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Background: Ferritin, an acute phase reactant, and the ferritin index (FI = observed ferritin level/upper limit of normal level for age and sex) may be prognostic biomarkers in septic shock and cardiac surgery patients. Objective: The purpose of this exploratory study is to assess the outcome associations of ferritin and FI levels in septic shock compared to post–cardiac surgery patients. Design: This was a prospective, double-centre, observational study. Setting: The study setting involved two adult intensive care units (ICUs) in Victoria, Australia. Participants: Sixty-one septic shock and 30 post–cardiac surgery patients participated in this study. Main outcome measures: We measured ferritin and FI on ICU admission (T1) and 24 h later (T2) to assess its correlation with mortality, illness severity, and hospital length of stay (LOS). Results: The baseline characteristics of patients in the septic shock group and cardiac surgery group were similar apart from illness severity scores (APACHE III and modified SOFA score). Septic shock patients had more physiological derangements as well as greater use and higher doses of norepinephrine at both T1 and T2. Septic shock patients had significantly higher median ferritin levels (372 μg/L versus 198 μg/L; p < 0.001 at T1, 457 μg/L versus 264 μg/L; p = 0.001 at T2) than post–cardiac surgery patients. Ferritin levels, however, did not have a linear correlation with illness severity or hospital mortality. Instead, there was an association between high ferritin levels at T2 and longer ICU (p = 0.017) and hospital LOS (p = 0.013). Females with septic shock had significantly higher FI (p < 0.001 at T1, p = 0.004 at T2) than males. Conclusion: In septic shock patients, ferritin levels and FI were twice the level compared to post-cardiac surgery patients. Both had no association with mortality, but levels above the median at 24 h were associated with longer ICU and hospital LOS.

Objective: The accuracy of different non-invasive body temperature measurement methods in intensive care unit (ICU) patients is uncertain. We aimed to study the accuracy of three commonly used methods. Design: Prospective observational study. Setting: ICUs of two tertiary Australian hospitals. Participants: Critically ill patients admitted to the ICU. Interventions: Invasive (intravascular and intra-urinary bladder catheter) and non-invasive (axillary chemical dot, tympanic infrared, and temporal scanner) body temperature measurements were taken at study inclusion and every 4 hours for the following 72 hours. Main outcome measures: Accuracy of non-invasive body temperature measurement methods was assessed by the Bland–Altman approach, accounting for repeated measurements and significant explanatory variables that were identified by regression analysis. Clinical adequacy was set at limits of agreement (LoA) of 1C compared with core temperature. Results: We studied 50 consecutive critically ill patients who were mainly admitted to the ICU after cardiac surgery. From over 375 observations, invasive core temperature (mostly pulmonary artery catheter) ranged from 33.9C to 39C. On average, the LoA between invasive and non-invasive measurements methods were about 3C. The temporal scanner showed the worst performance in estimating core temperature (bias, 0.66C; LoA, 1.23C, +2.55C), followed by tympanic infrared (bias, 0.44C; LoA, 1.73C, +2.61C) and axillary chemical dot methods (bias, 0.32°C; LoA, 1.64C, +2.28C). No methods achieved clinical adequacy even accounting for significant explanatory variables. Conclusions: The axillary chemical dot, tympanic infrared and temporal scanner methods are inaccurate measures of core temperature in ICU patients. These non-invasive methods appeared unreliable for use in ICU patients.

OBJECTIVE: To evaluate the haemodynamic effects of rapid fluid bolus therapy (FBT) (500 mL of 4% albumin over several minutes) versus combined FBT (rapid 200 mL FBT followed by a 300 mL infusion over 30 minutes). DESIGN: Single centre, prospective, before-and-after trial. SETTING: A tertiary intensive care unit in Australia. PARTICIPANTS: Fifty mechanically ventilated post-cardiac surgery patients. INTERVENTIONS: Rapid 4% albumin FBT versus combined FBT. MAIN OUTCOME MEASURES: We recorded haemodynamic parameters from before FBT to 30 minutes after FBT. A mean arterial pressure (MAP) response was defined by a MAP increase > 10%, and a cardiac index (CI) response was defined by a CI increase > 15%. RESULTS: Immediately after rapid FBT versus combined FBT, there was a CI response in 13 patients (52%) compared with five patients (20%) respectively (P = 0.038), and a MAP response in 11 patients (44%) in each group. However, from FBT administration to 30 minutes, there was a time and group interaction such that MAP was higher in the rapid FBT group (P = 0.003), as was the case for central venous pressure (P = 0.002) and mean pulmonary artery pressure (P < 0.001). Body temperature fell immediately and was lower with rapid FBT but became warmer than with combined FBT later (P < 0.001). At 30 minutes, a MAP response was seen in ten patients (40%) compared with nine patients (36%) (P < 0.99) and a CI response was present in eight patients (32%) compared with 11 patients (44%) (P = 0.56) in the rapid versus combined FBT groups respectively. CONCLUSION: Rapid FBT was superior to combined FBT in terms of mean MAP levels and immediate CI response. However, the number of MAP responders or CI responders was similar at 30 minutes.

Background In patients treated with continuous renal replacement therapy (CRRT), early net ultrafiltration (NUF) rates may be associated with differential outcomes. We tested whether higher early NUF rates are associated with increased mortality in CRRT patients. Methods We performed a retrospective, observational study of all patients treated with CRRT within 14 days of intensive care unit admission. We defined the early (first 48 h) NUF rate as the volume of fluid removed per hour adjusted for patient body weight and analysed as a categorical variable (>1.75, 1.01–1.75 and Results We studied 347 patients {median age 64 [interquartile range (IQR) 53–71] years and Acute Physiology and Chronic Health Evaluation III score 73 [IQR 54–90]}. Compared with NUF rates 1.75 mL/kg/h were associated with greater mortality rates in each epoch: Days 0–5, adjusted hazard ratio (aHR) 1.27 [95% confidence interval (CI) 1.21–1.33]; Days 6–10, aHR 1.62 (95% CI 1.55–1.68); Days 11–15, aHR 1.87 (95% CI 1.79–1.94); Days 16–26, aHR 1.92 (95% CI 1.84–2.01) and Days 27–28, aHR 4.18 (95% CI 3.98–4.40). For every 0.5 mL/kg/h NUF rate increase, mortality similarly increased during these epochs. Conclusion Compared with early NUF rates 1.75 mL/kg/h are associated with increased mortality. These observations provide the rationale for clinical trials to confirm or refute these findings.

Background: Emerging evidence indicates a relationship between glycemic variability during intensive care unit (ICU) admission and death. We assessed whether mean glucose, hypoglycemia occurrence, or premorbid glycemic control modified this relationship. Methods: In this retrospective, multicenter cohort study, we included adult patients admitted to five ICUs in Australia and Sweden with available preadmission glycated hemoglobin A1c (HbA1c) and three or more glucose readings. We calculated the glycemic lability index (GLI), a measure of glycemic variability, and the time-weighted average blood glucose (TWA-BG) from all glucose readings. We used logistic regression analysis with adjustment for hypoglycemia and admission characteristics to assess the independent association of GLI (above vs. below cohort median) and TWA-BG (above vs. below cohort median) with hospital mortality. Results: Among 2305 patients, 859 (37%) had diabetes, median GLI was 40 [mmol/L]2 /h/week, median TWA-BG was 8.2 mmol/L, 171 (7%) developed hypoglycemia, and 371 (16%) died. The adjusted odds ratio for death was 1.61 (95% CI, 1.19-2.15; P = .002) for GLI above versus below median and 1.06 (95% CI, 0.80-1.41; P = .67) for TWA-BG above versus below median. The relationship between GLI and mortality was not modified by TWA-BG (P [interaction] = 0.66), a history of diabetes (P [interaction] = 0.89) or by HbA1c ≥52 mmol/mol (vs.

Introduction: The contribution of fluid temperature to the effect of crystalloid fluid bolus therapy (FBT) in post-cardiac surgery patients is unknown. We evaluated the hemodynamic effects of FBT with fluid warmed to 40°C (warm FBT) versus room-temperature fluid. Methods: In this single centre prospective before-and-after study, we evaluated the effects of 500 ml of warm versus room-temperature compound sodium lactate administered over 15% of baseline immediately after FBT and effect dissipation if the CI returned to 10% increase and dissipation as return to Results: Hypotension (56%) and low CI (40%) typically triggered FBT. Temperature decreased >0.3°C in 13 (52%) patients after room-temperature FBT versus 0 (0%) after warm FBT (p 2, p = 0.01). However, dissipation was more common after room-temperature versus warm FBT (9/16 [56%] versus 1/11 [9%], p = 0.02). Conclusion: In postoperative cardiac surgery patients, warm FBT preserved core temperature and induced smaller but more sustained CI increases among responders. Fluid temperature appears to impact both core temperature and the duration of CI response.

OBJECTIVE: To study the temperature and haemodynamic effects of room versus body temperature 20% albumin fluid bolus therapy (FBT). DESIGN: Single-centre, prospective, before–after trial. SETTING: A tertiary intensive care unit (ICU) in Australia. PARTICIPANTS: Sixty ventilated post-cardiac surgery patients. INTERVENTION: Room versus body temperature 100 mL 20% albumin FBT. MAIN OUTCOME MEASURES: We recorded haemodynamic data from FBT start to 30 minutes after FBT. The cardiac index (CI) response was defined by a CI increase > 15%, and the mean arterial pressure (MAP) response was defined by a MAP increase > 10%. OUTCOMES: Immediately after FBT, median blood temperature decreased by -0.1°C (interquartile range [IQR], -0.1 to 0.0°C) with room temperature albumin versus 0.0°C (IQR, -0.1 to 0.0°C) with body temperature albumin (P < 0.001). The CI or MAP responses were similar. There was, however, a time and study group interaction for blood temperature (P < 0.001) for absolute and relative changes. In addition, mean pulmonary arterial pressure (PAP) (P = 0.002) increased more with body temperature albumin and remained higher for most of the observation period. CONCLUSION: Compared with room temperature albumin FBT, body temperature 20% albumin FBT prevents FBT-associated blood temperature fall and increases mean PAP. However, CI and MAP changes were the similar between the two groups, implying that fluid temperature has limited haemodynamic effects in these patients.

OBJECTIVES: The optimal time to initiate renal replacement therapy in critically ill patients with acute kidney injury is controversial. We investigated the effect of such earlier versus later initiation of renal replacement therapy on the primary outcome of 28-day mortality and other patient-centered secondary outcomes. DESIGN: We searched MEDLINE (via PubMed), EMBASE, and Cochrane databases to July 17, 2020, and included randomized controlled trials comparing earlier versus later renal replacement therapy. SETTING: Multiple centers involved in eight trials. PATIENTS: Total of 4,588 trial participants. INTERVENTION: Two independents investigators screened and extracted data using a predefined form. We selected randomized controlled trials in critically ill adult patients with acute kidney injury and compared of earlier versus later initiation of renal replacement therapy regardless of modality. MEASUREMENTS AND MAIN RESULTS: Overall, 28-day mortality was similar between earlier and later renal replacement therapy initiation (38.43% vs 38.06%, respectively; risk ratio, 1.01; [95% CI, 0.94-1.09]; I2 = 0%). Earlier renal replacement therapy, however, shortened hospital length of stay (mean difference, -2.14 d; [95% CI, -4.13 to -0.14]) and ICU length of stay (mean difference, -1.18 d; [95% CI, -1.95 to -0.42]). In contrast, later renal replacement therapy decreased the use of renal replacement therapy (relative risk, 0.69; [95% CI, 0.58-0.82]) and lowered the risk of catheter-related blood stream infection (risk ratio, 0.50, [95% CI, 0.29-0.86). Among survivors, renal replacement therapy dependence at day 28 was similar between earlier and later renal replacement therapy initiation (risk ratio, 0.98; [95% CI, 0.66-1.40]). CONCLUSIONS: Earlier or later initiation of renal replacement therapy did not affect mortality. However, earlier renal replacement therapy was associated with significantly shorter ICU and hospital length of stay, whereas later renal replacement therapy was associated with decreased use of renal replacement therapy and decreased risk of catheter-related blood stream infection. These findings can be used to guide the management of critically ill patients with acute kidney injury.

Background: The acute kidney injury (AKI) risk score helps detect moderate and severe AKI in the next 12–24 h. However, inappropriate urine collection may impact its results. Aim: The aim of this study was to evaluate the stability of NephroCheck® after urine storage at different temperatures. Methods: The urine sample was centrifuged and split into 3 tubes. One was tested as soon as possible by the laboratory. The other 2 samples were frozen at −20 and −80°C, and the NephroCheck® test was performed 8 weeks later. Results: The mean values of the AKI risk score were 1.19 ± 0.93, 1.15 ± 1.14, and 1.20 ± 1.11 (ng/mL)2/1,000 for fresh urine, −20, and −80°C, respectively (p = 0.70). Spearman’s rank correlation for −20 and −80°C versus immediate processing was strong with a rho of 0.82 and 0.98, respectively. Conclusion: The AKI risk score was relatively stable. Urine could be collected without dry ice or liquid nitrogen and kept for up to 8 weeks with either −20 or −80°C freezing with stable NephroCheck® results.

Introduction: Hyperammonemia is a life-threatening condition. However, clearance of ammonia via extracorporeal treatment has not been systematically evaluated. Methods: We searched EMBASE and MEDLINE databases. We included all publications reporting ammonia clearance by extracorporeal treatment in adult and pediatric patients with clearance estimated by direct dialysate ammonia measurement or calculated by formula. Two reviewers screened and extracted data independently. Results: We found 1,770 articles with 312 appropriate for assessment and 28 studies meeting eligibility criteria. Most of the studies were case reports. Hyperammonemia was typically secondary to inborn errors of metabolisms in children and to liver failure in adult patients. Ammonia clearance was most commonly reported during continuous renal replacement therapy (CRRT) and appeared to vary markedly from 2 to >250 mL/min/m2. When measured during intermittent hemodialysis (IHD), clearance was highest and correlated with blood flow rate (R2 = 0.853; p < 0.001). When measured during CRRT, ammonia clearance could be substantial and correlated with effluent flow rate (EFR; R2 = 0.584; p < 0.001). Neither correlated with ammonia reduction. Peritoneal dialysis (PD) achieved minimal clearance, and other extracorporeal techniques were rarely studied. Conclusions: Extracorporeal ammonia clearance varies widely with sometimes implausible values. Treatment modality, blood flow, and EFR, however, appear to affect such clearance with IHD achieving the highest values, PD achieving minimal values, and CRRT achieving substantial values especially at high EFRs. The role of other techniques remains unclear. These findings can help inform practice and future studies.

Processed electroencephalography (pEEG) is used to monitor depth of anaesthesia and/or sedation. A novel device (SedLine®) has been recently introduced into clinical practice. However, there are no published data on baseline SedLine values for awake adult subjects. We aimed to determine baseline values for SedLine-derived parameters in eyes-open and eyes-closed states. We performed a prospective observational study in healthy volunteers. SedLine EEG-derived parameters were recorded for 2 min with eyes closed and 8 min with eyes open. We determined the overall reference range for each value, as well as the reference range in each phase. We investigated changes in recorded parameters between the two phases, and the interaction between EMG, baseline characteristics, and Patient State Index (PSI). We collected data from 50 healthy volunteers, aged 23-63 years. Median PSI was 94 (92-95) with eyes open and 88 (87-91) with eyes closed (p

Objectives: During continuous renal replacement therapy, a high net ultrafiltration rate has been associated with increased mortality. However, it is unknown what might mediate its putative effect on mortality. In this study, we investigated whether the relationship between early (first 48 hr) net ultrafiltration and mortality is mediated by fluid balance, hemodynamic instability, or low potassium or phosphate blood levels using mediation analysis and the primary outcome was hospital mortality. Design: Retrospective, observational study. Setting: Mixed medical and surgical ICUs at Austin hospital, Melbourne, Australia. Patients: Critically ill patients treated with continuous renal replacement therapy within 14 days of ICU admission who survived greater than 48 hours. Interventions: None. Measurements and Main Results: We studied 347 patients (median [interquartile range] age: 64 yr [53-71 yr] and Acute Physiology and Chronic Health Evaluation III score: 73 (54-90)]. After adjustment for confounders, compared with a net ultrafiltration less than 1.01 mL/kg/hr, a net ultrafiltration rate greater than 1.75 mL/kg/hr was associated with significantly greater mortality (adjusted odds ratio, 1.15; 95% CI, 1.03-1.29;p= 0.011). Adjusted univariable mediation analysis found no suggestion of a causal mediation pathway for this effect by blood pressure, vasopressor therapy, or potassium levels, but identified a possible mediation effect for fluid balance (average causal mediation effect, 0.95; 95% CI, 0.89-1.00;p= 0.060) and percentage of phosphate measurements with hypophosphatemia (average causal mediation effect, 0.96; 95% CI, 0.92-1.00;p= 0.055). However, on multiple mediator analyses, these two variables showed no significant effect. In contrast, a high net ultrafiltration rate had an average direct effect of 1.24 (95% CI, 1.11-1.40;p

Importance In patients who undergo mechanical ventilation during surgery, the ideal tidal volume is unclear. Objective To determine whether low-tidal-volume ventilation compared with conventional ventilation during major surgery decreases postoperative pulmonary complications. Design, Setting, and Participants Single-center, assessor-blinded, randomized clinical trial of 1236 patients older than 40 years undergoing major noncardiothoracic, nonintracranial surgery under general anesthesia lasting more than 2 hours in a tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. The last date of follow-up was February 17, 2019. Interventions Patients were randomized to receive a tidal volume of 6 mL/kg predicted body weight (n = 614; low tidal volume group) or a tidal volume of 10 mL/kg predicted body weight (n = 592; conventional tidal volume group). All patients received positive end-expiratory pressure (PEEP) at 5 cm H2O. Main Outcomes and Measures The primary outcome was a composite of postoperative pulmonary complications within the first 7 postoperative days, including pneumonia, bronchospasm, atelectasis, pulmonary congestion, respiratory failure, pleural effusion, pneumothorax, or unplanned requirement for postoperative invasive or noninvasive ventilation. Secondary outcomes were postoperative pulmonary complications including development of pulmonary embolism, acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis, acute kidney injury, wound infection (superficial and deep), rate of intraoperative need for vasopressor, incidence of unplanned intensive care unit admission, rate of need for rapid response team call, intensive care unit length of stay, hospital length of stay, and in-hospital mortality. Results Among 1236 patients who were randomized, 1206 (98.9%) completed the trial (mean age, 63.5 years; 494 [40.9%] women; 681 [56.4%] undergoing abdominal surgery). The primary outcome occurred in 231 of 608 patients (38%) in the low tidal volume group compared with 232 of 590 patients (39%) in the conventional tidal volume group (difference, −1.3% [95% CI, −6.8% to 4.2%]; risk ratio, 0.97 [95% CI, 0.84-1.11];P = .64). There were no significant differences in any of the secondary outcomes. Conclusions and Relevance Among adult patients undergoing major surgery, intraoperative ventilation with low tidal volume compared with conventional tidal volume, with PEEP applied equally between groups, did not significantly reduce pulmonary complications within the first 7 postoperative days. Trial Registration ANZCTR Identifier:ACTRN12614000790640

Purpose Liberal use of oxygen may contribute to secondary brain injury in patients with hypoxic-ischaemic encephalopathy (HIE). However, there are limited data on the effect of different oxygen regimens on survival and neurological disability in HIE patients. Methods We undertook a post-hoc analysis of the 166 patients with suspected HIE enrolled in a trial comparing conservative oxygen therapy with usual oxygen therapy in 1000 mechanically ventilated ICU patients. The primary endpoint for the current analysis was death or unfavourable neurological outcome at day 180. Key secondary outcomes were day 180 mortality, and cause-specific mortality. Results Patients with HIE allocated to conservative oxygen spent less time in the ICU with an SpO2 ≥ 97% (26 h [interquartile range (IQR) 13–45 vs. 35 h [IQR 19–70], absolute difference, 9 h; 95% CI − 21.4 to 3.4). A total of 43 of 78 patients (55.1%) assigned to conservative oxygen and 49 of 72 patients (68.1%) assigned to usual oxygen died or had an unfavourable neurological outcome at day 180; odds ratio 0.58; 95% CI 0.3–1.12; P = 0.1 adjusted odds ratio 0.54; 95% CI 0.23–1.26; P = 0.15. A total of 37 of 86 patients (43%) assigned to conservative oxygen and 46 of 78 (59%) assigned to usual oxygen had died by day 180; odds ratio 0.53; 95% CI 0.28–0.98; P = 0.04; adjusted odds ratio 0.56; 95% CI 0.25–1.23; P = 0.15. Cause-specific mortality was similar by treatment group. Conclusions Conservative oxygen therapy was not associated with a statistically significant reduction in death or unfavourable neurological outcomes at day 180. The potential for important benefit or harm from conservative oxygen therapy in HIE patients is not excluded by these data. Electronic supplementary material The online version of this article (10.1007/s00134-020-06196-y) contains supplementary material, which is available to authorized users.

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.

PURPOSE OF REVIEW: To describe current practice, recent advances in knowledge and future directions for research related to the post return of spontaneous circulation (ROSC) ventilatory management of cardiac arrest patients. RECENT FINDINGS: Out-of-hospital cardiac arrest (OHCA) is a major public health problem with an estimated incidence of approximately one per 1000 persons per year. A priority of intensive care management of resuscitated OHCA patients is to reduce secondary reperfusion injury. Most OHCA patients are mechanically ventilated. Most of these require mechanical ventilation as they are unconscious and for oxygen (O2) management and carbon dioxide (CO2) control. Low levels of O2 and CO2 following OHCA is associated with poor outcome. Recently, very high fraction of inspired oxygen has been associated with poor outcomes and elevated CO2 levels have been associated with improved neurological outcomes. Moreover, it is increasingly being appreciated that the ventilator may be a tool to adjust physiological parameters to enhance the chances of favourable outcomes. Finally, ventilator settings themselves and the adoption of protective ventilation strategies may affect lung-brain interactions and are being explored as other avenues for therapeutic benefit. SUMMARY: Current evidence supports the targeting of normal arterial O2 and CO2 tensions during mechanical ventilation following ROSC after cardiac arrest. Use of protective lung strategies during mechanical ventilation in resuscitated cardiac arrest patients is advocated. The potential therapeutic benefits of conservative O2 therapy, mild hypercapnia and the optimal ventilator settings to use post-ROSC period will be confirmed or refuted in clinical trials.

BACKGROUND: Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio2) and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure, diminish lung and systemic oxidative injury, and thereby increase the number of ventilator-free days (days alive and free from mechanical ventilation). METHODS: We randomly assigned 1000 adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU to receive conservative or usual oxygen therapy. In the two groups, the default lower limit for oxygen saturation as measured by pulse oximetry (Spo2) was 90%. In the conservative-oxygen group, the upper limit of the Spo2 alarm was set to sound when the level reached 97%, and the Fio2 was decreased to 0.21 if the Spo2 was above the acceptable lower limit. In the usual-oxygen group, there were no specific measures limiting the Fio2 or the Spo2. The primary outcome was the number of ventilator-free days from randomization until day 28. RESULTS: The number of ventilator-free days did not differ significantly between the conservative-oxygen group and the usual-oxygen group, with a median duration of 21.3 days (interquartile range, 0 to 26.3) and 22.1 days (interquartile range, 0 to 26.2), respectively, for an absolute difference of -0.3 days (95% confidence interval [CI], -2.1 to 1.6; P = 0.80). The conservative-oxygen group spent more time in the ICU with an Fio2 of 0.21 than the usual-oxygen group, with a median duration of 29 hours (interquartile range, 5 to 78) and 1 hour (interquartile range, 0 to 17), respectively (absolute difference, 28 hours; 95% CI, 22 to 34); the conservative-oxygen group spent less time with an Spo2 exceeding 96%, with a duration of 27 hours (interquartile range, 11 to 63.5) and 49 hours (interquartile range, 22 to 112), respectively (absolute difference, 22 hours; 95% CI, 14 to 30). At 180 days, mortality was 35.7% in the conservative-oxygen group and 34.5% in the usual-oxygen group, for an unadjusted odds ratio of 1.05 (95% CI, 0.81 to 1.37). CONCLUSIONS: In adults undergoing mechanical ventilation in the ICU, the use of conservative oxygen therapy, as compared with usual oxygen therapy, did not significantly affect the number of ventilator-free days. (Funded by the Health Research Council of New Zealand; ICU-ROX Australian and New Zealand Clinical Trials Registry number, ACTRN12615000957594.).

Objective: To study the cardiovascular effect over 30 minutes following the end of fluid bolus therapy (FBT) with 20% albumin in patients after cardiac surgery. Design: Prospective observational study. Setting: Intensive care unit of a tertiary university-affiliated hospital. Participants: Twenty post-cardiac surgery mechanically ventilated patients with a clinical decision to administer FBT. Intervention: FBT with a 100 mL bolus of 20% albumin. Main outcome measures: Cardiac index (CI) response was defined by a  15% increase, while mean arterial pressure (MAP) response was defined by a  10% increase. Results: The most common indication for FBT was hypotension (40%). Median duration of infusion was 7 minutes (interquartile range [IQR], 3–9 min). At the end of FBT, five patients (25%) showed a CI response, which increased to almost half in the following 30 minutes and dissipated in one patient. MAP response occurred in 11 patients (55%) and dissipated in five patients (45%) by a median of 6 minutes (IQR, 6–10 min). CI and MAP responses coexisted in four patients (20%). An intrabolus MAP response occurred in 17 patients (85%) but dissipated in 11 patients (65%) within a median of 7 minutes (IQR, 2–11 min). On regression analysis, faster fluid bolus administration predicted MAP increase at the end of the bolus. Conclusion: In post-cardiac surgery patients, CI response to 20% albumin FBT was not congruous with MAP response over 30 minutes. Although hypotension was the main indication for FBT and a MAP response occurred in most of patients, such response was maximal during the bolus, dissipated in a few minutes, and was dissociated from the CI response.

OBJECTIVE: To conduct a pilot feasibility and physiologic efficacy study of high-dose vitamin C in patients with vasoplegia after cardiac surgery.DESIGN: Prospective, double-blind, randomized, controlled trial.SETTING: Two tertiary intensive care units (ICUs).PARTICIPANTS: Post-cardiac surgery patients with vasoplegia.INTERVENTIONS: The authors randomly assigned the patients to receive either high-dose intravenous vitamin C (1,500 mg every 6 hours) or placebo. The primary outcome was time from randomization to resolution of vasoplegia. Secondary outcomes included total norepinephrine equivalent dose in the first 2 days, ICU length of stay, ICU mortality, and in-hospital mortality.MEASUREMENTS AND MAIN RESULTS: The authors studied 50 patients (25 patients in each arms). The mean (standard deviation) time to resolution of vasoplegia was 27.0 (16.5) hours in the vitamin C group versus 34.7 (41.1) hours in the placebo group (mean decrease with vitamin C of 7.7 hours, 95% confidence interval -10.5 to 25.9, p = 0.40). The median (interquartile range) norepinephrine equivalent dose in the first 2 days was 64.9 (23.5-236.5) µg/kg versus 47.4 (21.4-265.9) µg/kg in the vitamin C and placebo group (p = 0.75). The median duration of ICU admission was similar (1.4 [0.5-2.5] days and 1.5 [0.5-3.3] days in the vitamin C and placebo group; p = 0.36). Only 1 patient, in the vitamin C arm, died.CONCLUSION: In patients with post-cardiac surgery vasoplegia, high-dose vitamin C infusion was feasible, appeared safe, and, within the limitations of a pilot study, did not achieve statistically faster resolution of vasoplegia.

The application of rapid, non-operator-dependent, non-invasive cardiac output monitoring (COM) may provide early physiological information in ED patients with haemodynamic instability (HI). Our primary objective was to assess the feasibility of measuring pre-intervention (baseline) cardiac index (CI) and associated haemodynamic parameters.We performed a prospective observational study of adults shortly after presentation to the ED of a large university hospital with tachycardia or hypotension or both. We applied non-invasive COM for 5 min and recorded CI, mean arterial pressure (MAP), stroke volume index (SVI) and systemic vascular resistance index (SVRI). We assessed for differences between those presenting with hypotension or hypotension and tachycardia with tachycardia alone and between those with or without suspected infection.We obtained haemodynamic parameters in 46 of 49 patients. In patients with hypotension or hypotension and tachycardia (n = 15) rather than tachycardia alone (n = 31), we observed a lower MAP (60.8 vs 87.7, P 0.0001), CI (2.8 vs 3.9, P = 0.0167) and heart rate (85.5 vs 115.4, P 0.0001). There was no difference in SVI (33.7 vs 33.4, P = 0.93) or SVRI (1970 vs 2088, P = 0.67). Patients with suspected infection had similar haemodynamic values except for a lower SVRI (1706 vs 2237, P = 0.011).Rapid, non-operator-dependent, non-invasive COM was possible in90% of ED patients presenting with HI. Compared with tachycardia alone, patients with hypotension had lower CI, MAP and heart rate, while those with suspected infection had a lower SVRI. This technology provides novel insights into the early state of the circulation in ED patients with HI.

To assess short-term creatinine changes as predictors of acute kidney injury (AKI) when used alone and in combination with AKI risk factors.In this prospective cohort study, we identified all creatinine measurements from frequent point-of-care arterial blood gas measurements from ICU admission until AKI. We evaluated the predictive value of small changes between these creatinine measurements for AKI development, alone and with AKI risk factors.Of 377 patients with 3235 creatinine measurements, generating 15,075 creatinine change episodes, 215 (57%) patients developed AKI, and 68 (18%) developed stage 2 or 3 AKI. In isolation, a creatinine increase over 4.1-7.3 h had a 0.65 area under the curve for predicting stage 2 or 3 AKI within 3-37.7 h. Combining creatinine increases of ≥1 μmol/L/h (≥0.0113 mg/dL/h) over 4-5.8 h with three AKI risk factors (cardiac surgery, use of vasopressors, chronic liver disease) had 83% sensitivity, 79% specificity and 0.87 area under the curve for stage 2 or 3 AKI occurring 8.7-25.6 h later.In combination with key risk factors, frequent point-of-care creatinine assessment on arterial blood gases to detect small, short-term creatinine changes provides a robust, novel, low-cost, and rapid method for predicting AKI in critically ill patients.

BACKGROUND: Studies in critically ill patients suggest a relationship between mechanical power (an index of the energy delivered by the ventilator, which includes driving pressure, respiratory rate, tidal volume and inspiratory pressure) and complications. OBJECTIVE: We aimed to assess the association between intra-operative mechanical power and postoperative pulmonary complications (PPCs). DESIGN: Post hoc analysis of a large randomised clinical trial. SETTING: University-affiliated academic tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. PATIENTS: Adult patients undergoing major noncardiothoracic, nonintracranial surgery. INTERVENTION: Dynamic mechanical power was calculated using the power equation adjusted by the respiratory system compliance (CRS). Multivariable models were used to assess the independent association between mechanical power and outcomes. MAIN OUTCOME MEASURES: The primary outcome was the incidence of PPCs within the first seven postoperative days. The secondary outcome was the incidence of acute respiratory failure. RESULTS: We studied 1156 patients (median age [IQR]: 64 [55 to 72] years, 59.5% men). Median mechanical power adjusted by CRS was 0.32 [0.22 to 0.51] (J min-1)/(ml cmH2O-1). A higher mechanical power was also independently associated with increased risk of PPCs [odds ratio (OR 1.34, 95% CI, 1.17 to 1.52); P

Rationale: The continuous infusion of fentanyl or morphine is often prescribed to assist with analgesia and sedation (analgosedation) during mechanical ventilation. Objectives: To compare the effec...

Purpose To assess the feasibility and physiological efficacy of adjunctive midodrine in patients with vasopressor-dependent hypotension. Materials and methods This was a pilot, open label, randomised controlled trial. Patients were enrolled from two tertiary intensive care units on low dose intravenous vasopressor therapy for more than 24 h. We randomly assigned patients to receive either adjunctive midodrine (10 mg every 8 h) or usual care. The primary efficacy outcome was time to cessation of intravenous vasopressor therapy. Secondary outcomes included protocol compliance, ICU and hospital length of stay. Results We screened 381 patients over 22-months and enrolled 62 (32 in midodrine group, 30 in usual care group). Median time to cessation of vasopressor infusion was 16.5 h for midodrine vs 19 h for usual care (p = 0.22). Time in ICU (50 [25.50, 74.00] hours for midodrine v 59 [38.50, 93.25] hours for usual care, p = 0.14) and hospital length of stay (9 days vs. 7.5 days, p = 0.92) were similar. Protocol compliance was 96.9%. One patient ceased midodrine early due to symptomatic bradycardia. Conclusions Adjunctive midodrine therapy was feasible with acceptable compliance, duration of therapy, and safety profile. However, at the chosen dose, there was no evidence of physiological or clinical efficacy.

BACKGROUND Approximately one third of Rapid Response Teams (RRT) involve end of life care (EOLC) issues. Intensive care unit (ICU) registrar experience in such calls is under-investigated. AIM To evaluate the proportion of RRT calls triaged as relating to EOLC issues, issues around communication regarding prognostication, registrar self-reported moral distress, and associations between RRT EOLC classification and patient outcomes. METHODS Prospective observational study of RRT calls in a tertiary referrals hospital between December 2016 and January 2017 using a standardised case report form and data from an electronic RRT database. RESULTS There were 401 RRT calls in the study period, and data were available for 270 calls (67%), of which 72%, 10%, and 18% were triaged as "obviously not EOLC call", "obvious EOLC call", and "uncertain EOLC call", respectively. Most discussions regarding prognostication occurred between registrars, and more than half were with a covering doctor (55%). Consensus on prognostication was achieved in 93% cases. Registrars reported distress in 19% of calls that obviously related to EOLC and 22% of calls that were uncertain, compared to

Introduction: Little is known about early (first 48 h) hourly and cumulative fluid balance (FB) during continuous renal replacement therapy (CRRT). Objectives: To study the characteristics and outcome associations of early hourly and cumulative FB. Methods: We studied FB in CRRT patients (2016–2018). Results: Among 350 patients, mean hourly FB became negative after 20 CRRT hours, but within 6 CRRT hours in patients with baseline fluid overload. A negative early FB was never achieved in patients receiving vasopressor therapy (p < 0.001). Mortality was 31%. The percentage of hourly negative FB was independently associated with decreased ICU mortality. A time-weighted hourly FB between 18.5 and –33 mL/h was also significantly and independently associated with decreased mortality. Conclusions: In CRRT patients, an early FB conservative approach is possible, modulated by patient characteristics, and associated with a low mortality. Moreover, avoidance of an early positive FB is associated with decreased mortality.

Background There is renewed interest in high-dose vitamin C interventions in clinical medicine due to its antioxidant properties, safe use and cost-effectiveness. Yet, randomised control trials (RCTs) employing these interventions are failing to include robust analytical methodology and proper sample handling and processing techniques. Consequently, comparisons between studies becomes impossible as there is no metrological traceability and results may be prone to pre-analytical errors. Content Through published vitamin C stability studies, method comparison papers and data from vitamin C external quality assurance programs, an assessment was made on the functionality of current methods for critically ill patient samples. Summary Data was obtained from two external quality assurance programs, two papers assessing sample stability and interlaboratory agreement and a publication on vitamin C method comparisons. A shift from spectrophotometric and enzymatic methodologies to high performance liquid chromatography (HPLC) greatly improved the variability and interlaboratory agreement. Therefore, the current analytical performance of vitamin C HPLC methodologies are acceptable for the requirements of a high-dose vitamin C RCTs. Outlook Recommendations across the total testing process of vitamin C have been provided to improve the quality of the results. The harmonisation of sample handling and processing procedures will further improve the reliability of current analytical methodologies.

Purpose Sepsis is a common reason for intensive care unit (ICU) admission and mortality in ICU patients. Despite increasing interest in treatment strategies limiting oxygen exposure in ICU patients, no trials have compared conservative vs. usual oxygen in patients with sepsis. Methods We undertook a post hoc analysis of the 251 patients with sepsis enrolled in a trial that compared conservative oxygen therapy with usual oxygen therapy in 1000 mechanically ventilated ICU patients. The primary end point for the current analysis was 90-day mortality. Key secondary outcomes were cause-specific mortality, ICU and hospital length of stay, ventilator-free days, vasopressor-free days, and the proportion of patients receiving renal replacement therapy in the ICU. Results Patients with sepsis allocated to conservative oxygen therapy spent less time in the ICU with an SpO2 ≥ 97% (23.5 h [interquartile range (IQR) 8–70] vs. 47 h [IQR 11–93], absolute difference, 23 h; 95% CI 8–38), and more time receiving an FiO2 of 0.21 than patients allocated to usual oxygen therapy (20.5 h [IQR 1–79] vs. 0 h [IQR 0–10], absolute difference, 20 h; 95% CI 14–26). At 90-days, 47 of 130 patients (36.2%) assigned to conservative oxygen and 35 of 120 patients (29.2%) assigned to usual oxygen had died (absolute difference, 7 percentage points; 95% CI − 4.6 to 18.6% points; P = 0.24; interaction P = 0.35 for sepsis vs. non-sepsis). There were no statistically significant differences between groups for secondary outcomes but point estimates of treatment effects consistently favored usual oxygen therapy. Conclusions Point estimates for the treatment effect of conservative oxygen therapy on 90-day mortality raise the possibility of clinically important harm with this intervention in patients with sepsis; however, our post hoc analysis was not powered to detect the effects suggested and our data do not exclude clinically important benefit or harm from conservative oxygen therapy in this patient group. Clinical Trials Registry ICU-ROX Australian and New Zealand Clinical Trials Registry number ACTRN12615000957594. Electronic supplementary material The online version of this article (10.1007/s00134-019-05857-x) contains supplementary material, which is available to authorized users.

Introduction During rapid response team (RRT) management of haemodynamic instability (HI), continuous non-invasive haemodynamic monitoring may provide supplemental physiological information. Objectives To continuously and non-invasively obtain the cardiac index (CI) and mean arterial pressure (MAP) in patients with HI at baseline and during RRT management using the ClearSight™ device. Methods We performed a prospective observational study in adult patients managed by the RRT for tachycardia or hypotension or both. We assessed changes from baseline in heart rate (HR), MAP, CI, stroke volume index (SVI) and systemic vascular resistance index (SVRI) (i) at 5-minutely intervals up to 20 min, and (ii) over the entire 20-min period. We analysed patients by RRT trigger (tachycardia/hypotension) and intervention (fluid bolus therapy [FBT]/ no FBT). Results We successfully recorded the CI in 47 of 50 (94%) patients. RRT reviews triggered by hypotension rather than tachycardia had a lower baseline HR (−45.4 bpm, p = Conclusions Continuous non-invasive measurement of haemodynamics during RRT management for HI was possible for 20 min. Patients with hypotension rather than tachycardia had lower baseline HR, MAP and CI values. There was a statistically significant but small increase in MAP at the 15–20 min time-block and overall, for both the tachycardia and FBT groups.

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.

We assessed the incidence, characteristics, outcomes and associations of small, short-term point-of-care creatinine increases in critically ill patients.We prospectively identified the first episode of small (1 μmol/L/h) short-term (3-4 h) point-of-care creatinine increase between two sequential arterial blood gas measurements. We followed patients for the subsequent development of Kidney Disease: Improving Global Outcomes (KDIGO) defined acute kidney injury (AKI) in the intensive care unit (ICU).Of 387 patients, 279 (72.1%) developed an episode of small short-term point-of-care creatinine increase and 212 (54.8%) developed AKI. Such episodes occurred at a median of 5 (IQR 2-10) hours after ICU admission, while AKI occurred at a median of 15 (IQR 9-28) hours after admission. Patients with such episodes were more likely to be mechanically ventilated on admission (83.9 vs. 44.4%; p .001) and had higher hospital mortality (10.9 vs. 3.7%, p = .03). Creatinine increase episodes had a sensitivity of 86% (95% CI 78-95) and specificity of 31% (95% CI 26-36) for subsequent AKI stages 2 and 3 in 24 h.Small, short-term point-of-care creatinine increase episodes are common. They are associated with illness severity, occur early, precede AKI by 10 h and are sensitive rather than specific markers of AKI.

Avoiding hypoxaemia is considered crucial in cardiac surgery patients admitted to the intensive care unit (ICU). However, avoiding hyperoxaemia may also be important. A conservative approach to oxygen therapy may reduce exposure to hyperoxaemia without increasing the risk of hypoxaemia. Using a before-and-after design, we evaluated the introduction of conservative oxygen therapy (target SpO2 88%–92% using the lowest FiO2) for cardiac surgical patients admitted to the ICU. We studied 9041 arterial blood gas (ABG) datasets: 4298 ABGs from 245 ‘conventional’ and 4743 ABGs from 298 ‘conservative’ oxygen therapy patients. During mechanical ventilation (MV) and while in the ICU, compared to the conventional group, conservative group patients had significantly lower FiO2 exposure and PaO2 values ( P 2 during MV, more conservative group patients were classified as normoxaemic (226 versus 62 patients, P

Background: Renal medullary hypoxia precedes the development of acute kidney injury in experimental sepsis and can now be assessed by continuous measurement of urinary oxygen tension (PuO2). Objectives: We aimed to test if PuO2 measurements in patients with septic shock would be similar to those shown in experimental sepsis and would detect changes induced by the administration of furosemide. Method: Pilot prospective observational cohort study in a tertiary intensive care unit (ICU). Seven adult patients with septic shock admitted to ICU had PuO2 measurements recorded minutely. There were 29 episodes of intravenous furosemide (20 mg n = 19; 40 mg n = 10). Results: The median pre-furosemide PuO2 was low at 21.2 mm Hg (interquartile range [IQR] 17.73–24.86) and increased to 26 mm Hg (IQR 20.27–29.95) at 20 min (p < 0.01), to 27.5 mm Hg (IQR 24.06–33.18) at 40 min (p < 0.01) and to 28.5 mm Hg (IQR 22.65–31.03) at 60 min (p < 0.01). The increase in PuO2 was greater in episodes with a diuretic response >2 mL/kg/h than during episodes without such a response (p < 0.01). Conclusions: PuO2 measurements in patients are reflective of the low values reported in experimental models of sepsis. PuO2 values increased following furosemide administration with a response independently associated with greater diuresis.

Modern near-infrared spectroscopy technology is increasingly adopted to measure cerebral tissue oxygen saturation. However, the normal range of cerebral tissue oxygen saturation in adults with such technology is unknown. We sought to measure cerebral tissue oxygen saturation in healthy volunteers using the novel O3 Regional Oximetry® device (Masimo Corporation, Irvine, CA, USA) and assess its relationship with key physical and haemodynamic characteristics. For ≥5 minutes, we continuously recorded cerebral tissue oxygen saturation, pulse oximetry, cardiac index and mean arterial pressure. We assessed for differences in cerebral tissue oxygen saturation between hemispheres, sex, skin type, comorbidity or smoking status, and for associations between cerebral tissue oxygen saturation and age, height, weight, SpO2and haemodynamic parameters. We recorded >32,000 observations in 98 volunteers aged 22 to 60 years, including 41 (42%) males. One-fifth had one or more co morbidities ( n=22, 22.5%), one-tenth were either current or former-smokers ( n=13, 13%), and most had a Fitzpatrick skin type of 3 or lower ( n=84, 86%). The mean combined average cerebral tissue oxygen saturation was 67.6% (95% confidence interval 66.8%–68.6%). We found statistically significant differences in cerebral tissue oxygen saturation according to hemisphere and an association between cerebral tissue oxygen saturation and mean arterial pressure and cardiac index. The combined average cerebral tissue oxygen saturation in 98 healthy volunteers was 67.6% with a narrow confidence interval and no combined average cerebral tissue oxygen saturation was below 56%. We also observed statistically significant yet quantitatively small cerebral tissue oxygen saturation differences between hemispheres, and an association between cerebral tissue oxygen saturation and mean arterial pressure and cardiac index.

Objectives To evaluate the functional outcome and health-related quality of life of in-hospital cardiac arrest survivors at 6 and 12 months. Design A longitudinal cohort study. Setting Seven metropolitan hospitals in Australia. Patients Data were collected for hospitalized adults (≥ 18 yr) who experienced in-hospital cardiac arrest, defined as "a period of unresponsiveness, with no observed respiratory effort and the commencement of external cardiac compressions." Interventions None. Measurements and main results Prior to hospital discharge, patients were approached for consent to participate in 6-month and 12-month telephone interviews. Outcomes included the modified Rankin Scale, Barthel Index, Euro-Quality of Life 5 Dimension 5 Level, return to work and hospital readmissions. Forty-eight patients (80%) consented to follow-up interviews. The mean age of participants was 67.2 (± 15.3) years, and 33 of 48 (68.8%) were male. Good functional outcome (modified Rankin Scale score ≤ 3) was reported by 31 of 37 participants (83.8%) at 6 months and 30 of 33 (90.9%) at 12 months. The median Euro-Quality of Life-5D index value was 0.73 (0.33-0.84) at 6 months and 0.76 (0.47-0.88) at 12 months. The median Euro-Quality of Life-Visual Analogue Scale score at 6 months was 70 (55-80) and 75 (50-87.5) at 12 months. Problems in all Euro-Quality of Life-5D-5 L dimension were reported frequently at both time points. Hospital readmission was reported by 23 of 37 patients (62.2%) at 6 months and 16 of 33 (48.5%) at 12 months. Less than half of previously working participants had returned to work by 12 months. Conclusions The majority of in-hospital cardiac arrest survivors had a good functional outcome and health-related quality of life at 6 months, and this was largely unchanged at 12 months. Despite this, many reported problems with mobility, self-care, usual activities, pain, and anxiety/depression. Return to work rates was low, and hospital readmissions were common.

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).Pilot, feasibility, multicentre, double-blind, randomised, placebo-controlled trial.Four interdisciplinary intensive care units (ICUs) in Australia.Critically ill patients with SIRS.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.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.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.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.Australian New Zealand Clinical Trials Registry (ACTRN 12614001165673).

Background Septic shock is associated with decreased vasopressor responsiveness. Experimental data suggest that central alpha2-agonists like dexmedetomidine (DEX) increase vasopressor responsiveness and reduce catecholamine requirements in septic shock. However, DEX may also cause hypotension and bradycardia. Thus, it remains unclear whether DEX is hemodynamically safe or helpful in this setting. Methods In this post hoc subgroup analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, an international randomized trial comparing early sedation with dexmedetomidine to usual care in critically patients receiving mechanical ventilation, we studied patients with septic shock admitted to two tertiary ICUs in Australia and Switzerland. The primary outcome was vasopressor requirements in the first 48 h after randomization, expressed as noradrenaline equivalent dose (NEq [μg/kg/min] = noradrenaline + adrenaline + vasopressin/0.4). Results Between November 2013 and February 2018, 417 patients were recruited into the SPICE III trial at both sites. Eighty-three patients with septic shock were included in this subgroup analysis. Of these, 44 (53%) received DEX and 39 (47%) usual care. Vasopressor requirements in the first 48 h were similar between the two groups. Median NEq dose was 0.03 [0.01, 0.07] μg/kg/min in the DEX group and 0.04 [0.01, 0.16] μg/kg/min in the usual care group (p = 0.17). However, patients in the DEX group had a lower NEq/MAP ratio, indicating lower vasopressor requirements to maintain the target MAP. Moreover, on adjusted multivariable analysis, higher dexmedetomidine dose was associated with a lower NEq/MAP ratio. Conclusions In critically ill patients with septic shock, patients in the DEX group received similar vasopressor doses in the first 48 h compared to the usual care group. On multivariable adjusted analysis, dexmedetomidine appeared to be associated with lower vasopressor requirements to maintain the target MAP. Trial registration The SPICE III trial was registered at ClinicalTrials.gov (NCT01728558).

BACKGROUND: Frequent assessment of urine output (UO), serum creatinine (sCr) and urinary cell cycle arrest biomarkers (CCAB) may improve acute kidney injury (AKI) prediction. OBJECTIVE: To study the performance of UO, short term sCr changes and urinary CCAB to predict severe AKI. METHODS: We measured 6 hours of UO, 6-hourly sCr changes, and urinary CCABs in all critically ill patients with cardiovascular or respiratory failure or early signs of renal stress between February and October 2018. We studied the association of such measurements, and their combination, with the development of AKI Stage 2 or 3 of the Kidney Disease: Improving Global Outcomes (KDIGO) definition at 12 hours. We evaluated predictive performance with logistic regression, area under the receiver operating characteristic (AUROC) curve, and net reclassification indices. We computed an optimal cut-off value for each biomarker. RESULTS: We assessed 622 patients and, as per the exclusion criteria, we enrolled 105 critically ill patients. After 12 hours of enrolment, AKI occurred in 32 patients (30%). UO, sCr change over 6 hours and CCABs were significantly associated with severe AKI at 12 hours, with all variables achieving an AUROC > 0.7 after adjustment. Combination of any of the two or three variables achieved an AUROC > 0.7 for subsequent severe AKI at 12 hours. The optimal predictive high specificity cut-off values were ≤ 0.4 mL/kg/h for UO, variation of +15 μmol/L over 6 hours in sCr, and ≥ 1.5 (ng/mL)2/1000 for CCABs. CONCLUSION: In this prospective study, an integrative approach using UO, short term sCr change and/or urinary CCABs showed a satisfactory performance for the prediction of severe AKI development at 12 hours.