Mark A. Malesker

Probiotics in the intensive care unit

Probiotics are living microorganisms that, when ingested in adequate amounts, provide benefits to the host. The benefits include either a shortened duration of infections or decreased susceptibility to pathogens. Proposed mechanisms of beneficial effects include improving gastrointestinal barrier function, modification of the gut flora by inducing host cell antimicrobial peptides and/or local release of probiotic antimicrobial factors, competition for epithelial adherence, and immunomodulation. With increasing intensive care unit (ICU) antibacterial resistance rates and fewer new antibiotics in the research pipeline, focus has been shifted to non-antibiotic approaches for the prevention and treatment of nosocomial infections. Probiotics offer promise to ICU patients for the prevention of antibiotic-associated diarrhea, Clostridium difficile infections, multiple organ dysfunction syndrome, and ventilator-associated pneumonia. Our current understanding of probiotics is confounded by inconsistency in probiotic strains studied, optimal dosages, study durations, and suboptimal sample sizes. Although probiotics are generally safe in the critically ill, adverse event monitoring must be rigorous in these vulnerable patients. Delineation of clinical differences of various effective probiotic strains, their mechanisms of action, and optimal dosing regimens will better establish the role of probiotics in various disorders. However, probiotic research will likely be hindered in the future given a recent ruling by the U.S. Food and Drug Administration.

Probiotic, prebiotic, and synbiotic use in critically ill patients.

Purpose of reviewTo summarize the existing data regarding the use of probiotics, prebiotics, and synbiotics in select disorders encountered in the intensive care unit setting. Recent findingsRecent systematic reviews and meta-analyses have more rigorously aggregated the fragmented primary data which suffers from multiple limitations. SummaryProbiotics are living microorganisms which, when ingested in adequate amounts, provide health benefits to the host. The mechanisms of these benefits include improved gastrointestinal barrier function, modification of the gut flora by inducing host cell antimicrobial peptides, releasing probiotic antimicrobial factors, competing for epithelial adherence, and immunomodulation to the advantage of the host. In the intensive care unit, probiotics appear to provide benefits in antibiotic-associated diarrhea, ventilator-associated pneumonia, and necrotizing enterocolitis. With increasing rates of antibiotic resistance among common nosocomial pathogens and fewer new antibiotics in the research pipeline, increasing attention has been placed on nonantibiotic approaches to the prevention and treatment of nosocomial infections. Existing studies of probiotics in critically ill patients are limited by heterogeneity in probiotic strains, dosages, duration of administration, and small sample sizes. Although probiotics are generally well tolerated and adverse events are very rare, the results of the PROPATRIA (Probiotics Prophylaxis in Patients with Predicted Severe Acute Pancreatitis) trial highlight the need for meticulous attention to safety monitoring. Better identification of the ideal characteristics of effective probiotics coupled with improved understanding of mechanisms of action will help to delineate the true beneficial effects of probiotics in various disorders.

Tools for Assessing Outcomes in Studies of Chronic Cough: CHEST Guideline and Expert Panel Report

BACKGROUND Since the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings. METHODS By following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel. RESULTS We recommend for adults, adolescents (≥ 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality-of-Life Questionnaire in adult and adolescent patients and the Parent Cough-Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges. CONCLUSIONS Validated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough.

Human Health Hazards of Veterinary Medications: Information for Emergency Departments

BACKGROUND There are over 5000 approved prescription and over-the-counter medications, as well as vaccines, with labeled indications for veterinary patients. Of these, there are several products that have significant human health hazards upon accidental or intentional exposure or ingestion in humans: carfentanil, clenbuterol (Ventipulmin), ketamine, tilmicosin (Micotil), testosterone/estradiol (Component E-H and Synovex H), dinoprost (Lutalyse/Prostamate), and cloprostenol (Estromate/EstroPlan). The hazards range from mild to life-threatening in terms of severity, and include bronchospasm, central nervous system stimulation, induction of miscarriage, and sudden death. OBJECTIVE To report medication descriptions, human toxicity information, and medical management for the emergent care of patients who may have had exposure to veterinary medications when they present to an emergency department (ED). DISCUSSION The intended use of this article is to inform and support ED personnel, drug information centers, and poison control centers on veterinary medication hazards. CONCLUSION There is a need for increased awareness of the potential hazards of veterinary medications within human medicine circles. Timely reporting of veterinary medication hazards and their medical management may help to prepare the human medical community to deal with such exposures or abuses when time is of the essence.

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.

Overview of the Management of Cough: CHEST Guideline and Expert Panel Report

This overview will demonstrate that cough is a common and potentially expensive health-care problem. Improvement in the quality of care of those with cough has been the focus of study for a variety of disciplines in medicine. The purpose of the Cough Guideline and Expert Panel is to synthesize current knowledge in a form that will aid clinical decision-making for the diagnosis and management of cough across disciplines and also identify gaps in knowledge and treatment options.

Acute isoniazid toxicity and the need for adequate pyridoxine supplies

A 25‐year‐old, 54‐kg Hispanic man who had recently started multidrug therapy for pulmonary tuberculosis presented in status epilepticus after ingesting 9 g of isoniazid in a suicide attempt. Successful management of this patient required collaboration between several institutions to provide the large amount of necessary intravenous pyridoxine. Ultimately, this single overdose depleted the supply of intravenous pyridoxine for a significant region of the state of Nebraska. Isoniazid is commonly used to treat tuberculosis, but it is encountered relatively infrequently as the cause of an acute overdose. Severe isoniazid overdoses may present as seizure activity that is refractory to conventional antiepileptic therapy. Although intravenous pyridoxine is an effective antidote for isoniazid overdoses in patients presenting with status epilepticus, this agent has few indications and is typically stocked in limited quantities. In regions with large populations of patients who receive antituberculosis therapy, collaborative networks must be created to ensure that adequate supplies of intravenous pyridoxine (≥ 20 g) are available for effective treatment of isoniazid poisonings.

Methodologies for the Development of the Management of Cough: CHEST Guideline and Expert Panel Report

BACKGROUND This series of guidance documents on cough, which will be published over time, is a hybrid of two processes: (1) evidence-based guidelines and (2) trustworthy consensus statements based on a robust and transparent process. METHODS The CHEST Guidelines Oversight Committee selected a nonconflicted Panel Chair and jointly assembled an international panel of experts in each clinical area with few, if any, conflicts of interest. PICO (population, intervention, comparator, outcome)-based key questions and parameters of eligibility were developed for each clinical topic to inform the comprehensive literature search. Existing guidelines, systematic reviews, and primary studies were assessed for relevance and quality. Data elements were extracted into evidence tables and synthesized to provide summary statistics. These, in turn, are presented to support the evidence-based graded recommendations. A highly structured consensus-based Delphi approach was used to provide expert advice on all guidance statements. Transparency of process was documented. RESULTS Evidence-based guideline recommendations and consensus-based suggestions were carefully crafted to provide direction to health-care providers and investigators who treat and/or study patients with cough. Manuscripts and tables summarize the evidence in each clinical area supporting the recommendations and suggestions. CONCLUSIONS The resulting guidance statements are based on a rigorous methodology and transparency of process. Unless otherwise stated, the recommendations and suggestions meet the guidelines for trustworthiness developed by the Institute of Medicine and can be applied with confidence by physicians, nurses, other health-care providers, investigators, and patients.

Probiotics: Mechanisms of Action and Clinical Applications

Probiotics are living microorganisms which when taken in adequate amount provides benefit to the host. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. Extrapolation of immunomodulatory effects found in the laboratory and in animal studies with outcomes in human trials presents a difficult challenge. Not all probiotics are created equal and the benefits are strain and dose specific. With newer strain-specific clinical trials and meta-analysis of the clinical trials, the beneficial role of probiotics in certain diseases has been evolving. Some uncertainity still exists with probiotics in other diseases with regard to the therapeutic role, strain-specificity, dosage and duration. Identification of clinical characteristics of effective probiotic strains, their mechanisms of action and testing of probiotic-based treatment may provide the true beneficial effect of probiotics in various disorders.

Probiotics: History and Evolution

Probiotics are viable microbial species, which are ingested for the purpose of altering the gastrointestinal flora in a manner, which confers health benefits. Currently available probiotic products include a wide array of bacterial and fungal species which are consumed in a variety of preparations. The use of microbials originated (unintentionally) centuries ago when people first noted the beneficial health effects of eating fermented foods. Modern probiotic-containing foods and products are the direct derivatives of these early fermented foods. The use of fermented milk and yogurt are the part of human history and their role has been with humanity, to date, between legends and historical data [1]. The present review outlines the origins of probioticcontaining foods and our subsequent refinement of these biologic agents.