Antibiotics for preventing respiratory tract infections in adults receiving intensive care.

BACKGROUND: Pneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7% and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to infections, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths. OBJECTIVES: The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care. SEARCH STRATEGY: We searched Medline, the Cochrane Acute Respiratory Infections Group trials register, proceedings of scientific meetings and reference lists of articles from January 1984 to December 1999. We also contacted investigators in the field. SELECTION CRITERIA: Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients. DATA COLLECTION AND ANALYSIS: Investigators were contacted for additional information. At least two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Overall 33 trials involving 5727 people were included. There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups. In 16 trials (involving 3361 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 30% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval 0.29 to 0.41) and total mortality (odds ratio 0.80, 95% confidence interval 0.69 to 0.93) in the treated group. On average 5 patients needed to be treated to prevent one infection and 23 patients to prevent one death. In 17 trials (involving 2366 patients) that tested topical antimicrobials the rates of respiratory tract infections and deaths in the control groups were 28% and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.56, 95% confidence interval 0.46 to 0.68) but not in total mortality (odds ratio 1.01, 95% confidence interval 0.84 to 1.22) in the treated group. REVIEWER'S CONCLUSIONS: A combination of topical and systemic prophylactic antibiotics can reduce respiratory tract infections and overall mortality in adult patients receiving intensive care. The design of the trials included in this systematic review does not allow to assess whether or not the treatment leads to antimicrobial resistance. Trials with different design are warranted to reliably address this question.

One model, several results: the paradox of the Hosmer-Lemeshow goodness-of-fit test for the logistic regression model.

BACKGROUND: The Hosmer-Lemeshow test, used extensively to assess the fit of the logistic regression model, is performed by several statistical packages. Recent studies have shown some problems in the use of this test when ties are present. These problems were attributed merely to the test implementation. METHODS: We analysed the order of the observations as an alternative explanation of the problem of ties. Using a data-set of 1393 intensive care unit (ICU) patients we performed the Hosmer-Lemeshow test with all possible subjects dispositions. RESULTS: We obtained about one million different P values, ranging from 0.01 to 0.95. DISCUSSION: It is already known that when the Hosmer-Lemeshow goodness-of-fit test is performed with a number of covariate patterns lower than the number of subjects, its result may be inaccurate. We showed that the extent of this problem could be relevant under particular conditions. We also suggest a strategy for estimating the extent of the problem and subsequent interpretation.

Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente).

BACKGROUND: Several studies have investigated the possible role of the adjuvant chemotherapy after curative resection for gastric cancer failing to show a clear indication; previous meta-analyses suggested small survival benefit of adjuvant chemotherapy, but the statistical methods used were open to criticisms. MATERIALS AND METHODS: Randomised trials were identified by means of Medline and CancerLit and by selecting references from relevant articles. Systematic review of all randomised clinical trials of adjuvant chemotherapy for gastric cancer compared with surgery alone, published before January 2000, were considered. Pooling of data was performed using the fixed effect model. Death for any cause was the study endpoint. The hazard ratio and its 95% confidence intervals (95% CI), derived according to the method of Parmar, were the statistics chosen for summarising the relative benefit of chemotherapy versus control. RESULTS: Overall 20 articles (21 comparisons) were considered for analysis. Three studies used single agent chemotherapy, seven combination of 5-fluorouracil (5-FU) with anthracyclin, ten combination of 5-FU without anthracyclines. Information on 3658 patients, 2180 deaths, was collected. Chemotherapy reduced the risk of death by 18% (hazard ratio 0.82, 95% CI: 0.75-0.89, P < 0.001). Association of Anthracyclines to 5-FU did not show a statistically significant improvement when compared with the effect of the other regimens. CONCLUSIONS: Chemotherapy produces a small survival benefit in patients with curatively resected gastric cancer. However, taking into account the limitations of literature based meta-analyses, adjuvant chemotherapy is still to be considered as an investigational approach.

Antibiotics for preventing respiratory tract infections in adults receiving intensive care.

OBJECTIVES: Pneumonia is an important cause of mortality in intensive care units. The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care. SEARCH STRATEGY: We searched MEDLINE, proceedings of scientific meetings and reference lists of articles from January 1984 to September 1997. We also contacted investigators in the field. SELECTION CRITERIA: Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients. DATA COLLECTION AND ANALYSIS: Trials were assessed for quality and investigators contacted for additional information. MAIN RESULTS: Overall 33 trials involving 5727 people were included. There was variation in the antibiotics used, patient characteristics and the risk of respiratory tract infections and mortality in the control groups. In 16 trials (involving 3493 patients) of a topical and systemic antibiotic combination, the average rates of respiratory tract infections and deaths in the control group were 33% and 28% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.36, 95% confidence interval 0.30 to 0. 43) and total mortality (odds ratio 0.80, 95% confidence interval 0. 68 to 0.93). On average five patients needed to be treated to prevent one infection and 23 treated to prevent one death. In 17 trials (involving 2366 patients) of topical antimicrobials the rates of respiratory tract infections and deaths in the control groups were 30% and 24% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.57, 95% confidence interval 0.46 to 0.69) but not in total mortality (odds ratio 1.01, 95% confidence interval 0.84 to 1.22). REVIEWER'S CONCLUSIONS: A combination of topical and systemic prophylactic antibiotics can reduce respiratory tract infections and overall mortality in adult patients receiving intensive care. [This abstract has been prepared centrally.]

Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women.

PURPOSE: A systematic review of randomized clinical trials (RCTs) was undertaken to assess the effectiveness of medical treatment for metastatic breast cancer. METHODS: RCTs published between 1975 and 1997 have been classified according to 12 therapeutic comparisons: (1) polychemotherapy (PCHT) agents versus single agent; (2) PCHT regimens with anthracycline versus PCHT without anthracycline; (3) other PCHT versus cyclophosphamide, methotrexate, and fluorouracil (CMF); (4) chemotherapy (CHT) with epirubicin versus CHT with doxorubicin; (5) CHT versus same CHT delivered with less intensive schedules; (6) other endocrine therapy (OET) versus tamoxifen; (7) OET plus tamoxifen versus tamoxifen alone; (8) OET versus medroxyprogesterone; (9) OET versus aromatase inhibitors; (10) OET versus megestrol; (11) endocrine therapy (ET) versus same ET at lower doses; and (12) CHT plus ET versus CHT. Tumor response rates, mortality hazards ratio (HR) and frequency of severe side effects were the outcome measures. RESULTS: A total of 189 eligible trials (31,510 patients) were identified. All provided response rates and 133 (70%) data or survival curves needed for calculation of the HR. In eight of 12 comparisons, statistically significant differences for response emerged (1, 2, 3, 5, 7, 8, 11, 12); all but no. 8 favored the first term of the comparison. Overall survival analysis showed better results of (a) PCHT versus single-agent CHT (HR=0.82; 95% confidence interval [CI], 0.75 to 0.90); (b) CHT with doxorubicin versus CHT with epirubicin (HR=1.13; 95% CI, 1.00 to 1.27); (c) CHT versus the same CHT delivered with less intensive schedules (HR=0.90; 95% CI, 0.83 to 0.97); (d) ET versus the same ET at lower doses (HR=0.86; 95% CI, 0.77 to 0.97). Quality of life was measured in only 2,995 of 31,510 patients (9.5%). CONCLUSION: Despite some evidence of effectiveness of specific regimens, the relevance of these findings is limited by the modest survival benefit and the lack of evaluation of the quality-of-life impact of these treatments.

Do specialists do it better? The impact of specialization on the processes and outcomes of care for cancer patients.

OBJECTIVE: To assess the impact of specialization on processes and outcomes of care for cancer patients. DATA SOURCE: Papers published in English between 1980 and 1995 and identified through MEDLINE and Embase (MeSH terms: NEOPLASM (exploded), and PHYSICIAN PRACTICE PATTERNS (or DECISION MAKING, ATTITUDE OF HEALTH PERSONNEL, QUALITY OF HEALTH CARE, DELIVERY OF HEALTH CARE, HEALTH EDUCATION or OUTCOME ASSESSMENT HEALTH CARE), or through the reference lists of review articles. STUDY SELECTION: Studies providing information on the association between quality of care indicators for cancer patients and clinician/centre degree of specialization. A total of 47 papers concerning 46 empirical studies were considered. DATA EXTRACTION: For studies using process of care indicators, the proportion of specific procedures performed by specialists and non-specialists was abstracted. For studies using outcome indicators (e.g., mortality), the effect of specialization was quantified in terms of odds ratio (OR) expressing relative reduction in risk of death. The quality of individual studies using process or outcome indicators was assessed according to study design, avoidance of selection bias in patient identification and data analysis, degree of adjustment of the comparison between clinicians/centres with different levels of specialization. DATA SYNTHESIS: Specialized centres/clinicians fared better both when process and outcome indicators were used. While the former varied widely in different studies and their clinical relevance was often questionable, mortality was consistently lower when care was provided by specialized centres/clinicians, with the effect size being greater in smaller studies. For breast cancer, where all the studies were of sufficiently good quality, a pooled estimate of the effect of specialization was performed which showed that specialized cancer care was associated with an 18% (95% CI: 12%-23%) reduction in mortality. CONCLUSIONS: Despite the fact that care provided by specialized centres/clinicians appeared to be better both when assessed in relation to process indicators and to mortality, this evidence should be considered far from conclusive because of major methodological flaws in these studies. Relative to current efforts to promote evidence-based policy-making, this review underscores the limited capability of scientific information to provide reliable guidelines for structuring better health care systems.

GIVIO-SITAC 01: A randomized trial of adjuvant 5-fluorouracil and folinic acid administered to patients with colon carcinoma--long term results and evaluation of the indicators of health-related quality of life. Gruppo Italiano Valutazione Interventi in Oncologia. Studio Italiano Terapia Adiuvante Colon.

BACKGROUND: In 1989, the authors began a randomized trial to determine whether 5-fluorouracil and high dose folinic acid (HD-FUFA) would increase the event free and overall survival of patients with resectable Dukes B and C (AJCC/UICC Stage II and Stage III) colon carcinoma, and to assess the toxicity of the treatment and its impact on selected health-related quality-of-life indicators. Early results were published as a part of an international multicenter pooled analysis (IMPACT) in 1995. The purpose of this report is to update the survival data for patients enrolled in the trial and describe their reported perceptions of their own health and quality of life. METHODS: The trial involved multiple treatment centers, with a centralized randomization between surgery alone and surgery with chemotherapy. The HD-FUFA regimen employed consisted of 5-fluorouracil (370 mg/m2) plus folinic acid (200 mg/m2) administered daily for 5 days every 4 weeks for 6 cycles. Patients' perceptions of their own health status were obtained by means of 3 self-administered questionnaires, which were completed by patients at the time of discharge from the treatment center and at 6 and 24 months after randomization. RESULTS: Overall, 888 patients with resected Dukes B2 and C colon carcinoma were enrolled in the trial. HD-FUFA significantly reduced mortality by 25% (95% confidence interval, 5-41%; P=0.02) and events by 31% (95% confidence interval, 14-45%; P < or = 0.001). Compliance with treatment was good; more than 80% of patients completed the planned therapy. Toxicity was mild, and oral mucositis was the main side effect. None of the health-related quality-of-life parameters investigated (emotional status, worry about the future, changes in social life, impact of the disease, follow-up, and global quality of life) seemed to be affected by the treatment to which patients were allocated. A positive trend in the evolution of patients' psychologic status was observed. CONCLUSIONS: Long term results of this SITAC study confirm that HD-FUFA is a well-tolerated, effective 6-month adjuvant regimen for patients with colon carcinoma that has no detrimental effect on their quality of life.

Effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials.

OBJECTIVE: To determine whether antibiotic prophylaxis reduces respiratory tract infections and overall mortality in unselected critically ill adult patients. DESIGN: Meta-analysis of randomised controlled trials from 1984 and 1996 that compared different forms of antibiotic prophylaxis used to reduce respiratory tract infections and mortality with aggregate data and, in a subset of trials, data from individual patients. SUBJECTS: Unselected critically ill adult patients; 5727 patients for aggregate data meta-analysis, 4343 for confirmatory meta-analysis with data from individual patients. MAIN OUTCOME MEASURES: Respiratory tract infections and total mortality. RESULTS: Two categories of eligible trials were defined: topical plus systemic antibiotics versus no treatment and topical preparation with or without a systemic antibiotic versus a systemic agent or placebo. Estimates from aggregate data meta-analysis of 16 trials (3361 patients) that tested combined treatment indicated a strong significant reduction in infection (odds ratio 0.35; 95% confidence interval 0.29 to 0.41) and total mortality (0.80; 0.69 to 0.93). With this treatment five and 23 patients would need to be treated to prevent one infection and one death, respectively. Similar analysis of 17 trials (2366 patients) that tested only topical antibiotics indicated a clear reduction in infection (0.56; 0.46 to 0.68) without a significant effect on total mortality (1.01; 0.84 to 1.22). Analysis of data from individual patients yielded similar results. No significant differences in treatment effect by major subgroups of patients emerged from the analyses. CONCLUSIONS: This meta-analysis of 15 years of clinical research suggests that antibiotic prophylaxis with a combination of topical and systemic drugs can reduce respiratory tract infections and overall mortality in critically ill patients. This effect is significant and worth while, and it should be considered when practice guidelines are defined.

Clinical profile of ioversol. A metaanalysis of 57 randomized, double-blind clinical trials.

RATIONALE AND OBJECTIVES: The authors characterize the clinical profile of ioversol, specifically in terms of radiographic efficacy and clinical tolerance. METHODS: Metaanalysis of data from all available randomized, double-blind trials, comparing ioversol with other nonionic contrast media in indicated procedures was conducted. A total of 3854 adult patients were studied (1931 ioversol, 1923 reference) from 57 clinical trials. RESULTS: Ioversol was considered diagnostic in 99.3% of examinations, with good to excellent enhancement quality in 89.3% of cases. In comparative evaluations, there was a 24% odds reduction of the investigator's nondiagnostic judgment and a 15% odds reduction of poor to fair quality in favor of ioversol. For tolerance, 20.2% and 3.3% of patients in the ioversol group reported moderate to severe sensation of heat and pain with a 10% odds reduction and a 3% odds increase, respectively. The incidence of drug-related adverse events was low: 76 (3.3%) patients in the ioversol group and 62 (2.9%) patients in control group. No statistically significant differences were noted. CONCLUSION: Based on these findings, the high-contrast efficacy and patient tolerance make ioversol a suitable agent, equivalent to other nonionic contrast media.

Clinical pharmacology of chronic oral etoposide in patients with small cell and non-small cell lung cancer.

We aimed to evaluate the pharmacokinetics and pharmacodynamics of etoposide given chronically by the p.o. route to patients with small cell and non-small cell lung cancer. Single daily p.o. doses of 100 mg etoposide were given for 21 consecutive days every 4 weeks to 39 previously untreated patients with small cell lung cancer and 10 patients with non-small cell lung cancer. Bioavailability was studied after one i.v. and one p.o. dose of 100 mg etoposide given 48 h before and on day 1 of treatment, respectively. Etoposide plasma levels were measured using the HPLC method. Inter- and intrapatient variability of the area under the curve of the concentration versus time (AUC) during the first cycle were evaluated using a limited sampling model; the variability of etoposide plasma concentrations (Ecs) during the first cycle was assessed by weekly blood samples taken 24 h after dosing. The overall bioavailability of etoposide (mean +/- SD) was 67% +/- 22% and was not affected by fasting. A much higher inter- than intrapatient variability of both the AUC and 24-h Ec determined on days 8, 15, and 22 was found. Neutropenia was dose limiting and of varying degrees (mean +/- SD of absolute neutrophil count nadir at the first cycle: 1.5 +/- 1.2 x 10(3)/microliter). Neutropenia WHO grade >/=3 occurred in 38% of the patients after the first cycle. Pharmacodynamic analyses showed a significant relationship between the mean 24-h Ec and neutropenia, expressed as log- of absolute neutrophil count nadir or as a relative decrease of neutrophils. A correlation between a critical value of mean 24-h Ec (0.34 microgram/ml) and a high probability of achieving a greater than 80% decrease in absolute neutrophil count was found. Two pharmacodynamic models (one previously described and one developed in this study) were used to evaluate the possibility of predicting neutropenia on the basis of individual etoposide pharmacokinetics and baseline absolute neutrophil count. Pharmacokinetic studies have shown a high interpatient variability and a relatively low intrapatient variability of AUC and 24-h Ec. The application of the pharmacodynamic models and mean 24-h Ec cutoff values has proven statistically valid to predict the occurrence of severe neutropenia. However, it remains to be demonstrated in a prospective manner whether the application of pharmacokinetic/ pharmacodynamic knowledge can improve the overall therapeutic outcome of chronic p.o. treatment with etoposide.

Patterns of care and survival in non small cell lung cancer: 15 years' experience in a general hospital.

BACKGROUND: Transferring results derived from clinical research into practice is particularly difficult in lung cancer where clear indications for treatment are defined only for selected subgroups of patients. Studies on hospital-based lung cancer population could provide data for quantifying this issue. PATIENTS AND METHODS: This was a follow-up study of consecutive, first-diagnosis cases referred to the in-and outpatient cancer clinics of a large italian general hospital between January 1975 and December 1990. Data were collected from medical records and recorded on ad hoc standardized forms. Analysis focused on changes in distribution over time of patient-related characteristics, prevalence of specific treatment strategies and survival of the study population. RESULTS: 1345 primary non small cell lung cancer cases were reviewed and 1125 were fully evaluable. In early stages (510/1125, 45%) only 237 patients actually underwent surgery. In this group surgery increased from 36 to 69% whereas chemotherapy decreased from 58 to 15%. In the advanced group (615/1125, 55%) chemotherapy was the preferred treatment but combined modalities tripled over time (from 4 to 12%). No significant changes in survival were observed within each group over time. CONCLUSION: Despite changes in the therapeutic approaches, mortality from lung cancer does not seem reduced over time. Since the proportion of cases that could potentially benefit from "active" treatments is small, for the large majority of patients a switch in clinical research from a cure to a care-oriented strategy should be considered.