JAMA. 2008;299(6):646-655.
Context The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated. Objective To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI. Design, Setting, and Patients A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005. Intervention Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H2O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H2O (increased recruitment strategy; n = 385). Main Outcome Measures The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure–free days at 28 days. Results The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure–free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements. Conclusions A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure. Trial Registration clinicaltrials.gov Identifier: NCT00188058
JAMA. 2005;293:723-729.
Context Perinatal arterial ischemic stroke (PAS) is a common cause of hemiplegic cerebral palsy. Risk factors for this condition have not been clearly defined. Objective To determine maternal and infant characteristics associated with PAS. Design, Setting, and Patients Case-control study nested within the cohort of all 199 176 infants born from 1997 through 2002 in the Kaiser Permanente Medical Care Program, a managed care organization providing care for more than 3 million residents of northern California. Case patients were confirmed by review of brain imaging and medical records (n = 40). Three controls per case were randomly selected from the study population. Main Outcome Measure Association of maternal and infant complications with risk of PAS. Results The population prevalence of PAS was 20 per 100 000 live births. The majority (85%) of infants with PAS were delivered at term. The following prepartum and intrapartum factors were more common among case than control infants: primiparity (73% vs 44%, P = .002), fetal heart rate abnormality (46% vs 14%, P<.001), emergency cesarean delivery (35% vs 13%, P = .002), chorioamnionitis (27% vs 11%, P = .03), prolonged rupture of membranes (26% vs 7%, P = .002), prolonged second stage of labor (25% vs 4%, P<.001), vacuum extraction (24% vs 11%, P = .04), cord abnormality (22% vs 6%, P = .01), preeclampsia (19% vs 5%, P = .01), and oligohydramnios (14% vs 3%, P = .01). Risk factors independently associated with PAS on multivariate analysis were history of infertility (odds ratio [OR], 7.5; 95% confidence interval [CI], 1.3-45.0), preeclampsia (OR, 5.3; 95% CI, 1.3-22.0), prolonged rupture of membranes (OR, 3.8; 95% CI, 1.1-12.8), and chorioamnionitis (OR, 3.4; 95% CI, 1.1-10.5). The rate of PAS increased dramatically when multiple risk factors were present. Conclusions Perinatal arterial ischemic stroke in infants is associated with several independent maternal risk factors. How these complications, along with their potential effects on the placenta and fetus, may play a role in causing perinatal stroke deserves further study.
JAMA. 2008;299(24):2857-2867.
Context Treating hypertension decreases mortality and disability from cardiovascular disease, but most hypertension remains inadequately controlled. Objective To determine if a new model of care that uses patient Web services, home blood pressure (BP) monitoring, and pharmacist-assisted care improves BP control. Design, Setting, and Participants A 3-group randomized controlled trial, the Electronic Communications and Home Blood Pressure Monitoring study was based on the Chronic Care Model. The trial was conducted at an integrated group practice in Washington state, enrolling 778 participants aged 25 to 75 years with uncontrolled essential hypertension and Internet access. Care was delivered over a secure patient Web site from June 2005 to December 2007. Interventions Participants were randomly assigned to usual care, home BP monitoring and secure patient Web site training only, or home BP monitoring and secure patient Web site training plus pharmacist care management delivered through Web communications. Main Outcome Measures Percentage of patients with controlled BP (<140/90 mm Hg) and changes in systolic and diastolic BP at 12 months. Results Of 778 patients, 730 (94%) completed the 1-year follow-up visit. Patients assigned to the home BP monitoring and Web training only group had a nonsignificant increase in the percentage of patients with controlled BP (<140/90 mm Hg) compared with usual care (36% [95% confidence interval {CI}, 30%-42%] vs 31% [95% CI, 25%-37%]; P = .21). Adding Web-based pharmacist care to home BP monitoring and Web training significantly increased the percentage of patients with controlled BP (56%; 95% CI, 49%-62%) compared with usual care (P < .001) and home BP monitoring and Web training only (P < .001). Systolic BP was decreased stepwise from usual care to home BP monitoring and Web training only to home BP monitoring and Web training plus pharmacist care. Diastolic BP was decreased only in the pharmacist care group compared with both the usual care and home BP monitoring and Web training only groups. Compared with usual care, the patients who had baseline systolic BP of 160 mm Hg or higher and received home BP monitoring and Web training plus pharmacist care had a greater net reduction in systolic BP (–13.2 mm Hg [95% CI, –19.2 to –7.1]; P < .001) and diastolic BP (–4.6 mm Hg [95% CI, –8.0 to –1.2]; P < .001), and improved BP control (relative risk, 3.32 [95% CI, 1.86 to 5.94]; P<.001). Conclusion Pharmacist care management delivered through secure patient Web communications improved BP control in patients with hypertension. Trial Registration clinicaltrials.gov Identifier: NCT00158639
JAMA. 2008;300(14):1665-1673.
Context Talking about death can be difficult. Without evidence that end-of-life discussions improve patient outcomes, physicians must balance their desire to honor patient autonomy against a concern of inflicting psychological harm. Objective To determine whether end-of-life discussions with physicians are associated with fewer aggressive interventions. Design, Setting, and Participants A US multisite, prospective, longitudinal cohort study of patients with advanced cancer and their informal caregivers (n = 332dyads), September 2002-February 2008. Patients were followed up from enrollment to death, a median of 4.4 months later. Bereaved caregivers' psychiatric illness and quality of life was assessed a median of 6.5 months later. Main Outcome Measures Aggressive medical care (eg, ventilation, resuscitation) and hospice in the final week of life. Secondary outcomes included patients' mental health and caregivers' bereavement adjustment. Results One hundred twenty-three of 332 (37.0%) patients reported having end-of-life discussions before baseline. Such discussions were not associated with higher rates of major depressive disorder (8.3% vs 5.8%; adjusted odds ratio [OR], 1.33; 95% confidence interval [CI], 0.54-3.32), or more worry (mean McGill score, 6.5 vs 7.0; P = .19). After propensity-score weighted adjustment, end-of-life discussions were associated with lower rates of ventilation (1.6% vs 11.0%; adjusted OR, 0.26; 95% CI, 0.08-0.83), resuscitation (0.8% vs 6.7%; adjusted OR, 0.16; 95% CI, 0.03-0.80), ICU admission (4.1% vs 12.4%; adjusted OR, 0.35; 95% CI, 0.14-0.90), and earlier hospice enrollment (65.6% vs 44.5%; adjusted OR, 1.65;95% CI, 1.04-2.63). In adjusted analyses, more aggressive medical care was associated with worse patient quality of life (6.4 vs 4.6; F = 3.61, P = .01) and higher risk of major depressive disorder in bereaved caregivers (adjusted OR, 3.37; 95% CI, 1.12-10.13), whereas longer hospice stays were associated with better patient quality of life (mean score, 5.6 vs 6.9; F = 3.70, P = .01). Better patient quality of life was associated with better caregiver quality of life at follow-up (β = .20; P = .001). Conclusions End-of-life discussions are associated with less aggressive medical care near death and earlier hospice referrals. Aggressive care is associated with worse patient quality of life and worse bereavement adjustment.
JAMA. 2007;298(22):2644-2653.
Context Lorazepam is currently recommended for sustained sedation of mechanically ventilated intensive care unit (ICU) patients, but this and other benzodiazepine drugs may contribute to acute brain dysfunction, ie, delirium and coma, associated with prolonged hospital stays, costs, and increased mortality. Dexmedetomidine induces sedation via different central nervous system receptors than the benzodiazepine drugs and may lower the risk of acute brain dysfunction. Objective To determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared with lorazepam. Design, Setting, Patients, and Intervention Double-blind, randomized controlled trial of 106 adult mechanically ventilated medical and surgical ICU patients at 2 tertiary care centers between August 2004 and April 2006. Patients were sedated with dexmedetomidine or lorazepam for as many as 120 hours. Study drugs were titrated to achieve the desired level of sedation, measured using the Richmond Agitation-Sedation Scale (RASS). Patients were monitored twice daily for delirium using the Confusion Assessment Method for the ICU (CAM-ICU). Main Outcome Measures Days alive without delirium or coma and percentage of days spent within 1 RASS point of the sedation goal. Results Sedation with dexmedetomidine resulted in more days alive without delirium or coma (median days, 7.0 vs 3.0; P = .01) and a lower prevalence of coma (63% vs 92%; P < .001) than sedation with lorazepam. Patients sedated with dexmedetomidine spent more time within 1 RASS point of their sedation goal compared with patients sedated with lorazepam (median percentage of days, 80% vs 67%; P = .04). The 28-day mortality in the dexmedetomidine group was 17% vs 27% in the lorazepam group (P = .18) and cost of care was similar between groups. More patients in the dexmedetomidine group (42% vs 31%; P = .61) were able to complete post-ICU neuropsychological testing, with similar scores in the tests evaluating global cognitive, motor speed, and attention functions. The 12-month time to death was 363 days in the dexmedetomidine group vs 188 days in the lorazepam group (P = .48). Conclusion In mechanically ventilated ICU patients managed with individualized targeted sedation, use of a dexmedetomidine infusion resulted in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion. Trial Registration clinicaltrials.gov Identifier: NCT00095251
JAMA. 2008;300(5):509-519.
Context Antiretroviral therapy can be associated with visceral adiposity and metabolic complications, increasing cardiovascular risk, and reduced growth hormone (GH) secretion may be a contributing factor. Objective To investigate the effects of low-dose physiological GH administration on body composition, glucose, and cardiovascular parameters in patients with human immunodeficiency virus (HIV) having abdominal fat accumulation and relative GH deficiency. Design, Setting, and Patients A randomized, double-blind, placebo-controlled trial of 56 patients with HIV, abdominal fat accumulation, and reduced GH secretion (peak GH <7.5 ng/mL) conducted at a US academic medical center between November 2003 and October 2007. Intervention Patients were randomly assigned to receive either subcutaneous GH or matching placebo titrated to the upper quartile of normal insulinlike growth factor 1 (IGF-1) range for 18 months. Starting dose was 2 µg/kg/d and increased to maximum dose of 6 µg/kg/d (average dose, 0.33 mg/d). Main Outcome Measures Change in body composition assessed by computed tomographic scan and dual-energy x-ray absorptiometry. Secondary outcomes included glucose, IGF-1, blood pressure (BP), and lipids. Treatment effect was the difference in the change between GH and placebo groups, using all available data. Results Fifty-five patients (26 with GH and 29 with placebo) were included in the safety analyses and 52 patients (25 with GH and 27 with placebo) were included in the efficacy analyses. Visceral adipose tissue area (treatment effect [last-value-carried-forward analysis {n = 56}, –19 cm2; 95% confidence interval {CI}, –37 to –0.3 cm2], –19 cm2; 95% CI, –38 to –0.5 cm2; P = .049); trunk fat (–0.8 kg; 95% CI, –1.5 to –0.04 kg; P = .04); diastolic BP (–7 mm Hg; 95% CI, –11 to –2 mm Hg; P = .006); and triglycerides (–7 mg/dL, P = .002) improved but 2-hour glucose levels on glucose tolerance testing increased in the GH group vs the placebo group (treatment effect, 22 mg/dL; 95% CI, 6-37 mg/dL; P = .009). The IGF-1 levels increased (treatment effect, 129 ng/mL; 95% CI, 95-164 ng/mL; P < .001). Adverse events were not increased for GH vs placebo (23%; 95% CI, 9%-44% vs 28%; 95% CI, 13%-47%; P = .70). Conclusions In HIV-associated abdominal fat accumulation and relative GH deficiency, low-dose GH received for 18 months resulted in significantly reduced visceral fat and truncal obesity, triglycerides, and diastolic BP, but 2-hour glucose levels on glucose tolerance testing were increased. Trial Registration clinicaltrials.gov Identifier: NCT00100698
JAMA. 2008;299(16):1903-1913.
Context A thin, cobalt-chromium stent eluting the antiproliferative agent everolimus from a nonadhesive, durable fluoropolymer has shown promise in preliminary studies in improving clinical and angiographic outcomes in patients with coronary artery disease. Objective To evaluate the safety and efficacy of an everolimus-eluting stent compared with a widely used paclitaxel-eluting stent. Design, Setting, and Patients The SPIRIT III trial, a prospective, randomized, single-blind, controlled trial enrolling patients at 65 academic and community-based US institutions between June 22, 2005, and March 15, 2006. Patients were 1002 men and women undergoing percutaneous coronary intervention in lesions 28 mm or less in length and with reference vessel diameter between 2.5 and 3.75 mm. Angiographic follow-up was prespecified at 8 months in 564 patients and completed in 436 patients. Clinical follow-up was performed at 1, 6, 9, and 12 months. Interventions Patients were randomized 2:1 to receive the everolimus-eluting stent (n = 669) or the paclitaxel-eluting stent (n = 333). Main Outcome Measures The primary end point was noninferiority or superiority of angiographic in-segment late loss. The major secondary end point was noninferiority assessment of target vessel failure events (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months. An additional secondary end point was evaluation of major adverse cardiac events (cardiac death, myocardial infarction, or target lesion revascularization) at 9 and 12 months. Results Angiographic in-segment late loss was significantly less in the everolimus-eluting stent group compared with the paclitaxel group (mean, 0.14 [SD, 0.41] mm vs 0.28 [SD, 0.48] mm; difference, –0.14 [95% CI, –0.23 to –0.05]; P .004). The everolimus stent was noninferior to the paclitaxel stent for target vessel failure at 9 months (7.2% vs 9.0%, respectively; difference, –1.9% [95% CI, –5.6% to 1.8%]; relative risk, 0.79 [95% CI, 0.51 to 1.23]; P < .001). The everolimus stent compared with the paclitaxel stent resulted in significant reductions in composite major adverse cardiac events both at 9 months (4.6% vs 8.1%; relative risk, 0.56 [95% CI, 0.34 to 0.94]; P = .03) and at 1 year (6.0% vs 10.3%; relative risk, 0.58 [95% CI, 0.37 to 0.90]; P = .02), due to fewer myocardial infarctions and target lesion revascularization procedures. Conclusions In this large-scale, prospective randomized trial, an everolimus-eluting stent compared with a paclitaxel-eluting stent resulted in reduced angiographic late loss, noninferior rates of target vessel failure, and fewer major adverse cardiac events during 1 year of follow-up. Trial Registration clinicaltrials.gov Identifier: NCT00180479
JAMA. 2008;299(6):637-645.
Context Low-tidal-volume ventilation reduces mortality in critically ill patients with acute lung injury and acute respiratory distress syndrome. Instituting additional strategies to open collapsed lung tissue may further reduce mortality. Objective To compare an established low-tidal-volume ventilation strategy with an experimental strategy based on the original "open-lung approach," combining low tidal volume, lung recruitment maneuvers, and high positive-end–expiratory pressure. Design and Setting Randomized controlled trial with concealed allocation and blinded data analysis conducted between August 2000 and March 2006 in 30 intensive care units in Canada, Australia, and Saudi Arabia. Patients Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250. Interventions The control strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of positive end-expiratory pressure (n = 508). The experimental strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O, recruitment maneuvers, and higher positive end-expiratory pressures (n = 475). Main Outcome Measure All-cause hospital mortality. Results Eighty-five percent of the 983 study patients met criteria for acute respiratory distress syndrome at enrollment. Tidal volumes remained similar in the 2 groups, and mean positive end-expiratory pressures were 14.6 (SD, 3.4) cm H2O in the experimental group vs 9.8 (SD, 2.7) cm H2O among controls during the first 72 hours (P < .001). All-cause hospital mortality rates were 36.4% and 40.4%, respectively (relative risk [RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19). Barotrauma rates were 11.2% and 9.1% (RR, 1.21; 95% CI, 0.83-1.75; P = .33). The experimental group had lower rates of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54; 95% CI, 0.34-0.86; P = .01), death with refractory hypoxemia (4.2% vs 8.9%; RR, 0.56; 95% CI, 0.34-0.93; P = .03), and previously defined eligible use of rescue therapies (5.1% vs 9.3%; RR, 0.61; 95% CI, 0.38-0.99; P = .045). Conclusions For patients with acute lung injury and acute respiratory distress syndrome, a multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy. This "open-lung" strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies. Trial Registration clinicaltrials.gov Identifier: NCT00182195
JAMA. 2008;299(14):1678-1689.
Context Individuals with diabetes are at increased risk for cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested. Objective To compare progression of subclinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and systolic blood pressure (SBP) of 115 mm Hg or lower vs standard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower. Design, Setting, and Participants A randomized, open-label, blinded-to-end point, 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma, Arizona, and South Dakota. Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events. Interventions Participants were randomized to aggressive (n=252) vs standard (n=247) treatment groups with stepped treatment algorithms defined for both. Main Outcome Measures Primary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness (IMT). Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events. Results Mean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (–0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (–0.02 mm2 vs 1.05 mm2; P < .001); and there was greater decrease in left ventricular mass index (–2.4 g/m2.7 vs –1.2 g/m2.7; P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87) did not differ significantly between groups. Conclusions Reducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outcomes. Trial Registration clinicaltrials.gov Identifier: NCT00047424
JAMA. 2008;300(10):1181-1196.
Context The increasing use of Internet-based learning in health professions education may be informed by a timely, comprehensive synthesis of evidence of effectiveness. Objectives To summarize the effect of Internet-based instruction for health professions learners compared with no intervention and with non-Internet interventions. Data Sources Systematic search of MEDLINE, Scopus, CINAHL, EMBASE, ERIC, TimeLit, Web of Science, Dissertation Abstracts, and the University of Toronto Research and Development Resource Base from 1990 through 2007. Study Selection Studies in any language quantifying the association of Internet-based instruction and educational outcomes for practicing and student physicians, nurses, pharmacists, dentists, and other health care professionals compared with a no-intervention or non-Internet control group or a preintervention assessment. Data Extraction Two reviewers independently evaluated study quality and abstracted information including characteristics of learners, learning setting, and intervention (including level of interactivity, practice exercises, online discussion, and duration). Data Synthesis There were 201 eligible studies. Heterogeneity in results across studies was large (I2 79%) in all analyses. Effect sizes were pooled using a random effects model. The pooled effect size in comparison to no intervention favored Internet-based interventions and was 1.00 (95% confidence interval [CI], 0.90-1.10; P < .001; n = 126 studies) for knowledge outcomes, 0.85 (95% CI, 0.49-1.20; P < .001; n = 16) for skills, and 0.82 (95% CI, 0.63-1.02; P < .001; n = 32) for learner behaviors and patient effects. Compared with non-Internet formats, the pooled effect sizes (positive numbers favoring Internet) were 0.10 (95% CI, –0.12 to 0.32; P = .37; n = 43) for satisfaction, 0.12 (95% CI, 0.003 to 0.24; P = .045; n = 63) for knowledge, 0.09 (95% CI, –0.26 to 0.44; P = .61; n = 12) for skills, and 0.51 (95% CI, –0.24 to 1.25; P = .18; n = 6) for behaviors or patient effects. No important treatment-subgroup interactions were identified. Conclusions Internet-based learning is associated with large positive effects compared with no intervention. In contrast, effects compared with non-Internet instructional methods are heterogeneous and generally small, suggesting effectiveness similar to traditional methods. Future research should directly compare different Internet-based interventions.
JAMA. 2008;299(20):2413-2422.
Context Based on concerns about the risk of infection, the jugular site is often preferred over the femoral site for short-term dialysis vascular access. Objective To determine whether jugular catheterization decreases the risk of nosocomial complications compared with femoral catheterization. Design, Setting, and Patients A concealed, randomized, multicenter, evaluator-blinded, parallel-group trial (the Cathedia Study) of 750 patients from a network of 9 tertiary care university medical centers and 3 general hospitals in France conducted between May 2004 and May 2007. The severely ill, bed-bound adults had a body mass index (BMI) of less than 45 and required a first catheter insertion for renal replacement therapy. Intervention Patients were randomized to receive jugular or femoral vein catheterization by operators experienced in placement at both sites. Main Outcome Measures Rates of infectious complications, defined as catheter colonization on removal (primary end point), and catheter-related bloodstream infection. Results Patient and catheter characteristics, including duration of catheterization, were similar in both groups. More hematomas occurred in the jugular group than in the femoral group (13/366 patients [3.6%] vs 4/370 patients [1.1%], respectively; P = .03). The risk of catheter colonization at removal did not differ significantly between the femoral and jugular groups (incidence of 40.8 vs 35.7 per 1000 catheter-days; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.62-1.16; P = .31). A prespecified subgroup analysis demonstrated significant qualitative heterogeneity by BMI (P for the interaction term < .001). Jugular catheterization significantly increased incidence of catheter colonization vs femoral catheterization (45.4 vs 23.7 per 1000 catheter-days; HR, 2.10; 95% CI, 1.13-3.91; P = .017) in the lowest tercile (BMI <24.2), whereas jugular catheterization significantly decreased this incidence (24.5 vs 50.9 per 1000 catheter-days; HR, 0.40; 95% CI, 0.23-0.69; P < .001) in the highest tercile (BMI >28.4). The rate of catheter-related bloodstream infection was similar in both groups (2.3 vs 1.5 per 1000 catheter-days, respectively; P = .42). Conclusion Jugular venous catheterization access does not appear to reduce the risk of infection compared with femoral access, except among adults with a high BMI, and may have a higher risk of hematoma. Trial Registration clinicaltrials.gov Identifier: NCT00277888
JAMA. 2008;299(10):1139-1148.
Context Behavioral weight loss interventions achieve short-term success, but re-gain is common. Objective To compare 2 weight loss maintenance interventions with a self-directed control group. Design, Setting, and Participants Two-phase trial in which 1032 overweight or obese adults (38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). Enrollment at 4 academic centers occurred August 2003-July 2004 and randomization, February-December 2004. Data collection was completed in June 2007. Interventions After the phase 1 weight-loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology–based intervention, or self-directed control. Main Outcome Changes in weight from randomization. Results Mean entry weight was 96.7 kg. During the initial 6-month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal-contact group regained less weight (4.0 kg) than those in the self-directed group (5.5 kg; mean difference at 30 months, –1.5 kg; 95% confidence interval [CI], –2.4 to –0.6 kg; P = .001). At 30 months, weight regain did not differ between the interactive technology–based (5.2 kg) and self-directed groups (5.5 kg; mean difference –0.3 kg; 95% CI, –1.2 to 0.6 kg; P = .51); however, weight regain was lower in the interactive technology–based than in the self-directed group at 18 months (mean difference, –1.1 kg; 95% CI, –1.9 to –0.4 kg; P = .003) and at 24 months (mean difference, –0.9 kg; 95% CI, –1.7 to –0.02 kg; P = .04). At 30 months, the difference between the personal-contact and interactive technology–based group was –1.2 kg (95% CI –2.1 to –0.3; P = .008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight. Conclusions The majority of individuals who successfully completed an initial behavioral weight loss program maintained a weight below their initial level. Monthly brief personal contact provided modest benefit in sustaining weight loss, whereas an interactive techonology–based intervention provided early but transient benefit. Trial Registration clinicaltrials.gov Identifier: NCT00054925
JAMA. 2008;299(22):2633-2641.
Context Stimulant medication can effectively treat 60% to 70% of youth with attention-deficit/hyperactivity disorder (ADHD). Yet many parents seek alternative therapies, and Hypericum perforatum (St John's wort) is 1 of the top 3 botanicals used. Objective To determine the efficacy and safety of H perforatum for the treatment of ADHD in children. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted between March 2005 and August 2006 at Bastyr University, Kenmore, Washington, among a volunteer sample of 54 children aged 6 to 17 years who met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for ADHD by structured interview. Intervention After a placebo run-in phase of 1 week, participants were randomly assigned to receive 300 mg of H perforatum standardized to 0.3% hypericin (n = 27) or a matched placebo (n = 27) 3 times daily for 8 weeks. Other medications for ADHD were not allowed during the trial. Main Outcome Measures Performance on the ADHD Rating Scale–IV (range, 0-54) and Clinical Global Impression Improvement Scale (range, 0-7), and adverse events. Results One patient in the placebo group withdrew because of an adverse event. No significant difference was found in the change in ADHD Rating Scale–IV scores from baseline to week 8 between the treatment and placebo groups: inattentiveness improved 2.6 points (95% confidence interval [CI], –4.6 to –0.6 points) with H perforatum vs 3.2 points (95% CI, –5.7 to –0.8 points) with placebo (P = .68) and hyperactivity improved 1.8 points (95% CI, –3.7 to 0.1 points) with H perforatum vs 2.0 points (95% CI, –4.1 to 0.1 points) with placebo (P = .89). There was also no significant difference between the 2 groups in the percentage of participants who met criteria for improvement (score 2) on the Clinical Global Impression Improvement Scale (H perforatum, 44.4%; 95% CI, 25.5%-64.7% vs placebo, 51.9%; 95% CI, 31.9%-71.3%; P = .59). No difference between groups was found in the number of participants who experienced adverse effects during the study period (H perforatum, 40.7%; 95% CI, 22.4%-61.2% vs placebo, 44.4%; 95% CI, 25.5%-64.7%; P = .78). Conclusion In this study, use of H perforatum for treatment of ADHD over the course of 8 weeks did not improve symptoms. Trial Registration clinicaltrials.gov Identifier: NCT00100295
JAMA. 2008;300(15):1784-1792.
Context Amiodarone effectively suppresses atrial fibrillation but causes many adverse events. Objective To compare major events in patients randomized to receive episodic amiodarone treatment with those who received continuous amiodarone treatment while still aiming to prevent atrial fibrillation. Design, Setting, and Participants A randomized trial of 209 ambulatory patients with recurrent symptomatic persistent atrial fibrillation, conducted from December 2002 through March 2007 at 7 Dutch medical centers. Intervention Patients were randomly assigned to receive either episodic or continuous amiodarone treatment after electrical cardioversion following amiodarone loading. Episodic amiodarone treatment was discontinued after a month of sinus rhythm and reinitiated if atrial fibrillation relapsed (1 month peri–electrical cardioversion). In the continuous treatment group amiodarone was maintained throughout. Main Outcome Measures The primary end point was a composite of amiodarone and underlying heart disease–related major events. The secondary end points were all-cause mortality and cardiovascular hospitalizations. Results After a median follow-up of 2.1 years (range, 0.4-2.5 years), 51 (48%) of those receiving episodic treatment vs 64 (62%) receiving continuous treatment had sinus rhythm (P = .05). There were 85 atrial fibrillation recurrences (80%) among the episodic treatment group vs 56 (54%) in the continuous treatment group (P < .001). No significant difference existed in the incidence of the primary composite end point between each group (37 [35%] episodic vs 34 [33%] continuous; incidence rate difference, 0.2; 95% confidence interval [CI], –10.2 to 10.6). However, there were nonstatistically significant differences in the incidence of amiodarone-related major events (20 [19%] episodic vs 25 [24%] continuous; incidence rate difference, –2.0; 95% CI, –8.7 to 4.6) and underlying heart disease–related major events (17 [16%] episodic vs 9 [9%] continuous; incidence rate difference, 3.6; 95% CI, –1.6 to 8.7). All-cause mortality and cardiovascular hospitalizations were higher among those receiving episodic treatment (56 [53%] vs 35 [34%], P = .02). Conclusions In this study population, there was no difference in the composite of amiodarone and cardiac major adverse events between groups. However, patients receiving episodic treatment had a significantly increased rate of atrial fibrillation recurrence and a significantly higher rate of all-cause mortality and cardiovascular hospitalizations. Trial Registration clinicaltrials.gov Identifier: NCT00392431
JAMA. 2001;286:700-707.
Context Whether venous catheterization at the femoral site is associated with an increased risk of complications compared with that at the subclavian site is debated. Objective To compare mechanical, infectious, and thrombotic complications of femoral and subclavian venous catheterization. Design and Setting Concealed, randomized controlled clinical trial conducted between December 1997 and July 2000 at 8 intensive care units (ICUs) in France. Patients Two hundred eighty-nine adult patients receiving a first central venous catheter. Interventions Patients were randomly assigned to undergo central venous catheterization at the femoral site (n = 145) or subclavian site (n = 144). Main Outcome Measures Rate and severity of mechanical, infectious, and thrombotic complications, compared by catheterization site in 289, 270, and 223 patients, respectively. Results Femoral catheterization was associated with a higher incidence rate of overall infectious complications (19.8% vs 4.5%; P<.001; incidence density of 20 vs 3.7 per 1000 catheter-days) and of major infectious complications (clinical sepsis with or without bloodstream infection, 4.4% vs 1.5%; P = .07; incidence density of 4.5 vs 1.2 per 1000 catheter-days), as well as of overall thrombotic complications (21.5% vs 1.9%; P<.001) and complete thrombosis of the vessel (6% vs 0%; P = .01); rates of overall and major mechanical complications were similar between the 2 groups (17.3% vs 18.8 %; P = .74 and 1.4% vs 2.8%; P = .44, respectively). Risk factors for mechanical complications were duration of insertion (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03-1.08 per additional minute; P<.001); insertion in 2 of the centers (OR, 4.52; 95% CI, 1.81-11.23; P = .001); and insertion during the night (OR, 2.06; 95% CI, 1.04-4.08; P = .03). The only factor associated with infectious complications was femoral catheterization (hazard ratio [HR], 4.83; 95% CI, 1.96-11.93; P<.001); antibiotic administration via the catheter decreased risk of infectious complications (HR, 0.41; 95% CI, 0.18-0.93; P = .03). Femoral catheterization was the only risk factor for thrombotic complications (OR, 14.42; 95% CI, 3.33-62.57; P<.001). Conclusion Femoral venous catheterization is associated with a greater risk of infectious and thrombotic complications than subclavian catheterization in ICU patients.
JAMA. 2008;300(1):71-80.
Context Although an invasive strategy is frequently used in patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. Objective To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. Data Sources Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. Study Selection Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. Data Extraction The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. Data Synthesis Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction = .09). Conclusions In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.
JAMA. 2008;299(11):1277-1290.
Context Mutations in the low-density lipoprotein receptor–related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. Objective To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. Design and Setting Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. Main Outcome Measures Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. Results The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10–8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10–9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10–5) and 8 mg/cm2 (P = 5.0 x 10–6) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. Conclusions Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10–7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
JAMA. 2008;300(8):915-923.
Context Lead, mercury, and arsenic have been detected in a substantial proportion of Indian-manufactured traditional Ayurvedic medicines. Metals may be present due to the practice of rasa shastra (combining herbs with metals, minerals, and gems). Whether toxic metals are present in both US- and Indian-manufactured Ayurvedic medicines is unknown. Objectives To determine the prevalence of Ayurvedic medicines available via the Internet containing detectable lead, mercury, or arsenic and to compare the prevalence of toxic metals in US- vs Indian-manufactured medicines and between rasa shastra and non–rasa shastra medicines. Design A search using 5 Internet search engines and the search terms Ayurveda and Ayurvedic medicine identified 25 Web sites offering traditional Ayurvedic herbs, formulas, or ingredients commonly used in Ayurveda, indicated for oral use, and available for sale. From 673 identified products, 230 Ayurvedic medicines were randomly selected for purchase in August-October 2005. Country of manufacturer/Web site supplier, rasa shastra status, and claims of Good Manufacturing Practices were recorded. Metal concentrations were measured using x-ray fluorescence spectroscopy. Main Outcome Measures Prevalence of medicines with detectable toxic metals in the entire sample and stratified by country of manufacture and rasa shastra status. Results One hundred ninety-three of the 230 requested medicines were received and analyzed. The prevalence of metal-containing products was 20.7% (95% confidence interval [CI], 15.2%-27.1%). The prevalence of metals in US-manufactured products was 21.7% (95% CI, 14.6%-30.4%) compared with 19.5% (95% CI, 11.3%-30.1%) in Indian products (P = .86). Rasa shastra compared with non–rasa shastra medicines had a greater prevalence of metals (40.6% vs 17.1%; P = .007) and higher median concentrations of lead (11.5 µg/g vs 7.0 µg/g; P = .03) and mercury (20 800 µg/g vs 34.5 µg/g; P = .04). Among the metal-containing products, 95% were sold by US Web sites and 75% claimed Good Manufacturing Practices. All metal-containing products exceeded 1 or more standards for acceptable daily intake of toxic metals. Conclusion One-fifth of both US-manufactured and Indian-manufactured Ayurvedic medicines purchased via the Internet contain detectable lead, mercury, or arsenic.
JAMA. 2008;299(14):1669-1677.
Context Transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) therapy has been used for patients with large hepatocellular carcinoma tumors, but the survival benefits of combined treatment are not known. Objective To compare rates of survival of patients with large hepatocellular carcinoma tumors who received treatment with TACE combined with RFA therapy (TACE-RFA), TACE alone, and RFA alone. Design, Setting, and Patients Randomized controlled trial conducted from January 2001 to May 2004 among 291 consecutive patients with hepatocellular carcinoma larger than 3 cm at a single center in China. Intervention Patients were randomly assigned to treatment with combined TACE-RFA (n = 96), TACE alone (n = 95), or RFA alone (n = 100). Main Outcome Measures The primary end point was survival and the secondary end point was objective response rate. Results During a median 28.5 months of follow-up, median survival times were 24 months in the TACE group (3.4 courses), 22 months in the RFA group (3.6 courses), and 37 months in the TACE-RFA group (4.4 courses). Patients treated with TACE-RFA had better overall survival than those treated with TACE alone (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.33-2.63; P < .001) or RFA (HR, 1.88; 95% CI, 1.34-2.65; P < .001). In a preplanned substratification analysis, survival was also better in the TACE-RFA group than in the RFA group for patients with uninodular hepatocellular carcinoma (HR, 2.50; 95% CI, 1.42-4.42; P = .001) and in the TACE-RFA group than the TACE group for patients with multinodular hepatocellular carcinoma (HR, 1.99; 95% CI, 1.31-3.00; P < .001). The rate of objective response sustained for at least 6 months was higher in the TACE-RFA group (54%) than with either TACE (35%; rate difference, 0.19; 95% CI, 0.06-0.33; P = .009) or RFA (36%; rate difference, 0.18; 95% CI, 0.05-0.32; P = .01) treatment alone. Conclusion In this patient group, TACE-RFA was superior to TACE alone or RFA alone in improving survival for patients with hepatocellular carcinoma larger than 3 cm. Trial Registration clinicaltrials.gov Identifier: NCT00479050
JAMA. 2008;299(9):1019-1026.
Context Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil. Objective To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. Design, Setting, and Participants Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions. Intervention Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m2 per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m2 once per week; n = 221) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m2 per day) was the same for all patients (50.4 Gy). Main Outcome Measures Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity. Results A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%). Conclusions The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant. Trial Registration clinicaltrials.gov Identifier: NCT00003216