Back pain, mental health and substance use are associated in adolescents.

BACKGROUND: During adolescence, prevalence of pain and health risk factors such as smoking, alcohol use and poor mental health all rise sharply. The aim of this study was to describe the relationship between back pain and health risk factors in adolescents. METHODS: Cross-sectional data from the Healthy Schools Healthy Futures study, and the Australian Child Wellbeing Project was used, mean age: 14-15 years. Children were stratified according to back pain frequency. Within each strata, the proportion of children that reported drinking alcohol or smoking or that experienced feelings of anxiety or depression was reported. Test-for-trend analyses assessed whether increasing frequency of pain was associated with health risk factors. RESULTS: Data was collected from ~2500 and 3900 children. Larger proportions of children smoked or drank alcohol within each strata of increasing pain frequency. The trend with anxiety and depression was less clear, although there was a marked difference between the children that reported no pain, and pain more frequently. CONCLUSION: Two large, independent samples show adolescents that experience back pain more frequently are also more likely to smoke, drink alcohol and report feelings of anxiety and depression. Pain appears to be part of the picture of general health risk in adolescents.

Telephone-based weight loss support for patients with knee osteoarthritis: a pragmatic randomised controlled trial.

OBJECTIVE: To determine the effectiveness of telephone-based weight loss support in reducing the intensity of knee pain in patients with knee osteoarthritis, who are overweight or obese, compared to usual care. DESIGN: We conducted a parallel randomised controlled trial (RCT), embedded within a cohort multiple RCT of patients on a waiting list for outpatient orthopaedic consultation at a tertiary referral hospital in NSW, Australia. Patients with knee osteoarthritis, classified as overweight or obese [body mass index (BMI) between ≥27 kg/m2 and <40 kg/m2] were randomly allocated to receive referral to an existing non-disease specific government funded 6-month telephone-based weight management and healthy lifestyle service or usual care. The primary outcome was knee pain intensity measured using an 11-point numerical rating scale (NRS) over 6-month follow-up. A number of secondary outcomes, including self-reported weight were measured. Data analysis was by intention-to-treat according to a pre-published analysis plan. RESULTS: Between May 19 and June 30 2015, 120 patients were randomly assigned to the intervention (59 analysed, one post-randomisation exclusion) or usual care (60 analysed). We found no statistically significant between group differences in pain intensity [area under the curve (AUC), mean difference 5.4, 95%CI: -13.7 to 24.5, P = 0.58] or weight change at 6 months (self-reported; mean difference -0.4, 95%CI: -2.6 to 1.8, P = 0.74). CONCLUSIONS: Among patients with knee osteoarthritis who are overweight, telephone-based weight loss support, provided using an existing 6-month weight management and healthy lifestyle service did not reduce knee pain intensity or weight, compared with usual care. TRIAL REGISTRATION NUMBER: ACTRN12615000490572.

Help-seeking experiences of men diagnosed with colorectal cancer: a qualitative study.

Advanced-stage diagnosis of colorectal cancer (CRC) leads to poor prognosis and reduced survival rates. The current study seeks to explore the reasons for diagnostic delays in a sample of Australian men with CRC. Semi-structured interviews were conducted in a purposive sample of 20 male CRC patients. Data collection ceased when no new data emerged. Interviews were audiotaped, transcribed and thematically analysed using Andersen's Model of Total Patient Delay as the theoretical framework. Most participants (18/20) had experienced lower bowel symptoms prior to diagnosis. Patient-related delays were more common than delays attributable to the health-care system. Data regarding patient delays fit within the first four stages of Andersen's model. The barriers to seeking timely medical advice were mainly attributed to misinterpretation of symptoms, fear of cancer diagnosis, reticence to discuss the symptoms or consulting a general practitioner. Treatment delays were a minor cause for delayed diagnosis. Delay in referral and scheduling for colonoscopy were among the system-delay factors. In many instances, delays resulted from men's failure to attribute their symptoms to cancer and, subsequently, delay in diagnosis.

A trial of a self-assessment tool of problems following treatment of colorectal cancer: a prospective study in Australia primary care.

Patients treated for colorectal cancer (CRC) experience considerable physical, social and psychological morbidity. In this study, 66 participants with stages I-III CRC were enrolled in this study. Participants completed the self-assessment tool for patients (SATp) over a 5-month period and visited a general practitioner with a copy of their SATp to assist in the management of any problems associated with CRC treatment. General practitioners' notes were reviewed for management actions. Of the 66 participants, 57 visited a general practitioner over the 5-month study period. A total of 547 problems were identified (median 7; IQR: 3-12.25). Participants with physical problems were more likely to consult their general practitioner (OR: 1.84, CI: 1.05-3.21, P = 0.03) compared to those with psychological problems. The number of problems experienced by participants did not have any influence on the decision to visit a general practitioner. Psychological problems (P < 0.01) significantly reduced over the 5-month study period. Regular use of the SATp facilitates the identification of long-term CRC treatment-related problems. Some of these problems could then be addressed in primary care.

Causal mechanisms in the clinical course and treatment of back pain.

In recent years, there has been increasing interest in studying causal mechanisms in the development and treatment of back pain. The aim of this article is to provide an overview of our current understanding of causal mechanisms in the field. In the first section, we introduce key concepts and terminology. In the second section, we provide a brief synopsis of systematic reviews of mechanism studies relevant to the clinical course and treatment of back pain. In the third section, we reflect on the findings of our review to explain how understanding causal mechanisms can inform clinical practice and the implementation of best practice. In the final sections, we introduce contemporary methodological advances, highlight the key assumptions of these methods, and discuss future directions to advance the quality of mechanism-related studies in the back pain field.

The adenoma carcinoma sequence: an indoctrinated model for tumorigenesis, but is it always a clinical reality?

OBJECTIVE: Evidence exists to support alternative pathways to the adenoma carcinoma sequence. Some mutations in key onco-suppressor genes relate to the anatomical site of the tumour. This link is typified by microsatellite instability and proximal neoplasia. However, rectal tumours are rarely considered separately. We hypothesized that tumour behaviour in the rectum may differ in terms of pathogenesis and malignant propensity. Therefore, we aimed to look for an association between the histopathological features of adenomas and their anatomical location as compared with the distribution of cancers. METHODS: A single centre prospective study was undertaken over a four-year period. Patients referred to a colorectal assessment clinic with bowel symptoms underwent a minimum investigation of flexible sigmiodoscopy. Neoplastic lesions were either biopsied or removed after noting distance from the anal margin. Adenomas, differentiated by size, villous architecture and degree of dysplasia were compared to both early and advanced carcinomas. RESULTS: Of 4089 patients, polyps were identified in 8.0% and cancer in 4.2%. There was a clear difference between the distribution of cancer and adenomas > 1 cm, P < 0.001. All degrees of dysplasia in large adenomas were more prevalent in the sigmoid colon as compared to cancer, P < 0.001. Seventy-five percent of high risk diminutive adenomas were rectal in origin. CONCLUSION: Our data provides indirect evidence to support the concept that a significant proportion of rectal cancers may arise via an alternative pathway to the Vogelstein model. Polyp behaviour along with malignant propensity may actually be site dependent, with rectal polyps harbouring a more aggressive phenotype.

Symptomatic presentation of early colorectal cancer.

INTRODUCTION: It is believed that increased detection of earlier stage colorectal cancer can only be achieved by screening asymptomatic individuals. We describe a referral pathway for a symptomatic population which achieves a 30% Dukes' A detection rate. PATIENTS AND METHODS: From October 1999, 4253 patients with distal colonic symptoms, referred by general practitioners, completed a patient consultation questionnaire (PCQ) linked to a computerised record. A weighted numerical score (WNS) was derived for each patient. Patients underwent flexible sigmoidoscopy, a diagnostic outcome was recorded and later Dukes' stage appended. Early and advanced colorectal cancers were separated and PCQ derived symptom profiles compared. Chi-square, Fisher exact, Student's t-test and logistic regression were used for statistical analysis. RESULTS: A total of 183 patients had cancer, 55 (30%) were Dukes' A early colorectal cancers, 112 were advanced colorectal cancers (Dukes' B-D) and 16 could not be staged. Early colorectal cancers had significant symptoms and comparable profile to advanced colorectal cancers. The tendency in advanced colorectal cancers was towards greater symptom prevalence for only a few primary and systemic symptoms, as reflected by a higher WNS of 75 (P = 0.001). CONCLUSIONS: Early colorectal cancers do have significant symptoms which can easily be captured by a PCQ and objective scoring tool in the secondary care setting. Detection of these cancers has the potential to improve survival.

Pitfalls in the construction of cancer guidelines demonstrated by the analyses of colorectal referrals.

INTRODUCTION: The aim of this study was to develop a system to compare and validate cancer referral guidelines, identifying the pitfalls in their development and provide a mechanism to evaluate their efficacy. PATIENTS AND METHODS: 3302 patients referred from primary care with colorectal symptoms over a 3-year period were assessed. All participants had a comprehensive history obtained via a questionnaire that incorporated all colorectal symptoms. The questionnaires were completed prior to assessment at the hospital. All patients were then assessed at the Colorectal One Stop Clinic (CROSC), underwent investigation and diagnosis achieved. All data were entered into a databank. Current prioritisation guidelines and tools that are used to assess colorectal referrals were applied to this colorectal databank to test their efficacy for cancer detection and referral prioritisation. Sensitivity and specificity for cancer detection and referral rates were assessed. RESULTS: Cancer was detected in 156 patients (4.7%). All prioritisation models (NHS guidelines, Weighted Numerical Score [WNS], Netherlands, Harvard, Mersey, and Somerset) differentiated cancer from non-cancer patients. The use of a few symptoms as risk predictors (e.g. NHS guidelines) causes a decrease in specificity in contrast to a comprehensive risk tool, for example, the WNS at a score of 50 (NHS 54.1%, WNS 62.9%). This results in a significantly higher referral rate (NHS 47.6%, WNS 39.4%) and identifies fewer cancers (NHS 80.1%, WNS 85.9%). Non-evidence based modifications of the NHS guidelines (Somerset and Mersey) caused a further deterioration in specificity, which was reflected in an increased referral rate. Using the WNS, which is objective and a continuous scale, allows adaptation of the referral threshold, balancing sensitivity and specificity to the resources available within a hospital. For example, the WNS of > or = 40 has a sensitivity of 96.8% for cancer detection. CONCLUSIONS: Accurate prospective data collection into a data bank allows testing of referral guidelines as well as providing an adjunct to guideline construction.

Variations in the evaluation of colorectal cancer risk.

OBJECTIVES: To test the variability in estimating cancer risk and demonstrate the consequences that subjectivity has on patient care. SUBJECTS AND METHODS: Forty-three clinicians were each asked to assess 40 symptomatic colorectal referrals. Each clinician was provided with a comprehensive history on the 40 patients. The clinicians graded the referral according to a malignancy risk score, decided on the required first line investigation and the priority of that investigation. The main outcome measures used was accuracy in cancer detection and appropriateness of investigations selected. RESULTS: There was a wide degree of variation among all clinicians grading both benign and malignant disease with the overall correct classification of 54% (P-value of <0.001). On average, the clinicians correctly diagnosed 71.3% of the cancer patients as compared to 44% of the benign patients. Of the cancer patients, 47% were correctly classified as an urgent referral whilst 52% of the benign patients were over classified and graded as an urgent referral. The mean number chosen by clinicians to have a flexible sigmoidoscopy as the appropriate first investigation was 13 (of 40 patients); this was despite the diagnosis being possible in all cases with a flexible sigmoidoscopy. The choice to use full colonic investigation was seen throughout all disciplines. Junior doctors demonstrated the highest tendency choosing full colonic investigation in 92.3%. Consultants and senior grades showed the least tendency to choose full colonic imaging although even here colonoscopy or barium enema represented 48.5%. CONCLUSION: Subjective assessment of cancer referrals is a significant problem that needs to be confronted. Improvements are needed to resolve the inherent problems of subjectivity and operator bias if uniform quality of patient care and best use of resources is to be achieved.

Low incidence of paradoxical bronchoconstriction with bronchodilator drugs administered by Respimat Soft Mist inhaler: results of phase II single-dose crossover studies.

BACKGROUND AND OBJECTIVES: Respimat Soft Mist Inhaler (SMI) is an innovative device that offers improved lung deposition and is an environmentally friendly alternative to conventional, chlorofluorocarbon-containing metered-dose inhalers (CFC-MDIs). The aqueous formulations of bronchodilator drugs administered from Respimat SMI contain low concentrations of ethylene diamine tetra-acetic acid (EDTA), a stabilising agent, and benzalkonium chloride (BAC), an antibacterial agent, both of which have been associated with bronchoconstriction when administered via nebulisers. The aim of this retrospective analysis was to compare the incidence of paradoxical bronchoconstriction with bronchodilator drugs administered via Respimat SMI or a CFC-MDI in patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: Nine randomised, active- and/or placebo-controlled, double-blind, crossover studies, in which asthmatic and COPD patients (n = 444 and n = 216, respectively) received a beta(2)-agonist and/or anticholinergic or placebo via Respimat SMI or CFC-MDI, were included in the analysis. The incidence of conditions indicative of paradoxical bronchoconstriction were collated and divided into four categories: (1) 'bronchospasm'; (2) two or more of the following events: 'other respiratory adverse events', 'rescue medication use' or 'asymptomatic drop in forced expiratory volume in one second' (FEV(1)); (3) either 'rescue medication use' or 'other respiratory adverse event'; (4) 'asymptomatic drop in FEV(1)'. RESULTS: The incidence of adverse events indicative of paradoxical bronchoconstriction was low in those patients using the Respimat SMI device, and similar to that seen in the CFC-MDI group. In addition, the incidence of adverse events indicative of paradoxical bronchoconstriction observed in the Respimat SMI group was similar for BAC + EDTA and BAC-only drug formulations. CONCLUSIONS: These studies demonstrate that, due to the extremely low absolute amounts of BAC and EDTA delivered to the lungs by the device, Respimat SMI is safe with regard to paradoxical bronchoconstriction in patients with asthma or COPD.

Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.

BACKGROUND: A study was undertaken to record exacerbations and health resource use in patients with COPD during 6 months of treatment with tiotropium, salmeterol, or matching placebos. METHODS: Patients with COPD were enrolled in two 6-month randomised, placebo controlled, double blind, double dummy studies of tiotropium 18 micro g once daily via HandiHaler or salmeterol 50 micro g twice daily via a metered dose inhaler. The two trials were combined for analysis of heath outcomes consisting of exacerbations, health resource use, dyspnoea (assessed by the transitional dyspnoea index, TDI), health related quality of life (assessed by St George's Respiratory Questionnaire, SGRQ), and spirometry. RESULTS: 1207 patients participated in the study (tiotropium 402, salmeterol 405, placebo 400). Compared with placebo, tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation. Fewer COPD exacerbations/patient year occurred in the tiotropium group (1.07) than in the placebo group (1.49, p<0.05); the salmeterol group (1.23 events/year) did not differ from placebo. The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo (not statistically different). For all causes (respiratory and non-respiratory) tiotropium, but not salmeterol, was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group. The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group (tiotropium 8.3 (0.8), salmeterol 11.1 (0.8), placebo 10.9 (0.8), p<0.05). SGRQ total score improved by 4.2 (0.7), 2.8 (0.7) and 1.5 (0.7) units during the 6 month trial for the tiotropium, salmeterol and placebo groups, respectively (p<0.01 tiotropium v placebo). Compared with placebo, TDI focal score improved in both the tiotropium group (1.1 (0.3) units, p<0.001) and the salmeterol group (0.7 (0.3) units, p<0.05). Evaluation of morning pre-dose FEV(1), peak FEV(1) and mean FEV(1) (0-3 hours) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo. CONCLUSIONS: Exacerbations of COPD and health resource usage were positively affected by daily treatment with tiotropium. With the exception of the number of hospital days associated with all causes, salmeterol twice daily resulted in no significant changes compared with placebo. Tiotropium also improved health related quality of life, dyspnoea, and lung function in patients with COPD.

Prediction of colorectal cancer by a patient consultation questionnaire and scoring system: a prospective study.

BACKGROUND: Current NHS guidelines for referral of patients with colorectal symptoms classify many as high risk but fail to identify a significant number of cancers in the low-risk group. We describe a practical scoring method to predict colorectal cancers. METHODS: From October, 1999, 2268 patients with distal colonic symptoms, referred by general practitioners, completed a patient consultation questionnaire linked to a computerised record. Referrals were prioritised with a malignancy risk score by a senior colorectal surgeon separately from the general practitioner's letter and from the questionnaire. A weighted numerical score was derived from weighting of primary symptoms and symptom complexes and was calculated automatically when the questionnaire data were entered into the computer program. Analysis by receiver-operating characteristics assessed the scoring systems. Sensitivities and specificities of scoring systems were compared with McNemar's test. FINDINGS: Of the 2268 patients, 95 had colorectal cancer. The average weighted numerical score was significantly higher for patients with cancer than for non-cancer patients (mean 76.5 [95% CI 72.2-80.9] vs 44.5 [43.6-45.4]; p<0.0001). At similar cancer detection rates, the malignancy risk score derived from the patient consultation questionnaire and the weighted numerical score graded lower proportions of referrals as urgent than did the current NHS guidelines (43.1% and 39.8% vs 49.8%; p<0.0001). INTERPRETATION: The patient consultation questionnaire depends on history alone and is easily reproducible. In conjunction with the weighted numerical score, which removes operator bias, it can be used as an accurate system for prediction of symptomatic colorectal cancer.

Prevention and diagnosis of venous thromboembolism in critically ill patients: a Canadian survey.

BACKGROUND: Venous thromboembolism (VTE) confers considerable morbidity and mortality in hospitalized patients, although few studies have focused on the critically ill population. The objective of this study was to understand current approaches to the prevention and diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) among patients in the intensive care unit (ICU). DESIGN: Mailed self-administered survey of ICU Directors in Canadian university affiliated hospitals. RESULTS: Of 29 ICU Directors approached, 29 (100%) participated, representing 44 ICUs and 681 ICU beds across Canada. VTE prophylaxis is primarily determined by individual ICU clinicians (20/29, 69.0%) or with a hematology consultation for challenging patients (9/29, 31.0%). Decisions are usually made on a case-by-case basis (18/29, 62.1%) rather than by preprinted orders (5/29, 17.2%), institutional policies (6/29, 20.7%) or formal practice guidelines (2/29, 6.9%). Unfractionated heparin is the predominant VTE prophylactic strategy (29/29, 100.0%) whereas low molecular weight heparin is used less often, primarily for trauma and orthopedic patients. Use of pneumatic compression devices and thromboembolic stockings is variable. Systematic screening for DVT with lower limb ultrasound once or twice weekly was reported by some ICU Directors (7/29, 24.1%) for specific populations. Ultrasound is the most common diagnostic test for DVT; the reference standard of venography is rarely used. Spiral computed tomography chest scans and ventilation-perfusion scans are used more often than pulmonary angiograms for the diagnosis of PE. ICU Directors recommend further studies in the critically ill population to determine the test properties and risk:benefit ratio of VTE investigations, and the most cost-effective methods of prophylaxis in medical-surgical ICU patients. INTERPRETATION: Unfractionated subcutaneous heparin is the predominant VTE prophylaxis strategy for critically ill patients, although low molecular weight heparin is prescribed for trauma and orthopedic patients. DVT is most often diagnosed by lower limb ultrasound; however, several different tests are used to diagnose PE. Fundamental research in critically ill patients is needed to help make practice evidence-based.

What is new since the last (1999) Canadian Asthma Consensus Guidelines?

The objective of the present document is to review the impact of new information on the recommendations made in the last (1999) Canadian Asthma Consensus Guidelines. It includes relevant published studies and observations or comments regarding what are considered to be the main issues in asthma management in children and adults in office, emergency department, hospital and clinical settings. Asthma is still insufficiently controlled in a large number of patients, and practice guidelines need to be integrated better with current care. This report re-emphasises the need for the following: objective measures of airflow obstruction to confirm the diagnosis of asthma suggested by the clinical evaluation; identification of contributing factors; and the establishment of a treatment plan to rapidly obtain and maintain optimal asthma control according to specific criteria. Recent publications support the essential role of asthma education and environmental control in asthma management. They further support the role of inhaled corticosteroids as the mainstay of anti-inflammatory therapy of asthma, and of both long acting beta2-agonists and leukotriene antagonists as effective means to improve asthma control when inhaled corticosteroids are insufficient. New developments, such as combination therapy, and recent major trials, such as the Children's Asthma Management Project (CAMP) study, are discussed.

Decreased antibody response among nursing home residents who received recalled influenza vaccine and results of revaccination, 1996-97.

In November 1996, 11 lots of one U.S. manufacturer's 1996-97 trivalent influenza vaccine were voluntarily recalled because of decreasing potency of the A/Nanchang/933/95 (H3N2) component. Because the elderly are at high risk of developing influenza-related complications, we assessed the postvaccination antibody titers of nursing home residents who received recalled vaccine and assessed the antibody response to revaccination. Blood samples were collected 3 weeks after vaccination from 86 residents at three nursing homes who received recalled vaccine and 86 residents at three other nursing homes who received a different manufacturer's vaccine. Medical records were reviewed. Residents of one nursing home were later revaccinated. Blood samples were collected on the day of revaccination and again in 3 weeks. Serum was tested by hemagglutination inhibition for antibody to all three components of the 1996-97 influenza vaccine. The geometric mean antibody titer (GMT) (33 vs 55; p=0.01) and the percentage of residents with an antibody titer > or = 1:40 (52 vs 67%; p=0.04) to the A/Nanchang/933/95 component were lower among residents who received recalled vaccine compared to those who received non-recalled vaccine, but had similar GMTs against the other two vaccine components. After revaccination, the GMT to A/Nanchang/933/95 increased from 24 on the day of revaccination to 39 (p=0.01) in residents from one nursing home. Therefore, vaccination with the recalled vaccine was associated with lower postvaccination antibody titers to A/Nanchang/933/95, but not against the other two vaccine components. Revaccination was moderately effective in increasing antibody titers. With annual changes in influenza vaccine strains, routine post-release stability testing of influenza vaccine should continue.

Preventive practicum training in healthcare organizations. The Meharry model.

BACKGROUND: Practicum training for preventive medicine residents often occurs in agencies whose community is geographically defined and whose governance is closely linked to public election. We were unsure about the financial ability of such departments to support training and are concerned that over-reliance on traditional health departments might not be best for either medically indigent populations or preventive medicine. We, therefore, sought to apply a public health model--based on a strategic partnership between nursing and preventive medicine--to a large health care organization. The result was formation of a mini-health department, suitable for fully accredited preventive medicine practicum training, within the Alvin C. York Veterans Affairs Medical Center, Murfreesboro, TN. This Center serves a defined population of 21,594 patients and about 1600 employees. The theoretical framework for the new department was based on demonstration of a close fit between the competencies expected of preventive medicine physicians by the American College of Preventive Medicine (ACPM) and activities required by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). Because of JCAHO requirements, many healthcare organizations already pay for preventive medicine services. CONCLUSIONS: By placing preventive medicine training faculty into existing budget slots at our institution, systemwide personnel costs for prevention decreased by about $36,000 per year, even as personnel funding for preventive medicine physicians increased from about $24,000 to $376,000 per year. Moreover, there was dramatic, sustained improvement in 17 indicators of preventive care quality as determined by an external peer review organization. In addition to providing a new venue for training, this model may also improve the quality and reach of preventive services, decreased fixed costs for service delivery, and yield new employment opportunities for preventive medicine physicians.

Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice.

STUDY OBJECTIVE: To compare quality of life and exercise capacity (primary aim), and drug usage (secondary aim), between groups of patients with irreversible chronic airflow limitation (CAL) who were undergoing theophylline Theo-Dur; Key Pharmaceuticals; Kenilworth, NJ) therapy guided by n of 1 trials or standard practice. DESIGN: Randomized study of n of 1 trials vs standard practice. SETTING: Outpatient departments in two tertiary care centers. PATIENTS: Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators, and who were unsure whether theophylline was helping them following open treatment, were randomized into n of 1 trials (N=34) or standard practice. INTERVENTIONS: The n of 1 trials (single-patient, randomized, double-blind, multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo) followed published guidelines. Standard practice patients stopped taking theophylline but resumed it if their dyspnea worsened. If their dyspnea then improved, theophylline was continued. In both groups, a decision about continuing or stopping the use of theophylline was made within 3 months of randomization. MEASUREMENTS AND RESULTS: The primary outcomes (the chronic respiratory disease questionnaire [CRQ] and 6-min walk) were measured at baseline, 6 months, and 12 months by personnel blinded to treatment group allocation. No between-group differences (n of 1 minus standard practice) were seen in within-group changes over time (1 year minus baseline) in the CRQ Physical Function score (point estimate on the difference, -2.8; 95% confidence limits [CLs], -8.2, 2.5), CRQ Emotional Function score (point estimate on the difference, 0.5; 95% CLs, -4.7, 5.7), or 6-min walk (point estimate on the difference, 8 m; 95% CLs, -26, 44 m). No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months. In 7 of 34 n of 1 trial patients (21%), dyspnea improved during theophylline treatment compared with placebo treatment. CONCLUSIONS: Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity, or reduce drug usa e, over 1 year compared to standard practice. Under the objective conditions of an n of 1 trial, 21% of patients with CAL responded to theophylline. There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators, but the use of n of 1 trials to guide this decision did not yield clinically important advantages over standard practice.

Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group.

BACKGROUND: A strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome. The goal is to reduce lung injury due to overdistention. However, the efficacy of this approach has not been established. METHODS: Within 24 hours of intubation, patients at high risk for the acute respiratory distress syndrome were randomly assigned to either pressure- and volume-limited ventilation (limited-ventilation group), with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less, or to conventional ventilation (control group), with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram. All other ventilatory variables were similar in the two groups. RESULTS: A total of 120 patients with similar clinical features underwent randomization (60 in each group). The patients in the limited-ventilation and control groups were exposed to different mean (+/-SD) tidal volumes (7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram, respectively; P<0.001) and peak inspiratory pressures (23.6+/-5.8 vs. 34.0+/-11.0 cm of water, P<0.001). Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group (relative risk, 1.07; 95 percent confidence interval, 0.72 to 1.57; P=0.72). In the limited-ventilation group, permissive hypercapnia (arterial carbon dioxide tension, >50 mm Hg) was more common (52 percent vs. 28 percent, P=0.009), more marked (54.4+/-18.8 vs. 45.7+/-9.8 mm Hg, P=0.002), and more prolonged (146+/-265 vs. 25+/-22 hours, P=0.017) than in the control group. The incidence of barotrauma, the highest multiple-organ-dysfunction score, and the number of episodes of organ failure were similar in the two groups; however, the numbers of patients who required paralytic agents (23 vs. 13, P=0.05) and dialysis for renal failure (13 vs. 5, P= 0.04) were greater in the limited-ventilation group than in the control group. CONCLUSIONS: In patients at high risk for the acute respiratory distress syndrome, a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity.

The clinical efficacy of combination nebulized anticholinergic and adrenergic bronchodilators vs nebulized adrenergic bronchodilator alone in acute asthma. Canadian Combivent Study Group.

The role of ipratropium bromide as adjunct therapy to beta-agonists in acute asthma is uncertain. We therefore decided to compare the use of 3 mg of salbutamol sulfate alone vs 3 mg salbutamol sulfate with 0.5 mg ipratropium bromide in patients with acute asthma. Patients presenting with acute asthma and an FEV1 less than 70% predicted were randomized to a single combination treatment vs salbutamol alone. All patients received supplemental oxygen and methylpred-nisolone, 125 mg, IV. Baseline measurements were repeated at 45 and 90 min and these included spirometry, oximetry, and vital signs. A total of 952 patients were screened of whom 342 patients were deemed eligible and were randomized in two groups of 171 patients. The mean (SE) age was 30 years (0.9) vs 29 years (0.7), women, 103 (60.2%) vs 110 (64%), 81 (47.4%) never-smoked vs 83 (48.5%), and duration of asthma in years 16.0 (0.8) vs 16.6 (0.8) were no different in the combination vs salbutamol alone group, respectively. Likewise, there was no significant difference in asthma therapy received in the 24 h prior to presentation; most notably, 151 (88.3%) vs 153 (89.5%) received inhaled beta-agonists in that period. Baseline FEV1 was 1.62 L (0.05 L) vs 1.53 L (0.03 L), and median time to treatment being received was no different between both groups. Both treatment arms improved significantly. The increase in FEV1 in the combination group was 0.6I L (0.04 L) and in the salbutamol alone group was 0.52 L (0.04 L) at 90 min. There was a trend toward greater bronchodilation in the combination group, but this did not reach statistical significance. Fewer hospitalizations, 5.9% vs 11.2%, occurred in the combination group, but this did not reach statistical significance. In conclusion, this large multicenter study failed to show a significantly better response to a combination of salbutamol and ipratropium bromide vs salbutamol alone.