Problematic meta-analyses: Bayesian and frequentist perspectives on combining randomized controlled trials and non-randomized studies.

PURPOSE: In the literature, the propriety of the meta-analytic treatment-effect produced by combining randomized controlled trials (RCT) and non-randomized studies (NRS) is questioned, given the inherent confounding in NRS that may bias the meta-analysis. The current study compared an implicitly principled pooled Bayesian meta-analytic treatment-effect with that of frequentist pooling of RCT and NRS to determine how well each approach handled the NRS bias. MATERIALS & METHODS: Binary outcome Critical-Care meta-analyses, reflecting the importance of such outcomes in Critical-Care practice, combining RCT and NRS were identified electronically. Bayesian pooled treatment-effect and 95% credible-intervals (BCrI), posterior model probabilities indicating model plausibility and Bayes-factors (BF) were estimated using an informative heavy-tailed heterogeneity prior (half-Cauchy). Preference for pooling of RCT and NRS was indicated for Bayes-factors > 3 or < 0.333 for the converse. All pooled frequentist treatment-effects and 95% confidence intervals (FCI) were re-estimated using the popular DerSimonian-Laird (DSL) random effects model. RESULTS: Fifty meta-analyses were identified (2009-2021), reporting pooled estimates in 44; 29 were pharmaceutical-therapeutic and 21 were non-pharmaceutical therapeutic. Re-computed pooled DSL FCI excluded the null (OR or RR = 1) in 86% (43/50). In 18 meta-analyses there was an agreement between FCI and BCrI in excluding the null. In 23 meta-analyses where FCI excluded the null, BCrI embraced the null. BF supported a pooled model in 27 meta-analyses and separate models in 4. The highest density of the posterior model probabilities for 0.333 < Bayes factor < 1 was 0.8. CONCLUSIONS: In the current meta-analytic cohort, an integrated and multifaceted Bayesian approach gave support to including NRS in a pooled-estimate model. Conversely, caution should attend the reporting of naïve frequentist pooled, RCT and NRS, meta-analytic treatment effects.

Modelling of intensive care unit (ICU) length of stay as a quality measure: a problematic exercise.

BACKGROUND: Intensive care unit (ICU) length of stay (LOS) and the risk adjusted equivalent (RALOS) have been used as quality metrics. The latter measures entail either ratio or difference formulations or ICU random effects (RE), which have not been previously compared. METHODS: From calendar year 2016 data of an adult ICU registry-database (Australia & New Zealand Intensive Care Society (ANZICS) CORE), LOS predictive models were established using linear (LMM) and generalised linear (GLMM) mixed models. Model fixed effects quality-metric formulations were estimated as RALOSR for LMM (geometric mean derived from log(ICU LOS)) and GLMM (day) and observed minus expected ICU LOS (OMELOS from GLMM). Metric confidence intervals (95%CI) were estimated by bootstrapping; random effects (RE) were predicted for LMM and GLMM. Forest-plot displays of ranked quality-metric point-estimates (95%CI) were generated for ICU hospital classifications (metropolitan, private, rural/regional, and tertiary). Robust rank confidence sets (point estimate and 95%CI), both marginal (pertaining to a singular ICU) and simultaneous (pertaining to all ICU differences), were established. RESULTS: The ICU cohort was of 94,361 patients from 125 ICUs (metropolitan 16.9%, private 32.8%, rural/regional 6.4%, tertiary 43.8%). Age (mean, SD) was 61.7 (17.5) years; 58.3% were male; APACHE III severity-of-illness score 54.6 (25.7); ICU annual patient volume 1192 (702) and ICU LOS 3.2 (4.9). There was no concordance of ICU ranked model predictions, GLMM versus LMM, nor for the quality metrics used, RALOSR, OMELOS and site-specific RE for each of the ICU hospital classifications. Furthermore, there was no concordance between ICU ranking confidence sets, marginal and simultaneous for models or quality metrics. CONCLUSIONS: Inference regarding adjusted ICU LOS was dependent upon the statistical estimator and the quality index used to quantify any LOS differences across ICUs. That is, there was no "one best model"; thus, ICU "performance" is determined by model choice and any rankings thereupon should be circumspect.

Hospital-acquired complications: the relative importance of hospital- and patient-related factors.

OBJECTIVE: To quantify the prevalence of hospital-acquired complications; to determine the relative influence of patient- and hospital-related factors on complication rates. DESIGN, PARTICIPANTS: Retrospective analysis of administrative data (Integrated South Australian Activity Collection; Victorian Admitted Episodes Dataset) for multiple-day acute care episodes for adults in public hospitals. SETTING: Thirty-eight major public hospitals in South Australia and Victoria, 2015-2018. MAIN OUTCOME MEASURES: Hospital-acquired complication rates, overall and by complication class, by hospital and hospital type (tertiary referral, major metropolitan service, major regional service); variance in rates (intra-class correlation coefficient, ICC) at the patient, hospital, and hospital type levels as surrogate measures of their influence on rates. RESULTS: Of 1 558 978 public hospital episodes (10 029 918 bed-days), 151 486 included a total of 214 286 hospital-acquired complications (9.72 [95% CI, 9.67-9.77] events per 100 episodes; 2.14 [95% CI, 2.13-2.15] events per 100 bed-days). Complication rates were highest in tertiary referral hospitals (12.7 [95% CI, 12.6-12.8] events per 100 episodes) and for episodes including intensive care components (37.1 [95% CI, 36.7-37.4] events per 100 episodes). For all complication classes, inter-hospital variation was determined more by patient factors (overall ICC, 0.55; 95% CI, 0.53-0.57) than by hospital factors (ICC, 0.04; 95% CI, 0.02-0.07) or hospital type (ICC, 0.01; 95% CI, 0.001-0.03). CONCLUSIONS: Hospital-acquired complications were recorded for 9.7% of hospital episodes, but patient-related factors played a greater role in determining their prevalence than the treating hospital.

Long-term clinical outcomes in patients with a working diagnosis of myocardial infarction with non-obstructed coronary arteries (MINOCA) assessed by cardiovascular magnetic resonance imaging.

BACKGROUND: Myocardial infarction with non-obstructed coronary arteries (MINOCA) is a distinct entity among patients presenting with troponin-positive acute chest pain. We have previously reported on the incremental diagnostic capability of cardiovascular magnetic resonance (CMR) in this cohort. There is paucity of evidence on the long-term (> 5 years) clinical outcomes of these patients as graded by their acute CMR diagnosis. METHODS AND RESULTS: A total of 229 patients with a working diagnosis of MINOCA who underwent CMR assessment during the acute admission (2010-2017) were prospectively studied. The primary endpoint was major adverse cardiac events (MACE) defined as a composite of all-cause mortality and cardiovascular readmissions, identified from hospital and primary care records. CMR performed at a median of 6 days (IQR 2, 8) from presentation provided a diagnosis in 85% of the patients (38% myocarditis, 28% acute myocardial infarction and 19% Takotsubo cardiomyopathy). Over a median follow-up of 7.1 years (IQR 3.7, 8.2), 56 (24%) patients experienced a MACE. We found a strong association between CMR diagnosis and MACE (log rank 30.47, p < 0.001). In multivariate analysis, age (hazard ratio = 1.07; 95% confidence interval = 1.05, 1.10; p < 0.001) and CMR diagnosis of acute myocardial infarction (hazard ratio = 8.87; 95% confidence interval = 2.58, 30.4; p = 0.001) were independent predictors of MACE. CONCLUSIONS: In a large cohort of patients with a working diagnosis of MINOCA, one in four suffer a MACE during long-term clinical follow-up. CMR diagnosis of acute myocardial infarction and age were significant predictors of MACE even in the absence of significant coronary artery obstruction.

Multivariate meta-analysis of critical care meta-analyses: a meta-epidemiological study.

BACKGROUND: Meta-analyses typically consider multiple outcomes and report univariate effect sizes considered as independent. Multivariate meta-analysis (MVMA) incorporates outcome correlation and synthesises direct evidence and related outcome estimates within a single analysis. In a series of meta-analyses from the critically ill literature, the current study contrasts multiple univariate effect estimates and their precision with those derived from MVMA. METHODS: A previous meta-epidemiological study was used to identify meta-analyses with either one or two secondary outcomes providing sufficient detail to structure bivariate or tri-variate MVMA, with mortality as primary outcome. Analysis was performed using a random effects model for both odds ratio (OR) and risk ratio (RR); borrowing of strength (BoS) between multivariate outcome estimates was reported. Estimate comparisons, ß coefficients, standard errors (SE) and confidence interval (CI) width, univariate versus multivariate, were performed using Lin's concordance correlation coefficient (CCC). RESULTS: In bivariate meta-analyses, for OR (n = 49) and RR (n = 48), there was substantial concordance (≥ 0.69) between estimates; but this was less so for tri-variate meta-analyses for both OR (n = 25; ≥ 0.38) and RR (≥ -0.10; n = 22). A variable change in the multivariate precision of primary mortality outcome estimates compared with univariate was present for both bivariate and tri-variate meta-analyses and for metrics. For second outcomes, precision tended to decrease and CI width increase for bivariate meta-analyses, but was variable in the tri-variate. For third outcomes, precision increased and CI width decreased. In bivariate meta-analyses, OR coefficient significance reversal, univariate versus MVMA, occurred once for mortality and 6 cases for second outcomes. RR coefficient significance reversal occurred in 4 cases; 2 were discordant with OR. For tri-variate OR meta-analyses reversal of coefficient estimate significance occurred in two cases for mortality, nine cases for second and 7 cases for third outcomes. In RR meta-analyses significance reversals occurred for mortality in 2 cases, 6 cases for second and 3 cases for third; there were 7 discordances with OR. BoS was greater in trivariate MVMAs compared with bivariate and for OR versus RR. CONCLUSIONS: MVMA would appear to be the preferred solution to multiple univariate analyses; parameter significance changes may occur. Analytic metric appears to be a determinant.

Modelling hospital outcome: problems with endogeneity.

BACKGROUND: Mortality modelling in the critical care paradigm traditionally uses logistic regression, despite the availability of estimators commonly used in alternate disciplines. Little attention has been paid to covariate endogeneity and the status of non-randomized treatment assignment. Using a large registry database, various binary outcome modelling strategies and methods to account for covariate endogeneity were explored. METHODS: Patient mortality data was sourced from the Australian & New Zealand Intensive Society Adult Patient Database for 2016. Hospital mortality was modelled using logistic, probit and linear probability (LPM) models with intensive care (ICU) providers as fixed (FE) and random (RE) effects. Model comparison entailed indices of discrimination and calibration, information criteria (AIC and BIC) and binned residual analysis. Suspect covariate and ventilation treatment assignment endogeneity was identified by correlation between predictor variable and hospital mortality error terms, using the Stata™ "eprobit" estimator. Marginal effects were used to demonstrate effect estimate differences between probit and "eprobit" models. RESULTS: The cohort comprised 92,693 patients from 124 intensive care units (ICU) in calendar year 2016. Patients mean age was 61.8 (SD 17.5) years, 41.6% were female and APACHE III severity of illness score 54.5(25.6); 43.7% were ventilated. Of the models considered in predicting hospital mortality, logistic regression (with or without ICU FE) and RE logistic regression dominated, more so the latter using information criteria indices. The LPM suffered from many predictions outside the unit [0,1] interval and both poor discrimination and calibration. Error terms of hospital length of stay, an independent risk of death score and ventilation status were correlated with the mortality error term. Marked differences in the ventilation mortality marginal effect was demonstrated between the probit and the "eprobit" models which were scenario dependent. Endogeneity was not demonstrated for the APACHE III score. CONCLUSIONS: Logistic regression accounting for provider effects was the preferred estimator for hospital mortality modelling. Endogeneity of covariates and treatment variables may be identified using appropriate modelling, but failure to do so yields problematic effect estimates.

Multivariate Meta-Analysis of the Mortality Effect of Prone Positioning in the Acute Respiratory Distress Syndrome.

BACKGROUND: The efficacy of prone positioning (PP) as therapy of the acute respiratory distress syndrome (ARDS) has varied in recent meta-analyses. The efficacy question was reviewed using a cohesive multivariate meta-analysis model incorporating all available common time-point data. METHODS: Data from a core group of 8 randomized controlled trials (2001-2013) utilized in 8 current meta-analyses (2014-2017) was extracted for common time points. Multivariate meta-analysis and meta-regression models for prone-hours per day, mechanical ventilation tidal-volume and baseline patient PaO2/FiO2, considered as continuous and categorical predictors, determined the pooled relative risk (RR) of mortality for prone versus supine positioning. RESULTS: Mortality RR at 28-30 days, 2-3 months and 6-months was not significant overall (P > 0.05). Meta-regression of categorical predictors indicated significant mortality reduction (P ≤ 0.001) for ≥ 12 prone-hours (versus < 12), lung protective ventilation (versus none) and moderate-severe ARDS (versus all ARDS). Meta-regressions of continuous predictors were also significant (P ≤ 0.021) and yielded treatment inflection points of efficacious therapy for ≥ 12 prone-hours per day, ≤ 8.5 mL/kg tidal volume and ≤ PaO2/FiO2 ratio of 130. CONCLUSIONS: The mortality treatment effect of PP in ARDS, was not demonstrated in the unadjusted meta-analysis model. Moderator effects indicated consistent significant benefit of prone positioning. In the absence of individual patient data, multivariate models provide more decisive conclusions than individual time point analyses.

Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS: The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS: Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION: In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING: Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.

Safety of the endotracheal tube for prolonged mechanical ventilation.

RATIONALE: The endotracheal tube (ETT) is the most common route for invasive mechanical ventilation (MV) yet controversy attends its long-term safety. OBJECTIVE: Assess the safety of ETT compared with tracheostomy tube (TT) for MV support in the intensive care unit (ICU). METHODS: Retrospective analysis of five year national dataset of 128,977 adults (age > 15-years) admitted for MV therapy with tracheostomy tube (TT; n = 4772) or without (ETT; n = 124,204), excluding those with neurological diagnoses or likely to require a surgical airway (n = 27,466), in 93 public health service ICUs across Australia, between July 2013-June 2018. MEASUREMENTS: Hospital survival (including liberation from MV) for ETT Group compared with TT Group using a probit regression model adjusted for confounding using fixed, endogenous and non-random treatment assignment covariates, and their interactions; analysed and plotted as marginal effects by duration of MV. RESULTS: Median duration of MV was 2 (IQR =1-4) days, predominantly via ETT (124,205; 96.3%), and 21,620 (16.7%) died. Temporal trend for ETT increased (OR = 1.06 per year, 95%CI =1.03-1.10) compared to TT, even for prolonged (>3 weeks) MV (38.1%). Higher risk-adjusted mortality was associated with longer duration of MV and after 9 days of MV with retention of ETT compared with TT - average (mortality) treatment effect 12.6% (95%CI =10.7-14.5). The latter was not significant after 30 days of MV. CONCLUSIONS: The safety of ETT compared with TT beyond short-term MV (≤9-days) is uncertain and requires prospective evaluation with additional data.

ECMO, ARDS and meta-analyses: Bayes to the rescue?

PURPOSE: A recent meta-analysis by Munshi et al. (Lancet Respiratory Medicine, 2019) claimed mortality treatment efficacy for extra corporeal membrane oxygenation (ECMO) in the acute respitratory syndrome (ARDS) despite very low meta-analytic study numbers (n = 2 (RCTs), risk-ratio (RR) 0·73 (95%CI: 0·58-0·92); n = 5 (2 RCT, 3 observational), RR 0·69 (95%CI: 0·50-0·95)). We explore this efficacy claim by a comprehensive re-analysis of the data. METHODS: Data were sourced from the two- and five-study meta-analyses, conducted using the Der-Simonian & Laird (DSL) method. A variety of frequentist (DSL, restricted maximum likelihood (REML), Paul-Mandel (PM), with/without Hartung-Knapp-Sidik-Jonkman variance correction), a beta-binomial model (BBN)) and Bayesian models (2 finite-mixture and several Markov-Chain-Monte-Carlo) were used to estimate treatment effects. Fragility-indices, the minimum patients changing mortality outcome needed to induce a conclusion change were also applied. RESULTS: For the 2-study and 5-study meta-analysis only the uncorrected frequentist estimators (DSL, REML, PM) demonstrated significant RR. Except for the BBN model, which was significant for the 2-study meta-analysis, intervals for all other models included the null. Both meta-analyses demonstrated fragility. CONCLUSIONS: Having canvassed the conduct of both meta-analyses presented by Munshi et al. and proffered alternative methods, we find no certainty regarding the efficacy of ECMO in ARDS.

Effect of angiotensin II receptor blocker and salt supplementation on short-term blood pressure variability in type 2 diabetes.

High blood pressure variability (BPV) has been associated with increased cardiovascular (CV) risk. The effect of dietary salt and renin-angiotensin-aldosterone system (RAAS) activity on short-term BPV in type 2 diabetes mellitus (T2DM) is not well characterised. We aimed to determine the effect of dietary salt (sodium chloride, NaCl) supplementation on 24-h mean arterial BPV (24hBPV) during angiotensin II receptor blocker (telmisartan) use and to evaluate the effects of age, sex, plasma renin activity (PRA) and serum aldosterone on 24hBPV. In a randomised, double-blind, crossover study, patients with T2DM (n = 28), treated with telmisartan received NaCl (100 mmol/24 h) or placebo capsules during 2 weeks of telmisartan. Following a 6-week washout, the protocol was repeated in reverse. 24hBPV was evaluated as a co-efficient of variation [CV (%) = mean/standard deviation] × 100). Twenty-four hour urinary sodium excretion, ambulatory BP and biochemical tests were performed at each phase. Results were analysed using a linear mixed model to generate predicted values for 24hBPV. Predicted 24hBPV was higher with telmisartan vs baseline (p = 0.01), with a trend towards reduced 24hBPV with salt (p = 0.052). Predicted 24hBPV was lower in females (p = 0.017), increasing age (p = 0.001) and increasing PRA (p = 0.011). In patients with T2DM, predicted 24hBPV increased from baseline with telmisartan, but there was no additional increase in predicted 24hBPV with salt supplementation. This suggests that in the short-term, salt supplementation has no apparent deleterious effects on 24hBPV. Long-term studies are required to evaluate the effect of 24hBPV on CV outcomes in patients with T2DM.

Risk related therapy in meta-analyses of critical care interventions: Bayesian meta-regression analysis.

PURPOSE: The relationship between treatment efficacy and patient risk is explored in a series of meta-analyses from the critical care domain, focusing on mortality outcome. METHODS: Systematic reviews of randomized controlled trials were identified by electronic search over the period 2002 to July 2018. A Bayesian meta-regression model was employed, using the risk difference metric to estimate the relationship between mortality difference and control arm risk, and estimate the mortality difference with and without adjusting for control arm risk. RESULTS: Of 780 initially identified published systematic reviews, 113 had appropriate mortality data comprising 123 analysable groups. The 123 meta-analyses were pharmaceutical therapeutic (59.3%), non-pharmaceutical therapeutic (24.4%) and nutritional (16.3%), with a 25% overall average control arm mortality. In 25/123 (20%) analyses, meta-regression indicated significant baseline risk (Bayesian 95% credible intervals excluding zero). In all analyses, the relationship between risk-difference and control arm risk was negative indicating a positive treatment effect with increasing control arm risk. Adjusted estimates identified six studies with significant positive treatment effects, not evident until after adjustment for control arm risk. CONCLUSION: Underlying risk-related therapy is apparent in meta-analyses of the critically-ill and identification is of importance to both the conduct and interpretation of these meta-analyses.

The search for biomarkers in the critically ill: a cautionary tale.

The search for biomarkers has been described as a dismal patchwork of fragmented research. We review biomarkers in sepsis in the critically ill in terms of conventional single circulating proteins. Despite sepsis biomarker publications trebling over the past 6 years, currently only one, procalcitonin, has materialised promise. We survey genomic biomarker initiatives, single nucleotide polymorphisms (SNPs) and gene signatures. Despite many SNP associations with sepsis susceptibility and a limited number of genome-wide association studies, the status of these associations is that of genomic signposts only. The standing of gene signatures in the paradigmatic discipline, breast cancer, is described. Uncertainties in the understanding of the sepsis process are documented - the dissociation between blood and tissue element activity, or compartmentalisation. The paradox of the active search for gene signatures to refine the sepsis phenotype and discover target subtypes for new therapies in the absence of such therapies is presented.

Reconsidering lactate as a sepsis risk biomarker.

OBJECTIVES: There has been renewed interest in lactate as a risk biomarker in sepsis and septic shock. However, the ability of the odds ratio (OR) and change in the area under the receiver operator characteristic curve (AUC-ROC) to assess biomarker added-value has been questioned. DESIGN, SETTING AND PARTICIPANTS: A sepsis cohort was identified from the ICU database of an Australian tertiary referral hospital using APACHE III diagnostic codes. Demographic information, APACHE III scores, 24-hour post-admission patient lactate levels, and hospital mortality were accessed. MEASUREMENTS AND MAIN RESULTS: Hospital mortality was modelled using a base predictive logistic regression model and sequential addition of admission lactate, lactate clearance ([lactateadmission-lactatefinal]/lactateadmission), and area under the lactate-time curve (LTC). Added-value was assessed using lactate index OR; AUC-ROC difference (base-model versus lactate index addition); net (mortality) reclassification index (NRI; range -2 to +2); and net benefit (NB), the number of true positives per patient adjusted for the number of false positives. The data set comprised 717 patients with mean(SD) age and APACHE III score 61.1(16.5) years and 68.3(28.2) respectively; 59.2% were male. Admission lactate was 2.3(2.5) mmol/l; with lactate of ≥ 4 mmol/L (37% hospital mortality) in 17% and patients with lactate < 4 mmol/L having 18% hospital mortality. The admission base-model had an AUC-ROC = 0.81 with admission lactate OR = 1.127 (95%CI: 1.038, 1.224), AUC-ROC difference of 0.0032 (-0.0037, 0.01615; P = 0.61), and NRI 0.240(0.030, 0.464). The over-time model had an AUC-ROC = 0.86 with (i) clearance OR = 0.771, 95%CI: 0.578, 1.030; P = 0.08; AUC-ROC difference 0.001 (-0.003, 0.014; P = 0.78), and NRI 0.109(-0.193, 0.425) and (ii) LTC OR = 0.997, 95%CI: 0.989, 1.005, P = 0.49; AUC-ROC difference 0.004 (-0.002, 0.004; P = 0.34), and NRI 0.111(-0.222, 0.403). NB was not incremented by any lactate index. CONCLUSIONS: Lactate added-value assessment is dependent upon the performance of the underlying predictive model and should incorporate risk reclassification and net benefit measures.

Continuous transversus abdominis plane block vs intermittent bolus for analgesia after abdominal surgery: a randomized trial.

BACKGROUND: Continuous and intermittent bolus techniques of transversus abdominis plane (TAP) blocks have been used for analgesia after abdominal surgery. Although both are effective, there are no studies comparing them. The aim of this study is to compare analgesia and cost-effectiveness between these groups. METHODS: After obtaining ethical approval, 20 American Society of Anesthesiologists ASA grade I to III patients undergoing elective abdominal surgery were recruited with 10 patients allocated to each arm. Bilateral ultrasound-guided TAP blocks were performed with an initial bolus of 0.5% ropivacaine 20 mL per side, followed by catheter insertion. After surgery, the continuous infusion group received 0.2% ropivacaine 8 mL/hour on each side and the intermittent bolus group received doses of 0.2% ropivacaine 20 mL per side every 8 hours for 48 hours. Both groups received intravenous fentanyl patient-controlled analgesia and regular oral paracetamol. Parameters recorded included numerical rating scores for pain and post-operative analgesic consumption at baseline (time 0) and at 1 hour, 1 day and 2 days post-operatively. The duration of catheter insertion, complications, patient satisfaction and information regarding costs were also recorded. Patient satisfaction was assessed utilizing a 4-point "Likert" scale on day 2 and on day 30. Pain and Likert scores were analysed by non-parametric sum rank test and all two-sampled t-tests assumed unequal variances. RESULTS: There was no difference between duration of TAP block, anesthetic and surgical technique and length of stay (p=0.23). Primary outcomes: pain scores at rest and cough were not significantly different (p=0.20) between the groups. Satisfaction scores were similar at day 2 and 30 (p=0.77). However, the bolus group was more cost-effective (AU$347.98 vs AU$429.43). CONCLUSION: Continuous or bolus TAP blocks are effective analgesic techniques in abdominal surgery, with bolus technique being more economical.

Protein delivery and clinical outcomes in the critically ill: a systematic review and meta-analysis.

OBJECTIVES: Protein is a fundamental component of critical care nutrition, but there has been uncertainty about the optimal amount. We undertook this systematic review and meta-analysis to examine the relationship between delivered protein and mortality in randomised controlled trials (RCTs) of nutritional interventions involving critically ill adults. Secondary outcomes included the effect of protein dose on lengths of stay, mechanical ventilation and incidence of infections. METHODS: We reviewed the relevant English-language literature published between 1966 and 2015 and identified RCTs comparing different strategies of nutritional support lasting at least 48 hours in critically ill adults. Articles were included if mortality was reported and the difference in delivered protein between interventions was significant (P < 0.05). We calculated summary estimates for mortality as odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects estimator, and we used meta-regression to assess the effect of delivered protein on mortality. RESULTS: From 3016 assessed records, 357 full-text articles were reviewed and 14 studies, investigating various interventions and routes of nutrition and comprising 3238 patients, were included. The mean protein delivered was 42.95 g/day (SD, 20.45 g/day) or 0.67 g//kg/day (SD, 0.38 g/kg/day) in patients receiving less protein, and 67.15 g/day (SD, 28.47 g/day) or 1.02 g/kg/day (SD, 0.42 g/kg/day) in the higher protein group. Provision of less protein did not influence mortality risk (pooled OR, 0.935; 95% CI, 0.716 -1.219; P = 0.618; I2 = 48.2%). Meta-regression analysis did not show a relationship between mean daily protein delivered and mortality (P = 0.433; I2 = 50.18%). There were no differences between groups in any secondary outcomes. CONCLUSIONS: Delivery of varying amounts of nutritional protein was not associated with any effect on mortality.

New initiatives in critical care: distinguishing hype from hope.

Recent viewpoints on critical care have expressed frustration at the slow development of new therapeutic agents and the failure of investigator-initiated trials. Several new directions have been proposed: personalised medicine and the embracing of "omic" technologies, resolving the heterogeneity of treatment effects, and adaptive trial designs. We examine these approaches in the context of analysis of randomised controlled trials (RCTs). The curse of treatment effect heterogeneity is found not only in critical care but also in cancer oncology. We find the uncritical appeal to personalised medicine to be misplaced because such treatments are not identified at the personal level, but at the group or stratified level. The analysis of RCTs has foundered over the problem of accounting for the centre effect and rejecting the random effects approach. Enthusiasm for adaptive trial designs has been articulated at the rhetorical, not the substantive, level.

Calorie delivery and clinical outcomes in the critically ill: a systematic review and meta-analysis.

OBJECTIVES: To determine the effect of calorie delivery on hospital mortality among critically ill adults receiving enteral nutrition (EN). Secondary outcomes included the effect of calorie delivery on intensive care unit and hospital length of stay (LOS), duration of mechanical ventilation (MV) and incidence of new-onset pneumonia. METHODS: We identified randomised clinical trials of EN, with or without supplemental parenteral nutrition (PN), involving adult ICU patients for whom mortality data were available, and when there was a significant difference in calorie supplementation between intervention arms (P < 0.05). We searched English language electronic databases (1946-2014), bibliographies of nutrition society guidelines and high-impact nutrition and critical care journals. We calculated summary odds ratio (OR) estimates and 95% confidence intervals using a random effects estimator, and used meta-regression to assess the effect on mortality of average calories delivered. RESULTS: Of 1545 articles identified, 16 eligible studies involving 3473 patients were included. Five studies involved supplemental PN. Mean calorie delivery ranged from 126 kcal/day (SD, 115 kcal/day) to 2086 kcal/day (SD, 460 kcal/day). Mortality was 26.0% in the lower calorie delivery group and 26.5% in the higher calorie delivery group. There was no effect of increased calorie delivery on mortality (OR, 1.02; 95% CI , 0.85-1.24; P = 0.27; I2 = 16.3%). ICU and hospital LOS and incidence of newonset pneumonia did not differ between groups. Duration of MV was decreased with lower calorie delivery (weighted mean difference, 2.92 days; 95% CI, -4.49 to -1.35 days; P < 0.001; I2 = 14.7%). Meta-regression analysis did not show an overall effect on mortality of average calories delivered (P = 0.73; I2 = 40.8%). CONCLUSION: Delivery of increased calories via the enteral route, with or without supplemental PN, was not associated with a survival benefit.