Sat Sharma

Critically Ill Patients With 2009 Influenza A(H1N1) Infection in Canada

CONTEXT Between March and July 2009, the largest number of confirmed cases of 2009 influenza A(H1N1) infection occurred in North America. OBJECTIVE To describe characteristics, treatment, and outcomes of critically ill patients in Canada with 2009 influenza A(H1N1) infection. DESIGN, SETTING, AND PATIENTS A prospective observational study of 168 critically ill patients with 2009 influenza A(H1N1) infection in 38 adult and pediatric intensive care units (ICUs) in Canada between April 16 and August 12, 2009. MAIN OUTCOME MEASURES The primary outcome measures were 28-day and 90-day mortality. Secondary outcomes included frequency and duration of mechanical ventilation and duration of ICU stay. RESULTS Critical illness occurred in 215 patients with confirmed (n = 162), probable (n = 6), or suspected (n = 47) community-acquired 2009 influenza A(H1N1) infection. Among the 168 patients with confirmed or probable 2009 influenza A(H1N1), the mean (SD) age was 32.3 (21.4) years; 113 were female (67.3%) and 50 were children (29.8%). Overall mortality among critically ill patients at 28 days was 14.3% (95% confidence interval, 9.5%-20.7%). There were 43 patients who were aboriginal Canadians (25.6%). The median time from symptom onset to hospital admission was 4 days (interquartile range [IQR], 2-7 days) and from hospitalization to ICU admission was 1 day (IQR, 0-2 days). Shock and nonpulmonary acute organ dysfunction was common (Sequential Organ Failure Assessment mean [SD] score of 6.8 [3.6] on day 1). Neuraminidase inhibitors were administered to 152 patients (90.5%). All patients were severely hypoxemic (mean [SD] ratio of Pao(2) to fraction of inspired oxygen [Fio(2)] of 147 [128] mm Hg) at ICU admission. Mechanical ventilation was received by 136 patients (81.0%). The median duration of ventilation was 12 days (IQR, 6-20 days) and ICU stay was 12 days (IQR, 5-20 days). Lung rescue therapies included neuromuscular blockade (28% of patients), inhaled nitric oxide (13.7%), high-frequency oscillatory ventilation (11.9%), extracorporeal membrane oxygenation (4.2%), and prone positioning ventilation (3.0%). Overall mortality among critically ill patients at 90 days was 17.3% (95% confidence interval, 12.0%-24.0%; n = 29). CONCLUSION Critical illness due to 2009 influenza A(H1N1) in Canada occurred rapidly after hospital admission, often in young adults, and was associated with severe hypoxemia, multisystem organ failure, a requirement for prolonged mechanical ventilation, and the frequent use of rescue therapies.

Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial

Context Physicians use multiple medications to treat chronic obstructive pulmonary disease (COPD). Contribution In this multicenter trial, 449 adults with moderate or severe COPD were randomly assigned to receive tiotropium and placebo, tiotropium and salmeterol, or tiotropium and fluticasonesalmeterol for 1 year. About 63%, 65%, and 60% of patients, respectively, had exacerbations. The third group, but not the second group, had better lung function and fewer hospitalizations than the first group. Caution Many patients discontinued assigned medications. Implications Adding fluticasonesalmeterol to tiotropium may improve lung function and decrease hospitalizations, but it does not affect reduce exacerbations in patients with moderate or severe COPD. The Editors Most patients with moderate or severe chronic obstructive pulmonary disease (COPD) experience chronic progressive dyspnea that is not alleviated by short-acting bronchodilators. It is therefore not surprising that many patients are treated with multiple inhaled medications to optimize their lung function and minimize symptoms (1). Published guidelines on COPD state that the goals of pharmacologic therapy should be to control symptoms, improve health status, and reduce the frequency of COPD exacerbations (2, 3), and many published guidelines advocate combining different classes of long-acting bronchodilators or inhaled steroids to achieve these goals (2, 3). In the past several years, several studies have shown that treatment of COPD with the long-acting anticholinergic tiotropium (47); the long-acting 2-agonist salmeterol (810); or products that combine inhaled steroids and long-acting 2-agonists, such as fluticasonesalmeterol or budesonideformoterol (1114), improve dyspnea and quality of life and decrease exacerbation rates compared with placebo. However, no studies have assessed whether therapy with a combination of these products provides greater clinical benefit than does therapy with these agents used alone. 2-Agonists and anticholinergics work by different mechanisms to cause bronchodilation (15), and inhaled corticosteroids may have an anti-inflammatory effect in COPD (16). Thus, it makes theoretical and intuitive sense that combining these therapies might be more beneficial than therapy with 1 agent alone. However, safety concerns, such as side effects associated with long-term use of long-acting 2-agonists and inhaled corticosteroids, and economic issues related to the additional costs of these medications may argue against routine use of inhaled medication polypharmacy without evidence of efficacy. We therefore conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether combining tiotropium with salmeterol or fluticasonesalmeterol produces greater improvements in clinical outcomes for adults with moderate or severe COPD compared with tiotropium therapy alone. Methods Design We designed a parallel-group, 3-group, randomized, double-blind, placebo-controlled trial in patients with moderate or severe COPD that was conducted from October 2003 to January 2006. The study protocol has been published elsewhere (17). The research ethics boards of all participating centers approved the study, and all trial participants provided written informed consent. Setting and Participants We enrolled patients with diagnosed moderate or severe COPD from 27 Canadian medical centers. Twenty centers were academic hospitalbased pulmonary clinics, 5 were community-based pulmonary clinics, and 2 were community-based primary care clinics. Eligible patients had to have had at least 1 exacerbation of COPD that required treatment with systemic steroids or antibiotics within the 12 months before randomization. Additional inclusion criteria were age older than 35 years; a history of 10 pack-years or more of cigarette smoking; and documented chronic airflow obstruction, with an FEV1FVC ratio less than 0.70 and a postbronchodilator FEV1 less than 65% of the predicted value. We excluded patients with a history of physician-diagnosed asthma before 40 years of age; those with a history of physician-diagnosed chronic congestive heart failure with known persistent severe left ventricular dysfunction; those receiving oral prednisone; those with a known hypersensitivity or intolerance to tiotropium, salmeterol, or fluticasonesalmeterol; those with a history of severe glaucoma or severe urinary tract obstruction, previous lung transplantation or lung volume reduction surgery, or diffuse bilateral bronchiectasis; and those who were pregnant or were breastfeeding. Persons with a recent COPD exacerbation requiring oral or intravenous antibiotics or steroids were required to wait until treatment with these agents had been discontinued for 28 days before entering the study. Randomization and Interventions We randomly assigned patients to 1 of 3 treatment groups for 52 weeks: tiotropium (Spiriva [Boehringer Ingelheim Pharma, Ingelheim, Germany]), 18 g once daily, plus placebo inhaler, 2 puffs twice daily; tiotropium, 18 g once daily, plus salmeterol (Serevent [GlaxoSmithKline, Research Triangle Park, North Carolina]), 25 g/puff, 2 puffs twice daily; or tiotropium, 18 g once daily, plus fluticasonesalmeterol (Advair [GlaxoSmithKline]), 250/25 g/puff, 2 puffs twice daily. Randomization was done through central allocation of a randomization schedule that was prepared from a computer-generated random listing of the 3 treatment allocations, blocked in variable blocks of 9 or 12 and stratified by site. Neither research staff nor patients were aware of the treatment assignment before or after randomization. All study patients were provided with inhaled albuterol and were instructed to use it when necessary to relieve symptoms. Any treatment with inhaled corticosteroids, long-acting 2-agonists, and anticholinergics that the patient may have been using before entry was discontinued on entry into the study. Therapy with other respiratory medications, such as oxygen, antileukotrienes, and methylxanthines, was continued in all patient groups. Tiotropium was administered by using a Handihaler device (Boehringer Ingelheim). Study drugs were administered through a pressurized metered-dose inhaler using a spacer device (Aerochamber Plus, Trudell Medical, London, Ontario, Canada), and patients were taught the correct inhalation technique to ensure adequate drug delivery. The metered-dose inhalers containing placebo, salmeterol, and fluticasonesalmeterol were identical in taste and appearance, and they were enclosed in identical tamper-proof blinding devices. The medication canisters within the blinding devices were stripped of any identifying labeling. Adherence to therapy was assessed by weighing the returned inhaler canisters. Measurements and Outcomes The primary outcome was the proportion of patients in each treatment group who experienced a COPD exacerbation within 52 weeks of randomization. Respiratory exacerbations were defined, according to the 2000 Aspen Lung Conference Consensus definition, as a sustained worsening of the patients respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD (18). An acute change in regular COPD medications was defined as physician-directed, short-term use of oral or intravenous steroids, oral or intravenous antibiotics, or both therapies. Secondary outcomes were the mean number of COPD exacerbations per patient-year; the total number of exacerbations that resulted in urgent visits to a health care provider or emergency department; the number of hospitalizations for COPD; the total number of hospitalizations for all causes; and changes in health-related quality of life, dyspnea, and lung function. Health-related quality of life was assessed by using the St. Georges Respiratory Questionnaire (19), dyspnea was assessed by using the Transitional Dyspnea Index (20) and the dyspnea domain of the Chronic Respiratory Disease Questionnaire (21), and lung function was assessed by measuring the FEV1 according to established criteria of the American Thoracic Society. Follow-up Procedures Patients were monitored for exacerbations by monthly telephone calls. Exacerbations and all secondary outcomes were also assessed through patient visits at baseline and at 4, 20, 36, and 52 weeks after randomization. For every suspected exacerbation, we contacted both the patient and the patients treating physician to ensure that the medical encounter had been prompted by acute respiratory symptoms and a full report, including physician, emergency department, and hospital records that described the circumstances of each suspected exacerbation, was prepared. The assembled data from the visit for the suspected exacerbation were presented to a blinded adjudication committee for review, and the committee confirmed whether the encounter met the study definition of COPD exacerbation. For the purposes of the trial, we considered that a patient had experienced a new COPD exacerbation if he or she had not been receiving oral steroids and antibiotics for at least 14 days after the previous exacerbation. Patients were followed for the full 52-week duration of the trial, and primary and secondary outcomes were recorded throughout the 1-year period regardless of whether patients had experienced an exacerbation or discontinued treatment with study medications. We did not break the study blinding for patients who prematurely discontinued treatment with study medications. Adverse events were captured by the research coordinators through monthly patient telephone interviews and at scheduled patient visits by using checklists of potential side effects. Physicians rated events as expected or unexpected, and they were asked to rate event severity and attribute causality of adverse events to the study drugs. Statistical Analysis We designed the study to detect an 18% absolute d

Overdiagnosis of asthma in obese and nonobese adults

Background: It is unclear whether asthma is overdiagnosed in developed countries, particularly among obese individuals, who may be more likely than nonobese people to experience dyspnea. Methods: We conducted a longitudinal study involving nonobese (body mass index 20–25) and obese (body mass index ≥ 30) individuals with asthma that had been diagnosed by a physician. Participants were recruited from 8 Canadian cities by means of random-digit dialing. A diagnosis of current asthma was excluded in those who did not have evidence of acute worsening of asthma symptoms, reversible airflow obstruction or bronchial hyperresponsiveness, despite being weaned off asthma medications. We stopped asthma medications in those in whom a diagnosis of asthma was excluded and assessed their clinical outcomes over 6 months. Results: Of 540 individuals with physician-diagnosed asthma who participated in the study, 496 (242 obese and 254 nonobese) could be conclusively assessed for a diagnosis of asthma. Asthma was ultimately excluded in 31.8% (95% confidence interval [CI] 26.3%–37.9%) in the obese group and in 28.7% (95% CI 23.5%–34.6%) in the nonobese group. Overdiagnosis of asthma was no more likely to occur among obese individuals than among nonobese individuals (p = 0.46). Of those in whom asthma was excluded, 65.5% did not need to take asthma medication or seek health care services because of asthma symptoms during a 6-month follow-up period. Interpretation: About one-third of obese and nonobese individuals with physician-diagnosed asthma did not have asthma when objectively assessed. This finding suggests that, in developed countries such as Canada, asthma is overdiagnosed.

Obstructive Sleep Apnea : Effects of Continuous Positive Airway Pressure on Cardiac Remodeling as Assessed by Cardiac Biomarkers, Echocardiography, and Cardiac MRI

BACKGROUND Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular morbidity and mortality. Although previous echocardiographic studies have demonstrated short-term improvement in cardiovascular remodeling in patients with OSA receiving continuous positive airway pressure (CPAP) therapy, a long-term study incorporating cardiac biomarkers, echocardiography, and cardiac MRI (CMR) has not been performed to date. METHODS A prospective study of 47 patients with OSA was performed between 2007 and 2010. Cardiac biomarkers, including C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T (TnT), were measured at baseline and serially over 1 year. All patients underwent baseline and serial transthoracic echocardiography (TTE) and CMR to assess cardiac remodeling. RESULTS Following 12 months of CPAP therapy, levels of CRP, NT-proBNP, and TnT did not change significantly from normal baseline values. As early as 3 months after initiation of CPAP, TTE revealed an improvement in right ventricular end-diastolic diameter, left atrial volume index, right atrial volume index, and degree of pulmonary hypertension, which continued to improve over 1 year of follow-up. Finally, left ventricular mass, as determined by CMR, decreased from 159 ± 12 g/m(2) to 141 ± 8 g/m(2) as early as 6 months into CPAP therapy and continued to improve until completion of the study at 1 year. CONCLUSION Both systolic and diastolic abnormalities in patients with OSA can be reversed as early as 3 months into CPAP therapy, with progressive improvement in cardiovascular remodeling over 1 year as assessed by both TTE and CMR.

Outcome of patients admitted to the intensive care unit for acute exacerbation of idiopathic pulmonary fibrosis

RATIONALE The aim of this study was to evaluate the outcome of intensive care unit (ICU) admission in patients with idiopathic pulmonary fibrosis (IPF) who develop acute respiratory failure of unknown etiology. METHODS A retrospective study at University of Manitoba hospitals reviewed all patients admitted to the ICU from November 1988 to December 2000 with IPF requiring mechanical ventilation for unknown causes of acute respiratory failure. Survival at hospital discharge was assessed as the primary end point and ICU length of stay as a secondary end point. In the absence of open lung biopsy, major and minor clinical criteria (as per American Thoracic Society statements) were used for the diagnosis of IPF. Infections were ruled out by extensive surveillance cultures and/or bronchoscopy with bronchoalveolar lavage. RESULTS Eighty-eight charts were reviewed and 25 patients met the inclusion criteria. The mean (+/- SD) age was 69+/-11 years (range 42 to 96 years) and 23 patients were male. With the exception of one survivor who was discharged home, 21 patients died while receiving mechanical ventilation, and three patients died in hospital shortly after ICU discharge (one day, 22 days and 67 days). Intubation and mechanical ventilation were administered to 21 patients, with a mean duration of 11+/-6 days (range two to 27 days); the other four patients were treated with noninvasive ventilation. The average duration of symptoms before ICU admission was 22+/-26 days. All patients were treated with systemic corticosteroids, while eight patients received additional chemotherapy. CONCLUSIONS In the absence of a reversible cause, patients with IPF who develop acute exacerbation of IPF may not benefit from ICU admission and mechanical ventilation. However, it is imperative that a diagnostic workup be performed to rule out an infectious or other reversible cause of respiratory failure before admission to the ICU is denied.

A Comparison of Obese and Nonobese People With Asthma Exploring an Asthma-Obesity Interaction

OBJECTIVE The objectives of our study were to compare patient characteristics and severity of disease in obese and normal-weight-confirmed people with asthma and to explore reasons for misdiagnosis of asthma, including potential interactions with obesity. METHODS We randomly selected patients with physician-diagnosed asthma from eight Canadian cities. Asthma diagnosis was confirmed via a sequential lung function testing algorithm. Logistic analysis was conducted to compare obese and normal-weight-confirmed people with asthma and to assess characteristics associated with misdiagnosis of asthma. Interaction with obesity was investigated. RESULTS Complete assessments were obtained on 496 subjects who reported physician-diagnosed asthma (242 obese and 254 normal-weight subjects); 346 had asthma confirmed with sequential lung testing, and in 150 subjects a diagnosis of asthma was ruled out. Obese subjects with asthma were significantly more likely to be men, have a history of hypertension and gastroesophageal reflux disease, and have a lower FEV(1) compared with normal-weight subjects with asthma. Older subjects, men, and subjects with higher FEV(1) were more likely to have received misdiagnoses of asthma. Obesity was not an independent predictor of misdiagnosis, however there was an interaction between obesity and urgent visits for respiratory symptoms. The odds ratio for receiving a misdiagnosis of asthma for obese individuals as compared with normal-weight individuals was 4.08 (95% CI, 1.23-13.5) for those with urgent visits in the past 12 months. CONCLUSIONS Obese people with asthma have lower lung function and more comorbidities compared with normal-weight people with asthma. Obese individuals who make urgent visits for respiratory symptoms are more likely to receive a misdiagnosis of asthma.

Bupropion for Smoking Cessation in Patients Hospitalized With Acute Myocardial Infarction: A Randomized, Placebo-Controlled Trial

OBJECTIVES The purpose of this study was to examine smoking cessation rates among smokers with AMI to determine whether bupropion, started in-hospital, is safe and can improve cessation rates at 1 year. BACKGROUND Bupropion doubles quit rates in otherwise healthy smokers and patients with stable cardiovascular disease. Although 2 previous trials examined the use of bupropion in patients hospitalized with acute cardiovascular disease, these studies have been inconclusive with respect to its safety and efficacy in patients with acute myocardial infarction (AMI). METHODS We conducted a multicenter, double-blind, placebo-controlled, randomized trial in smokers hospitalized with AMI. Participants received bupropion or placebo for 9 weeks and were followed for 12 months. Both groups received low-intensity counseling. Point prevalence abstinence was assessed by 7-day recall and biochemical validation of expired carbon monoxide. RESULTS A total of 392 patients were randomized (mean age 53.9 ± 10.3 years); 83.5% were male; 64.9% had ST-segment elevation myocardial infarction). Patients smoked a mean of 23.2 ± 10.6 cigarettes/day for a mean of 32.9 ± 12.4 years. At 12 months, point prevalence abstinence rates were 37.2% in the bupropion group and 32.0% in the placebo group (p = 0.33; % difference after adjusting for between center differences 3.9%). Continuous abstinence rates were 26.8% and 22.2%, respectively (p = 0.34). Major adverse cardiac event rates were similar (13.0% vs. 11.0%, respectively; p = 0.64). CONCLUSIONS Two-thirds of patients return to smoking by 12 months after AMI. Bupropion is well tolerated and seems to be safe to use in the immediate post-AMI period. However, bupropion is not effective for smoking cessation in patients post-AMI.

Septic shock, multiple organ failure, and acute respiratory distress syndrome.

In 1914, Schottmueller wrote “Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes signs of illness.” In the last few decades, the evidence that sepsis results from an exaggerated systemic inflammatory host response induced by infecting organisms is compelling; inflammatory mediators are the key players in the pathogenesis of septic shock and multiorgan failure. Sepsis and its sequelae represent a continuum of clinical syndrome encompassing systemic inflammation, coagulopathy, and hemodynamic abnormalities. Severe sepsis and septic shock continue to be the major causes of morbidity and mortality in the United States; sepsis deaths currently match mortality from myocardial infarction. Despite significant advances in our understanding of the pathophysiology and technological innovations in the supportive management, mortality from septic shock remains excessive. After many disappointments with strategies to manipulate the inflammatory response, modulation of coagulation cascade to decrease sepsis mortality has become a clinical reality. This review will highlight and discuss recent advances in the pathophysiology and management of sepsis.

Radiological imaging in pneumonia: recent innovations.

Purpose of review Pneumonia is one of the major infectious diseases responsible for significant morbidity and mortality throughout the world. Radiological imaging plays a prominent role in the evaluation and treatment of patients with pneumonia. This paper reviews recent innovations in the radiologic diagnosis and management of suspected pulmonary infections. Recent findings Chest radiography is the most commonly used imaging tool in pneumonias because of availability and an excellent cost–benefit ratio. Computed tomography is mandatory in unresolved cases or when complications of pneumonia are suspected. A specific radiologic pattern can suggest a diagnosis in many cases. Bacterial pneumonias are classified into four main groups: community-acquired, aspiration, healthcare-associated and hospital-acquired pneumonia. The radiographic patterns of community-acquired pneumonia may be variable and are often related to the causative agent. Aspiration pneumonia involves the lower lobes with bilateral multicentric opacities. The radiographic patterns of healthcare-associated and hospital-acquired pneumonia are variable, most commonly showing diffuse multifocal involvement and pleural effusion. Summary Combination of pattern recognition with knowledge of the clinical setting is the best approach to the radiologic interpretation of pneumonia. Radiological imaging will narrow the differential diagnosis of direct additional diagnostic measures and serve as an ideal tool for follow-up examinations.

Clinical ResearchClinical TrialBupropion for Smoking Cessation in Patients Hospitalized With Acute Myocardial Infarction: A Randomized, Placebo-Controlled Trial

OBJECTIVES The purpose of this study was to examine smoking cessation rates among smokers with AMI to determine whether bupropion, started in-hospital, is safe and can improve cessation rates at 1 year. BACKGROUND Bupropion doubles quit rates in otherwise healthy smokers and patients with stable cardiovascular disease. Although 2 previous trials examined the use of bupropion in patients hospitalized with acute cardiovascular disease, these studies have been inconclusive with respect to its safety and efficacy in patients with acute myocardial infarction (AMI). METHODS We conducted a multicenter, double-blind, placebo-controlled, randomized trial in smokers hospitalized with AMI. Participants received bupropion or placebo for 9 weeks and were followed for 12 months. Both groups received low-intensity counseling. Point prevalence abstinence was assessed by 7-day recall and biochemical validation of expired carbon monoxide. RESULTS A total of 392 patients were randomized (mean age 53.9 ± 10.3 years); 83.5% were male; 64.9% had ST-segment elevation myocardial infarction). Patients smoked a mean of 23.2 ± 10.6 cigarettes/day for a mean of 32.9 ± 12.4 years. At 12 months, point prevalence abstinence rates were 37.2% in the bupropion group and 32.0% in the placebo group (p = 0.33; % difference after adjusting for between center differences 3.9%). Continuous abstinence rates were 26.8% and 22.2%, respectively (p = 0.34). Major adverse cardiac event rates were similar (13.0% vs. 11.0%, respectively; p = 0.64). CONCLUSIONS Two-thirds of patients return to smoking by 12 months after AMI. Bupropion is well tolerated and seems to be safe to use in the immediate post-AMI period. However, bupropion is not effective for smoking cessation in patients post-AMI.