David M. Shade

Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients

OBJECTIVE To assess the safety and potential efficacy of a mechanical ventilation strategy designed to reduce stretch-induced lung injury in acute respiratory distress syndrome. DESIGN Prospective, randomized, controlled clinical trial. SETTING Eight intensive care units in four teaching hospitals. PATIENTS Fifty-two patients with acute respiratory distress syndrome. INTERVENTIONS Traditional tidal volume patients: tidal volume 10-12 mL/kg ideal body weight, reduced if inspiratory plateau pressure was > 55 cm H2O (7.3 kPa). Small tidal volume patients: tidal volume 5-8 mL/kg ideal body weight, to keep plateau pressure < 30 cm H2O (4.0 kPa). MEASUREMENTS AND MAIN RESULTS Mean tidal volumes during the first 5 days in traditional and small tidal volume patients were 10.2 and 7.3 mL/kg, respectively (p < .001), with mean plateau pressure = 30.6 and 24.9 cm H2O (3.3 kPa), respectively (p < .001). There were no significant differences in requirements for positive end-expiratory pressure or FIO2, fluid intakes/outputs, requirements for vasopressors, sedatives, or neuromuscular blocking agents, percentage of patients that achieved unassisted breathing, ventilator days, or mortality. CONCLUSIONS The reduced tidal volume strategy used in this study was safe. Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a) the sample size was too small to discern small treatment effects; b) the differences in tidal volumes and plateau pressures were modest; or c) reduced tidal volume ventilation is not beneficial.

Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial

IMPORTANCE Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. OBJECTIVE The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. DESIGN, SETTING, AND PARTICIPANTS The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. INTERVENTIONS Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. MAIN OUTCOMES AND MEASURES Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. RESULTS Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. CONCLUSIONS AND RELEVANCE Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00898807.

Effect of obesity on clinical presentation and response to treatment in asthma.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.

Allergic Rhinitis and Sinusitis in Asthma: Differential Effects on Symptoms and Pulmonary Function

BACKGROUND Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. METHODS A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. RESULTS More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). CONCLUSION Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.

Original Research: ASTHMAAllergic Rhinitis and Sinusitis in Asthma: Differential Effects on Symptoms and Pulmonary Function

BACKGROUND Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. METHODS A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. RESULTS More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). CONCLUSION Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.

Does Age Impact the Obese Asthma Phenotype?: Longitudinal Asthma Control, Airway Function, and Airflow Perception Among Mild Persistent Asthmatics

BACKGROUND The relationship between obesity and asthma remains inadequately defined. Studies about how obesity affects asthma control and lung function show conflicting results. Additional focus on the effect of age as a modifier may make clearer the interaction between obesity and asthma phenotype. We sought to use a diverse and well-phenotyped cohort of asthmatic patients to determine how age impacts the relationship between obesity and spirometry, peak flow variability, airflow perception, and asthma control. METHODS The characteristics of 490 patients with mild persistent asthma taken from 2,794 study visits from a prospective trial studying strategies of step-down therapy were included in this post hoc analysis. A longitudinal mixed-effect model was used to determine if age affects the relationship between obesity and asthma characteristics, including spirometry, asthma control, airway pH, and perception of airflow changes. RESULTS The effect of obesity on asthma outcomes changes with age and gender. Obese 6- to 11-year-old children had the largest reduction in lung function but reported relatively fewer asthma symptoms than did similar nonobese asthmatics. Obese 12- to 17-year-olds showed a trend toward greater airflow obstruction and asthma symptoms compared with nonobese asthmatics. Adults in general displayed few obesity-related alterations in asthma phenotype. Female gender among 12- to 17- and 18- to 44-year-olds was associated with greater obesity-related asthma impairment. CONCLUSIONS Age is a significant effect modifier on the relationship between obesity and asthma phenotype. With increasing age, the influence of obesity on the asthma phenotype is generally reduced. The asthma phenotype may be most impacted by obesity among children and women. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00156819; URL: www.clinicaltrials.gov.

Exercise Testing in Severe Emphysema: Association with Quality of Life and Lung Function

Six-minute walk testing (6MWT) and cardiopulmonary exercise testing (CPX) are used to evaluate impairment in emphysema. However, the extent of impairment in these tests as well as the correlation of these tests with each other and lung function in advanced emphysema is not well characterized. During screening for the National Emphysema Treatment Trial, maximum ergometer CPX and 6MWT were performed in 1,218 individuals with severe COPD with an average FEV1 of 26.9 ± 7.1 % predicted. Predicted values for 6MWT and CPX were calculated from reference equations. Correlation coefficients and multivariable regression models were used to determine the association between lung function, quality of life (QOL) scores, and exercise measures. The two forms of exercise testing were correlated with each other (r = 0.57, p < 0.0001). However, the impairment of performance on CPX was greater than on the 6MWT (27.6 ± 16.8 vs. 67.9 ± 18.9 % predicted). Both exercise tests had similar correlation with measures of QOL, but maximum exercise capacity was better correlated with lung function measures than 6-minute walk distance. After adjustment, 6MWD had a slightly greater association with total SGRQ score than maximal exercise (effect size 0.37 ± 0.04 vs. 0.25 ± 0.03 %predicted/unit). Despite advanced emphysema, patients are able to maintain 6MWD to a greater degree than maximum exercise capacity. Moreover, the 6MWT may be a better test of functional capacity given its greater association with QOL measures whereas CPX is a better test of physiologic impairment.

Changes in QTc Interval in the Citalopram for Agitation in Alzheimer's Disease (CitAD) Randomized Trial

Background A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group. Methods CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimers disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1∶1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began. Results Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fishers exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fishers exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death. Conclusion Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation. Trial Registration ClinicalTrials.gov NCT00898807

Original ResearchAsthmaDoes Age Impact the Obese Asthma Phenotype?: Longitudinal Asthma Control, Airway Function, and Airflow Perception Among Mild Persistent Asthmatics

BACKGROUND The relationship between obesity and asthma remains inadequately defined. Studies about how obesity affects asthma control and lung function show conflicting results. Additional focus on the effect of age as a modifier may make clearer the interaction between obesity and asthma phenotype. We sought to use a diverse and well-phenotyped cohort of asthmatic patients to determine how age impacts the relationship between obesity and spirometry, peak flow variability, airflow perception, and asthma control. METHODS The characteristics of 490 patients with mild persistent asthma taken from 2,794 study visits from a prospective trial studying strategies of step-down therapy were included in this post hoc analysis. A longitudinal mixed-effect model was used to determine if age affects the relationship between obesity and asthma characteristics, including spirometry, asthma control, airway pH, and perception of airflow changes. RESULTS The effect of obesity on asthma outcomes changes with age and gender. Obese 6- to 11-year-old children had the largest reduction in lung function but reported relatively fewer asthma symptoms than did similar nonobese asthmatics. Obese 12- to 17-year-olds showed a trend toward greater airflow obstruction and asthma symptoms compared with nonobese asthmatics. Adults in general displayed few obesity-related alterations in asthma phenotype. Female gender among 12- to 17- and 18- to 44-year-olds was associated with greater obesity-related asthma impairment. CONCLUSIONS Age is a significant effect modifier on the relationship between obesity and asthma phenotype. With increasing age, the influence of obesity on the asthma phenotype is generally reduced. The asthma phenotype may be most impacted by obesity among children and women. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00156819; URL: www.clinicaltrials.gov.

Obesity in children with poorly controlled asthma: Sex differences†

Obesity increases asthma risk, and may alter asthma severity. In adults, sex appears to modify the effect of obesity on asthma. Among children, the effect of sex on the relationship between obesity and asthma severity remains less clear, particularly when considering race.