Dan Chateau

Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.

OBJECTIVE Our goal was to determine the impact of the initiation of inappropriate antimicrobial therapy on survival to hospital discharge of patients with septic shock. METHODS The appropriateness of initial antimicrobial therapy, the clinical infection site, and relevant pathogens were retrospectively determined for 5,715 patients with septic shock in three countries. RESULTS Therapy with appropriate antimicrobial agents was initiated in 80.1% of cases. Overall, the survival rate was 43.7%. There were marked differences in the distribution of comorbidities, clinical infections, and pathogens in patients who received appropriate and inappropriate initial antimicrobial therapy (p < 0.0001 for each). The survival rates after appropriate and inappropriate initial therapy were 52.0% and 10.3%, respectively (odds ratio [OR], 9.45; 95% CI, 7.74 to 11.54; p < 0.0001). Similar differences in survival were seen in all major epidemiologic, clinical, and organism subgroups. The decrease in survival with inappropriate initial therapy ranged from 2.3-fold for pneumococcal infection to 17.6-fold with primary bacteremia. After adjustment for acute physiology and chronic health evaluation II score, comorbidities, hospital site, and other potential risk factors, the inappropriateness of initial antimicrobial therapy remained most highly associated with risk of death (OR, 8.99; 95% CI, 6.60 to 12.23). CONCLUSIONS Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Efforts to increase the frequency of the appropriateness of initial antimicrobial therapy must be central to efforts to reduce the mortality of patients with septic shock.

A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study.

Objective:To assess whether a potential benefit with combination antibiotic therapy is restricted to the most critically ill subset of patients, particularly those with septic shock. Data Sources:OVID MEDLINE (1950–October 2009), EMBASE (1980–October 2009), the Cochrane Central Register of Controlled Trials (to third quarter 2009), the ClinicalTrial.gov database, and the SCOPUS database. Study Selection:Randomized or observational studies of antimicrobial therapy of serious bacterial infections potentially associated with sepsis or septic shock. Fifty studies met entry criteria. Data Extraction:Study design, mortality/clinical response, and other variables were extracted independently by two reviewers. When possible, study datasets were split into mutually exclusive groups with and without shock or critical illness. Data Synthesis:Although a pooled odds ratio indicated no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856; 95% confidence interval, 0.71–1.03; p = .0943; I2 = 45.1%), stratification of datasets by monotherapy mortality risk demonstrated substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds ratio of death, 0.51; 95% confidence interval, 0.41–0.64; I2 = 8.6%). Of those datasets that could be stratified by the presence of shock/critical illness, the more severely ill group consistently demonstrated increased efficacy of a combination therapy strategy (odds ratio, 0.49; 95% confidence interval, 0.35–0.70; p < .0001; I2 = 0%). An increased risk of death was found in low-risk patients (risk of death ≤15% in the monotherapy arm) exposed to combination therapy (odds ratio, 1.53; 95% confidence interval, 1.16–2.03; p = .003; I2 = 8.2%). Meta-regression indicated that efficacy of combination therapy was dependent only on the risk of death in the monotherapy group. Conclusion:Combination antibiotic therapy improves survival and clinical response of high-risk, life-threatening infections, particularly those associated with septic shock but may be detrimental to low-risk patients.

Frequent Users of Emergency Departments: Developing Standard Definitions and Defining Prominent Risk Factors

STUDY OBJECTIVE We identify factors that define frequent and highly frequent emergency department (ED) users. METHODS Administrative health care records were used to define less frequent (1 to 6 visits), frequent (7 to 17 visits), and highly frequent (≥18 visits) ED users. Analyses were conducted to determine the most unique demographic, disease, and health care use features of these groups. RESULTS Frequent users composed 9.9% of all ED visits, whereas highly frequent users composed 3.6% of visits. Compared with less frequent users, frequent users were defined most strongly by their substance abuse challenges and by their many visits to primary care and specialist physicians. Substance abuse also distinguished highly frequent from frequent ED users strongly; 67.3% versus 35.9% of these patient groups were substance abusers, respectively. Also, 70% of highly frequent versus only 17.8% of frequent users had a long history of frequent ED use. Last, highly frequent users did not use other health care services proportionally more than their frequent user counterparts, suggesting that these former patients use EDs as a main source of care. CONCLUSION This research develops objective thresholds of frequent and highly frequent ED use. Although substance abuse is prominent in both groups, only highly frequent users seem to visit EDs in place of other health care services. Future analyses can investigate these patterns of health care use more closely, including how timely access to primary care affects ED use. Cluster analysis also has value for defining frequent user subgroups who may benefit from different yet equally effective treatment options.

The Relative Efficacies of Gastroprotective Strategies in Chronic Users of Nonsteroidal Anti-inflammatory Drugs

BACKGROUND & AIMS There are numerous gastroprotective strategies recommended for reducing the risk of upper gastrointestinal (GI) complications in long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs). The relative efficacy of the different strategies alone or in combination is uncertain. METHODS We used the Manitoba Population Health Research Data Repository to perform a population-based matched case-control analysis. All NSAID users (nonselective and cyclooxygenase [COX]-2-specific) users admitted to the hospital with a primary diagnosis for an upper gastrointestinal complication were matched to NSAID-using controls in the community. We used conditional logistic regression analysis to determine the relative efficacy of different gastroprotective strategies (proton pump inhibitors [PPIs], COX-2 inhibitors, and low-dose/high-dose misoprostol) either alone or in combination and to adjust for multiple pertinent covariates. RESULTS A total of 1382 NSAID/COX-2 users with upper GI complications were matched to 33,957 age- and sex-matched controls. Cotherapy with PPIs or misoprostol or use of a COX-2 inhibitor all significantly reduced the risk of upper GI complications. COX-2 inhibitors were not statistically more likely to prevent upper GI complications than PPIs, although they were superior to low-dose misoprostol. The combination of COX-2 inhibitors with a PPI was associated with the greatest degree of upper GI complication risk reduction. CONCLUSIONS All of the commonly accepted gastroprotective strategies reduce the risk of upper GI complications in NSAID users, although the combination of COX-2 inhibitors with PPIs promotes the greatest risk reduction for NSAID-related upper GI complications. Celecoxib use specifically may be superior to the combination of nonselective NSAIDs with a PPI.

Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis

Objective Previous observational studies suggest that the use of proton pump inhibitors (PPIs) may increase the risk of hospitalisation for community-acquired pneumonia (HCAP). However, the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies. Our objective was, therefore, to examine the risk of HCAP with PPIs prescribed prophylactically in new users of non-steroidal anti-inflammatory drugs (NSAIDs). Design We formed eight restricted cohorts of new users of NSAIDs, aged ≥40 years, using a common protocol in eight databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, US MarketScan and the UKs General Practice Research Database (GPRD)). This specific patient population was studied to minimise bias due to unmeasured confounders. High-dimensional propensity scores were used to estimate site-specific adjusted ORs (aORs) for HCAP at 6 months in PPI patients compared with unexposed patients. Fixed-effects meta-analytic models were used to estimate overall effects across databases. Results Of the 4 238 504 new users of NSAIDs, 2.3% also started a PPI. The cumulative 6-month incidence of HCAP was 0.17% among patients prescribed PPIs and 0.12% in unexposed patients. After adjustment, PPIs were not associated with an increased risk of HCAP (aOR=1.05; 95% CI 0.89 to 1.25). Histamine-2 receptor antagonists yielded similar results (aOR=0.95, 95% CI  0.75 to 1.21). Conclusions Our study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of HCAP.

Evidence-based prescribing of antibiotics for children: role of socioeconomic status and physician characteristics

Background: Evidence-based guidelines for antibiotic use are well established, but nonadherence to these guidelines continues. This study was undertaken to determine child, household and physician factors predictive of nonadherence to evidence-based antibiotic prescribing in children. Methods: The prescription and health care records of 20 000 Manitoba children were assessed for 2 criteria of nonadherence to evidence-based antibiotic prescribing during the period from fiscal year 1996 (April 1996 to March 1997) to fiscal year 2000: receipt of an antibiotic for a viral respiratory tract infection (VRTI) and initial use of a second-line agent for acute otitis media, pharyngitis, pneumonia, urinary tract infection or cellulitis. The likelihood of nonadherence to evidence-based prescribing, according to child demographic characteristics, physician factors (specialty and place of training) and household income, was determined from hierarchical linear modelling. Child visits were nested within physicians, and the most parsimonious model was selected at p < 0.05. Results: During the study period, 45% of physician visits for VRTI resulted in an antibiotic prescription, and 20% of antibiotic prescriptions were for second-line antibiotics. Relative to general practitioners, the odds ratio for antibiotic prescription for a VRTI was 0.51 (95% confidence interval [CI] 0.42–0.62) for pediatricians and 1.58 (95% CI 1.03–2.42) for other specialists. The likelihood that an antibiotic would be prescribed for a VRTI was 0.99 for each successive

Neurodevelopmental Assessment in Kindergarten in Children Exposed to General Anesthesia before the Age of 4 Years: A Retrospective Matched Cohort Study.

10 000 increase in household income. Pediatricians and other specialists were more likely than general practitioners to prescribe second-line antibiotics for initial therapy. Both criteria for nonadherence to evidence-based prescribing were 40% less likely among physicians trained in Canada or the United States than among physicians trained elsewhere. Interpretation: The links that we identified between nonadherence to evidence-based antibiotic prescribing in children and physician specialty and location of training suggest opportunities for intervention. The independent effect of household income indicates that parents also have an important role.

Predictors of arm morbidity following breast cancer surgery

Background:Animal studies demonstrate general anesthetic (GA) toxicity in the developing brain. Clinical reports raise concern, but the risk of GA exposure to neurodevelopment in children remains uncertain. Methods:The authors undertook a retrospective matched cohort study comparing children less than 4 yr of age exposed to GA to those with no GA exposure. The authors used the Early Development Instrument (EDI), a 104-component questionnaire, encompassing five developmental domains, completed in kindergarten as the outcome measure. Mixed-effect logistic regression models generated EDI estimates for single versus multiple GA exposure and compared both single and multiple exposures by the age of 0 to 2 or 2 to 4 yr. Known sociodemographic and physical confounders were incorporated as covariates in the models. Results:A total of 18,056 children were studied: 3,850 exposed to a single GA and 620 exposed to two or more GA, who were matched to 13,586 nonexposed children. In children less than 2 yr of age, there was no independent association between single or multiple GA exposure and EDI results. Paradoxically, single exposure between 2 and 4 yr of age was associated with deficits, most significant for communication/general knowledge (estimate, −0.7; 95% CI, −0.93 to −0.47; P < 0.0001) and language/cognition (estimate, −0.34; 95% CI, −0.52 to −0.16; P < 0.0001) domains. Multiple GA exposure at the age of 2 to 4 yr did not confer greater risk than single GA exposure. Conclusions:These findings refute the assumption that the earlier the GA exposure in children, the greater the likelihood of long-term neurocognitive risk. The authors cannot confirm an association between multiple GA exposure and increased risk of neurocognitive impairment, increasing the probability of confounding to explain the results.

Suicide and suicide attempts in children and adolescents in the child welfare system

Objective: Arm morbidity post‐breast cancer surgery is increasingly being recognized as a chronic problem for some women following breast cancer surgery. The purpose of this study was to examine demographic, disease, and treatment‐related predictors of a comprehensive array of chronic arm morbidity (pain, lymphedema, functional disability, and range of motion) post‐breast cancer surgery.

Pediatric appendicitis rupture rate: disparities despite universal health care

Background: Few population studies have examined the psychiatric outcomes of children and adolescents in the child welfare system, and no studies have compared outcomes before and after entry into care. Our objective was to assess the relative rate (RR) of suicide, attempted suicide, admission to hospital and visits to physicians’ offices among children and adolescents in care compared with those not in care. We also examined these outcomes within the child welfare population before and after entry into care. Methods: We used population-level data to identify children and adolescents 5 to 17 years of age who were in care in Manitoba for the first time between Apr. 1, 1997, and Mar. 31, 2006, and a comparison cohort not in care. We compared the two cohorts to obtain RRs for the specified outcomes. We also determined RRs within the child welfare population relative to the same population two years before entry into care. Results: We identified 8279 children and adolescents in care for the first time and a comparison cohort of 353 050 children and adolescents not in care. Outcome rates were higher among those in care than in the comparison cohort for suicide (adjusted RR 3.54, 95% confidence interval [CI] 2.11–5.95), attempted suicide (adjusted RR 2.11, 95% CI 1.84–2.43) and all other outcomes. However, adjusted RRs for attempted suicide (RR 0.27, 95% CI 0.21–0.34), admissions to hospital and physician visits decreased after entry into care. Interpretation: Children and adolescents in care were at greater risk of suicide and attempting suicide than those who were not in care. Rates of suicide attempts and hospital admissions within this population were highest before entry into care and decreased thereafter.