Boosting enrollment in neurology trials with Local Identification and Outreach Networks (LIONs).

OBJECTIVE: Our purpose was to develop a geographically localized, multi-institution strategy for improving enrolment in a trial of secondary stroke prevention. METHODS: We invited 11 Connecticut hospitals to participate in a project named the Local Identification and Outreach Network (LION). Each hospital provided the names of patients with stroke or TIA, identified from electronic admission or discharge logs, to researchers at a central coordinating center. After obtaining permission from personal physicians, researchers contacted each patient to describe the study, screen for eligibility, and set up a home visit for consent. Researchers traveled throughout the state to enroll and follow participants. Outside the LION, investigators identified trial participants using conventional recruitment strategies. We compared recruitment success for the LION and other sites using data from January 1, 2005, through June 30, 2007. RESULTS: The average monthly randomization rate from the LION was 4.0 participants, compared with 0.46 at 104 other Insulin Resistance Intervention after Stroke (IRIS) sites. The LION randomized on average 1.52/1,000 beds/month, compared with 0.76/1,000 beds/month at other IRIS sites (p = 0.03). The average cost to randomize and follow one participant was $8,697 for the LION, compared with $7,198 for other sites. CONCLUSION: A geographically based network of institutions, served by a central coordinating center, randomized substantially more patients per month compared with sites outside of the network. The high enrollment rate was a result of surveillance at multiple institutions and greater productivity at each institution. Although the cost per patient was higher for the network, compared with nonnetwork sites, cost savings could result from more rapid completion of research.

Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke.

OBJECTIVES: To determine the prevalence of impaired insulin sensitivity among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. METHODS: Eligible subjects were nondiabetic men and women over age 45 years who were hospitalized with a TIA or ischemic stroke. To measure insulin sensitivity, subjects underwent an oral glucose tolerance test between 2 and 6 months after their event. Impaired insulin sensitivity was defined by a value of < or =2.5 on the Composite Insulin Sensitivity Index derived from insulin and glucose values during the test. RESULTS: Between July 2000 and June 2001, we identified 177 eligible patients, among whom 105 declined to participate and 72 enrolled. The median age of participants was 71 years and 46 (64%) were men. The baseline event was stroke for 57 subjects (79%). A history of myocardial infarction (MI) was reported by 14 subjects (19%), and 16 (22%) were obese (body mass index > 30). Fasting glucose was normal (<110 mg/dL) for 58 (80%) participants and impaired (110 to 125 mg/dL) for 14 (20%). Among 72 participants, the median insulin sensitivity index value was 2.6 (range 0.9 to 10.2). The prevalence of impaired insulin sensitivity was 36 of 72 (50%, 95% CI 38% to 62%). Impaired insulin sensitivity was more prevalent among younger patients and patients with obesity, lacunar stroke etiology, and disability (Rankin grade >1). CONCLUSION: Impaired insulin sensitivity is highly prevalent among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. This finding has important therapeutic implications if treatment to improve insulin sensitivity is shown to reduce risk for subsequent stroke and heart disease.

Use of Ephedra-containing products and risk for hemorrhagic stroke.

This case-control study examined the association between Ephedra use and risk for hemorrhagic stroke. For use of Ephedra at any dose during the 3 days before the stroke, the adjusted OR was 1.00 (95% CI 0.32 to 3.11). For daily doses of < or =32 mg/day, the OR was 0.13 (95% CI 0.01 to 1.54), and for >32 mg/day, the OR was 3.59 (95% CI 0.70 to 18.35). Ephedra is not associated with increased risk for hemorrhagic stroke, except possibly at higher doses.

Insulin resistance and risk for stroke.

BACKGROUND AND PURPOSE: Resistance to insulin-mediated glucose uptake by peripheral tissues is a cardinal defect in type 2 diabetes mellitus. Insulin resistance is also common among nondiabetic individuals, and may be an important risk factor for stroke in both populations. The authors review the definition, epidemiology, and treatment of insulin resistance. METHODS: The authors searched Medline (1977-2001) and reviewed bibliographies to identify pertinent English-language publications. RESULTS: Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. The principal pathophysiologic defect is impaired intracellular signaling in muscle tissue leading to defective glycogen synthesis. Insulin resistance is associated with numerous metabolic, hematologic, and cellular events that promote atherosclerosis and coagulation. The association between insulin resistance and risk for stroke has been examined in four case-control studies and five prospective observational cohort studies. Six of the nine studies are methodologically sound and provide evidence that insulin resistance is associated with risk for stroke. CONCLUSION: Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.

A clinical trial of estrogen-replacement therapy after ischemic stroke.

BACKGROUND: Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of estradiol-17beta per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. RESULTS: During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Estrogen therapy did not reduce the risk of death alone (relative risk, 1.2; 95 percent confidence interval, 0.8 to 1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk, 2.9; 95 percent confidence interval, 0.9 to 9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits. CONCLUSIONS: Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.

A quality-of-life instrument for young hemorrhagic stroke patients.

BACKGROUND AND PURPOSE: Hemorrhagic stroke has a high initial mortality rate. While survivors often recover motor function, many experience significant changes in their quality of life (QOL). Available outcome measures assess neurological impairment, disability, or handicap, yet often inadequately characterize the full impact of a stroke on patients' lives. In this study, we develop and validate a QOL instrument specific for young patients with hemorrhagic strokes. METHODS: Methodological guidelines for instrument development were initially established. Based on the content of 40 open-ended patient interviews, a 54-item instrument (HSQuale) was developed. The reliability (test-retest and internal consistency) and validity (content and construct) of HSQuale were assessed in another 71 patients (18 to 49 years of age, 63% women, 77% white), at 1 year after their hemorrhagic stroke. Comparisons were made between HSQuale and other commonly used outcome measures. RESULTS: HSQuale demonstrated reproducibility (test-retest kappa, 0.40 to 0.96) and internal consistency (Cronbach alpha >/=0.80 for 5 of 7 domains). HSQuale scores had broad frequency distributions (

Social support as a buffer to the psychological impact of stressful life events in women with breast cancer.

BACKGROUND: Three theoretical models by which social support may influence the impact of stressful life events on cancer patients' psychological state were tested: 1) the additive model, in which social support and stressful life events each directly influence cancer patients' adjustment, irrespective of the magnitude of the other; 2) the buffering hypothesis, in which stressful events occurring in the presence of social support should produce less distress than if they occur in its absence; and 3) both additive and buffering models. METHODS: One hundred seventy-nine patients who had Stage II breast cancer (median age, 56 yrs; 68% disease free), treated a mean of 6.8 years since entry to Cancer and Leukemia Group B (CALGB) 8541, were interviewed by telephone concerning their psychosocial adjustment. The following measures were used: Medical Outcome Study Social Support Survey (MOS-SSS), Life Experience Survey (LES) a measure of stressful life events within the past 12 months, European Organization for Research on the Treatment of Cancer (EORTC QLQ-C30) a measure of quality of life, Mental Health Inventory (MHI), and the Systems of Belief Inventory (SBI) a measure of spiritual and religious involvement. RESULTS: Hierarchical regression analyses revealed that less than excellent levels of social support (P < 0.01), greater negative impact of LES fateful life events (e.g., death of family member) (P < 0.05), personal illness or injury (P < 0.05), and all other negative life events in the past year (< 4; P < 0.01) were significant predictors of greater MHI psychological distress, in addition to being divorced or separated (P < 0.001), and more recently treated for cancer on CALGB 8541 (P < 0.05). The interaction of LES scores with MOS-SSS or SBI social support, used to test the buffering hypothesis, did not significantly improve the prediction of MHI psychological distress. CONCLUSIONS: The results supported the additive model, with both stressful life events and social support independently and significantly affecting patients' emotional state. However, the level of social support needed to be very high to reduce the likelihood of severe psychological distress.

Phenylpropanolamine and the risk of hemorrhagic stroke.

BACKGROUND: Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study. METHODS: Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient. RESULTS: There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants. CONCLUSIONS: The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Blood pressure exceeding national guidelines among women after stroke.

BACKGROUND AND PURPOSE: After a transient ischemic attack or stroke, the risk for recurrence may be reduced by treatment of hypertension. The purpose of this study was to determine how commonly blood pressure exceeds national guidelines among patients who have had one of these events. METHODS: Subjects were 644 women participating in a randomized trial of estrogen for secondary stroke prevention. We measured blood pressure 1 month after the stroke or TIA while patients were under the care of their personal physicians. Among 536 patients, a second measure was made at an average of 2.9 years after the first. RESULTS: The mean age of participants was 71 years, and 73% reported a history of hypertension. At baseline, only 44% (280/644) of the women had blood pressure values within national guidelines (<140/90 mm Hg). With separate guidelines used for diabetics (<130/85 mm Hg) and nondiabetics (<140/90 mm Hg), the proportions of women within the guidelines were 27% and 44%, respectively. Overall, 39% of patients were within the diabetes-adjusted guidelines. Among patients whose blood pressure exceeded 140/90 mm Hg at first examination, 55% were still in excess at follow-up. Features associated with severe hypertension at first examination (>160/100 mm Hg) were history of hypertension, education less than college, and higher cognitive functioning. CONCLUSIONS: Blood pressure values in excess of national guidelines are common after stroke and TIA, especially among diabetic patients. Efforts to lower blood pressure control may enhance secondary prevention.

The stroke prognosis instrument II (SPI-II) : A clinical prediction instrument for patients with transient ischemia and nondisabling ischemic stroke.

BACKGROUND AND PURPOSE: In 1991 we developed the Stroke Prognosis Instrument (SPI-I) to stratify patients with transient ischemic attack or ischemic stroke by prognosis for stroke or death in 2 years. In this article we validate and improve SPI-I (creating SPI-II). METHODS: To validate SPI-I, we applied it to 4 test cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated new predictive variables identified in 1 of the test cohorts and validated it in the other 3 cohorts. RESULTS: For SPI-I, pooled rates (all 4 test cohorts) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 24%, respectively (P<0.01, log-rank test). SPI-II was created by adding congestive heart failure and prior stroke to SPI-I. Each patient's risk group was determined by the total score for 7 factors: congestive heart failure (3 points); diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke for the index event (not transient ischemic attack) (2 points); hypertension (1 point); and coronary artery disease (1 point). Risk groups I, II, and III comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI-I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%, respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In receiver operator characteristic analysis, the area under the curve was 0.59 (95% CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II, confirming the better performance of the latter. CONCLUSIONS: Compared with SPI-I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI-II is ready for use in research design and may have a role in patient counseling.

Postmenopausal estrogen replacement therapy is associated with adverse breast cancer prognostic indices.

Previous studies have reported that breast cancer patients who used estrogen replacement therapy (ERT) have more favorable tumor characteristics and decreased mortality compared with nonusers. However, these findings may be due partly to increased medical surveillance in ERT users and detection of early stage tumors. Postmenopausal women with biopsy-proven breast cancer (n = 108) were identified based on their participation in screening mammography. Based on self-administered questionnaires completed at the time of mammography, 29 of these were users of ERT. Tumor characteristics (histology size, nodal status, and estrogen receptor content) of ERT users were compared with those of nonusers. After adjusting for potentially confounding variables, the odds ratios (OR) describing the relationship between ERT use and the risk of invasive histopathology (OR = 1.35, 95% CI = 0.48, 3.75), positive nodes (OR = 2.43, 95% CI = 0.59, 10.10), size > or = 2.0 cm (OR = 2.34, CI = 0.66, 8.27), or negative estrogen receptor status (OR = 1.08, 95% CI = 0.18, 9.38) were > 1, although none reached statistical significance. When the subjects were separated into two prognostic groups based on the presence or absence of adverse prognostic indices, ERT users had a statistically significantly increased risk of being in the poor prognostic group (tumor size > or = 2.0 cm or positive nodes or negative estrogen receptor content) (OR = 4.48, 95% CI = 1.10, 18.30). The risk was highest in current users (OR = 6.28, 95% CI = 1.16, 34.00), users for 5 or more years (OR = 7.77, 95% CI = 1.09, 55.60), and users of nonconjugated estrogen (OR = 9.63, 95% CI = 1.18, 78.60). Although our sample size is small and we do not currently have information on long-term outcomes, the findings from this screening population suggest that ERT may have an adverse effect on important breast cancer prognostic indices.

Stratified randomization for clinical trials.

Trialists argue about the usefulness of stratified randomization. For investigators designing trials and readers who use them, the argument has created uncertainty regarding the importance of stratification. In this paper, we review stratified randomization to summarize its purpose, indications, accomplishments, and alternatives. In order to identify research papers, we performed a Medline search for 1966-1997. The search yielded 33 articles that included original research on stratification or included stratification as the major focus. Additional resources included textbooks. Stratified randomization prevents imbalance between treatment groups for known factors that influence prognosis or treatment responsiveness. As a result, stratification may prevent type I error and improve power for small trials (<400 patients), but only when the stratification factors have a large effect on prognosis. Stratification has an important effect on sample size for active control equivalence trials, but not for superiority trials. Theoretical benefits include facilitation of subgroup analysis and interim analysis. The maximum desirable number of strata is unknown, but experts argue for keeping it small. Stratified randomization is important only for small trials in which treatment outcome may be affected by known clinical factors that have a large effect on prognosis, large trials when interim analyses are planned with small numbers of patients, and trials designed to show the equivalence of two therapies. Once the decision to stratify is made, investigators need to chose factors carefully and account for them in the analysis.

Postmenopausal estrogen use and invasive versus in situ breast cancer risk.

To examine the effect of cancer histopathology on the relationship between estrogen-replacement therapy (ERT) use and breast cancer risk, we performed a case-control study of 109 postmenopausal women 45 years or older with in situ or invasive breast cancer matched to 545 controls. When in situ and invasive tumors were combined, the overall odds ratio (OR) describing the association between ERT use and breast cancer risk was not statistically significantly elevated (adjusted OR = 1.48, 95% confidence interval [CI] = 0.89-2.47). When the analyses were confined to women with invasive disease, risk estimates were uniformly higher (adjusted OR = 1.85, 95% CI = 1.00-3.45). In contrast, the overall estimate for the relationship between ERT use and in situ breast cancer was close to 1 (adjusted OR = 1.08, 95% CI = 0.42-2.77). The positive association between ERT use and invasive breast cancer we observed, and the lack of association in women with in situ disease, may represent a distinct biological difference or may be related to the small sample size of our study.

Estrogen after ischemic stroke: clinical basis and design of the Women's Estrogen for Stroke Trial.

BACKGROUND AND PURPOSE: Observational studies have found that women who take estrogen after menopause are less likely to have a stroke than women who do not take estrogen. Although these findings indicate that estrogen may prevent stroke, an alternative explanation for the improved outcome of estrogen users is that they are healthier before starting therapy than nonusers. To test the therapeutic effect of estrogen with research methods that avoid this selection bias, we designed a randomized controlled trial. TRIAL DESIGN: The Women's Estrogen For Stroke Trial (WEST) is a double-blind, randomized trial with a primary goal of determining whether 1 mg 17beta-estradiol daily, when compared with placebo, reduces the risk of recurrent stroke or death among postmenopausal women who have experienced a transient ischemic attack or nondisabling ischemic stroke. Exclusion criteria include use of estrogen at the time of stroke, breast or uterine cancer, inability to speak English, and estimated survival less than 5 years. Once randomized, women remain under the care of their personal physicians for management of stroke risk factors. For early detection of endometrial hyperplasia and cancer, asymptomatic women receive medroxyprogesterone yearly (5 mg for 12 days) and vaginal ultrasonography or biopsy at the end of the trial. Unscheduled uterine bleeding is evaluated with biopsy. A total of 652 women are sought at 20 hospitals in Connecticut and one in Massachusetts. CONCLUSIONS: The WEST promises to provide critical guidance to women and their physicians regarding the effectiveness of estrogen in secondary stroke prevention.

A new index of prognostic severity for chronic asthma.

OBJECTIVE: To develop a prognostic clinical index for adults with chronic stable asthma. DESIGN: Analysis of data from a 48-week randomized, crossover trial of regular vs as-needed inhaled beta-agonist therapy. PATIENTS: Eligible patients included 70 men and women between the ages of 15 and 64 years with asthma for > 1 year. OUTCOME MEASURE: Asthma deterioration within 20 weeks, defined as either a marked decline in FEV1 (> or = 1.0 L or > or = 30% from baseline) or initiation of systemic corticosteroid therapy for asthma exacerbation. RESULTS: Three baseline factors independently predicted asthma deterioration: frequent symptoms on waking in the 4 weeks before baseline, past hospitalization for asthma, and age 35 years or older. Based on cross-stratification and consolidation of these prognostic factors, an index was developed that stratified subjects into four risk groups with distinctive deterioration rates of 9%, 21%, 39%, and 67% (p<0.001). CONCLUSION: For adults with chronic stable asthma, three simple clinical factors can be combined to stratify effectively for risk of subsequent asthma deterioration.

Functional recovery after myocardial infarction in men: the independent effects of social class.

BACKGROUND: Social class has been repeatedly associated with cardiovascular-related illness and death, but no studies have examined the effect of social class on recovery from myocardial infarction. Moreover, few studies have simultaneously evaluated a broad array of f1p4graphic, clinical, and psychosocial factors that may influence health outcomes after myocardial infarction. OBJECTIVE: To determine whether social class remains independently associated with functional recovery after myocardial infarction, even after controlling for clinical, demographic, and psychosocial factors known to influence outcomes after infarction. DESIGN: Analysis of prospective data from a multicenter, randomized, double-blind clinical trial. SETTING: 25 hospitals or clinical settings in the United States and Canada that participated in the Beta Blocker Heart Attack Trial, including the Health Insurance Plan substudy. PATIENTS: 2145 men 29 to 69 years of age who were hospitalized with acute myocardial infarction and were recruited into the Beta Blocker Heart Attack Trial. MEASUREMENTS: The primary outcome was change in New York Heart Association functional class between baseline assessment and 12 months after infarction, dichotomized as improved or not improved (that is, no change, decline in at least one category, or death). RESULTS: Social class maintained its independent effect on improved functional status, even after controlling for pertinent prognostic factors. Persons of high social class were significantly more likely than persons of low or middle social class to have improved functional status 1 year after infarction. Certain clinical, demographic, and psychosocial features were related to recovery, but the effect of social class could not be explained by these additional features. CONCLUSIONS: Social class has a substantial influence on recovery from myocardial infarction and may explain differences in clinical outcomes.

The evolving clinical status of patients after a myocardial infarction: the importance of post-hospital data for mortality prediction.

Studies predicting mortality after myocardial infarction (MI) usually rely on in-hospital data, and combine patients admitted for the first MI with recurrent MI patients. Since treatment decisions are often made or modified at the first outpatient clinic visit, this study was designed to evaluate the importance of post-hospital data on mortality prediction after a first myocardial infarction (MI). An inception cohort of patients enrolled in the Beta-Blocker in Heart Attack Trial (n = 2830) was included. Forty-three variables (including in-hospital and post-hospital data) were evaluated using stepwise logistic regression. Ten variables were independently associated with 1-year mortality: five used in-hospital data (history of hypertension, hypercholesterolemia, congestive heart failure [CHF], ventricular tachycardia, and age); and five variables depended on post-hospital data collected at the first outpatient visit (CHF after discharge, New York Heart Association functional class, heart rate, pulmonary rates, and smoking). Two predictive systems were developed that partitioned patients into one of four classes with distinct mortality risks: a composite system using the 10 in- and post-hospital variables, and a system using only the 5 in-hospital variables. Mortality risk for the composite system classes ranged from 0.6 to 20.0% (I [n = 861], 0.6%; II [n = 1151], 2.3%; III [n =698], 4.3%; IV [n = 120], 20.0%). In contrast, the range of mortality risk using the in-hospital data only system was less (1 to 8.3%). Most importantly, a distinct gradient within each class of the in-hospital data only system was created by the addition of the post-hospital data. This study demonstrates that risk stratification after an acute first MI is improved by the addition of post-hospital data.

The effect of acute renal failure on mortality. A cohort analysis.

OBJECTIVE: To determine if the high mortality in acute renal failure is explained by underlying illnesses (comorbidity). DESIGN: Cohort analytic study. SETTING: An 826-bed general hospital providing primary, secondary, and tertiary care. PATIENTS: From 16,248 inpatients undergoing radiocontrast procedures between 1987 and 1989, we identified 183 index subjects who developed contrast media-associated renal failure (defined as an increase in serum creatinine level of at least 25%, to at least 177 micromol/L [2 mg/dL], within 2 days of receiving contrast material) and 174 paired subjects, matched for age and baseline serum creatinine level, who underwent similar contrast procedures without developing renal failure. MAIN OUTCOME MEASURE: Death during hospitalization. RESULTS: The mortality rate in subjects without renal failure was 7%, compared with 34% in the corresponding index subjects with renal failure (odds ratio, 6.5; P<.001). After adjusting for differences in comorbidity, renal failure was associated with an odds ratio of dying of 5.5. Subjects who died after developing renal failure had complicated clinical courses characterized by sepsis, bleeding, delirium, and respiratory failure; most of these complications developed after the onset of renal failure. Deaths from renal causes were rare. CONCLUSIONS: The high mortality rate in acute renal failure is not explained by the underlying conditions alone. Renal failure appears to increase the risk of developing severe nonrenal complications that lead to death and should not be regarded as a treatable complication of serious illness.