Twenty percent human albumin solution fluid bolus administration therapy in patients after cardiac surgery-II: a multicentre randomised controlled trial.

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.

Early Net Ultrafiltration during Continuous Renal Replacement Therapy: Impact of Admission Diagnosis and Association with Mortality.

INTRODUCTION: Continuous renal replacement therapy (CRRT) is common in the intensive care unit (ICU) but a high net ultrafiltration rate (UFNET) calculated with daily data may increase mortality. We aimed to study early UFNET practice using minute-by-minute CRRT machine recordings and to assess its association with admission diagnosis and mortality. METHODS: We studied CRRT treatments in three adult ICUs over 7 years. We calculated early UFNET rates minute-by-minute and categorized UFNET into tertiles of mean UFNET in the first 72 h and admission diagnosis. We applied Cox-proportional hazards modelling with censoring of patients who died within 72 h. RESULTS: We studied 1,218 patients, 154,712 h, and 9,282,729 min of CRRT (5,702 circuits). Mean early UFNET was 1.52 (1.46-1.57) mL/kg/h. Early UFNET tertiles were similar to, but somewhat higher than, previously reported values at 0.00-1.20 mL/kg/h, 1.21-1.93 mL/kg/h, and >1.93 mL/kg/h. UFNET values were similar whether evaluated at 24 or 72 h or for the entire duration of CRRT. There was, however, significant variation in UFNET practice by admission diagnosis: higher in respiratory diseases (pneumonia p = 0.01, other p < 0.0001) and cardiovascular disease (p = 0.005) but lower in cardiothoracic surgery (p = 0.04), renal (p = 0.0003) and toxicology-associated diagnoses (p = 0.01). Higher UFNET was associated with an increased hazard of death, HR 1.24 (1.13-1.37), independent of admission diagnosis, weight, age, sex, presence of end-stage kidney disease, and severity of illness. CONCLUSION: Early UFNET practice varies significantly by admission diagnosis. Higher early UFNET is independently associated with mortality. Impacts of UFNET on mortality may vary by admission diagnosis. Further work is required to elucidate the nature and mechanisms responsible for this association.

Study protocol for TARGET protein: The effect of augmented administration of enteral protein to critically ill adults on clinical outcomes: A cluster randomised, cross-sectional, double cross-over, clinical trial.

Background: It is unknown whether increasing dietary protein to 1.2-2.0 g/kg/day as recommended in international guidelines compared to current practice improves outcomes in intensive care unit (ICU) patients. The TARGET Protein trial will evaluate this. Objective: To describe the study protocol for the TARGET Protein trial. Design setting and participants: TARGET Protein is a cluster randomised, cross-sectional, double cross-over, pragmatic clinical trial undertaken in eight ICUs in Australia and New Zealand. Each ICU will be randomised to use one of two trial enteral formulae for three months before crossing over to the other formula, which is then repeated, with enrolment continuing at each ICU for 12 months. All patients aged ≥16 years in their index ICU admission commencing enteral nutrition will be eligible for inclusion. Eligible patients will receive the trial enteral formula to which their ICU is allocated. The two trial enteral formulae are isocaloric with a difference in protein dose: intervention 100g/1000 ml and comparator 63g/1000 ml. Staggered recruitment commenced in May 2022. Main outcomes measures: The primary outcome is days free of the index hospital and alive at day 90. Secondary outcomes include days free of the index hospital at day 90 in survivors, alive at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. Conclusion: TARGET Protein aims to determine whether augmented enteral protein delivery reduces days free of the index hospital and alive at day 90. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001484831).

A pilot study of agreement between noninvasive thermometers and the core temperature of postoperative cardiothoracic surgical patients.

OBJECTIVE: Reliable and accurate temperature assessment is fundamental for clinical monitoring; noninvasive thermometers of various designs are widely used in intensive care units, sometimes without a specific assessment of their suitability and interchangeability. This study evaluated agreement of four noninvasive thermometers with a pulmonary artery catheter temperature. METHODS: This prospective method comparison study was conducted in an Australian adult intensive care unit. One hundred postoperative adult cardiothoracic surgery patients who had a pulmonary artery catheter (Edwards Lifescience) in situ were identified. The temperature reading from the pulmonary artery catheter was compared to contemporaneous measurements returned by four different thermometers-temporal Artery (TA, Technimed), Per Axilla (Axilla, Welch Allyn), Tympanic (Tymp, Covidien), and the NexTemp® (NEXT, Medical Indicators [used per axilla]). The time required to obtain each noninvasive temperature measurement was recorded. RESULTS: Agreements between each noninvasive temperature and the pulmonary artery catheter standard were assessed using summary statistics and the Bland-Altman method comparison approach. A clinically acceptable maximum difference from the standard was defined as ±0.5 °C. Temperature agreement with the pulmonary artery standard (mean difference °C [95% limits of agreement °C]) was greatest for Tymp (-0.20 [-0.92 to 0.52]), intermediate for AXILLA (-0.37 [-1.3 to 0.59]) and NEXT (-0.71 [-1.7 to 0.27]), and least for TA (-0.60 [-2.0 to 0.81]). The proportion of measurements within ±0.5 °C of the standard were TYMP (81%), AXILLA (63%), TA (45%), and NEXT (30%). The time to obtain measurements varied, with the Tymp and TA estimates immediate, the AXILLA a mean of 40 s (standard deviation = 11 s), while NEXT results were at the manufacturer-recommended 3-min point. CONCLUSIONS: Tympanic thermometers showed closest agreement with the pulmonary artery standard. Deviations by more than 0.5 °C from that standard were relatively common with all noninvasive devices.

Common microbial isolates in an adult intensive care unit before and after its relocation and expansion.

Objective: To describe the prevalence of common and clinically relevant microbial isolates before and after the migration of a 24-bed, open plan, adult intensive care unit (ICU) to a new extended design of 32 single rooms, supporting an expanded clinical oncology casemix while continuing all existing clinical services. Design: Retrospective, observational descriptive analysis covering the period 5 May 2014 to 4 May 2018 - the 2 years before and after the ICU relocation on 5 May 2016. Setting: A university-associated, tertiary teaching hospital and state trauma centre in Victoria, Australia. Patients: Adult ICU patients. Main outcome measures: Bacterial isolate frequency and incident rate ratios (IRRs) during the study period. Results: When compared with the old ICU, the incidence rates per 1000 occupied bed-days in the new ICU were lower for bacterial isolates overall (IRR, 0.88; 95% CI, 0.83-0.93), for coagulase-negative staphylococci (IRR, 0.64; 95% CI, 0.55-0.75) and for vancomycin-resistant enterococci (IRR, 0.50; 95% CI, 0.32-0.80). The incidence rates per 1000 occupied bed-days between ICU locations were unchanged for Staphylococcus aureus (IRR, 1.1; 95% CI, 0.91-1.3), extended-spectrum beta-lactamase-producing organisms (IRR, 1.4; 95% CI, 0.78-2.6) and carbapenemase-producing Enterobacterales (IRR, 0.85; 95% CI, 0.11-6.4). Conclusion: Within the limits of a before-after design and clinically directed sampling, relocation to a new ICU with single rooms and a growing oncological patient casemix was accompanied by no overall change in the apparent prevalence of the nosocomial pathogens S. aureus, extended-spectrum beta-lactamase-producing organisms or carbapenemase-producing Enterobacterales. These finding suggest that advanced physical infrastructure, including patient accommodation in single rooms, may play a role in overall safe delivery of critical care.

Study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-ll (HAS FLAIR-II) trial.

Background: Fluid bolus therapy with 20% albumin may shorten the duration of vasopressor therapy in patients after cardiac surgery. Objective: To describe the study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial. Design, setting, participants and intervention: HAS FLAIR-II is a phase 2b, multicentre, parallel group, openlabel, randomised controlled trial that will be conducted at six Australian intensive care units. Patients requiring fluid bolus therapy after cardiac surgery will be randomly assigned in a 1:1 ratio to the intervention of fluid bolus therapy with 20% albumin or a comparator of fluid bolus therapy with a crystalloid solution. Main outcome measures: The primary outcome measure is the cumulative duration of vasopressor therapy. Secondary outcomes include vasopressor use, service utilisation, and mortality. All analyses will be conducted on an intention-to-treat basis. Results and conclusion: The study protocol and statistical analysis plan will guide the conduct and analysis of the HAS FLAIR-II trial, such that analytical and reporting biases are minimised. Trial registration: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN No. 12620000137998).

Assessment of muscle mass using ultrasound with minimal versus maximal pressure compared with computed tomography in critically ill adult patients.

BACKGROUND: Preserved skeletal muscle mass identified using computed tomography (CT) predicts improved outcomes from critical illness; however, CT imaging have few limitations such that it involves a radiation dose and transferring patients out of the intensive care unit. This study aimed to assess in critically ill patients the relationship between muscle mass estimates obtained using minimally invasive ultrasound techniques with both minimal and maximal pressure compared with CT images at the third lumber vertebra level. METHODS: All patients were treated in a single Australian intensive care unit. Eligible patients had paired assessments, within a 72-h window, of muscle mass by ultrasound (quadriceps muscle layer thickness in centimetres, with maximal and minimal pressure) and CT axial cross-sectional area (cm2). Data are presented as mean (standard deviation), median (interquartile range), and frequencies [n (%)]. RESULTS: Thirty-five patients [mean (standard deviation) age = 55 (16) years, median (interquartile range) body mass index = 27 (25-32) kg/m2, and 26 (74%) men] contributed 41 paired measurements. Quadriceps muscle thickness measured using the maximal pressure technique was a strong independent predictor of lumbar muscle cross-sectional area. Within a multivariate mixed linear regression model and adjusting for sex, age, and body mass index, for every 1 cm increase in quadriceps muscle layer thickness, the lumbar muscle cross-sectional area increased by 35 cm2 (95% confidence interval = 11-59 cm2). Similar univariate associations were observed using minimal pressure; however, as per multivariate analysis, there was no strength in this relationship [8 cm2 (95% confidence interval = -5 to 22 cm2)]. CONCLUSION: Ultrasound assessment of the quadriceps muscle using maximal pressure reasonably predicts the skeletal muscle at the third lumbar vertebra level of critically ill patients. However, there is substantial uncertainty within these regression estimates, and this may reduce the current utility of this technique as a minimally invasive surrogate for CT assessment of skeletal muscle mass.

Successful implementation of a short message service (SMS) as intensive care to family communication tool.

BACKGROUND: Regularly informing families of the condition of their relative can be difficult. Text messaging via mobile telephones may achieve such communication effectively. OBJECTIVE: To test the hypotheses that we could efficiently deliver real-time short message service (SMS) updates to families and that these SMS updates would be accepted and welcomed. DESIGN: Prospective observational study. PARTICIPANTS: Cohort of 91 cardiac surgery patients and 156 family participants. INTERVENTION: At five distinct landmark events, we sent pre-written SMS updates to designated mobile numbers. We used the sendQuick (TalariaX) mobile messaging platform via the internet in our hospital. To alleviate privacy concerns, all patients were referred to as "your loved one". The message confirmed the passing of each landmark and directed the families towards the next one. After the patient's discharge, families were followed up with a telephone call and a five-point Likert scale questionnaire. RESULTS: We successfully sent all five SMS messages for 72 patients to 114 participants (73%). Among 114 participants, all agreed the SMS service was reassuring and that the SMS messages were easy to follow and kept participants informed. Almost all felt the SMS service did not increase anxiety and all disagreed with the SMS service being intrusive. All surveyed participants stated that they would recommend the service to other families. CONCLUSION: We successfully instituted real-time SMS updates. All surveyed participants agreed that these messages were reassuring, informative and easy to follow and that they would recommend the SMS service to other families.

The effect of a low carbohydrate formula on glycaemia in critically ill enterally-fed adult patients with hyperglycaemia: A blinded randomised feasibility trial.

BACKGROUND: Enteral nutrition is a source of carbohydrate that may exacerbate hyperglycaemia. Its treatment, insulin, potentially exacerbates glycaemic variability. METHODS: This was a prospective, parallel group, blinded, randomised feasibility trial. Patients were eligible if 18 years or over when admitted to the intensive care unit and receiving enteral nutrition (EN) exclusively with two consecutive blood glucose > 10 mmol/L. A standardized glucose management protocol determined administration of insulin. Key outcome measures were insulin administered and glycaemic variability (coefficient of variation) over the first 48 h. RESULTS: 41 patients were randomized to either standard EN (14.1 g/100 mL carbohydrate; n = 20) or intervention EN (7.4 g/100 mL carbohydrate; n = 21). Overall 59% were male, mean (±SD) age of 62.3 years ± 10.4, APACHE II score of 16.5 ± 7.8 and a median (IQR) Body Mass Index 29.0 kg/m2 (25.2-35.5). Most patients (73%) were mechanically ventilated. Approximately half (51%) were identified as having diabetes prior to ICU admission. Patients in the intervention arm received less insulin over the 48 h study period than those in the control group (mean insulin units over study period (95% CI) 45.0 (24.4-68.7) vs. 107 (56.1-157.9) units; p = 0.02) and had lower mean glycaemic variability (12.6 vs. 15.9%, p = 0.01). There was a small difference in the mean percentage of energy requirements met (intervention: 72.9 vs. control: 79.1%; p = 0.4) or protein delivered (78.2 vs. 85.4%; p = 0.3). CONCLUSIONS: A low carbohydrate formula was associated with reduced insulin use and glycaemic variability in enterally-fed critically ill patients with hyperglycaemia. Further large trials are required to determine the impact of this formula on clinical outcomes. Registered under Australian and New Zealand Clinical Trials Registry, ANZCTR number: 12614000166673.

20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients After Cardiac Surgery (the HAS FLAIR Study).

OBJECTIVE: To compare the effects of fluid bolus therapy using 20% albumin versus crystalloid on fluid balance, hemodynamic parameters, and intensive care unit (ICU) treatment effects in post-cardiac surgery patients. DESIGN: Sequential period open-label pilot study. SETTING: University teaching hospital. PARTICIPANTS: One hundred adult cardiac surgery patients who were prescribed fluid bolus therapy to correct hypotension or perceived hypovolemia or to optimize cardiac index during the first 24 hours in the ICU. INTERVENTIONS: The first 50 patients were treated with crystalloid fluid bolus therapy in the first period (control), and 50 patients with up to 2 treatments of 100 mL of 20% albumin fluid bolus therapy in the second period (intervention), followed by crystalloid therapy if needed. MEASUREMENTS AND MAIN RESULTS: Demographic characteristics were similar at baseline. The intervention was associated with a less positive median fluid balance in the first 24 hours (albumin: 1,100 [650-1,960] v crystalloid: 1,970 [1,430-2,550] p = 0.001), fewer episodes of fluid bolus therapy (3 [2-5] v 5 [4-7]; p < 0.0001) and a lesser volume of fluid bolus therapy (700 [200-1,450] v 1,500 mL/24 h [1,100-2,250]; p < 0.0001). The intervention also was associated with a decreased median overall dose of norepinephrine in the first 24 hours of ICU stay (19 [0-52] v 47 µg/kg/24 hours [0-134]; p = 0.025) and shorter median time to cessation of norepinephrine (17 [5-28] v 28 hours [20-48]; p = 0.002). CONCLUSION: Post-cardiac surgery fluid bolus therapy with 20% albumin when compared with crystalloid fluid resulted in less positive fluid balance as well as several hemodynamic and potential ICU treatment advantages.

Erythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial.

BACKGROUND: Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO). METHODS: Pre-planned analysis of patients included in the EPO-TBI (ClinicalTrials.gov NCT00987454) trial who were randomized to weekly EPO (40 000 units) or placebo (0.9% sodium chloride) subcutaneously up to three doses or until intensive care unit (ICU) discharge. Creatinine levels and urinary output (up to 7 days) were categorized according to the Kidney Disease Improving Global Outcome (KDIGO) classification. Severity of TBI was categorized with the International Mission for Prognosis and Analysis of Clinical Trials in TBI. RESULTS: Of 3348 screened patients, 606 were randomized and 603 were analyzed. Of these, 82 (14%) patients developed AKI according to KDIGO (60 [10%] with KDIGO 1, 11 [2%] patients with KDIGO 2, and 11 [2%] patients with KDIGO 3). Male gender (hazard ratio [HR] 4.0 95% confidence interval [CI] 1.4-11.2, P = 0.008) and severity of TBI (HR 1.3 95% CI 1.1-1.4, P < 0.001 for each 10% increase in risk of poor 6 month outcome) predicted time to AKI. KDIGO stage 1 (HR 8.8 95% CI 4.5-17, P < 0.001), KDIGO stage 2 (HR 13.2 95% CI 3.9-45.2, P < 0.001) and KDIGO stage 3 (HR 11.7 95% CI 3.5-39.7, P < 0.005) predicted time to mortality. EPO did not influence time to AKI (HR 1.08 95% CI 0.7-1.67, P = 0.73) or creatinine levels during ICU stay (P = 0.09). CONCLUSIONS: Acute kidney injury is more common in male patients and those with severe compared to moderate TBI and appears associated with worse outcome. EPO does not prevent AKI after TBI.

Early repeat computed tomographic imaging in transferred trauma and neurosurgical patients: Incidence, indications and impact.

INTRODUCTION: Computed tomographic (CT) imaging is widely available in Australian rural and remote hospitals and is often performed prior to patient transfer to definitive tertiary hospital care. We hypothesised that critically ill trauma and neurosurgical patients might have CT scans repeated after interhospital transfer and that the utility of this practice might be low in relation to the additional financial cost and radiation exposure. METHODS: We conducted a retrospective review of clinical records to determine the proportion of trauma and neurosurgical patients transferred to our tertiary ICU from other hospitals between 1 June 2013 and 30 June 2014 who underwent a repeat CT scan. The additional effective radiation dose was estimated using the dose length product method and the Australian Medicare Benefits Schedule was used to estimate the associated cost. RESULTS: Of the 247 patients transferred for trauma and neurosurgical indications, many (144; 58%) had undergone CT imaging at the referring hospital. Repeat scans were performed in 60 (42%) already imaged patients (24% of all transferred patients), most frequently for changed clinical indications. While in 11 (18%) of those 60 already imaged patients the repeat scan led to an identifiable change in management, for another 13 (22%) patients the repeat scans appeared to be potentially avoidable. The median cost of a repeat scan was AU$250 and the median additional effective radiation dose was 2.74 mSv per patient. CONCLUSION: Repeat CT scans for patients already imaged prior to transfer were relatively common, occurring mostly for apparently valid clinical reasons. However, the additional radiation risk and financial cost of these repeat scans appeared on retrospective audit to be potentially avoidable in approximately one in five cases.

Cause and Timing of Death and Subgroup Differential Effects of Erythropoietin in the EPO-TBI Study.

The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) (p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization.

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.

Erythropoietin in patients with traumatic brain injury and extracranial injury-A post hoc analysis of the erythropoietin traumatic brain injury trial.

BACKGROUND: Erythropoietin (EPO) may reduce mortality after traumatic brain injury (TBI). Secondary brain injury is exacerbated by multiple trauma, and possibly modifiable by EPO. We hypothesized that EPO decreases mortality more in TBI patients with multiple trauma, than in patients with TBI alone. METHODS: A post hoc analysis of the EPO-TBI randomized controlled trial conducted in 2009 to 2014. To evaluate the impact of injuries outside the brain, we calculated an extracranial Injury Severity Score (ISS) that included the same components of the ISS, excluding head and face components. We defined multiple trauma as two injured body regions with an Abbreviated Injury Scale (AIS) score of 3 or higher. Cox regression analyses, allowing for potential differential responses per the presence or absence of extracranial injury defined by these injury scores, were used to assess the effect of EPO on time to mortality. RESULTS: Of 603 included patients, the median extracranial ISS was 6 (interquartile range, 1-13) and 258 (43%) had an AIS score of 3 or higher in at least two body regions. On Cox regression, EPO was associated with decreased mortality in patients with greater extracranial ISS (interaction p = 0.048) and weakly associated with differential mortality with multiple trauma (AIS score > 3 or in two regions, interaction p = 0.17). At 6 months in patients with extracranial ISS higher than 6, 10 (6.8%) of 147 EPO-treated patients compared with 26 (17%) of 154 placebo-treated patients died (risk reduction, 10%; 95% confidence interval, 2.9-17%; p = 0.007). CONCLUSION: In this post hoc analysis, EPO administration was associated with a potential differential improvement in 6-month mortality in TBI patients with more severe extracranial injury. These findings need confirmation in future clinical and experimental studies. LEVEL OF EVIDENCE: Therapeutic study, level III.

Erythropoiesis-stimulating Agents in Critically Ill Trauma Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a meta-analysis of all relevant randomized controlled trials assessing the effect of erythropoiesis-stimulating agents (ESAs) in critically ill trauma patients. BACKGROUND: ESAs have effects beyond erythropoiesis. The administration of the ESA epoetin alfa to critically ill trauma patients has been associated with a reduction in mortality. METHODS: We performed a systematic review and meta-analysis with trial sequential analysis. We searched Medline, Medline in Process, and other nonindexed citations, EMBASE, and the Cochrane Database from inception until September 9, 2015, for randomized controlled trials comparing ESAs to placebo (or no ESA). RESULTS: We identified 9 eligible studies that randomly assigned 2607 critically ill patients after trauma to an ESA or placebo (or no ESA). Compared with placebo (or no ESA), ESA therapy was associated with a substantial reduction in mortality [risk ratio (RR) 0.63, 95% confidence interval (CI) 0.49-0.79, P = 0.0001, I = 0%). In patients with traumatic brain injury, ESA therapy did not increase the number of patients surviving with moderate disability or good recovery (RR 1.00, 95% CI 0.88-1.15, P = 0.95, I = 0%). With the dosing regimens employed in the included studies, ESA therapy did not increase the risk of lower limb proximal deep venous thrombosis (RR 0.97, 95% CI 0.72-1.29, P = 0.78, I = 0%). CONCLUSIONS: The administration of ESAs to critically ill trauma patients is associated with a significant improvement in mortality without an increase in the rate of lower limb proximal deep venous thrombosis. Given the worldwide public health significance of these findings research to validate or refute them is required.

Sodium reduction during cardiopulmonary bypass: Plasma-Lyte 148 versus trial fluid as pump primes.

OBJECTIVES: We compared effects on plasma sodium concentrations plus calculated plasma tonicity of two "balanced" crystalloid solutions used as 2 L pump primes during cardiopulmonary bypass (CPB): Plasma-Lyte 148 (sodium concentration, 140 mmol/L; potassium concentration, 5 mmol/L) versus a bicarbonate-balanced fluid (sodium concentration, 140 mmol/L; potassium concentration, 0 mmol/L). DESIGN, SETTING AND PARTICIPANTS: We analysed pooled data from two prospective interventional studies performed in university-affiliated hospitals, from 50 patients undergoing elective cardiac surgery. INTERVENTIONS: Participants were allocated equally to Plasma-Lyte 148 or bicarbonate-balanced fluid, with plasma electrolytes measured by direct ion selective electrodes immediately before bypass (pre-CPB), within 3 minutes of commencement (T2), and before bypass cessation (end-CPB). RESULTS: Plasma sodium fell at T2 in 46 patients (92%) (P<0.0005). With Plasma-Lyte 148, the mean sodium decreased by 3.0 mmol/L (SD, 1.7 mmol/L), and with bicarbonate-balanced fluid it decreased by 2.2 mmol/L (SD, 1.1 mmol/L) (P=0.002). The mean tonicity fell by >5 mOsm/kg for both groups (P<0.0005). At end-CPB, the mean sodium for both groups remained reduced by >2 mmol/L (P<0.0005). In the group receiving Plasma-Lyte 148, 52% of patients were hyponatraemic (sodium<135 mmol/L) at T2 and end-CPB. CONCLUSIONS: Sodium reductions were common with both priming solutions, but more severe with Plasma-Lyte 148. Crystalloid priming solutions require sodium concentrations>140mmol/L to ensure normonatraemia throughout CPB.

Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution.

INTRODUCTION: As even small concentrations of acetate in the plasma result in pro-inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio-pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB. METHODS: Thirty adult patients were systematically allocated 1:1 to CPB prime with either bicarbonate-balanced fluid (24 mmol/L bicarbonate) or Plasma-Lyte 148. Arterial blood acetate, gluconate and interleukin-6 (IL-6) levels were measured immediately before CPB (T1), three minutes after CPB commencement (T2), immediately before CPB separation (T3), and four hours post separation (T4). RESULTS: Acetate concentrations (normal 0.04 to 0.07 mmol/L) became markedly elevated at T2, where the Plasma-Lyte group (median 3.69, range (2.46 to 8.55)) exceeded the bicarbonate group (0.16 (0.02 to 3.49), P < 0.0005). At T3, levels had declined but the differential pattern remained apparent (Plasma-Lyte 0.35 (0.00 to 1.84) versus bicarbonate 0.17 (0.00 to 0.81)). Normal circulating acetate concentrations were not restored until T4. Similar gluconate concentration profiles and inter-group differences were seen, with a slower T3 decay. IL-6 increased across CPB, peaking at T4, with no clear difference between groups. CONCLUSIONS: Use of acetate containing prime solutions result in supraphysiological plasma concentrations of acetate. The use of acetate-free prime fluid in CPB significantly reduced but did not eliminate large acetate surges in cardiac surgical patients. Complete elimination of acetate surges would require the use of acetate free bolus fluids and cardioplegia solutions. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000267055.

Antibiotic prophylaxis for cardiac surgery in Australia.

OBJECTIVE: To evaluate national practice for antibiotic prophylaxis in cardiac surgery with respect to the use of protocols, agent selection and duration of administration. DESIGN, SETTING AND PARTICIPANTS: Two point-prevalence surveys of intensive care units in 24 public and 27 private hospitals performing cardiac surgery in Australia, conducted in 2004 and 2008, using a structured telephone questionnaire of the attending senior intensive care clinician in each unit. MAIN OUTCOME MEASURES: Existence of a protocol in the unit for antibiotic prophylaxis, specific antibiotic agents used and their duration of administration. RESULTS: Between 2004 and 2008, reported protocol use increased from 58% to 80% (P = 0.02), while concordance with version 13 of the Australian Therapeutic guidelines: antibiotic for both choice of agent and timing (duration of administration) remained around 10%. Use of multiple agents was common, as was continued antibiotic administration after completion of surgery. Over 4 years, the proportion of cardiac surgical units reporting vancomycin administration for routine valve surgery prophylaxis doubled to 62% (P < 0.001). CONCLUSION: Despite an increase in reported protocol use for antibiotic prophylaxis in cardiac surgery, concordance with national antibiotic guidelines remained low, with duration of antibiotic administration deviating most from recommendations. Prophylactic vancomycin use appears to have increased substantially in recent years. Clinical implementation of recommended perioperative cardiac surgical antibiotic prophylaxis may not occur until supported by evidence from either a large prospective randomised study or standardised national surveillance of cardiac surgical site infection rates.