Assessment of the comparative agreement between chest radiographs and CT scans in intensive care units.

PURPOSE: Chest radiographs in critically ill patients can be difficult to interpret due to technical and clinical factors. We sought to determine the agreement of chest radiographs and CT scans, and the inter-observer variation of chest radiograph interpretation, in intensive care units (ICUs). METHODS: Chest radiographs and corresponding thoracic computerised tomography (CT) scans (as reference standard) were collected from 45 ICU patients. All radiographs were analysed by 20 doctors (radiology consultants, radiology trainees, ICU consultants, ICU trainees) from 4 different centres, blinded to CT results. Specificity/sensitivity were determined for pleural effusion, lobar collapse and consolidation/atelectasis. Separately, Fleiss' kappa for multiple raters was used to determine inter-observer variation for chest radiographs. RESULTS: The median sensitivity and specificity of chest radiographs for detecting abnormalities seen on CTs scans were 43.2% and 85.9% respectively. Diagnostic sensitivity for pleural effusion was significantly higher among radiology consultants but no specialty/experience distinctions were observed for specificity. Median inter-observer kappa coefficient among assessors was 0.295 ("fair"). CONCLUSIONS: Chest radiographs commonly miss important radiological features in critically ill patients. Inter-observer agreement in chest radiograph interpretation is only "fair". Consultant radiologists are least likely to miss thoracic radiological abnormalities. The consequences of misdiagnosis by chest radiographs remain to be determined.

A group concept mapping and ethnographic study of intensive care rehabilitation culture.

BACKGROUND: Early physical activity and physical rehabilitation are advocated in the critical care unit for patients recovering from critical illness. Despite this, there are still many factors associated with implementation of early physical rehabilitation into routine critical care and practice. One such factor that has been consistently identified is unit culture, yet there is little understanding of how or why the culture of a critical care unit impacts on implementation of early rehabilitation. AIM: To develop a detailed understanding of the cultural barriers and enablers to the promotion and implementation of physical activity and early mobilization in National Health Service (NHS) critical care units in the United Kingdom (UK). STUDY DESIGN: A mixed-methods, two-phase study incorporating online group concept mapping (GCM) and ethnography. GCM will be conducted to provide a multistakeholder co-authored conceptual framework of rehabilitation culture. Ethnographic observations and interviews will be conducted of culture and behaviours in relation to the implementation and promotion of early physical activity and rehabilitation in two NHS critical care units in the North East of England. RESULTS: The results of the Group Concept Mapping and ethnographic observations and interviews will be triangulated to develop a contextual framework of rehabilitation culture in critical care. RELEVANCE TO CLINICAL PRACTICE: This study will provide a detailed understanding of barriers and facilitators in relation to providing a positive rehabilitation culture in the critical care unit.

Tissue factor expression in monocyte subsets during human immunothrombosis, endotoxemia and sepsis.

INTRODUCTION: Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown. METHODS: Monocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units. RESULTS: Contact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes. CONCLUSION: Tissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.

Efficacy and safety of proton pump inhibitors versus histamine-2 receptor blockers in the cardiac surgical population: insights from the PEPTIC trial.

OBJECTIVES: The comparative effectiveness and safety of proton pump inhibitors (PPIs) versus histamine-2 receptor blockers for stress ulcer prophylaxis in the cardiac surgical intensive care unit population is uncertain. Although the Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) trial reported a higher risk of mortality in the PPI arm with no difference in gastrointestinal bleeding, detailed information on surgical variables and clinically relevant surgical subgroups was not available. METHODS: The analysis included all Canadian cardiac surgery patients enrolled in the PEPTIC trial. Data were electronically linked using unique patient identifiers to a clinical information system. Outcomes of interest included in-hospital mortality, gastrointestinal bleeding, Clostridium difficile infections, ventilator-associated conditions and length of stay. RESULTS: We studied 823 (50.6%) randomized to PPIs and 805 (49.4%) to histamine-2-receptor blockers. In the intention-to-treat analysis, there were no differences in hospital mortality [PPI: 4.3% vs histamine-2 receptor blockers: 4.8%, adjusted odds ratio (aOR) 0.97, 95% confidence interval (CI) 0.55-1.70], gastrointestinal bleeding (3.9% vs 4.8%, aOR 1.09, 95% CI 0.66-1.81), C. difficile infections (0.9% vs 0.1%, aOR 0.18, 95% CI 0.02-1.59), ventilator-associated conditions (1.6% vs 1.7%, aOR 0.92, 95% CI 0.85-1.00) or median length of stay (9.2 vs 9.8 days, adjusted risk ratio 1.06, 85% CI 0.99-1.13). No significant treatment differences were observed among subgroups of interest or per-protocol populations. CONCLUSIONS: In a secondary analysis of cardiac surgery patients enrolled in the PEPTIC trial in Canada, no differences in effectiveness or safety were observed between use of PPIs and histamine-2 receptor blockers for stress ulcer prophylaxis. CLINICAL TRIAL REGISTRATION NUMBER: anzctr.org.au identifier: ACTRN12616000481471.

Phosphoinositide 3-Kinase δ Inhibition Improves Neutrophil Bacterial Killing in Critically Ill Patients at High Risk of Infection.

Acquired neutrophil dysfunction frequently develops during critical illness, independently increasing the risk for intensive care unit-acquired infection. PI3Kδ is implicated in driving neutrophil dysfunction and can potentially be targeted pharmacologically. The aims of this study were to determine whether PI3Kδ inhibition reverses dysfunction in neutrophils from critically ill patients and to describe potential mechanisms. Neutrophils were isolated from blood taken from critically ill patients requiring intubation and mechanical ventilation, renal support, or blood pressure support. In separate validation experiments, neutrophil dysfunction was induced pharmacologically in neutrophils from healthy volunteers. Phagocytosis and bacterial killing assays were performed, and activity of RhoA and protein kinase A (PKA) was assessed. Inhibitors of PI3Kδ, 3-phosphoinositide-dependent protein kinase-1 (PDK1), and PKA were used to determine mechanisms of neutrophil dysfunction. Sixty-six patients were recruited. In the 27 patients (40.9%) with impaired neutrophil function, PI3Kδ inhibition consistently improved function and significantly increased bacterial killing. These findings were validated in neutrophils from healthy volunteers with salbutamol-induced dysfunction and extended to demonstrate that PI3Kδ inhibition restored killing of clinical isolates of nine pathogens commonly associated with intensive care unit-acquired infection. PI3Kδ activation was associated with PDK1 activation, which in turn phosphorylated PKA, which drove phosphorylation and inhibition of the key regulator of neutrophil phagocytosis, RhoA. These data indicate that, in a significant proportion of critically ill patients, PI3Kδ inhibition can improve neutrophil function through PDK1- and PKA-dependent processes, suggesting that therapeutic use of PI3Kδ inhibitors warrants investigation in this setting.

Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells.

A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-ß and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-ß, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-ß and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.

Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial.

Importance: Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown. Objective: To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis. Design, Setting, and Participants: Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital. Interventions: Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs). Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay. Results: Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group. Conclusions and Relevance: Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication. Trial Registration: anzctr.org.au Identifier: ACTRN12616000481471.

Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.

BACKGROUND: Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1ß and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1ß and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia. METHODS: VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1ß and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 104 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425. FINDINGS: Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0·58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes. INTERPRETATION: Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect. FUNDING: UK Department of Health and the Wellcome Trust.

Family satisfaction with critical care in the UK: a multicentre cohort study.

OBJECTIVE: To assess family satisfaction with intensive care units (ICUs) in the UK using the Family Satisfaction in the Intensive Care Unit 24-item (FS-ICU-24) questionnaire, and to investigate how characteristics of patients and their family members impact on family satisfaction. DESIGN: Prospective cohort study nested within a national clinical audit database. SETTING: Stratified, random sample of 20 adult general ICUs participating in the Intensive Care National Audit & Research Centre Case Mix Programme. PARTICIPANTS: Family members of patients staying at least 24 hours in ICU were recruited between May 2013 and June 2014. INTERVENTIONS: Consenting family members were sent a postal questionnaire 3 weeks after the patient died or was discharged from ICU. Up to four family members were recruited per patient. MAIN OUTCOME MEASURES: Family satisfaction was measured using the FS-ICU-24 questionnaire. MAIN RESULTS: A total of 12 346 family members of 6380 patients were recruited and 7173 (58%) family members of 4615 patients returned a completed questionnaire. Overall and domain-specific family satisfaction scores were high (mean overall family satisfaction 80, satisfaction with care 83, satisfaction with information 76 and satisfaction with decision-making 73 out of 100) but varied significantly across adult general ICUs studied and by whether the patient survived ICU. For family members of ICU survivors, characteristics of both the family member (age, ethnicity, relationship to patient (next-of-kin and/or lived with patient) and visit frequency) and the patient (acute severity of illness and receipt of invasive mechanical ventilation) were significant determinants of family satisfaction, whereas, for family members of ICU non-survivors, only patient characteristics (age, acute severity of illness and duration of stay) were significant. CONCLUSIONS: Overall family satisfaction in UK adult general ICUs was high but varied significantly. Adjustment for differences in family member/patient characteristics is important to avoid falsely identifying ICUs as statistical outliers. TRIAL REGISTRATION NUMBER: ISRCTN47363549.

IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in Literature.

Immunoglobulin G4-related disease (IgG4-RD) is known for forming soft tissue mass lesions that may have compressive effects. It is an extremely rare disease that most frequently affects the pancreas causing autoimmune pancreatitis. It can also affect the gallbladder, salivary glands, and lacrimal glands causing respective organ-specific complications. In our report, we describe an IgG4-RD case that affected the spinal cord. A 60-year-old female presented with cervical spinal cord compression caused by IgG4-RD leading to several neurological deficits. Pathological examination of the excisional biopsy of the mass revealed dense lymphoplasmacytic cells infiltration and stromal fibrosis with IgG4 and plasma cells. The patient showed a dramatic response to the administration of systemic steroids with almost resolution of her neurological symptoms. This case highlights the first case in literature for IgG4-RD of the extradural tissue causing spinal compression. Hereby, we also demonstrate the dramatic response of IgG4-RD to the administration of systemic steroids as the patient had no recurrence after 5 years of close follow-up, the longest reported period of follow-up reported in the literature to date.

Patient experience and reflective learning (PEARL): a mixed methods protocol for staff insight development in acute and intensive care medicine in the UK.

INTRODUCTION: Patient and staff experiences are strongly influenced by attitudes and behaviours, and provide important insights into care quality. Patient and staff feedback could be used more effectively to enhance behaviours and improve care through systematic integration with techniques for reflective learning. We aim to develop a reflective learning framework and toolkit for healthcare staff to improve patient, family and staff experience. METHODS & ANALYSIS: Local project teams including staff and patients from the acute medical units (AMUs) and intensive care units (ICUs) of three National Health Service trusts will implement two experience surveys derived from existing instruments: a continuous patient and relative survey and an annual staff survey. Survey data will be supplemented by ethnographic interviews and observations in the workplace to evaluate barriers to and facilitators of reflective learning. Using facilitated iterative co-design, local project teams will supplement survey data with their experiences of healthcare to identify events, actions, activities and interventions which promote personal insight and empathy through reflective learning. Outputs will be collated by the central project team to develop a reflective learning framework and toolkit which will be fed back to the local groups for review, refinement and piloting. The development process will be mapped to a conceptual theory of reflective learning which combines psychological and pedagogical theories of learning, alongside theories of behaviour change based on capability, opportunity and motivation influencing behaviour. The output will be a locally-adaptable workplace-based toolkit providing guidance on using reflective learning to incorporate patient and staff experience in routine clinical activities. ETHICS & DISSEMINATION: The PEARL project has received ethics approval from the London Brent Research Ethics Committee (REC Ref 16/LO/224). We propose a national cluster randomised step-wedge trial of the toolkit developed for large-scale evaluation of impact on patient outcomes.

Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis.

BACKGROUND: Critically ill patients with impaired neutrophil phagocytosis have significantly increased risk of nosocomial infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) improves phagocytosis by neutrophils ex vivo. This study tested the hypothesis that GM-CSF improves neutrophil phagocytosis in critically ill patients in whom phagocytosis is known to be impaired. METHODS: This was a multicentre, phase IIa randomised, placebo-controlled clinical trial. Using a personalised medicine approach, only critically ill patients with impaired neutrophil phagocytosis were included. Patients were randomised 1:1 to subcutaneous GM-CSF (3 µg/kg/day) or placebo, once daily for 4 days. The primary outcome measure was neutrophil phagocytosis 2 days after initiation of GM-CSF. Secondary outcomes included neutrophil phagocytosis over time, neutrophil functions other than phagocytosis, monocyte HLA-DR expression and safety. RESULTS: Thirty-eight patients were recruited from five intensive care units (17 randomised to GM-CSF). Mean neutrophil phagocytosis at day 2 was 57.2% (SD 13.2%) in the GM-CSF group and 49.8% (13.4%) in the placebo group, p=0.73. The proportion of patients with neutrophil phagocytosis≥50% at day 2, and monocyte HLA-DR, appeared significantly higher in the GM-CSF group. Neutrophil functions other than phagocytosis did not appear significantly different between the groups. The most common adverse event associated with GM-CSF was fever. CONCLUSIONS: GM-CSF did not improve mean neutrophil phagocytosis at day 2, but was safe and appeared to increase the proportion of patients with adequate phagocytosis. The study suggests proof of principle for a pharmacological effect on neutrophil function in a subset of critically ill patients.

A cluster randomised, crossover, registry-embedded clinical trial of proton pump inhibitors versus histamine-2 receptor blockers for ulcer prophylaxis therapy in the intensive care unit (PEPTIC study): study protocol.

BACKGROUND: The balance of risks and benefits with using proton pump inhibitors (PPIs) versus histamine-2 receptor blockers (H2RB) for stress ulcer prophylaxis in patients who are invasively ventilated in the intensive care unit (ICU) is uncertain. OBJECTIVE: To describe the study protocol and statistical analysis plan for the Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) study. DESIGN, SETTING AND PARTICIPANTS: Protocol for a prospective, multicentre, randomised, open-label, cluster crossover, registry-embedded trial to be conducted in 50 ICUs in Australia, Canada, Ireland, New Zealand and the United Kingdom. The PEPTIC study will compare two approaches to stress ulcer prophylaxis in mechanically ventilated adults implemented at the level of the ICU. One approach is to use PPIs as the default therapy and the other approach is to use H2RBs as the default therapy when stress ulcer prophylaxis is prescribed. Each ICU, by random allocation, will use one approach for 6 months and will then switch to the opposite approach for the next 6 months. The PEPTIC study began recruitment in August 2016 and will complete recruitment in January 2019. MAIN OUTCOME MEASURES: The primary end point will be in-hospital mortality. Secondary outcomes include clinically significant upper gastrointestinal bleeding, Clostridium difficile infection, ICU length of stay and hospital length of stay. RESULTS AND CONCLUSIONS: The PEPTIC study will compare the effect on in-hospital mortality of implementing, at the level of the ICU, the use of PPI as the preferred agent for stress ulcer prophylaxis in mechanically ventilated adults in the ICU with using H2RB as the preferred agent. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12616000481471).

The Effect of Perioperative Cimetidine Administration on Time to Colorectal Cancer Recurrence.

BACKGROUND: Studies have reported that the perioperative use of cimetidine, a histamine type 2 receptor antagonist, in addition to chemotherapy in patients with lymph node-positive colorectal cancer (CRC) improves the survival. STUDY QUESTION: To determine if time to CRC recurrence could be prolonged with cimetidine. STUDY DESIGN: Cimetidine was prescribed to American Joint on Cancer Committee (AJCC) stage III CRC patients perioperatively. Tumor recurrence was defined as the time (in days) between tumor resection and CRC recurrence. Medical charts of patients diagnosed with CRC between 1996 and 2006 were reviewed. Inclusion criteria were patients with (a) AJCC stage III CRC, (b) who had undergone surgical resection of the tumor, and (c) who received chemotherapy (5-fluorouracil). MEASURES AND OUTCOMES: AJCC stage III CRC patients who did and did not receive cimetidine as part of the treatment regimen were compared with respect to their clinical outcomes using univariate analysis and Kaplan-Meier modeling. RESULTS: Between 1996 and 2006, 38 patients met our inclusion criteria. Twenty-six percent (10/38) received perioperative cimetidine (mean daily dose, 750 mg; mean duration, 369 days; mean total cumulative cimetidine dose, 274,070 mg/d) in addition to chemotherapy. Time to recurrence and cancer deaths were prolonged in the chemotherapy plus cimetidine group compared with the group that received chemotherapy alone (mean ± SD: 1078 ± 290 vs. 446 ± 62; P = 0.03). In addition, we found a significant positive relationship between the duration of cimetidine therapy (days) and survival duration (correlation coefficient = 0.94, P = 0.02) and time until cancer recurrence (correlation coefficient = 0.99, P = 0.04). Moreover, there was a significant positive relationship between the total cumulative cimetidine dose and survival duration (correlation coefficient = 0.92, P = 0.03). CONCLUSIONS: Prolonged duration of cimetidine may be superior to shorter courses in prolonging recurrence of CRC and thus survival.

Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients.

RATIONALE: Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP. OBJECTIVES: To characterize subglottic host defense dysfunction in mechanically ventilated patients in the ICU; to determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth. METHODS: Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 min); isolation and culture of primary subglottic epithelial cells from control patients; laboratory analysis of host innate immune defenses. MEASUREMENTS AND MAIN RESULTS: Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in the ICU was characterized by neutrophilic inflammation, significantly increased proinflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic impairment was reversible on treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium. CONCLUSIONS: Mechanical ventilation in the ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil function and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.

Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial.

BACKGROUND: Early physical rehabilitation in the intensive care unit (ICU) has been shown to improve short-term clinical outcomes but long-term benefit has not been proven and the optimum intensity of rehabilitation is not known. METHODS: We conducted a randomised, parallel-group, allocation-concealed, assessor-blinded, controlled trial in patients who had received at least 48 hours of invasive or non-invasive ventilation. Participants were randomised in a 1:1 ratio, stratified by admitting ICU, admission type and level of independence. The intervention group had a target of 90 min physical rehabilitation per day, the control group a target of 30 min per day (both Monday to Friday). The primary outcome was the Physical Component Summary (PCS) measure of SF-36 at 6 months. RESULTS: We recruited 308 participants over 34 months: 150 assigned to the intervention and 158 to the control group. The intervention group received a median (IQR) of 161 (67-273) min of physical rehabilitation on ICU compared with 86 (31-139) min in the control group. At 6 months, 62 participants in the intervention group and 54 participants in the control group contributed primary outcome data. In the intervention group, 43 had died, 11 had withdrawn and 34 were lost to follow-up, while in the control group, 56 had died, 5 had withdrawn and 43 were lost to follow-up. There was no difference in the primary outcome at 6 months, mean (SD) PCS 37 (12.2) in the intervention group and 37 (11.3) in the control group. CONCLUSIONS: In this study, ICU-based physical rehabilitation did not appear to improve physical outcomes at 6 months compared with standard physical rehabilitation. TRIAL REGISTRATION NUMBER: ISRCTN 20436833.

Reducing the incidence of pressure ulcers in critical care units: a 4-year quality improvement.

QUALITY PROBLEM: Critical care patients often have several risk factors for pressure ulceration and implementing prevention interventions have been shown to decrease risk. INITIAL ASSESSMENT: We identified a high incidence of pressure ulcers in the four adult critical care units in our organization. Therefore, avoiding pressure ulceration was an important quality priority. CHOICE OF SOLUTION: We undertook a quality improvement programme aimed at reducing the incidence of pressure ulceration using an evidence-based bundle approach. IMPLEMENTATION: A bundle of technical and non-technical interventions were implemented supported by clinical leadership on each unit. Important components were evidence appraisals; changes to mattresses; focussed risk assessment alongside mandating patients at very high risk to be repositioned two hourly; and staff training to increase awareness of how to prevent pressure ulcers. EVALUATION: Pressure ulcer numbers, incidence and categories were collected continuously and monitored monthly by unit staff. Pressure ulcer rates reduced significantly from 8.08/100 patient admissions to 2.97/100 patient admissions, an overall relative rate reduction of 63% over 4 years. The greatest reduction was seen in the most severe category of pressure ulceration. The average estimated cost saving was £2.6 million (range £2.1-£3.1). LESSONS LEARNED: A quality improvement programme including technical and non-technical interventions, data feedback to staff and clinical leadership was associated with a sustained reduction in the incidence of pressure ulceration in the critically ill. Strategies used in this programme may be transferable to other critical care units to bring more widespread patient benefit.