A 34-year-old woman with seven previous cesarean deliveries and a history of scant prenatal care presented at 32 weeks' gestation with constant, vague lower abdominal pain that had worsened over the past day. Her vital signs were normal, and the examination was notable for tenderness in both lower quadrants. Laboratory tests revealed a hematocrit value of 39% and a white-cell count of 18,300 per cubic millimeter with 8% bands. The fetal status was reassuring, on the basis of a reactive heart-rate tracing with rare variable decelerations. Infrequent uterine contractions were noted, and the cervix was long and closed with no evidence of ruptured membranes on speculum examination. Abdominal ultrasonography was notable for oligohydramnios, which severely limited the quality of the study and precluded diagnostic amniocentesis, but the fetal measurements were appropriate for the gestational age. Abdominal computed tomography (CT) was performed, owing to worsening maternal pain and concern about appendicitis. The CT scan revealed a fetal hand protruding through the lower uterine segment (Panel A, arrow). The patient initially declined surgery, but a cesarean section performed 12 hours later showed complete disruption of the hysterotomy scar from a previous delivery, with a fetal hand in the maternal abdomen (Panel B). The site of uterine rupture in the lower uterine segment was extended laterally to permit delivery of the fetus, and then the hysterotomy was repaired in the usual fashion. A vigorous male infant with a 5-minute Apgar score of 9 was delivered. The mother's postpartum course was uneventful, and she was discharged home on postoperative day 4. The infant remained in the neonatal intensive care unit, owing to prematurity, and was discharged in good condition on day 20 of life. Subacute, noncatastrophic, complete dehiscence of the uterine scar is rare.

Alexandra Grosvenor Eller, M.D.
Barbra Fisher, M.D., Ph.D.
University of Utah School of Medicine, Salt Lake City, UT 84132

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This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.

A healthy 25-year-old brunette woman reports a 12-month history of skin depigmentation. She first noticed patches of skin whitening on her hips; her physician prescribed an imidazole cream for a presumed fungal infection, but there was no improvement. After a vacation at the beach, she noticed additional depigmented patches on her elbows, shins, upper eyelids, and lower chin. A dermatologist made a diagnosis of vitiligo and recommended a sunscreen but offered little hope for treatment. She feels stigmatized by her appearance. How should she be evaluated and treated?
The Clinical Problem

Vitiligo is the most common depigmenting disorder, with a prevalence of approximately 0.5% in the world population. Almost half of patients with vitiligo present before 20 years of age. The two sexes are equally affected, and there are no apparent differences in rates of occurrence according to skin type or race.1,2

Nonsegmental (or generalized) vitiligo and segmental vitiligo have distinctive clinical features and natural histories (Table 1Table 1Typical Features of Segmental and Nonsegmental Vitiligo. and Figure 1Figure 1Nonsegmental and Segmental Vitiligo.). Nonsegmental vitiligo is the most common form of the disease (accounting for 85 to 90% of cases overall), but segmental vitiligo, because it generally has an earlier onset, may account for 30% of childhood cases.3 Both nonsegmental and segmental vitiligo can initially present as focal vitiligo, which is characterized by a small affected area (<15 cm2).4 On rare occasions nonsegmental and segmental vitiligo coexist, and in such cases, segmental lesions are less responsive to treatment.5

A loss of epidermal melanocytes is the pathologic hallmark of vitiligo.5,6 In completely depigmented areas, inflammation is usually absent, but mononuclear cells have been identified at the margin of the depigmented areas in cases of nonsegmental vitiligo, especially in rapidly progressing disease.7 The initial cause of nonsegmental vitiligo is still debated but appears to involve immunologic factors, oxidative stress, or a sympathetic neurogenic disturbance. In nonsegmental vitiligo, the upward migration of melanocytes 24 hours after mechanical trauma in perilesional areas highlights the importance of Koebner's phenomenon (a cutaneous disease-specific response to a nonspecific, usually traumatic, stimulus such as pressure or friction) in the pathogenesis of the disease. In segmental vitiligo, a neurogenic sympathetic disturbance is considered a key precipitating factor,3 but observations also suggest a genetic anomaly restricted to the segment (mosaicism).

Some genes track with vitiligo in populations of European descent, either as part of an autoimmune diathesis or with vitiligo in isolation. In the autoimmune group, variants in the gene encoding NACHT leucine-rich-repeat protein 1, or NALP1, have recently been identified.8
Strategies and Evidence
Evaluation
Diagnosis

In patients presenting with patchy depigmentation, a thorough history and physical examination, including examination with Wood's lamp (Figure 2Figure 2Wood's Lamp Examination.), should focus on ruling out other disorders (Table 2Table 2 Major Differential Diagnoses for Nonsegmental Vitiligo. ). Occupational exposures may cause depigmentation or exacerbate underlying vitiligo.10 In nonsegmental vitiligo, typical macules show homogeneous depigmentation and have well-defined borders. A loss of hair pigment is usually not seen until the late stages of the disease. A hyperpigmented rim at the interface of depigmented and normally pigmented skin is commonly seen after sun exposure. Pinpoint depigmentation may precede patchy depigmentation in rapidly progressing disease. Macules in segmental vitiligo may have a more irregular border and less homogeneous pigment loss than those in nonsegmental vitiligo.4 In patients with dark skin, there can be prominent involvement of mucosae. Several disorders may be confused with segmental vitiligo, especially nevus depigmentosus11 (see Fig. 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). It is rarely necessary to perform a skin biopsy to confirm the diagnosis.
Assessment

An assessment form created by the Vitiligo European Task Force (VETF) may be useful in evaluation (an updated version of the form is available in the Supplementary Appendix).4 Patients should routinely be asked whether there is a family history of vitiligo and premature hair graying and whether there is a family or personal history of thyroid disease or other autoimmune diseases (e.g., alopecia areata, rheumatoid arthritis, diabetes, and pernicious anemia).12 Halo nevi (nevi with surrounding depigmentation) are 8 to 10 times as common in patients with vitiligo as in the general population9; they should be discussed as part of the personal and family history taking and assessed during the physical examination (including examination with Wood's lamp in the case of fair-skinned patients). Multiple halo nevi are a marker of cellular autoimmunity against nevus cells and may indicate an increased risk of vitiligo in patients with a family history of the disease. Skin color and ability to tan should be noted (information on phototype is important in establishing a plan for phototherapy), as should the distribution of the vitiligo (including genital depigmentation, which patients may not report because of embarrassment) and its duration and level of activity (progressive, regressive, or stable over the previous 6 months). In some patients with nonsegmental vitiligo, an acceleration phase occurs, with rapid disease progression over a period of weeks to months, warranting more urgent intervention (e.g., a short course of corticosteroids). A scoring system for assessment of the extent of disease, its stage, and the degree of spreading4 (whether the disease is progressing, stable, or regressing) is included in the VETF form in the Supplementary Appendix. Patients should be asked about previous episodes of repigmentation, details of prior therapy and its usefulness, and any trauma preceding the skin changes (as in Koebner's phenomenon) (Figure 3Figure 3Koebner's Phenomenon.).13 Patients should be asked about how vitiligo affects their daily life (e.g., as assessed on a visual analogue scale ranging from no effect to a large effect).

Because nonsegmental vitiligo is associated with an increased risk of autoimmune thyroid disease, especially Hashimoto's thyroiditis,14 the thyrotropin level should be measured annually, especially in patients with antibodies to thyroid peroxidase at initial screening. The frequencies of associated autoimmune diseases in patients with vitiligo appear to vary with skin type or race.15,16 Any symptoms or signs of organ-specific autoimmune diseases should prompt investigation. 17 A particularly high index of suspicion is warranted in patients with a personal or family history of autoimmune disease.
Treatment

In treatment studies, efficacy is typically assessed in terms of the proportion of treated patients in whom a specified degree of repigmentation is achieved, with more than 50% or more than 75%, depending on the study,18 often considered a good response. However, these criteria are debatable insofar as complete repigmentation, especially in visible areas, may be needed for a high degree of satisfaction on the patient's part. Moreover, the evaluation of repigmentation is not well standardized.19 A quantitative objective score (Vitiligo Area Scoring Index)20 and the VETF score4 have been proposed. Clinical photographs and, if possible, photographs taken under ultraviolet light are recommended for accurate monitoring of repigmentation.

Commonly used repigmentation therapies whose efficacy is supported by data from randomized trials include ultraviolet light (for the whole body or targeted to lesions) and topical agents (corticosteroids and calcineurin inhibitors). Camouflaging or depigmenting treatments (in widespread disease) are other options. Table 3Table 3Management Strategies for Vitiligo in Adults. outlines stepwise treatment approaches. The involvement of a psychologist or psychiatrist may be helpful for patients who have difficulty coping with the diagnosis.
Ultraviolet Light

Narrow-band ultraviolet B (UVB) radiation, which delivers peak emission at 311 nm, is currently the preferred treatment for adults and children with nonsegmental vitiligo, as long as there is access to a specialized treatment center. In a randomized trial comparing the use of topical photochemotherapy (psoralen and ultraviolet A radiation [PUVA], a standard treatment in the past) with twice-weekly narrow-band UVB radiation among adults with vitiligo, repigmentation was significantly more likely with narrow-band UVB radiation than with PUVA (occurring in 67% of patients vs. 46% at 4 months). After 1 year of narrow-band UVB treatment, 63% of patients had more than 75% repigmentation.21 The same narrow-band UVB regimen applied to children (mean age, 9.9 years) for up to 1 year resulted in more than 75% repigmentation in 53% of patients; the disease stabilized with therapy in 80% of the children who had active disease at study entry.22 The superiority of narrow-band UVB treatment was also confirmed in a double-blind, randomized trial in which it was compared with oral PUVA in 50 patients with nonsegmental vitiligo23; an improvement of more than 50% was noted after 48 sessions in 53% of patients treated with narrow-band UVB as compared with 23% of those treated with PUVA. The color match of repigmented skin was considered to be excellent in all patients treated with narrow-band UVB radiation but in only 44% of those treated with PUVA. Patients in the PUVA group also had greater erythema and had nausea (due to ingestion of oral psoralen).

Narrow-band UVB therapy is usually given twice weekly — but not on 2 successive days — in sessions lasting 5 to 10 minutes. The simplest approach is to use a fixed starting dose (0.21 J per square centimeter), regardless of the skin phototype, and to increase the dose by 20% with each session until the minimal erythema dose (i.e., the lowest dose that results in visible erythema on depigmented skin at 24 hours) has been reached.24 The optimal dose may differ at different sites; areas responsive to lower doses can be shielded until the optimal dose has been reached for areas requiring higher doses.24 In two studies,21,24 twice-weekly treatment with narrow-band UVB for 1 year in patients with nonsegmental vitiligo resulted in repigmentation of 75% of affected areas in 48%24 and 63%21 of patients. At least 3 months of treatment is warranted before the condition can be classified as nonresponsive, and approximately 9 months of treatment is usually required to achieve the maximal repigmentation. There is no apparent relationship between the degree of initial depigmentation and the response to narrow-band UVB treatment,21 but the duration of disease is inversely correlated with the degree of treatment-induced repigmentation.24 The best results are achieved on the face, followed by the trunk and limbs. The poorest outcomes have been noted for lesions on the hands and feet. Relapses are common at all sites; in approximately two thirds of patients, depigmentation recurs within a year in repigmented areas.23

The response of segmental vitiligo to narrow-band UVB treatment is at best limited.24 Preliminary data suggest that the use of targeted high-exposure doses of UVB radiation (excimer laser or monochromatic excimer lamp, both at 308 nm), which may reach deeper targets (e.g., amelanotic melanocytes of the hair follicle) while minimizing irradiation of uninvolved skin, may improve outcomes for patients with limited areas of nonsegmental vitiligo.25-27 The red light emitted with helium–neon laser phototherapy has also been reported to promote repigmentation in patients with segmental vitiligo, although data are limited.28
Topical Therapies

Topical therapies, including corticosteroids and calcineurin inhibitors, may be effective in cases of nonsegmental or segmental vitiligo in which the disease is localized. Combined topical and ultraviolet-light treatments are often considered when there has been no response to phototherapy alone after 3 months or when the goal is to accelerate the response and reduce cumulative exposure to ultraviolet light. As compared with PUVA, which promotes a predominantly perifollicular pattern of repigmentation, topical corticosteroids and calcineurin inhibitors result in more diffuse repigmentation, which occurs more quickly but is less stable.29 A systematic review of randomized trials and case series showed that class 3 (potent) topical corticosteroids (e.g., betamethasone) were significantly more effective than placebo in treating localized vitiligo, resulting in more than 75% repigmentation in 56% of patients.18

Topical calcineurin inhibitors are generally preferred for face and neck lesions because they do not cause skin atrophy30 and can promote repigmentation without inducing immunosuppression.31 Their efficacy is enhanced by occlusion with a polyethylene foil32 or exposure to ultraviolet radiation delivered by high-fluency UVB devices,25 but it is not clear whether conventional narrow-band UVB treatment enhances efficacy.33 More data are needed to determine the effectiveness of combining calcineurin inhibitors with UVB or other sources of light, such as the red light emitted by helium–neon laser.34 The usefulness of these agents as the sole form of therapy for sites protected from the sun, such as genitals and nipples, requires further study. Concerns have been raised about the risks of cutaneous or extracutaneous cancer with the use of topical calcineurin inhibitors, but data providing strong support for such an association are lacking.35 It is unclear whether the use of a topical corticosteroid in combination with UVB radiation is superior to UVB radiation alone.
Surgery

Surgical methods, including minigrafting,36 transplantation of autologous epidermal cell suspensions,37 application of ultrathin epidermal grafts,38 and a combination of these approaches, are used in some cases of focal or segmental vitiligo if medical approaches fail (see Fig. 2 in the Supplementary Appendix). Ultraviolet-light therapy is generally combined with these methods. Patients with nonsegmental vitiligo are considered good candidates for surgical treatments, depending on their availability and cost, if the disease has stabilized (during the previous 1 to 2 years) and is limited in extent (covering no more than 2 to 3% of body-surface area). The survival of transplanted melanocytes is more likely in segmental vitiligo than in nonsegmental vitiligo, since the grafted cells can be harvested from disease-free areas. Koebner's phenomenon limits efficacy (on the hands in particular). In one randomized trial involving patients with nonsegmental vitiligo who were carefully selected for stable disease, the combination of cellular transplantation plus treatment with ultraviolet light resulted in repigmentation of at least 70% of the treated area as compared with a near absence of repigmentation in the group treated with a noncellular dressing plus ultraviolet light.39
Other Therapies

Topical remedies can be used to mask skin disfigurement on a temporary, semipermanent, or permanent basis. They include self-tanning agents; stains; dyes; whitening lotions; tinted cover creams; powder, liquid, and stick foundations; fixing powders and sprays; cleansers; semipermanent and permanent tattoos; and dyes for white hair on the face and head. Dihydroxyacetone (DHA) is the most frequently used self-tanning agent (for recommendations on the use of DHA, see Table 1 of the Supplementary Appendix). The higher the concentration, the better the response observed, particularly in patients who have darker phototypes.40 Self-tanning interventions may improve quality of life.41 Chemical or laser depigmentation is an option in a small subgroup of carefully selected patients, but the results are variable.42

Sunscreens are needed if there is a risk of sunburn on nonphotoprotected skin, but they are not recommended on a routine basis because moderate sun exposure (heliotherapy) provides benefits associated with exposure to ultraviolet light, and because there is a theoretical risk that the friction caused by repeated application of sunscreen might exacerbate the disease. Depigmented skin in vitiligo tends to show increased tolerance to UVB light over time (photoadaptation), with the extent of tolerance based in part on skin phototype.43
Areas of Uncertainty

The basic mechanisms of melanocyte loss and those limiting follicular or marginal repigmentation remain unclear. Development of a formal system for staging skin inflammation in rapidly progressing disease would be helpful in guiding decisions about more aggressive interventions. Additional randomized trials using both objective and patient-oriented measures are needed to compare the effectiveness of various therapies and to guide optimal management of the disease. Longer-term follow-up is needed to better establish the safety of UVB therapy and calcineurin inhibitors.

Topical calcipotriene (a vitamin D3 analogue) is sometimes used for localized disease, but trials have indicated that it has limited or no effect when used alone and that it results in at most a minor increase in repigmentation when used in combination with ultraviolet radiation or topical corticosteroids.44 Data on the efficacy of topical antioxidants and natural health products are limited. Data from open-label studies have suggested that the use of systemic corticosteroids may arrest disease progression,45,46 but data from randomized trials of this and other systemic immunosuppressive agents are lacking.
Guidelines

Guidelines for the management of vitiligo in adults and children have been published by the British Association of Dermatologists,47 and guidelines for surgery are available from the Indian Association of Dermatologists, Venereologists, and Leprologists Dermatosurgery Task Force.48 The recommendations in this article are generally consistent with these guidelines.
Conclusions and Recommendations

In a case such as the one in the vignette, the initial assessment should focus on the extent of disease, possible aggravation of disease due to friction or pressure on affected areas, and the possibility that other associated autoimmune diseases — in particular, thyroid disease — may be involved. Attention must be paid to the psychological effects of the condition and to whether a referral is needed for psychological support. Patients should be informed that vitiligo is a chronic, relapsing disorder, that repigmentation is a slow process, and that reactivation of the disease in different body regions or the reappearance of lesions in treated regions may occur. Narrow-band UVB radiation has proved to be effective in the treatment of widespread disease, and we recommend it as first-line therapy. In the case of localized disease, we recommend starting treatment with a potent topical corticosteroid or topical calcineurin inhibitor; on the face, calcineurin inhibitors are currently preferred because of the potential side effects of prolonged application of corticosteroids, although the long-term safety of calcineurin inhibitors requires further study. Camouflage techniques may also be helpful, particularly in dark-skinned patients with lesions on their face or hands. Cellular transplantation, or grafting, is an option in specialized centers for selected patients with stable and limited lesions that are unresponsive to other forms of therapy.

An audio version of this article is available at NEJM.org.

Drs. Taïeb and Picardo are coordinators of the VETF, whose meetings in Paris have been supported by Pierre Fabre Laboratories. Dr. Picardo serves as the president of the European Society for Pigment Cell Research, which received a donation from Galderma Laboratories to organize a workshop on vitiligo at the 2008 International Pigment Cell Conference. No other potential conflict of interest relevant to this article was reported.
Source Information

From the Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Diseases, Centre Hospitalier Universitaire of Bordeaux, Bordeaux, France (A.T.); and San Gallicano Dermatological Institute, Rome (M.P.).

Address reprint requests to Dr. Taïeb at the Department of Dermatology, Hôpital Saint André, 1 rue Jean Burguet, 33075 Bordeaux, France, or at alain.taieb@chu-bordeaux.fr.

We thank Dr. Yvon Gauthier for providing an earlier version of Figure 3 and for discussing an earlier draft of the manuscript and Alida de Pase for offering advice on camouflage techniques.

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Cigarette smoking has been identified as the second leading risk factor for death from any cause worldwide.1,2 In 2000, an estimated 4.83 million deaths were attributed to cigarette smoking globally, with nearly half occurring in the developing world.1,3 Because many low- and middle-income countries are still in early stages of the tobacco epidemic, the number of smoking-related deaths in these nations will probably increase during the next decades.3-5

With a population of 1.3 billion, China is the world's largest producer and consumer of tobacco and bears a large proportion of deaths attributable to smoking worldwide.6,7 Even though several prospective cohort studies have examined the relationship between tobacco smoking and mortality in the Chinese population,8-11 the number of deaths attributable to smoking in China is still uncertain. Most previous prospective cohort studies in China were conducted in regional or occupational groups with a relatively small sample size9-11 or did not have an active follow-up procedure for mortality.8

We used data from a large, prospective cohort study in a nationally representative sample of Chinese adults to examine the effect of tobacco smoking on deaths from any cause and from certain specific causes, as well as to estimate the population attributable risk and the number of deaths attributable to smoking in men and women in 2005. We offer these estimates as China moves forward with tobacco-control initiatives, reflecting its commitments through its ratification of the World Health Organization (WHO) Framework Convention on Tobacco Control.12
Methods
Study Population

In 1991, the China National Hypertension Survey was carried out in all 30 provinces, autonomous regions, and municipalities of mainland China with the use of a multistage design of random cluster sampling to select a nationally representative sample of the Chinese general population who were 15 years of age or older.13 The overall response rate was 89.5%. In 1999 and 2000, investigators from each province were invited to participate in the China National Hypertension Survey Epidemiology Follow-up Study. Of the 30 provinces, 13 were not included in the follow-up study because contact information was not available for study subjects. However, the sampling process was conducted independently within each province in 1991, and the 17 provinces that were included in the follow-up study were evenly distributed in different geographic regions representing various levels of economic development in China. From the 17 provinces, 169,871 study subjects (83,533 men and 86,338 women) who were 40 years of age or older at their baseline examination were eligible to participate in the follow-up study.

For this report, we excluded 14,740 subjects who had missing information regarding tobacco-smoking status, since data on smoking were not collected in two provinces. The baseline characteristics of subjects from the remaining 15 provinces that were included in this analysis were similar to those in the 15 excluded provinces. In the two groups, respectively, the mean baseline ages were 55.9 and 55.3 years; the percentages of subjects who had a high-school education were 24.0% and 23.4%; who consumed alcohol, 19.8% and 18.7%; who were physically inactive, 37.0% and 36.6%; and who had ever smoked cigarettes, 37.9% and 36.7%. Of 155,131 eligible subjects (76,134 men and 78,997 women) from the 15 provinces that were included in this analysis, a total of 144,088 (92.9%) underwent successful follow-up.
Baseline Examination

Baseline data were collected at a single clinic visit by specially trained physicians and nurses with the use of standardized methods with stringent levels of quality control.13 Data on demographic characteristics, medical history, and lifestyle risk factors were obtained with the use of a standard questionnaire administered by trained staff. Tobacco smoking was defined as having smoked at least one cigarette per day for 1 year or more, and one cigarette was considered to be equivalent to 1 g of tobacco.14 For subjects who reported past or current tobacco smoking, information on the number of cigarettes or grams of tobacco smoked per day, along with the duration of tobacco smoking, was also collected. Work-related physical activity was assessed, since leisure-time physical activity was uncommon at that time in China. Data on the amount and type of alcohol consumption during the past year were collected. Body weight and height were measured while subjects were wearing light indoor clothing without shoes, and the body-mass index was calculated. Three blood-pressure measurements were taken after the subject had been seated quietly for 5 minutes with the use of a standard mercury sphygmomanometer, according to a standard protocol.15
Follow-up Data Collection

The follow-up examination, which was conducted between 1999 and 2000, included tracking subjects or their proxies to a current address, performing in-depth interviews to ascertain disease status and vital information, and obtaining hospital records and death certificates. Of all deaths reported, vital information was provided by family members (75.0%), primary care physicians (12.6%), other health care providers (3.8%), and employers, relatives, or friends (8.5%). If a subject died while he or she was hospitalized, the subject's hospital record — including medical history, findings from physical examination, laboratory findings, autopsy findings, and discharge diagnosis — was abstracted by trained staff with the use of a standard form. Photocopies of selected sections of the subject's inpatient record, discharge summary, electrocardiogram, spirometry, chest radiograph, and pathology reports were also obtained. If death occurred outside the hospital, a detailed medical history was obtained from a family member or health care provider. Subjects' previous medical records were also obtained, if available. The majority of deaths (98.6%) that were reported during follow-up were verified by death certificates, medical records, or both.

An end-point assessment committee at the Chinese Academy of Medical Sciences in Beijing reviewed medical history information and death certificates and determined the final underlying cause of death with the use of prespecified criteria.16 Two committee members independently verified the diagnosis, and discrepancies were adjudicated by discussion involving additional committee members. All committee members were unaware of the subjects' baseline risk factors. Causes of death were coded according to the International Classification of Diseases, Ninth Revision.

This study was approved by the institutional review board at Tulane University Health Sciences Center in New Orleans and the ethics committee at the Cardiovascular Institute and Fu Wai Hospital in Beijing. Written informed consent was obtained from all study subjects or their proxies at the follow-up visit. The study's steering committee had the final responsibility for the decision to submit the manuscript for publication.
Statistical Analysis

Person-years of follow-up were calculated from the date of baseline examination until the date of death or follow-up interview for each subject. Age-standardized mortality was calculated with the use of the 5-year age-specific mortality and age distribution of the Chinese population from year 2000 census data. Relative risks were calculated for subjects who had ever smoked with the use of lifelong nonsmokers as the reference category because current and former smokers had similar rates of death from any cause. Only a small number of subjects (3533 in total, including 2965 men and 568 women) reported being former smokers. Cox proportional-hazards models were used to adjust for prespecified covariates, including baseline age, level of education, alcohol consumption, level of physical activity, and the presence or absence of hypertension, overweight status, and self-reported diabetes, as well as geographic region (north vs. south) and urbanization (rural vs. urban), since the prevalence of cigarette smoking and mortality vary according to geographic region and level of urbanization in China. To examine the dose–response relationship between tobacco smoking and mortality in men and women, subjects who had ever smoked were divided into three groups, according to the number of pack-years smoked (<16.1, 16.1 to 30.3, and ≥30.3).

The multivariable-adjusted relative risks of death associated with smoking were obtained for each subgroup according to the level of urbanization (urban vs. rural), sex, and age group (40 to 54, 55 to 64, and ≥65 years). These estimates, along with the subgroup-specific proportion of smokers from a national survey,7 were used to calculate the population attributable risk and 95% confidence intervals for each subgroup.17 The population attributable risk was calculated with the use of the following equation (in which PAR denotes the population attributable risk, P the proportion of smokers, and RR relative risk):

PAR = (P × [RR − 1]) ÷ (P × [RR − 1] + 1).

The overall relative risks or population attributable risks of death associated with smoking were calculated for men and women by pooling the subgroup-specific estimates of the natural logarithms of relative risks or population attributable risks for subjects of each sex and were weighted according to the size of the population in China in 2005 for each subgroup. The numbers of deaths attributable to smoking in each subgroup were then calculated by multiplying the population attributable risks according to the subgroup-specific rates of death from the study and population size in China in 2005. The total numbers of deaths attributable to smoking in men and women in urban and rural areas were calculated by summing these estimates among appropriate subgroups.

Methods to estimate variances that take into account sample clustering were used in Cox proportional-hazards models.18 All analyses were conducted with the use of SAS statistical software, version 9.1 (SAS Institute). All reported P values are two-sided and have not been adjusted for multiple testing.
Results
Study Subjects

Baseline characteristics of study subjects according to smoking status are presented in Table 1Table 1Baseline Characteristics of the Subjects, According to Smoking Status.. Both female and male smokers were more likely to consume alcohol and less likely to have a high-school education and to be overweight or obese than their counterparts who had never smoked. On average, male smokers were younger and less likely to be physically inactive or to have hypertension or diabetes than were male nonsmokers. In contrast, female smokers tended to be older and were more likely to be physically inactive and to have hypertension or diabetes than female nonsmokers.

During an average of 8.3 years of follow-up (1,115,417 person-years), a total of 17,863 subjects (10,140 men and 7723 women) died. There was a significant, dose–response association between pack-years smoked and death from any cause in both men and women after adjustment for multiple risk factors (P<0.001 for trend) (Table 2Table 2Relative Risk of Death from Any Cause among Former or Current Smokers, as Compared with Lifelong Nonsmokers, According to the Number of Pack-Years.).

The multivariable-adjusted relative risk of death from any cause was significantly higher in smokers than in nonsmokers for men and women in all age groups (Table 3Table 3Relative Risk, Prevalence of Smoking, Population Attributable Risk, and the Absolute Number of Deaths Attributable to Smoking in China in 2005.). There was some evidence that the relative risk of death from any cause that was associated with tobacco smoking was higher in women than in men (P=0.02 for interaction). However, the prevalence of smoking and the population attributable risk were higher for men than for women, with cigarette smoking accounting for 12.9% of deaths among men and 3.1% of deaths among women. Population attributable risks were similar for subjects in all three age groups (40 to 54, 55 to 64, and ≥65 years), but the number of deaths attributable to smoking increased with age in both men and women because of the higher rates of death in the elderly.

It was estimated that a total of 673,000 deaths (95% confidence interval [CI], 564,700 to 781,400) were attributable to smoking in Chinese adults who were 40 years of age or older in 2005: 538,200 (95% CI, 455,800 to 620,600) in men and 134,800 (95% CI, 108,900 to 160,800) in women. The estimated numbers of smoking-related deaths were 327,500 (95% CI, 193,600 to 461,400) in rural areas and 345,500 (95% CI, 296,700 to 394,400) in urban areas (Figure 1Figure 1Number of Deaths Attributable to Smoking in 2005 in China, According to Sex and Urbanization.).

Cause-specific mortality from cancer, cardiovascular disease, and respiratory disease was significantly associated with cigarette smoking (Table 4Table 4Relative Risk, Population Attributable Risk, and Absolute Number of Deaths Attributable to Smoking in China, According to Sex and Cause of Death.). The estimated numbers of deaths attributable to smoking were as follows: cancer, 268,200 (95% CI, 214,500 to 321,900), including 240,400 (95% CI, 198,800 to 282,000) in men and 27,800 (95% CI, 15,800 to 39,900) in women; cardiovascular disease, 146,200 (95% CI, 79,200 to 213,100), including 126,600 (95% CI, 75,600 to 177,700) in men and 19,600 (95% CI, 3600 to 35,500) in women; and respiratory disease, 66,800 (95% CI, 20,300 to 113,300), including 48,600 (95% CI, 13,700 to 83,500) in men and 18,200 (95% CI, 6600 to 29,900) in women.

Lung cancer had the highest population attributable risk associated with cigarette smoking: 50.6% in men and 14.8% in women. The three leading diseases associated with deaths attributable to smoking were lung cancer, stroke, and chronic obstructive pulmonary disease in men and chronic obstructive pulmonary disease, lung cancer, and stroke in women. Together, these diseases accounted for approximately 45.1% of deaths attributable to smoking in men and 31.8% of those in women.
Discussion

The results of our study involving a nationally representative sample of Chinese adults indicate that tobacco smoking is a major preventable cause of death in China. On the basis of observed risks, we estimate that tobacco smoking was responsible for about 673,000 premature deaths in Chinese adults who were 40 years of age or older in 2005. The number of deaths attributable to smoking was much greater among men than among women. Lung cancer was the leading cause of deaths attributable to smoking in men, and chronic obstructive pulmonary disease was the leading cause of such deaths in women.

These findings have important public health implications. Tobacco smoking is highly prevalent and is associated with substantially increased morbidity and mortality as well as health expenditures in China.6,7,19 More troublesome, the prevalence of tobacco smoking has been continuously high in adult men, and the average age of smoking initiation has been dropping during recent decades.20,21 Data from our study and others provide strong evidence that tobacco smoking causes an increased risk of cancer, vascular disease, and respiratory disease in China and elsewhere.5,8-11,22-25 These data are a reminder of the urgent need for continued strengthening of national programs in China on smoking prevention and cessation. These efforts should include the full set of strategies recommended by the 2008 WHO report on the global tobacco epidemic.26

Unlike studies in Western populations, our study showed that the numbers of death from any cause were similar among former and current smokers. Smoking cessation has been relatively uncommon in China, and most smokers quit cigarette smoking because of chronic illness. The median age of smoking cessation was 61.0 years in men and 60.0 years in women among former smokers who died during follow-up. Our study reported a lower relative risk associated with smoking than did studies in Western populations,25 but our results were similar to those of other studies conducted in the Chinese population.5 The magnitude of the relative risks probably reflects the lower numbers of cigarettes smoked in the past and the later age of smoking initiation in subjects currently dying from smoking-related diseases.27 Further investigations are warranted to explain the observed lower relative risk.

Other studies have estimated the smoking-related burden of disease in China. Liu and colleagues compared the smoking habits of 700,000 adults who died from cancer or from respiratory or vascular causes with those of 200,000 adults who died from other causes.5 The underlying cause of death was obtained from local administrative records, and smoking information was recalled by family members. A validation study suggested that local administrative records on the underlying cause of death might not be reliable for some diseases in China.28 In addition, several potential confounding factors (e.g., lifestyle risk factors in the medical history) were not considered in their study. In our study, data on baseline tobacco smoking and other variables were carefully collected with the use of stringent quality-control procedures. In addition, the follow-up rate was high, and almost all deaths were confirmed. Potential confounding factors, including lifestyle risk factors, were considered in the analysis.29 Despite the differences in the two studies, the estimate by Liu et al. that 600,000 deaths were attributable to smoking in 1990 is reasonably close to our estimate of 670,000 in 2005. Neither study estimated the effect of passive smoking on mortality. In addition, exposure to tobacco smoke was assessed by questionnaire in both studies. Although validation of smoking histories against biochemical markers would have been useful, smoking information was collected during an era when smoking was accepted, and a bias to deny or minimize smoking would have been unlikely.

Our study was limited by the availability of hospital records for only 71.0% of subjects who died. The classification of cause of death may be less accurate for subjects without hospital records. In addition, the mortality follow-up was conducted during the 1990s in our study, which reflects the patterns of health care and disease burden at that time. Smoking-related diseases, such as cancer and cardiovascular disease, are now more common causes of death in China. Our study might underestimate current deaths attributable to smoking in China. Furthermore, despite the adjustment for several potentially confounding factors in the multivariable analyses, smokers and nonsmokers may still differ with respect to other factors that contribute to disease risk. Finally, we estimated the number of deaths attributable to smoking that would have been prevented if the entire population in China had never been exposed to smoking; we could not estimate the number of deaths that were avoidable by smoking cessation.

Ezzati and Lopez estimated that the leading causes of deaths from smoking worldwide in 2000 were cardiovascular disease (753 million in men and 269 million in women), cancer (664 million in men and 160 million in women), and respiratory disease (310 million in men and 138 million in women).3 On the basis of a case–control study, it has been predicted that smoking will cause about 930,000 adult deaths in India by 2010, mainly from tuberculosis and respiratory disease in men and women and heart disease and cancer in men.22,23 The three leading causes of death attributable to smoking in the United States were cancer, cardiovascular disease, and respiratory disease in men and cardiovascular disease, cancer, and respiratory disease in women.24 Respiratory disease was the leading cause of death attributable to smoking in South Africa.30 Our findings for China are similar with regard to the leading causes of death attributable to smoking: cancer, cardiovascular disease, and respiratory disease.

These new estimates of the number of deaths attributable to smoking speak to the urgency of an agenda for a strong national tobacco-control program in China. Fortunately, there is far more tobacco-control activity than there was previously. The government is moving forward with implementation of tobacco-control measures and has strengthened its tobacco-control capacity within the Chinese Center for Disease Control. However, the government's role in tobacco control is in conflict with the selling of tobacco through its state-owned company and reliance on tobacco revenues.31,32 In addition, mortality and morbidity will not be reduced in the short term without the adoption of measures to increase smoking cessation among the approximately 300 million current smokers in the country. These new estimates on mortality attributable to smoking document the potential human toll of inaction.

Supported by a national grant-in-aid (9750612 N) from the American Heart Association; a grant (U01-HL072507) from the National Heart, Lung, and Blood Institute of the National Institutes of Health; a grant (1999-272) from the Ministry of Health, Beijing; and a grant (2006BAI01A01) from the Ministry of Science and Technology, Beijing.

No potential conflict of interest relevant to this article was reported.
Source Information

From the Department of Evidence Based Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and the National Center for Cardiovascular Disease, Beijing (D.G., X.W., J. Huang, M.Z., Ji-chun Chen, X.D.); the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine (T.N.K., C.-S.C., J. He), and the Department of Medicine, Tulane University School of Medicine (Jing Chen, J. He) — both in New Orleans; and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore (J.M.S., M.J.K.).

Address reprint requests to Dr. Gu at the Department of Evidence Based Medicine, Fu Wai Hospital, 167 Beilishi Rd., Beijing, 100037, China, or at gudf@yahoo.com.
Appendix

The following investigators participated in this study: Steering Committee: J. He (coprincipal investigator), D. Gu (coprincipal investigator), J. Chen, R. Hui, M.J. Klag, L. Kong, S. Tao, J. Wang, P.K. Whelton, X. Wu, and C. Yao. The following institutions and principal investigators participated in the study: United States: Tulane University Health Sciences Center, New Orleans: C.-S. Chen, J. Chen, J. He, T.N. Kelly, K. Reynolds, P.K. Whelton, R.P. Wildman; Johns Hopkins Bloomberg School of Public Health, Baltimore: M.J. Klag. China: Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing: J. Chen, X. Duan, W. Gan, D. Gu, G. Huang, J. Huang, S. Tao, X. Wu, W. Yang, J. Zhao, M. Zhu; Chinese Ministry of Health, Beijing: L. Kong; Tianjin City Bureau of Public Health, Tianjin: G. Zheng; Tianjin City Center of Disease Control and Prevention, Tianjin: G. Song; Guangdong Provincial People's Hospital and Cardiovascular Institute, Guangdong: X. Liu, J. Mai; Anzhen Hospital, Capital University of Medical Sciences, and Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing: C. Yao; Capital Iron and Steel Company's Hospital, Beijing: X. Yu; Fangshan District Hospital, Beijing: X. Xu; Zhejiang Provincial Center for Cardiovascular Disease Prevention and Research, Zhejiang: H. Jin, X. Tang; Fujian Provincial People's Hospital, Fujian: X. Pu, L. Yu; Shandong Provincial Academy of Medical Sciences, Shandong: S. Zhang; Guangxi Medical University, Guangxi: L. Zhu; Xi'an Jiaotong University Medical School, Shanxi: J. Mo; Henan Provincial Academy of Medical Sciences, Henan: J. Guo; Tongji Medical College and School of Public Health, Huazhong University of Science and Technology, Hubei: Y. Hu, Y. Yu; Sichuan Provincial Center of Disease Control and Prevention, Sichuan: X. Wu; West China College of Medicine, Sichuan University, Sichuan: J. Wang; Nanjing Medical University, Jiangsu: H. Shen, C. Yao; Beihua University Medical School, Jilin: L. Xu, G. Zhao; Inner Mongolia Hospital, Inner Mongolia: X. Gao, J. Zhou; First Clinical College of Harbin Medical University, Heilongjiang: Y. Li; Daqing City Center of Disease Control and Prevention, Heilongjiang: Z. Li; Hebei Provincial Academy of Medical Sciences, Hebei: H. Zhang; Zhongshan Hospital and Institute of Cardiovascular Diseases, Fudan University, Shanghai: X. Pan.

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The partial pressure of atmospheric oxygen falls progressively as barometric pressure decreases with increasing altitude. Correspondingly, the ability to perform work (e.g., walking or climbing) diminishes with the decreased availability of atmospheric oxygen for aerobic respiration.1,2 At the summit of Mount Everest (8848 m [29,029 ft]), the highest point on the earth's surface, the partial pressure of inspired oxygen (PIO2) is believed to be very close to the limit that acclimatized humans can tolerate while maintaining functions such as ambulation and cognition.3 Hillary and Tenzing used supplemental oxygen to achieve the first ascent of Everest in 1953. It was not until 25 years after their ascent that the first ascent of Everest without supplemental oxygen was made by Messner and Habeler.4 Currently, less than 4% of persons who climb Everest do so without the use of supplemental oxygen (Salisbury R., Himalayan database: personal communication).

The only published measurements of the partial pressure of oxygen in arterial blood (PaO2) at such a low barometric pressure were reported in two studies — Operation Everest II and Operation Everest III (Comex '97) — that were designed to simulate an ascent of Mount Everest by placing subjects in a hypobaric chamber.5,6 The subjects in the two studies had a mean (±SD) resting PaO2 of 30.3±2.1 mm Hg (4.04±0.28 kPa)5 and 30.6±1.4 mm Hg (4.08±0.19 kPa),6 respectively, at a barometric pressure equivalent to the summit of Mount Everest (253.0 mm Hg, or 33.73 kPa). Such profound hypoxemia was tolerable because the subjects had been gradually acclimatized to the simulated altitude over a period of 37 to 40 days. In 1981, the partial pressures of oxygen and carbon dioxide (PaCO2) at end expiration were measured in a single person on Everest's summit after the person had been breathing without supplemental oxygen for approximately 10 minutes.7 With the use of a classic Bohr integration, the PaO2 for this climber was estimated to be 28 mm Hg (3.73 kPa).

We made direct field measurements of PaO2 and arterial oxygen content (CaO2) in climbers breathing ambient air at these extreme altitudes.
Methods
Study Participants

We obtained approval for this study from the University College London Committee on the Ethics of Non-NHS Human Research. All participants gave written informed consent. The subjects in this study were 10 healthy climbers (9 men and 1 woman, ranging in age from 22 to 48 years), who were ascending Everest by its southeast ridge as part of a medical research expedition (Caudwell Xtreme Everest).8,9

All subjects had ascended higher than 6800 m (22,310 ft) without incident on previous expeditions, and all were well acclimatized, with no evidence of ill effects from high altitude or of other illnesses. Subjects who were ascending higher than 7950 m (26,083 ft) had all previously ascended higher than that altitude without incident.
Collection of Blood Samples

Arterial blood samples were obtained in London, at an altitude of 75 m (246 ft); at the Everest base camp, at an altitude of 5300 m (17,388 ft); in Camp 2, at an altitude of 6400 m (20,997 ft); in Camp 3, at an altitude of 7100 m (23,294 ft); and during the descent from the summit at a feature known as the Balcony, at an altitude of 8400 m (27,559 ft) (Figure 1Figure 1Barometric Pressure (PB) and Partial Pressure of Inspired Oxygen (PIO2) in Blood Samples Obtained from Subjects Breathing Ambient Air at Various Altitudes between London and the Summit of Mount Everest.). The samples that were obtained in London and at the Everest base camp were obtained with the subject at rest, with the use of indwelling radial arterial cannulae that were placed as part of other study protocols; these samples were analyzed immediately. Samples obtained at an altitude higher than the Everest base camp were obtained from the right femoral artery, identified by digital palpation. Intraarterial placement of the needle (21-gauge) was confirmed by pulsatile filling of a heparinized 2-ml oiled glass syringe (Fisher Scientific). Syringes were immediately sealed with an airtight cap and placed in a plastic bag, which in turn was placed in an ice-water slurry inside an insulated vacuum flask. The flask was rapidly transported to a laboratory at Camp 2 in the Western Cwm; the length of time for this transfer to be completed was recorded. Barometric pressure was measured at the altitude at which the blood samples were taken, with the use of a handheld digital barometer (GPB 2300, Greisinger Electronic). Arterial samples were obtained by two investigators, both of whom had extensive experience with cannulation of the femoral artery and blood sampling.
Supplemental Oxygen

Supplemental oxygen was used only at or above Camp 3 (7100 m), with the following flow rates: 2 to 3 liters per minute while the subject was climbing and 0.5 liter per minute while the subject was sleeping. Supplemental oxygen was infrequently used while the subjects were resting at Camp 3 and Camp 4 (7950 m). At Camp 3, arterial samples were obtained after the subjects had been breathing ambient air for at least 4 hours. At the Balcony, samples were obtained after the subjects had been breathing ambient air for 20 minutes in order to achieve an adequate washout of supplemental oxygen.
Analysis of Blood Samples

Arterial blood samples were analyzed with the use of the RapidLab 348 (Siemens Medical Solutions Diagnostics) blood gas analyzer, which does not contain a co-oximeter. The PaO2, the PaCO2, and the pH were measured. Values for the bicarbonate concentration, blood base excess, and oxygen saturation (SaO2) were calculated with the use of formulas currently approved by the Clinical Laboratory Standards Institute10 (Table 1Table 1Equations Used for the Calculation of Arterial Blood Gas Values and Arterial Oxygen Content.). The blood lactate concentration was measured with a separate device (Lactate Scout, EKF Diagnostic). Barometric pressure was measured at the site of analysis with the use of the same model of barometer as that used at the sampling site.

The blood gas analyzer was altered from its original specification so that it would function at high altitude. The analyzer's internal barometer was bypassed with a fixed resistor so that the analyzer always read as if the barometric pressure was a constant 450 mm Hg (60.0 kPa), regardless of altitude. This modification was necessary in order to circumvent an inbuilt mechanism that prevented the analysis of samples at a barometric pressure lower than 400 mm Hg (53.3 kPa). To replicate the barometric-pressure correction that the machine would normally apply in its unmodified form, true gas partial-pressure values were obtained by inserting the machine-derived values into Equation 1, shown in Table 1. This calculation is identical to that performed internally by the arterial blood gas analyzer during normal function at lower altitudes.

The subjects' temperatures at the time of sampling were assumed to be the same as the temperature of the blood gas analyzer — namely, 37.0°C (98.6°F). The analyzer was validated in a hypobaric chamber at the equivalent of 4000 m (13,123 ft) and then revalidated in the field, at 5300 m and 6400 m, the altitudes at which measurements of arterial blood gas were performed in this study. Validation involved the analysis of aqueous trilevel quality-control solutions (RapidQC Plus, Bayer HealthCare) with known values of pH, PaO2, and PaCO2. Two-point calibration of the RapidLab 348 gas sensors and electrodes was performed automatically according to the manufacturer's specifications with the use of standard gases and electrolyte solutions, respectively. Each arterial blood sample was analyzed three times, and the mean of these values is reported. Because the pulse oximeters available to us were not calibrated below 70% SaO2, we chose to calculate SaO2 using Equation 2, shown in Table 1. All reported values for SaO2 are calculated values, except for the values for four subjects at an altitude of 5300 m; for these subjects, values obtained by peripheral-pulse oximetry (Onyx 9500, Nonin) are reported owing to an isolated failure of the pH electrode on the blood gas machine, an electrode that was subsequently replaced. All measured and calculated values for SaO2 at an altitude of 5300 m fell within the calibrated range of the pulse oximeter.

The hemoglobin concentration was measured in venous blood collected from subjects in London before the expedition, at the Everest base camp (at 2-week intervals during the expedition), and at Camp 2, with the use of a handheld photometric device (HemoCue Whole Blood Hemoglobin System, HemoCue). Venous samples were obtained at the same time as arterial samples in London, at the Everest base camp, and at Camp 2. For the hemoglobin concentration at Camp 3 and the Balcony, we used the mean of the hemoglobin values obtained at the Everest base camp 9 days before and 8 days after the arterial sample at the Balcony was obtained (Figure 1); these values were used in the calculation of CaO2, bicarbonate concentration, and blood base excess.

The partial pressure of alveolar oxygen (PaO2) at the time of sampling was estimated by applying the alveolar gas equation to the calculated PIO2 (Equations 5 and 6 in Table 1). The resting respiratory exchange ratios necessary for these calculations were obtained for three of the subjects at the South Col of Everest on the day before summiting, with the use of breath-by-breath analysis equipment (MetaMax 3B, Cortex Biophysik).
Results
Collection of Samples

The climbers reached the summit of Mount Everest on the morning of May 23, 2007, after having spent 60 days at an elevation higher than 2500 m (8202 ft). The location, altitude, barometric pressure, and PIO2 for each sampling site are shown in Figure 1. All femoral arterial blood samples were obtained without complications on the first attempt. Ten samples were obtained in London, nine at the Everest base camp, nine at Camp 2, six at Camp 3, and four at 8400 m. The reasons for not obtaining samples were as follows: at the Everest base camp, one subject was unwell; at Camp 2, one subject was unwell; at Camp 3, four subjects were not present when the Sherpa was available to transport the sample; and at the Balcony, two subjects did not reach this altitude, and four subjects were not present when the Sherpa was available to transport the sample. One sample at Camp 2 repeatedly clotted in the arterial blood gas machine, so no data are available for that sample. In all cases, the interval between sampling and analysis was less than 2 hours.
Arterial Blood Gases

Measured PaO2 and hemoglobin values, along with calculated SaO2 and CaO2 values, are shown in Figure 2Figure 2Changes in the Arterial Mean Partial Pressure of Oxygen, Oxygen Saturation, Hemoglobin Concentration, and Oxygen Content in Climbers on Mount Everest.. The CaO2 value at sea level was maintained up to an altitude of 7100 m and fell below baseline only at 8400 m; at this altitude, the mean CaO2 for the four subjects was calculated to be 145.8 ml per liter. Mean PaCO2 values fell with increasing altitude, from 36.6 mm Hg (4.88 kPa) at sea level to 20.4 mm Hg (2.72 kPa) at 5300 m, 18.2 mm Hg (2.43 kPa) at 6400 m, and 16.7 mm Hg (2.23 kPa) at 7100 m; corresponding pH values were 7.40, 7.46, 7.51, and 7.53.

The results of the arterial blood gas analysis and the hemoglobin and lactate concentrations in four subjects at 8400 m are shown in Table 2Table 2Arterial Blood Gas Measurements and Calculated Values for Pulmonary Gas Exchange from Four Subjects at an Altitude of 8400 m, during Descent from the Summit of Mount Everest.. The mean PaO2 and PaCO2 values were 24.6 mm Hg (3.28 kPa) and 13.3 mm Hg (1.77 kPa), respectively. The mean PIO2 value at 8400 m was calculated to be 47.0 mm Hg (6.27 kPa) at the time of arterial sampling. Calculated values for PaO2, resting respiratory exchange ratios, and the alveolar–arterial oxygen difference in four subjects at 8400 m are shown in Table 2. The mean PaO2 and the mean alveolar–arterial oxygen difference were 30.0 mm Hg (4.00 kPa) and 5.4 mm Hg (0.72 kPa), respectively. None of the subjects were considered, on clinical grounds, to have high-altitude pulmonary edema during the study period.
Discussion

These measurements of arterial blood gases and hemoglobin levels in climbers on Mount Everest provide a picture of the pattern and limits of changes in human blood gases in response to hypobaric hypoxia on the earth's highest mountain. Because of adverse weather conditions, we were unable to obtain arterial samples at the summit of Mount Everest as originally planned. Consequently, the samples at the highest altitude were obtained during the descent from the summit. A small shelter was erected at the first safe location, an area known as the Balcony, which is located at an altitude of 8400 m, and the blood sampling took place in this shelter. The values for PaO2 and SaO2 reported here are, to our knowledge, among the lowest ever documented in humans. The results of a study of alveolar breath samples obtained from divers suggest that breathhold divers may have PaO2 levels that are lower than 30 mm Hg (4.0 kPa), but no direct measurements have been reported.11 Similar values have been reported in a study of samples obtained at a high altitude, but in that study, measurements were obtained from subjects who had high-altitude pulmonary edema.12,13

Decreases in PaO2 are broadly proportional to the fall in barometric pressure with increasing altitude, whereas SaO2 is relatively well maintained (in relation to barometric-pressure changes) owing to the characteristics of the oxygen–hemoglobin dissociation curve and the effects of respiratory acclimatization (decreased PaCO2). Increases in the hemoglobin concentration compensate for the fall in SaO2 such that CaO2 is maintained until a person reaches an altitude of at least 7100 m. Thus, changes in CaO2 do not provide an explanation for the significant limitations in individual performance previously reported at these altitudes (a reduction in maximum oxygen consumption of 30 to 35% at 5300 m1,7). CaO2 at 8400 m is significantly lower than that at sea level, and the marked interindividual variability at this altitude is related predominantly to differences in SaO2, probably reflecting a combination of variation in ventilatory acclimatization, hypoxic ventilatory response, hypoxic ventilatory depression, and the alveolar–arterial oxygen difference, as discussed below.

At the highest altitude at which samples were obtained, the subjects had an impressive adaptive response (i.e., acclimatization) to prolonged and extreme environmental hypoxia. Persons who are not acclimatized lose consciousness within 2 to 3 minutes when they are exposed suddenly to levels of ambient hypoxia equivalent to those at altitudes higher than 8534 m (27,999 ft).14 In contrast, our subjects had apparently clear cognition, as evidenced by effective radio communication and, in the case of two of the subjects, the performance of complication-free sampling of arterial blood gases. The absence of obvious neurocognitive abnormalities suggests that cerebral hypoxia was not manifested as a substantial dysfunction at the time of blood sampling. This is of interest in view of the evidence that there is a risk of long-term cognitive deficit and structural neurologic damage from exposure to these extreme altitudes.15-17 Despite chronic hypoxemia, none of the subjects in this study had clinically significant hyperlactatemia (mean lactate concentration, 2.2 mmol per liter at the highest altitude), consistent with findings in resting subjects exposed to hypobaric hypoxia.5 This suggests that anaerobic metabolism does not contribute substantially to energy production at an extreme altitude while a person is at rest. An alternative, or additional, explanation is the possibility of increased lactate use as a fuel source at extreme altitudes.18

We cannot exclude the possibility that the use of supplemental oxygen at and above Camp 3 was a confounding influence on the acclimatization process and thus on PaO2 and PaCO2. Supplemental oxygen benefits climbers subjectively and improves SaO2 in the resting state and during exercise.19 During this study, the safety benefits related to supplemental oxygen were considered to be of overriding importance while the subjects were climbing on Mount Everest.20 We believe that the 20-minute rest period that the subjects had without supplemental oxygen before arterial sampling should have been more than adequate to ensure a washout of supplemental oxygen from the circulation. However, the effects on ventilation of suddenly removing supplemental oxygen at such an altitude are unknown. Climbers who reach the summit of Mount Everest without using supplemental oxygen may have more effective ventilatory acclimatization than those who use supplemental oxygen, and they may therefore have a higher PaO2 while breathing ambient air than do those who choose to use supplemental oxygen. Removing supplemental oxygen in a hypoxic environment is known to trigger two sequential yet variable phenomena. The hypoxic ventilatory response leads to hyperventilation within minutes after exposure to hypoxia and is followed by hypoxic ventilatory depression approximately 10 to 30 minutes after exposure.21 The effect of these opposing responses to hypoxia on the PaO2 and PaCO2 values in this study is difficult to quantify. Interindividual variability in the hypoxic ventilatory response and hypoxic ventilatory depression may account for the variability in arterial blood gas values in our subjects as compared with the results of a study involving subjects in a hypobaric chamber, in which supplemental oxygen was not used immediately before sampling.5

The methods of storage and transportation of the blood samples in this study were used by our group on two previous expeditions to extreme altitudes and were shown to be effective. The time lapse between sampling and analysis was 2 hours or less in all cases. The effect of storing blood in this manner has been described previously22; the partial pressure of oxygen in the blood samples rose approximately 0.75 mm Hg (0.1 kPa) after 2 hours of storage. Our own experiments at sea level have shown a similar mean rise in the partial pressure of oxygen (1.1 mm Hg [0.15 kPa]) in samples of venous blood after 2 hours. Therefore, any effect of the duration of storage and transportation on the reported values would tend to lead to a small overestimation of measured PaO2.

Our findings are consistent with the results of the previous three studies of PaO2 in extreme hypobaric conditions.5-7 The mean measured PaO2 in our study was 24.6 mm Hg (3.28 kPa) at 8400 m, as compared with 30.3 mm Hg (4.04 kPa)5 or 30.6 mm Hg (4.08 KPa)6 at a simulated altitude of 8848 m, and 28.0 mm Hg (3.73 kPa) as estimated by West et al. from an alveolar gas sample obtained at 8848 m.7 The mean PaO2 in our subjects was lower than these values, despite the fact that our subjects were at a slightly higher barometric pressure (lower altitude). The PaCO2 reported in the study by West et al.7 was only 7.5 mm Hg (1.0 kPa), slightly more than half the mean PaCO2 reported in this study (13.3 mm Hg [1.78 kPa]). This finding may be explained by the fact that the subject from whom the alveolar gas sample was collected in the study of West et al.7 was known to have an extremely brisk hypoxic ventilatory response.23 Possible explanations for the differences between the data in this study and the results of previous hypobaric-chamber studies may be related to differences in ascent profiles, activity levels, and the use of supplemental oxygen. In the hypobaric-chamber studies, the subjects were exposed to hypobaric conditions for a period of 37 to 40 days,5,6 as compared with 60 days in this study (Figure 1), and although they underwent periodic exercise tests, activity levels were much lower than those in our subjects, who were climbing to the summit of Everest. Whereas subjects in our study used supplemental oxygen as described, subjects in Operation Everest II were similarly exposed to an elevated fraction of inspired oxygen either because the chamber pressure was increased at night to help them sleep or during the conduct of pulmonary artery catheterization studies.5,24

At an altitude of 8400 m, the mean calculated PaO2 was 30.0 mm Hg (4.00 kPa), and the mean calculated alveolar–arterial oxygen difference was 5.4 mm Hg (0.72 kPa) (Table 2). It is known that the alveolar–arterial oxygen difference decreases as the PIO2 falls.25 Both theoretical considerations and empirical data suggest that the alveolar–arterial oxygen difference should be less than 2 mm Hg (0.27 kPa) under these conditions26; Sutton et al. report a mean alveolar–arterial oxygen difference of 1.5 mm Hg (0.20 kPa) in resting healthy persons at the simulated altitude of 8848 m.5

Hypoxia associated with an increased alveolar–arterial oxygen difference may be attributable to shunting, a ventilation–perfusion mismatch, or a limitation in pulmonary diffusion. We speculate that the relatively high alveolar–arterial oxygen difference in the subjects in this study may be the result of subclinical high-altitude pulmonary edema contributing to both a ventilation–perfusion mismatch and impairment of pulmonary diffusion. An alternative explanation might be disequilibrium in pulmonary alveolar–end-capillary diffusion, which has been shown to occur in conditions of hypobaric hypoxia.27,28 Previous investigators have observed an increased alveolar–arterial oxygen gradient after strenuous exercise in subjects exposed to hypobaric hypoxia,25,29,30 and this may be a key difference between the results of this study and those of previous investigations involving subjects in a hypobaric chamber.

In our study, arterial blood sampling was performed with subjects in the supine position, and this factor may have confounded measurements through mechanisms such as increased basal atelectasis or central fluid shifts that can be detrimental to pulmonary gas exchange. PaO2 has been reported to be inversely related to the alveolar–arterial oxygen difference30; this finding may explain the low PaO2 in Subject 2 (19.1 mm Hg [2.55 kPa]), the subject in the group who had the highest alveolar–arterial oxygen difference. The respiratory exchange ratios in subjects who had just reached the summit of Mount Everest may be higher than those that were measured at a resting steady state the previous day on the South Col at 7950 m. However, such an elevation in respiratory exchange ratios would only serve to increase the alveolar–arterial oxygen difference and increase the significance of these findings. For example, if the respiratory exchange ratio was assumed to be 1.0 in all four subjects at the time of blood sampling, the mean alveolar–arterial oxygen difference would be 9.1 mm Hg (1.21 kPa), instead of 5.4 mm Hg (0.72 kPa).

Tissue hypoxia is a universal phenomenon among persons who are critically ill31 and is often the result of arterial hypoxemia. In conjunction with the initiating factor and the presence of any coexisting condition, hypoxia triggers numerous adaptive and maladaptive systemic responses that remain poorly understood. Defining the limits of hypoxia tolerance is of direct relevance to physicians who care for critically ill patients because many interventions that are aimed at restoring or maintaining cellular oxygenation have proven ineffective or even detrimental. For example, a high PIO2 can have pulmonary toxic effects.32 Moreover among patients with established critical illness, increasing the hemoglobin concentration to increase oxygen carriage may not provide a clinical benefit,33 and a goal-directed elevation of systemic oxygen can be detrimental.34 Useful insights may be gained by examining the biophysiologic responses of healthy persons who are exposed to low levels of environmental oxygen.

In summary, we report field measurements of the partial pressure of oxygen and carbon dioxide, pH, and hemoglobin and lactate concentrations in the arterial blood of humans at extreme altitudes. We speculate that the calculated alveolar–arterial oxygen difference in these subjects suggests a degree of functional limitation in pulmonary diffusion or subclinical pulmonary edema, conditions that may explain why the values for PaO2 are lower than expected.

Drs. Grocott and Martin contributed equally to this article.

Supported by Mr. John Caudwell, BOC Medical (now part of Linde Gas Therapeutics), Eli Lilly, the London Clinic, Smiths Medical, Deltex Medical, and the Rolex Foundation (unrestricted grants), the Association of Anaesthetists of Great Britain and Ireland, the United Kingdom Intensive Care Foundation, and the Sir Halley Stewart Trust. Dr. Martin is a Critical Care Scholar of the London Clinic, and Dr. Levett is a Fellow of the Association of Anaesthetists of Great Britain and Ireland. Some of this work was undertaken at University College London Hospital–University College London Comprehensive Biomedical Research Centre, which received a proportion of funding from the United Kingdom Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. Caudwell Xtreme Everest is a research project coordinated by the Centre for Altitude, Space, and Extreme Environment Medicine, University College London. Membership, roles, and responsibilities of the Caudwell Xtreme Everest Research Group can be found at www.caudwell-xtreme-everest.co.uk/team.

Dr. Grocott reports receiving lecture fees from Eli Lilly and BOC Medical and grant support from BOC Medical, Eli Lilly, and Smiths Medical; Dr. Martin, lecture fees from Siemens; and Dr. McMorrow, grant support from Smiths Medical. No other potential conflict of interest relevant to this article was reported.
Source Information

From the Centre for Altitude, Space, and Extreme Environment Medicine, University College London Institute of Human Health and Performance, London.

Address reprint requests to Dr. Grocott at the Centre for Altitude, Space, and Extreme Environment Medicine, University College London Institute of Human Health and Performance, 1st Fl., Charterhouse Bldg., Archway Campus, Highgate Hill, London N19 5LW, United Kingdom, or at mike.grocott@ucl.ac.uk.

The members of the Caudwell Xtreme Everest Research Group are listed in the Appendix.

We thank the staff of Siemens, in particular Robert Mayall and Steve Carey, for their continual support to us in carrying out these measurements; Pasang Tenzing Sherpa for carrying the samples from the Balcony to Camp 2 in less than 2 hours; the Caudwell Xtreme Everest volunteers who trekked to the Everest base camp; and Tom Hornbein, Erik Swenson, Monty Mythen, and Mervyn Singer for their advice during the preparation of the manuscript.
Appendix

The members of the Caudwell Xtreme Everest Research Group are as follows: Investigators — V. Ahuja, G. Aref-Adib, R. Burnham, A. Chisholm, K. Clarke, D. Coates, M. Coates, D. Cook, M. Cox, S. Dhillon, C. Dougall, P. Doyle, P. Duncan, M. Edsell, L. Edwards, L. Evans, P. Gardiner, M. Grocott, P. Gunning, N. Hart, J. Harrington, J. Harvey, C. Holloway, D. Howard, D. Hurlbut, C. Imray, C. Ince, M. Jonas, J. van der Kaaij, M. Khosravi, N. Kolfschoten, D. Levett, H. Luery, A. Luks, D. Martin, R. McMorrow, P. Meale, K. Mitchell, H. Montgomery, G. Morgan, J. Morgan, A. Murray, M. Mythen, S. Newman, M. O'Dwyer, J. Pate, T. Plant, M. Pun, P. Richards, A. Richardson, G. Rodway, J. Simpson, C. Stroud, M. Stroud, J. Stygal, B. Symons, P. Szawarski, A. Van Tulleken, C. Van Tulleken, A. Vercueil, L. Wandrag, M. Wilson, J. Windsor; Scientific Advisory Group — B. Basnyat, C. Clarke, T. Hornbein, J. Milledge, J. West.

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Several trials have shown that intensive glucose control in patients with type 2 diabetes mellitus reduces the progression of microvascular disease,1,2 but the effect on macrovascular complications remains uncertain. In epidemiologic studies, the association between glucose control and cardiovascular disease has not been consistent.3-6 Small short-term trials have suggested either benefit or adverse effects.7,8

Two recent studies, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial (ClinicalTrials.gov number, NCT00145925)9 and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (NCT00000620),10 reported no significant decrease in cardiovascular events with intensive glucose control. The ACCORD trial ended its intensive therapy early, after 3.5 years, because of a significant increase in deaths in the intensive-therapy group. The primary goal of the Veterans Affairs Diabetes Trial (VADT) was to compare the effects of intensive and standard glucose control on cardiovascular events.
Methods
Study Design

The design of our open-label study targeting patients with poorly controlled type 2 diabetes has been reported previously.11 Selection criteria included an inadequate response to maximal doses of an oral agent or insulin therapy. Exclusion criteria included a glycated hemoglobin level of less than 7.5%, the occurrence of a cardiovascular event during the previous 6 months, advanced congestive heart failure, severe angina, a life expectancy of less than 7 years, a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 40, a serum creatinine level of more than 1.6 mg per deciliter (141 μmol per liter), and an alanine aminotransferase level of more than three times the upper limit of the normal range.11

The study was sponsored by the Veterans Affairs Cooperative Studies Program. Medications and financial support were provided by Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, Roche, Kos Pharmaceuticals, and Amylin. These companies had no role in the design of the study, in the accrual or analysis of the data, or in the preparation of the manuscript. All authors vouch for the accuracy and completeness of the data and the analysis.

Protocol and consent forms were approved by the institutional review board at each of the 20 participating sites. All patients provided written informed consent. An independent data and safety monitoring committee whose members were aware of study-group assignments monitored safety and efficacy.
Treatment Protocol

Patients were randomly assigned with the use of a permuted-block design with a block size of six and stratified according to study site, the previous occurrence of a macrovascular event, and current insulin use. The randomization codes were generated by the study's biostatistician at the Hines Cooperative Studies Program Coordinating Center. Study sites did not have access to the codes. In both study groups, patients with a BMI of 27 or more were started on two oral agents, metformin plus rosiglitazone; those with a BMI of less than 27 were started on glimepiride plus rosiglitazone. Patients in the intensive-therapy group were started on maximal doses, and those in the standard-therapy group were started on half the maximal doses. Before any change in oral medications, insulin was added for patients in the intensive-therapy group who did not achieve a glycated hemoglobin level of less than 6% and for those in the standard-therapy group with a level of less than 9%. Subsequent changes in medication were determined according to protocol guidelines and local assessment. The guidelines allowed for the use of any approved drug at the discretion of the investigator. The goal for glycated hemoglobin levels was an absolute reduction of 1.5 percentage points in the intensive-therapy group, as compared with the standard-therapy group.

Other modifiable cardiovascular risk factors were treated identically in the two study groups. Treatment guidelines (based on recommendations of the American Diabetes Association, which were updated as necessary) for blood pressure and lipid control, as well as for dietary, exercise, and diabetes education, were provided to all patients.12 All patients were prescribed aspirin and a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) unless contraindicated.
Primary and Secondary Outcomes

The primary outcome was the time to the first occurrence of any one of a composite of cardiovascular events, adjudicated by an end-point committee that was unaware of assignments to study groups. The cardiovascular events were documented myocardial infarction; stroke; death from cardiovascular causes; new or worsening congestive heart failure; surgical intervention for cardiac, cerebrovascular, or peripheral vascular disease; inoperable coronary artery disease; and amputation for ischemic gangrene.

Secondary cardiovascular outcomes included new or worsening angina, new transient ischemic attacks, new intermittent claudication, new critical limb ischemia, and death from any cause. Secondary outcomes also included microvascular complications (retinopathy, nephropathy, and neuropathy). Adverse events, including hypoglycemia, were monitored.
Microvascular and Neuropathy Outcomes

Patients underwent a standard annual ophthalmologic examination. Stereo seven-field fundus photographs were obtained at baseline and at 5 years by certified photographers in 17 participating hospitals.13,14 The 23-point Early Treatment Diabetic Retinopathy Study grading scale was used to define progression to new proliferative diabetic retinopathy.15 The progression of retinopathy was defined as a 2-point increase on the scale. New, clinically important macular edema was defined according to standards reported previously.16 The glomerular filtration rate (GFR) was estimated on the basis of serum creatinine levels.17 Severe nephropathy was defined as a doubling of the serum creatinine level, a creatinine level of more than 3 mg per deciliter (265 μmol per liter), or a GFR of less than 15 ml per minute. The progression of albuminuria was defined as an increase of albuminuria for at least two successive yearly visits without reversion to an improved level. New neuropathy was assessed in a complete annual physical examination. Mononeuropathies were defined as mononeuropathy, mononeuropathy multiplex, or femoral neuropathy. Peripheral neuropathies were defined as radiculoneuropathy, polyneuropathy, diabetic amyotrophy, or neuropathic ulcer. Autonomic neuropathies were defined as symptomatic orthostatic hypotension, gastroparesis, neurogenic bladder, or diabetic diarrhea. The type of neuropathy was defined as the first outcome that was reached.
Statistical Analysis

The planned sample size of 1700 patients provided a power of 86% to detect a relative difference of 21% in the rate of the composite cardiovascular outcome (40.0% in the standard-therapy group vs. 31.6% in the intensive-therapy group), assuming no difference until the third year, 2 years of data accrual, 5 years of follow-up, a dropout rate of 5%, and a two-sided alpha of 0.05, adjusted for seven interim analyses with the use of O'Brien–Fleming boundaries.18,19 The expected number of events was 684. The 6-year event rate of 40% in the standard-therapy group was derived from the results of the Veterans Affairs Diabetes Feasibility Trial.8

Prespecified subgroups included patients who had received insulin therapy at baseline and those who had already had a cardiovascular event. Subgroups that were not prespecified (e.g., according to age, ethnic background, and duration of disease) are not reported here. All analyses were based on the intention-to-treat principle. Survival analysis compared the time from randomization to the occurrence of the first primary outcome. Data from patients without an event were censored at the date of withdrawal from the study or the final follow-up visit. Deaths occurring after withdrawal from the study were included in the analysis.

Kaplan–Meier survival curves were generated by the product-limit method. Intergroup differences were evaluated with the use of the log-rank test. The Cox proportional-hazards model was used to calculate estimates of relative risk and 95% confidence intervals for the two study groups. The heterogeneity of treatment effects in prespecified subgroups was assessed by including interaction terms in Cox models. The chi-square test was used to analyze differences in proportions unless events were rare, such as progression of nephropathy and retinopathy, in which case Fisher's exact test was used. Data are expressed as means and standard deviations or as medians with interquartile ranges when specified. All reported P values are two-sided and have not been adjusted for multiple comparisons. Because of the interim analyses, the critical value for statistical significance of the primary outcome was 0.0357.
Results
Patients

From December 1, 2000, to May 30, 2003, a total of 1791 patients were enrolled in the study, with follow-up ending on May 30, 2008 (Figure 1Figure 1Enrollment and Outcomes.). The main reasons for exclusion were that patients had low glycated hemoglobin levels (34% of patients), were not receiving a maximal dose of an oral antidiabetic medication or insulin (16%), did not want to participate (12%), or had a high serum creatinine level (8%). Baseline and follow-up data are shown in Table 1Table 1Characteristics of the Patients at Baseline and Follow-up.. No significant differences in risk factors at baseline or at follow-up were seen between the two groups, except for weight changes at follow-up. The mean age of patients was 60.4 years, and diabetes had been diagnosed a mean of 11.5 years earlier. The mean BMI was 31.3. The mean glycated hemoglobin level at baseline was 9.4%. Hypertension (which was defined as current treatment for hypertension or a blood pressure of 140/90 mm Hg or more) was present in 72% of patients, and 40% had already had a cardiovascular event. A history of microvascular complications was reported in 62% of the patients. At baseline, 52% of the patients were receiving insulin.

The mean baseline blood pressure was 132/76 mm Hg in the two groups. After 6 years, for patients who were still in follow-up, the mean blood pressure was 125/69 mm Hg in the standard-therapy group and 127/68 mm Hg in the intensive-therapy group. In both groups, mean lipid levels improved during the study, and levels of low-density lipoprotein cholesterol decreased to 80 mg per deciliter (2.1 mmol per liter). Levels of high-density lipoprotein (HDL) cholesterol increased to 41 mg per deciliter (1.1 mmol per liter) in the standard-therapy group and to 40 mg per deciliter (1.0 mmol per liter) in the intensive-therapy group. Levels of triglycerides decreased to 159 mg per deciliter (1.79 mmol per liter) in the standard-therapy group and to 151 mg per deciliter (1.70 mmol per liter) in the intensive-therapy group. The use of antiplatelet drugs increased to 91% and 94% of patients in the two groups, respectively, and statin use increased to 83% and 86% of patients, respectively.16 Weight and BMI were significantly greater (by 9 lb [4 kg] and 1.5, respectively; P=0.01) in the intensive-therapy group after treatment.

At 3 months, median glycated hemoglobin levels had decreased in both groups and had stabilized at 6 months, with a level of 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. This result achieved the prespecified goal of an absolute between-group difference of 1.5 percentage points (Figure 2Figure 2Changes in Median Glycated Hemoglobin Levels from Baseline through 78 Months.). No significant benefit in the time to the first occurrence of a cardiovascular event was observed in the intensive-therapy group (hazard ratio, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14) (Figure 3AFigure 3Kaplan–Meier Curves for the Time until the First Occurrence of a Primary or Secondary Outcome.). Both groups had fewer events than predicted. The predicted event rate was 40.0% in the standard-therapy group and 31.6% in the intensive-therapy group, a relative reduction of 21.0%. The observed event rate was 33.5% in the standard-therapy group and 29.5% in the intensive-therapy group, a relative reduction of 11.9%. There was no evidence that the effect of treatment varied according to either insulin status at baseline or the previous occurrence of a cardiovascular event (P=0.37 and P=0.92, respectively).

There were no significant differences in individual components of the primary and secondary outcomes (Appendix 1 and Appendix 2, respectively, in the Supplementary Appendix, available with the full text of this article at NEJM.org). There was no significant difference in the time to death from cardiovascular causes (P=0.26) (Figure 3B). No significant differences in the rate of deaths from cardiovascular causes were seen in the two groups. (The causes of 33 deaths from cardiovascular causes in the standard-therapy group and 40 deaths in the intensive-therapy group are listed in Appendix 3 in the Supplementary Appendix.) In the intensive-therapy group, the number of sudden deaths (11 deaths) was nearly three times the number in the standard-therapy group (4 deaths, P=0.08).

There were 95 deaths from any cause in the standard-therapy group and 102 in the intensive-therapy group (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62) (Figure 3C). Major causes of death from noncardiovascular causes are listed in Appendix 4 in the Supplementary Appendix. No significant differences were seen in any category. The most common adverse event was hypoglycemia, with significantly more episodes in the intensive-therapy group than in the standard-therapy group in every category (P<0.001) (Table 2Table 2Hypoglycemic Episodes.). Other events meeting the criteria of severe adverse events are listed in Appendix 4 in the Supplementary Appendix. More patients in the intensive-therapy group had at least one serious adverse event (24.1%) than in the standard-therapy group (17.6%, P=0.05). Dyspnea was the most common specified serious adverse event and was more frequent in the intensive-therapy group (P=0.006).
Microvascular Results

There were no significant differences between the two study groups in the number of new eye procedures (Table 3Table 3 Microvascular Outcomes. ). The cumulative rates of events in all patients, including those who had undergone eye procedures at baseline, did not differ significantly. Fundus photographs showed no significant differences in progression to proliferative diabetic retinopathy (P=0.27) or in progression to clinically important macular edema (P=0.31). There was a nonsignificant trend toward a beneficial effect in the intensive-therapy group with respect to diabetic retinopathy, with an increased incidence of at least two steps in severity in the standard-therapy group (P=0.07). The between-group difference in new onset of retinopathy was not significant (P=0.27).

The GFR declined to 76 ml per minute by year 6 (P<0.001) with no difference between the two study groups (P=0.36). Severe renal changes were unaffected by treatment (P=0.35). Any worsening of albumin excretion was greater in the standard-therapy group (P = 0.01); progression to macroalbuminuria was also significant (P = 0.04).

There was a nonsignificant increase in autonomic neuropathy in the intensive-therapy group (P=0.07). No other significant changes in neuropathy were seen.
Discussion

The major cause of death and complications in patients with type 2 diabetes is cardiovascular disease. More than 60% of all patients with type 2 diabetes die of cardiovascular disease, and an even greater percentage have serious complications. The prevalence of vascular disease, hypertension, dyslipidemia, and other abnormalities is very high, and the consequences of these abnormalities are burdensome to patients, their families, and society.20

Interventions such as lifestyle changes, control of blood pressure and lipids, and antiplatelet therapy can reduce the development, progression, and complications associated with type 2 diabetes.21 Glucose control may reduce microvascular complications, but not cardiovascular complications. Even with microvascular complications, blood-pressure control has a greater effect than glucose control. 22 In patients with advanced type 2 diabetes, the unanswered question is whether glucose control independently reduces cardiovascular complications.

Population surveys, cross-sectional studies, and short-term intervention trials have produced mixed results in attempts to answer this question.3-8 The United Kingdom Prospective Diabetes Study (UKPDS) showed a nonsignificant trend toward improvement in the rate of myocardial infarction (P=0.052) in patients with newly diagnosed disease, but the trial was complicated by less-than-strict blood-pressure and lipid control, according to current standards.1,22 Nevertheless, the trend was accepted by many observers as evidence of the importance of glucose control for macrovascular complications.

The Diabetes Control and Complications Trial (DCCT) did not show a significant reduction in cardiovascular events with intensive control in young patients with type 1 diabetes,2 but a follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, showed a delayed benefit.23 Ten years after both groups reached similar glycated hemoglobin levels, the patients in the previous intensive-therapy group had significantly fewer cardiovascular events than those in the standard-therapy group.

Similar results were seen in the 10-year follow-up of the UKPDS.24 One year after the end of the trial, no significant difference in glycated hemoglobin levels was present. Despite this finding, in the original intensive-therapy group, there was a reduction in the risk of microvascular complications (15%, P=0.01), of any diabetes-related outcome (9%, P=0.04), of myocardial infarction (15%, P=0.01), and of death from any cause (13%, P=0.007). This delayed effect may have been associated with the cumulative effects of hyperglycemia.

Our study, along with the ADVANCE and ACCORD studies, examined different populations with different approaches and came to similar conclusions. Intensive glucose control did not reduce cardiovascular events in patients with previously diagnosed type 2 diabetes. The ACCORD study was terminated at 3.5 years because of increased mortality in the intensive-therapy group. The ADVANCE study showed a reduction in the progression of albuminuria, but there were no changes in the rates of severe nephropathy, retinopathy, or cardiovascular events.

The mean age of patients in the ACCORD study was 62 years, and the duration of diabetes was 10 years, with 35% of patients receiving insulin at baseline. The mean age in our study was 60 years, with 52% of patients receiving insulin and the remainder receiving a maximal dose of an oral agent; diabetes had been diagnosed a mean of 11.5 years earlier. The ADVANCE study had an older population (mean, 66 years) with a shorter disease duration of 8 years and 1.5% of patients receiving insulin at baseline.

In the three studies, baseline glycated hemoglobin levels were 7.2% in the ADVANCE study, 8.1% in the ACCORD study, and 9.4% in our study. After intensive therapy, glycated hemoglobin levels were 6.4% in the ACCORD and ADVANCE studies and 6.9% in our study; after standard therapy, the values were 7.5%, 7.0%, and 8.4%, respectively. None of these studies showed a decrease in cardiovascular events. The rates of hypoglycemia and weight gain were greater in the intensive-therapy group in all three trials.

In our study, we followed a population of veterans for up to 7.5 years (median, 5.6 years). Cardiovascular risk factors were controlled, and the between-group difference in glycated hemoglobin levels was maintained.25,26 Microvascular complications were minimally affected by intensive glucose control. No significant differences in retinopathy, major nephropathy, or neuropathy were seen. A significant reduction (P = 0.01) in any worsening of albumin excretion was observed in the intensive-therapy group; progression to macroalbuminuria was also significant (P = 0.04). Overall, the benefit of decreasing the glycated hemoglobin level from 8.4% to 6.9% appeared to be minimal, except in the progression of albuminuria.

Our study had several limitations. Since we were studying veterans, the patients were predominantly men, and extrapolation of our findings to women must be done with caution. Changes in therapeutic agents have occurred since the design of our protocol. The protocol specified that any approved drug could be used, but the availability of new agents was limited. The study was designed to limit the effect of differences in agents used, but it remains possible that newer agents might have different effects. Since studies with intensive control of risk factors were not available at the time of the protocol development, the study may have been underpowered. This concern is lessened by the very similar results in the ACCORD and ADVANCE studies.9,10

Such factors as levels of HDL cholesterol, weight gain, systolic blood pressure, and pharmacologic agents could play a role in the observed lack of benefit of intensive glucose control and need to be examined in detail. Another possibility is a delayed benefit of intensive control, as seen at the 10-year follow-up in the DCCT–EDIC and UKPDS studies.

Nevertheless, the results of this and other studies do not indicate that intensive glucose control in this population decreased the rate of cardiovascular events. In addition, it appears that intensive glucose control had minimal effects on hard microvascular complications (severe renal changes, decreased GFR, laser treatment, cataract extraction, vitrectomy, and new neuropathy) during a period of 5 to 6 years. Intensive glycemic control earlier in the disease course may produce benefit, especially if severe hypoglycemia is avoided. For now, appropriate management of hypertension, dyslipidemia, and other cardiovascular risk factors appears to be the most effective approach to preventing cardiovascular morbidity and mortality.

This article (10.1056/NEJMoa0808431) was published on December 17, 2008, and was last updated on September 2, 2009, at NEJM.org.

Supported by the Veterans Affairs Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development; the American Diabetes Association; and the National Eye Institute. Pharmaceutical and other supplies and financial assistance were provided by GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Amylin, and Kos Pharmaceuticals.

Dr. Duckworth reports receiving consulting fees from Novo Nordisk, GlaxoSmithKline, and Caremark and lecture fees from Sanofi-Aventis; Dr. Abraira, receiving lecture fees from Sanofi-Aventis and Takeda; Dr. Reaven, receiving consulting and lecture fees from Takeda Pharmaceuticals and grant support from Takeda Pharmaceuticals and Amylin and having an equity interest in Merck, Pfizer, Eli Lilly, and Johnson & Johnson; Dr. Zieve, receiving lecture fees from GlaxoSmithKline and Kos Pharmaceuticals and grant support from Kos Pharmaceuticals, GlaxoSmithKline, Hoffmann–La Roche, Amylin Pharmaceuticals, and Novo Nordisk; Dr. Marks, receiving consulting fees from Eli Lilly and Novo Nordisk, lecture fees from Pfizer, Merck, and Takeda, and grant support from Eli Lilly, Mannkind, Merck, and Pfizer; and Dr. Davis, receiving consulting fees and grant support from Sanofi-Aventis and Amylin and lecture fees from Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
Source Information

From the Phoenix Veterans Affairs (VA) Health Care Center, Phoenix, AZ (W.D., P.D.R.); Miami VA Medical Center, Miami (C.A., J.M.); Hines VA Cooperative Studies Program Coordinating Center (T.M., D.R., M.M., M.E.V., W.G.H.) and Hines VA Hospital (N.E.) — both in Hines, IL; Hunter Holmes McGuire VA Medical Center, Richmond, VA (F.J.Z.); Tennessee Valley Health Care System, Nashville (S.N.D.); VA Ann Arbor Healthcare System, Ann Arbor, MI (R.H.); VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM (S.R.W.); Southern Arizona VA Health Care System, Tucson (S.G.); and the Cooperative Studies Program Central Office, VA Office of Research and Development, Washington, DC (G.D.H.).

Address reprint requests to Dr. Duckworth at the Phoenix VA Health Care System, 650 E. Indian School Rd., Phoenix, AZ 85012, or at william.duckworth@va.gov.

Investigators in the Veterans Affairs Diabetes Trial (VADT) are listed in the Appendix.

We thank coordinators Susan Collier and Christina Paul for their help in the preparation of the manuscript and Rebecca Miller for assistance in the preparation of the final draft and for her consistent support throughout the study.
Appendix

The following persons participated in the VADT study: Study Cochairs: C. Abraira, Miami Veterans Affairs (VA) Medical Center, Miami; W.C. Duckworth, Carl T. Hayden VA Medical Center, Phoenix, AZ. Miami Office: C. Paul, D. Arca, L. Cason, R. Martinez Zolotor, L. Williams. Phoenix Office: S.L. Collier, N. Ahmed, A. Boyd. Hines VA Cooperative Studies Program (CSP) Coordinating Center: D. Reda, director; T. Moritz, study biostatistician; R. Anderson, subprotocol biostatistician; M.E. Vitek, quality assurance specialist; T. Paine, national study coordinator; L. Thottapurathu, statistical programmer; P. Luo, subprotocol statistical programmer; K. Bukowski, database programmer; D. Motyka, database programmer; V. Barillas, statistical assistant; R. Brown, statistical assistant; B. Christine, statistical assistant; L. Anfinsen, statistical programmer; M. Biondic, database programmer; R. Havlicek, statistical assistant; J. Kubal, national study coordinator, statistical assistant; M. McAuliffe, statistical assistant; M. McCarren, study biostatistician; M. Rachelle, statistical assistant; L. Rose, national study coordinator; J. Sacks, subprotocol biostatistician; T. Sindowski, statistical assistant; J. Thomas, national study coordinator; C. Zahora, national study coordinator. CSP Coordinating Center, Albuquerque, NM: M.R. Sather, director; S. Warren, study pharmacist; J. Day, pharmaceutical project manager; J. Haroldson, study pharmacist. Executive Committee: C. Abraira, W. Duckworth, S.N. Davis, N. Emanuele, S. Goldman, R. Hayward, J. Marks, T. Moritz, P. Reaven, D. Reda, S. Warren, F. Zieve, W. Wendell, J. Haroldson, P. Harper, W.G. Henderson, R.R. Henry, M.S. Kirkman, M. McCarren, J. Sacks. Data and Safety Monitoring Committee: J. Gavin, E. Chew, B. Howard, T. Karrison, I.V. Pacold, D. Seigel, F. Vinicor, B. Massie, consultant. End-Points Committee: S. Goldman, S. Rapcsak, G. Sethi, M. Sharon, H. Thai, K. Zadina, J. Christensen, D. Morrison, P. Spooner, A. Westerband. Consultants: B. Materson, E. Brinton, R. Klein, J.A. Colwell, E.J. Schaefer, C.S. Gass. Central Laboratories: C-peptide: D.A. Ehrmann, P. Rue; Biochemistry: E.J. Schaefer, J.R. McNamara; MAVERIC Core Laboratory: M. Brophy, D. Humphries, D. Govan, L. McDonnell, L. Carlton, Y. Weng; Cost-Effectiveness: R.A. Hayward, S. Krein; Electrocardiography: S. Goldman, K. Zadina; Fundus Photograph Reading Center: M. Davis, director; K. Glander, project coordinator.

The following investigators and sites participated in the study: Charleston, SC: J. Soule, S. Caulder, C. Pittman, O. Alston, R.K. Mayfield, G. Moffitt, J. Sagel, F. Sanacor, E. Ganaway; Miami: J. Marks, L. Okur, L. Jones, H. Florez, D. Pfeifer, L. Samos, A.L. Taylor; Lyons/East Orange, NJ: M.B. Zimering, A. Sama, F. Rosenberg, H. Garcia, N. Ertel, L. Pogach, J.J. Shin, F. Caldarella, C. Carseli, M. Shah; Fresno, CA: P. Ginier, G. Arakel, Y. Fu, D. Tayloe, J.E. Allen, E. Fox, P.G. Hensley; Hines, IL: N. Emanuele, K. Kahsen, P. Linnerud, L. Agrawal, N. Azad; Houston: M. Marcelli, G.R. Cunningham, N.M. Nichols, E. Cordero, R. Hijazi, F. Roman, P. Datta, M. Garcia Touza; Indianapolis: A. Lteif, K.L. Moore, C. Lazar-Robinson, S. Gupta, M.S. Kirkman, M. Mendez, Z. Haider, L. Risley; Lexington, KY: D. Karounos, L. Barber, J. Hibbard, J.W. Anderson, L.R. Reynolds, J. Carlsen, R.W. Collins, A. Ehtisham; Long Beach, CA: M.L. Kashyap, B. Matheus, T. Rahbarnia, A.N. Vo, N. Downey, L. Fox, R.M. Gonzales, C.D. Meyers, S. Tavintharan; Minneapolis: F.Q. Nuttall, L. Cupersmith, K. Dardick, L. Kollman, A. Georgopoulos, C. Niewoehner; Nashville: S.N. Davis, P. Harper, D. Davis, J. Devin, A. Marney, J. Passyn-Dunn, J. Perkins, J. Stafford, A. Powers, L. Balch, P. Harris; Omaha, NE: R.J. Anderson, D. Dunning, S. Ludwig, M. Vogel, C. DeSouza, R. Ecklund, S. Doran, C. Korolchuk, M. McElmeel, S. Wagstaff; Phoenix, AZ: P. Reaven, B. Solie, J. Matchette, C. Meyer, S. Vela, N. Aslam, E. Brinton, J. Clark, A. Domb, L. McDonald, L. Shurtz; Pittsburgh: R.H. Rao, J.N. Beattie, C. Franko, F.R. DeRubertis, D. Kelly, M. Maser, J. Paul; Richmond, VA: F. Zieve, S.J. Clark, A. Grimsdale, S. Fredrickson, J. Levy, D. Schroeder; Salem, VA: A. Iranmanesh, B. Dunn, D. Arsura, C. Kovesdy, S. Hanna, A. Iranmanesh, C. Florow, F. Remandaban, E. Smith; San Diego, CA: R.R. Henry, M. Keller, V. Aroda, C. Choe, S. Edelman, A. Gasper, D. MaFong, S. Mudaliar, D. Oh, R. Bandukwala, A. Chang, S. Chaudhary, S. Chinnapongse, L. Christiansen, N. Chu, D. Kim, M. Lupo, C. Manju, R. Plodkowski, R. Sathyaprakash, J. Wilson, J. Yu, G. Macaraeg, S. Tornes; San Antonio, TX: R. DeFronzo, L. Johnson, K. Cusi, D. Tripathy, M. Bajaj, J. Blodgett, S. Kayshup, M.H. Vasquez, B. Walz, T. Weaver; San Juan, Puerto Rico: J. Benabe, Z. Mercado, B. Padilla, J. Serrano-Rodriguez, C. Rosado, E. Mejias, T. Tejera, C. Geldrez, E. Gonzalez-Melendez, M. Natal, M. Rios Jimenez; Tucson, AZ: J.H. Shah, W.S. Wendel, L. Scott, L.A. Gurnsey, F.A. Kwiecinski, T. Boyden, M.G. Goldschmid, V. Easton.

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