Patient blood management guideline for adults with critical bleeding.

INTRODUCTION: The management of patients with critical bleeding requires a multidisciplinary approach to achieve haemostasis, optimise physiology, and guide blood component use. The 2011 Patient blood management guidelines: module 1 - critical bleeding/massive transfusion were updated and published. Systematic reviews were conducted for pre-specified research questions, and recommendations were based on meta-analyses of included studies. MAIN RECOMMENDATIONS: The critical bleeding/massive transfusion guideline includes seven recommendations and 11 good practice statements addressing: major haemorrhage protocols (MHPs) facilitating a multidisciplinary approach to haemorrhage control, correction of coagulopathy and normalisation of physiological derangement; measurement of physiological, biochemical and metabolic parameters in critical bleeding/massive transfusion; the optimal ratio of red blood cells to other blood components; the use of tranexamic acid; viscoelastic haemostatic assays; and cell salvage. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: The new guideline recommends MHPs be established as standard of care in all institutions managing patients with critical bleeding. In addition to routine physiological markers, the new guideline recommends temperature, biochemistry and coagulation profiles be measured early and frequently, providing parameters that define critical derangements. Ratio-based MHPs should include no fewer than four units of fresh frozen plasma and one adult unit of platelets for every eight units of red blood cells. In the setting of trauma and obstetric haemorrhage, administration of tranexamic acid within three hours of bleeding onset is recommended. The use of recombinant activated factor VII (rFVIIa) is not recommended. There was insufficient evidence to make recommendations on the use of viscoelastic haemostatic assays or cell salvage as part of MHPs.

Activin A level is associated with physical function in critically ill patients.

BACKGROUND: Activin A is a potent negative regulator of muscle mass elevated in critical illness. It is unclear whether muscle strength and physical function in critically ill humans are associated with elevated activin A levels. OBJECTIVES: The objective of this study was to investigate the relationship between serum activin A levels, muscle strength, and physical function at discharge from the intensive care unit (ICU) and hospital. METHODS: Thirty-six participants were recruited from two tertiary ICUs in Melbourne, Australia. Participants were included if they were mechanically ventilated for >48 h and expected to have a total ICU stay of >5 days. The primary outcome measure was the Six-Minute Walk Test distance at hospital discharge. Secondary outcome measures included handgrip strength, Medical Research Council Sum Score, Physical Function ICU Test Scored, Six-Minute Walk Test, and Timed Up and Go Test assessed throughout the hospital admission. Total serum activin A levels were measured daily in the ICU. RESULTS: High peak activin A was associated with worse Six-Minute Walk Test distance at hospital discharge (linear regression coefficient, 95% confidence interval, p-value: -91.3, -154.2 to -28.4, p = 0.007, respectively). Peak activin A concentration was not associated with the secondary outcome measures. CONCLUSIONS: Higher peak activin A may be associated with the functional decline of critically ill patients. Further research is indicated to examine its potential as a therapeutic target and a prospective predictor for muscle wasting in critical illness. STUDY REGISTRATION: ACTRN12615000047594.

Diabetes mellitus, glycaemic control, and severe COVID-19 in the Australian critical care setting: A nested cohort study.

BACKGROUND: Internationally, diabetes mellitus is recognised as a risk factor for severe COVID-19. The relationship between diabetes mellitus and severe COVID-19 has not been reported in the Australian population. OBJECTIVE: The objective of this study was to determine the prevalence of and outcomes for patients with diabetes admitted to Australian intensive care units (ICUs) with COVID-19. METHODS: This is a nested cohort study of four ICUs in Melbourne participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project. All adult patients admitted to the ICU with COVID-19 from 20 February 2020 to 27 February 2021 were included. Blood glucose and glycated haemoglobin (HbA1c) data were retrospectively collected. Diabetes was diagnosed from medical history or an HbA1c ≥6.5% (48 mmol/mol). Hospital mortality was assessed using logistic regression. RESULTS: There were 136 patients with median age 58 years [48-68] and median Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 14 [11-19]. Fifty-eight patients had diabetes (43%), 46 patients had stress-induced hyperglycaemia (34%), and 32 patients had normoglycaemia (23%). Patients with diabetes were older, were with higher APACHE II scores, had greater glycaemic variability than patients with normoglycaemia, and had longer hospital length of stay. Overall hospital mortality was 16% (22/136), including nine patients with diabetes, nine patients with stress-induced hyperglycaemia, and two patients with normoglycaemia. CONCLUSION: Diabetes is prevalent in patients admitted to Australian ICUs with severe COVID-19, highlighting the need for prevention strategies in this vulnerable population.

People in intensive care with COVID-19: demographic and clinical features during the first, second, and third pandemic waves in Australia.

OBJECTIVE: To compare the demographic and clinical features, management, and outcomes for patients admitted with COVID-19 to intensive care units (ICUs) during the first, second, and third waves of the pandemic in Australia. DESIGN, SETTING, AND PARTICIPANTS: People aged 16 years or more admitted with polymerase chain reaction-confirmed COVID-19 to the 78 Australian ICUs participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project during the first (27 February - 30 June 2020), second (1 July 2020 - 25 June 2021), and third COVID-19 waves (26 June - 1 November 2021). MAIN OUTCOME MEASURES: Primary outcome: in-hospital mortality. SECONDARY OUTCOMES: ICU mortality; ICU and hospital lengths of stay; supportive and disease-specific therapies. RESULTS: 2493 people (1535 men, 62%) were admitted to 59 ICUs: 214 during the first (9%), 296 during the second (12%), and 1983 during the third wave (80%). The median age was 64 (IQR, 54-72) years during the first wave, 58 (IQR, 49-68) years during the second, and 54 (IQR, 41-65) years during the third. The proportion without co-existing illnesses was largest during the third wave (41%; first wave, 32%; second wave, 29%). The proportion of ICU beds occupied by patients with COVID-19 was 2.8% (95% CI, 2.7-2.9%) during the first, 4.6% (95% CI, 4.3-5.1%) during the second, and 19.1% (95% CI, 17.9-20.2%) during the third wave. Non-invasive (42% v 15%) and prone ventilation strategies (63% v 15%) were used more frequently during the third wave than during the first two waves. Thirty patients (14%) died in hospital during the first wave, 35 (12%) during the second, and 281 (17%) during the third. After adjusting for age, illness severity, and other covariates, the risk of in-hospital mortality was similar for the first and second waves, but 9.60 (95% CI, 3.52-16.7) percentage points higher during the third than the first wave. CONCLUSION: The demographic characteristics of patients in intensive care with COVID-19 and the treatments they received during the third pandemic wave differed from those of the first two waves. Adjusted in-hospital mortality was highest during the third wave.

The Effect of a Liberal Approach to Glucose Control in Critically Ill Patients with Type 2 Diabetes: A Multicenter, Parallel-Group, Open-Label Randomized Clinical Trial.

Rationale: Blood glucose concentrations affect outcomes in critically ill patients, but the optimal target blood glucose range in those with type 2 diabetes is unknown. Objectives: To evaluate the effects of a "liberal" approach to targeted blood glucose range during ICU admission. Methods: This mutlicenter, parallel-group, open-label randomized clinical trial included 419 adult patients with type 2 diabetes expected to be in the ICU on at least three consecutive days. In the intervention group intravenous insulin was commenced at a blood glucose >252 mg/dl and titrated to a target range of 180-252 mg/dl. In the comparator group insulin was commenced at a blood glucose >180 mg/dl and titrated to a target range of 108-180 mg/dl. The primary outcome was incident hypoglycemia (<72 mg/dl). Secondary outcomes included glucose metrics and clinical outcomes. Measurements and Main Results: By Day 28, at least one episode of hypoglycemia occurred in 10 of 210 (5%) patients assigned the intervention and 38 of 209 (18%) patients assigned the comparator (incident rate ratio, 0.21 [95% confidence interval (CI), 0.09 to 0.49]; P < 0.001). Those assigned the intervention had greater blood glucose concentrations (daily mean, minimum, maximum), less glucose variability, and less relative hypoglycemia (P < 0.001 for all comparisons). By Day 90, 62 of 210 (29.5%) in the intervention and 52 of 209 (24.9%) in the comparator group had died (absolute difference, 4.6 percentage points [95% CI, -3.9% to 13.2%]; P = 0.29). Conclusions: A liberal approach to blood glucose targets reduced incident hypoglycemia but did not improve patient-centered outcomes. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN 12616001135404).

Age of red blood cells is not associated with in-hospital mortality in massively transfused patients.

BACKGROUND: Studies comparing mortality following massive transfusion (MT) with fresher versus longer-stored red blood cells (RBCs) have focused on trauma patients. The Australian and New Zealand Massive Transfusion Registry collects data on all adult MT cases (≥5 RBCs within 4 hours, any bleeding context, ≥18 years) at participating hospitals. METHODS: Years 2007 to 2018 data from 29 hospitals were analyzed to quantify the association between mortality and RBC storage time in adult MT cases. We ran three logistic regression models separately on each of seven bleeding contexts, with in-hospital mortality as the outcome and, in turn, (1) mean storage time (STmean) quartiles, (2) proportion of RBCs ≥30 days old (propOLD), and (3) scalar age of blood index as predictors. RESULTS: A total of 8,685 adult MT cases involving transfusion of 126,622 RBCs were analyzed with Australian and New Zealand data analyzed separately. Mean storage times for these cases were (by quartile in ascending order) as follows: Australia, 12.5 days (range, 3.1-15.5 days), 17.7 (15.5-19.9), 22.3 (19.9-24.9), and 29.8 (24.9-41.7); New Zealand, 11.3 days (3.6-13.7), 15.3 (13.7-16.8), 18.7 (16.8-20.7), and 24.5 (20.7-35.6). The odds ratios comparing in-hospital mortality for each quartile with that of the control first quartile (freshest blood), proportion of longer-stored (≥30 days) RBCs, and scalar age of blood index were not statistically significant across all bleeding contexts. CONCLUSION: We find no correlation between in-hospital mortality and storage time of transfused RBCs in a large cohort of adult MT patients representing all bleeding contexts. These results are consistent with those of recent large multicenter trials. LEVEL OF EVIDENCE: Epidemiologic, level III; Therapeutic, level IV.

Comparison of baseline characteristics, treatment and celinical outcomes of critically ill COVID-19 patients admitted in the first and second waves in Australia.

Objective: To report longitudinal differences in baseline characteristics, treatment, and outcomes in patients with coronavirus disease 2019 (COVID-19) admitted to intensive care units (ICUs) between the first and second waves of COVID-19 in Australia. Design, setting and participants: SPRINT-SARI Australia is a multicentre, inception cohort study enrolling adult patients with COVID-19 admitted to participating ICUs. The first wave of COVID-19 was from 27 February to 30 June 2020, and the second wave was from 1 July to 22 October 2020. Results: A total of 461 patients were recruited in 53 ICUs across Australia; a higher number were admitted to the ICU during the second wave compared with the first: 255 (55.3%) versus 206 (44.7%). Patients admitted to the ICU in the second wave were younger (58.0 v 64.0 years; P = 0.001) and less commonly male (68.9% v 60.0%; P = 0.045), although Acute Physiology and Chronic Health Evaluation (APACHE) II scores were similar (14 v 14; P = 0.998). High flow oxygen use (75.2% v 43.4%; P < 0.001) and non-invasive ventilation (16.5% v 7.1%; P = 0.002) were more common in the second wave, as was steroid use (95.0% v 30.3%; P < 0.001). ICU length of stay was shorter (6.0 v 8.4 days; P = 0.003). In-hospital mortality was similar (12.2% v 14.6%; P = 0.452), but observed mortality decreased over time and patients were more likely to be discharged alive earlier in their ICU admission (hazard ratio, 1.43; 95% CI, 1.13-1.79; P = 0.002). Conclusion: During the second wave of COVID-19 in Australia, ICU length of stay and observed mortality decreased over time. Multiple factors were associated with this, including changes in clinical management, the adoption of new evidence-based treatments, and changes in patient demographic characteristics but not illness severity.

Comparison of Critical Care Occupancy and Outcomes of Critically Ill Patients during the 2020 COVID-19 Winter Surge and 2009 H1N1 Influenza Pandemic in Australia.

Rationale: Both 2009 pandemic influenza A (H1N1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are transmitted by respiratory secretions and in severe cases result in a viral pneumonitis, requiring intensive care unit (ICU) admission. However, no studies have compared the clinical characteristics and outcomes of such patients. Objectives: To report and compare the demographic characteristics, treatments, use of critical care resources, and outcomes of patients admitted to an Australian ICU with H1N1 influenza during the winter of 2009, and SARS-CoV-2 during the winter of 2020. Methods: This was a multicenter project, using national data from previous and ongoing epidemiological studies concerning severe acute respiratory infections in Australia. All ICUs admitting patients with H1N1 or coronavirus disease (COVID-19) were included and contributed data. We compared clinical characteristics and outcomes of patients with H1N1 admitted to ICU in the winter of 2009 versus patients with COVID-19 admitted to ICU in the winter of 2020. The primary outcome was in-hospital mortality. Potential years of life lost (PYLL) were calculated according to sex-adjusted life expectancy in Australia. Results: Across the two epochs, 861 patients were admitted to ICUs; 236 (27.4%) with COVID-19 and 625 (72.6%) with H1N1 influenza. The number of ICU admissions and bed-days occupied were higher with 2009 H1N1 influenza. Patients with COVID-19 were older, more often male and overweight, and had lower Acute Physiology and Chronic Health Evaluation II scores at ICU admission. The highest age-specific incidence of ICU admission was among infants (0-1 yr of age) for H1N1, and among the elderly (≥65 yr) for COVID-19. Unadjusted in-hospital mortality was similar (11.5% in COVID-19 vs. 16.1% in H1N1; odds ratio, 0.68 [95% confidence interval (95% CI), 0.42-1.06]; P = 0.10). The PYLL was greater with H1N1 influenza than with COVID-19 at 154.1 (95% CI, 148.7-159.4) versus 13.6 (95% CI, 12.2-15.1) PYLL per million inhabitants. Conclusions: In comparison with 2009 H1N1 influenza, COVID-19 admissions overwinter in Australia resulted in fewer ICU admissions, and lower bed-day occupancy. Crude in-hospital mortality was similar, but because of demographic differences in affected patients, deaths due to 2009 H1N1 influenza led to an 11-fold increase in the number of PYLL in critically ill patients.

Outcomes for patients with COVID-19 admitted to Australian intensive care units during the first four months of the pandemic.

OBJECTIVES: To describe the characteristics and outcomes of patients with COVID-19 admitted to intensive care units (ICUs) during the initial months of the pandemic in Australia. DESIGN, SETTING: Prospective, observational cohort study in 77 ICUs across Australia. PARTICIPANTS: Patients admitted to participating ICUs with laboratory-confirmed COVID-19 during 27 February - 30 June 2020. MAIN OUTCOME MEASURES: ICU mortality and resource use (ICU length of stay, peak bed occupancy). RESULTS: The median age of the 204 patients with COVID-19 admitted to intensive care was 63.5 years (IQR, 53-72 years); 140 were men (69%). The most frequent comorbid conditions were obesity (40% of patients), diabetes (28%), hypertension treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (24%), and chronic cardiac disease (20%); 73 patients (36%) reported no comorbidity. The most frequent source of infection was overseas travel (114 patients, 56%). Median peak ICU bed occupancy was 14% (IQR, 9-16%). Invasive ventilation was provided for 119 patients (58%). Median length of ICU stay was greater for invasively ventilated patients than for non-ventilated patients (16 days; IQR, 9-28 days v 3 days; IQR, 2-5 days), as was ICU mortality (26 deaths, 22%; 95% CI, 15-31% v four deaths, 5%; 95% CI, 1-12%). Higher Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores on ICU day 1 (adjusted hazard ratio [aHR], 1.15; 95% CI, 1.09-1.21) and chronic cardiac disease (aHR, 3.38; 95% CI, 1.46-7.83) were each associated with higher ICU mortality. CONCLUSION: Until the end of June 2020, mortality among patients with COVID-19 who required invasive ventilation in Australian ICUs was lower and their ICU stay longer than reported overseas. Our findings highlight the importance of ensuring adequate local ICU capacity, particularly as the pandemic has not yet ended.

Cytokine and lipid metabolome effects of low-dose acetylsalicylic acid in critically ill patients with systemic inflammation: a pilot, feasibility, multicentre, randomised, placebo-controlled trial.

OBJECTIVE: The systemic inflammatory response syndrome (SIRS) is a dysregulated response that contributes to critical illness. Adjunctive acetylsalicylic acid (ASA) treatment may offer beneficial effects by increasing the synthesis of specialised proresolving mediators (a subset of polyunsaturated fatty acid-derived lipid mediators). DESIGN: Pilot, feasibility, multicentre, double-blind, randomised, placebo-controlled trial. SETTING: Four interdisciplinary intensive care units (ICUs) in Australia. PARTICIPANTS: Critically ill patients with SIRS. INTERVENTIONS: ASA 100 mg 12-hourly or placebo, administered within 24 hours of ICU admission and continued until ICU day 7, discharge or death, whichever came first. MAIN OUTCOME MEASURES: Interleukin-6 (IL-6) serum concentration at 48 hours after randomisation and, in a prespecified subgroup of patients, serum lipid mediator concentrations measured by mass spectrometry. RESULTS: The trial was discontinued in December 2017 due to slow recruitment and after the inclusion of 48 patients. Compared with placebo, ASA did not decrease IL-6 serum concentration at 48 hours. In the 32 patients with analysis of lipid mediators, low-dose ASA increased the concentration of 15-hydroxyeicosatetraenoic acid, a proresolving precursor of lipoxin A4, and reduced the concentration of the proinflammatory cytochrome P-dependent mediators 17-HETE (hydroxyeicosatetraenoic acid), 18-HETE and 20-HETE. In the eicosapentaenoic acid pathway, ASA significantly increased the concentration of the anti-inflammatory mediators 17,18-DiHETE (dihydroxyeicosatetraenoic acid) and 14,15-DiHETE. CONCLUSIONS: In ICU patients with SIRS, low-dose ASA did not significantly alter serum IL-6 concentrations, but it did affect plasma concentrations of certain lipid mediators. The ability to measure lipid mediators in clinical samples and to monitor the effect of ASA on their levels unlocks a potential area of biological investigation in critical care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN 12614001165673).

Study protocol and statistical analysis plan for the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial.

BACKGROUND: Contemporary glucose management of intensive care unit (ICU) patients with type 2 diabetes is based on trial data derived predominantly from patients without type 2 diabetes. This is despite the recognition that patients with type 2 diabetes may be relatively more tolerant of hyperglycaemia and more susceptible to hypoglycaemia. It is uncertain whether glucose targets should be more liberal in patients with type 2 diabetes. OBJECTIVE: To detail the protocol, analysis and reporting plans for a randomised clinical trial - the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial - which will evaluate the risks and benefits of targeting a higher blood glucose range in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A multicentre, parallel group, open label phase 2B randomised controlled clinical trial of 450 critically ill patients with type 2 diabetes. Patients will be randomised 1:1 to liberal blood glucose (target 10.0-14.0 mmol/L) or usual care (target 6.0-10.0 mmol/L). MAIN OUTCOME MEASURES: The primary endpoint is incident hypoglycaemia (< 4.0 mmol/L) during the study intervention. Secondary endpoints include biochemical and feasibility outcomes. RESULTS AND CONCLUSION: The study protocol and statistical analysis plan described will delineate conduct and analysis of the trial, such that analytical and reporting bias are minimised. TRIAL REGISTRATION: This trial has been registered on the Australian New Zealand Clinical Trials Registry (ACTRN No. 12616001135404) and has been endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group.

Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial.

Importance: It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. Objective: To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. Design, Setting, and Participants: Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. Interventions: Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. Main Outcomes and Measures: The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. Results: Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. Conclusions and Relevance: In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. Trial Registration: ClinicalTrials.gov Identifier: NCT03333278.

Opinions and practices of blood glucose control in critically ill patients with pre-existing type 2 diabetes in Australian and New Zealand intensive care units.

BACKGROUND: Approximately 9000 patients with type-2 diabetes mellitus (T2DM) are admitted to an intensive care unit (ICU) in Australia and New Zealand annually. For these patients, recent exploratory data suggest that targeting a more liberal blood glucose range during ICU admission may be safe and potentially beneficial. However, the current approach to blood glucose management of patients with T2DM in Australia and New Zealand ICUs is not well described, and there is uncertainty about clinician equipoise for trials of liberal glycaemic control in these patients. AIM: The aim is to describe self-reported blood glucose management in patients with T2DM by intensivists working in Australian and New Zealand ICUs and to establish whether equipoise exists for a trial of liberal versus standard glycaemic control in such patients. METHOD: An online questionnaire of Australia and New Zealand intensivists conducted in July-September 2016. RESULTS: Seventy-one intensivists responded. Forty-five (63%) used a basic nomogram to titrate insulin. Sixty-six (93%) reported that insulin was commenced at blood glucose concentrations >10 mmol/L and titrated to achieve a blood glucose concentration between 6.0 and 10.0 mmol/L. A majority of respondents (75%) indicated that there was insufficient evidence to define optimal blood glucose targets in patients with T2DM, and 59 (83%) were prepared to enrol such patients in a clinical trial to evaluate a more liberal approach. CONCLUSION: A majority of respondents were uncertain about the optimal blood glucose target range for patients with T2DM and would enrol such patients in a comparative trial of conventional versus liberal blood glucose control.

Effect of age of red cells for transfusion on patient outcomes: a systematic review and meta-analysis.

Longer storage duration of red blood cell (RBC) units prior to transfusion has been associated with worse outcomes in observational studies. We performed a systematic review, including recently published randomized trials, to determine if storage age of RBCs is associated with mortality, morbidity or adverse events in patients. Searches were performed up to 21st July 2017 in Medline (OvidSP), 20 July in EMBASE (OvidSP) and June 2017 in Cochrane Library. Eligible studies were randomized controlled trials comparing transfusion of fresher or freshest available with older or standard issue RBCs. Human volunteer and autologous RBC transfusion studies were excluded. Data were extracted from published reports independently by 2 authors and strength of evidence assessed according to GRADE criteria. The primary outcome was latest-reported mortality. Sixteen trials randomizing 31,359 patients were identified. Transfusion with fresher compared with older RBC was not associated with risk of death (relative risk [RR] 1.04, 95% CI 0.98-1.09; P=.20, I2=0%, high quality evidence), but was associated with higher risk of transfusion reactions (RR 1.35, 95% CI 1.04-1.76; P=.02; I2=0%; high quality evidence) and infection (RR 1.08, 95% CI 1.00-1.17; P=.05; I2=0%, moderate evidence). Trial sequential analysis showed required information size has now been reached to exclude a 10% relative risk increase or decrease in mortality. Transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection. The current evidence does not support a change from current usual transfusion practice.

Smoking cessation therapy in Australian and New Zealand intensive care units: a multicentre point prevalence study.

OBJECTIVE: To obtain an accurate estimate of smoking prevalence and smoking cessation support practices, including nicotine replacement therapy (NRT), in Australian and New Zealand intensive care units (ICUs). DESIGN, SETTING AND PARTICIPANTS: Cross-sectional, observational study using data obtained from adult ICUs participating in the Australian and New Zealand Intensive Care Society Clinical Trials Group Point Prevalence Program in 2016. MAIN OUTCOME MEASURES: Prevalence and intensity of current smoking, baseline characteristics of smokers in comparison with non-smokers and frequency of NRT use while admitted to the ICU. RESULTS: Smoking data were present for 551 of 671 adult ICU patients from 47 ICUs on 2 study days in 2016. Of these 551 patients, 112 were current smokers (20.3%; 95% CI, 17.0-23.9%). No significant differences in severity of illness or mortality were observed between smokers and non-smokers. NRT was prescribed to 30/112 smokers (26.8%), and in 28 of those 30 patients (93%) it was administered via nicotine patch alone. Routine prescribing of NRT was practised in 28/47 ICUs (60%), and 24/47 ICUs (51%) had formal protocols or guidelines in place related to supporting smoking cessation. CONCLUSIONS: The prevalence of smoking in Australian and New Zealand ICUs patients is high. Over half of participating ICUs reported the routine prescription of NRT despite uncertainty regarding the practice. Further research evaluating the safety and efficacy of NRT is required.

Erythropoietin to Reduce Mortality in Traumatic Brain Injury: A Post-hoc Dose-effect Analysis.

OBJECTIVE: We aimed to assess whether the dosing regimen of erythropoietin shows a relationship to mortality in critically ill patients with traumatic brain injury (TBI). BACKGROUND: Erythropoietin may decrease mortality in patients with TBI; however, the optimal dosing regimen remains uncertain. METHODS: We conducted a post-hoc analysis of a multicenter, randomized trial of weekly erythropoietin versus placebo in patients with moderate and severe TBI admitted to intensive care. We assessed whether the cumulative dosage of erythropoietin was differentially associated with all-cause patient mortality evaluated at 6 months after injury. RESULTS: There was a nonlinear relationship between dose and mortality (P = 0.008) that remained after adjustment for site and severity of illness (P = 0.01). Six-month mortality was lower in randomized patients who received 1 [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.33-1.01; P = 0.06] or 2 doses of erythropoietin (HR 0.31, 95% CI 0.12-0.80; P = 0.02) compared with those who received no doses. No benefit was seen with 3 doses (HR 1.55, 95% CI 0.66-3.62; P = 0.33). There was no differential effect of dose on functional neurological outcomes. Results across subgroups and secondary intention to treat analyses were consistent with primary findings. CONCLUSIONS: This post-hoc, hypothesis-generating analysis found potential reductions in mortality following 1 or 2 weekly doses of 40,000 IU of erythropoietin in intensive care unit patients with moderate or severe TBI, but not with 3 doses. These findings will inform the design of future trials of erythropoietin in critically ill patients with TBI and trauma.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.