditional factors may influence time to defibrilla-
tion, leading to residual confounding.
Table 3. Summary of Study End Points and Adjusted Survival Rates with Delayed Defibrillation.*
End Point
≤2 Minutes
to Defibrillation
(N = 4744)

>2 Minutes
to Defibrillation
(N = 2045)
Unadjusted
Odds Ratio
(95% CI)
Adjusted
Odds Ratio
(95% CI)† P Value
Survival outcomes — no./total no. (%)
Return of spontaneous circulation 3165/4744 (66.7) 1003/2045 (49.0) 0.48 (0.43–0.53) 0.55 (0.49–0.62) <0.001
Survival to 24 hr 2607/4744 (55.0) 765/2045 (37.4) 0.48 (0.43–0.54) 0.52 (0.46–0.58) <0.001
Survival to discharge 1863/4744 (39.3) 455/2045 (22.2) 0.44 (0.39–0.50) 0.48 (0.42–0.54) <0.001
Neurologic outcomes — no./total no. (%)‡ 0.71 (0.57–0.89) 0.74 (0.57–0.95) 0.02
No major disability 931/1549 (60.1) 197/381 (51.7)
Moderate disability 437/1549 (28.2) 134/381 (35.2)
Severe disability 152/1549 (9.8) 36/381 (9.4)
Coma or vegetative state 29/1549 (1.9) 14/381 (3.7)
Functional outcomes — no./total no. (%)‡ 0.67 (0.52–0.87) 0.74 (0.56–0.96) 0.02
No major disability 533/1542 (34.6) 100/381 (26.2)
Moderate disability 638/1542 (41.4) 164/381 (43.0)
Severe disability 342/1542 (22.2) 103/381 (27.0)
Coma or vegetative state 29/1542 (1.9) 14/381 (3.7)
* Patients for whom the time to defibrillation was more than 2 minutes had lower unadjusted and adjusted survival rates, as well as lower
rates of survival to discharge with intact neurologic and functional status, than those for whom the time was 2 minutes or less. CI denotes
confidence interval.
† Odds ratios are adjusted for age, sex, race, initial cardiac rhythm, admitting diagnosis, presence or absence of congestive heart failure and
myocardial infarction at admission, presence or absence of previous congestive heart failure and myocardial infarction, presence or absence
of coexisting medical conditions at the time of cardiac arrest, use or nonuse of a hospital-wide code blue, use or nonuse of treatment inter-
ventions (intraaortic balloon pump, pulmonary-artery catheter, and hemodialysis), type of hospital bed, and hospital size.

‡ Neurologic and functional outcomes are given only for those who survived until hospital discharge. Model comparisons were made between
survivors discharged with no major disability and those with a moderate degree of disability or worse.
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T h e n e w eng l a nd jo ur na l o f m edi c in e
n engl j med 358;1 www.nejm.org january 3, 2008
16
Second, data on time to defibrillation relied on
reported times of cardiac arrest and defibrillation
from hospital records. The use of multiple clocks
and the lack of synchronization between the tim-
ing of cardiac monitors and defibrillators within
a hospital may lead to variability and discrepan-
cies in calculating time to defibrillation.
17,18
This
variability in measurement would be expected to
bias our findings toward the null hypothesis, sug-
gesting that we may be underestimating the as-
sociation between delayed defibrillation and sur-
vival. In addition, because time to defibrillation
was recorded in minutes, our analysis primarily
explored its association with survival at the skewed
upper end of this variable’s distribution. The ef-
fect of time to defibrillation within short intervals
of less than a minute could not be assessed.
Third, the results related to neurologic and
functional status should be interpreted with cau-
tion, since these data were missing for 16% of
patients surviving to hospital discharge. Finally,
although hospitals in the NRCPR represent nearly

15% of the large hospitals (>250 beds) in the
United States, their participation is voluntary. Per-
formance characteristics, quality of care, and sur-
vival outcomes may be different in nonparticipat-
ing hospitals.
In conclusion, we found that delays in the time
to defibrillation are common in hospitalized pa-
tients with cardiac arrest due to a ventricular ar-
rhythmia, and we identified several patient- and
hospital-related factors associated with delayed
time to defibrillation. In our analysis, such delays
were associated with substantially worse clinical
outcomes, with each additional minute of delay
resulting in worse survival.
Supported in part by a Cardiovascular Multidisciplinary Re-
search training grant from the National Institutes of Health
(NIH) and the Ruth L. Kirchstein Service Award (to Dr. Chan)
and by a Clinical Research Scholar Program grant from the NIH
(K12 RR017607-01, to Dr. Nallamothu).
Dr. Nichol reports receiving consulting fees from InnerCool,
Paracor Medical, and Northfield Laboratories; receiving travel
compensation from Radiant Medical; receiving research grant
funding from Medtronic; and having served on advisory boards
to the American Heart Association, the National Registry of
Cardiopulmonary Resuscitation, and the Medic One Founda-
tion. No other potential conflict of interest relevant to this arti-
cle was reported.
We thank Dr. Timothy Hofer for his insightful comments and
suggestions on the manuscript.
45

Survival to Discharge (%)
35
40
30
25
15
10
20
5
0
≤1 2 3 4 5 6
>6
Minutes to Defibrillation
AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.

REG F
Enon
1st
2nd
3rd
Chan
2 of 2
01-03-08
ARTIST: ts
35801 ISSUE:
22p3
Minutes
to Defib-
rillation
≤1
2
3
4
5
6
>6
No. of
Patients
750
3994
472
291
394
145
743

Survived
to Dis-
charge
1577
286
160
67
98
27
103
Unadjusted
Odds Ratio
(95% CI)
Reference
0.94 (0.81–1.10)
0.78 (0.64–0.96)
0.46 (0.35–0.61)
0.51 (0.40–0.64)
0.35 (0.23–0.54)
0.25 (0.20–0.31)
Adjusted
Odds Ratio
(95% CI)
Reference
1.02 (0.85–1.21)
0.84 (0.67–1.05)
0.50 (0.37–0.67)
0.54 (0.42–0.70)
0.39 (0.25–0.61)
0.27 (0.21–0.34)

P Value
—
0.85
0.12
<0.001
<0.001
<0.001
<0.001
Figure 2. Unadjusted and Adjusted Rates of Survival to Hospital Discharge
According to Time to Defibrillation.
A graded inverse association was seen between time to defibrillation and
survival rate (P for trend <0.001). CI denotes confidence interval.
Appendix
The American Heart Association National Registry of Cardiopulmonary Resuscitation investigators are as follows: G. Nichol, M. Mancini,
R. Berg, M.A. Peberdy, E. Allen, S. Braithwaite, J. Gosbee, E. Hunt, G.L. Larkin, G. Mears, V. Nadkarni, T. Truitt, J. Potts, B. Abella, R.
Geocadin, K. Kern, B. Eigel, and J. Ornato.
References
Eisenberg MS, Mengert TJ. Cardiac re-
suscitation. N Engl J Med 2001;344:1304-
13.
Ballew KA, Philbrick JT. Causes of
variation in reported in-hospital CPR sur-
vival: a critical review. Resuscitation 1995;
30:203-15.
Nadkarni VM, Larkin GL, Peberdy
MA, et al. First documented rhythm and
clinical outcome from in-hospital cardiac
1.
2.
3.

arrest among children and adults. JAMA
2006;295:50-7.
Peberdy MA, Kaye W, Ornato JP, et al.
Cardiopulmonary resuscitation of adults
in the hospital: a report of 14720 cardiac
arrests from the National Registry of Car-
diopulmonary Resuscitation. Resuscita-
tion 2003;58:297-308.
Ewy GA, Ornato JP. 31st Bethesda Con-
ference: emergency cardiac care — task
4.
5.
force 1: cardiac arrest. J Am Coll Cardiol
2000;35:832-46.
Cummins RO, Ornato JP, Thies WH,
Pepe PE. Improving survival from sudden
cardiac arrest: the “chain of survival” con-
cept: a statement for health professionals
from the Advanced Cardiac Life Support
Subcommittee and the Emergency Cardiac
Care Committee, American Heart Associa-
tion. Circulation 1991;83:1832-47.
6.
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2008 Massachusetts Medical Society. All rights reserved.
Del ayed Time to Defibrill ation After In-Hospital Car diac Ar rest
n engl j med 358;1 www.nejm.org january 3, 2008
17
Fredriksson M, Aune S, Thorén AB,
Herlitz J. In-hospital cardiac arrest — an
Utstein style report of seven years experi-

ence from the Sahlgrenska University Hos-
pital. Resuscitation 2006;68:351-8.
Herlitz J, Aune S, Bång A, et al. Very
high survival among patients defibrillat-
ed at an early stage after in-hospital ven-
tricular fibrillation on wards with and
without monitoring facilities. Resuscita-
tion 2005;66:159-66.
Hajbaghery MA, Mousavi G, Akbari
H. Factors influencing survival after in-
hospital cardiopulmonary resuscitation.
Resuscitation 2005;66:317-21.
Skrifvars MB, Rosenberg PH, Finne P,
et al. Evaluation of the in-hospital Utstein
template in cardiopulmonary resuscita-
tion in secondary hospitals. Resuscitation
2003;56:275-82.
Cummins RO, Chamberlain D, Haz-
inski MF, et al. Recommended guidelines
for reviewing, reporting, and conducting
research on in-hospital resuscitation: the
in-hospital ‘Utstein style.’ Circulation 1997;
95:2213-39.
7.
8.
9.
10.
11.
Cummins RO, Sanders A, Mancini E,
Hazinski MF. In-hospital resuscitation: ex-

ecutive summary. Ann Emerg Med 1997;
29:647-9.
Jacobs I, Nadkarni V, Bahr J, et al.
Cardiac arrest and cardiopulmonary re-
suscitation outcome reports: update and
simplification of the Utstein templates
for resuscitation registries: a statement
for healthcare professionals from a task
force of the International Liaison Com-
mittee on Resuscitation (American Heart
Association, European Resuscitation Coun-
cil, Australian Resuscitation Council, New
Zealand Resuscitation Council, Heart and
Stroke Foundation of Canada, InterAmeri-
can Heart Foundation, Resuscitation
Councils of Southern Africa). Circulation
2004;110:3385-97.
Zaritsky A, Nadkarni V, Hazinski MF,
et al. Recommended guidelines for uni-
form reporting of pediatric advanced life
support: the pediatric Utstein style: a state-
ment for healthcare professionals from a
task force of the American Academy of Pe-
diatrics, the American Heart Association,
12.
13.
14.
and the European Resuscitation Council.
Circulation 1995;92:2006-20.
Zaritsky A, Nadkarni V, Hazinski MF,

et al. Recommended guidelines for uni-
form reporting of pediatric advanced life
support: the pediatric Utstein style: a state-
ment for healthcare professionals from a
task force of the American Academy of Pe-
diatrics, the American Heart Association,
and the European Resuscitation Council.
Resuscitation 1995;30:95-115.
Jennett B, Bond M. Assessment of out-
come after severe brain damage. Lancet
1975;1:480-4.
Castrén M, Kurola J, Nurmi J, Marti-
kainen M, Vuori A, Silfvast T. Time mat-
ters; what is the time in your defibrillator?
An observational study in 30 emergency
medical service systems. Resuscitation
2005;64:293-5.
Kaye W, Mancini ME, Truitt TL. When
minutes count — the fallacy of accurate
time documentation during in-hospital
resuscitation. Resuscitation 2005;65:285-
90.
Copyright © 2008 Massachusetts Medical Society.
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n engl j med 358;4 www.nejm.org january 24, 2008
331
The new england

journal of medicine
established in 1812 january 24, 2008 vol. 358 no. 4
Drug-Eluting Stents vs. Coronary-Artery Bypass Grafting
in Multivessel Coronary Disease
Edward L. Hannan, Ph.D., Chuntao Wu, M.D., Ph.D., Gary Walford, M.D., Alfred T. Culliford, M.D., Jeffrey P. Gold, M.D.,
Craig R. Smith, M.D., Robert S.D. Higgins, M.D., Russell E. Carlson, M.D., and Robert H. Jones, M.D.
A bs t r ac t
From the University at Albany, Albany, NY
(E.L.H., C.W.); St. Joseph’s Hospital, Syra-
cuse, NY (G.W.); New York University
Medical Center, New York (A.T.C.); Medi-
cal University of Ohio, Toledo (J.P.G.);
Columbia–Presbyterian Medical Center,
New York (C.R.S.); Rush University Medi-
cal Center, Chicago (R.S.D.H.); Mercy
Hospital, Buffalo, NY (R.E.C.); and Duke
University Medical Center, Durham, NC
(R.H.J.). Address reprint requests to Dr.
Hannan at the Department of Health
Policy, Management, and Behavior, School
of Public Health, State University of New
York, University at Albany, 1 University Pl.,
Rensselaer, NY 12144-3456, or at elh03@
health.state.ny.us.
N Engl J Med 2008;358:331-41.
Copyright © 2008 Massachusetts Medical Society.
Background
Numerous studies have compared the outcomes of two competing interventions for
multivessel coronary artery disease: coronary-artery bypass grafting (CABG) and
coronary stenting. However, little information has become available since the intro-

duction of drug-eluting stents.
Methods
We identified patients with multivessel disease who received drug-eluting stents or
underwent CABG in New York State between October 1, 2003, and December 31,
2004, and we compared adverse outcomes (death, death or myocardial infarction,
or repeat revascularization) through December 31, 2005, after adjustment for dif-
ferences in baseline risk factors among the patients.
Results
In comparison with treatment with a drug-eluting stent, CABG was associated with
lower 18-month rates of death and of death or myocardial infarction both for patients
with three-vessel disease and for patients with two-vessel disease. Among patients
with three-vessel disease who underwent CABG, as compared with those who re-
ceived a stent, the adjusted hazard ratio for death was 0.80 (95% confidence interval
[CI], 0.65 to 0.97) and the adjusted survival rate was 94.0% versus 92.7% (P = 0.03);
the adjusted hazard ratio for death or myocardial infarction was 0.75 (95% CI, 0.63
to 0.89) and the adjusted rate of survival free from myocardial infarction was 92.1%
versus 89.7% (P<0.001). Among patients with two-vessel disease who underwent
CABG, as compared with those who received a stent, the adjusted hazard ratio for
death was 0.71 (95% CI, 0.57 to 0.89) and the adjusted survival rate was 96.0%
versus 94.6% (P = 0.003); the adjusted hazard ratio for death or myocardial infarction
was 0.71 (95% CI, 0.59 to 0.87) and the adjusted rate of survival free from myocar-
dial infarction was 94.5% versus 92.5% (P<0.001). Patients undergoing CABG also
had lower rates of repeat revascularization.
Conclusions
For patients with multivessel disease, CABG continues to be associated with lower
mortality rates than does treatment with drug-eluting stents and is also associated
with lower rates of death or myocardial infarction and repeat revascularization.
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