Michael R. Jacobs

Hospital Admissions Resulting from Preventable Adverse Drug Reactions

BACKGROUND: Adverse drug reactions (ADRs) are a significant cause of hospital admissions. These events can lead to significant morbidity and mortality and financial costs. ADRs that may be preventable might be considered a form of medication error. OBJECTIVE: To assess the potential preventability of ADRs directly related to a patients hospital admission. METHODS: A retrospective chart review of 437 ADRs occurring during an 11-month period was conducted at a university hospital. A subset of these events leading to hospital admissions was identified for further review. Those that resulted in admission were further examined to determine probability of causality, severity, and preventability. RESULTS: Over 11 months, 158 ADRs were directly related to hospital admission. The relationship of these admissions to drug exposure was determined to be probable or highly probable in 154 (97.4%) of these cases. From this group, 96 (62.3%) of these events were considered potentially preventable, with 23 (24%) considered severe to life-threatening. Characteristics associated with these ADRs included documentation of a toxic drug concentration or abnormal laboratory value (80%), inadequate monitoring of a patients drug therapy (67%), inappropriate dose (51%), patient noncompliance (33%), drug—drug interaction (26%), contraindication to therapy (3%), and documented allergy (1%). These ADRs resulted in 595 hospital days, with an average length of stay of 6.1 days. CONCLUSIONS: ADRs leading to hospital admissions are often preventable. Approximately 25% of these events were serious to life-threatening. Most resulted from inadequate monitoring of therapy or inappropriate dosing. Patient noncompliance and drug interactions were also common causes. Multidisciplinary prevention strategies among physicians, pharmacists, other healthcare professionals, and patients focusing on communication and education should be targeted.

Clinical Response and Side Effects of Metoclopramide: Associations With Clinical, Demographic, and Pharmacogenetic Parameters

Objectives: Metoclopramide is associated with variable efficacy and side effects when used in the treatment of gastroparesis. Aim: To determine associations of clinical and pharmacogenetic parameters with response and side effects to metoclopramide in patients with upper gastrointestinal symptoms suggestive of gastroparesis. Methods: Gastroparetic patients treated with metoclopramide were enrolled. Clinical parameters recorded were age, sex, weight, diabetic status, gastric emptying result, daily dose, effectiveness, and side effects. DNA was isolated from salivary samples; 20 single nucleotide polymorphisms were genotyped in 8 candidate genes (ABCB1, ADRA1D, CYP1A2, CYP2D6, DRD2, DRD3, HTR4, KCNH2). Results: One hundred gastroparetic patients treated with metoclopramide participated. Dose averaged 33±16 mg/d for 1.1±1.7 years. Responders (53 of 100 patients) were older (48±15 vs. 38±11 y; P=0.0004) and heavier (body mass index of 28±7 vs. 25±7; P=0.0125). Efficacy was associated with polymorphisms in KCNH2 (rs1805123, P=0.020) and ADRA1D (rs2236554, P=0.035) genes. Side effects, occurred in 64 patients, were more common in females (83% vs. 64%; P=0.037), nondiabetics (77% vs. 47%; P=0.004), and patients with normal gastric emptying (41% vs. 17%; P=0.015). Side effects were associated with polymorphisms in CYP2D6 (rs1080985, P=0.045; rs16947, P=0.008; rs3892097, P=0.049), KCNH2 (rs3815459, P=0.015), and serotonin 5-HT4 receptor HTR4 gene (rs9325104, P=0.026). Conclusions: Side effects to metoclopramide were more common in nondiabetic patients with normal gastric emptying. Polymorphisms in CYP2D6, KCNH2, and 5-HT4 receptor HTR4 genes were associated with side effects, whereas polymorphisms in KCNH2 and ADRA1D genes were associated with clinical response. Clinical parameters and pharmacogenetic testing may be useful in identifying patients before treatment with metoclopramide to enhance efficacy and minimize side effects.

Hospitalized Acute Exacerbation of COPD Impairs Flow and Nitroglycerin-Mediated Peripheral Vascular Dilation

Vascular function, as measured by flow mediated dilation (FMD) and nitroglycerin mediated dilation (NMD), is impaired in COPD. Increases in systemic inflammatory mediators during acute exacerbations of COPD (AECOPD) may further impair vascular function and may account for the increased prevalence of cardiovascular disease in COPD patients. Similarly it may account for the increased morbidity and mortality in COPD patients hospitalized with acute exacerbations. We hypothesized that FMD and NMD would be impaired during AECOPD requiring hospitalization and that vascular function would improve upon AECOPD resolution. We used FMD and NMD to evaluate vascular function in 19 patients hospitalized with AECOPD. FMD and NMD were repeated approximately three months later in 8 of these patients. In these eight patients significant improvements were observed in FMD (2.6 ± 1.5% vs 5.1 ± 2.4%, p = 0.04) and NMD (5.0 ± 2.6% vs 13.3 ± 4.5, p = 0.02) after resolution of their exacerbation. We conclude that endothelial and vascular smooth muscle function is markedly impaired during AECOPD requiring hospitalization and improves following resolution. The systemic vascular impairment that occurs during AECOPD may partially explain the observed increased in cardiac morbidity and mortality that occur in this population.

The Effect of Chronic Sputum Production on Respiratory Symptoms in Severe COPD

Background: Chronic sputum production is a significant but variable complaint in COPD; its effect on symptom burden has not been comprehensively described. We sought to characterize the daily burden of chronic sputum production in severe COPD and the phenotype of those with chronic sputum symptoms. Methods: We studied 50 outpatients with severe COPD who used an electronic diary to document peak expiratory flow (PEF) and respiratory symptoms daily for up to 2 years. A sputum index was derived based on complaints of sputum quantity, color, and consistency, and patients were divided into groups based on average daily sputum index (Low, Medium, High). The presence and severity of respiratory symptoms were scored by a novel method using daily changes in symptoms and PEF from baseline and were categorized into mild, moderate, and severe. Percent emphysema was measured using quantitative CT. Results: In the 14,500 observation days, severe symptom days were greater in the Medium and High groups (379/6089, 1609/4091, and 2624/4317 observation days in Low, Medium, and High, p < 0.0001). The same trend was found even when sputum complaints were removed from the symptom severity score. Observed/predicted PEF ratio was lower in the High group (0.56 ± 0.24, 0.55 ± 0.19, and 0.42 ± 0.12 in each group, p < 0.05 for High compared to Medium and Low). Percent emphysema inversely correlated with average sputum index and quantity (r = −0.449 and r = −0.584, respectively, p < 0.05). Conclusions: Increased sputum production in severe COPD is frequently encountered daily and is associated with more respiratory symptoms, worse airflow obstruction, and less emphysema.

Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial

Background COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2). Methods This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 μmoles, or 150 μmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests. Results Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1.45 and there was no consistent pattern among the three groups; the changes were not statistically significantly different from baseline. Changes in measures of inflammation and pulmonary function tests were not different among the groups. Sulforaphane was well tolerated at both dose levels. Conclusion Sulforaphane administered for four weeks at doses of 25 μmoles and 150 μmoles to patients with COPD did not stimulate the expression of Nrf2 target genes or have an effect on levels of other anti-oxidants or markers of inflammation. Trial Registration Clinicaltrials.gov: NCT01335971.

Use of a SmartPhone/Tablet-Based Bidirectional Telemedicine Disease Management Program Facilitates Early Detection and Treatment of COPD Exacerbation Symptoms

INTRODUCTION Early treatment of worsening chronic obstructive pulmonary disease (COPD) symptoms speeds recovery, improves quality of life, and reduces the need for hospitalization. Patients may fail to recognize worsening symptoms leading to delays in treatment. A telemedicine application could facilitate detection and treatment of worsening symptoms. To work, such an application requires consistent use by patients and quick responses from healthcare providers. We conducted a quality assurance assessment of our system to see if we were meeting these goals. MATERIALS AND METHODS Thirty patients were provided a smartphone application for daily COPD symptom reporting. Reports between November 2012 and September 2013 were reviewed. Symptoms reports and interventions were time-stamped by the application. Adherence reporting was calculated as the number of reports made divided by the number of days enrolled in the program for each patient. Time to intervention was calculated as the time a report was submitted to the time a treatment recommendation was sent to the patient. RESULTS There were 4,434 symptom reports made over 5,178 patient-days of observation for an average reporting compliance of 85.6%. Median reporting compliance was 90.7% (interquartile range, 83.8-98%). Four hundred seventy-five symptom reports resulted in an alert. The average response time for all alerts was 6.64 h, with a median response time of 5.75 h. CONCLUSIONS From this quality assessment we were able to conclude that patient adherence to the reporting system exceeded 90% for over half of the participants. Furthermore, over 50% of worsening COPD symptom reports were responded to in less than 6 h with patient-specific treatment recommendations.

Exploring genetic variability in drug therapy by selecting a minimum subset of the most informative single nucleotide polymorphisms through approximation of a markov blanket in a kernel-induced space

Genome-wide analysis of single nucleotide polymorphisms (SNP) can potentially be helpful in exploring the role of genetic variability in drug therapy. However, two major problems with such an analysis are the need for a large number of interrogated genomes, and the resulting high-dimensional data where the number of SNPs used as features is much larger than the number of subjects. The aim of this study is to identify informative SNPs associated with clinical efficacy and side effects of domperidone treatment for gastroparesis from DNA microarray experiments by applying our feature selection method, which approximates the Markov Blanket in a kernel-induced space. DNA samples extracted from the saliva of 46 patients treated with domperidone were analyzed using Affymetrix 6.0 SNP microarrays. Experimental evaluations on this SNP microarray dataset provide evidence that our feature selection method can remove useless SNP features more accurately than existing Markov Blanket based alternatives.

Could digital health applications improve the health of COPD patients

COPD is a disease for which there is no cure with the majority of cases resulting from cigarette smoking or environmental exposures [1]. COPD patients have symptoms nearly every day although the symptom burden is quite variable among patients. Pulmonary function and symptoms worsen over time, and are often punctuated by episodes of acute deterioration (exacerbations) that may last from several days to weeks. Exacerbations can be treated in an outpatient setting, in the emergency department, or in the hospital depending on their severity. Exacerbations that require care in the emergency room or hospitalization are associated with greater morbidity and mortality compared to those treated as an outpatient [2]. Therapeutic interventions that can improve the health of patients with COPD include smoking cessation, various pharmacological interventions for both daily maintenance therapy and treatment of exacerbations, pulmonary rehabilitation, routine vaccinations, and oxygen therapy [1,3]. In addition to these interventions, COPD patients can also benefit through increased symptom awareness (also called self-actualization) to promote early recognition of worsening symptoms and the timely institution of rescue therapy [4]. Each of these interventions offers a potential avenue for digital health applications to improve the health of COPD patients. Despite this, it is rare to find a COPD patient using any kind of digital application to assist in the management of their condition, which begs the question, ‘Why?’ Not all mobile medical applications are equal. The distinctions are discussed in an US FDA guidance issued in February 2015 that identifies two major categories of mobile medical applications [5]. The first category includes those mobile applications that the FDA intends to regulate. Examples of this category include: (1) applications that connect to an FDA-regulated medical device to control the device or one that provides active patient monitoring or analyzes patient-specific medical data; (2) applications that use attachments that make a mobile platform function in the same way as a regulated medical device; and (3) mobile applications that collect and analyze data to provide a patient-specific diagnosis or treatment recommendation. An example of this type of mobile application is the Propeller Sensor Model 2014-R (Reciprocal Labs, Corp. Madison, WI). The device has a 510 (k) approval and is available by prescription only. This application uses Bluetooth technology and a sensor that attaches to the patient’s inhaler to record and monitor inhaler use. The device records inhaler use and this information can be stored for review at a later time by the patient, caregiver, or health-care practitioner, or transmitted. Because these types of devices are designed for patient diagnostic or management purposes a more stringent FDA review process is required. Similarly, the information obtained is intended to be reviewed and analyzed by a health-care provider to make medical decisions. Decisions made on the basis of this information would be subject to the same medical-legal concerns as with any other test or procedure results. The second category of mobile applications consists of those that provide general guidance or information to a patient on how to manage their disease without making specific treatment recommendations, help organize the patient’s medical record, or assist in communicating with health-care providers. The FDA does not intend to regulate these applications; however, it may regulate these devices in what is termed ‘enforcement discretion.’ Most of the mobile medical applications that are easily downloadable fall into this category because, by definition, they are considered to present a minimal risk to the user. The FDA guidance provides a number of examples of mobile medical applications from this second category that could prove useful in the management of COPD. COPD patients might find applications that help them to stop smoking, stick with pulmonary rehabilitation exercises, and remind them to take prescribed medications quite useful. Applications that utilize global positioning system location information to help the patient identify known areas where environmental conditions may worsen their symptoms might also have a place for selected patients. While the mobile applications described in this second category are easily accessible, little information exists as to how useful they are in achieving the desired outcome. This leaves patients and physicians in a quandary as to which app to select for use and assumes that the patient and physician can agree on the behavior that needs to be supported [6]. Should the patient receive assistance for smoking cessation, or is medication adherence more important? Should symptoms be recorded to be downloaded and discussed at a later time, or should they EXPERT REVIEW OF RESPIRATORY MEDICINE, 2016 VOL. 10, NO. 4, 377–378 http://dx.doi.org/10.1586/17476348.2016.1157476

DNA microarray SNP associations with clinical efficacy and side effects of domperidone treatment for gastroparesis

BACKGROUND Domperidone treatment for gastroparesis is associated with variable efficacy as well as the potential for side effects. DNA microarray single nucleotide polymorphism (SNP) analysis may help to elucidate the role of genetic variability on the therapeutic effectiveness and toxicity of domperidone. AIM The aim of this study was to identify SNPs that are associated with clinical efficacy and side effects of domperidone treatment for gastroparesis from DNA microarray experiments. This will help develop a strategy for rational selection of patients for domperidone therapy. METHODS DNA samples extracted from the saliva of 46 patients treated with domperidone were analyzed using Affymetrix 6.0 SNP microarrays. Then least angle regression (LARS) was used to select SNPs that are related to domperidone efficacy and side effects. Decision tree based prediction models were constructed with the most correlated features selected by LARS. RESULTS Using the most stable SNP selected by LARS a prediction model for side effects of domperidone achieved (95 ± 0)% true negative rate (TN) and (78 ± 11)% true positive rate (TP) in nested leave-one-out tests. For domperidone efficacy, the prediction based on five most stable SNPs achieved (85 ± 7)% TP and (61±4)% TN. Five identified SNPs are related to ubiquitin mediated proteolysis, epithelial cell signaling, leukocyte, cell adhesion, and tight junction signaling pathways. Genetic polymorphisms in three genes that are related to cancer and hedgehog signaling were found to significantly correlate with efficacy of domperidone. CONCLUSION LARS was found to be a useful tool for statistical analysis of domperidone-related DNA microarray data generated from a small number of patients.

Hospitalizations and ED Visits in COPD: A Collision of Socioeconomic Realities with Chronic Comorbid Medical Illnesses

Treating acute exacerbations of chronic obstructive pulmonary disease (AECOPD) represents the major cost associated with this condition, primarily because of overuse of hospital and emergency department (ED) resources.1-3 Although hospitalization and ED-based care is needed in urgent situations that fail optimal therapy, many hospitalizations and re-hospitalizations stem from failure to receive optimal outpatient care. A number of pharmacologic interventions including bronchodilators, corticosteroids, phosphodiesterase-4 inhibitors, and macrolide antibiotics have been shown to reduce the frequency of COPD exacerbations but none has been consistently shown to substantially reduce the rates of hospitalization.4 Similarly, the effects of pulmonary rehabilitation and disease management programs have shown inconsistent impact on hospital utilization rates.5-7 However, new drugs or treatments may not be the answer. No matter how good a COPD therapy is, if patients cannot or do not receive it, hospital and ED admission rates will remain unchanged. Understanding who the patients are that require hospital or ED admission will hopefully facilitate creative multimodality approaches to solve this problem. In this issue of Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation Kumbhare and colleagues report on their analysis of data from the 2012 Behavioral Risk Factor Surveillance System survey where respondents completed the optional COPD module questions. Their findings mostly support the conclusions of other investigators who have shown increased risk for exacerbations that require hospitalization for those COPD patients who have multiple comorbidities, low physical activity, and lower socioeconomic status. They were surprised to find that there were no differences in tobacco use between those admitted for COPD exacerbation and those who were not and that those who were admitted to the hospital were younger than those not admitted. While no one can argue the general negative effects of smoking, it is quite possible that those not admitted to the hospital continued to smoke simply because their disease, while present, was not severe enough to result in hospitalization. Also, while increasing age does generally correlate with increased rates of COPD hospitalization, older age has also been shown to have 2 Department of Pharmacy Practice, School of Pharmacy, Temple University, Philadelphia, Pennsylvania