Long-Term Echocardiographic and Clinical Outcomes After Invasive and Non-Invasive Therapies for Sub-Massive and Massive Acute Pulmonary Embolism.

AIM: Acute pulmonary embolism (PE) is a significant cause of mortality in the hospital setting. The objective of this study was to outline the long-term outcomes after surgical and non-surgical management for patients with massive and submassive PE. METHODS: Population cohort observational study evaluating all patients who presented to three tertiary hospitals in the state of Western Australia with access to cardiothoracic services over 5 years (2013-2018). Reviewed notes of all patients as well as radiology, linked mortality data and all available echocardiography studies at the primary hospital. RESULTS: In total, 245 patients were identified, of which 41 received surgical management and 204 non-surgical management; demographic data was similar. Clinically, the surgical group had higher rates of shock requiring vasopressors, severe bradycardia, or cardiopulmonary resuscitation prior to intervention. The 28-day mortality was not statistically significantly different between the surgical embolectomy group (2/41 [4.2%]) and the non-surgical group (17/201 [8.3%]) (p=0.382). There was no difference in 12-month mortality, including when this was adjusted for vasopressors, right ventricular (RV) strain, troponin, and brain natriuretic peptide. In the massive PE sub-group, 28-day mortality was not significantly different: 2/29 (6.9%) surgical group vs 7/34 (20.2%) non-surgical group (p=0.064). Higher rates of severe RV impairment and dilatation were present in the surgical group. All patients with available echocardiography studies at outpatient follow-up returned to normal or mild RV impairment. CONCLUSION: Patients who presented with massive or submassive PE had similar outcomes whether treated with surgical or non-surgical management. Surgical embolectomy is a safe option in a cardiothoracic centre setting.

Using machine learning to predict bleeding after cardiac surgery.

OBJECTIVES: The primary objective was to predict bleeding after cardiac surgery with machine learning using the data from the Australia New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database, cardiopulmonary bypass perfusion database, intensive care unit database and laboratory results. METHODS: We obtained surgical, perfusion, intensive care unit and laboratory data from a single Australian tertiary cardiac surgical hospital from February 2015 to March 2022 and included 2000 patients undergoing cardiac surgery. We trained our models to predict either the Papworth definition or Dyke et al.'s universal definition of perioperative bleeding. Our primary outcome was the performance of our machine learning algorithms using sensitivity, specificity, positive and negative predictive values, accuracy, area under receiver operating characteristics curve (AUROC) and area under precision-recall curve (AUPRC). RESULTS: Of the 2000 patients undergoing cardiac surgery, 13.3% (226/2000) had bleeding using the Papworth definition and 17.2% (343/2000) had moderate to massive bleeding using Dyke et al.'s definition. The best-performing model based on AUPRC was the Ensemble Voting Classifier model for both Papworth (AUPRC 0.310, AUROC 0.738) and Dyke definitions of bleeding (AUPRC 0.452, AUROC 0.797). CONCLUSIONS: Machine learning can incorporate routinely collected data from various datasets to predict bleeding after cardiac surgery.

Intravenous vitamin C for vasoplegia: A double-blinded randomised clinical trial (VALENCIA trial).

PURPOSE: To determine whether intravenous vitamin C compared with placebo, reduces vasopressor requirements in patients with vasoplegic shock. METHODS: Double-blinded, randomised clinical trial (RCT) conducted in two intensive care units in Perth, Australia. Vasopressor requirements at enrolment needed to be >10 µg/min noradrenaline after hypovolaemia was clinically excluded. Patients received either intravenous 1.5 g sodium ascorbate in 100 ml normal saline every 6 h for 5 days, or placebo (100 ml normal saline). The primary outcome was duration of vasopressor usage in hours. Secondary outcomes were ICU and hospital length of stay, and 28-day, ICU and hospital mortality. RESULTS: Of the 71 patients randomised (35 vitamin C, 36 placebo group), the median vasopressor duration was 44 h [95% CI, 37-54 h] and 55 h [95% CI, 33-66 h]) in the vitamin C and placebo groups (p = 0.057). ICU and hospital length of stay, mortality outcomes were similar between groups. CONCLUSIONS: In this RCT of patients with vasoplegic shock of at least moderate severity, the use of IV vitamin C compared with placebo did not significantly reduce the duration of vasopressors. TRIAL REGISTRATION: Prospective registration - trial number ACTRN12617001392358.

Effect of Deferoxamine on Post-Transfusion Iron, Inflammation, and In Vitro Microbial Growth in a Canine Hemorrhagic Shock Model: A Randomized Controlled Blinded Pilot Study.

Red blood cell (RBC) transfusion is associated with recipient inflammation and infection, which may be triggered by excessive circulating iron. Iron chelation following transfusion may reduce these risks. The aim of this study was to evaluate the effect of deferoxamine on circulating iron and inflammation biomarkers over time and in vitro growth of Escherichia coli (E. coli) following RBC transfusion in dogs with atraumatic hemorrhage. Anesthetized dogs were subject to atraumatic hemorrhage and transfusion of RBCs, then randomized to receive either deferoxamine or saline placebo of equivalent volume (n = 10 per group) in a blinded fashion. Blood was sampled before hemorrhage and then 2, 4, and 6 h later. Following hemorrhage and RBC transfusion, free iron increased in all dogs over time (both p < 0.001). Inflammation biomarkers interleukin-6 (IL6), CXC motif chemokine-8 (CXCL8), interleukin-10 (IL10), and keratinocyte-derived chemokine (KC) increased in all dogs over time (all p < 0.001). Logarithmic growth of E. coli clones within blood collected 6 h post-transfusion was not different between groups. Only total iron-binding capacity was different between groups over time, being significantly increased in the deferoxamine group at 2 and 4 h post-transfusion (both p < 0.001). In summary, while free iron and inflammation biomarkers increased post-RBC transfusion, deferoxamine administration did not impact circulating free iron, inflammation biomarkers, or in vitro growth of E. coli when compared with placebo.

Iron and erythropoietin to heal and recover after intensive care (ITHRIVE): A pilot randomised clinical trial.

Objective: To determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit. Design: An investigator-initiated, parallel group, placebo-controlled, randomised feasibility trial. Setting: A tertiary intensive care unit (ICU) in Perth, Western Australia. Participants: Adults with anaemia (haemoglobin <100 g/L), requiring ICU-level care for more than 48 h, and likely to be ready for ICU discharge within 24 h. Interventions: A single dose of IV ferric carboxymaltose and Epoetin alfa (active group) or an equal volume of 0.9% saline (placebo group). Main outcome measures: Study feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to day 90 (DAH90). Results: The 40-participant planned sample size included twenty in each group and was enrolled between 1/9/2021 and 2/3/2022. Participants spent a median of 3.4 days (interquartile range 2.8-5.1) in the ICU prior to enrolment and had a mean baseline haemoglobin of 83.7 g/L (standard deviation 6.7). The recruitment rate was 6.7 participants per month [95% confidence interval (CI) 4.8-9.0], DAH90 follow-up was 100% (95% CI 91.2%-100%), and 39 (97.5%, 95% CI 86.8%-99.9%) participants received the allocated study intervention. No serious adverse events were reported. Conclusion: The iron and erythropoietin to heal and recover after intensive care (ITHRIVE) pilot demonstrated feasibility based on predefined participant recruitment, study drug administration, and follow-up thresholds.

Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Effect of high-flow nasal therapy on patient-centred outcomes in patients at high risk of postoperative pulmonary complications after cardiac surgery: a study protocol for a multicentre adaptive randomised controlled trial.

BACKGROUND: High-flow nasal therapy is a non-invasive form of respiratory support that delivers low-level, flow dependent positive airway pressure. The device can be better tolerated by patients than alternatives such as continuous positive airway pressure. The primary objective is to determine if prophylactic high-flow nasal therapy after tracheal extubation can result in an increase in the number of days alive and at home within the first 90 days after surgery, when compared with standard oxygen therapy. The co-primary objective is to estimate the incremental cost-effectiveness and cost-utility of high-flow nasal therapy vs standard oxygen therapy at 90 days, from the view-point of the public sector, the health service and patients. METHODS: This is an adaptive, multicentre, international parallel-group, randomised controlled trial with embedded cost-effectiveness analysis comparing the use of high-flow nasal therapy with control in patients at high risk of respiratory complications following cardiac surgery. Participants will be randomised before tracheal extubation and allocated either high-flow nasal therapy or standard oxygen therapy for a minimum of 16 h immediately post extubation. Participants will be followed up until 90 days after surgery. The total sample size needed to detect a 2-day increase in DAH90 with 90% power with an intention to treat analysis is 850 patients. The adaptive design includes an interim sample size re-estimation which will provide protection against deviations from the original sample size assumptions made from the single-centre pilot study and will allow for a maximum sample size increase to 1152 patients. DISCUSSION: Evidence to support routine use of high-flow nasal therapy will inform the development of effective enhanced recovery care bundles. Reducing complications should reduce length of stay and re-admission to hospital and provide an important focus for cost reduction. However; high-quality studies evaluating the clinical and cost effectiveness of high-flow nasal therapy after cardiothoracic surgery are lacking. TRIAL REGISTRATION: The study has been registered with ISRCTN ( ISRCTN14092678 , 13/05/2020) Clinicaltrials.gov Registration Pending.

Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis.

Importance: Intravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain. Objective: To examine the risk of infection associated with intravenous iron compared with oral iron or no iron. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform. Study Selection: Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility. Data Extraction and Synthesis: Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection. Main Outcomes and Measures: The primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences. Results: A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay. Conclusions and Relevance: In this large systematic review and meta-analysis, intravenous iron was associated with an increased risk of infection. Well-designed studies, using standardized definitions of infection, are required to understand the balance between this risk and the potential benefits.

A randomised controlled trial of succinylated gelatin (4%) fluid on urinary acute kidney injury biomarkers in cardiac surgical patients.

BACKGROUND: Fluid resuscitation is frequently required for cardiac surgical patients admitted to the intensive care unit. The ideal fluid of choice in regard to efficacy and safety remains uncertain. Compared with crystalloid fluid, colloid fluid may result in less positive fluid balance. However, some synthetic colloids are associated with increased risk of acute kidney injury (AKI). This study compared the effects of succinylated gelatin (4%) (GEL) with compound sodium lactate (CSL) on urinary AKI biomarkers in patients after cardiac surgery. METHODS: Cardiac surgical patients who required an intravenous fluid bolus of at least 500 mL postoperatively were randomly allocated to receive GEL or CSL as the resuscitation fluid of choice for the subsequent 24 h. Primary outcomes were serial urinary neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C concentrations measured at baseline, 1 h, 5 h and 24 h after enrolment, with higher concentrations indicating greater kidney injury. Secondary biomarker outcomes included urinary clusterin, α1-microglobulin and F2-isoprostanes concentrations. Differences in change of biomarker concentration between the two groups over time were compared with mixed-effects regression models. Statistical significance was set at P < 0.05. RESULTS: Forty cardiac surgical patients (n = 20 per group) with similar baseline characteristics were included. There was no significant difference in the median volume of fluid boluses administered over 24 h between the GEL (1250 mL, Q1-Q3 500-1750) and CSL group (1000 mL, Q1-Q3 500-1375) (P = 0.42). There was a significantly greater increase in urinary cystatin C (P < 0.001), clusterin (P < 0.001), α1-microglobulin (P < 0.001) and F2-isoprostanes (P = 0.020) concentrations over time in the GEL group, compared to the CSL group. Change in urinary NGAL concentration (P = 0.68) over time was not significantly different between the groups. The results were not modified by adjustment for either urinary osmolality or EuroSCORE II predicted risk of mortality. CONCLUSIONS: This preliminary randomised controlled trial showed that use of succinylated gelatin (4%) for fluid resuscitation after cardiac surgery was associated with increased biomarker concentrations of renal tubular injury and dysfunction, compared to crystalloid fluid. These results generate concern that use of intravenous gelatin fluid may contribute to clinically relevant postoperative AKI. Trial registration ANZCTR.org.au, ACTRN12617001461381. Registered on 16th October, 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373619&isReview=true .

Gut microbiota in surgical and critically ill patients.

Microbiota-defined as a collection of microbial organisms colonising different parts of the human body-is now recognised as a pivotal element of human health, and explains a large part of the variance in the phenotypic expression of many diseases. A reduction in microbiota diversity, and replacement of normal microbes with non-commensal, pathogenic or more virulent microbes in the gastrointestinal tract-also known as gut dysbiosis-is now considered to play a causal role in the pathogenesis of many acute and chronic diseases. Results from animal and human studies suggest that dysbiosis is linked to cardiovascular and metabolic disease through changes to microbiota-derived metabolites, including trimethylamine-N-oxide and short-chain fatty acids. Dysbiosis can occur within hours of surgery or the onset of critical illness, even without the administration of antibiotics. These pathological changes in microbiota may contribute to important clinical outcomes, including surgical infection, bowel anastomotic leaks, acute kidney injury, respiratory failure and brain injury. As a strategy to reduce dysbiosis, the use of probiotics (live bacterial cultures that confer health benefits) or synbiotics (probiotic in combination with food that encourages the growth of gut commensal bacteria) in surgical and critically ill patients has been increasingly reported to confer important clinical benefits, including a reduction in ventilator-associated pneumonia, bacteraemia and length of hospital stay, in small randomised controlled trials. However, the best strategy to modulate dysbiosis or counteract its potential harms remains uncertain and requires investigation by a well-designed, adequately powered, randomised controlled trial.

Prophylactic Intra-Aortic Balloon Counterpulsation in High Risk Cardiac Surgery: The PINBALL Pilot Multicentre, Registry-Linked, Randomised, Controlled Feasibility Trial.

BACKGROUND: Prophylactic intra-aortic balloon counterpulsation (IABC) is commonly used in selected patients undergoing coronary artery bypass graft (CABG) surgery, but definitive evidence is lacking. The aim of the multicentre PINBALL Pilot randomised controlled trial (RCT) was to assess the feasibility of performing a definitive trial to address this question. METHODS: Patients listed for CABG surgery with impaired left ventricular function and at least one additional risk factor for postoperative low cardiac output syndrome were eligible for inclusion if the treating surgical team was uncertain as to the benefit of prophylactic IABC. The primary outcome of feasibility was based on exceeding a pre-specified recruitment rate, protocol compliance and follow-up. RESULTS: The recruitment rate of 0.5 participants per site per month did not meet the feasibility threshold of two participants per site per month and the study was stopped early after enrolment of 24 out of the planned sample size of 40 participants. For 20/24 (83%) participants, preoperative IABC use occurred according to study assignment. Six (6)-month follow-up was available for all enrolled participants, [IABC 1 death (8%) vs. control 1 death (9%), p = 0.95]. CONCLUSION: The PINBALL Pilot recruitment rate was insufficient to demonstrate feasibility of a multicentre RCT of prophylactic IABC in high risk patients undergoing CABG surgery.

Identification of The Canidae Iron Regulatory Hormone Hepcidin.

Hepcidins are an evolutionarily conserved class of liver-expressed peptide, from which the twenty-five amino acid hormone, hepcidin-25 (herein hepcidin), has gained significant notoriety as the master regulator of iron homeostasis in mammals. Hepcidin maintains iron homeostasis by controlling the dietary absorption of iron and the mechanisms of recycling cellular iron stores. With the physiological significance of this hormone well established, it has emerged as an informative biomarker. In a comparison of the genome, transcriptome and peptidome of Canis lupis familiaris, we reveal the size of the hepcidin peptide in the canine, previous reports of which were contradictory to the evolutionary conservation predicted by genome annotation. Here, measurement of the peptide by mass spectrometry, following isolation from greyhound blood serum, revealed an amino acid sequence and peptide mass, differing from all accounts to date, yet demonstrating perfect sequence identity to that of the greater Canidae lineage of the Carnivora. Importantly, in the greyhound, the measured hepcidin peptide showed a similar temporal pattern to total serum iron, consistent with our understanding of hepcidin regulating iron homeostasis, in agreement with human diagnostics, and providing added translational evidence of the measured peptide being the iron regulatory hormone of the Canidae.

Intravenous iron therapy for non-anaemic, iron-deficient adults.

BACKGROUND: Iron deficiency is one of the most common nutritional deficiencies, and has a number of physiological manifestations. Early, or non-anaemic iron deficiency can result in fatigue and diminished exercise capacity. Oral iron preparations have a high incidence of intolerable side effects, and are ineffective in certain forms of iron deficiency. Consequently, intravenous iron preparations are increasingly used in the treatment of non-anaemic iron deficiency. The newer, more stable iron preparations in particular purport to have a lower incidence of side effects, and are now used across a range of different patient populations. OBJECTIVES: To assess the effects of intravenous iron therapy in the treatment of adults with non-anaemic iron deficiency. SEARCH METHODS: On 18 October 2019 we electronically searched CENTRAL, MEDLINE, Embase, two further databases and two trials registries 2019. We handsearched the references of full-text extracted studies, and contacted relevant study authors for additional data. SELECTION CRITERIA: We included randomised controlled trials that compared any intravenous iron preparation to placebo in adults. We excluded other forms of comparison such as oral iron versus placebo, intramuscular iron versus placebo, or intravenous iron studies where other iron preparations were used as the comparator. We also excluded studies involving erythropoietin therapy or obstetric populations. DATA COLLECTION AND ANALYSIS: Two review authors screened references for eligibility, extracted data and assessed risk of bias. We resolved differences in opinion through discussion and consensus, and where necessary, involved a third review author to adjudicate disputes. We contacted study authors to request additional data where appropriate. The primary outcome measures were haemoglobin concentration at the end of follow-up, and quality-of-life scores at end of follow-up. Secondary outcome measures were serum ferritin, peak oxygen consumption (as measured by cardiopulmonary exercise testing), adverse effects (graded as mild to moderate and severe) and bacterial infection. We pooled data for continuous outcomes, which we then reported as mean differences (MDs) with 95% confidence intervals (CIs). We reported quality-of-life metrics as standardised mean difference (SMD), and then converted them back into a more familiar measure, the Piper Fatigue Scale. We analysed dichotomous outcomes as risk ratios (RRs). Given an expected degree of heterogeneity, we used a random-effects model for all outcomes. We performed the analysis with the software package Review Manager 5. MAIN RESULTS: This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I2 = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I2 = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI -0.89 to 6.43; I2 = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size. AUTHORS' CONCLUSIONS: Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.

Safety and efficacy of erythropoiesis-stimulating agents in critically ill patients admitted to the intensive care unit: a systematic review and meta-analysis.

PURPOSE: Severe immune dysregulation is common in patients admitted to the intensive care unit (ICU) and is associated with adverse outcomes. Erythropoietin-stimulating agents (ESAs) have immune-modulating and anti-apoptotic effects. However, their safety and efficacy in critically ill patients remain uncertain. We evaluated whether ESAs, administered to critically unwell adult patients admitted to the ICU, reduced mortality at hospital discharge. METHODS: The search strategy was conducted according to a predetermined protocol and included OVID MEDLINE, OVID EMBASE and The Cochrane Central Register of Controlled Trials from inception until 20 May 2019. Publications were eligible for inclusion if they were randomized controlled trials (RCTs) including adult patients admitted to an ICU, that identified and reported a group receiving ESA therapy compared to a group not receiving ESA therapy and reported mortality. There were no language restrictions. RESULTS: The systematic review included 21 studies with 5452 participants. In-hospital mortality, reported in 16 studies of which only one was at low risk of bias, was lower in the ESA group (276 of 2187 patients, 12.6%) than the comparator group (339 out of 2204 patients, 15.4%), [relative risk (RR) 0.82, 95% CI 0.71-0.94, P = 0.006, I2 = 0.0%]. The RR of SAEs and thromboembolic events for the ESA and comparator groups were similar, RR 1.11 (95% CI 0.94-1.31, P = 0.228, I2 66%) and 1.22 (95% CI 0.95-1.58, P = 0.086, I2 47%), respectively. CONCLUSIONS: In heterogenous populations of critically ill adults, evidence from RCTs of mainly low or unclear quality, suggests that ESA therapy may decrease mortality.

Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review.

INTRODUCTION: The benefits and risk of intravenous iron have been documented in previous systematic reviews and continue to be the subject of randomised controlled trials (RCTs). An ongoing issue that continues to be raised is the relationship between administering iron and developing infection. This is supported by biological plausibility from animal models. We propose an update of a previously published systematic review and meta-analysis with the primary focus being infection. METHODS AND ANALYSIS: We will include RCTs and non-randomised studies (NRS) in this review update. We will search the relevant electronic databases. Two reviewers will independently extract data. Risk of bias for RCTs and NRS will be assessed using the relevant tools recommended by The Cochrane Collaboration. Data extracted from RCTs and NRS will be analysed and reported separately. Pooled data from RCTs will be analysed using a random effects model. We will also conduct subgroup analyses to identify any patient populations that may be at increased risk of developing infection. We will provide a narrative synthesis on the definitions, sources and responsible pathogens for infection in the included studies. Overall quality of evidence on the safety outcomes of mortality and infection will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: This systematic review will only investigate published studies and therefore ethical approval is not required. The results will be broadly distributed through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42018096023).

Iron Metabolism: An Emerging Therapeutic Target in Critical Illness.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2019. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2019 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .