Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004

Context  Neurologic illness is an infrequent but severe adverse event associated with smallpox vaccination. The reinstatement of smallpox vaccination in the United States in response to possible bioterrorism renewed concerns about vaccine-related adverse neurologic events. Objective  To determine rates and describe the clinical features of neurologic events associated with smallpox vaccination. Design and Setting  We assessed reports of adverse events obtained through active case reporting and review of data reported to the Vaccine Adverse Event Reporting System among 665 000 persons vaccinated against smallpox by the Departments of Defense (n = 590 400) and Health and Human Services (n = 64 600) during the 2002-2004 US Smallpox Vaccination Program. Main Outcome Measure  Adverse neurologic events temporally associated with smallpox vaccination. Results  Between December 16, 2002, and March 11, 2004, 214 neurologic adverse events temporally associated with smallpox vaccination were reported; 111 reports involved Department of Health and Human Services and 103 involved Department of Defense vaccinees. Fifty-four percent of these events occurred within 1 week of vaccination, and 53% were among primary vaccinees. The most common neurologic adverse event was headache (95 cases), followed by nonserious limb paresthesias (n = 17) or pain (n = 13) and dizziness or vertigo (n = 13). Serious neurologic adverse events included 13 cases of suspected meningitis, 3 cases of suspected encephalitis or myelitis, 11 cases of Bell palsy, 8 seizures (including 1 death), and 3 cases of Guillain-Barré syndrome. Among these 39 events, 27 (69%) occurred in primary vaccinees and all but 2 occurred within 12 days of vaccination. Conclusions  During the 2002-2004 smallpox vaccination campaign, reported neurologic events were generally mild and self-limited, and no neurologic syndrome was identified at a rate above baseline estimates. Serious neurologic adverse events, such as postvaccinal encephalitis, Bell palsy, and Guillain-Barré syndrome, occurred in accordance with expected ranges.      

Effectiveness of long-term psychodynamic psychotherapy: a meta-analysis

Falk Leichsenring, DSc; Sven Rabung, PhD

JAMA. 2008;300(13):1551-1565.

Context  The place of long-term psychodynamic psychotherapy (LTPP) within psychiatry is controversial. Convincing outcome research for LTPP has been lacking.

Objective  To examine the effects of LTPP, especially in complex mental disorders, ie, patients with personality disorders, chronic mental disorders, multiple mental disorders, and complex depressive and anxiety disorders (ie, associated with chronic course and/or multiple mental disorders), by performing a meta-analysis.

Data Sources  Studies of LTPP published between January 1, 1960, and May 31, 2008, were identified by a computerized search using MEDLINE, PsycINFO, and Current Contents, supplemented by contact with experts in the field.

Study Selection  Only studies that used individual psychodynamic psychotherapy lasting for at least a year, or 50 sessions; had a prospective design; and reported reliable outcome measures were included. Randomized controlled trials (RCTs) and observational studies were considered. Twenty-three studies involving a total of 1053 patients were included (11 RCTs and 12 observational studies).

Data Extraction  Information on study characteristics and treatment outcome was extracted by 2 independent raters. Effect sizes were calculated for overall effectiveness, target problems, general psychiatric symptoms, personality functioning, and social functioning. To examine the stability of outcome, effect sizes were calculated separately for end-of-therapy and follow-up assessment.

Results  According to comparative analyses of controlled trials, LTPP showed significantly higher outcomes in overall effectiveness, target problems, and personality functioning than shorter forms of psychotherapy. With regard to overall effectiveness, a between-group effect size of 1.8 (95% confidence interval [CI], 0.7-3.4) indicated that after treatment with LTPP patients with complex mental disorders on average were better off than 96% of the patients in the comparison groups (P = .002). According to subgroup analyses, LTPP yielded significant, large, and stable within-group effect sizes across various and particularly complex mental disorders (range, 0.78-1.98).

Conclusions  There is evidence that LTPP is an effective treatment for complex mental disorders. Further research should address the outcome of LTPP in specific mental disorders and should include cost-effectiveness analyses.

     

Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review

Context  The benefits of therapeutic hypothermia as a treatment for traumatic brain injury (TBI) remain unclear. Objective  To explore the effects of depth, duration, and rate of rewarming after discontinuation of hypothermia on mortality and neurologic outcome in adults after TBI. Data Sources  An electronic search of MEDLINE (OVID), EMBASE, Current Contents, the Cochrane library and a hand search of key journals were performed. Corresponding authors of identified studies were contacted for additional unpublished or ongoing clinical trials. Study Selection  All randomized controlled trials of therapeutic hypothermia for at least 24 hours vs normothermia in adults with TBI. Data Extraction  Demographic and clinical data, hypothermia interventions and cointerventions, mortality and neurologic outcomes, and methodological quality were abstracted by 2 independent reviewers. Data Synthesis  Twelve trials met eligibility criteria and were included in the analysis. We also performed subanalyses by different hypothermia interventions (ie, depth, duration, and rapidity of rewarming after hypothermia) and methodological quality. Therapeutic hypothermia was associated with a 19% reduction in the risk of death (95% confidence interval [CI], 0.69-0.96) and a 22% reduction in the risk of poor neurologic outcome (95% CI, 0.63-0.98) compared with normothermia. Hypothermia longer than 48 hours was associated with a reduction in the risks of death and of poor neurologic outcome (relative risk [RR], 0.70; 95% CI, 0.56-0.87 and RR, 0.65; 95% CI, 0.48-0.89, respectively) compared with normothermia. Hypothermia to a target temperature between 32°C and 33°C, a duration of 24 hours, and rewarming within 24 hours were all associated with reduced risks of poor neurologic outcome compared with normothermia. Assessment of methodological quality did not reveal evidence of bias. Conclusions  Therapeutic hypothermia may reduce the risks of mortality and poor neurologic outcome in adults with TBI. Outcomes were influenced, however, by depth and duration of hypothermia as well as rate of rewarming (≤24 hours) after discontinuation of hypothermia. Nonetheless, the evidence is not yet sufficient to recommend routine use of therapeutic hypothermia for TBI outside of research settings.      

Management and outcomes of care of fever in early infancy

Context  Fever in infants challenges clinicians in distinguishing between serious conditions, such as bacteremia or bacterial meningitis, and minor illnesses. To date, the practice patterns of office-based pediatricians in treating febrile infants and the clinical outcomes resulting from their care have not been systematically studied. Objectives  To characterize the management and clinical outcomes of fever in infants, develop a clinical prediction model for the identification of bacteremia/bacterial meningitis, and compare the accuracy of various strategies. Design  Prospective cohort study. Setting  Offices of 573 practitioners from the Pediatric Research in Office Settings (PROS) network of the American Academy of Pediatrics in 44 states, the District of Columbia, and Puerto Rico. Patients  Consecutive sample of 3066 infants aged 3 months or younger with temperatures of at least 38°C seen by PROS practitioners from February 28, 1995, through April 25, 1998. Main Outcome Measures  Management strategies, illness frequency, and rates and accuracy of treating bacteremia/bacterial meningitis. Results  The PROS clinicians hospitalized 36% of the infants, performed laboratory testing in 75%, and initially treated 57% with antibiotics. The majority (64%) were treated exclusively outside of the hospital. Bacteremia was detected in 1.8% of infants (2.4% of those tested) and bacterial meningitis in 0.5%. Well-appearing infants aged 25 days or older with fever of less than 38.6°C had a rate of 0.4% for bacteremia/bacterial meningitis. Frequency of other illnesses included urinary tract infection, 5.4%; otitis media, 12.2%; upper respiratory tract infection, 25.6%; bronchiolitis, 7.8%; and gastroenteritis, 7.2%. Practitioners followed current guidelines in 42% of episodes. However, in the initial visit, they treated 61 of the 63 cases of bacteremia/bacterial meningitis with antibiotics. Neither current guidelines nor the model developed in this study performed with greater accuracy than observed practitioner management. Conclusions  Pediatric clinicians in the United States use individualized clinical judgment in treating febrile infants. In this study, relying on current clinical guidelines would not have improved care but would have resulted in more hospitalizations and laboratory testing.      

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial

Context  In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. Objective  To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. Design, Setting, and Patients  Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. Interventions  Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). Main Outcome Measures  The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. Results  The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. Conclusions  Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. Trial Registration  umin.ac.jp/ctr Identifier: C000000412      

Association of posttherapy positron emission tomography with tumor response and survival in cervical carcinoma

Context  Retrospective studies have demonstrated that the use of positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) in the posttherapy evaluation of patients with cervical carcinoma is predictive of survival outcome. Objective  To validate the association between the metabolic response on the 3-month posttherapy FDG-PET and long-term survival outcome. Design, Setting, and Patients  A prospective cohort study designed to validate our previous finding that the results of a 3-month posttherapy FDG-PET are predictive of long-term clinical outcome. A total of 92 women were treated with external irradiation, brachytherapy, and concurrent chemotherapy from January 2003 through September 2006. Posttherapy whole-body FDG-PET was performed 2 to 4 months (mean, 3 months) after completion of therapy. Main Outcome Measures  The primary outcome end points were metabolic response, progression-free survival, and cause-specific survival. Results  Posttherapy FDG-PET showed a complete metabolic response in 65 patients (70%), a partial metabolic response in 15 (16%), and progressive disease in 12 (13%). Their 3-year progression-free survival rates were 78%, 33%, and 0%, respectively (P < .001). Multivariate analysis demonstrated that the hazard ratio (HR) for risk of recurrence based on the posttherapy metabolic response showing progressive disease was 32.57 (95% confidence interval [CI], 10.22-103.82). A partial metabolic response had an HR of 6.30 (95% CI, 2.73-14.56). These were more predictive of survival outcome than the pretreatment lymph node status (HR, 3.54; 95% CI, 1.54-8.09). Conclusion  In this single-site study population of women with cervical cancer, 3-month posttherapy FDG uptake, as detected by whole-body PET, was predictive of survival.      

Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis

Context  Children with cerebrospinal fluid (CSF) pleocytosis are routinely admitted to the hospital and treated with parenteral antibiotics, although few have bacterial meningitis. We previously developed a clinical prediction rule, the Bacterial Meningitis Score, that classifies patients at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/µL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10 000 cells/µL, and a history of seizure before or at the time of presentation. Objective  To validate the Bacterial Meningitis Score in the era of widespread pneumococcal conjugate vaccination. Design, Setting, and Patients  A multicenter, retrospective cohort study conducted in emergency departments of 20 US academic medical centers through the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. All children aged 29 days to 19 years who presented at participating emergency departments between January 1, 2001, and June 30, 2004, with CSF pleocytosis (CSF white blood cells 10 cells/µL) and who had not received antibiotic treatment before lumbar puncture. Main Outcome Measure  The sensitivity and negative predictive value of the Bacterial Meningitis Score. Results  Among 3295 patients with CSF pleocytosis, 121 (3.7%; 95% confidence interval [CI], 3.1%-4.4%) had bacterial meningitis and 3174 (96.3%; 95% CI, 95.5%-96.9%) had aseptic meningitis. Of the 1714 patients categorized as very low risk for bacterial meningitis by the Bacterial Meningitis Score, only 2 had bacterial meningitis (sensitivity, 98.3%; 95% CI, 94.2%-99.8%; negative predictive value, 99.9%; 95% CI, 99.6%-100%), and both were younger than 2 months old. A total of 2518 patients (80%) with aseptic meningitis were hospitalized. Conclusions  This large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool. The risk of bacterial meningitis is very low (0.1%) in patients with none of the criteria. The Bacterial Meningitis Score may be helpful to guide clinical decision making for the management of children presenting to emergency departments with CSF pleocytosis.      

Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial

Context  Newborns admitted to neonatal intensive care units (NICUs) undergo a variety of painful procedures and stressful events. Because the effect of continuous morphine infusion in preterm neonates has not been investigated systematically, there is confusion regarding whether morphine should be used routinely in this setting. Objective  To evaluate the effects of continuous intravenous morphine infusion on pain responses, incidence of intraventricular hemorrhage (IVH), and poor neurologic outcome (severe IVH, periventricular leukomalacia, or death). Design, Setting, and Patients  A randomized, double-blind, placebo-controlled trial conducted between December 2000 and October 2002 in 2 level III NICUs in the Netherlands of 150 newborns who had received ventilatory support (inclusion criteria: postnatal age younger than 3 days and ventilation for less than 8 hours; exclusion criteria: severe asphyxia, severe IVH, major congenital malformations, and administration of neuromuscular blockers). Interventions  Intravenous morphine (100 µg/kg and 10 µg/kg per hour) or placebo infusion was given for 7 days (or less because of clinical necessity in several cases). Main Outcome Measures  The analgesic effect of morphine, as assessed using validated scales; the effect of morphine on the incidence of IVH; and poor neurologic outcome. Results  The analgesic effect did not differ between the morphine and placebo groups, judging from the following median (interquartile range) pain scores: Premature Infant Pain Profile, 10.1 (8.2-11.6) vs 10.0 (8.2-12.0) (P = .94); Neonatal Infant Pain Scale, 4.8 (3.7-6.0) vs 4.8 (3.2-6.0) (P = .58); and visual analog scale, 2.8 (2.0-3.9) vs 2.6 (1.8-4.3) (P = .14), respectively. Routine morphine infusion decreased the incidence of IVH (23% vs 40%, P = .04) but did not influence poor neurologic outcome (10% vs 16%, P = .66). In addition, analyses were adjusted for the use of additional open-label morphine (27% of morphine group vs 40% of placebo group, P = .10). Conclusions  Lack of a measurable analgesic effect and absence of a beneficial effect on poor neurologic outcome do not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support. Follow-up is needed to evaluate the long-term effects of morphine infusions on the neurobehavioral outcomes of prematurity.      

Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial

Context  Many physicians believe that the pulmonary artery catheter (PAC) is useful for the diagnosis and treatment of cardiopulmonary disturbances; however, observational studies suggest that its use may be harmful. Objective  To determine the effects on outcome of the early use of a PAC in patients with shock mainly of septic origin, acute respiratory distress syndrome (ARDS), or both. Design, Setting, and Patients  A multicenter randomized controlled study of 676 patients aged 18 years or older who fulfilled the standard criteria for shock, ARDS, or both conducted in 36 intensive care units in France from January 30, 1999, to June 29, 2001. Intervention  Patients were randomly assigned to either receive a PAC (n = 335) or not (n = 341). The treatment was left to the discretion of each individual physician. Main Outcome Measures  The primary end point was mortality at 28 days. The principal secondary end points were day 14 and 90 mortality; day 14 organ system, renal support, and vasoactive agents–free days; hospital, intensive care unit, and mechanical ventilation–free days at day 28. Results  The 2 groups were similar at baseline. There were no significant differences in mortality with or without the PAC at day 14: 49.9% vs 51.3% (mortality relative risk [RR], 0.97; 95% confidence interval [CI], 0.84-1.13; P = .70); day 28: 59.4% vs 61.0% (RR, 0.97; 95% CI, 0.86-1.10; P = .67); or day 90: 70.7% vs 72.0% (RR, 0.98; 95% CI, 0.89-1.08; P = .71). At day 14, the mean (SD) number of days free of organ system failures with or without the PAC (2.3 [3.6] vs 2.4 [3.5]), renal support (7.4 [6.0] vs 7.5 [5.9]), and vasoactive agents (3.8 [4.8] vs 3.9 [4.9]) did not differ. At day 28, mean (SD) days in hospital with or without the PAC (0.9 [3.6] vs 0.9 [3.3]), in the intensive care unit (3.4 [6.8] vs 3.3 [6.9]), or mechanical ventilation use (5.2 [8.5] vs 5.0 [8.5]) did not differ. Conclusion  Clinical management involving the early use of a PAC in patients with shock, ARDS, or both did not significantly affect mortality and morbidity.      

Contemporary clinical profile and outcome of prosthetic valve endocarditis

Context  Prosthetic valve endocarditis (PVE) is associated with significant mortality and morbidity. The contemporary clinical profile and outcome of PVE are not well defined. Objectives  To describe the prevalence, clinical characteristics, and outcome of PVE, with attention to health care–associated infection, and to determine prognostic factors associated with in-hospital mortality. Design, Setting, and Participants  Prospective, observational cohort study conducted at 61 medical centers in 28 countries, including 556 patients with definite PVE as defined by Duke University diagnostic criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to August 2005. Main Outcome Measure  In-hospital mortality. Results  Definite PVE was present in 556 (20.1%) of 2670 patients with infective endocarditis. Staphylococcus aureus was the most common causative organism (128 patients [23.0%]), followed by coagulase-negative staphylococci (94 patients [16.9%]). Health care–associated PVE was present in 203 (36.5%) of the overall cohort. Seventy-one percent of health care–associated PVE occurred within the first year of valve implantation, and the majority of cases were diagnosed after the early (60-day) period. Surgery was performed in 272 (48.9%) patients during the index hospitalization. In-hospital death occurred in 127 (22.8%) patients and was predicted by older age, health care–associated infection (62/203 [30.5%]; adjusted odds ratio [OR], 1.62; 95% confidence interval [CI], 1.08-2.44; P = .02), S aureus infection (44/128 [34.4%]; adjusted OR, 1.73; 95% CI, 1.01-2.95; P = .05), and complications of PVE, including heart failure (60/183 [32.8%]; adjusted OR, 2.33; 95% CI, 1.62-3.34; P<.001), stroke (34/101 [33.7%]; adjusted OR, 2.25; 95% CI, 1.25-4.03; P = .007), intracardiac abscess (47/144 [32.6%]; adjusted OR, 1.86; 95% CI, 1.10-3.15; P = .02), and persistent bacteremia (27/49 [55.1%]; adjusted OR, 4.29; 95% CI, 1.99-9.22; P<.001). Conclusions  Prosthetic valve endocarditis accounts for a high percentage of all cases of infective endocarditis in many regions of the world. Staphylococcus aureus is now the leading cause of PVE. Health care–associated infection significantly influences the clinical characteristics and outcome of PVE. Complications of PVE strongly predict in-hospital mortality, which remains high despite prompt diagnosis and the frequent use of surgical intervention.      

Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials

Context  The US Food and Drug Administration (FDA) has issued warnings that use of antidepressant medications poses a small but significantly increased risk of suicidal ideation/suicide attempt for children and adolescents. Objective  To assess the efficacy and risk of reported suicidal ideation/suicide attempt of antidepressants for treatment of pediatric major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders. Data Sources and Study Selection  PubMed (1988 to July 2006), relevant US and British regulatory agency reports, published abstracts of important scientific meetings (1998-2006), clinical trial registries, and information from authors. Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine) in participants younger than 19 years with MDD, OCD, or non-OCD anxiety disorders. Data Extraction  Information was extracted on study characteristics, efficacy outcomes, and spontaneously reported suicidal ideation/suicide attempt. Data Synthesis  Twenty-seven trials of pediatric MDD (n = 15), OCD (n = 6), and non-OCD anxiety disorders (n = 6) were selected, and risk differences for response and for suicidal ideation/suicide attempt estimated by random-effects methods. Pooled risk differences in rates of primary study-defined measures of responder status significantly favored antidepressants for MDD (11.0%; [95% confidence interval {CI}, 7.1% to 14.9%]), OCD (19.8% [95% CI, 13.0% to 26.6%), and non-OCD anxiety disorders (37.1% [22.5% to 51.7%]), corresponding to a number needed to treat (NNT) of 10 (95% CI, 7 to 15), 6 (4 to 8), and 3 (2 to 5), respectively. While there was increased risk difference of suicidal ideation/suicide attempt across all trials and indications for drug vs placebo (0.7%; 95% CI, 0.1% to 1.3%) (number needed to harm, 143 [95% CI, 77 to 1000]), the pooled risk differences within each indication were not statistically significant: 0.9% (95% CI, –0.1% to 1.9%) for MDD, 0.5% (–1.2% to 2.2%) for OCD, and 0.7% (–0.4% to 1.8%) for non-OCD anxiety disorders. There were no completed suicides. Age-stratified analyses showed that for children younger than 12 years with MDD, only fluoxetine showed benefit over placebo. In MDD trials, efficacy was moderated by age, duration of depression, and number of sites in the treatment trial. Conclusions  Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.      

Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial

Context  Enoxaparin has demonstrated advantages over unfractionated heparin in low- to moderate-risk patients with non–ST-segment elevation acute coronary syndromes (ACS) treated with a conservative strategy. Objectives  To compare the outcomes of patients treated with enoxaparin vs unfractionated heparin and to define the role of enoxaparin in patients with non–ST-segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach. Design, Setting, and Participants  The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10 027 high-risk patients with non–ST-segment elevation ACS to be treated with an intended early invasive strategy were recruited. Interventions  Subcutaneous enoxaparin (n = 4993) or intravenous unfractionated heparin (n = 4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician. Main Outcome Measures  The primary efficacy outcome was the composite clinical end point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke. Results  The primary end point occurred in 14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed between enoxaparin and unfractionated heparin groups, respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%] vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P = .008) but nonsignificant excess in GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P = .08) and transfusions (17.0% vs 16.0%, P = .16). Conclusions  Enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with non–ST-segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the advantages of convenience should be balanced with the modest excess of major bleeding.      

Do We Know What Inappropriate Laboratory Utilization Is?: A Systematic Review of Laboratory Clinical Audits

Objective.— Laboratory utilization has steadily increased, and some studies suggest inappropriate utilization. Therefore, we wished to assess studies that measure inappropriate laboratory use in light of methodological criteria. Design.— Systematic review of published studies. Data Sources.— MEDLINE, HEALTHSTAR, and EMBASE databases were searched from 1966 to September 1997 using a broad and inclusive strategy with no language restriction. In addition, the references of all retrieved studies and 3 textbooks on diagnostic testing were hand-searched. Study Selection.— All studies that provided and applied criteria for inappropriate laboratory use. Data Extraction.— Studies were categorized based on whether the criteria were implicit (objective criteria for inappropriate utilization not provided or very broad) or explicit. Guidelines for evaluation were applied to each study by a single reviewer. Data Synthesis.— Forty-four eligible studies were identified. Eleven studies used implicit criteria for inappropriate laboratory utilization and contained small numbers of patients or physicians. Most did not adequately assess the reliability of the implicit criteria. Thirty-three studies used explicit criteria based on the appropriateness of test choice, frequency, and timing, as well as the probability of a positive result. There were large variations in the estimates of inappropriate laboratory use (4.5%-95%). Evidence supporting the explicit criteria was frequently weak by the standards suggested for therapeutic maneuvers, but was nonetheless compelling based on principles of physiology, pharmacology, and probability. Conclusions.— Many studies identify inappropriate laboratory use based on implicit or explicit criteria that do not meet methodological standards suggested for audits of therapeutic maneuvers. Researchers should develop alternative evidentiary standards for measuring inappropriateness of laboratory test use.      

Lack of improvement in patients with acute stroke after treatment with thrombolytic therapy: predictors and association with outcome

Context  The focus of thrombolytic therapy in acute stroke has been on favorable outcome at 3 months. Few studies have analyzed outcome at 24 hours. An early and reliable prediction of poor outcome has implications for clinical management and discharge planning. Objective  To evaluate predictors of lack of improvement at 24 hours after receiving alteplase and their relationship with poor outcome at 3 months. Design, Setting, and Participants  Prospective cohort of consecutive patients with acute stroke who received alteplase and were admitted to a university hospital from January 1999 to March 2003. Participants were recruited from 2 academic centers in a major city in Ontario and 33 affiliated hospitals from 7 counties. Main Outcome Measures  Lack of improvement defined as a difference between the National Institutes of Health Stroke Scale score at baseline and at 24 hours of 3 points or less. Poor outcome at 3 months defined by a modified Rankin Scale score of 3 to 5 or death. Results  Among 216 patients with acute stroke who were treated with alteplase, 111 (51.4%) had a lack of improvement at 24 hours. After adjusting for age, sex, and stroke severity, baseline glucose level on admission (odds ratio [OR] 2.89; 95% confidence interval [CI], 1.40-5.99 for a glucose level >144 mg/dL [>8 mmol/L]), cortical involvement (OR, 2.66; 95% CI, 1.36-5.20), and time to treatment (OR, 1.01; 95% CI, 1.0-1.02 for each 1 minute increase in time to treatment) were independent predictors of lack of improvement. At 3 months, 43 patients (20.2%) had died; of the 170 survivors, 75 patients (44%) had poor outcomes. After adjusting for age, sex, and stroke severity, lack of improvement at 24 hours was an independent predictor of poor outcome (OR, 12.9; 95%CI, 5.7-29.6) and death (OR, 7.5; 95% CI, 2.9-19.6). Patients with a lack of improvement had longer lengths of hospitalization (14.5 vs 9.6 days; P = .02). Conclusions  Among patients with acute stroke treated with thrombolytic therapy, lack of improvement at 24 hours is associated with poor outcome and death at 3 months. Elevated glucose level, time to thrombolytic therapy, and cortical involvement were predictors of lack of improvement.      

Patterns and trends in food portion sizes, 1977-1998

Context  While general consensus holds that food portion sizes are increasing, no empirical data have documented actual increases. Objective  To determine trends in food portion sizes consumed in the United States, by eating location and food source. Design, Setting, and Participants  Nationally representative data from the Nationwide Food Consumption Survey (1977-1978) and the Continuing Survey of Food Intake by Individuals (1989-1991, 1994-1996, and 1998). The sample consists of 63 380 individuals aged 2 years and older. Main Outcome Measure  For each survey year, average portion size consumed from specific food items (salty snacks, desserts, soft drinks, fruit drinks, french fries, hamburgers, cheeseburgers, pizza, and Mexican food) by eating location (home, restaurant, or fast food). Results  Portion sizes vary by food source, with the largest portions consumed at fast food establishments and the smallest at other restaurants. Between 1977 and 1996, food portion sizes increased both inside and outside the home for all categories except pizza. The energy intake and portion size of salty snacks increased by 93 kcal (from 1.0 to 1.6 oz [28.4 to 45.4 g]), soft drinks by 49 kcal (13.1 to 19.9 fl oz [387.4 to 588.4 mL]), hamburgers by 97 kcal (5.7 to 7.0 oz [161.6 to 198.4 g]), french fries by 68 kcal (3.1 to 3.6 oz [87.9 to 102.1 g]), and Mexican food by 133 kcal (6.3 to 8.0 oz [178.6 to 226.8 g]). Conclusion  Portion sizes and energy intake for specific food types have increased markedly with greatest increases for food consumed at fast food establishments and in the home.      

Liver transplantation and opioid dependence

Context  Chronic hepatitis C is the leading cause for liver transplantation in the United States. Intravenous drug use, the major risk factor, accounts for approximately 60% of hepatitis C virus transmission. Information from the United Network of Organ Sharing (UNOS) does not address substance use among liver transplantation patients. Objective  To identify addiction-related criteria for admission to the UNOS liver transplantation waiting list and posttransplantation problems experienced by patients who are prescribed maintenance methadone. Design, Setting, and Participants  Mail survey of all 97 adult US liver transplantation programs (belonging to UNOS) in March 2000 with telephone follow-up conducted in May and June 2000. Main Outcome Measures  Programs' acceptance and management of patients with past or present substance use disorder. Results  Of the 97 programs surveyed, 87 (90%) responded. All accept applicants with a history of alcoholism or other addictions, including heroin dependence. Eighty-eight percent of the responding programs require at least 6 months of abstinence from alcohol; 83% from illicit drugs. Ninety-four percent have addiction treatment requirements. Consultations from substance abuse specialists are obtained by 86%. Patients receiving methadone maintenance are accepted by 56% of the responding programs. Approximately 180 patients receiving methadone maintenance are reported to have undergone liver transplantation. Conclusions  Most liver transplantation programs have established policies for patients with substance use disorders. Opiate-dependent patients receiving opiate replacement therapy seem underrepresented in transplantation programs. Little anecdotal evidence for negative impact of opiate replacement therapy on liver transplantation outcome was found. Policies requiring discontinuation of methadone in 32% of all programs contradict the evidence base for efficacy of long-term replacement therapies and potentially result in relapse of previously stable patients.      

Biochemical diagnosis of pheochromocytoma: which test is best?

Context  Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined. Objective  To determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma. Design, Setting, and Participants  Multicenter cohort study of patients tested for pheochromocytoma at 4 referral centers between 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor. Main Outcome Measures  Test sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid. Results  Sensitivities of plasma free metanephrines (99% [95% confidence interval {CI}, 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%-91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines. Conclusion  Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.      

Myocardial injury and long-term mortality following moderate to severe carbon monoxide poisoning

Context  Carbon monoxide (CO) poisoning is a common cause of toxicological morbidity and mortality. Myocardial injury is a frequent consequence of moderate to severe CO poisoning. While the in-hospital mortality for these patients is low, the long-term outcome of myocardial injury in this setting is unknown. Objective  To determine the association between myocardial injury and long-term mortality in patients following moderate to severe CO poisoning. Design, Setting, and Participants  Prospective cohort study of 230 consecutive adult patients treated for moderate to severe CO poisoning with hyperbaric oxygen and admitted to the Hennepin County Medical Center, a regional center for treatment of CO poisoning, between January 1, 1994, and January 1, 2002. Follow-up was through November 11, 2005. Main Outcome Measure  All-cause mortality. Results  Myocardial injury (cardiac troponin I level 0.7 ng/mL or creatine kinase-MB level 5.0 ng/mL and/or diagnostic electrocardiogram changes) occurred in 85 (37%) of 230 patients. At a median follow-up of 7.6 years (range: in-hospital only to 11.8 years), there were 54 deaths (24%). Twelve of those deaths (5%) occurred in the hospital as a result of a combination of burn injury and anoxic brain injury (n = 8) or cardiac arrest and anoxic brain injury (n = 4). Among the 85 patients who sustained myocardial injury from CO poisoning, 32 (38%) eventually died compared with 22 (15%) of 145 patients who did not sustain myocardial injury (adjusted hazard ratio, 2.1; 95% confidence interval, 1.2-3.7; P = .009). Conclusion  Myocardial injury occurs frequently in patients hospitalized for moderate to severe CO poisoning and is a significant predictor of mortality.