Society of Critical Care Medicine and American Society of Health-System Pharmacists Guideline for the Prevention of Stress-Related Gastrointestinal Bleeding in Critically Ill Adults.

RATIONALE: Critically ill adults can develop stress-related mucosal damage from gastrointestinal hypoperfusion and reperfusion injury, predisposing them to clinically important stress-related upper gastrointestinal bleeding (UGIB). OBJECTIVES: The objective of this guideline was to develop evidence-based recommendations for the prevention of UGIB in adults in the ICU. DESIGN: A multiprofessional panel of 18 international experts from dietetics, critical care medicine, nursing, and pharmacy, and two methodologists developed evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guideline development including task force selection and voting. METHODS: The panel members identified and formulated 13 Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and then assessed the certainty of the evidence using the GRADE approach. We used the evidence-to-decision framework to formulate the recommendations. Good practice statements were included to provide additional guidance. RESULTS: The panel generated nine conditional recommendations and made four good practice statements. Factors that likely increase the risk for clinically important stress-related UGIB in critically ill adults include coagulopathy, shock, and chronic liver disease. There is no firm evidence for mechanical ventilation alone being a risk factor. Enteral nutrition probably reduces UGIB risk. All critically ill adults with factors that likely increase the risk for stress-related UGIB should receive either proton pump inhibitors or histamine-2 receptor antagonists, at low dosage regimens, to prevent UGIB. Prophylaxis should be discontinued when critical illness is no longer evident or the risk factor(s) is no longer present despite ongoing critical illness. Discontinuation of stress ulcer prophylaxis before transfer out of the ICU is necessary to prevent inappropriate prescribing. CONCLUSIONS: The guideline panel achieved consensus regarding the recommendations for the prevention of stress-related UGIB. These recommendations are intended for consideration along with the patient's existing clinical status.

Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU: 2023.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care hospitals have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes (PICO) format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation Approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among unselected patients. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system. CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

Executive Summary: Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care facilities have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based clinical practice guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among "unselected" patients due to the absence of data regarding the benefit and the potential harms of false positive alarms, the risk of alarm fatigue, and cost. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system (GPS). CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) possess a conserved mobile catalytic loop, the WPD-loop, which brings an aspartic acid into the active site where it acts as an acid/base catalyst. Prior experimental and computational studies, focused on the human enzyme PTP1B and the PTP from Yersinia pestis, YopH, suggested that loop conformational dynamics are important in regulating both catalysis and evolvability. We have generated a chimeric protein in which the WPD-loop of YopH is transposed into PTP1B, and eight chimeras that systematically restored the loop sequence back to native PTP1B. Of these, four chimeras were soluble and were subjected to detailed biochemical and structural characterization, and a computational analysis of their WPD-loop dynamics. The chimeras maintain backbone structural integrity, with somewhat slower rates than either wild-type parent, and show differences in the pH dependency of catalysis, and changes in the effect of Mg2+. The chimeric proteins' WPD-loops differ significantly in their relative stability and rigidity. The time required for interconversion, coupled with electrostatic effects revealed by simulations, likely accounts for the activity differences between chimeras, and relative to the native enzymes. Our results further the understanding of connections between enzyme activity and the dynamics of catalytically important groups, particularly the effects of non-catalytic residues on key conformational equilibria.

Hydrogen-deuterium exchange mass spectrometry of Mtr4 with diverse RNAs reveals substrate-dependent dynamics and interfaces in the arch.

Mtr4 is a eukaryotic RNA helicase required for RNA decay by the nuclear exosome. Previous studies have shown how RNA en route to the exosome threads through the highly conserved helicase core of Mtr4. Mtr4 also contains an arch domain, although details of potential interactions between the arch and RNA have been elusive. To understand the interaction of Saccharomyces cerevisiae Mtr4 with various RNAs, we have characterized RNA binding in solution using hydrogen-deuterium exchange mass spectrometry, and affinity and unwinding assays. We have identified RNA interactions within the helicase core that are consistent with existing structures and do not vary between tRNA, single-stranded RNA and double-stranded RNA constructs. We have also identified novel RNA interactions with a region of the arch known as the fist or KOW. These interactions are important for RNA unwinding and vary in strength depending on RNA structure and length. They account for Mtr4 discrimination between different RNAs. These interactions further drive Mtr4 to adopt a closed conformation characterized by reduced dynamics of the arch arm and intra-domain contacts between the fist and helicase core.

Pharmacist-Led Intervention on the Inappropriate Use of Stress Ulcer Prophylaxis Pharmacotherapy in Intensive Care Units: A Systematic review.

Background: Pharmacist's direct intervention or participation in multidisciplinary management teams can improve the clinical outcome and quality of life of patients. We aimed to determine the effectiveness of pharmacist-led interventions on the inappropriate use of stress ulcer prophylaxis (SUP) pharmacotherapy in intensive care units (ICUs). Methods: A systematic review was performed for relevant studies using searched PubMed, EMBASE (Ovid), the Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), and four Chinese databases from the establishment of databases to 12 March 2020. We conducted a descriptive analysis of participants, the intervention content and delivery, and the effects on inappropriate medication rates. Results: From 529 records, 8 studies from 9 articles were included in the systematic review. The time of appropriateness judgment and the criteria of "appropriate" varied from included studies. Pharmacist interventions mainly included clarifying indications for SUP pharmacotherapy, education and awareness campaign, reviewed patients on SUP pharmacotherapy during rounds, and adjustments of drug use. Five (62.5%) studies found a significant intervention effect during hospitalization, while 2 (25%) studies at ICU transfer and 2 (25%) studies at hospital discharge. 4 (50%) studies identified the complications related to SUP pharmacotherapy and found no significant difference. 4 (50%) studies declared the pharmacist-led interventions were associated with cost savings. Conclusion: Pharmacist-led intervention is associated with a decrease in inappropriate use of SUP pharmacotherapy during hospitalization, at ICU transferred and hospital discharged, and a lot of medical cost savings. Further research is needed to determine whether pharmacist-led intervention is cost-effective.

Significant Loop Motions in the SsoPTP Protein Tyrosine Phosphatase Allow for Dual General Acid Functionality.

Conformational dynamics are important factors in the function of enzymes, including protein tyrosine phosphatases (PTPs). Crystal structures of PTPs first revealed the motion of a protein loop bearing a conserved catalytic aspartic acid, and subsequent nuclear magnetic resonance and computational analyses have shown the presence of motions, involved in catalysis and allostery, within and beyond the active site. The tyrosine phosphatase from the thermophilic and acidophilic Sulfolobus solfataricus (SsoPTP) displays motions of its acid loop together with dynamics of its phosphoryl-binding P-loop and the Q-loop, the first instance of such motions in a PTP. All three loops share the same exchange rate, implying their motions are coupled. Further evidence of conformational flexibility comes from mutagenesis, kinetics, and isotope effect data showing that E40 can function as an alternate general acid to protonate the leaving group when the conserved acid, D69, is mutated to asparagine. SsoPTP is not the first PTP to exhibit an alternate general acid (after VHZ and TkPTP), but E40 does not correspond to the sequence or structural location of the alternate general acids in those precedents. A high-resolution X-ray structure with the transition state analogue vanadate clarifies the role of the active site arginine R102, which varied in structures of substrates bound to a catalytically inactive mutant. The coordinated motions of all three functional loops in SsoPTP, together with the function of an alternate general acid, suggest that catalytically competent conformations are present in solution that have not yet been observed in crystal structures.

Mtr4 RNA helicase structures and interactions.

Mtr4 is a Ski2-like RNA helicase that plays a central role in RNA surveillance and degradation pathways as an activator of the RNA exosome. Multiple crystallographic and cryo-EM studies over the past 10 years have revealed important insight into the Mtr4 structure and interactions with protein and nucleic acid binding partners. These structures place Mtr4 at the center of a dynamic process that recruits RNA substrates and presents them to the exosome. In this review, we summarize the available Mtr4 structures and highlight gaps in our current understanding.

Hydromorphone Compared to Fentanyl in Patients Receiving Extracorporeal Membrane Oxygenation.

Fentanyl is commonly used in critically ill patients receiving extracorporeal membrane oxygenation (ECMO). Fentanyl's lipophilicity and protein binding may contribute to a sequestration of the drug in the ECMO circuit. Hydromorphone lacks these characteristics potentially leading to a more predictable drug delivery and improved pain and sedation management among ECMO patients. This study compared hydromorphone to fentanyl in patients receiving ECMO. This retrospective study included adult patients receiving ECMO for ≥48 hours. Patients were excluded if they required neuromuscular blockade, received both fentanyl and hydromorphone during therapy, or had opioid use before hospitalization. Baseline characteristics included patient demographics, ECMO indication and settings, and details regarding mechanical ventilation. The primary outcome was opioid requirements at 48 hours post cannulation described in morphine milligram equivalent (MME). Secondary endpoints included 24-hour opioid requirements, concurrent sedative use, and differences in pain and sedation scores. No differences were noted between the patients receiving fentanyl (n = 32) or hydromorphone (n = 20). Patients receiving hydromorphone required lower MME compared to fentanyl at 24 hours (88 [37-121] vs. 131 [137-227], p < 0.01) and 48 hours (168 [80-281] vs. 325 [270-449], p < 0.01). The proportion of within-goal pain and sedation scores between groups was similar at 24 and 48 hours. Sedative requirements did not differ between the groups. Patients receiving hydromorphone required less MME compared to fentanyl without any differences in sedative requirements, or agitation-sedation scores at 48 hours. Prospective studies should be completed to validate these findings.

Capacity Building for Research in Critical Care: A Pilot Program in the Eastern Mediterranean Region.

Research productivity in the Eastern Mediterranean Region is relatively low in all fields, including critical care. We describe a capacity-building research program that was piloted with 11 clinicians from the Eastern Mediterranean Region, who had minimal research experience. The program was conducted over 1 year, with a structure that specifically addressed factors that contribute to low research productivity. We describe the structure of the program, the faculty involved, the feasibility, and challenges faced, as well as the impact of the program on research output. At a small scale, the program was generally feasible and demonstrated promising results. Evaluating the feasibility of conducting such a program over a longer period of time and with a larger group of participants is necessary since research capacity-building programs require multiple years to demonstrate a significant impact on research output.

Evaluation of a community pharmacy-based influenza and group A streptococcal pharyngitis disease management program using polymerase chain reaction point-of-care testing.

OBJECTIVES: The purpose of this study was to demonstrate the feasibility of implementing a Clinical Laboratory Improvement Amendments-waived real-time polymerase chain reaction (PCR) molecular test into a community pharmacy setting as part of a collaborative influenza and group A Streptococcus (GAS) disease management program. SETTING AND PARTICIPANTS: Two community pharmacy sites in Tennessee. PRACTICE DESCRIPTION: Patients presenting to the pharmacy with symptoms consistent with influenza or GAS from November 1, 2016, to April 30, 2018. PRACTICE INNOVATION: Influenza and GAS management programs based on previously developed protocols occurred at 2 community pharmacies in Tennessee. Pharmacies used the Cobas Liat testing system (Roche Diagnostics). Based on test results and under a collaborative practice agreement, pharmacists dispensed prescription medications for patients with a positive test: oseltamivir for influenza and amoxicillin for GAS. Patients with negative tests were treated with over-the-counter (OTC) medications or referred. Patients testing negative for GAS were asked to consent to having a second throat swab sent for culture. EVALUATION: Number of patients tested, point-of-care test results, and treatment received. RESULTS: Two hundred and two patients received care at the 2 pharmacies (116 for influenza, 46 for GAS, and 43 for both). Sixty (38%) tested positive for influenza, with 51 receiving an antiviral prescription, and 16 (18%) tested positive and were treated for GAS. No patient testing negative for either or positive for influenza was dispensed an antibiotic. For patients consenting to a follow-up culture, all GAS cultures sent for confirmatory testing were negative. CONCLUSION: A protocol-driven community pharmacy-based disease management program using real-time PCR testing for influenza and GAS was able to offer appropriate treatment to patients without overuse of antibiotics.

Structural basis of Type IV CRISPR RNA biogenesis by a Cas6 endoribonuclease.

Prokaryotic CRISPR-Cas adaptive immune systems rely on small non-coding RNAs derived from CRISPR loci to recognize and destroy complementary nucleic acids. However, the mechanism of Type IV CRISPR RNA (crRNA) biogenesis is poorly understood. To dissect the mechanism of Type IV CRISPR RNA biogenesis, we determined the x-ray crystal structure of the putative Type IV CRISPR associated endoribonuclease Cas6 from Mahella australiensis (Ma Cas6-IV) and characterized its enzymatic activity with RNA cleavage assays. We show that Ma Cas6-IV specifically cleaves Type IV crRNA repeats at the 3' side of a predicted stem loop, with a metal-independent, single-turnover mechanism that relies on a histidine and a tyrosine located within the putative endonuclease active site. Structure and sequence alignments with Cas6 orthologs reveal that although Ma Cas6-IV shares little sequence homology with other Cas6 proteins, all share common structural features that bind distinct crRNA repeat sequences. This analysis of Type IV crRNA biogenesis provides a structural and biochemical framework for understanding the similarities and differences of crRNA biogenesis across multi-subunit Class 1 CRISPR immune systems.

Evaluating the Published Critical Care Research from the World Health Organization Eastern Mediterranean Region.

OBJECTIVES: Evaluation of published research in a region provides insight into relevant aspects of clinical care and research priorities. This study aimed to provide a comprehensive assessment of the type of critical care research published in the World Health Organization Eastern Mediterranean region (EMR) over a 10-year period. RESULTS: During the study period (2007-2016), the search strategy revealed 4303 publications, of which 1537 were included in the analysis; studies were excluded for the following reasons: not critical care, conducted in non-EMR countries, editorials, case reports, in-vitro or animal studies, as well as those conducted in multiple countries and those that evaluated foreign military personal. Countries varied in the number of publications produced, ranging from none in Somalia to 620 in Iran. The majority of the studies were observational (78%), evaluated adults (73%), and the most common areas of research were infectious (29%) and respiratory (10%) diseases. Median sample size was 120 and the mean (SD) impact factor of the journals in which the articles were published was 1.02 (0.7).

A Multicenter, Prospective, Observational Study to Determine Predictive Factors for Multidrug-Resistant Pneumonia in Critically Ill Adults: The DEFINE Study.

OBJECTIVE: This study was conducted to describe the prevalence, epidemiology, and clinical outcomes of multidrug-resistant (MDR) organism (MDRO) pneumonia in critically ill patients. METHODS: A multicenter, prospective, observational study of patients admitted to 60 intensive care units (ICUs), from 34 hospitals, in the United States from November to December 2016. Adults (> 18 yrs) receiving antimicrobial therapy at least 5 days for pneumonia were included. Patients were classified into two categories, with or without MDRO, and subcategorized by pneumonia type. MEASUREMENTS AND MAIN RESULTS: Demographics, medication histories, and health care exposure were collected during ICU admission and compared using t test and chi-square tests. Multivariate logistic regression was used to determine predictive factors for MDRO pneumonia and hospital mortality. Of 652 patients, 92 patients (14.1%) developed MDR pneumonia. Predictors of MDRO pneumonia were acid suppression therapy within the previous 90 days (odds ratio [OR] 1.88 [1.14-3.09]; p=0.013), mechanical ventilation (OR 1.96 [1.14-3.35]; p<0.001), and history of MDRO infection (OR 4.74 [2.21-10.18]; p<0.001). Appropriate initial antimicrobial selection occurred in 58 patients (63%) with MDRO pneumonia compared to 464 patients (82.7%) in patients without MDRO pneumonia (p<0.001). MDRO pneumonia was not associated with hospital mortality (18.5% vs 17.6%, p=0.087). CONCLUSIONS: In a broad cohort of critically ill patients, MDRO pneumonia is infrequent, and associated with factors describing the intensity of health care provided. Presence of MDRO pneumonia is not associated with hospital mortality. Further study is needed to clarify risk factors for multidrug-resistant pneumonia in critically ill patients.

Academic conflict of interest.

PURPOSE: We set out to summarize the current challenges in academic conflict of interest. METHODS: This is a narrative review by a multidisciplinary, multinational panel of academic officers including deans of medical/pharmacy schools. RESULTS AND CONCLUSIONS: Disclosing conflict of interest has become the appropriate professional behavior since the 1990s in response to the necessity to fix moral and financial fences around medical activities. The nature of the conflict of interest is academic when either the conflict relates to academic duties and/or the nature of the interest is academic. People usually distinguish between real conflict of interest, when private interest overtly influences one's professional obligations; potential conflict of interest, when there is no obvious direct link between a person interests and current duties without ruling out that expected changes in duties cause a situation of conflict; and apparent conflict of interest, when the risk does not really exist, but serious doubts remain. Areas at risk of academic conflict of interest include peer review process for grant evaluation or journals, scientific communications such as elaborating and disseminating clinical guidelines, lecturing at meeting, advising decision-makers, teaching activities, and mentoring. The management of academic conflict of interest should consider actions in four domains, i.e., education, prevention, measures for enforcement and solving, and communication. Academic conflicts of interest are as frequent as financial conflicts but more difficult to identify and assess, and much less addressed in the literature. Generating more evidence from high-quality research is mandated to improve the management of academic and more generally non-financial conflicts of interest.

Impact of chronic hypertension on time to goal mean arterial pressure and clinical outcomes in critically ill patients with septic shock requiring vasopressors.

PURPOSE: Mean arterial pressure (MAP) reflects the adequacy of tissue perfusion. In septic shock, vasopressors are recommended to target MAP ≥65 mmHg. The impact of chronic hypertension (HTN) on MAP achievement and outcomes are uncertain. MATERIALS AND METHODS: This retrospective, cohort study compared time to goal MAP in critically ill patients with septic shock admitted between May 2014 and July 2016. Between-group differences of patients with and without HTN were compared using appropriate statistical tests. To adjust for imbalances in baseline characteristics, inverse probability of treatment weighting (IPTW) procedure was performed. RESULTS: Of the 133 included patients, 75 (56.4%) had a history of HTN. Baseline characteristics were mostly similar. Patients with HTN had higher in-hospital (49.3 vs. 31.0%, p = .035) and 28-day mortality (53.3 vs. 31.0%, p = .011). After weighting and adjustment for imbalanced variables, patients with HTN achieved goal MAP more rapidly than those without (HR: 1.84, 95% CI: 1.14-2.96; p = .012). However, they also have higher odds of dying within 28 days of discharge (OR: 3.04, 95% CI: 1.11-8.38; p = .031). CONCLUSIONS: Patients with HTN achieved goal MAP more rapidly but had higher odds of mortality.