A randomised controlled feasibility trial of a clinical protocol to manage hypotension during major non-cardiac surgery.

Intra-operative hypotension is a risk factor for postoperative morbidity and mortality. Minimally invasive monitors that derive other haemodynamic parameters, such as stroke volume, may better inform the management of hypotension. As a prelude to a multicentre randomised controlled trial, we conducted a single-centre feasibility trial of a protocol to treat hypotension as informed by minimally invasive haemodynamic monitoring during non-cardiac surgery. We recruited adults aged ≥40 years with cardiovascular risk factors who underwent non-cardiac surgery requiring invasive arterial pressure monitoring. Participants were randomly allocated to usual care, or a clinical protocol informed by an arterial waveform contour analysis monitor. Participants, outcome assessors, clinicians outside operating theatres and analysts were blinded to treatment allocation. Feasibility was evaluated based on: consent rate; recruitment rate; structured feedback from anaesthesia providers; and between-group differences in blood pressure, processes-of-care and outcomes. The consent rate among eligible patients was 33%, with 30 participants randomly allocated to the protocol and 30 to usual care. Anaesthesia providers rated the protocol to be feasible and acceptable. The protocol was associated with reduced fluid balance and hypotension exposure in the peri-operative setting. Postoperative complications included: acute myocardial injury in 18 (30%); acute kidney injury in 17 (28%); and surgical site infection in 7 (12%). The severity of complications was rated as moderate or severe in 25 (42%) participants. In summary, this single-centre study confirmed the feasibility of a multicentre trial to assess the efficacy and safety of a physiologically guided treatment protocol for intra-operative hypotension based on minimally invasive haemodynamic monitors.

Comparative analyses of published cost effectiveness models highlight critical considerations which are useful to inform development of new models.

Background: Comparative analyses of published cost effectiveness models provide useful insights into critical issues to inform the development of new cost effectiveness models in the same disease area.Objective: The purpose of this study was to describe a comparative analysis of cost-effectiveness models and highlight the importance of such work in informing development of new models. This research uses genotypic antiretroviral resistance testing after first line treatment failure for Human Immunodeficiency Virus (HIV) as an example.Method: A literature search was performed, and published cost effectiveness models were selected according to predetermined eligibility criteria. A comprehensive comparative analysis was undertaken for all aspects of the models.Results: Five published models were compared, and several critical issues were identified for consideration when developing a new model. These include the comparator, time horizon and scope of the model. In addition, the composite effect of drug resistance prevalence, antiretroviral therapy efficacy, test performance and the proportion of patients switching to second-line ART potentially have a measurable effect on model results. When considering CD4 count and viral load, dichotomizing patients according to higher cost and lower quality of life (AIDS) versus lower cost and higher quality of life (non-AIDS) status will potentially capture differences between resistance testing and other strategies, which could be confirmed by cross-validation/convergent validation. A quality adjusted life year is an essential outcome which should be explicitly explored in probabilistic sensitivity analysis, where possible.Conclusions: Using an example of GART for HIV, this study demonstrates comparative analysis of previously published cost effectiveness models yields critical information which can be used to inform the structure and specifications of new models.

Predictors of Post-operative Pain and Opioid Consumption in Patients Undergoing Liver Surgery.

BACKGROUND: Post-operative pain management is a critical component of perioperative care. Patients at risk of poorly controlled post-operative pain may benefit from early measures to optimize pain management. We sought to identify risk factors for post-operative pain and opioid consumption in patients undergoing liver resection. METHODS: This is a multi-institutional prospective nested cohort study of patients undergoing open liver resection. Opioid consumption and pain scores were collected following surgery. To estimate the effects of patient factors on opioid consumption (oral morphine equivalents-OME) and on pain scores (NRS-11), we used generalized linear models and multivariable linear regression model, respectively. RESULTS: One hundred and fifty-three patients who underwent open liver resection between 2013 and 2016 were included in the study. The mean patient age was 62.2 years, and 43.3% were female. Younger patients were significantly more likely to use more opioids in the early post-operative period (16.7 OME/10 years, p < 0.001). Patient factors that were significantly associated with increased NRS-11 pain scores also included younger patient age (difference in pain score of 0.3/10 years with cough and 0.2/10 years at rest, p < 0.01 for both) as well as a history of analgesic use (difference in pain score of 0.9 with cough and 0.6 at rest, p < 0.01 and p = 0.07, respectively). CONCLUSION: Younger patients and those with a history of analgesic use are more likely to report higher post-operative pain and require higher doses of opioids. Early identification of these patients, and measures to better manage their pain, may contribute to optimal perioperative care.

Use of prothrombin complex concentrate for management of coagulopathy after cardiac surgery: a propensity score matched comparison to plasma.

BACKGROUND: An important cause of coagulopathy in cardiac surgery is impaired thrombin generation. While plasma is often used to correct this element of the coagulopathy, studies in vitro suggest that prothrombin complex concentrates (PCCs) might be more effective. Comparative data, however, are scant. METHODS: We compared the outcomes of those who received only plasma with those who received PCCs (with or without plasma) for management of coagulopathy in patients who underwent cardiac surgery with cardiopulmonary bypass at a single institution from 2012 to 2016. Propensity score matching was used to obtain between-group balance. Primary outcome was avoidance of perioperative red cell transfusions. Other outcomes were incidence of massive transfusion (more than nine red cell units), refractory bleeding (requiring factor VIIa), and adverse events. RESULTS: Of 6362 patients, 1151 (18.2%) received plasma without any PCCs, and 204 (3.2%) received PCCs, either with (n=125) or without plasma (n=79). Overall, patient risk-profile was higher in the PCCs group. In a well-balanced propensity score match that included 117 patients per group, the odds ratio (OR) for red cell avoidance was 2.4-fold [95% confidence interval (CI) 1.2-4.8] higher in the PCCs group. Massive transfusion (OR 0.58; 95% CI 0.33-1.0) and refractory bleeding (OR 0.49; 95% CI 0.24-1.03) incidences were almost significantly lower in the PCCs group. The adverse event profiles were similar. CONCLUSIONS: Our exploratory study suggests that the use of PCCs as part of a multifaceted coagulation management strategy may have blood-sparing effects. Their incorporation into clinical practice, however, must await determination of their risk-benefit profile via multicentre randomised trials.

Alum Activates the Bovine NLRP3 Inflammasome.

There has been a move away from vaccines composed of whole or inactivated antigens toward subunit-based vaccines, which although safe, provide less immunological protection. As a result, the use of adjuvants to enhance and direct adaptive immune responses has become the focus of much targeted bovine vaccine research. However, the mechanisms by which adjuvants work to enhance immunological protection in many cases remains unclear, although this knowledge is critical to the rational design of effective next generation vaccines. This study aimed to investigate the mechanisms by which alum, a commonly used adjuvant in bovine vaccines, enhances IL-1ß secretion in bovine peripheral blood mononuclear cells (PBMCs). Unlike the case with human PBMCs, alum promoted IL-1ß secretion in a subset of bovine PBMCs without priming with a toll-like receptor agonist. This suggests that PBMCs from some cattle are primed to produce this potent inflammatory cytokine and western blotting confirmed the presence of preexisting pro-IL-1ß in PBMCs from a subset of 8-month-old cattle. To address the mechanism underlying alum-induced IL-1ß secretion, specific inhibitors identified that alum mediates lysosomal disruption which subsequently activates the assembly of an NLRP3, ASC, caspase-1, and potentially caspase-8 containing complex. These components form an inflammasome, which mediates alum-induced IL-1ß secretion in bovine PBMCs. Given the demonstrated role of the NLRP3 inflammasome in regulating adaptive immunity in murine systems, these results will inform further targeted research into the potential of inflammasome activation for rational vaccine design in cattle.

Greater intravenous fluid volumes are associated with prolonged recovery after colorectal surgery: a retrospective cohort study.

BACKGROUND: We carried out a retrospective assessment of whether perioperative fluid volume was associated with length of hospital stay (LOS) after colorectal surgery. METHODS: A single-centre chart review was conducted on colorectal surgeries that took place between January 2008 and December 2013. The primary outcome was LOS, with prolonged LOS defined as greater than median LOS. Secondary outcomes included postoperative pulmonary oedema, acute renal failure, myocardial infarction, and mortality. Univariate analysis, multivariable logistic regression, and quantile regression analyses were conducted to examine the association between perioperative fluid volume and prolonged LOS. RESULTS: Of the 1242 procedures, 57% were elective, 62% oncological, and 31% laparoscopic. The median LOS was 8.2 days (interquartile range 5.2, 14.7). Patients received 3.2 (sd 1.5) litres of fluid in the perioperative period (operating and recovery rooms), predominantly crystalloid. The volume (in litres) of perioperative fluid was independently associated with prolonged LOS (odds ratio 1.23, 95% confidence interval 1.10-1.36, P<0.01). This association persisted across the spectrum of definitions for prolonged LOS (10th-90th percentile). Logistic regression analysis also revealed that prolonged LOS was associated with age >65 yr, Charlson Co-morbidity Index ≥3, use of colloids, emergent surgery, estimated blood loss >200 ml, preoperative anaemia, erythrocyte transfusion, open surgeries, and surgical duration >4 h (C-statistic=0.79, Hosmer-Lemeshow=0.36). CONCLUSIONS: Greater perioperative fluid volume was independently associated with prolonged duration of recovery across a spectrum of surgical risk profiles. Fluid restriction should be considered a part of the care package in enhanced recovery after surgery programmes for colorectal surgery.

Red cell transfusion and the immune system.

Understanding the complex immunological consequences of red cell transfusion is essential if we are to use this valuable resource wisely and safely. The decision to transfuse red cells should be made after serious considerations of the associated risks and benefits. Immunological risks of transfusion include major incompatibility reactions and transfusion-related acute lung injury, while other immunological insults such as transfusion-related immunomodulation are relatively underappreciated. Red cell transfusions should be acknowledged as immunological exposures, with consequences weighed against expected benefits. This article reviews immunological consequences and the emerging evidence that may inform risk-benefit considerations in clinical practice.

Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass.

We conducted a study to assess pharmacokinetics of high-dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High-dose tranexamic acid involved a bolus of 30 mg.kg(-1) infused over 15 min followed by a 16 mg.kg(-1) .h(-1) infusion until chest closure with a 2 mg.kg(-1) load within the pump prime. Tranexamic acid followed first-order kinetics best described using a two-compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra-operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high-dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high-risk cardiac surgery needs to be refined.

Glasgow supported self-management trial (GSuST) for patients with moderate to severe COPD: randomised controlled trial.

OBJECTIVE: To determine whether supported self management in chronic obstructive pulmonary disease (COPD) can reduce hospital readmissions in the United Kingdom. DESIGN: Randomised controlled trial. SETTING: Community based intervention in the west of Scotland. PARTICIPANTS: Patients admitted to hospital with acute exacerbation of COPD. INTERVENTION: Participants in the intervention group were trained to detect and treat exacerbations promptly, with ongoing support for 12 months. MAIN OUTCOME MEASURES: The primary outcome was hospital readmissions and deaths due to COPD assessed by record linkage of Scottish Morbidity Records; health related quality of life measures were secondary outcomes. RESULTS: 464 patients were randomised, stratified by age, sex, per cent predicted forced expiratory volume in 1 second, recent pulmonary rehabilitation attendance, smoking status, deprivation category of area of residence, and previous COPD admissions. No difference was found in COPD admissions or death (111/232 (48%) v 108/232 (47%); hazard ratio 1.05, 95% confidence interval 0.80 to 1.38). Return of health related quality of life questionnaires was poor (n=265; 57%), so that no useful conclusions could be made from these data. Pre-planned subgroup analysis showed no differential benefit in the primary outcome relating to disease severity or demographic variables. In an exploratory analysis, 42% (75/150) of patients in the intervention group were classified as successful self managers at study exit, from review of appropriateness of use of self management therapy. Predictors of successful self management on stepwise regression were younger age (P=0.012) and living with others (P=0.010). COPD readmissions/deaths were reduced in successful self managers compared with unsuccessful self managers (20/75 (27%) v 51/105 (49%); hazard ratio 0.44, 0.25 to 0.76; P=0.003). CONCLUSION: Supported self management had no effect on time to first readmission or death with COPD. Exploratory subgroup analysis identified a minority of participants who learnt to self manage; this group had a significantly reduced risk of COPD readmission, were younger, and were more likely to be living with others. TRIAL REGISTRATION: Clinical trials NCT 00706303.

Increasing response rates to lifestyle surveys: a pragmatic evidence review.

AIMS: Lifestyle surveys are often a key component of a local Joint Strategic Needs Assessment (JSNA), undertaken to inform public health planning. They are usually administered to a large number of people in order to provide a comprehensive profile of population health. However, declining response rates coupled with the under-representation of certain population groups in lifestyle survey data has led to doubts concerning the reliability of findings. In order to inform the design of their own lifestyle survey, NHS Calderdale commissioned an evidence-based review of the methodological literature relating to the administration of lifestyle surveys, with the specific aim of identifying practical and resource-efficient strategies shown to be effective for maximizing whole-population response rates. METHODS: A pragmatic review of the published literature was undertaken, specifically to explore the most practical and resource-efficient ways to maximize lifestyle survey response rates to the most commonly used methods (postal surveys, face-to-face interviews, telephone interviews and electronic surveys). Electronic databases including MEDLINE, CINAHL, DARE, EMBASE and PsychINFO were searched. Empirical evidence published in the last 10 years was identified and citation tracking performed on all retrieved articles. An internet search for 'grey literature' was also conducted. RESULTS: The postal questionnaire remains an important lifestyle survey tool, but reported response rates have decreased rapidly in recent years. Interviews and telephone surveys are recommended in order to supplement data from postal questionnaires and increase response rates in some population groups, but costs may be prohibitive. Electronic surveys are a cheaper alternative, but the empirical evidence on effectiveness is inconclusive. Careful planning and tailoring of survey design to the characteristics of target populations can increase response rates and representativeness of lifestyle survey data. CONCLUSIONS: The results of this pragmatic review could provide a valuable resource for those involved in the design and administration of lifestyle surveys.