Monocyte Function and Clinical Outcomes in Febrile and Afebrile Patients With Severe Sepsis.

INTRODUCTION: Absence of fever is associated with higher mortality in septic patients, but the reason for this is unknown. Immune dysfunction may be a potential link between failure to mount a fever and poor outcomes. The purpose of this study was to evaluate monocyte function and clinical surrogates of immunity (i.e., mortality and acquisition of secondary infections) in febrile and afebrile septic patients. METHODS: Single-center, prospective cohort study of 92 critically ill septic patients. Patients were categorized into febrile (≥38.0°C) and afebrile (<38.0°C) groups based on temperature measurements within 24 hours of sepsis diagnosis. HLA-DR expression and LPS-induced TNF-α production were quantified on days 1-2, days 3-4, and days 6-8 after sepsis diagnosis. A repeated measures mixed models analysis was used to compare these markers between the two groups. RESULTS: Forty-four patients (47.8%) developed a fever within 24 h of sepsis diagnosis. There were no significant differences in HLA-DR expression or LPS-induced TNF-α production between febrile and afebrile patients at any individual time point. However, HLA-DR expression significantly increased between days 1-2 and days 6-8 (median difference 8118 [IQR 1,662, 9,878] antibodies/cell, P = 0.002) in febrile patients, but not in afebrile patients (median difference 403 [-3,382, 3,507] antibodies/cell, P = 0.25). Afebrile patients demonstrated higher 28-day mortality (37.5% vs 18.2%) and increased acquisition of secondary infections (35.4% vs. 15.9%). CONCLUSIONS: Absence of fever is associated with suppressed HLA-DR expression over time, a finding suggestive of monocyte dysfunction in sepsis, as well as worse clinical outcomes.

Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to examine the impact of antipyretic therapy on mortality in critically ill septic adults. DATA SOURCES: Literature searches were implemented in Ovid Medline, Embase, Scopus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, and ClinicalTrials.gov through February 2016. STUDY SELECTION: Inclusion criteria were observational or randomized studies of septic patients, evaluation of antipyretic treatment, mortality reported, and English-language version available. Studies were excluded if they enrolled pediatric patients, patients with neurologic injury, or healthy volunteers. Criteria were applied by two independent reviewers. DATA EXTRACTION: Two reviewers independently extracted data and evaluated methodologic quality. Outcomes included mortality, frequency of shock reversal, acquisition of nosocomial infections, and changes in body temperature, heart rate, and minute ventilation. Randomized and observational studies were analyzed separately. DATA SYNTHESIS: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38°C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation. CONCLUSIONS: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.

Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study.

BACKGROUND: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-ɑ) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-ɑ production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients. METHODS: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1-2, days 3-4, and days 6-8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-ɑ production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection. RESULTS: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3-4 (p = 0.04) and days 6-8 (p = 0.002). The change in HLA-DR from days 1-2 to days 6-8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1-2 to days 3-4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-ɑ production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection. CONCLUSIONS: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-ɑ production in adult medical and surgical critically ill patients.

Assessing the utility of an online registry for patients monitoring their own warfarin therapy.

AIMS: To evaluate the utility of an online self-report registry for patient self-monitoring and self-management (PSM) of warfarin therapy. METHODS: A prospective observational study of UK-based patients undertaking PSM and recording their international normalised ratio (INR) data via an online registry. Consenting participants recorded INR test dates, results and warfarin dosages using the online registry for a period of 12 months. Participants reported demographic data, disease characteristics and treatment-related adverse events and provided feedback via a survey. Data accuracy was assessed through comparison of INR results recorded online with results stored on 19 INR testing devices. Percentage time spent within therapeutic time in range (TTR) was also examined. RESULTS: Eighty-seven per cent (39/45) completed the study period. Age ranged from 26 to 83 years, 44% had undertaken PSM for >5 years. Sixty-six per cent (25/38) reported that the registry was easy to navigate and use. Forty-two participants contributed a total of 1669 INR results. Agreement between self-reported INR results and source INR data was high (99%). Mean TTR was 76% (SD 18.58) with 83% having >60% TTR. CONCLUSIONS: Findings suggest that an online PSM registry is feasible, accurate and acceptable to patients. These findings require confirmation in a larger cohort of PSM patients. An online self-report registry could provide a valuable resource for gathering real world evidence of clinical effectiveness and safety of these developing models of care.

An international longitudinal registry of patients with atrial fibrillation at risk of stroke (GARFIELD): the UK protocol.

BACKGROUND: Atrial fibrillation (AF) is an independent risk factor for stroke and a significant predictor of mortality. Evidence-based guidelines for stroke prevention in AF recommend antithrombotic therapy corresponding to the risk of stroke. In practice, many patients with AF do not receive the appropriate antithrombotic therapy and are left either unprotected or inadequately protected against stroke. The purpose of the Global Anticoagulant Registry in the FIELD (GARFIELD) is to determine the real-life management and outcomes of patients newly diagnosed with non-valvular AF. METHODS/DESIGN: GARFIELD is an observational, international registry of newly diagnosed AF patients with at least one additional investigator-defined risk factor for stroke. The aim is to enrol 55,000 patients at more than 1000 centres in 50 countries worldwide. Enrolment will take place in five independent, sequential, prospective cohorts; the first cohort includes a retrospective validation cohort. Each cohort will be followed up for 2 years. The UK stands to be a significant contributor to GARFIELD, aiming to enrol 4,582 patients, and reflecting the care environment in which patients with AF are managed. The UK protocol will also focus on better understanding the validity of the two main stroke risk scores (CHADS2 and CHA2DS2VASC) and the HAS-BLED bleeding risk score, in the context of a diverse patient population. DISCUSSION: The GARFIELD registry will describe how therapeutic strategies, patient care, and clinical outcomes evolve over time. This study will provide UK-specific comprehensive data that will allow a range of evaluations both at a national level and in relation to global data and contribute to a better understanding of AF management in the UK. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01090362.

Point of Care INR testing devices: performance of the Roche CoaguChek XS and XS Plus in the UK NEQAS BC external quality assessment programme for healthcare professionals: four years' experience.

BACKGROUND: Vitamin K antagonists have been used for many decades and have been traditionally monitored by the measurement of the International Normalised Ratio (INR) in the laboratory. Introduction of Point of Care (POC) testing devices to measure INR has resulted in many tests being undertaken in primary care. External Quality Assessment (EQA) of these POC devices is recommended to ensure accuracy and reliability of INR results outside a laboratory setting. AIM: To assess the quality of INR results for users of two POC devices (CoaguChek XS and CoaguChek XS Plus) over a four-year period. METHODS: Four surveys (two samples) were sent in each 12-month period. The median INR value of each sample was calculated and the percentage deviation from this median determined. Any results greater than 15% from the median were considered to be outside consensus which indicated a possible problem within the testing system. RESULTS: Variability of INR results in this UK National External Quality Assessment Scheme (NEQAS) programme was comparable to that in the UK NEQAS EQA programme for laboratory INR testing. Occurrence of persistent problems was lower in the POC programme than the laboratory programme. CONCLUSIONS: Utilisation of an EQA programme for POC devices in primary care is feasible and necessary. Our data suggest for those health professionals using EQA, the reliability and accuracy of INR testing matches the quality of laboratory testing.

Does self-management of oral anticoagulation therapy improve quality of life and anxiety?

BACKGROUND: Research related to service requirements for anticoagulation management has focussed on clinical and health economic outcomes and paid little attention to the impact of treatment and service delivery on patients' quality of life. This was the first large UK study to evaluate the effect of patient self-management (PSM) of oral anticoagulation on treatment-related quality of life (TRQoL) and anxiety in comparison with routine care (RC) and to explore the effect of level of therapeutic control on TRQoL and anxiety across and within each model of care. METHODS: A quantitative survey, set in primary care in the West Midlands. The subjects were 517 randomized controlled trial participants, 242 receiving PSM and 275 RC. Postal questionnaires at baseline and 12 months comprised the State Trait Anxiety Inventory and a treatment-specific measure of positive (satisfaction and self-efficacy) and negative aspects (daily hassles, strained social network and psychological distress) of TRQoL. Change in anxiety and TRQoL scores were compared between PSM and RC. Subgroup analysis was based upon level of therapeutic control (high, medium and low). RESULTS: Overall, 83% (n = 202) PSM and 55% (n = 161) RC patients contributed data. Anxiety scores were similar in both groups. PSM demonstrated greater improvement in self-efficacy than RC across the study period. A statistically significant between-group difference (PSM versus RC) in the self-efficacy also existed in subgroups with medium and high levels of therapeutic control. CONCLUSIONS: PSM is not associated with increased anxiety and has a positive effect upon some aspects of TRQoL compared to RC.

Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomised controlled trial.

OBJECTIVES: To assess whether screening improves the detection of atrial fibrillation (cluster randomisation) and to compare systematic and opportunistic screening. DESIGN: Multicentred cluster randomised controlled trial, with subsidiary trial embedded within the intervention arm. SETTING: 50 primary care centres in England, with further individual randomisation of patients in the intervention practices. PARTICIPANTS: 14,802 patients aged 65 or over in 25 intervention and 25 control practices. INTERVENTIONS: Patients in intervention practices were randomly allocated to systematic screening (invitation for electrocardiography) or opportunistic screening (pulse taking and invitation for electrocardiography if the pulse was irregular). Screening took place over 12 months in each practice from October 2001 to February 2003. No active screening took place in control practices. MAIN OUTCOME MEASURE: Newly identified atrial fibrillation. RESULTS: The detection rate of new cases of atrial fibrillation was 1.63% a year in the intervention practices and 1.04% in control practices (difference 0.59%, 95% confidence interval 0.20% to 0.98%). Systematic and opportunistic screening detected similar numbers of new cases (1.62% v 1.64%, difference 0.02%, -0.5% to 0.5%). CONCLUSION: Active screening for atrial fibrillation detects additional cases over current practice. The preferred method of screening in patients aged 65 or over in primary care is opportunistic pulse taking with follow-up electrocardiography. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19633732 [controlled-trials.com].

Accuracy of diagnosing atrial fibrillation on electrocardiogram by primary care practitioners and interpretative diagnostic software: analysis of data from screening for atrial fibrillation in the elderly (SAFE) trial.

OBJECTIVE: To assess the accuracy of general practitioners, practice nurses, and interpretative software in the use of different types of electrocardiogram to diagnose atrial fibrillation. DESIGN: Prospective comparison with reference standard of assessment of electrocardiograms by two independent specialists. SETTING: 49 general practices in central England. PARTICIPANTS: 2595 patients aged 65 or over screened for atrial fibrillation as part of the screening for atrial fibrillation in the elderly (SAFE) study; 49 general practitioners and 49 practice nurses. INTERVENTIONS: All electrocardiograms were read with the Biolog interpretative software, and a random sample of 12 lead, limb lead, and single lead thoracic placement electrocardiograms were assessed by general practitioners and practice nurses independently of each other and of the Biolog assessment. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values. RESULTS: General practitioners detected 79 out of 99 cases of atrial fibrillation on a 12 lead electrocardiogram (sensitivity 80%, 95% confidence interval 71% to 87%) and misinterpreted 114 out of 1355 cases of sinus rhythm as atrial fibrillation (specificity 92%, 90% to 93%). Practice nurses detected a similar proportion of cases of atrial fibrillation (sensitivity 77%, 67% to 85%), but had a lower specificity (85%, 83% to 87%). The interpretative software was significantly more accurate, with a specificity of 99%, but missed 36 of 215 cases of atrial fibrillation (sensitivity 83%). Combining general practitioners' interpretation with the interpretative software led to a sensitivity of 92% and a specificity of 91%. Use of limb lead or single lead thoracic placement electrocardiograms resulted in some loss of specificity. CONCLUSIONS: Many primary care professionals cannot accurately detect atrial fibrillation on an electrocardiogram, and interpretative software is not sufficiently accurate to circumvent this problem, even when combined with interpretation by a general practitioner. Diagnosis of atrial fibrillation in the community needs to factor in the reading of electrocardiograms by appropriately trained people.

SMART: self-management of anticoagulation, a randomised trial [ISRCTN19313375].

BACKGROUND: Oral anticoagulation monitoring has traditionally taken place in secondary care because of the need for a laboratory blood test, the international normalised ratio (INR). The development of reliable near patient testing (NPT) systems for INR estimation has facilitated devolution of testing to primary care. Patient self-management is a logical progression from the primary care model. This study will be the first to randomise non-selected patients in primary care, to either self-management or standard care. METHOD: The study was a multi-centred randomised controlled trial with patients from 49 general practices recruited. Those suitable for inclusion were aged 18 or over, with a long term indication for oral anticoagulation, who had taken warfarin for at least six months. Patients randomised to the intervention arm attended at least two training sessions which were practice-based, 1 week apart. Each patient was assessed on their capability to undertake self management. If considered capable, they were given a near patient INR testing monitor, test strips and quality control material for home testing. Patients managed their own anticoagulation for a period of 12 months and performed their INR test every 2 weeks. Control patients continued with their pre-study care either attending hospital or practice based anticoagulant clinics. DISCUSSION: The methodology used in this trial will overcome concerns from previous trials of selection bias and relevance to the UK health service. The study will give a clearer understanding of the benefits of self-management in terms of clinical and cost effectiveness and patient preference.