Management of patients with fibrosing interstitial lung diseases.

PURPOSE: This article summarizes the appropriate use and pharmacology of treatments for fibrosing interstitial lung diseases, with a specific focus on the antifibrotic agents nintedanib and pirfenidone. SUMMARY: The interstitial lung diseases are a heterogenous group of parenchymal lung disorders with a common feature-infiltration of the interstitial space with derangement of the normal capillary-alveolar anatomy. Diseases characterized by fibrosis of the interstitial space are referred to as the fibrosing interstitial lung diseases and often show progression over time: idiopathic pulmonary fibrosis is the most common fibrotic interstitial lung disease. Historically, therapies for fibrosing lung diseases have been limited in number, questionable in efficacy, and associated with potential harms. Food and Drug Administration (FDA) approval of the antifibrotic agents nintedanib and pirfenidone for idiopathic pulmonary fibrosis in 2014 heralded an era of reorganization of therapy for the fibrotic interstitial lung diseases. Subsequent investigations have led to FDA approval of nintedanib for systemic sclerosis-associated interstitial lung disease and interstitial lung diseases with a progressive phenotype. Although supportive care and pulmonary rehabilitation should be provided to all patients, the role(s) of immunomodulators and/or immune suppressing agents vary by the underlying disease state. Several agents previously used to treat fibrotic lung diseases (N-acetylcysteine, anticoagulation, and pulmonary vasodilators) lack efficacy or cause harm. CONCLUSION: With the introduction of effective pharmacotherapy for fibrosing interstitial lung disease, pharmacists have an increasingly important role in the interdisciplinary team managing these patients.

Sepsis, the Administration of IV Fluids, and Respiratory Failure: A Retrospective Analysis-SAIFR Study.

BACKGROUND: Although resuscitation with IV fluids is the cornerstone of sepsis management, consensus regarding their association with improvement in clinical outcomes is lacking. RESEARCH QUESTION: Is there a difference in the incidence of respiratory failure in patients with sepsis who received guideline-recommended initial IV fluid bolus of 30 mL/kg or more conservative resuscitation of less than 30 mL/kg? STUDY DESIGN AND METHODS: This was a retrospective analysis of prospectively collected clinical data conducted at an academic medical center in Omaha, Nebraska. We abstracted data from 214 patients with sepsis admitted to a single academic medical center between June 2017 and June 2018. Patients were stratified by receipt of guideline-recommended fluid bolus. The primary outcome was respiratory failure defined as an increase in oxygen flow rate or more intense oxygenation and ventilation support; oxygen requirement and volume were measured at admission, 6 h, 12 h, 24 h, and at discharge. Subgroup analyses were conducted in high-risk patients with congestive heart failure (CHF) as well as those with chronic kidney disease (CKD). RESULTS: A total of 62 patients (29.0%) received appropriate bolus treatment. The overall rate of respiratory failure was not statistically different between patients who received appropriate bolus or did not (40.3% vs 36.8%; P = .634). Likewise, no differences were observed in time to respiratory failure (P = .645) or risk of respiratory failure (adjusted hazard ratio, 1.1 [95% CI, 0.7-1.7]; P = .774). Results were similar within the high-risk CHF and CKD subgroups. INTERPRETATION: In this single-center retrospective study, we found that by broadly defining respiratory failure as an increase in oxygen requirements, a conservative initial IV fluid resuscitation strategy did not correlate with decreased rates of hypoxemic respiratory failure.

Diffuse Alveolar Hemorrhage Following Pirfenidone Initiation.

INTRODUCTION: Diffuse alveolar hemorrhage (DAH) is bleeding into the alveolar space of the lungs. Pirfenidone is an antifibrotic agent that is approved for the treatment of idiopathic pulmonary fibrosis (IPF). The most commonly reported side effects include gastrointestinal and skin-related events. We present 3 cases of hemoptysis and DAH among patients on pirfenidone therapy for IPF. CASE SUMMARIES: An 88-year-old female, a 75-year-old male, and a 73-year-old male all with IPF on pirfenidone presented with hemoptysis and chest computed tomography (CT) findings of usual interstitial pneumonia (UIP) with superimposed opacities. In 2 patients, DAH was confirmed with bronchoscopy. Corticosteroids were initiated and pirfenidone discontinued in all patients, and 2 patients improved while the third continued to deteriorate. Nintedanib was initiated in the remaining 2 patients at follow-up visit with no further issues. DISCUSSION: IPF is a chronic, progressive, fibrotic interstitial lung disease (ILD) which appears to be increasing in the United States and has a relatively short survival. Nintedanib and pirfenidone were the first Food and Drug Administration (FDA)-approved agents for the treatment of IPF in October 2014. We present 3 cases of DAH in patients with IPF receiving pirfenidone. Symptoms occurred within 2 months of pirfenidone initiation and resolved with discontinuation of pirfenidone and initiation of systemic corticosteroids in 2 patients; however, one case was complicated by concomitant discontinuation of aspirin. The mechanism by which DAH occurred in our patients remains unclear. CONCLUSION: We report the first cases of possible pirfenidone-induced DAH. Further studies are warranted to explore this reaction, but prescribers should be cognizant of this potential issue when choosing to prescribe pirfenidone.

Idiopathic Pulmonary Fibrosis: A Case Discussion.

OBJECTIVE: The purpose of this report is to describe the case of a 68-year-old man who was treated for idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease that is characterized by progressive deterioration of pulmonary function. He was initially prescribed pirfenidone and developed significant gastric distress. The treatment was transitioned to nintedanib. This article will provide the pharmacist with a therapeutic overview of IPF, as well as review the unique process involved with drug acquisition, dosing, patient education, and monitoring of pirfenidone and nintedanib. SETTINGS: Community pharmacy, nursing facility pharmacy, consultant pharmacy practice. PRACTICE CONSIDERATIONS: Pirfenidone and nintedanib are the only medications in the United States approved to treat IPF. These treatments have distinctive properties that differ from past therapies for IPF. CONCLUSION: It is important for pharmacists to understand the treatment recommendations for IPF and to review the process for acquisition, dosing, and administration of pirfenidone and nintedanib to better assist physicians and patients and improve therapeutic outcomes.

Role of statins in delirium prevention in critical ill and cardiac surgery patients: A systematic review and meta-analysis.

BACKGROUND: The data evaluating the role of statins in delirium prevention in the intensive care unit are conflicting and limited. METHODS: We performed a systematic review and meta-analysis of literature from 1975 to 2015. All English-language adult studies evaluating delirium incidence in statin and statin nonusers were included and studies without a control group were excluded. Mantel-Haenszel model was used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Statistical significance was defined as CI not including unity and P value less than .05. RESULTS: Of a total 57 identified studies, 6 were included. The studies showed high heterogeneity (I2 = 73%) for all and moderate for cardiac surgery studies (I2 = 55%). Of 289 773 patients, statins were used in 22 292 (7.7%). Cardiac surgery was performed in 4382 (1.5%) patients and 2321 (53.0%) used statins. Delirium was noted in 710 (3.2%) and 3478 (1.3%) of the patients in the statin and nonstatin groups, respectively, with no difference between groups in the total cohort (RR, 1.05 [95% CI, 0.85-1.29]; P = .56) or in cardiac surgery patients (RR, 1.03 [95% CI, 0.68-1.56]; P = .89). CONCLUSIONS: In critically ill and cardiac surgery patients, this meta-analysis did not show a benefit with statin therapy in the prevention of delirium.

High-Risk Smoking Behaviors and Barriers to Smoking Cessation Among Homeless Individuals.

BACKGROUND: Although tobacco practices and the effects of tobacco use among the general American population are well described, minimal data exist regarding tobacco use and barriers to smoking cessation among homeless individuals. METHODS: Anonymous, voluntary surveys based on a previously implemented instrument were completed by 100 smoking individuals residing at a homeless shelter. These surveys assessed high-risk smoking behaviors and respondents' perceived barriers to long-term smoking cessation. RESULTS: Ninety percent of study participants reported engaging in at least one of the high-risk tobacco practices. Nicotine replacement therapy was perceived by respondents to be the most desired form of smoking cessation aid. Excessive stress with use of tobacco smoking to alleviate stress and anxiety was the most significant self-perceived barrier to smoking cessation. CONCLUSIONS: High-risk tobacco practices are remarkably common among smoking homeless individuals. Despite literature consistently showing that non-nicotine tobacco cessation pharmacotherapies (varenicline, buproprion) have higher smoking cessation rates, nicotine replacement monotherapy was perceived as more valuable by survey respondents. Although lack of financial resources was expected to be the biggest barrier to successful cessation, social stressors and the use of smoking to cope with homelessness were perceived as a greater obstacle in this cohort. Given the paucity of data on the long-term effects of the high-risk tobacco behaviors reported by these homeless smokers, this study highlights the need for further investigations regarding tobacco use and tobacco cessation in this vulnerable population.

Development and validation of a risk calculator for predicting postoperative pneumonia.

OBJECTIVE: To identify preoperative factors associated with an increased risk of postoperative pneumonia and subsequently develop and validate a risk calculator. PATIENTS AND METHODS: The American College of Surgeons' National Surgical Quality Improvement Program, a multicenter, prospective data set (2007-2008) was used. Univariate and multivariate logistic regression analyses were performed. The 2007 data set (N=211,410) served as the training set, and the 2008 data set (N=257,385) served as the validation set. RESULTS: In the training set, 3825 patients (1.8%) experienced postoperative pneumonia. Patients who experienced postoperative pneumonia had a significantly higher 30-day mortality (17.0% vs 1.5%; P<.001). On multivariate logistic regression analysis, 7 preoperative predictors of postoperative pneumonia were identified: age, American Society of Anesthesiologists class, chronic obstructive pulmonary disease, dependent functional status, preoperative sepsis, smoking before operation, and type of operation. The risk model based on the training data set was subsequently validated on the validation data set, with model performance being very similar (C statistic: 0.860 and 0.855, respectively). The high C statistic indicates excellent predictive performance. The risk model was used to develop an interactive risk calculator. CONCLUSION: Preoperative variables associated with an increased risk of postoperative pneumonia include age, American Society of Anesthesiologists class, chronic obstructive pulmonary disease, dependent functional status, preoperative sepsis, smoking before operation, and type of operation. The validated risk calculator provides a risk estimate for postoperative pneumonia and is anticipated to aid in surgical decision making and informed patient consent.

Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies.

BACKGROUND: Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. METHODS: We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. FINDINGS: Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20-29 and simplified acute physiology score [SAPS 2] 35-58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1·13 (95% CI 0·98-1·31). The overall daily risk of discharge after ventilator-associated pneumonia was 0·74 (0·68-0·80), leading to an overall cumulative risk for dying in the ICU of 2·20 (1·91-2·54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2·97, 95% CI 2·24-3·94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2·49 [1·81-3·44] for patients with APACHE scores of 20-29 and 2·72 [1·95-3·78] for those with SAPS 2 scores of 35-58). INTERPRETATION: The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay. FUNDING: None.

Impact of COPD on postoperative outcomes: results from a national database.

BACKGROUND: Although COPD affects large sections of the population, its effects on postoperative outcomes have not been rigorously studied. The objectives of this study were to describe the prevalence of COPD in patients undergoing surgery and to analyze the associations between COPD and postoperative morbidity, mortality, and hospital length of stay. METHODS: Patients with COPD who underwent surgery were identified from the National Surgical Quality Improvement Program database (2007-2008). Univariate and multivariate analyses were performed on this multicenter, prospective data set (N = 468,795). RESULTS: COPD was present in 22,576 patients (4.82%). These patients were more likely to be older, men, white, smokers, and taking corticosteroids and had a lower BMI (P < .0001 for each). Median length of stay was 4 days for patients with COPD vs 1 day in those without COPD (P < .0001). Thirty-day morbidity rates were 25.8% and 10.2% for patients with and without COPD, respectively (P < .0001). Thirty-day death rates were 6.7% and 1.4% for patients with and without COPD, respectively (P < .0001). After controlling for > 50 comorbidities through logistic regression modeling, COPD was independently associated with higher postoperative morbidity (OR, 1.35; 95% CI, 1.30-1.40; P < .0001) and mortality (OR, 1.29; 95% CI, 1.19-1.39; P < .0001). Multivariate analyses with each individual postoperative complication as the outcome of interest showed that COPD was associated with increased risk for postoperative pneumonia, respiratory failure, myocardial infarction, cardiac arrest, sepsis, return to the operating room, and renal insufficiency or failure (P < .05 for each). CONCLUSIONS: COPD is common among patients undergoing surgery and is associated with increased morbidity, mortality, and length of stay.

Predictors of pulmonary complications after bariatric surgery.

BACKGROUND: Postoperative pneumonia (PP) and respiratory failure (PRF) are known to be the most common nonwound complications after bariatric surgery. Our objective was to identify their current prevalence after bariatric surgery and to study the preoperative factors associated with them using data from the American College of Surgeons' National Surgical Quality Improvement Program. METHODS: Patients undergoing bariatric surgery were identified from the National Surgical Quality Improvement Program (2006-2008), a multicenter, prospective database. Univariate analysis and multivariate logistic regression analysis were performed. RESULTS: Of 32,889 patients, PP was diagnosed in 187 patients (.6%) and PRF in 204 patients (.6%). The overall 30-day morbidity rate was 6.4%, with PP and PRF accounting for 18.7%. The 30-day mortality rate was greater for the patients with PP and PRF than those without (4.3% versus .16% and 13.7% versus .10%, P < .0001). The hospital length of stay was also longer in patients with PP/PRF (P < .0001). On multivariate analysis, congestive heart failure (odds ratio 5.3, 95% confidence interval 1.20-23.26) and stroke (odds ratio 4.1, 95% confidence interval 1.42-11.49) were the greatest preoperative risk factors for PP. Previous percutaneous coronary intervention (odds ratio 2.8, 95% confidence interval 1.64-4.74) and dyspnea at rest (odds ratio 2.64, 95% confidence interval 1.13-6.13) were the factors most strongly associated with PRF. Bleeding disorder, age, chronic obstructive pulmonary disease, and type of surgery were risk factors for both (P < .05). Smoking also predisposed to PP, and diabetes mellitus, anesthesia time, and increasing weight also predisposed to PRF (P < .05 for all). CONCLUSION: Although PP and PRF are infrequent, they account for one fifth of the postoperative morbidity and are associated with significantly increased 30-day mortality. They can be predicted by various risk factors, emphasizing the importance of patient optimization and careful selection before bariatric surgery.

Development and validation of a risk calculator predicting postoperative respiratory failure.

BACKGROUND: Postoperative respiratory failure (PRF) (requiring mechanical ventilation > 48 h after surgery or unplanned intubation within 30 days of surgery) is associated with significant morbidity and mortality. The objective of this study was to identify preoperative factors associated with an increased risk of PRF and subsequently develop and validate a risk calculator. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP), a multicenter, prospective data set (2007-2008), was used. The 2007 data set (n = 211,410) served as the training set and the 2008 data set (n = 257,385) as the validation set. RESULTS: In the training set, 6,531 patients (3.1%) developed PRF. Patients who developed PRF had a significantly higher 30-day mortality (25.62% vs 0.98%, P < .0001). On multivariate logistic regression analysis, five preoperative predictors of PRF were identified: type of surgery, emergency case, dependent functional status, preoperative sepsis, and higher American Society of Anesthesiologists (ASA) class. The risk model based on the training data set was subsequently validated on the validation data set. The model performance was very similar between the training and the validation data sets (c-statistic, 0.894 and 0.897, respectively). The high c-statistics (area under the receiver operating characteristic curve) indicate excellent predictive performance. The risk model was used to develop an interactive risk calculator. CONCLUSIONS: Preoperative variables associated with increased risk of PRF include type of surgery, emergency case, dependent functional status, sepsis, and higher ASA class. The validated risk calculator provides a risk estimate of PRF and is anticipated to aid in surgical decision making and informed patient consent.

Reoperative antireflux surgery for dysphagia.

BACKGROUND: Troublesome dysphagia is a common indication for redo antireflux surgery (Re-ARS). This study is aimed to analyze the efficacy of Re-ARS in resolving dysphagia and to identify risk factors for persistent or new-onset dysphagia after Re-ARS. METHODS: A prospectively maintained database was retrospectively reviewed to identify patients after Re-ARS. Dysphagia severity was graded on a scale of 0 to 3 before and after Re-ARS based on responses to a standardized questionnaire. Patients reporting grade 2 or 3 symptoms were considered to have significant dysphagia. Satisfaction was graded using a 10-point analog scale. RESULTS: Between December 2003 and July 2008, 106 patients underwent Re-ARS. Significant preoperative dysphagia was reported by 54 patients, and impaired esophageal motility was noted in 31 patients. Remedial surgery included redo fundoplication (n = 87), Collis gastroplasty with redo fundoplication (n = 16), and takedown of the fundoplication or hiatal closure alone (n = 3). At least 1 year follow-up period (mean 21.8 months) was available for 92 patients. For patients with significant preoperative dysphagia (n = 46), the mean symptom score declined from 2.35 to 0.78 (p < 0.0001). Persistent dysphagia was reported by 13 patients and new-onset dysphagia by 4 patients. No patients reported grade 3 dysphagia after Re-ARS. Dilations were used to treat 11 patients. Multivariate logistic regression analysis identified Collis gastroplasty (p = 0.03; adjusted odds ratio [OR], 5.74) and preoperative dysphagia (p = 0.01; adjusted OR, 6.80) as risk factors for significant postoperative dysphagia. The overall satisfaction score was 8.3, but certain subsets had significantly lower satisfaction scores. These subsets included patients with esophageal dysmotility (7.1; p = 0.04), patients who required Collis gastroplasty (7.0; p = 0.09), and patients with esophageal dysmotility who required Collis gastroplasty (5.0; p < 0.01). CONCLUSION: Although dysphagia is a common symptom among patients requiring Re-ARS, intervention provides a significant benefit. Patients with preoperative dysphagia, especially those requiring Collis gastroplasty, are at increased risk for persistent dysphagia and decreased satisfaction after Re-ARS.

A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.

The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.

Health-related quality of life after lung volume reduction surgery.

Many studies have demonstrated short-term physiologic benefits and improvements in various measures of health-related quality of life (HRQOL) after lung volume reduction surgery (LVRS). However, LVRS involves short-term risks of morbidity, disability, and mortality. Few reports describe the long-term effects of LVRS on patients with emphysema. Rational decision making about LVRS depends on whether the expected improvement in quality of life from LVRS outweighs the expected disability and morbidity and the potential mortality from the procedure. This report describes the HRQOL and survival outcomes of patients with emphysema after LVRS.