Thus, varicose veins in the absence of skin changes are not indicative of chronic venous insufficiency.. Varicose veins were present in 40 percent of men and 16 percent of women, whereas
Trang 1haps 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-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 vascular and cerebrovascular events in patients treated for hu- man immunodeficiency virus infection N Engl J Med 2003;348:
Cardio-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 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
ca-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;
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Trang 2Chronic 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 jbergan@ucsd.edu.
N Engl J Med 2006;355:488-98.
Copyright © 2006 Massachusetts Medical Society.
Chronic venous disease of the lower limbs is manifested by a
range of signs, the most obvious of which are varicose veins and venous 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
ul-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 C0 to C6 (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 C0,s to C6, whereas the term “chronic venous insufficiency” is generally restricted to disease
of greater severity (i.e., classes C4 to C6 ) 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.9Risk factors for chronic venous disease include heredity, age, female sex, obesity
Trang 3mechanisms of disease
D B
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.
Trang 4$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
SYMP TOMS AND QUALIT Y OF LIFESymptoms traditionally ascribed to chronic ve-nous disease include aching, heaviness, a feeling
of swelling, cramps, itching, tingling, and 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
rest-conditions, and the duration of chronic venous ease.18
dis-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.19Venous leg ulcers, the most severe manifestation
of chronic venous disease, are usually painful20and affect the quality of life.21 A large-scale study
of 2404 patients using the generic Medical comes Study 36-item Short-Form General Health Survey questionnaire found a significant associa-tion between the quality of life and the severity
Out-of venous disease.22 Similarly, a correlation 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 C5 and C6 has been likened to the impairment associated with heart failure.23
be-VENOUS HYPERTENSIONDespite 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 ficial or deep venous system or in both A review
super-of 1153 cases super-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.*
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
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
Trang 5mechanisms of disease
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 vewith-ins Competent venous valves
ensure that venous blood flows toward the heart,
thereby emptying the deep and superficial
ve-nous systems and reducing veve-nous 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 DISE ASE
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 observed in segments of saphenous veins from patients with chronic ve-nous insufficiency.28 An important step forward came when Ono et al.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 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
Cul-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
80 90
70 60
40 30
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.)
Trang 6of extracellular matrix material in varicose veins.
Elevated levels of the cytokines transforming growth factor β1 (TGF-β1) 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-β1 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 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
sug-When a rat mesenteric venule was 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.46,47Leukocyte rolling, adhesion, and migration, as well as microhemorrhage and parenchymal-cell death, were all increased at the high-pressure site
experimen-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 pathways50,51 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
Trang 7mechanisms of disease
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 irregularitichang-es in vchang-essel walls may induce
regions of disturbed and even turbulent flow All
of these events can initiate and maintain
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 CHANGESVenous hypertension seems central to the skin changes in chronic venous disease In a sample
of 360 lower limbs of patients with a wide 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
spec-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 changes67 has been superseded by the theory that chronic inflamma-tion has a key role in skin changes of chronic venous disease
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 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
pro-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.)
Trang 840 to 60 minutes is depleted of leukocytes, cially in patients with chronic venous disease.68,69This finding suggests that leukocytes accumulate
espe-in the leg under conditions of high venous 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-
pres-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 acute72 and chronic73 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 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-
pa-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 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
in-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
inhibiting
Angiotensin II Endothelin-1 Platelet-derived growth factor
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.)
Trang 9mechanisms of disease
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-β1 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-β1 as compared with
normal skin or skin from the thigh region of the
same patients.86 The TGF-β1 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-β1, stimulating collagen production by
der-mal fibroblasts, which culminates in derder-mal
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.91IMPLICATIONS FOR TR E ATMENTAlthough 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 wall changes
vein-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 connections are shown.
Trang 10inter-T h e ne w e ngl a nd jou r na l o f m e dicine
n engl j med 355;5 www.nejm.org august 3, 2006496
life94 in patients with chronic venous disease
Evidence is accumulating that surgery aimed at preventing venous reflux can aid healing and prevent the recurrence of ulcers95,96; 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 cers In the long term, improved understanding of the cellular and molecular mechanisms involved may allow the identification of additional targets for pharmacologic intervention
ul-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.
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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.
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in-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.
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Porto LC, Ferreira MA, Costa AM, da
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Silveira PR Immunolabeling of type IV
collagen, laminin, and alpha-smooth
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JB Extracellular matrix remodeling in the
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Henin D, Verbeuren T, Michel J-B, Jacob
M-P Smooth muscle cell modulation and
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an in situ study J Pathol 2001;193:398-407.
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Pascarella L, Schmid-Schönbein GW,
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NH Fluid dynamics of venous valve sure Ann Biomed Eng 1995;23:750-9.
clo-Lurie F, Kistner RL, Eklof B, Kessler D
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Traub O, Berk BC Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force
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BC, Tamaki T Stress and vascular es: atheroprotective effect of laminar fluid shear stress in endothelial cells: possible role of mitogen-activated protein kinases
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Global analysis of shear stress-responsive genes in vascular endothelial cells J Ath- eroscler Thromb 2003;10:304-13.
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J, Yan C Endothelial atheroprotective and anti-inflammatory mechanisms Ann N Y Acad Sci 2001;947:93-109.
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Shear stress magnitude and directionality modulate growth factor gene expression
in preconditioned vascular endothelial cells
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in circulating leukocytes Circ Res 2000;
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of the endothelial surface layer on mission of fluid shear stress to endothe- lial cells Biorheology 2001;38:143-50.
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Mulivor AW, Lipowsky HH Role of the glycocalyx in leukocyte-endothelial cell adhesion Am J Physiol Heart Circ Physiol 2002;283:H1282-H1291.
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G, Christopoulos D, Vasdekis S, Clarke H
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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;
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 vated cutaneous leukocyte concentration
Ele-in a rodent model of acute venous tension J Surg Res 1998;74:59-63.
hyper-Hahn TL, Unthank JL, Lalka SG creased hindlimb leukocyte concentration
In-in a chronic rodent model of venous tension J Surg Res 1999;81:38-41.
hyper-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
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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, gan JJ Leukocyte activation in patients with venous insufficiency J Vasc Surg 1999;30:148-56.
Ber-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 ship between the number of capillaries in the skin of the venous ulcer-bearing area
relation-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 congestion 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
Shoab SS, Scurr JH, Coleridge-Smith
PD Increased plasma vascular endothelial growth factor among patients with chron-
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1998;28:535-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-β1 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, thal E, Rubinow A Overload of iron in the 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.
Loewen-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 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.
defe-Zamboni P, Tognazzo S, Izzo M, et al
Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration
Andreozzi GM, Cordova R, Scomparin
MA, Martini R, D’Eri A, Andreozzi F fects of elastic stocking on quality of life
Ef-of patients with chronic venous 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.
insuffi-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 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.
médi-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.
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.
Trang 13and 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 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-
dextrotrans-er abilities.9 The group that underwent 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
hypother-in the classroom and conthypother-inuous 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
Trang 14These 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 acteristic of injury in term infants, such as dam-age to the basal ganglia or the cerebral cortex in
char-a wchar-atershed pchar-attern
The results of spectroscopic and diffusion sor imaging (DTI) also suggested that the brain tissue of these infants resembled that of prema-
ten-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 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
in-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 ery of oxygen and other substrates to the fetal brain secondary to disordered fetal circulation associated with the congenital heart lesion.11
deliv-However, other developmental and genetic ences may also be important For example, exten-sive white-matter anomalies have been identified
influ-in influ-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 mental status at eight years in children with dextro-transposi- tion of the great arteries: the Boston Circulatory Arrest Trial
Neurodevelop-J Thorac Cardiovasc Surg 2003;126:1385-96.
Trang 15n 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
circula-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 thejournal’ 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
Trang 16n engl j med 358;1 www.nejm.org january 3, 2008
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*
Abs tr act
From Saint Luke’s Mid-America Heart 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,
In-CT (H.M.K.); the University of 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 pchan@cc-pc.com.
Washing-*The American Heart Association
Nation-al Registry of Cardiopulmonary tation Investigators are listed in the Ap- pendix.
Resusci-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
Trang 17T h e ne w e ngl a nd jou r na l o f m e dicine
n engl j med 358;1 www.nejm.org january 3, 200810
Between 370,000 and 750,000
hospital-ized patients have a cardiac arrest and 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
un-a hospitun-alizun-ation un-are ventriculun-ar fibrillun-ation un-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 tion occurs in U.S hospitals and its potential ef-fect on survival are unclear
defibrilla-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 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
defini-Methods
Study Design
The study design of the NRCPR has been described
in detail.4 Briefly, the NRCPR is a prospective, 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
mul-by the absence of a palpable central pulse, apnea, and unresponsiveness The NRCPR protocol spec-
ifies that all consecutive patients with cardiac rests and without do-not-resuscitate orders be screened by dedicated staff at participating hospi-tals Cases are identified by centralized collection
ar-of cardiac-arrest flow sheets, reviews ar-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 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
in-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
Trang 18Delayed Time to Defibrillation After In-Hospital Cardiac Arrest
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 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
vari-Multivariable models were then created to 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),
in-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 arrhythmic drugs or epinephrine
anti-170 Had an implantable cardioverter– defibrillator
766 Had missing data on arrest or lation times
defibril-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:
4-C H/T
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ICM CASE
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Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
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REG F
Enon
1st 2nd 3rd
Figure 1 Study Cohort.
Of the initial 14,190 cases of in-hospital cardiac arrest due to pulseless tricular tachycardia or ventricular fibrillation listed in the National Registry
ven-of Cardiopulmonary Resuscitation, 6789 eligible patients were included in the final study population.
Trang 19at 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 ses to explore the relationship between time to defibrillation and survival to hospital discharge across a range of times
analy-All models used generalized estimating tions with an unstructured correlation matrix to account for the potential effects of clustering of
equa-Table 1 Baseline Characteristics According to Time to Defibrillation.*
Characteristic
≤2 Minutes
to Defibrillation (N = 4744)
>2 Minutes
to Defibrillation
Ventricular fibrillation — no (%) 3276 (69.1) 1454 (71.1) 0.08 Hospital-wide code blue —no (%) 4141 (87.3) 1889 (92.4) <0.001
Trang 20Delayed Time to Defibrillation After In-Hospital Cardiac Arrest
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 esults
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 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
asso-Return of spontaneous circulation occurred in
4168 patients (61.4%), 3372 patients (49.7%) vived to 24 hours after their cardiac arrest, and
sur-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
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 (%)
Therapeutic interventions — no (%)
* 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.
Trang 21circu-After adjustment for patient- and 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
hospital-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 taneous circulation (adjusted odds ratio, 0.55; 95%
spon-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)
Discussion
We found that 30.1% of patients with cardiac 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
ar-or functional status These findings suppar-ort 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 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
relation-as relation-asystole, at the time of cardiac arrest).7,9,10 over, these studies were generally small and in-volved a limited number of hospitals In contrast, our analysis focused only on patients with cardiac
More-Table 2 Factors Associated with Delayed Time to Defibrillation in
Multivariable Analysis.*
Race or ethnic group‡
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
* 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.