Lauren Griffith

Determining a minimal important change in a disease-specific quality of life questionnaire

This study was carried out to determine whether the minimal important difference, in evaluative quality of life instruments which use a 7-point scale, is similar across individual domains and for both improvement and deterioration. Thirty nine adults with asthma were studied, using an 8 week cohort with assessments at 0, 4 and 8 weeks. The outcomes were the Asthma Quality of Life Questionnaire and global rating of change. For overall asthma-specific quality of life and for all individual domains (activities, emotions, symptoms), the minimal important difference of quality of life score per item was very close to 0.5 (range: 0.42-0.58); differences of approximately 1.0 represented a moderate change (range: 0.77-1.51); differences greater than 1.5 represented large changes. Changes for improvement and deterioration were very similar. The changes in quality of life score that represent a minimal important difference are very similar to those observed for other evaluative instruments. The observation that the minimal important difference is consistent across domains and for both improvement and deterioration will facilitate interpretation of results of studies examining quality of life.

The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials

When little or no data directly comparing two treatments are available, investigators often rely on indirect comparisons from studies testing the treatments against a control or placebo. One approach to indirect comparison is to pool findings from the active treatment arms of the original controlled trials. This approach offers no advantage over a comparison of observational study data and is prone to bias. We present an alternative model that evaluates the differences between treatment and placebo in two sets of clinical trials, and preserves the randomization of the originally assigned patient groups. We apply the method to data on sulphamethoxazole-trimethoprim or dapsone/pyrimethamine as prophylaxis against Pneumocystis carinii in HIV infected patients. The indirect comparison showed substantial increased benefit from the former (odds ratio 0.37, 95% CI 0.21 to 0.65), while direct comparisons from randomized trials suggests a much smaller difference (risk ratio 0.64, 95% CI 0.45 to 0.90; p-value for difference of effect = 0.11). Direct comparisons of treatments should be sought. When direct comparisons are unavailable, indirect comparison meta-analysis should evaluate the magnitude of treatment effects across studies, recognizing the limited strength of inference.

Measuring quality of life in children with asthma

The Paediatric Asthma Quality of Life Questionnaire contains 23 items that children with asthma have identified as troublesome in their daily lives. The aim was to evaluate the measurement properties of the questionnaire. The study design consisted of a 9 week single cohort study with assessments at 1, 5 and 9 weeks. Patients participating in the study were fifty-two children, 7–17 years of age, with a wide range of asthma severity. At each clinic visit, a trained interviewer administered the Paediatric Asthma Quality of Life Questionnaire, the Feeling Thermometer, a clinical asthma control questionnaire and measured spirometry. For 1 week before each clinic visit, patients recorded morning peak flow rates, medication use and symptoms in a diary. The Paediatric Asthma Quality of Life Questionnaire was able to detect quality of life changes in those patients who altered their health status either as a result of treatemnt or natural fluctuations in their asthma (p<0.001) and to differentiate these patients from those who remained stable (p<0.0001). It was reproducible in patients who were stable (ICC=0.95), which also indicates the instruments strength to discriminate between subjects of different impairment levels. The questionnaire showed good levels of both longitudinal and cross-sectional correlations with the conventional asthma indices and with general quality of life. The results were consistent across individual domains and different age strata. The Paediatric Asthma Quality of Life Questionnaire has good measurement properties and is valid both as an evaluative and a discriminative instrument. It captures aspects of asthma most important to the patient and adds additional information to conventional clinical outcomes.

Risk Factors for Gastrointestinal Bleeding in Critically Ill Patients

Background The efficacy of prophylaxis against stress ulcers in preventing gastrointestinal bleeding in critically ill patients has led to its widespread use. The side effects and cost of prophylaxis, however, necessitate targeting preventive therapy to those patients most likely to benefit. Methods We conducted a prospective multicenter cohort study in which we evaluated potential risk factors for stress ulceration in patients admitted to intensive care units and documented the occurrence of clinically important gastrointestinal bleeding (defined as overt bleeding in association with hemodynamic compromise or the need for blood transfusion). Results Of 2252 patients, 33 (1.5 percent; 95 percent confidence interval, 1.0 to 2.1 percent) had clinically important bleeding. Two strong independent risk factors for bleeding were identified: respiratory failure (odds ratio, 15.6) and coagulopathy (odds ratio, 4.3). Of 847 patients who had one or both of these risk factors, 31 (3.7 percent; 95 percent confidence ...

Incidence of and Risk Factors for Ventilator-Associated Pneumonia in Critically Ill Patients

A recent international prevalence study involving more than 1000 intensive care units indicated that pneumonia is responsible for almost half of the infections in critically ill patients in Europe [1]. Ventilator-associated pneumonia accounts for approximately 90% of infections in patients requiring assisted ventilation [2, 3]. An independent contribution to mortality conferred by ventilator-associated pneumonia was recently suggested [4, 5]. Although debate persists about the mortality attributable to ventilator-associated pneumonia among other causes of death in critically ill patients [1, 4-7], there is little doubt that ventilator-associated pneumonia causes substantial morbidity by increasing the duration of mechanical ventilation and intensive care unit stay [4, 5]. It is therefore important to understand the factors that are predictive of ventilator-associated pneumonia, to identify patients at highest risk, and to target these patients for the most effective preventive strategies as determined by randomized trials [8, 9]. Risk factors for nosocomial pneumonia have been evaluated in hospitalized elderly persons [10], heterogeneous groups of hospitalized patients breathing spontaneously or requiring assisted ventilation [11], and similar mixed populations admitted to the intensive care unit [2, 12-15]. Investigations in ventilated critically ill patients only are needed to identify independent predictors of ventilator-associated pneumonia. Most studies of risk factors for ventilator-associated pneumonia have been conducted at single institutions, and different predictors have been examined. In cohort studies using multivariable analyses [16-21], only reintubation [17, 19, 21] and antibiotic use [18, 20] were identified as risk factors in more than one report. However, a direct relation between antibiotics and pneumonia was found in one study [18], whereas an inverse relation was found in another [20]. We examined factors associated with ventilator-associated pneumonia. We explored baseline and time-dependent characteristics, including measures of illness severity, factors relating to mechanical ventilation, variables in the gastropulmonary route of infection, and drug exposure. Methods Patients We used a multicenter national database of 1200 patients who received mechanical ventilation for 48 hours or more and were enrolled from October 1992 to May 1996 in a double-blind, concealed, randomized trial of sucralfate compared with ranitidine to determine rates of ventilator-associated pneumonia and gastrointestinal bleeding [22]. Patients were followed until death, discharge, or clinical suspicion of ventilator-associated pneumonia as determined by the attending intensivist. Bronchoalveolar lavage or protected specimen brush was indicated for patients with a clinical suspicion of ventilator-associated pneumonia. A diagnosis of ventilator-associated pneumonia was considered only in patients who were receiving mechanical ventilation or who stopped receiving ventilation for less than 48 hours. In the absence of a reference standard for diagnosing pneumonia in critically ill patients [23, 24], each patients clinical, laboratory, and radiographic data were independently reviewed by one of four pairs of adjudicators blinded to treatment group. The readers in each adjudication pair decided on the presence or absence of ventilator-associated pneumonia, resolving any disagreement through discussion. Consensus was achieved on all cases. The adjudicated outcome was used for the primary analysis [177 cases]. However, each case of pneumonia was classified according to four additional definitions: 1) the bedside clinicians diagnosis [233 cases]; 2) the modified Centers for Disease Control and Prevention criteria [25], which require a new radiographic infiltrate persistent for 48 hours or more plus a body temperature greater than 38.5 C or less than 35.0 C, a leukocyte count of more than 10 cells 109/L or less than 3 cells 109/L, purulent sputum or change in character of sputum, or isolation of pathogenic bacteria from an endotracheal aspirate [211 cases]; 3) a Clinical Pulmonary Infection score of 7 or more [26] [194 cases]; or 4) a positive culture from bronchoalveolar lavage (>104 colony-forming units/mL) or protected specimen brush (<103 colony-forming units/mL) (97 cases). Statistical Analysis We expressed continuous variables as the mean (SD) or as the median and interquartile range if their distribution was skewed. We used the Student t-test to compare continuous variables and the chi-square test to compare proportions. All statistical tests were two-tailed. We performed a forward stepwise Cox proportional-hazards regression analysis to evaluate potential risk factors for ventilator-associated pneumonia. The Cox model assesses the effect of each risk factor on the hazard rate of ventilator-associated pneumonia over time, adjusted for other factors in the model and allowing for censoring because of death or discharge. The hazard function in the Cox model can be used to estimate the event rate per day over the duration of stay in the intensive care unit. Independent variables recorded at baseline included age; sex; primary diagnosis; medical or surgical status; hospital admission in the fall or winter compared with spring or summer; location before admission to the intensive care unit; treatment center; Acute Physiology and Chronic Health Evaluation II score; Acute Physiology score; Multiple Organ Dysfunction score [27]; Glasgow Coma Scale score; and chronic comorbid conditions, such as alcoholism, a smoking history of 10 or more pack-years, asthma, bronchiectasis, pulmonary fibrosis, cancer, and HIV infection; organ transplantation; and recent corticosteroid therapy or chemotherapy. Additional independent variables evaluated daily throughout the intensive care unit stay were classified as illness severity measures (daily Multiple Organ Dysfunction score and change in Multiple Organ Dysfunction score from baseline), ventilation variables (mechanical ventilation, change or reinsertion of endotracheal tube, discontinuation and reinstitution of mechanical ventilation, and tracheostomy), nutritional variables (nasoenteral nutrition, gastrostomy feeding, jejunostomy feeding, enteral nutrition through any route, central parenteral nutrition, peripheral parenteral nutrition, and insulin requirement of more than 15 U/d), witnessed aspiration, and drug exposure (stress-ulcer prophylaxis with ranitidine or sucralfate, paralytic agents, and antibiotics). The Multiple Organ Dysfunction Score combines measures of physiologic dysfunction in six domains: the cardiovascular system (heart rate x right atrial pressure/mean arterial pressure), pulmonary system (Pao 2:Fio 2 ratio), the renal system (serum creatinine concentration), the hepatic system (serum bilirubin level), the hematologic system (platelet count), and the central nervous system (Glasgow Coma Scale score) [25]. These continuous variables are constructed in 5 categories so that 0 represents normal function and 4 reflects marked physiologic derangement and is associated with a mortality rate greater than 50%. Composite scores provide a quantitative measure of global physiologic dysfunction at a discrete point in the intensive care unit stay. For individual domains, either the raw data or their score provides a measure of dysfunction in the system of interest. Variables that were associated with ventilator-associated pneumonia in the univariable analysis and had a P value less than 0.10 were entered into a multivariable regression analysis. Factors were considered significant if the P value was less than 0.05 in the multivariable analysis. We calculated risk ratios and 95% CIs for all significant predictors of ventilator-associated pneumonia in the multivariable analysis using all five definitions. We tested for all pairwise interactions between significant risk factors in the multivariable model. We also tested for interactions between predictors in the multivariable model and factors that were significant in the univariable analysis. Finally, we investigated the possibility that the effects of risk factors may vary over the duration of stay in the intensive care unit; this was done by using a nonproportional Cox model testing the interaction of each variable in the final model with time. For example, we hypothesized that the influence of antibiotics on ventilator-associated pneumonia may vary over time. Time was considered both a continuous variable and a discretized variable by using 3-day and 5-day intervals. We did not consider antibiotics administered 24 hours before the diagnosis of ventilator-associated pneumonia, so that drugs prescribed in response to early ventilator-associated pneumonia would be excluded [28]. Role of Study Sponsor Our funding sources had no role in the acquisition, analysis, or interpretation of data or in the submission of this report. Results Of the 1200 patients enrolled in this study, 186 were excluded (85 were discharged, 71 died, and 30 had pneumonia in the first 48 hours), leaving 1014 patients ventilated for 48 hours or more who were free of pneumonia at admission to the intensive care unit. Of these patients, 177 (17.5%) developed ventilator-associated pneumonia 9.0 5.9 days after admission (median, 7 days [interquartile range, 5 to 10 days]). The characteristics of patients with and without ventilator-associated pneumonia are shown in Table 1. The total duration of mechanical ventilation among patients with ventilator-associated pneumonia was 19.3 16.0 days (median, 15 days [interquartile range, 9 to 23 days]) compared with 10.2 10.5 days (median, 7 days [interquartile range, 4 to 11 days]) in other patients (P < 0.001). Among the 177 patients with ventilator-associated pneumonia, 131 (74.0%) had bronchoscopic testing with bronchoalveolar lavage or protected specimen brush. Patients in the following admitting diagnostic categories

A Comparison of Sucralfate and Ranitidine for the Prevention of Upper Gastrointestinal Bleeding in Patients Requiring Mechanical Ventilation

BACKGROUND Critically ill patients who require mechanical ventilation are at increased risk for gastrointestinal bleeding from stress ulcers. There are conflicting data on the effect of histamine H2-receptor antagonists and the cytoprotective agent sucralfate on rates of gastrointestinal bleeding, ventilator-associated pneumonia, and mortality. METHODS In a multicenter, randomized, blinded, placebo-controlled trial, we compared sucralfate with the H2-receptor antagonist ranitidine for the prevention of upper gastrointestinal bleeding in 1200 patients who required mechanical ventilation. Patients received either nasogastric sucralfate suspension (1 g every six hours) and an intravenous placebo or intravenous ranitidine (50 mg every eight hours) and a nasogastric placebo. RESULTS The patients in the two groups had similar base-line characteristics. Clinically important gastrointestinal bleeding developed in 10 of 596 (1.7 percent) of the patients receiving ranitidine, as compared with 23 of 604 (3.8 percent) of those receiving sucralfate (relative risk, 0.44; 95 percent confidence interval, 0.21 to 0.92; P=0.02). In the ranitidine group, 114 of 596 patients (19.1 percent) had ventilator-associated pneumonia, as compared with 98 of 604 (16.2 percent) in the sucralfate group (relative risk, 1.18; 95 percent confidence interval, 0.92 to 1.51; P=0.19). There was no significant difference between the groups in mortality in the intensive care unit (ICU) (23.5 percent in the ranitidine group and 22.9 percent in the sucralfate group) or the duration of the stay in the ICU (median, nine days in both groups). CONCLUSIONS Among critically ill patients requiring mechanical ventilation, those receiving ranitidine had a significantly lower rate of clinically important gastrointestinal bleeding than those treated with sucralfate. There were no significant differences in the rates of ventilator-associated pneumonia, the duration of the stay in the ICU, or mortality.

A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group.

BACKGROUND Critically ill patients who require mechanical ventilation are at increased risk for gastrointestinal bleeding from stress ulcers. There are conflicting data on the effect of histamine H2-receptor antagonists and the cytoprotective agent sucralfate on rates of gastrointestinal bleeding, ventilator-associated pneumonia, and mortality. METHODS In a multicenter, randomized, blinded, placebo-controlled trial, we compared sucralfate with the H2-receptor antagonist ranitidine for the prevention of upper gastrointestinal bleeding in 1200 patients who required mechanical ventilation. Patients received either nasogastric sucralfate suspension (1 g every six hours) and an intravenous placebo or intravenous ranitidine (50 mg every eight hours) and a nasogastric placebo. RESULTS The patients in the two groups had similar base-line characteristics. Clinically important gastrointestinal bleeding developed in 10 of 596 (1.7 percent) of the patients receiving ranitidine, as compared with 23 of 604 (3.8 percent) of those receiving sucralfate (relative risk, 0.44; 95 percent confidence interval, 0.21 to 0.92; P=0.02). In the ranitidine group, 114 of 596 patients (19.1 percent) had ventilator-associated pneumonia, as compared with 98 of 604 (16.2 percent) in the sucralfate group (relative risk, 1.18; 95 percent confidence interval, 0.92 to 1.51; P=0.19). There was no significant difference between the groups in mortality in the intensive care unit (ICU) (23.5 percent in the ranitidine group and 22.9 percent in the sucralfate group) or the duration of the stay in the ICU (median, nine days in both groups). CONCLUSIONS Among critically ill patients requiring mechanical ventilation, those receiving ranitidine had a significantly lower rate of clinically important gastrointestinal bleeding than those treated with sucralfate. There were no significant differences in the rates of ventilator-associated pneumonia, the duration of the stay in the ICU, or mortality.

Measuring quality of life in the parents of children with asthma

Parents and primary caregivers of children with asthma are limited in normal daily activities and experience anxieties and fears due to the childs illness. We have developed the Paediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ) to measure these impairments. The objective of this study was to evaluate the measurement properties of the PACQLQ. A 9-week single cohort study was conducted with assessments at 1, 5 and 9 weeks. Participants in the study were primary caregivers of 52 children (age 7–17 years) with symptomatic asthma, recruited from notices in the local media and paediatric asthma clinics. Caregivers completed the PACQLQ, Impact-on-Family Scale and Global Rating of Change Questionnaires. Patients completed the Paediatric Asthma Quality of Life Questionnaire and an asthma control questionnaire. Spirornetry and β-agonist use were recorded. The PACQLQ was able to detect quality of life changes in those caregivers who changed (p<0.001) and to differentiate these from the caregivers whose quality of life remained stable (p<0.0001). The PACQLQ is reproducible in subjects who are stable (ICC=0.84), and showed acceptable levels of longitudinal and cross-sectional correlations with the childs asthma status and health-related quality of life and with other measures of caregiver health-related quality of life. The PACQLQ functions well as both an evaluative and a discriminative instrument.

Interpreting treatment effects in randomised trials

The need to measure the impact of treatments on health related quality of life has led to a rapid increase in the variety of instruments available and in their use as measures of outcome in clinical trials. One limitation of instruments that purport to measure health related quality of life is difficulty interpreting their results. In the past decade, investigators have progressed in making these questionnaire results interpretable. For example, we have shown that when questionnaires present response options in the form of seven point scales with verbal descriptions for each option (see box), the smallest difference that patients consider important is often approximately 0.5 per question. A moderate difference corresponds to a change of approximately 1.0 per question, and changes of greater than 1.5 can be considered large. Thus, for example, in a domain with four items, patients will consider a 1 point change in two or more items as important. This finding applies across different areas of function, including dyspnoea, fatigue, and emotional function in patients with chronic airflow limitation1; and symptoms, emotional function, and activity limitations in adults2 and children3 with asthma, parents of children with asthma,4 and adults with rhinoconjunctivitis.5 Initially, we used comparisons in the same patient to establish this difference, but more recently we have replicated this finding using differences between patients.6 #### Summary points Several questionnaires on quality of life related to health are available, but interpreting their results may be difficult For some questionnaires, we now know that the smallest change in score that patients consider important is 0.5 Even if the mean difference between a treatment and a control is appreciably less than the smallest change that is important, treatment may have an important impact on many patients A method for estimating the proportion of patients who …

The influence of dietary and nondietary calcium supplementation on blood pressure: an updated metaanalysis of randomized controlled trials.

We updated our previous systematic review of the effect of supplemental calcium on blood pressure. We extended our previous searches on MEDLINE and EMBASE to May 1997 and examined citations from relevant articles. We contacted the authors of eligible trials to ensure the accuracy and completeness of data, and to identify unpublished trials. We included any study in which investigators randomized hypertensive or normotensive people to calcium supplementation or alternative therapy and measured blood pressure for at least 2 weeks. In addition to 32 trials included in the prior metaanalysis, 10 new trials contributed to this metaanalysis. Two pairs of independent reviewers abstracted data and assessed the validity of the study data according to six quality criteria. We calculated the differences in blood pressure change between the calcium supplementation and control groups and pooled the estimates with each trial weighted with the inverse of the variance using a random effects model. The predictors of blood pressure reduction that we examined included method of supplementation, baseline blood pressure, and the methodologic quality of the studies. The pooled analysis shows a reduction in systolic blood pressure of -1.44 mm Hg (95% confidence interval -2.20 to -0.68; P < .001) and in diastolic blood pressure of -0.84 mm Hg (95% confidence interval -1.44 to -0.24; P < .001). We found statistically significant heterogeneity of results across trials (P < or = .02), which persisted when we looked at the nondietary trials alone, but not when we restricted our analysis to dietary trials. Although there was a trend toward larger effects with dietary interventions, none of the possible mediators of blood pressure reduction explained differences in treatment effect. We conclude that calcium supplementation leads to a small reduction in systolic and diastolic blood pressure. The effect of supplemental calcium in the diet is at least as great as nondietary supplementation.