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. 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;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. 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;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;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(7):778-784.
Context Treatment recommendations assume that repeated mass antibiotic distributions can control, but not eradicate or even locally eliminate, the ocular strains of chlamydia that cause trachoma. Elimination may be an important end point because of concern that infection will return to communities that have lost immunity to chlamydia after antibiotics are discontinued. Objective To determine whether biannual treatment can eliminate ocular chlamydial infection from preschool children and to compare results with the World Health Organization–recommended annual treatment. Design, Setting, and Participants A cluster-randomized clinical trial of biannual vs annual mass azithromycin administrations to all residents of 16 rural villages in the Gurage Zone, Ethiopia, from March 2003 to April 2005. Interventions At scheduled treatments, all individuals aged 1 year or older were offered a single dose of oral azithromycin either annually or biannually. Main Outcome Measure Village prevalence of ocular chlamydial infection and presence of elimination at 24 months in preschool children determined by polymerase chain reaction, correcting for baseline prevalence. Antibiotic treatments were performed after sample collections. Results Overall, 14 897 of 16 403 eligible individuals (90.8%) received their scheduled treatment. In the villages in which residents were treated annually, the prevalence of infection in preschool children was reduced from a mean of 42.6% (range, 14.7%-56.4%) to 6.8% (range, 0.0%-22.0%) at 24 months. In the villages in which residents were treated biannually, infection was reduced from 31.6% pretreatment (range, 6.1%-48.6%) to 0.9% (range, 0.0%-4.8%) at 24 months. Biannual treatment was associated with a lower prevalence at 24 months (P = .03, adjusting for baseline prevalence). At 24 months, no infection could be identified in 6 of 8 of those treated biannually and in 1 of 8 of those treated annually (P = .049, adjusting for baseline prevalence). Conclusion Local elimination of ocular chlamydial infection appears feasible even in the most severely affected areas, although it may require biannual mass antibiotic distributions at a high coverage level. Trial Registration clinicaltrials.gov Identifier: NCT00221364
JAMA. 2007;298(21):2497-2506.
Context At 30-day follow-up, patients with moderate- and high-risk acute coronary syndromes (ACS) undergoing early invasive treatment in the ACUITY trial with bivalirudin monotherapy vs heparin plus glycoprotein (GP) IIb/IIIa inhibitors had noninferior rates of adverse ischemic events with reduced rates of major bleeding. Deferred upstream use of GP IIb/IIIa inhibitors for selective administration to patients undergoing percutaneous coronary intervention (PCI) resulted in a significant reduction in major bleeding, although a small increase in composite ischemia could not be excluded. Objective To determine 1-year ischemic outcomes for patients in the ACUITY trial. Design, Setting, and Patients A prospective, randomized, open-label trial with 1-year clinical follow-up at 450 academic and community-based institutions in 17 countries. A total of 13 819 patients with moderate- and high-risk ACS undergoing invasive treatment were enrolled between August 23, 2003, and December 5, 2005. Interventions Patients were assigned to heparin plus GP IIb/IIIa inhibitors (n = 4603), bivalirudin plus GP IIb/IIIa inhibitors (n = 4604), or bivalirudin monotherapy (n = 4612). Of these patients, 4605 were assigned to routine upstream GP IIb/IIIa administration and 4602 were deferred to selective GP IIb/IIIa inhibitor administration. Main Outcome Measure Composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) at 1 year. Results Composite ischemia at 1 year occurred in 15.4% of patients assigned to heparin plus GP IIb/IIIa inhibitors and 16.0% assigned to bivalirudin plus GP IIb/IIIa inhibitors (compared with heparin plus GP IIb/IIIa inhibitors, HR, 1.05; 95% CI, 0.95-1.16; P = .35), and 16.2% assigned to bivalirudin monotherapy (HR, 1.06; 95% CI, 0.95-1.17; P = .29). Mortality at 1 year occurred in an estimated 3.9% of patients assigned to heparin plus GP IIb/IIIa inhibitors, 3.9% assigned to bivalirudin plus GP IIb/IIIa inhibitors (HR, 0.99; 95% CI, 0.80-1.22; P = .92), and 3.8% assigned to bivalirudin monotherapy (HR, 0.96; 95% CI, 0.77-1.18; P = .67). Composite ischemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (HR, 1.08; 95% CI, 0.97-1.20; P = .15). Conclusions At 1 year, no statistically significant difference in rates of composite ischemia or mortality among patients with moderate- and high-risk ACS undergoing invasive treatment with the 3 therapies was found. There was no statistically significant difference in the rates of composite ischemia between patients receiving routine upstream administration of GP IIb/IIIa inhibitors vs deferring their use for patients undergoing PCI. Trial Registration clinicaltrials.gov Identifier: NCT00093158
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;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;300(4):413-422.
Context Cytomegalovirus (CMV) infection is associated with adverse clinical outcomes in immunosuppressed persons, but the incidence and association of CMV reactivation with adverse outcomes in critically ill persons lacking evidence of immunosuppression have not been well defined. Objective To determine the association of CMV reactivation with intensive care unit (ICU) and hospital length of stay in critically ill immunocompetent persons. Design, Setting, and Participants We prospectively assessed CMV plasma DNAemia by thrice-weekly real-time polymerase chain reaction (PCR) and clinical outcomes in a cohort of 120 CMV-seropositive, immunocompetent adults admitted to 1 of 6 ICUs at 2 separate hospitals at a large US tertiary care academic medical center between 2004 and 2006. Clinical measurements were assessed by personnel blinded to CMV PCR results. Risk factors for CMV reactivation and association with hospital and ICU length of stay were assessed by multivariable logistic regression and proportional odds models. Main Outcome Measures Association of CMV reactivation with prolonged hospital length of stay or death. Results The primary composite end point of continued hospitalization (n = 35) or death (n = 10) by 30 days occurred in 45 (35%) of the 120 patients. Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P < .001) and the average CMV area under the curve (AUC) in log10 copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3-3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9-9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1-4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days. Conclusions These preliminary findings suggest that reactivation of CMV occurs frequently in critically ill immunocompetent patients and is associated with prolonged hospitalization or death. A controlled trial of CMV prophylaxis in this setting is warranted.
JAMA. 2008;300(12):1423-1431.
Context The health and policy implications of regional variation in incidence and outcome of out-of-hospital cardiac arrest remain to be determined. Objective To evaluate whether cardiac arrest incidence and outcome differ across geographic regions. Design, Setting, and Patients Prospective observational study (the Resuscitation Outcomes Consortium) of all out-of-hospital cardiac arrests in 10 North American sites (8 US and 2 Canadian) from May 1, 2006, to April 30, 2007, followed up to hospital discharge, and including data available as of June 28, 2008. Cases (aged 0-108 years) were assessed by organized emergency medical services (EMS) personnel, did not have traumatic injury, and received attempts at external defibrillation or chest compressions or resuscitation was not attempted. Census data were used to determine rates adjusted for age and sex. Main Outcome Measures Incidence rate, mortality rate, case-fatality rate, and survival to discharge for patients assessed or treated by EMS personnel or with an initial rhythm of ventricular fibrillation. Results Among the 10 sites, the total catchment population was 21.4million, and there were 20 520 cardiac arrests. A total of 11 898(58.0%) had resuscitation attempted; 2729 (22.9% of treated) had initial rhythm of ventricular fibrillation or ventricular tachycardia or rhythms that were shockable by an automated external defibrillator; and 954(4.6% of total) were discharged alive. The median incidence of EMS-treated cardiac arrest across sites was 52.1 (interquartile range [IQR], 48.0-70.1)per 100 000 population; survival ranged from 3.0% to 16.3%, with a median of 8.4% (IQR, 5.4%-10.4%). Median ventricular fibrillation incidence was 12.6 (IQR, 10.6-5.2) per 100 000 population; survival ranged from 7.7% to 39.9%, with a median of 22.0% (IQR, 15.0%-24.4%),with significant differences across sites for incidence and survival (P<.001). Conclusion In this study involving 10 geographic regions in North America,there were significant and important regional differences in out-of-hospital cardiac arrest incidence and outcome.
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;297:1784-1792.
Context With routine childhood vaccination using heptavalent pneumococcal conjugate vaccine, one concern has been the potential for emergence and expansion of replacement disease caused by serotypes not contained in the heptavalent conjugate vaccine. Objective To determine whether replacement disease is associated with the overall decline in invasive pneumococcal disease among Alaska Native children. Design, Setting, and Patients Alaska statewide longitudinal population-based laboratory surveillance of invasive Streptococcus pneumoniae infections from January 1, 1995, through December 31, 2006. Main Outcome Measures Incidence and types of pneumococcal disease in children younger than 2 years. Results In the first 3 years after introduction of routine vaccination with heptavalent pneumococcal conjugate vaccine, overall invasive pneumococcal disease decreased 67% in Alaska Native children younger than 2 years (from 403.2 per 100 000 in 1995-2000 to 134.3 per 100 000 per year in 2001-2003, P<.001). However, between 2001-2003 and 2004-2006, there was an 82% increase in invasive disease in Alaska Native children younger than 2 years to 244.6/100 000 (P = .02). Since 2004, the invasive pneumococcal disease rate caused by nonvaccine serotypes has increased 140% compared with the prevaccine period (from 95.1 per 100 000 in 1995-2000 to 228.6 in 2004-2006, P = .001). During the same period, there was a 96% decrease in heptavalent vaccine serotype disease. Serotype 19A accounted for 28.3% of invasive pneumococcal disease among Alaska children younger than 2 years during 2004-2006. There was no significant increase in nonvaccine disease in non–Native Alaska children younger than 2 years. Conclusions Alaska Native children are experiencing replacement invasive pneumococcal disease with serotypes not covered by heptavalent pneumococcal conjugate vaccine. The demonstration of replacement invasive pneumococcal disease emphasizes the importance of ongoing surveillance and development of expanded valency vaccines.
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;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(4):417-424.
Context Disease variation can be substantial even in conditions with a single gene etiology such as cystic fibrosis (CF). Simultaneously studying the effects of genes and environment may provide insight into the causes of variation. Objective To determine whether secondhand smoke exposure is associated with lung function and other outcomes in individuals with CF, whether socioeconomic status affects the relationship between secondhand smoke exposure and lung disease severity, and whether specific gene-environment interactions influence the effect of secondhand smoke exposure on lung function. Design, Setting, and Participants Retrospective assessment of lung function, stratified by environmental and genetic factors. Data were collected by the US Cystic Fibrosis Twin and Sibling Study with missing data supplemented by the Cystic Fibrosis Foundation Data Registry. All participants were diagnosed with CF, were recruited between October 2000 and October 2006, and were primarily from the United States. Main Outcome Measures Disease-specific cross-sectional and longitudinal measures of lung function. Results Of 812 participants with data on secondhand smoke in the home, 188 (23.2%) were exposed. Of 780 participants with data on active maternal smoking during gestation, 129 (16.5%) were exposed. Secondhand smoke exposure in the home was associated with significantly lower cross-sectional (9.8 percentile point decrease; P < .001) and longitudinal lung function (6.1 percentile point decrease; P = .007) compared with those not exposed. Regression analysis demonstrated that socioeconomic status did not confound the adverse effect of secondhand smoke exposure on lung function. Interaction between gene variants and secondhand smoke exposure resulted in significant percentile point decreases in lung function, namely in CFTR non-F508 homozygotes (12.8 percentile point decrease; P = .001), TGFβ1–509 TT homozygotes (22.7 percentile point decrease; P = .006), and TGFβ1 codon 10 CC homozygotes (20.3 percentile point decrease; P = .005). Conclusions Any exposure to secondhand smoke adversely affects both cross-sectional and longitudinal measures of lung function in individuals with CF. Variations in the gene that causes CF (CFTR) and a CF-modifier gene (TGFβ1) amplify the negative effects of secondhand smoke exposure.
JAMA. 2008;299(17):2056-2065.
Context Group B streptococcus is a leading infectious cause of morbidity in newborns and causes substantial disease in elderly individuals. Guidelines for prevention of perinatal disease through intrapartum chemoprophylaxis were revised in 2002. Candidate vaccines are under development. Objective To describe disease trends among populations that might benefit from vaccination and among newborns during a period of evolving prevention strategies. Design and Setting Analysis of active, population-based surveillance in 10 states participating in the Active Bacterial Core surveillance/Emerging Infections Program Network. Main Outcome Measures Age- and race-specific incidence of invasive group B streptococcal disease. Results There were 14 573 cases of invasive group B streptococcal disease during 1999-2005, including 1348 deaths. The incidence of invasive group B streptococcal disease among infants from birth through 6 days decreased from 0.47 per 1000 live births in 1999-2001 to 0.34 per 1000 live births in 2003-2005 (P < .001), a relative reduction of 27% (95% confidence interval [CI], 16%-37%). Incidence remained stable among infants aged 7 through 89 days (mean, 0.34 per 1000 live births) and pregnant women (mean, 0.12 per 1000 live births). Among persons aged 15 through 64 years, disease incidence increased from 3.4 per 100 000 population in 1999 to 5.0 per 100 000 in 2005 (21 for trend, 57; P < .001), a relative increase of 48% (95% CI, 32%-65%). Among adults 65 years or older, incidence increased from 21.5 per 100 000 to 26.0 per 100 000 (21 for trend, 15; P < .001), a relative increase of 20% (95% CI, 8%-35%). All 4882 isolates tested were susceptible to penicillin, ampicillin, and vancomycin, but 32% and 15% were resistant to erythromycin and clindamycin, respectively. Serotypes Ia, Ib, II, III, and V accounted for 96% of neonatal cases and 88% of adult cases. Conclusions Among infants from birth through 6 days, the incidence of group B streptococcal disease was lower in 2003-2005 relative to 1999-2001. This reduction coincided with the release of revised disease prevention guidelines in 2002. However, the disease burden in adults is substantial and increased significantly during the study period.
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