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Background: The combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear., Methods: In a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption., Results: Out of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156-334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5-4.5), 3 (2-4), 3 (2-6) and 3 (2-5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes., Conclusions: Enteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution., Competing Interests: Declarations. Conflicts of interest: BV, JM, NH and SF are supported by a Leadership Fellowship and AB from an Ideas Grant from the National Health and Medical Research Council of Australia. BV and NH receive institutional research support from Baxter for the conduct of a clinical trial in patients with diabetic ketoacidosis. AB is supported by an Australian Research Council Future Fellowship and grants from the Translational Research Institute, Australian Infectious diseases Research Centre and Metro South health. JD, MR and LM are supported by a grant from the Hospital Research Foundation. MY is supported by a grant from the Baker Foundation and the Australian Research Council. SF has received consulting fees from RevImmune Inc and is Director of Sepsis Australia (honorary) and Asia Pacific Sepsis Alliance (honorary). All other others do not report any conflict of interest., (© 2024. Crown.)

Purpose: Patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) frequently develop arterial hyperoxaemia, which may be harmful. However, lower oxygen saturation targets may also lead to harmful episodes of hypoxaemia., Methods: In this registry-embedded, multicentre trial, we randomly assigned adult patients receiving VA-ECMO in an intensive care unit (ICU) to either a conservative (target SaO 2 92-96%) or to a liberal oxygen strategy (target SaO 2 97-100%) through controlled oxygen administration via the ventilator and ECMO gas blender. The primary outcome was the number of ICU-free days to day 28. Secondary outcomes included ICU-free days to day 60, mortality, ECMO and ventilation duration, ICU and hospital lengths of stay, and functional outcomes at 6 months., Results: From September 2019 through June 2023, 934 patients who received VA-ECMO were reported to the EXCEL registry, of whom 300 (192 cardiogenic shock, 108 refractory cardiac arrest) were recruited. We randomised 149 to a conservative and 151 to a liberal oxygen strategy. The median number of ICU-free days to day 28 was similar in both groups (conservative: 0 days [interquartile range (IQR) 0-13.7] versus liberal: 0 days [IQR 0-13.7], median treatment effect: 0 days [95% confidence interval (CI) - 3.1 to 3.1]). Mortality at day 28 (59/159 [39.6%] vs 59/151 [39.1%]) and at day 60 (64/149 [43%] vs 62/151 [41.1%] were similar in conservative and liberal groups, as were all other secondary outcomes and adverse events. The conservative group experienced 44 (29.5%) major protocol deviations compared to 2 (1.3%) in the liberal oxygen group (P < 0.001)., Conclusions: In adults receiving VA-ECMO in ICU, a conservative compared to a liberal oxygen strategy, did not affect the number of ICU-free days to day 28., (© 2024. The Author(s).)

Purpose: After cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT., Methods: We conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance., Results: Of 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0-19.6) hours with 20% albumin and 10.8 (IQR 0-22.8) hours with crystalloids (difference - 3.8 h, 95% confidence interval [CI] - 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference - 701 mL, 95% CI - 872 to - 530)., Conclusions: In patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy., (© 2024. The Author(s).)

Acute kidney injury (AKI) is associated with persistent renal dysfunction, the receipt of dialysis, dialysis dependence, and mortality. Accordingly, the concept of major adverse kidney events (MAKE) has been adopted as an endpoint for assessing the impact of AKI. However, applied criteria or observation periods for operationalizing MAKE appear to vary across studies. To evaluate this heterogeneity for MAKE evaluation, we performed a systematic scoping review of studies that employed MAKE as an AKI endpoint. Four major academic databases were searched, and we identified 122 studies with increasing numbers over time. We found marked heterogeneity in applied criteria and observation periods for MAKE across these studies, with some even lacking a description of criteria. Moreover, 13 different observation periods were employed, with 30 days and 90 days as the most common. Persistent renal dysfunction was evaluated by estimated glomerular filtration rate (34%) or serum creatinine concentration (48%); however, 37 different definitions for this component were employed in terms of parameters, cut-off criteria, and assessment periods. The definition for the dialysis component also showed significant heterogeneity regarding assessment periods and duration of dialysis requirement (chronic vs temporary). Finally, MAKE rates could vary by 7% [interquartile range: 1.7-16.7%] with different observation periods or by 36.4% with different dialysis component definitions. Our findings revealed marked heterogeneity in MAKE definitions, particularly regarding component assessment and observation periods. Dedicated discussion is needed to establish uniform and acceptable standards to operationalize MAKE in terms of selection and applied criteria of components, observation period, and reporting criteria for future trials on AKI and related conditions., (© 2024. The Author(s).)

Purpose: Critically ill patients are vulnerable to penicillin allergy labels that may be incorrect. The validity of skin testing in intensive care units (ICUs) is uncertain. Many penicillin allergy labels are low risk, and validated tools exist to identify those amenable to direct oral challenge. This pilot randomised controlled trial explored the feasibility, safety, and validity of direct enteral challenge for low-risk penicillin allergy labels in critical illness., Methods: Consenting patients with a low-risk penicillin allergy label (PAL) (PEN-FAST risk assessment score < 3) in four ICUs (Melbourne, Australia) were randomised 1:1 to penicillin (250 mg amoxicillin or implicated penicillin) direct enteral challenge versus routine care (2-h post-randomisation observation for each arm). Repeat challenge was performed post -ICU in the intervention arm. Patients were reviewed at 24 h and 5 days after each challenge/observation., Results: We screened 533 patients. 130 (24.4%) were eligible and 80/130 (61.5%) enrolled (age median 64.5 years (interquartile range, IQR 53.5, 74), PEN-FAST median 1 (IQR 0,1)), with 40 (50%) randomised to direct enteral challenge. A positive challenge rate of 2.5% was identified. No antibiotic-associated serious adverse events were identified. 32/40 (80%) received a repeat challenge (zero positive). Post-randomisation, 13 (32%) of the intervention arm and 4 (10%) of the control arm received penicillin (odds ratio, OR 4.33 [1.27, 14.78] p = 0.019)., Conclusion: These findings support the safety, validity, and feasibility of direct enteral challenge for critically ill patients with PEN-FAST assessed low-risk penicillin allergy. The absence of false negative results was confirmed by subsequent negative repeat challenges. A relatively low recruitment to screened ratio suggests that more inclusive eligibility criteria and integration of allergy assessment into routine ICU processes are needed to optimise allergy delabelling in critical illness., (© 2024. The Author(s).)

Purpose: Acute kidney disease (AKD) is a significant health care burden worldwide. However, little is known about this complication after major surgery., Methods: We conducted an international prospective, observational, multi-center study among patients undergoing major surgery. The primary study endpoint was the incidence of AKD (defined as new onset of estimated glomerular filtration rate (eCFR) < 60 ml/min/1.73 m 2 present on day 7 or later) among survivors. Secondary endpoints included the relationship between early postoperative acute kidney injury (AKI) (within 72 h after major surgery) and subsequent AKD, the identification of risk factors for AKD, and the rate of chronic kidney disease (CKD) progression in patients with pre-existing CKD., Results: We studied 9510 patients without pre-existing CKD. Of these, 940 (9.9%) developed AKD after 7 days of whom 34.1% experiencing an episode of early postoperative-AKI. Rates of AKD after 7 days significantly increased with the severity (19.1% Kidney Disease Improving Global Outcomes [KDIGO] 1, 24.5% KDIGO2, 34.3% KDIGO3; P < 0.001) and duration (15.5% transient vs 38.3% persistent AKI; P < 0.001) of early postoperative-AKI. Independent risk factors for AKD included early postoperative-AKI, exposure to perioperative nephrotoxic agents, and postoperative pneumonia. Early postoperative-AKI carried an independent odds ratio for AKD of 2.64 (95% confidence interval [CI] 2.21-3.15). Of 663 patients with pre-existing CKD, 42 (6.3%) had worsening CKD at day 90. In patients with CKD and an episode of early AKI, CKD progression occurred in 11.6%., Conclusion: One in ten major surgery patients developed AKD beyond 7 days after surgery, in most cases without an episode of early postoperative-AKI. However, early postoperative-AKI severity and duration were associated with an increased rate of AKD and early postoperative-AKI was strongly associated with AKD independent of all other potential risk factors., (© 2024. The Author(s).)

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety., Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition., Results: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group., Conclusion: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified., (© 2024. The Author(s).)

Purpose: The incidence, patient features, risk factors and outcomes of surgery-associated postoperative acute kidney injury (PO-AKI) across different countries and health care systems is unclear., Methods: We conducted an international prospective, observational, multi-center study in 30 countries in patients undergoing major surgery (> 2-h duration and postoperative intensive care unit (ICU) or high dependency unit admission). The primary endpoint was the occurrence of PO-AKI within 72 h of surgery defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary endpoints included PO-AKI severity and duration, use of renal replacement therapy (RRT), mortality, and ICU and hospital length of stay., Results: We studied 10,568 patients and 1945 (18.4%) developed PO-AKI (1236 (63.5%) KDIGO stage 1500 (25.7%) KDIGO stage 2209 (10.7%) KDIGO stage 3). In 33.8% PO-AKI was persistent, and 170/1945 (8.7%) of patients with PO-AKI received RRT in the ICU. Patients with PO-AKI had greater ICU (6.3% vs. 0.7%) and hospital (8.6% vs. 1.4%) mortality, and longer ICU (median 2 (Q1-Q3, 1-3) days vs. 3 (Q1-Q3, 1-6) days) and hospital length of stay (median 14 (Q1-Q3, 9-24) days vs. 10 (Q1-Q3, 7-17) days). Risk factors for PO-AKI included older age, comorbidities (hypertension, diabetes, chronic kidney disease), type, duration and urgency of surgery as well as intraoperative vasopressors, and aminoglycosides administration., Conclusion: In a comprehensive multinational study, approximately one in five patients develop PO-AKI after major surgery. Increasing severity of PO-AKI is associated with a progressive increase in adverse outcomes. Our findings indicate that PO-AKI represents a significant burden for health care worldwide., (© 2023. The Author(s).)

Background: There is controversy regarding the optimal renal-replacement therapy (RRT) modality for critically ill patients with acute kidney injury (AKI)., Methods: We conducted a secondary analysis of the STandard versus Accelerated Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial to compare outcomes among patients who initiated RRT with either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). We generated a propensity score for the likelihood of receiving CRRT and used inverse probability of treatment with overlap-weighting to address baseline inter-group differences. The primary outcome was a composite of death or RRT dependence at 90-days after randomization., Results: We identified 1590 trial participants who initially received CRRT and 606 who initially received IHD. The composite outcome of death or RRT dependence at 90-days occurred in 823 (51.8%) patients who commenced CRRT and 329 (54.3%) patients who commenced IHD (unadjusted odds ratio (OR) 0.90; 95% confidence interval (CI) 0.75-1.09). After balancing baseline characteristics with overlap weighting, initial receipt of CRRT was associated with a lower risk of death or RRT dependence at 90-days compared with initial receipt of IHD (OR 0.81; 95% CI 0.66-0.99). This association was predominantly driven by a lower risk of RRT dependence at 90-days (OR 0.61; 95% CI 0.39-0.94)., Conclusions: In critically ill patients with severe AKI, initiation of CRRT, as compared to IHD, was associated with a significant reduction in the composite outcome of death or RRT dependence at 90-days., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria. This study aims to describe the epidemiology of SA-AKI., Methods: This is a retrospective cohort study carried out in 12 intensive care units (ICUs) from 2015 to 2021. We studied the incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes of SA-AKI based on the ADQI definition., Results: Out of 84,528 admissions, 13,451 met the SA-AKI criteria with its incidence peaking at 18% in 2021. SA-AKI patients were typically admitted from home via the emergency department (ED) with a median time to SA-AKI diagnosis of 1 day (interquartile range (IQR) 1-1) from ICU admission. At diagnosis, most SA-AKI patients (54%) had a stage 1 AKI, mostly due to the low urinary output (UO) criterion only (65%). Compared to diagnosis by creatinine alone, or by both UO and creatinine criteria, patients diagnosed by UO alone had lower renal replacement therapy (RRT) requirements (2.8% vs 18% vs 50%; p < 0.001), which was consistent across all stages of AKI. SA-AKI hospital mortality was 18% and SA-AKI was independently associated with increased mortality. In SA-AKI, diagnosis by low UO only, compared to creatinine alone or to both UO and creatinine criteria, carried an odds ratio of 0.34 (95% confidence interval (CI) 0.32-0.36) for mortality., Conclusion: SA-AKI occurs in 1 in 6 ICU patients, is diagnosed on day 1 and carries significant morbidity and mortality risk with patients mostly admitted from home via the ED. However, most SA-AKI is stage 1 and mostly due to low UO, which carries much lower risk than diagnosis by other criteria., (© 2023. The Author(s).)

Purpose: Recombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown., Methods: We conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010-2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5-8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI., Results: Of 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47-1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI [Formula: see text] 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2-22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome., Conclusion: EPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI., (© 2023. The Author(s).)

Purpose: To assess whether pre-existing chronic kidney disease (CKD) modified the relationship between the strategy for renal-replacement theraphy (RRT) initiation and clinical outcomes in the STARRT-AKI trial., Methods: This was a secondary analysis of a multi-national randomized trial. We included patients who had documented pre-existing estimated glomerular filtration rate (eGFR) data prior to hospitalization, and we defined CKD as an eGFR ≤ 59 mL/min/1.73 m 2 . The primary outcome was all-cause mortality at 90 days. Secondary outcomes included RRT dependence and RRT-free days at 90 days. We used logistic and linear regression and interaction testing to explore the effect of RRT initiation strategy on outcomes by CKD status., Results: We studied 1121 patients who had pre-hospital measures of kidney function. Of these, 432 patients (38.5%) had CKD. The median (IQR) baseline serum creatinine was 130 (114-160) and 76 (64-90) µmol/L for those with and without CKD, respectively. Patients with CKD were older and more likely to have cardiovascular comorbidities and diabetes mellitus. Patients with CKD had higher 90-day mortality (47% vs. 40%, p < 0.001) compared to those without CKD, though this was not significant after covariate adjustment (adjusted odds ratio [aOR], 1.05; 95% CI, 0.79-1.41). Patients with CKD were more likely to remain RRT dependent at 90 days (14% vs. 8%; aOR, 1.89; 95% CI, 1.05-3.43). CKD status did not modify the effect of RRT initiation strategy on 90-day mortality. Among patients with CKD, allocation to the accelerated strategy conferred more than threefold greater odds of RRT dependence at 90 days (aOR 3.18; 95% CI, 1.41-7.91) compared with the standard strategy, whereas RRT initiation strategy had no effect on this outcome among those without CKD (aOR 0.71; 95% CI, 0.34-1.47, p value for interaction, 0.009)., Conclusion: In this secondary analysis of the STARRT-AKI trial, an accelerated strategy of RRT initiation conferred a higher risk of 90-day RRT dependence among patients with pre-existing CKD; however, no effect was observed in the absence of CKD., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Intensive care unit (ICU) patients with end-organ failure will require specialised machines or extracorporeal therapies to support the failing organs that would otherwise lead to death. ICU patients with severe acute kidney injury may require renal replacement therapy (RRT) to remove fluid and wastes from the body, and patients with severe cardiorespiratory failure will require extracorporeal membrane oxygenation (ECMO) to maintain adequate oxygen delivery whilst the underlying pathology is evaluated and managed. The presence of ECMO and RRT machines can further augment the existing pharmacokinetic (PK) alterations during critical illness. Significant changes in the apparent volume of distribution (V d ) and drug clearance (CL) for many important drugs have been reported during ECMO and RRT. Conventional antimicrobial dosing regimens rarely consider the impact of these changes and consequently, are unlikely to achieve effective antimicrobial exposures in critically ill patients receiving ECMO and/or RRT. Therefore, an in-depth understanding on potential PK changes during ECMO and/or RRT is required to inform antimicrobial dosing strategies in patients receiving ECMO and/or RRT. In this narrative review, we aim to discuss the potential impact of ECMO and RRT on the PK of antimicrobials and antimicrobial dosing requirements whilst receiving these extracorporeal therapies. The potential benefits of therapeutic drug monitoring (TDM) and dosing software to facilitate antimicrobial therapy for critically ill patients receiving ECMO and/or RRT are also reviewed and highlighted., (© 2022. The Author(s).)

Multiple organ failure following a septic event derives from immune dysregulation. Many of the mediators of this process are humoral factors (cytokines), which could theoretically be cleared by direct adsorption through a process called hemoperfusion. Hemoperfusion through devices, which bind specific molecules like endotoxin or theoretically provide non-specific adsorption of pro-inflammatory mediators has been attempted and studied for several decades with variable results. More recently, technological evolution has led to the increasing application of adsorption due to more biocompatible and possibly more efficient biomaterials. As a result, new indications are developing in this field, and novel tools are available for clinical use. This narrative review will describe current knowledge regarding technical concepts, safety, and clinical results of hemoperfusion. Finally, it will focus on the most recent literature regarding adsorption applied in critically ill patients and their indications, including recent randomized controlled trials and future areas of investigation. Clinical trials for the assessment of efficacy of hemoperfusion in septic patients should apply the explanatory approach. This includes a highly selected homogenous patient population. Enrichment criteria such as applying genetic signature and molecular biomarkers allows the identification of subphenotypes of patients. The intervention must be delivered by a multidisciplinary team of trained personnel. The aim is to maximize the signals for efficacy and safety. In a homogenous cohort, confounding uncontrolled variables are less likely to exist. Trials with highly selected populations have a high internal validity but poor generalizability. The parallel design described in the figure is robust and usually is required by regulatory agencies for the approval of a new treatment. Allocation concealment and randomization are key to minimize bias such as confirmation bias, observer bias. The intervention should be delivered following a strict protocol. Deviations from the protocol might negatively influence the potential effects of the therapies. Surrogates such as cytokine measurement are adequate primary outcomes in phase 3 trials with small sample size because there is a higher likelihood of finding positive results concerning surrogate markers than in respect with clinical outcomes. Once a trial shows positive results concerning surrogate markers, a rationale for another phase 3 trial exploring clinical outcomes is built, justifying the allocation of financial sources to the intended trial., (© 2022. The Author(s).)

Purpose: To compare the prevalence, characteristics, drug treatment for delirium, and outcomes of patients with Natural Language Processing (NLP) diagnosed behavioral disturbance (NLP-Dx-BD) vs Confusion Assessment Method for intensive care unit (CAM-ICU) positivity., Methods: In three combined medical-surgical ICUs, we obtained data on demographics, treatment with antipsychotic medications, and outcomes. We applied NLP to caregiver progress notes to diagnose behavioral disturbance and analyzed simultaneous CAM-ICU., Results: We assessed 2313 patients with a median lowest Richmond Agitation-Sedation Scale (RASS) score of - 2 (- 4.0 to - 1.0) and median highest RASS score of 1 (0 to 1). Overall, 1246 (53.9%) patients were NLP-Dx-BD positive (NLP-Dx-BD pos ) and 578 (25%) were CAM-ICU positive (CAM-ICU pos ). Among NLP-Dx-BD pos patients, 539 (43.3%) were also CAM-ICU pos . In contrast, among CAM-ICU pos patients, 539 (93.3%) were also NLP-Dx-BD pos . The use of antipsychotic medications was highest in patients in the CAM-ICU pos and NLP-Dx-BD pos group (24.3%) followed by the CAM-ICU neg and NLP-Dx-BD pos group (10.5%). In NLP-Dx-BD neg patients, antipsychotic medication use was lower at 5.1% for CAM-ICU pos and NLP-Dx-BD neg patients and 2.3% for CAM-ICU neg and NLP-Dx-BD neg patients (overall P < 0.001). Regardless of CAM-ICU status, after adjustment and on time-dependent Cox modelling, NLP-Dx-BD was associated with greater antipsychotic medication use. Finally, regardless of CAM-ICU status, NLP-Dx-BD pos patients had longer duration of ICU and hospital stay and greater hospital mortality (all P < 0.001)., Conclusion: More patients were NLP-Dx-BD positive than CAM-ICU positive. NLP-Dx-BD and CAM-ICU assessment describe partly overlapping populations. However, NLP-Dx-BD identifies more patients likely to receive antipsychotic medications. In the absence of NLP-Dx-BD, treatment with antipsychotic medications is rare., (© 2022. The Author(s).)

Purpose: Acute illness severity predicts mortality in intensive care unit (ICU) patients, however, its predictive value decreases over time in ICU. Typically after 10 days, pre-ICU (antecedent) characteristics become more predictive of mortality, defining the onset of persistent critical illness (PerCI). How patient frailty affects development and death from PerCI is unknown., Methods: We conducted a secondary analysis of data from a prospective binational cohort study including 269,785 critically ill adults from 168 ICUs in Australia and New Zealand, investigating whether frailty measured with the Clinical Frailty Scale (CFS) changes the timing of onset and risk of developing PerCI and of subsequent in-hospital mortality. We assessed associations between frailty (CFS ≥ 5) and mortality prediction using logistic regression and area under the receiver operating characteristics (AUROC) curves., Results: 2190 of 50,814 (4.3%) patients with frailty (CFS ≥ 5) versus 6624 of 218,971 (3%) patients without frailty (CFS ≤ 4) developed PerCI (P < 0.001). Among patients with PerCI, 669 of 2190 (30.5%) with frailty and 1194 of 6624 without frailty (18%) died in hospital (P < 0.001). The time point defining PerCI onset did not vary with frailty degree; however, with increasing length of ICU stay, inclusion of frailty progressively improved mortality discrimination (0.1% AUROC improvement on ICU day one versus 3.6% on ICU day 17)., Conclusion: Compared to patients without frailty, those with frailty have a higher chance of developing and dying from PerCI. Moreover the importance of frailty as a predictor of mortality increases with ICU length of stay. Future work should explore incorporation of frailty in prognostic models, particularly for long-staying patients., (© 2022. The Author(s).)

We aimed to compare the effects of vitamin C, glucocorticoids, vitamin B1, combinations of these drugs, and placebo or usual care on longer-term mortality in adults with sepsis or septic shock. MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and WHO-ICTRP were searched. The final search was carried out on September 3rd, 2021. Multiple reviewers independently selected randomized controlled trials (RCTs) comparing very-high-dose vitamin C (≥ 12 g/day), high-dose vitamin C (< 12, ≥ 6 g/day), vitamin C (< 6 g/day), glucocorticoid (< 400 mg/day of hydrocortisone), vitamin B1, combinations of these drugs, and placebo/usual care. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. The primary outcome was longer-term mortality (90-days to 1-year). Secondary outcomes were severity of organ dysfunction over 72 h, time to cessation of vasopressor therapy, and length of stay in intensive care unit (ICU). Forty-three RCTs (10,257 patients) were eligible. There were no significant differences in longer-term mortality between treatments and placebo/usual care or between treatments (10 RCTs, 7,096 patients, moderate to very-low-certainty). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, - 29.8 h [95% CI - 44.1 to - 15.5]) and ICU stay (incremental mean difference, - 1.3 days [95% CI - 2.2 to - 0.3]). Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality., (© 2021. The Author(s).)

Purpose: We compared a restrictive fluid management strategy to usual care among critically ill patients with acute kidney injury (AKI) who had received initial fluid resuscitation., Methods: This multicenter feasibility trial randomized 100 AKI patients 1:1 in seven ICUs in Europe and Australia. Restrictive fluid management included targeting negative or neutral daily fluid balance by minimizing fluid input and/or enhancing urine output with diuretics administered at the discretion of the clinician. Fluid boluses were administered as clinically indicated. The primary endpoint was cumulative fluid balance 72 h from randomization., Results: Mean (SD) cumulative fluid balance at 72 h from randomization was - 1080 mL (2003 mL) in the restrictive fluid management arm and 61 mL (3131 mL) in the usual care arm, mean difference (95% CI) - 1148 mL (- 2200 to - 96) mL, P = 0.033. Median [IQR] duration of AKI was 2 [1-3] and 3 [2-7] days, respectively (median difference - 1.0 [- 3.0 to 0.0], P = 0.071). Altogether, 6 out of 46 (13%) patients in the restrictive fluid management arm and 15 out of 50 (30%) in the usual care arm received renal replacement therapy (RR 0.42; 95% CI 0.16-0.91), P = 0.043. Cumulative fluid balance at 24 h and 7 days was lower in the restrictive fluid management arm. The dose of diuretics was not different between the groups. Adverse events occurred more frequently in the usual care arm., Conclusions: In critically ill patients with AKI, a restrictive fluid management regimen resulted in lower cumulative fluid balance and less adverse events compared to usual care. Larger trials of this intervention are justified.

Purpose: To quantify potential heterogeneity of treatment effect (HTE), of early sedation with dexmedetomidine (DEX) compared with usual care, and identify patients who have a high probability of lower or higher 90-day mortality according to age, and other identified clusters., Methods: Bayesian analysis of 3904 critically ill adult patients expected to receive invasive ventilation > 24 h and enrolled in a multinational randomized controlled trial comparing early DEX with usual care sedation., Results: HTE was assessed according to age and clusters (based on 12 baseline characteristics) using a Bayesian hierarchical models. DEX was associated with lower 90-day mortality compared to usual care in patients > 65 years (odds ratio [OR], 0.83 [95% credible interval [CrI] 0.68-1.00], with 97.7% probability of reduced mortality across broad categories of illness severity. Conversely, the probability of increased mortality in patients ≤ 65 years was 98.5% (OR 1.26 [95% CrI 1.02-1.56]. Two clusters were identified: cluster 1 (976 patients) mostly operative, and cluster 2 (2346 patients), predominantly non-operative. There was a greater probability of benefit with DEX in cluster 1 (OR 0.86 [95% CrI 0.65-1.14]) across broad categories of age, with 86.4% probability that DEX is more beneficial in cluster 1 than cluster 2., Conclusion: In critically ill mechanically ventilated patients, early sedation with dexmedetomidine exhibited a high probability of reduced 90-day mortality in older patients regardless of operative or non-operative cluster status. Conversely, a high probability of increased 90-day mortality was observed in younger patients of non-operative status. Further studies are needed to confirm these findings.

Purpose: Liberal use of oxygen may contribute to secondary brain injury in patients with hypoxic-ischaemic encephalopathy (HIE). However, there are limited data on the effect of different oxygen regimens on survival and neurological disability in HIE patients., Methods: We undertook a post-hoc analysis of the 166 patients with suspected HIE enrolled in a trial comparing conservative oxygen therapy with usual oxygen therapy in 1000 mechanically ventilated ICU patients. The primary endpoint for the current analysis was death or unfavourable neurological outcome at day 180. Key secondary outcomes were day 180 mortality, and cause-specific mortality., Results: Patients with HIE allocated to conservative oxygen spent less time in the ICU with an SpO 2  ≥ 97% (26 h [interquartile range (IQR) 13-45 vs. 35 h [IQR 19-70], absolute difference, 9 h; 95% CI - 21.4 to 3.4). A total of 43 of 78 patients (55.1%) assigned to conservative oxygen and 49 of 72 patients (68.1%) assigned to usual oxygen died or had an unfavourable neurological outcome at day 180; odds ratio 0.58; 95% CI 0.3-1.12; P = 0.1 adjusted odds ratio 0.54; 95% CI 0.23-1.26; P = 0.15. A total of 37 of 86 patients (43%) assigned to conservative oxygen and 46 of 78 (59%) assigned to usual oxygen had died by day 180; odds ratio 0.53; 95% CI 0.28-0.98; P = 0.04; adjusted odds ratio 0.56; 95% CI 0.25-1.23; P = 0.15. Cause-specific mortality was similar by treatment group., Conclusions: Conservative oxygen therapy was not associated with a statistically significant reduction in death or unfavourable neurological outcomes at day 180. The potential for important benefit or harm from conservative oxygen therapy in HIE patients is not excluded by these data.

Purpose: To investigate the impact of hydrocortisone treatment and illness severity on health-related quality of life (HRQoL) at 6 months in septic shock survivors from the ADRENAL trial., Methods: Using the EuroQol questionnaire (EQ-5D-5L) at 6 months after randomization we assessed HRQoL in patient subgroups defined by hydrocortisone or placebo treatment, gender, illness severity (APACHE II < or ≥ 25), and severity of shock (baseline peak catecholamine doses < or ≥ 15 mcg/min). Additionally, in subgroups defined by post-randomisation variables; time to shock reversal (days), treatment with renal replacement therapy (RRT), and presence of bacteremia., Results: At 6 months, there were 2521 survivors. Of these 2151 patients (85.3%-1080 hydrocortisone and 1071 placebo) completed 6-month follow-up. Overall, at 6 months the mean EQ-5D-5L visual analogue scale (VAS) was 70.8, mean utility score 59.4. Between 15% and 30% of patients reported moderate to severe problems in any given HRQoL domain. There were no differences in any EQ-5D-5L domain in patients who received hydrocortisone vs. placebo, nor in the mean VAS (p = 0.6161), or mean utility score (p = 0.7611). In all patients combined, males experienced lower pain levels compared to females [p = 0.0002). Neither higher severity of illness or shock impacted reported HRQoL. In post-randomisation subgroups, longer time to shock reversal was associated with increased problems with mobility (p = < 0.0001]; self-care (p = 0.0.0142), usual activities (p = <0.0001] and pain (p = 0.0384). Amongst those treated with RRT, more patients reported increased problems with mobility (p = 0.0307) and usual activities (p = 0.0048) compared to those not treated. Bacteraemia was not associated with worse HRQoL in any domains of the EQ-5D-5L., Conclusions: Approximately one fifth of septic shock survivors report moderate to extreme problems in HRQoL domains at 6 months. Hydrocortisone treatment for septic shock was not associated with improved HRQoL at 6 months. Female gender was associated with worse pain at 6 months.

Purpose: Patients with persistent critical illness may account for up to half of all intensive care unit (ICU) bed-days. It is unknown if there is hospital variation in the development of persistent critical illness and if hospital performance affects the incidence of persistent critical illness., Methods: This is a retrospective analysis of Veterans admitted to the Veterans Administration (VA) ICUs from 2015 to 2017. Hospital performance was defined by the risk- and reliability-adjusted 30-day mortality. Persistent critical illness was defined as an ICU length of stay of at least 11 days. We used 2-level multilevel logistic regression models to assess variation in risk- and reliability-adjusted probabilities in the development of persistent critical illness., Results: In the analysis of 100 hospitals which encompassed 153,512 hospitalizations, 4.9% (N = 7640/153,512) developed persistent critical illness. There was variation in the development of persistent critical illness despite controlling for patient characteristics (intraclass correlation: 0.067, 95% CI 0.049-0.091). Hospitals with higher risk- and reliability-adjusted 30-day mortality had higher probabilities of developing persistent critical illness (predicted probability: 0.057, 95% CI 0.051-0.063, p < 0.01) compared to those with lower risk- and reliability-adjusted 30-day mortality (predicted probability: 0.046, 95% CI 0.041-0.051, p < 0.01). The median odds ratio was 1.4 (95% CI 1.33-1.49) implying that, for two patients with the same physiology on admission at two different VA hospitals, the patient admitted to the hospital with higher adjusted mortality would have 40% greater odds of developing persistent critical illness., Conclusion: Hospitals with higher risk- and reliability-adjusted 30-day mortality have a higher probability of developing persistent critical illness. Understanding the drivers of this variation may identify modifiable factors contributing to the development of persistent critical illness.

Acute kidney injury after cardiac surgery (AKICS) is common. Previous studies examining the role that mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) may have on AKICS have not taken into account how baseline central venous pressure (CVP) and mean perfusion pressure (MPP) (i.e. MAP - CVP) can influence its evolution. To assess whether the change in MPP to the kidneys (i.e. delta MPP or DMPP) during CPB compared to baseline is an independent predictor of AKICS. After ethical approval, a retrospective observational study was performed on all patients undergoing CPB between October 2013 and June 2015 at a university-affiliated hospital. Known risk factors for the development of AKICS were recorded, as were the MPP values at baseline and during CPB. From this, statistical modelling was performed to identify predictors of postoperative AKICS. 664 patients were identified. Analysis was performed on 513 patients after exclusion. On logistic regression, significant and independent predictors of AKICS included: d20DMPP (cumulative duration of MPP values during CPB that were 20% below baseline and exceeded three consecutive minutes) (P = 0.010); baseline CVP; age; pre-operative creatinine level; and left ventricular (LV) dysfunction (ejection fraction (EF) < 45%). On alternative modelling, the cumulative number of MPP values during CPB that were 10% below baseline was also independently associated with AKICS (P = 0.003). Modelling without taking into account CVP also supported this association. The duration of differences in perfusion pressure to the kidneys during CPB compared to baseline is an independent predictor of AKICS.

Purpose: Sepsis is a common reason for intensive care unit (ICU) admission and mortality in ICU patients. Despite increasing interest in treatment strategies limiting oxygen exposure in ICU patients, no trials have compared conservative vs. usual oxygen in patients with sepsis., Methods: We undertook a post hoc analysis of the 251 patients with sepsis enrolled in a trial that compared conservative oxygen therapy with usual oxygen therapy in 1000 mechanically ventilated ICU patients. The primary end point for the current analysis was 90-day mortality. Key secondary outcomes were cause-specific mortality, ICU and hospital length of stay, ventilator-free days, vasopressor-free days, and the proportion of patients receiving renal replacement therapy in the ICU., Results: Patients with sepsis allocated to conservative oxygen therapy spent less time in the ICU with an SpO 2  ≥ 97% (23.5 h [interquartile range (IQR) 8-70] vs. 47 h [IQR 11-93], absolute difference, 23 h; 95% CI 8-38), and more time receiving an FiO 2 of 0.21 than patients allocated to usual oxygen therapy (20.5 h [IQR 1-79] vs. 0 h [IQR 0-10], absolute difference, 20 h; 95% CI 14-26). At 90-days, 47 of 130 patients (36.2%) assigned to conservative oxygen and 35 of 120 patients (29.2%) assigned to usual oxygen had died (absolute difference, 7 percentage points; 95% CI - 4.6 to 18.6% points; P = 0.24; interaction P = 0.35 for sepsis vs. non-sepsis). There were no statistically significant differences between groups for secondary outcomes but point estimates of treatment effects consistently favored usual oxygen therapy., Conclusions: Point estimates for the treatment effect of conservative oxygen therapy on 90-day mortality raise the possibility of clinically important harm with this intervention in patients with sepsis; however, our post hoc analysis was not powered to detect the effects suggested and our data do not exclude clinically important benefit or harm from conservative oxygen therapy in this patient group., Clinical Trials Registry: ICU-ROX Australian and New Zealand Clinical Trials Registry number ACTRN12615000957594.

Purpose: It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confirm the feasibility of such a protocol with a view to conducting a larger trial., Methods: We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge., Results: Compared with usual temperature management, active management significantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature difference between groups was greatest in the first 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51-1.96, P = 1.0). There were no statistically significant differences between groups in ICU-free days or survival to day 90., Conclusions: Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small., Trial Registration: Australian and New Zealand Clinical Trials Registry Number, ACTRN12616001285448.

Purpose: One potential way to protect patients from the physiological demands that are a consequence of fever is to aim to prevent fever and to treat it assiduously when it occurs. Our primary hypothesis was that more active fever management would increase survival among patient subgroups with limited physiological reserves such as older patients, patients with higher illness acuity, and those requiring organ support., Methods: We conducted an individual-level patient data meta-analysis of randomised controlled trials to compare the outcomes of ICU patients who received more active fever management with the outcomes of patients who received less active fever management. The primary outcome variable of interest was the unadjusted time to death after randomisation., Results: Of 1413 trial participants, 707 were assigned to more active fever management and 706 were assigned to less active fever management. There was no statistically significant heterogeneity in the effect of more active compared with less active fever management on survival in any of the pre-specified subgroups that were chosen to identify patients with limited physiological reserves. Overall, more active fever management did not result in a statistically significant difference in survival time compared with less active fever management [hazard ratio 0.91; (95% CI 0.75-1.10), P = 0.32]., Conclusions: Our findings do not support the hypothesis that more active fever management increases survival compared with less active fever management overall or in patients with limited physiological reserves.

Purpose: Persistent critical illness has been described as a subtype of chronic critical illness, characterized as a transition after ICU admission where primary diagnosis and illness acuity are no better at predicting outcome than pre-hospital characteristics. Herein we describe the occurrence and outcomes associated with persistent critical illness in a large Canadian health region., Methods: In this multi-center observational cohort study, all patients aged older than 14 years admitted to 12 ICUs in Alberta, Canada, between June 2012 and December 2014 were included. Primary outcome was in-hospital mortality. Predictors at ICU admission were separated into: (1) antecedent characteristics component (e.g., demographics, chronic health component of the APACHE II score, comorbid conditions); and (2) acute illness component (e.g., APACHE II score at admission, SOFA score, primary diagnostic category, surgical status, acute organ support). Using multiple statistical methods and randomly splitting the cohort into development and validation samples for risk scoring using logistic regression, we examined mortality prediction of each of these components to characterize the timing of transition to persistent critical illness., Results: We included 17,783 patients with a median (IQR) age 61 years (49-71), 62% were male, and mean APACHE II score was 19.0 (7.9). In-hospital mortality was 16.8%. Among patients alive and in ICU, the acute illness component, which accurately predicted outcome at the time of admission [area under the receiver operating characteristics curve (AUC) 0.861; 95% CI 0.860-0.862], progressively lost predictive ability and was no longer more predictive than antecedent characteristics after 9 days. This transition defined the onset of persistent critical illness and comprised 16.1% (n = 2856) of the cohort. Transition ranged between 5 and 21 days across subgroups. In-hospital mortality was greater for those with persistent critical illness [23.9% vs. 15.5%, odds ratio (OR) 1.54; 95% CI 1.43-1.67, p < 0.001]. Persistently critically ill patients accounted for 54.5% of 97844 ICU bed-days and 36.3% of 420119 hospital bed-days, respectively., Conclusions: Persistent critical illness occurred in one in six patients admitted to Alberta ICUs and portended greater risk of death, prolonged ICU and hospital stay, and disproportionate use of health resources compared to patients without persistent critical illness.

Purpose: To determine if a regimen of restricted fluids and early vasopressor compared to usual care is feasible for initial resuscitation of hypotension due to suspected sepsis., Methods: A prospective, randomised, open-label, clinical trial of a restricted fluid resuscitation regimen in the first 6 h among patients in the emergency department (ED) with suspected sepsis and a systolic blood pressure under 100 mmHg, after minimum 1000 ml of IV fluid. Primary outcome was total fluid administered within 6 h post randomisation., Results: There were 99 participants (50 restricted volume and 49 usual care) in the intention-to-treat analysis. Median volume from presentation to 6 h in the restricted volume group was 2387 ml [first to third quartile (Q1-Q3) 1750-2750 ml]; 30 ml/kg (Q1-Q3 32-39 ml/kg) vs. 3000 ml (Q1-Q3 2250-3900 ml); 43 ml/kg (Q1-Q3 35-50 ml/kg) in the usual care group (p < 0.001). Median duration of vasopressor support was 21 h (Q1-Q3 9-42 h) vs. 33 h (Q1-Q3 15-50 h), (p = 0.13) in the restricted volume and usual care groups, respectively. At 90-days, 4 of 48 (8%) in the restricted volume group and 3 of 47 (6%) in the usual care group had died. Protocol deviations occurred in 6/50 (12%) in restricted group and 11/49 (22%) in the usual care group, and serious adverse events in four cases (8%) in each group., Conclusions: A regimen of restricted fluids and early vasopressor in ED patients with suspected sepsis and hypotension appears feasible. Illness severity was moderate and mortality rates low. A future trial is necessary with recruitment of high-risk patients to determine effects on clinical outcomes in this setting.

Purpose: We set out to assess the resuscitation fluid requirements and physiological and clinical responses of intensive care unit (ICU) patients resuscitated with 20% albumin versus 4-5% albumin., Methods: We performed a randomised controlled trial in 321 adult patients requiring fluid resuscitation within 48 h of admission to three ICUs in Australia and the UK., Results: The cumulative volume of resuscitation fluid at 48 h (primary outcome) was lower in the 20% albumin group than in the 4-5% albumin group [median difference - 600 ml, 95% confidence interval (CI) - 800 to - 400; P < 0.001]. The 20% albumin group had lower cumulative fluid balance at 48 h (mean difference - 576 ml, 95% CI - 1033 to - 119; P = 0.01). Peak albumin levels were higher but sodium and chloride levels lower in the 20% albumin group. Median (interquartile range) duration of mechanical ventilation was 12.0 h (7.6, 33.1) in the 20% albumin group and 15.3 h (7.7, 58.1) in the 4-5% albumin group (P = 0.13); the proportion of patients commenced on renal replacement therapy after randomization was 3.3% and 4.2% (P = 0.67), respectively, and the proportion discharged alive from ICU was 97.4% and 91.1% (P = 0.02)., Conclusions: Resuscitation with 20% albumin decreased resuscitation fluid requirements, minimized positive early fluid balance and was not associated with any evidence of harm compared with 4-5% albumin. These findings support the safety of further exploration of resuscitation with 20% albumin in larger randomised trials., Trial Registration: http://www.anzctr.org.au . Identifier ACTRN12615000349549.