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

Introduction: The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. Methods: We continuously measured renal medullary oxygen tension (MPO2) in 24 sheep, and urinary PO2 (UPO2) as an index of MPO2 in 92 patients, before and after induction of CPB. Results: In laterally recumbent sheep with a right thoracotomy (n = 20), even before CPB commenced MPO2 fell from (mean ± SEM) 52 ± 4 to 41 ±5 mmHg simultaneously with reduced arterial pressure (from 108 ± 5 to 88 ± 5 mmHg). In dorsally recumbent sheep with a medial sternotomy (n = 4), MPO2 was even more severely reduced (to 12 ± 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used (n = 7), after commencing CPB, MPO2 fell abruptly to 24 ±6 mmHg within 20–30 minutes. MPO2 during CPB was not improved by adding donor blood to the prime (n = 13). In patients undergoing cardiac surgery, UPO2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO2 then fell by a further 12 ± 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. Conclusions: Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration. [ABSTRACT FROM AUTHOR]

Background: Data on long-term outcomes after sepsis-associated critical illness have mostly come from small cohort studies, with no information about the incidence of new disability. We investigated whether sepsis-associated critical illness was independently associated with new disability at 6 months after ICU admission compared with other types of critical illness.Methods: We conducted a secondary analysis of a multicenter, prospective cohort study in six metropolitan intensive care units in Australia. Adult patients were eligible if they had been admitted to the ICU and received more than 24 h of mechanical ventilation. There was no intervention.Results: The primary outcome was new disability measured with the WHO Disability Assessment Schedule 2.0 (WHODAS) 12 level score compared between baseline and 6 months. Between enrollment and follow-up at 6 months, 222/888 (25%) patients died, 100 (35.5%) with sepsis and 122 (20.1%) without sepsis (P < 0.001). Among survivors, there was no difference for the incidence of new disability at 6 months with or without sepsis, 42/106 (39.6%) and 106/300 (35.3%) (RD, 0.00 (- 10.29 to 10.40), P = 0.995), respectively. In addition, there was no difference in the severity of disability, health-related quality of life, anxiety and depression, post-traumatic stress, return to work, financial distress or cognitive function.Conclusions: Compared to mechanically ventilated patients of similar acuity and length of stay without sepsis, patients with sepsis admitted to ICU have an increased risk of death, but survivors have a similar risk of new disability at 6 months. Trial registration NCT03226912, registered July 24, 2017. [ABSTRACT FROM AUTHOR]

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 effect of fentanyl versus morphine on patient-centered outcomes in ventilated patients. Methods: We conducted a cluster-randomized, cluster-crossover trial between July 2019 and August 2020 in two adult ICUs. We compared two continuous infusion regimens (fentanyl versus morphine). One ICU was randomized to the fentanyl-morphine sequence and the other to the morphine-fentanyl sequence. The primary outcome was the number of ventilator-free days at Day 28. Secondary outcomes included, among others, duration of mechanical ventilation in survivors and ICU-free days at Day 28. Measurements and Main Results: Via cluster allocation, we randomized 737 patients. Of these, 56 were excluded because of the opt-out consent process, leaving 681 (344 to fentanyl and 337 to morphine) for primary analysis (median [interquartile range] age, 59 [44-69] years). Median ventilator-free days at Day 28 were 26.1 (20.7-27.3) in the fentanyl versus 25.3 (19.1-27.2) in the morphine group (median difference, 0.79 [95% confidence interval, 0.31 to 1.28], P = 0.001). ICU-free days were greater (P < 0.001) and length of stay in the ICU for survivors shorter (P < 0.001) in the fentanyl group. All other secondary outcomes were not statistically different by treatment group. Conclusions: Among adult patients requiring mechanical ventilation, compared with morphine, fentanyl infusion significantly increased the median number of ventilator-free days at Day 28. The choice of opioid infusion agent may affect clinical outcomes and requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Frailty is associated with poor outcomes in critical illness. However, it is unclear whether frailty screening on admission to the ICU can be conducted routinely at the population level and whether it has prognostic importance.Research Question: Can population-scale frailty screening with the Clinical Frailty Scale (CFS) be implemented for critically ill adults in Australia and New Zealand (ANZ) and can it identify patients at risk of negative outcomes?Study Design and Methods: We conducted a binational prospective cohort study of critically ill adult patients admitted between July 1, 2018, and June 30, 2020, in 175 ICUs in ANZ. We classified frailty with the CFS on admission to the ICU. The primary outcome was in-hospital mortality; secondary outcomes were length of stay (LOS), discharge destination, complications (delirium, pressure injury), and duration of survival.Results: We included 234,568 critically ill patients; 45,245 (19%) were diagnosed as living with frailty before ICU admission. Patients with vs without frailty had higher in-hospital mortality (16% vs 5%; P < .001), delirium (10% vs 4%; P < .001), longer LOS in the ICU and hospital, and increased new chronic care discharge (3% vs 1%; P < .001), with worse outcomes associated with increasing CFS category. Of patients with very severe frailty (CFS score, 8), 39% died in hospital vs 2% of very fit patients (CFS score, 1; multivariate categorical CFS score, 8 [reference, 1]; OR, 7.83 [95% CI, 6.39-9.59]; P < .001). After adjustment for illness severity, frailty remained highly significantly predictive of mortality, including among patients younger than 50 years, with improvement in the area under the receiver operating characteristic curve of the Acute Physiology and Chronic Health Evaluation III-j score to 0.882 (95% CI, 0.879-0.885) from 0.868 (95% CI, 0.866-0.871) with the addition of frailty (P < .001).Interpretation: Large-scale population screening for frailty degree in critical illness was possible and prognostically important, with greater frailty (especially CFS score of ≥ 6) associated with worse outcomes, including among younger patients. [ABSTRACT FROM AUTHOR]

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

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

Background: A threshold Clinical Frailty Scale (CFS) of 5 (indicating mild frailty) has been proposed to guide ICU admission for UK patients with coronavirus disease 2019 (COVID-19) pneumonia. However, the impact of frailty on mortality with (non-COVID-19) pneumonia in critical illness is unknown. We examined the triage utility of the CFS in patients with pneumonia requiring ICU.Methods: We conducted a retrospective cohort study of adult patients admitted with pneumonia to 170 ICUs in Australia and New Zealand from January 1, 2018 to September 31, 2019. We classified patients as: non-frail (CFS 1-4) frail (CFS 5-8), mild/moderately frail (CFS 5-6),and severe/very severely frail (CFS 7-8). We evaluated mortality (primary outcome) adjusting for site, age, sex, mechanical ventilation, pneumonia type and illness severity. We also compared the proportion of ICU bed-days occupied between frailty categories.Results: 1852/5607 (33%) patients were classified as frail, including1291/3056 (42%) of patients aged >65 yr, who would potentially be excluded from ICU admission under UK-based COVID-19 triage guidelines. Only severe/very severe frailty scores were associated with mortality (adjusted odds ratio [aOR] for CFS=7: 3.2; 95% confidence interval [CI]: 1.3-7.8; CFS=8 [aOR: 7.2; 95% CI: 2.6-20.0]). These patients accounted for 7% of ICU bed days. Vulnerability (CFS=4) and mild frailty (CFS=5) were associated with a similar mortality risk (CFS=4 [OR: 1.6; 95% CI: 0.7-3.8]; CFS=5 [OR: 1.6; 95% CI: 0.7-3.9]).Conclusions: Patients with severe and very severe frailty account for relatively few ICU bed days as a result of pneumonia, whilst adjusted mortality analysis indicated little difference in risk between patients in vulnerable, mild, and moderate frailty categories. These data do not support CFS ≥5 to guide ICU admission for pneumonia. [ABSTRACT FROM AUTHOR]

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Little is known about the prevalence, predictors, and outcomes of late vasopressor administration which evolves after admission to the ICU.Research Question: What is the epidemiology of late vasopressor administration in the ICU?Study Design and Methods: We retrospectively studied a cohort of veterans admitted to the Veterans Administration ICUs for ≥ 4 days from 2014 to 2017. The timing of vasopressor administration was categorized as early (only within the initial 3 days), late (on day 4 or later and none on day 3), and continuous (within the initial 2 days through at least day 4). Regressions were performed to identify patient factors associated with late vasopressor administration and the timing of vasopressor administration with posthospitalization discharge mortality.Results: Among the 62,206 hospitalizations with at least 4 ICU days, late vasopressor administration occurred in 5.5% (3,429 of 62,206). Patients with more comorbidities (adjusted OR [aOR], 1.02 per van Walraven point; 95% CI, 1.02-1.03) and worse severity of illness on admission (aOR, 1.01 per percentage point risk of death; 95% CI, 1.01-1.02) were more likely to receive late vasopressor therapy. Nearly 50% of patients started a new antibiotic within 24 h of receiving late vasopressor therapy. One-year mortality after survival to discharge was higher for patients with continuous (adjusted hazard ratio [aHR], 1.48; 95% CI, 1.33-1.65) and late vasopressor administration (aHR, 1.26; 95% CI, 1.15-1.38) compared with only early vasopressor administration.Interpretation: Late vasopressor administration was modestly associated with comorbidities and admission illness severity. One-year mortality was higher among those who received late vasopressor administration compared with only early vasopressor administration. Research to understand optimization of late vasopressor therapy administration may improve long-term mortality. [ABSTRACT FROM AUTHOR]

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 ). [ABSTRACT FROM AUTHOR]

Rationale: The characteristics and outcomes of patients presenting with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) requiring intensive care unit (ICU) admission are poorly understood and there are sparse epidemiological data.Objectives: The objectives were to describe epidemiology and outcomes of patients admitted to an ICU with COPD and to evaluate whether outcomes varied over time.Methods: We studied adult ICU admissions across Australia and New Zealand between 2005 and 2017 with a diagnosis of AECOPD and used an admission diagnosis of asthma as comparator for trends over time. We measured changes in characteristics and outcomes over time using logistic regression, adjusting for illness severity using the Australian New Zealand Risk of Death model.Results: We studied 31,991 admissions with AECOPD and 11,096 with asthma. Mean (standard deviation) age for AECOPD patients was 68.3 (11.2) years, with 35.4% mechanically ventilated. For patients with AECOPD, the percentage of deaths in an ICU was 8.7% and in a hospital was 15.4% of admissions, with the proportion of 69.2% discharged home and 5.6% discharged to a high-level care facility. During the study period, the proportion of ICU admissions with AECOPD per 10,000 admissions decreased at an annual rate of 2.0 (95% confidence interval [CI], 0.8-3.2; P = 0.009) but their admission rate per million population increased annually by 4.5 (95% CI, 3.7-5.3; P < 0.0001). There was a linear reduction in mortality for AECOPD but not for asthma admissions (odds ratio annual decline: AECOPD, 0.94 [0.93-0.95] and asthma, 1.01 [0.97-1.05]; P = 0.001) and an increase in AECOPD admissions discharged to home (odds ratio annual increase, AECOPD, 1.04 [1.03-1.05] and asthma, 1.01 [0.99-1.03]; P = 0.01). The reduction in mortality was sustained after adjusting for illness severity.Conclusions: Across Australia and New Zealand, the rate of ICU admissions due to AECOPD is increasing but mortality rates are decreasing, with a corresponding increase in the home discharge rates. [ABSTRACT FROM AUTHOR]

Rationale: The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared with a lesser amount of calories are unknown.Objectives: Our hypotheses were that achieving approximately 100% of recommended calorie intake during critical illness would increase quality-of-life scores, return to work, and key life activities and reduce death and disability 6 months later.Methods: We conducted a multicenter, blinded, parallel group, randomized clinical trial, with 3,957 mechanically ventilated critically ill adults allocated to energy-dense (1.5 kcal/ml) or routine (1.0 kcal/ml) enteral nutrition.Measurements and Main Results: Participants assigned energy-dense nutrition received more calories (percent recommended energy intake, mean [SD]; energy-dense: 103% [28] vs. usual: 69% [18]). Mortality at Day 180 was similar (560/1,895 [29.6%] vs. 539/1,920 [28.1%]; relative risk 1.05 [95% confidence interval, 0.95-1.16]). At a median (interquartile range) of 185 (182-193) days after randomization, 2,492 survivors were surveyed and reported similar quality of life (EuroQol five dimensions five-level quality-of-life questionnaire visual analog scale, median [interquartile range]: 75 [60-85]; group difference: 0 [95% confidence interval, 0-0]). Similar numbers of participants returned to work with no difference in hours worked or effectiveness at work (n = 818). There was no observed difference in disability (n = 1,208) or participation in key life activities (n = 705).Conclusions: The delivery of approximately 100% compared with 70% of recommended calorie intake during critical illness does not improve quality of life or functional outcomes or increase the number of survivors 6 months later. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Critically ill patients with diabetes mellitus (DM) are at increased risk of in-hospital complications and the optimal glycemic target for such patients remains unclear. A more liberal approach to glucose control has recently been suggested for patients with DM, but uncertainty remains regarding its impact on complications.Methods: We aimed to test the hypothesis that complications would be more common with a liberal glycemic target in ICU patients with DM. Thus, we compared hospital-acquired complications in the first 400 critically ill patients with DM included in a sequential before-and-after trial of liberal (glucose target: 10-14 mmol/L) vs conventional (glucose target: 6-10 mmol/L) glucose control.Results: Of the 400 patients studied, 165 (82.5%) patients in the liberal and 177 (88.5%) in the conventional-control group were coded for at least one hospital-acquired complication (P = 0.09). When comparing clinically relevant complications diagnosed between ICU admission and hospital discharge, we found no difference in the odds for infectious (adjusted odds ratio [aOR] for liberal-control: 1.15 [95% CI: 0.68-1.96], P = 0.60), cardiovascular (aOR 1.40 [95% CI: 0.63-3.12], P = 0.41) or neurological complications (aOR: 1.07 [95% CI: 0.61-1.86], P = 0.81), acute kidney injury (aOR 0.83 [95% CI: 0.43-1.58], P = 0.56) or hospital mortality (aOR: 1.09 [95% CI: 0.59-2.02], P = 0.77) between the liberal and the conventional-control group.Conclusion: In this prospective before-and-after study, liberal glucose control was not associated with an increased risk of hospital-acquired infectious, cardiovascular, renal or neurological complications in critically ill patients with diabetes. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the admission characteristics and hospital outcomes for Indigenous and non-Indigenous patients admitted to intensive units (ICUs) after major trauma.Design, Setting: Retrospective analysis of Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database data from 92 Australian ICUs for the 6-year period, 2010-2015.Participants: Patients older than 17 years of age admitted to public hospital ICUs with a primary diagnosis of trauma.Main Outcome Measures: ICU and overall hospital lengths of stay, hospital discharge destination, and ICU and overall hospital mortality rates for Indigenous and non-Indigenous patients.Results: 23 804 people were admitted to Australian public hospital ICUs after major trauma; 1754 (7.4%) were Indigenous Australians. The population-standardised incidence of admissions was consistently higher for Indigenous Australians than for non-Indigenous Australians (847 per million v 251 per million population; incidence ratio, 3.37; 95% CI, 3.19-3.57). Overall hospital mortality rates were similar for Indigenous and non-Indigenous patients (adjusted odds ratio [aOR], 1.04; 95% CI, 0.82-1.31). Indigenous patients were more likely than non-Indigenous patients to be discharged to another hospital (non-Indigenous v Indigenous: aOR, 0.84; 95% CI, 0.72-0.96) less likely to be discharged home (non-Indigenous v Indigenous: aOR, 1.17; 95% CI, 1.04-1.31).Conclusion: The population rate of trauma-related ICU admissions was substantially higher for Indigenous than non-Indigenous patients, but hospital mortality rates after ICU admission were similar. Indigenous patients were more likely to be discharged to a another hospital and less likely to be discharged home than non-Indigenous patients. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend an initial intravenous (IV) fluid bolus of 30 ml/kg isotonic crystalloid for patients with sepsis and hypotension. However, there is a lack of evidence from clinical trials to support this. Accumulating observational data suggest harm associated with the injudicious use of fluids in sepsis. There is currently equipoise regarding liberal or restricted fluid-volume resuscitation as first-line treatment for sepsis-related hypotension. A randomised trial comparing these two approaches is, therefore, justified.Methods/design: The REstricted Fluid REsuscitation in Sepsis-associated Hypotension trial (REFRESH) is a multicentre, open-label, randomised, phase II clinical feasibility trial. Participants will be patients presenting to the emergency departments of Australian metropolitan hospitals with suspected sepsis and a systolic blood pressure of < 100 mmHg, persisting after a 1000-ml fluid bolus with isotonic crystalloid. Participants will be randomised to either a second 1000-ml fluid bolus (standard care) or maintenance rate fluid only, with the early commencement of a vasopressor infusion to maintain a mean arterial pressure of > 65 mmHg, if required (restricted fluid). All will receive further protocolised fluid boluses (500 ml or 250 ml, respectively), if required during the 6-h study period. The primary outcome measure is total volume administered in the first 6 h. Secondary outcomes include fluid volume at 24 h, organ support 'free days' to day 28, 90-day mortality, and a range of feasibility and process-of-care measures. Participants will also undergo serial measurement, over the first 24 h, of biomarkers of inflammation, endothelial cell activation and glycocalyx degradation for comparison between the groups.Discussion: This is the first randomised trial examining fluid volume for initial resuscitation in septic shock in an industrialised country. A pragmatic, open-label design will establish the feasibility of undertaking a large, international, multicentre trial with sufficient power to assess clinical outcomes. The embedded biomarker study aims to provide mechanistic plausibility for a larger trial by defining the effects of fluid volume on markers of systemic inflammation and the vascular endothelium.Trial Registration: Australia and New Zealand Clinical Trials Registry, ID: ACTRN12616000006448. Registered on 12 January 2016. [ABSTRACT FROM AUTHOR]

Purpose: To use the World Health Organisation's International Classification of Functioning to measure disability following critical illness using patient-reported outcomes.Methods: A prospective, multicentre cohort study conducted in five metropolitan intensive care units (ICU). Participants were adults who had been admitted to the ICU, received more than 24 h of mechanical ventilation and survived to hospital discharge. The primary outcome was measurement of disability using the World Health Organisation's Disability Assessment Schedule 2.0. The secondary outcomes included the limitation of activities and changes to health-related quality of life comparing survivors with and without disability at 6 months after ICU.Results: We followed 262 patients to 6 months, with a mean age of 59 ± 16 years, and of whom 175 (67%) were men. Moderate or severe disability was reported in 65 of 262 (25%). Predictors of disability included a history of anxiety/depression [odds ratio (OR) 1.65 (95% confidence interval (CI) 1.22, 2.23), P = 0.001]; being separated or divorced [OR 2.87 (CI 1.35, 6.08), P = 0.006]; increased duration of mechanical ventilation [OR 1.04 (CI 1.01, 1.08), P = 0.03 per day]; and not being discharged to home from the acute hospital [OR 1.96 (CI 1.01, 3.70) P = 0.04]. Moderate or severe disability at 6 months was associated with limitation in activities, e.g. not returning to work or studies due to health (P < 0.002), and reduced health-related quality of life (P < 0.001).Conclusion: Disability measured using patient-reported outcomes was prevalent at 6 months after critical illness in survivors and was associated with reduced health-related quality of life. Predictors of moderate or severe disability included a prior history of anxiety or depression, separation or divorce and a longer duration of mechanical ventilation.Trial Registration: NCT02225938. [ABSTRACT FROM AUTHOR]

Background: Critical illness is associated with increased risk of fragility fracture and loss of bone mineral density (BMD), although the impact of medication exposures (bone anti-fracture therapy or glucocorticoids) and time remain unexplored. The objective of this study was to describe the association of time after ICU admission, and post-ICU administration of bone anti-fracture therapy or glucocorticoids after critical illness, with change in BMD.Methods: In this prospective observational study, conducted in a tertiary hospital ICU, we studied adult patients requiring mechanical ventilation for at least 24 hours and measured BMD annually for 2 years after ICU discharge. We performed mixed linear modelling to describe the association of time, and post-ICU administration of anti-fracture therapy or glucocorticoids, with annualised change in BMD.Results: Ninety-two participants with a mean age of 63 (±15) years had at least one BMD assessment after ICU discharge. In women, a greater loss of spine BMD occurred in the first year after critical illness (year 1: -1.1 ± 2.0% vs year 2: 3.0 ± 1.7%, p = 0.02), and anti-fracture therapy use was associated with reduced loss of BMD (femur 3.1 ± 2.4% vs -2.8 ± 1.7%, p = 0.04, spine 5.1 ± 2.5% vs -3.2 ± 1.8%, p = 0.01). In men anti-fracture and glucocorticoid use were not associated with change in BMD, and a greater decrease in BMD occurred in the second year after critical illness (year 1: -0.9 ± 2.1% vs year 2: -2.5 ± 2.1%, p = 0.03).Conclusions: In women a greater loss of spine BMD was observed in the first year after critical illness, and anti-fracture therapy use was associated with an increase in BMD. In men BMD loss increased in the second year after critical illness. Anti-fracture therapy may be an effective intervention to prevent bone loss in women after critical illness. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the prevalence, risk factors, prophylactic treatment and impact on mortality for venous thromboembolism (VTE) in patients with moderate to severe traumatic brain injury (TBI) treated in the intensive care unit.Methods: A post hoc analysis of the erythropoietin in traumatic brain injury (EPO-TBI) trial that included twice-weekly lower limb ultrasound screening. Venous thrombotic events were defined as ultrasound-proven proximal deep venous thrombosis (DVT) or clinically detected pulmonary embolism (PE). Results are reported as events, percentages or medians and interquartile range (IQR). Cox regression analysis was used to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time to VTE and death.Results: Of 603 patients, 119 (19.7%) developed VTE, mostly comprising DVT (102 patients, 16.9%) with a smaller number of PE events (24 patients, 4.0%). Median time to DVT diagnosis was 6 days (IQR 2-11) and to PE diagnosis 6.5 days (IQR 2-16.5). Mechanical prophylaxis (MP) was used in 91% of patients on day 1, 97% of patients on day 3 and 98% of patients on day 7. Pharmacological prophylaxis was given in 5% of patients on day 1, 30% of patients on day 3 and 57% of patients on day 7. Factors associated with time to VTE were age (HR per year 1.02, 95% CI 1.01-1.03), patient weight (HR per kg 1.01, 95% CI 1-1.02) and TBI severity according to the International Mission for Prognosis and Analysis of Clinical Trials risk of poor outcome (HR per 10% increase 1.12, 95% CI 1.01-1.25). The development of VTE was not associated with mortality (HR 0.92, 95% CI 0.51-1.65).Conclusions: Despite mechanical and pharmacological prophylaxis, VTE occurs in one out of every five patients with TBI treated in the ICU. Higher age, greater weight and greater severity of TBI increase the risk. The development of VTE was not associated with excess mortality. [ABSTRACT FROM AUTHOR]

Importance: The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.Objective: Externally validate and assess the discriminatory capacities of an increase in SOFA score by 2 or more points, 2 or more SIRS criteria, or a qSOFA score of 2 or more points for outcomes among patients who are critically ill with suspected infection.Design, Setting, and Participants: Retrospective cohort analysis of 184 875 patients with an infection-related primary admission diagnosis in 182 Australian and New Zealand intensive care units (ICUs) from 2000 through 2015.Exposures: SOFA, qSOFA, and SIRS criteria applied to data collected within 24 hours of ICU admission.Main Outcomes and Measures: The primary outcome was in-hospital mortality. In-hospital mortality or ICU length of stay (LOS) of 3 days or more was a composite secondary outcome. Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC). Adjusted analyses were performed using a model of baseline risk determined using variables independent of the scoring systems.Results: Among 184 875 patients (mean age, 62.9 years [SD, 17.4]; women, 82 540 [44.6%]; most common diagnosis bacterial pneumonia, 32 634 [17.7%]), a total of 34 578 patients (18.7%) died in the hospital, and 102 976 patients (55.7%) died or experienced an ICU LOS of 3 days or more. SOFA score increased by 2 or more points in 90.1%; 86.7% manifested 2 or more SIRS criteria, and 54.4% had a qSOFA score of 2 or more points. SOFA demonstrated significantly greater discrimination for in-hospital mortality (crude AUROC, 0.753 [99% CI, 0.750-0.757]) than SIRS criteria (crude AUROC, 0.589 [99% CI, 0.585-0.593]) or qSOFA (crude AUROC, 0.607 [99% CI, 0.603-0.611]). Incremental improvements were 0.164 (99% CI, 0.159-0.169) for SOFA vs SIRS criteria and 0.146 (99% CI, 0.142-0.151) for SOFA vs qSOFA (P <.001). SOFA (AUROC, 0.736 [99% CI, 0.733-0.739]) outperformed the other scores for the secondary end point (SIRS criteria: AUROC, 0.609 [99% CI, 0.606-0.612]; qSOFA: AUROC, 0.606 [99% CI, 0.602-0.609]). Incremental improvements were 0.127 (99% CI, 0.123-0.131) for SOFA vs SIRS criteria and 0.131 (99% CI, 0.127-0.134) for SOFA vs qSOFA (P <.001). Findings were consistent for both outcomes in multiple sensitivity analyses.Conclusions and Relevance: Among adults with suspected infection admitted to an ICU, an increase in SOFA score of 2 or more had greater prognostic accuracy for in-hospital mortality than SIRS criteria or the qSOFA score. These findings suggest that SIRS criteria and qSOFA may have limited utility for predicting mortality in an ICU setting. [ABSTRACT FROM AUTHOR]

Background: Platelets are commonly transfused to critically ill patients. Reports suggest an association between platelet transfusion and infection. However, there is no large study to have determined whether platelet transfusion in critically ill patients is associated with hospital-acquired infection.Methods: We conducted a multi-centre study using prospectively maintained databases of two large academic intensive care units (ICUs) in Australia. Characteristics of patients who received platelets in ICUs between 2008 and 2014 were compared to those of patients who did not receive platelets. Association between platelet administration and infection (bacteraemia and/or bacteriuria) was modelled using multiple logistic regression and Cox regression, with blood components as time-varying covariates. A propensity covariate adjustment was also performed to verify results.Results: Of the 18,965 patients included, 2250 (11.9%) received platelets in ICU with a median number of 1 platelet unit (IQR 1-3) administered. Patients who received platelets were more severely ill at ICU admission (mean Acute Physiology and Chronic Health Evaluation III score 65 (SD 29) vs 52 (SD 25), p < 0.01) and had more comorbidities (31% vs 19%, p < 0.01) than patients without platelet transfusion. Invasive mechanical ventilation (87% vs 57%, p < 0.01) and renal replacement therapy (20% vs 4%, p < 0.01) were more frequently administered in patients receiving platelets than in patients without platelets. On univariate analysis, platelet transfusion was associated with hospital-acquired infection in the ICU (7.7% vs 1.4%, p < 0.01). After adjusting for confounders, including other blood components administered, patient severity, centre, year, and diagnosis category, platelet transfusions were independently associated with infection (adjusted OR 2.56 95% CI 1.98-3.31, p < 0.001). This association was also found in survival analysis with blood components as time-varying covariates (adjusted HR 1.85, 95% CI 1.41-2.41, p < 0.001) and when only bacteraemia was considered (adjusted OR 3.30, 95% CI 2.30-4.74, p <0.001). Platelet transfusions remained associated with infection after propensity covariate adjustment.Conclusions: After adjustment for confounders, including patient severity and other blood components, platelet transfusion was independently associated with ICU-acquired infection. Further research aiming to better understand this association and to prevent this complication is warranted. [ABSTRACT FROM AUTHOR]

Rationale: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis.Objectives: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics.Methods: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis.Measurements and Main Results: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure.Conclusions: Compared with intermittent dosing, administration of β-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality. [ABSTRACT FROM AUTHOR]

Rationale: The ICU Mobility Scale (IMS) is a measure of mobility milestones in critically ill patients.Objectives: This study aimed to determine the validity and responsiveness of the IMS from a prospective cohort study of adults admitted to the intensive care unit (ICU).Methods: Construct and predictive validity were assessed by comparing IMS values at ICU discharge in 192 patients to other variables using Spearman rank correlation coefficient, Mann-Whitney U tests, and logistic regression. Responsiveness was assessed using change over time, effect size, floor and ceiling effects, and percentage of patients showing change.Measurements and Main Results: The IMS at ICU discharge demonstrated a moderate correlation with muscle strength (r = 0.64, P < 0.001). There was a significant difference between the IMS at ICU discharge in patients with ICU-acquired weakness (median, 4.0; interquartile range, 3.0-5.0) compared with patients without (median, 8.0; interquartile range, 5.0-8.0; P < 0.001). Increasing IMS values at ICU discharge were associated with survival to 90 days (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.14-1.66) and discharge home (OR, 1.16; 95% CI, 1.02-1.32) but not with return to work at 6 months (OR, 1.09; 95% CI, 0.92-1.28). The IMS was responsive with a significant change from study enrollment to ICU discharge (d = 0.8, P < 0.001), with IMS values increasing in 86% of survivors during ICU admission. No substantial floor (14% scored 0) or ceiling (4% scored 10) effects were present at ICU discharge.Conclusions: Our findings support the validity and responsiveness of the IMS as a measure of mobility in the ICU. [ABSTRACT FROM AUTHOR]

Objective: To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy.Design: Post hoc analysis of data from a multicenter, randomized, controlled trial.Setting: Thirty-five ICUs in Australia and New Zealand.Patients: Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study.Interventions: Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes.Measurements and Main Results: Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111 g/L; p < 0.001). Mean daily hemoglobin was 88 ± 7 and 99 ± 12 g/L in transfused and nontransfused patients. Among transfused patients, 228 (46.7%) had died by day 90 when compared with 426 (43.6%) of nontransfused patients (p = 0.27). Survivors received on average 316 ± 261 mL of RBC, whereas nonsurvivors received 302 ± 362 mL (p = 0.42). On multivariate Cox regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital.Conclusions: In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials. [ABSTRACT FROM AUTHOR]

Importance: Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation.Objective: To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation.Design, Setting, and Participants: The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded.Interventions: Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician.Main Outcomes and Measures: Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori.Results: Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007).Conclusions and Relevance: Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these.Trial Registration: clinicaltrials.gov Identifier: NCT01151865. [ABSTRACT FROM AUTHOR]

Purpose: To study the impact of pre-morbid glycemic control on the association between acute hypoglycemia in intensive care unit (ICU) patients and subsequent hospital mortality in critically ill patients.Methods: We performed a multicenter, multinational, retrospective observational study of patients with available HbA1c levels within the 3-month period preceding ICU admission. We separated patients into three cohorts according to pre-admission HbA1c levels (<6.5, 6.5-7.9, ≥8.0%, respectively). Based on published data, we defined a glucose concentration of 40-69 mg/dL (2.2-3.8 mmol/L) as moderate hypoglycemia and <40 mg/dL (<2.2 mmol/L) as severe hypoglycemia. We applied logistic regression analysis to study the impact of pre-morbid glycemic control on the relationship between acute hypoglycemia and mortality.Results: A total of 3084 critically ill patients were enrolled in the study. Among these patients, with increasing HbA1c levels from <6.5, to 6.5-7.9, and to ≥8.0%, the incidence of both moderate (3.8, 11.1, and 16.4%, respectively; p < 0.001) and severe (0.9, 2.5, and 4.3%, respectively; p < 0.001) hypoglycemia progressively and significantly increased. The relationship between the occurrence of hypoglycemic episodes in the ICU and in-hospital mortality was independently and significantly affected by pre-morbid glucose control, as assessed by adjusted odds ratio (OR) and 95 % confidence interval (CI) for hospital mortality: (1) moderate hypoglycemia: in patients with <6.5, 6.5-7.9, and ≥8.0 % of HbA1c level-OR 0.54, 95% CI 0.25-1.16; OR 0.82, 95 % CI 0.33-2.05; OR 3.42, 95 % CI 1.29-9.06, respectively; (2) severe hypoglycemia: OR 1.50, 95% CI 0.42-5.33; OR 1.59, 95% CI 0.36-7.10; OR 23.46, 95% CI 5.13-107.28, respectively (interaction with pre-morbid glucose control, p = 0.009). We found that the higher the glucose level before admission to the ICU, the higher the mortality risk when patients experienced hypoglycemia.Conclusions: In critically ill patients, chronic pre-morbid hyperglycemia increases the risk of hypoglycemia and modifies the association between acute hypoglycemia and mortality. [ABSTRACT FROM AUTHOR]

Background: Optimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality.Methods/design: We designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient's blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients' demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics.Discussion: Using the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT.Trial Registration: Australian New Zealand Clinical Trial Registry ( ACTRN12613000241730 ) registered 28 February 2013. [ABSTRACT FROM AUTHOR]

Rationale: There are no randomized controlled trials comparing different oxygenation targets for intensive care unit (ICU) patients.Objectives: To determine whether a conservative oxygenation strategy is a feasible alternative to a liberal oxygenation strategy among ICU patients requiring invasive mechanical ventilation (IMV).Methods: At four multidisciplinary ICUs, 103 adult patients deemed likely to require IMV for greater than or equal to 24 hours were randomly allocated to either a conservative oxygenation strategy with target oxygen saturation as measured by pulse oximetry (SpO2) of 88-92% (n = 52) or a liberal oxygenation strategy with target SpO2 of greater than or equal to 96% (n = 51).Measurements and Main Results: The mean area under the curve and 95% confidence interval (CI) for SpO2 (93.4% [92.9-93.9%] vs. 97% [96.5-97.5%]), SaO2 (93.5% [93.1-94%] vs. 96.8% [96.3-97.3%]), PaO2 (70 [68-73] mm Hg vs. 92 [89-96] mm Hg), and FiO2 (0.26 [0.25-0.28] vs. 0.36 [0.34-0.39) in the conservative versus liberal oxygenation arm were significantly different (P < 0.0001 for all). There were no significant between-group differences in any measures of new organ dysfunction, or ICU or 90-day mortality. The percentage time spent with SpO2 less than 88% in conservative versus liberal arm was 1% versus 0.3% (P = 0.03), and percentage time spent with SpO2 greater than 98% in conservative versus liberal arm was 4% versus 22% (P < 0.001). The adjusted hazard ratio for 90-day mortality in the conservative arm was 0.77 (95% CI, 0.40-1.50; P = 0.44) overall and 0.49 (95% CI, 0.20-1.17; P = 0.10) in the prespecified subgroup of patients with a baseline PaO2/FiO2 less than 300.Conclusions: Our study supports the feasibility of a conservative oxygenation strategy in patients receiving IMV. Larger randomized controlled trials of this intervention appear justified. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN 12613000505707). [ABSTRACT FROM AUTHOR]

Rationale: Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with intermittent dosing.Objectives: To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis.Methods: We conducted a randomized controlled trial in 25 intensive care units (ICUs). Participants commenced on piperacillin-tazobactam, ticarcillin-clavulanate, or meropenem were randomized to receive the prescribed antibiotic via continuous or 30-minute intermittent infusion for the remainder of the treatment course or until ICU discharge. The primary outcome was the number of alive ICU-free days at Day 28. Secondary outcomes were 90-day survival, clinical cure 14 days post antibiotic cessation, alive organ failure-free days at Day 14, and duration of bacteremia.Measurements and Main Results: We enrolled 432 eligible participants with a median age of 64 years and an Acute Physiology and Chronic Health Evaluation II score of 20. There was no difference in ICU-free days: 18 days (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24).Conclusions: In critically ill patients with severe sepsis, there was no difference in outcomes between β-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886). [ABSTRACT FROM AUTHOR]

The article presents the reply to Picod et al which includes The renin–angiotensin–aldosterone system (RAAS) is disordered in patients with catecholamine-resistant vasodilatory shock (CRVS), inadequate activation of the ATR1 in some patients and renin levels are common in patients with CRVS.

Purpose: The choice of vascular access catheter may affect filter life during continuous renal replacement therapy (CRRT). In particular, differences in catheter design might affect the incidence of circuit clotting related to catheter malfunction. Design and setting: Sequential controlled study in a tertiary, adult intensive care unit (ICU). Aim: To compare circuit life when CRRT was performed with a Niagara™ catheter or a Medcomp™ catheter. Patients and measurements: We studied 46 patients with acute kidney injury requiring CRRT, all delivered with catheters in the femoral position. We obtained information on age, gender, disease severity score [acute physiology and chronic health evaluation (APACHE II) and APACHE III], filter life, heparin dose per hour, daily systemic hemoglobin concentration, platelet count, international normalized ratio (INR), and activated partial thromboplastin time (APTT) during CRRT. Results: We studied 254 circuits in 46 patients. Of these, 26 patients (140 circuits) used the Niagara catheter and 20 patients (114 circuits) used the Medcomp catheter. Median circuit life in the two groups were 11 h and 7.3 h, respectively ( p < 0.01). Patients using Medcomp catheters had a lower platelet count ( p = 0.04) and a lower hemoglobin concentration ( p = 0.01), but INR ( p = 0.16), APTT ( p = 0.46), anticoagulant treatment ( p = 0.89), and heparin dose per hour ( p = 0.24) were similar. After correcting for confounding variables by multivariable linear regression analysis, it was found that the choice of catheter is not an independent predictor of circuit life. On Kaplan-Meier survival analysis, circuit life was not significantly different between the two catheters ( p = 0.87). Conclusion: The choice of either the Niagara or Medcomp catheter does not appear to be a significant independent determinant of circuit life during CRRT. [ABSTRACT FROM AUTHOR]

Background. A blood urea nitrogen (BUN)/creatinine ratio (BCR) >20 (0.081 in international unit) is used to distinguish pre-renal azotemia (PRA) and acute tubular necrosis (ATN). However, there is little evidence that BCR can distinguish between these two conditions and/or is clinically useful. Methods. We conducted a retrospective study using a large hospital database. Patients were divided into three groups: ‘low BCR’ (if BCR when acute kidney injury (AKI) developed was ≤20), ‘high BCR’ (if BCR when AKI developed was >20) and ‘no AKI’ if patients did not satisfy any of the Risk, Injury, Failure, Loss and End-stage kidney disease criteria for AKI during hospitalization. Results. Among 20 126 study patients, 3641 (18.1%) had AKI. Among these patients, 1704 (46.8%) had a BCR <20 at AKI diagnosis (‘low BCR’) and 1937 (53.2%) had a BCR >20 (‘high BCR’). The average BCR for the two groups was 15.8 versus 26.1 (P < 0.001). Hospital mortality was significantly less in the ‘low-BCR’ group (18.4 versus 29.9%, P < 0.001). Multivariable logistic regression analysis for hospital mortality (‘no AKI’ as a reference) showed that the odds ratio of ‘high BCR’ (5.73) was higher than that of ‘low BCR’ (3.32). Conclusions. Approximately half of the patients with AKI have a BCR >20, the traditional threshold of diagnosing PRA. Unlike PRA patients who have a lower mortality than ATN patients, high BCR patients had higher hospital mortality compared with low BCR patients, which was confirmed with multivariable analysis. These findings do not support BCR as a marker of PRA. [ABSTRACT FROM PUBLISHER]

Background. A pre-morbid ‘baseline’ creatinine is required in order to diagnose and stage acute kidney injury (AKI) using the RIFLE classification. Estimation of baseline creatinine by solving the Modification of Diet in Renal Disease (MDRD) equation assuming a glomerular filtration rate of 75 ml/min/1.73 m2 has been widely used but never validated.Methods. We analysed four cohorts of intensive care unit (ICU) patients from three centres (two from Pittsburgh and one from Mayo and Austin). Three cohorts consisted of preselected patients without AKI (Pittsburgh 1 n = 1048, Mayo n = 737, Austin n = 333), and measured creatinine values in these cohorts were taken to represent baseline creatinine values. The last cohort (Pittsburgh 2 n = 468) consisted of unselected ICU patients with baseline creatinine values recorded within 1 year before ICU admission. Using the Pittsburgh 1 cohort, we derived an equation using the same anthropometric variables as the MDRD equation: baseline creatinine = 0.74 − 0.2 (if female) + 0.08 (if black) + 0.003 × age (in years). We then compared measured creatinine in the Mayo and Austin cohorts and recorded creatinine in the Pittsburgh 2 cohort to the estimated creatinine from: (i) the MDRD equation; (ii) our new equation; (iii) a gender-fixed creatinine of 0.8 mg/dl for females and 1.0 mg/dl for males.Results. Using any of the three methods, the median absolute error of the estimates was of the order of 0.1–0.2 mg/dl, and overall accuracy was similar. When the definition of AKI was limited to the severity grades of Injury and Failure, all three methods were able to generate 78–90% reliable results for preselected normal range cohorts, and 63–70% for the unselected cohort of ICU patients.Conclusions. Estimates of incidence of AKI in the critically ill using RIFLE classification can be affected by the bias and limited accuracy of methods to estimate baseline creatinine. Whenever possible, recorded creatinine values should be used as a reference of baseline. The use of the MDRD equation to estimate baseline creatinine when it is unknown may over- or underestimate some mild (Risk) AKI cases but is unlikely to misclassify patients in Injury and Failure. [ABSTRACT FROM AUTHOR]

Objective: Little information is available regarding current practice in continuous renal replacement therapy (CRRT) for the treatment of acute renal failure (ARF) and the possible clinical effect of practice variation.Design: Prospective observational study.Setting: A total of 54 intensive care units (ICUs) in 23 countries.Patients and Participants: A cohort of 1006 ICU patients treated with CRRT for ARF.Interventions: Collection of demographic, clinical and outcome data.Measurements and Results: All patients except one were treated with venovenous circuits, most commonly as venovenous hemofiltration (52.8%). Approximately one-third received CRRT without anticoagulation (33.1%). Among patients who received anticoagulation, unfractionated heparin (UFH) was the most common choice (42.9%), followed by sodium citrate (9.9%), nafamostat mesilate (6.1%), and low-molecular-weight heparin (LMWH; 4.4%). Hypotension related to CRRT occurred in 19% of patients and arrhythmias in 4.3%. Bleeding complications occurred in 3.3% of patients. Treatment with LMWH was associated with a higher incidence of bleeding complications (11.4%) compared to UFH (2.3%, p = 0.0083) and citrate (2.0%, p = 0.029). The median dose of CRRT was 20.4 ml/kg/h. Only 11.7% of patients received a dose of > 35 ml/kg/h. Most (85.5%) survivors recovered to dialysis independence at hospital discharge. Hospital mortality was 63.8%. Multivariable analysis showed that no CRRT-related variables (mode, filter material, drug for anticoagulation, and prescribed dose) predicted hospital mortality.Conclusions: This study supports the notion that, worldwide, CRRT practice is quite variable and not aligned with best evidence. [ABSTRACT FROM AUTHOR]

Objective: To measure renal blood flow (RBF) and renal function during recovery from experimental septic acute kidney injury (AKI).Design: Controlled experimental study.Subjects: Nine merino ewes.Setting: University physiology laboratory.Intervention: We recorded systemic and renal hemodynamics during a 96-h observation period (control) via implanted transit-time flow probes. We then compared this period with 96[Symbol: see text]h of septic AKI (48 h of Escherichia coli infusion) and subsequent recovery (48 h of observation after stopping E. coli).Measurements and Results: Compared with the control period, E. coli infusion induced hyperdynamic sepsis (increased cardiac output and decreased blood pressure) and septic AKI (serum creatinine 65.4 +/- 8.7 vs. 139.9 +/- 33.0 micromol/l; creatinine clearance 73.8 +/- 12.2 vs. 40.2 +/- 17.2 ml/min; p < 0.05) with a mortality of 22%. RBF increased (278.8 +/- 33.9 vs. 547.9 +/- 124.8 ml/min; p < 0.05) as did renal vascular conductance (RVC). During recovery, we observed a decrease in RVC and RBF with all values returning to control levels. Indices of tubular function [fractional excretion of sodium (FENa) and urea (FEUn) and urinary sodium concentration (UNa)], which had been affected by sepsis, returned to control values after 18 h of recovery, as did serum creatinine.Conclusions: Infusion of E. coli induced a hyperdynamic circulatory state with hyperemic AKI. Recovery was associated with relative renal vasoconstriction and reduction in RBF and RVC back to control levels. Indices of tubular function normalized more rapidly than changes in RBF. [ABSTRACT FROM AUTHOR]

Background and Aims: Continuous veno-venous haemofiltration (CVVH) is an established treatment for acute renal failure (ARF). Recently, extended intermittent dialytic techniques have been proposed for the treatment of ARF. The aim of this study was to compare these two approaches.Setting: Intensive care unit of tertiary hospital.Subjects: Sixteen critically ill patients with ARF.Design: Randomised controlled trial.Intervention: We randomised sixteen patients to three consecutive days of treatment with either CVVH (8) or extended daily dialysis with filtration (EDDf) (8) and compared small-solute, electrolyte and acid-base control.Results: There was no significant difference between the two therapies for urea or creatinine levels over 3 days. Of 80 electrolyte measurements taken before treatment, 19 were abnormal. All values were corrected as a result of treatment, except for one patient in the CVVH group who developed hypophosphataemia (0.54 mmol/l) at 72 h. After 3 days of treatment, there was a mild but persistent metabolic acidosis in the EDDf group compared to the CVVH group (median bicarbonate: 20 mmol/l vs. 29 mmol/l: p=0.039; median base deficit: -4 mEq/l vs. -2.1 mEq/l, p=0.033).Conclusions: CVVH and EDDf as prescribed achieved similar control of urea, creatinine and electrolytes. Acidosis was better controlled with CVVH. [ABSTRACT FROM AUTHOR]

Objective: To compare measurement of cardiac output (CO) by means of the FloTrac CO monitor with the pulmonary artery catheter (PAC).Design: Prospective observational study.Setting: Intensive care unit of a tertiary hospital.Patients: Six post-operative cardiac surgery patients with existing arterial cannulas and PACs.Interventions: Attachment of the FloTrac CO monitor and transducer to an existing arterial cannula. Simultaneous measurements of CO, indexed to body surface area (cardiac index, CI) by the FloTrac CO monitor and by either a bolus thermodilution or continuous CO PAC. Statistical analysis of observations.Measurements and Results: We performed CO measurements in six patients every 1-4 h after cardiac surgery. Comparison of all measurements showed a limited correlation for CI with the two devices (r (2)=0.1218, bias=0.21, 95% limits of agreement -0.81, 1.23). CI measurements obtained with the intermittent bolus PAC had better correlation with the FloTrac CI values (r (2) = 0.2693, bias=-0.0057, 95% limits of agreement -1.2042, 1.1929) than did those obtained with the continuous CO PAC (r (2)=0.0557, bias=0.2436, 95% limits of agreement -0.7350, 1.2222). When analysed according to heart rhythm, CI values measured during atrial pacing showed the best correlation (r (2)=0.377, bias=-0.0244, 95% limits of agreement -0.5226, 0.5714).Conclusions: CO measurements obtained using the FloTrac CO monitor show a limited correlation with those acquired using the PAC, relatively wide limits of agreement but no clear bias. Further evaluation is required before this device can be recommended for use in the clinical setting. [ABSTRACT FROM AUTHOR]

Objective: To study the effect of epinephrine (EPI) infusion on vital organ blood flow and metabolic variables during sepsis.Design and Setting: Randomised placebo-controlled animal trial in an animal laboratory.Animals: Seven merino cross-ewes.Interventions: Chronic implantation of flow probes (aorta, renal, mesenteric and coronary artery and sagittal sinus). Induction of sepsis by intravenous injection of E. coli. Random allocation of sheep to EPI (0.4 microg kg(-1) min(-1)) or vehicle for 6 h.Measurements and Results: E. coli induced hypotension and hyperlactataemia and increased cardiac output, renal, mesenteric and coronary blood flows. Compared to vehicle, EPI restored mean arterial blood pressure (69 vs. 86 mmHg) and further increased cardiac output (6.4 vs. 7.1 l/min). EPI, however, decreased renal blood flow (330 vs. 247 ml/min) and renal conductance. EPI also reduced mesenteric and coronary conductance without changes in flows. Compared to vehicle, EPI increased urine output (293 vs. 544 ml/6 h) but not creatinine clearance. EPI increased lactate (1.8 vs. 15.7 mmol/l) with accompanying acidosis (serum bicarbonate: 25.2 vs. 15.7 mmol/l), hyperglycaemia (2.6 vs. 13.5 mmol/l) and hypokalaemia (4.3 vs. 3.0 mmol/l).Conclusions: Hyperdynamic sepsis increased blood flow to heart, gut and kidney. Although EPI infusion further increased cardiac output, blood pressure and myocardial performance, it was also associated with potent metabolic effects, decreased mesenteric, coronary and renal conductance and a significant reduction in renal blood flow. [ABSTRACT FROM AUTHOR]

Objective: To study the effect of norepinephrine (NE) infusion on cerebral, coronary, renal and mesenteric blood flow during sepsis.Design and Setting: Randomised placebo-controlled animal trial in the animal laboratory of university physiology institute.Animals: Seven merino cross-ewes.Interventions: Chronic implantation of flow probes (aorta, renal, mesenteric and coronary artery and sagittal sinus). Induction of sepsis by intravenous bolus of E. coli (3 x 10(9)). After the onset of hyperdynamic sepsis sheep were randomly allocated to either NE (0.4 microg kg(-1) min(-1)) or placebo for 6 h.Measurements and Results: E. coli induced hypotension, fever, oliguria, tachycardia and tachypnoea. It increased cardiac output and renal, mesenteric and coronary blood flows. Sagittal flow remained unchanged. Compared to placebo NE infusion restored mean arterial blood pressure and further increased cardiac output. The increases in renal, mesenteric and coronary blood flow were unaffected. Sagittal flow was also unaltered. Compared to placebo NE increased myocardial performance, mean urine output and creatinine clearance at 2 h.Conclusions: We conclude that hyperdynamic sepsis increases blood flow to heart, gut and kidney and that NE further increases cardiac output, blood pressure, myocardial performance, and urine output and creatinine clearance while maintaining regional blood flow. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of changing the amount of pre-dilution replacement fluid on the sieving coefficient (SC) and mass transfer of small solutes during isovolaemic high-volume haemofiltration (HVHF).Design and Setting: Prospective interventional study in the intensive care unit of a tertiary university hospital.Patients: Eight patients with septic shock.Interventions: Isovolaemic HVHF (6 l/h of replacement fluid) was performed. The proportion of replacement fluid delivered in pre-filter was altered to progressively decrease it from 6 to 0 l/h. Samples were simultaneously taken from the "pre-filter", "post-filter" and ultrafiltrate (UF) sampling ports.Measurements and Results: Sodium, potassium, chloride, total calcium, total magnesium, phosphate, total CO(2), urea, creatinine and glucose concentrations were measured in each sample. The sieving coefficients of chloride, total CO(2), phosphate, urea and glucose were higher than 1 in most pre-dilution states. The sieving coefficients of sodium, potassium, calcium, magnesium, total CO(2) and urea decreased significantly with decreasing pre-dilution fluid rate. The sieving coefficients of chloride and glucose increased with decreasing pre-dilution fluid rate. There was a significant mass gain of sodium and glucose under all pre-dilution conditions. Mass chloride gains decreased with decreasing pre-dilution rates and changed into chloride loss during 6 l/h of post-dilution. Decreasing pre-dilution improved urea and creatinine mass removal.Conclusions: Small solute SC and mass transfer during isovolaemic HVHF are significantly affected by the proportion of replacement fluid administered pre-filter. Isovolaemic HVHF is neither isonatraemic nor isochloraemic. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of high-volume hemofiltration (HVHF) with lactate-buffered replacement fluids on acid-base balance.Design: Randomized crossover study.Setting: Intensive Care Unit of Tertiary Medical CenterParticipants: Ten patients with septic shock and acute renal failure.Interventions: Random allocation to 8 h of isovolemic high-volume hemofiltration (ultrafiltration rate: 6 l/h) or 8 h of isovolemic continuous venovenous hemofiltration (ultrafiltration rate: 1 l/h) with lactate-buffered replacement fluid with subsequent crossover.Measurements and Results: We measured blood gases, electrolytes, albumin, and lactate concentrations and completed quantitative biophysical analysis of acid-base balance changes. Before high-volume hemofiltration, patients had a slight metabolic alkalosis [pH: 7.42; base excess (BE) 2.4 mEq/l] despite hyperlactatemia (lactate: 2.51 mmol/l). After 2 h of high-volume hemofiltration, the mean lactate concentration increased to 7.30 mmol/l ( p=0.0001). However, a decrease in chloride, strong ion difference effective, and strong ion gap (SIG) compensated for the effect of iatrogenic hyperlactatemia so that the pH only decreased to 7.39 ( p=0.05) and the BE to -0.15 ( p=0.001). After 6 h, despite persistent hyperlactatemia (7 mmol/l), the pH had returned to 7.42 and the BE to 2.45 mEq/l. These changes remained essentially stable at 8 h. Similar but less intense changes occurred during continuous venovenous hemofiltration.Conclusions: HVHF with lactate-buffered replacement fluids induces iatrogenic hyperlactatemia. However, such hyperlactatemia only has a mild and transient acidifying effect. A decrease in chloride and strong ion difference effective and the removal of unmeasured anions all rapidly compensate for this effect. [ABSTRACT FROM AUTHOR]

Objectives: Norepinephrine use in patients after cardiac surgery is controversial because of the fear that norepinephrine might decrease kidney function through regional vasoconstriction. Accordingly, we studied the renal effects of norepinephrine use for hypotensive vasodilatation after cardiac surgery.Design and Setting: Retrospective controlled study in the cardiothoracic ICU of tertiary hospital. PATIENTS. 100 cardiac surgery patients with post-operative hypotensive vasodilatation and 100 control cardiac surgery patients.Intervention: Treatment of hypotension (MAP<70 mmHg) with continuous norepinephrine infusion.Measurements and Results: We collected data on demographic and surgical characteristics, haemodynamics, serum creatinine and mortality. Just after surgery the norepinephrine group had a significantly higher mean central venous pressure, lower mean arterial pressure, and lower systemic vascular resistance index with a similarly elevated mean cardiac index. Despite norepinephrine administration at a mean peak dose of 7.3+/-6.4 micro g/min the mean post-operative change in creatinine was not different between two groups on days 0, 2 or 4 after surgery.Conclusions: Norepinephrine does not increase post-operative serum creatinine concentrations in patients with hypotensive vasodilatation after cardiac surgery. Concerns related to its potential adverse effects on the kidney function in this setting appear unjustified. [ABSTRACT FROM AUTHOR]

Objective: To test whether norepinephrine (NE) infusion at 0.4 microg kg(-1) min(-1) adversely affects regional blood flow in the normal mammalian circulation.Design and Setting: Randomized cross-over experimental animal study in a university-affiliated physiology institute.Subjects: Six merino ewes.Interventions: Staged insertion of transit-time flow probes around the ascending aorta and circumflex coronary, superior mesenteric and left renal arteries. In conscious animals with chronically embedded flow probes randomization to either 6 h of placebo (saline) or drug (NE at 0.4 microg kg(-1) min(-1)).Measurements and Results: Compared to placebo, NE significantly increased mean arterial pressure (84.4 vs. 103.8 mmHg), heart rate (61.0 vs. 74.6 bpm) and cardiac output (3.76 vs. 4.78 l/min). These changes were associated with an increase in coronary blood flow (24.2 vs. 37.4 ml/min) and renal blood flow (215.2 vs. 282.0 ml/min) but no change in mesenteric blood flow. The increase in renal and coronary blood flow was associated with an increase in regional conductance (regional vasodilatation), while mesenteric conductance fell (mesenteric vasoconstriction). Urine output (91+/-17 vs. 491+/-360 ml/h) and creatinine clearance (61+/-18 vs. 89+/-12 ml/min) increased during NE infusion.Conclusions: NE infusion does not induce vital organ ischaemia in the normal mammalian circulation. Furthermore, it results in a significant increase in coronary and renal blood flow with a concomitant improvement in urine output and creatinine clearance. [ABSTRACT FROM AUTHOR]

The article reports on the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial which compared early goal-directed therapy (EGDT) with usual care in managing patients with septic shock admitted at the emergency department. Topics covered include analysis of the volume of intravenous fluid administered, central venous pressure (CVP) and mean arterial blood pressure (MAP) during the first 6 hours of the ARISE trial and relationship between CVP and fluid administration in septic patients.

Aim: The effect of conservative versus liberal oxygen therapy on mortality rates in post cardiac arrest patients is uncertain.Methods: We undertook an individual patient data meta-analysis of patients randomised in clinical trials to conservative or liberal oxygen therapy after a cardiac arrest. The primary end point was mortality at last follow-up.Results: Individual level patient data were obtained from seven randomised clinical trials with a total of 429 trial participants included. Four trials enrolled patients in the pre-hospital period. Of these, two provided protocol-directed oxygen therapy for 60 min, one provided it until the patient was handed over to the emergency department staff, and one provided it for a total of 72 h or until the patient was extubated. Three trials enrolled patients after intensive care unit (ICU) admission and generally continued protocolised oxygen therapy for a longer period, often until ICU discharge. A total of 90 of 221 patients (40.7%) assigned to conservative oxygen therapy and 103 of 206 patients (50%) assigned to liberal oxygen therapy had died by this last point of follow-up; absolute difference; odds ratio (OR) adjusted for study only; 0.67; 95% CI 0.45 to 0.99; P = 0.045; adjusted OR, 0.58; 95% CI 0.35 to 0.96; P = 0.04.Conclusion: Conservative oxygen therapy was associated with a statistically significant reduction in mortality at last follow-up compared to liberal oxygen therapy but the certainty of available evidence was low or very low due to bias, imprecision, and indirectness.Prospero Registration Number: CRD42019138931. [ABSTRACT FROM AUTHOR]

Background: The association between intraoperative oliguria during major abdominal surgery and the subsequent development of postoperative acute kidney injury (AKI) remains poorly defined. We hypothesised that, in such patients, intraoperative oliguria would be an independent predictor of subsequent AKI.Methods: We performed a post hoc analysis of data from the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial of conservative vs liberal fluid therapy during and after major abdominal surgery. We used χ2, logistic regression, and fractional polynomials to study the association between intraoperative oliguria defined as a urinary output <0.5 ml kg-1 h-1 and the development of postoperative AKI defined by the Kidney Disease Improving Global Outcomes consensus criteria.Results: We included 2444 of 2983 patients from the RELIEF trial in this study. A total of 889 patients (36%) met oliguric criteria intraoperatively. Oliguria occurred in 35% of those without AKI, and 44%, 48%, and 45% of those who developed postoperative AKI Stages 1-3, respectively (P<0.001 for trend). Intraoperative oliguria was associated with an increased risk of AKI, risk ratio: 1.38 (95% confidence interval: 1.14-1.44; P<0.001), but greater intensity of oliguria (urine output <0.3 ml kg-1 h-1) did not increase this risk further. Most patients with oliguria did not develop AKI; the positive predictive value of oliguria was 25.5%, and the negative predictive value was 81.6%.Conclusions: Intraoperative oliguria, defined as urine output <0.5 ml kg-1 h-1, was relatively common and was associated with postoperative AKI. However, the predictive utility of oliguria for AKI was low, whilst its absence had a good predictive value for an AKI-free postoperative course.Clinical Trial Registration: NCT01424150. [ABSTRACT FROM AUTHOR]

Objectives: To determine if the early goal-directed mobilization intervention could be delivered to patients receiving mechanical ventilation with increased maximal levels of activity compared with standard care.Design: A pilot randomized controlled trial.Setting: Five ICUs in Australia and New Zealand.Participants: Fifty critically ill adults mechanically ventilated for greater than 24 hours.Intervention: Patients were randomly assigned to either early goal-directed mobilization (intervention) or to standard care (control). Early goal-directed mobilization comprised functional rehabilitation treatment conducted at the highest level of activity possible for that patient assessed by the ICU mobility scale while receiving mechanical ventilation.Measurements and Main Results: The ICU mobility scale, strength, ventilation duration, ICU and hospital length of stay, and total inpatient (acute and rehabilitation) stay as well as 6-month post-ICU discharge health-related quality of life, activities of daily living, and anxiety and depression were recorded. The mean age was 61 years and 60% were men. The highest level of activity (ICU mobility scale) recorded during the ICU stay between the intervention and control groups was mean (95% CI) 7.3 (6.3-8.3) versus 5.9 (4.9-6.9), p = 0.05. The proportion of patients who walked in ICU was almost doubled with early goal-directed mobilization (intervention n = 19 [66%] vs control n = 8 [38%]; p = 0.05). There was no difference in total inpatient stay (d) between the intervention versus control groups (20 [15-35] vs 34 [18-43]; p = 0.37). There were no adverse events.Conclusions: Key Practice Points: Delivery of early goal-directed mobilization within a randomized controlled trial was feasible, safe and resulted in increased duration and level of active exercises. [ABSTRACT FROM AUTHOR]

Background: Optimal cerebral oxygenation is considered fundamental to cerebral protection in cardiac arrest (CA) patients. Hypercapnia increases cerebral blood flow and may also improve cerebral oxygenation. It is uncertain, however, whether this effect occurs in mechanically ventilated early survivors of CA.Methods: We enrolled mechanically ventilated resuscitated patients within 36h of their cardiac arrest. We performed a prospective double cross-over physiological study comparing the impact of normocapnia (PaCO2 35-45mmHg) vs. mild hypercapnia (PaCO2 45-55mmHg) on regional cerebral tissue oxygen saturation (SctO2) assessed by near infrared spectroscopy (NIRS).Results: We studied seven adult CA patients with a median time to return of spontaneous circulation of 28min at a median of 26h and 30min after CA. During normocapnia (median EtCO2 of 32mmHg [30-41mmHg] and PaCO2 of 37mmHg [32-45mmHg]) the median NIRS-derived left frontal SctO2 was 61% [52-65%] and the right frontal SctO2 was 61% [54-68%]. However, during mild hypercapnia (median EtCO2 of 49mmHg [40-57mmHg] and PaCO2 of 52mmHg [43-55mmHg) the median left frontal SctO2 increased to 69% [59-78%] and the right frontal SctO2 increased to 73% [61-76%])(p=0.001, for all comparisons).Conclusion: During the early post-resuscitation period, in mechanically ventilated CA patients, mild hypercapnia increases cerebral oxygenation as assessed by NIRS. Further investigations of the effect of prolonged mild hypercapnia on cerebral oxygenation and patient outcomes appear justified. [ABSTRACT FROM AUTHOR]