Acute brain dysfunction (delirium) is common in sepsis, and many survivors develop persistent cognitive impairment. Cerebral hypoperfusion and edema are implicated, yet it is unknown whether intracranial hypertension contributes to the neurological sequelae of sepsis, and no therapies specifically target cerebral hemodynamic dysfunction. Intravenous megadose sodium ascorbate has been reported to reverse cerebral tissue ischemia and hypoxia and reduce vasopressor requirements in preclinical and clinical studies. Here, we test for the first time the effects of sepsis and megadose sodium ascorbate on intracranial pressure (ICP), cerebral perfusion pressure (CPP) and pressor responsiveness to norepinephrine in a clinically relevant ovine model of Gram-negative sepsis. Adult Merino ewes were surgically instrumented with lateral cerebral ventricular catheters and carotid arterial and jugular venous catheters. Non-anesthetized sheep were infused with intravenous live Escherichia coli for 31-h. After 23-h of sepsis animals received bolus fluid resuscitation (30 mL/kg from 23-23.5-h; sodium lactate) and were randomized to receive intravenous 3 g/kg of sodium ascorbate (n = 7) or fluid-matched placebo (n = 6), as a bolus followed by a 7-h infusion. ICP and mean arterial pressure (MAP) were measured continuously. Changes in MAP to escalating norepinephrine doses were recorded at baseline and 23-h of sepsis, and after treatment at 27.5 and 31-h of sepsis. Sepsis reduced MAP and CPP and increased heart rate and ICP (all P < 0.01). By 31-h of sepsis, sodium ascorbate improved MAP compared with placebo (75 ± 5 to 87 ± 11 vs. 69 ± 11 to 66 ± 7 mmHg; P = 0.020). In addition, sodium ascorbate normalised ICP, whereas it remained elevated with placebo (17.0 ± 3.4 to 9.3 ± 1.9 vs. 20.6 ± 3.7 to 19.3 ± 5.0 mmHg; P = 0.024). Sodium ascorbate improved CPP versus no effect with placebo (61 ± 11 to 75 ± 5 mmHg vs. 48 ± 16 to 49 ± 12 mmHg; P = 0.046). MAP responsiveness to norepinephrine was impaired at 23-h of sepsis in both groups and was fully restored at 27.5- and 31-h of sepsis by sodium ascorbate but not by placebo. Norepinephrine did not increase ICP in either group. We demonstrate that sepsis elevates ICP to clinically relevant levels when measured directly via a lateral cerebral ventricular catheter, contributing to reduced CPP. Intravenous megadose sodium ascorbate ameliorates the intracranial hypertension, improves CPP, and reverses vasopressor hypo-responsiveness without increasing ICP in a clinically relevant ovine model of sepsis. These findings identify elevated ICP as a modifiable component of septic neuro-cardiovascular hemodynamic dysfunction and support sodium ascorbate as a potential therapy to mitigate both systemic and cerebral derangements in sepsis.

RATIONALE:Critical illness impairs the muscle protein synthetic response to protein administration. Whether increased protein dose can overcome this anabolic resistance is unknown. OBJECTIVES:To assess the impact of a single intraduodenal bolus of 40 g protein compared to 20 g of protein in mechanically ventilated critically ill patients on the primary outcome of postprandial muscle protein synthesis rates. METHODS:Mechanically ventilated patients were randomized to 40 or 20 g of whey protein isolate delivered intraduodenally over 1 h. Primed continuous intravenous L-[ring-13C6]-phenylalanine and L-[3,5-2H2]-tyrosine infusions were applied with repeated arterial blood and skeletal muscle tissue sampling over 2 h fasting and 6 h postprandial periods to assess plasma amino acid responses and rates of fasting and postprandial muscle protein synthesis (primary outcome). Data are mean ± SD and area under the curve (AUC), analyzed with ANCOVA adjusted for fasting rate and paired t-tests (P < .05). MEASUREMENTS AND MAIN RESULTS:Twenty patients (n = 10/group: 40 g: 90% male, 49 ± 21 y and 20 g: 80% male, 51 ± 13 y) were studied. Postprandial muscle protein synthesis rates (primary outcome) did not differ between groups (40 g vs 20 g: 0.030 ± 0.012 vs 0.025 ± 0.010%·h-1; adjusted mean difference 0.007 (95% CI, -0.003 to 0.016) %·h-1; P = .152). Postprandial plasma leucine and tyrosine availability (AUC) were higher following 40 g vs 20 g protein (leucine: 263 ± 87 vs 194 ± 54 µmol·L-1, P = .005; tyrosine: 92 ± 24 vs 63 ± 17 µmol·L-1, P = .006). Fasting muscle protein synthesis rates did not differ between groups (40 g vs 20 g: 0.020 ± 0.012 vs 0.025 ± 0.023%·h-1; P = .558). The post hoc uncontrolled analysis of muscle protein synthesis rates from fasting to postprandial periods increased in the 40 g group only (P = .005). CONCLUSION:Higher enteral protein does not further augment postprandial muscle protein synthesis rates to overcome -anabolic resistance during critical illness, despite increased plasma amino acid availability. TRIAL REGISTRATION NUMBER:Australia New Zealand Clinical Trials Registry Identifier: ACTRN12620000776909.

Septic shock urgently requires new treatments. We reported that low circulating concentrations of the native glucocorticoid carrier, corticosteroid-binding globulin (CBG), predict a 3-fold increase in human septic shock mortality. To explore this, we used our murine model of high-grade polymicrobial sepsis (cecal ligation and puncture [CLP]) to test CBG therapy. We prefitted adult male C57BL/6 mice (n = 106) with wireless arterial telemetry, then induced high-grade CLP. Mice were randomized with or without intravenous CBG therapy at 6 hours (3.5 mg/kg) and 30 hours (2.5 mg/kg). Terminal bloods, collected on humane endpoints or at 96 hours, were assessed for inflammation and organ damage; positron emission tomography was used to assess [124I]I-CBG biodistribution. CLP mice developed septic shock leading to multi-organ failure and 58% mortality. CBG therapy reduced mortality to 17% (a relative decrease of 72%), reduced hypotension duration by 75%, and lowered organ damage markers. CBG transiently suppressed the pro-inflammatory cytokine peak at 12 hours (45%-59%) and markedly augmented anti-inflammatory interleukin-10 and interferon-β1 (2-fold to 96 hours). The decrease in corticosterone alongside this profile suggests an intrinsic anti-inflammatory response. Combined with PET-confirmed [124I]I-CBG targeting to the injury site, these data suggest CBG survival benefits are due to targeted delivery or direct immunomodulation. While host responses involve a complex interplay of neuroendocrine and metabolic factors, our findings demonstrate marked improvements in disease progression and mortality with CBG therapy in murine-modeled septic shock. These results provide a strong impetus for a study of CBG therapy in patients with septic shock.

Gastric emptying, which exhibits a substantial interindividual, but much lesser intraindividual, variation in health and is frequently disordered (particularly delayed) in diabetes, is now appreciated to be a major determinant of postprandial glycemia. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted in the proximal and distal small intestine, respectively, in response to nutrients. GLP-1, together with peptide tyrosine-tyrosine (PYY), stimulates potent negative feedback on gastric emptying. Modulation of gastric emptying, through dietary, pharmacologic, and surgical therapies, has been utilized in current clinical practice for the treatment of hyperglycemia, particularly relating to type 2 diabetes. We review the complex, interdependent relationships between gastric emptying, small intestinal transit, glucose absorption, neurohormonal regulatory responses, and postprandial glycemia. We discuss how this has informed fundamental advances in the understanding and rational management of obesity, stress hyperglycemia, type 1 and 2 diabetes, and gestational diabetes, and we provide recommendations for research priorities that have the potential to impact practice. We also discuss the frequent complication of abnormally delayed gastric emptying (gastroparesis) in both type 1 and type 2 diabetes, the implications for management of diabetes, and the impact of treatment on gastric emptying. With the increasing recognition of the importance of gastric emptying in the management of conditions associated with disordered glucose metabolism, and the advent and increasing use of GLP-1 receptor agonists, an improved definition of the interactions between gastrointestinal motility (gastric emptying and small intestinal transit) and enteropancreatic hormonal responses is essential.

Objective Mega-dose intravenous sodium ascorbate, the base-salt of vitamin C, is under investigation as a therapy in critical illness. At pharmacologic concentrations sodium ascorbate may interfere with point-of-care (POC) biochemical measurements. This study aims to characterise the impact of ascorbate on point-of-care (POC) lactate and glucose assays. Design Prospective investigator initiated in vitro study using human and ovine blood samples. Setting Blood samples from humans were collected within the clinical trials unit of the Royal Adelaide Hospital. Blood samples from sheep were collected within the South Australian Health and Medical Research Institute (SAHMRI) Pre-clinical Imaging and Research Laboratories (PIRL). Participants Nineteen healthy adults and three sheep. Interventions Whole blood was spiked with 30% sodium ascorbate to achieve concentrations of 5, 10, and 20mmol/L. Main Outcome measures Lactate and glucose levels were compared with baseline across multiple POC devices, blood gas analysers, and a laboratory colorimetric reference assay. Results Increasing ascorbate caused spurious decreases in blood lactate measured by the colorimetric assay and two POC devices (Epoc® and the StatStrip Xpress®). False increases in blood lactate were observed with one POC device (iSTAT 1®) and with two blood gas analysers (RAPIDPoint® 500 and Radiometer ABL90 Flex), although the latter was not clinically significant. The StatProfile® Prime Plus blood gas analyser showed no interference. For glucose, increasing ascorbate caused spurious elevations in glucose with four POC glucometers (FreeStyle Optium Neo, StatStrip Xpress®, HemoCue® Glucose 201, and Epoc®) and a false decrease with the RAPIDPoint® 500. No interference was observed with the StatProfile® Prime Plus, Radiometer ABL90 Flex, or laboratory assay. Conclusions At pharmacologic concentrations, ascorbate can cause both falsely high and low lactate and glucose readings, depending on the device used. These findings help inform the selection of appropriate devices for future clinical trials of mega-dose ascorbate.

Background and Aim Critically ill patients experience acute muscle wasting, associated with impaired clinical outcomes. It has been suggested that greater dietary protein delivery may attenuate muscle wasting and improve outcomes, but the optimal dose is unknown. The aim of this systematic review and meta-analysis was to evaluate the effect of enteral protein delivered to achieve doses recommended within international guidelines (1.2-2.0 g/kg bodyweight/day) compared to enteral protein delivered below international guidelines (<1.2 g/kg/day) on mortality and clinical, patient-centred, and muscle outcomes. Methods A systematic review of databases MEDLINE, EMBASE, CINAHL, and CENTRAL was performed from database inception through to 2 July 2025. Randomised controlled trials (RCTs) of adult critically ill patients comparing ‘greater protein’ delivery (1.2-2.0 g/kg/day) versus ‘lesser protein’ delivery (<1.2 g/kg/day) predominantly via enteral nutrition (EN), with similar energy delivery, were identified. Risk ratios were pooled for binary outcomes and mean differences or standardised mean differences for continuous outcomes using random-effects models. Subgroup analyses investigated the effect of exclusive EN; acute kidney injury (AKI) as defined within individual trials; and higher severity of illness (Sequential Organ Failure Assessment score ≥ 9) for the primary outcome (mortality). Results From a total of 10,414 citations, 14 RCTs were included, comprising n=6553 patients (n=3248 greater protein; n=3305 lesser protein) from 13 individual patient RCTs and one cluster randomised cross-over trial. Greater protein delivery did not affect mortality (pooled RR 1.01, 95% CI 0.92, 1.12, p=0.795; I2=0%; τ2=0.00; 12 RCTs: greater protein n=3197; lesser protein n=3243). Other clinical outcomes were not different; however, the point estimate suggested decreased quality of life for greater protein compared to lesser protein (pooled standardised mean difference -0.11, 95% CI -0.24, 0.01, p=0.081; I2=0%; τ2=0.00; 2 RCTs, n=921: greater protein n=456; lesser protein n=465). In patients with an AKI (as defined within individual trials), greater protein delivery was associated with increased mortality (pooled effect estimate 1.29, 95% CI 1.05, 1.58, p=0.015; I2=0%; τ2=0.00; 3 RCTs, n=755: greater protein n=390; lesser protein n=365), with ICEMAN evaluation suggesting that the evidence for effect modification was of moderate credibility. Conclusions Greater protein delivery does not reduce mortality or improve any clinical outcomes compared with lesser protein, and may be associated with increased mortality in patients with AKI, though subgroup definitions varied across trials. Systematic review registration CRD42025547923

PURPOSE OF REVIEW:As the use of long-acting glucagon-like peptide-1 (GLP-1) drugs in the community grows rapidly, an increasing number of patients in the ICU will be affected by the preexisting GLP-1 therapy. This review highlights recent major advances in the use of GLP-1 drugs and their impact on gastrointestinal function, aiming to assist intensive care clinicians in developing informed management strategies. RECENT FINDINGS:Although the gastrointestinal inhibitory effects of GLP-1 therapy are well established, this is not clearly associated with inpatient complications. The risk of pulmonary aspiration peri-operatively is low and GLP-1 therapy does not clearly increase this risk peri-operatively. Similarly, there is no clear association with either small intestinal obstruction or acute pancreatitis. The potential impact on enteral nutrition provision is unlikely to be detrimental in the acute phase of critical illness. SUMMARY:A systematic approach is necessary to assess gastrointestinal function and monitor for complications. Gastric ultrasound and prokinetic therapy may be useful peri-operatively to detect retained gastric contents and mitigate the risk of pulmonary aspiration. Future research may elaborate the role of GLP-1 therapy in the acute setting for stress hyperglycaemia in the critically ill.

Objective:Patients in the intensive care unit (ICU) suffer from disturbed sleep and pharmacological sleep aids are frequently prescribed despite limited data on their efficacy. The objective of this study was to assess the effect of a single nocturnal dose of the benzodiazepine temazepam on sleep duration and quality in ICU patients. Design:Prospective, single-centre, blinded, placebo-controlled, parallel-group, randomised clinical trial. Setting:A tertiary ICU in Australia. Participants:Adult ICU patients whose treating clinician considered that a pharmacological sleep aid was indicated. Interventions:A single weight- and age-adjusted dose of temazepam (10-30 mg) or a matching placebo was administered enterally at 21:00 h. Main outcome measures:The primary outcome was total sleep time between 21:00 and 07:00 h by hourly structured nurse assessment. Secondary outcomes included the evaluation of sleep quality, independently determined by the bedside nurse and patient using the Richards-Campbell Sleep Questionnaire. Results:Between October 2020 and May 2024, 56 patients received temazepam (n = 28) or placebo (n = 28). The mean (standard deviation) total sleep time with temazepam was 349 (120) vs. placebo 291 (124) minutes; difference = 57 min (95% confidence intervals: -11 to 130); p = 0.10. No differences in total Richards-Campbell Sleep Questionnaire sleep quality were observed when assessed by the nurse (57 (17) vs. 49 (23), p = 0.15) or by the patient (50 (28) vs. 51 (23), p = 0.70). Conclusion:A single dose of temazepam was not observed to improve the duration or quality of nocturnal sleep for patients in the ICU. Trial registration:Retrospectively registered with the Australian and New Zealand Clinical Trials Registry on 11th June 2021 (ACTRN 12621000742875).

Background An obesity paradox has been described in general and selected intensive care populations, whereby obese patients experience lower mortality than healthy-weight patients despite physiological disadvantages. Whether this paradox exists among a selected group of patients with acute hypoxaemic respiratory failure (AHRF) requiring mechanical ventilation remains uncertain. We examined the association between body mass index (BMI) and in-hospital mortality in a large, contemporary cohort of mechanically ventilated intensive care unit (ICU) patients with AHRF. Methods This retrospective cohort study used the ANZICS Adult Patient Database (2020–2024). We included unplanned adult ICU admissions requiring invasive mechanical ventilation with AHRF, defined as admission PaO2/FiO2 <300 mm Hg. The primary outcome was in-hospital mortality, assessed using hierarchical logistic regression after adjustment for confounders. The nonlinear association between respiratory failure severity and mortality was modelled using restricted cubic splines. The secondary outcomes included organ support use, tracheostomy receipt, duration of ventilation, and ICU and hospital length of stay. Results Among 40 352 eligible patients, overall unadjusted in-hospital mortality was 21% (22.7% in healthy-weight patients). After adjustment, mortality was lower in preobese patients (BMI 25–29.9 kg/m2; adjusted odds ratio [aOR] 0.92, 95% confidence interval [CI] 0.85–0.99), obesity class 1 (BMI 30–34.9 kg/m2; aOR 0.85, 95% CI 0.79–0.93), and obesity class 2 (BMI 35–39.9 kg/m2; aOR 0.88, 95% CI 0.79–0.98). The association weakened after adjustment and did not extend to obesity class 3 (BMI ≥40 kg/m2). There was no significant interaction between BMI and respiratory failure severity (p = 0.08). Conclusion Among patients ventilated for AHRF, overweight and moderately obese BMI categories were associated with modestly lower in-hospital mortality. This association is conditional on the decision to intubate and is compatible with a modest degree of selection bias. The conclusions should be interpreted as a prognostic association within ventilated patients rather than the presence of obesity improving survival.

Sepsis remains the leading cause of death in intensive care units globally, with catecholamine-resistant shock posing a persistent therapeutic challenge. Norepinephrine is the primary vasopressor used to treat hypotension in sepsis, but its efficacy is often limited by multifactorial loss of pressor responsiveness, including adrenergic receptor desensitisation, excess nitric oxide, systemic inflammation, and endothelial injury. Ascorbate (vitamin C) has emerged as a potential adjunct therapy because it supports endothelial function, reduces oxidative stress, activates the immune system and enhances endogenous vasopressor synthesis. Despite restoration of systemic hemodynamics with fluids and vasopressors, the frontal cortex remains particularly vulnerable to microcirculatory ischemia and hypoxia, contributing to sepsis-associated encephalopathy through hypoperfusion, hypoxia, hyperthermia, oxidative stress, neuroinflammation, and mitochondrial dysfunction, ultimately leading to neuronal injury and delirium. Plasma levels of ascorbate are profoundly depleted in sepsis and correlate with disease severity. Cerebral cortical neurons actively concentrate ascorbate at levels up to 250-fold higher than plasma, underscoring its importance in maintaining redox homeostasis and metabolism in the brain. While the conventional intravenous vitamin C formulation, ascorbic acid, has been associated with harm in clinical trials, emerging preclinical and early clinical data suggest that intravenous sodium ascorbate, a pH–neutral formulation of vitamin C, may restore noradrenaline sensitivity and re-establish frontal cortical microvascular perfusion and oxygenation. This review discusses the mechanistic rationale and therapeutic potential of sodium ascorbate in sepsis, including its ability to cross the blood-brain barrier. By stabilising cardiovascular and cerebrovascular function, sodium ascorbate may represent a promising adjunctive therapy to improve the management of sepsis.

Objectives:Obtaining an accurate smoking history can be challenging in critically ill patients. The objective of this study was to determine the prevalence of nicotine exposure using a point-of-care urine cotinine test in a heterogeneous cohort of critically ill patients and to compare this to the smoking history in the medical record. Design setting and participants:In 481 adult patients we prospectively undertook a urine cotinine test within 24 h of admission using a point-of-care binary colorimetric assay with a detection threshold of 200 ng/mL. Smoking history was retrieved from the electronic medical record. Main outcome measures and results:Urinary cotinine was detected in 151 of 481 patients (31.4%), exceeding the 134 participants with a documented history of current smoking by 3.5% (relative increase 12.7%). A positive urine cotinine test was reported in 12% (40/347) of participants not known to be actively smoking, including 18 'former smokers', 12 'non-smokers', and 10 in whom smoking status was unknown. Cotinine-positive participants were ventilated for longer than cotinine-negative patients; a median of 71 h vs. 44 h (median difference of 30h, 95% CrI: 5.6 to 56); they were more likely to have a "code-grey" event; 34 of 151 (23%) vs. 24/330 (7.3%); median relative risk of 3.1 (95% CrI, 1.9-5.1); and were more likely to "discharge against medical advice"; 12/125 (10%) vs 3/275 (1%), with a median relative risk of 9.7 (95% CrI, 3.0-46). Conclusions:Urinary cotinine testing offers a point-of-care determination of current tobacco smoking status in the critically ill.

Intracranial hypertension is a major modifiable pathway of secondary brain injury after acute neurological insults. Osmotherapy is an early cornerstone of tiered intracranial pressure management. Hypertonic saline and mannitol reliably reduce intracranial pressure through osmotic reduction in brain water, with additional haemodynamic and rheological effects. However, neither agent has shown consistent improvement in survival or long-term neurological recovery. Current practice is therefore guided by physiological rather than patient-centred outcomes. This review summarises the physiological basis, clinical evidence, and practical limitations of conventional osmotherapy, and explores investigational chloride-free osmotherapies including sodium lactate, sodium bicarbonate, sodium ascorbate, and sodium acetate. Chloride-free therapies aim to preserve sodium-driven osmotic efficacy while reducing chloride exposure or targeting metabolic and oxidative pathways implicated in secondary brain injury. At present, evidence is limited to small physiological trials, retrospective cohort studies, and mechanistic human studies. Future progress requires large collaborative trials that combine pragmatic treatment comparisons with multimodal neuromonitoring, biochemical safety endpoints and patient-centred outcomes.

Septic shock has an unacceptably high mortality rate and unmet need for new therapeutics. Murine models are crucial for research, yet methodologies often differ. This study characterised standard- and high-grade caecal ligation and puncture (CLP) murine models of septic shock by integrating ultraminiature arterial telemetry with comprehensive plasma biomarker analysis. Standard-grade and high-grade CLP was performed in 8–10 week old, male C57BL/6 mice (n = 98), with a subset implanted with arterial telemetry to monitor real-time circulatory function. Plasma markers of inflammation and organ damage were measured at multiple intervals up to 168 h post-CLP. Standard-grade and high-grade CLP showed distinct progressions; episodes of hypotension began 5–6 h after CLP in 30% of standard-grade and all high-grade CLP mice, with respective 168 h mortality of 40% and 71%. Recurrent episodes of hypotension 5–39 h after CLP were universally lethal. The coincidence of hypotension and elevated plasma lactate defined the onset of septic shock after high-grade CLP, which was always lethal. Inflammatory cytokines and markers of liver, renal, and cardiac damage were markedly elevated to 168 h after high-grade CLP, in contrast to standard-grade CLP, which returned to baseline by 48 h. Elevated plasma IL-6, TNFα, and corticosterone, along with reduced albumin, were significantly correlated with mortality. In conclusion, this research refines murine CLP models by providing a precise, dynamic map of the progression to septic shock. The high-grade CLP model consistently models early and late-stage physiological deterioration and serves as a robust model for evaluating the efficacy of novel therapies aimed at human septic shock.

Guidelines recommend augmenting enteral protein during critical illness, but the impact on patient outcomes is uncertain. To determine whether augmenting enteral protein increases days alive and free from hospitalization. This cluster randomized, crossover, open-label trial recruited critically ill patients receiving enteral nutrition from 8 intensive care units (ICUs) in Australia and New Zealand from May 23, 2022, to August 23, 2023, with final follow-up on November 21, 2023. Two isocaloric enteral formulae were compared: augmented protein (100 g protein/L) vs usual protein (63 g protein/L). ICUs used formulae sequentially for 3 months over a 12-month period; 4 ICUs commenced with augmented protein and 4 commenced with usual protein. The primary outcome was the number of days free of admittance to the index hospital and alive at day 90. Secondary outcomes included days free of the index hospital at day 90 in survivors; alive at day 90; durations of invasive ventilation, ICU, and hospital admission; incidences of tracheostomy insertion and new kidney replacement therapy; and hospital discharge destination. A total of 3397 patients were included (median [IQR] age, 61 (48-71) years; 2157 [64%] male). The median (IQR) number of days free of the index hospital and alive at day 90 was 62 (0-77) days in the augmented protein group and 64 (0-77) days in the usual protein group, with an adjusted-for-period between-group median difference of −1.97 (95% CI, −7.24 to 3.30) days (P = .46). At day 90, a total of 1221 of 1681 patients (72.6%) were alive in the augmented protein group and 1269 of 1716 (74.0%) were alive in the usual protein group (risk ratio, 0.99 [95% CI, 0.95-1.03]). Between-group differences for secondary outcomes included the following: difference in median days free of hospital in survivors, 0.01 (95% CI, −1.94 to 1.96) days; difference in mean duration of invasive ventilation, 6.8 (95% CI, −3.0 to 16.5) hours; cause-specific hazard ratios for durations of ICU admission (time to live ICU discharge), 0.93 (95% CI, 0.88-1.00) and hospital admission (time to live hospital discharge), 0.96 (95% CI, 0.90-1.02); and risk ratio for tracheostomy, 1.15 (95% CI, 0.66-2.01) and new kidney replacement therapy, 0.97 (95% CI, 0.81-1.16). Discharge destinations were similar. Augmenting enteral protein during critical illness did not improve number of days free of the index hospital and alive at day 90. ANZCTR Identifier: ACTRN12621001484831

BACKGROUND:Previous studies have shown cardiovascular benefits of SGLT2 inhibitors. The aim of this study was to evaluate the cardiovascular effects of perioperative SGLT2 inhibition in patients undergoing cardiac surgery. METHODS:In this open-label pilot study, adult patients undergoing cardiac surgery were randomized to receive a daily dose of empagliflozin (10 mg; oral) 3 days before surgery until 2 days after surgery, or standard of care. Blood pressure, heart rate, postoperative diuresis, intravenous fluid administration, fluid balance, and vasoactive support were compared between groups during the first 24 postoperative hours. RESULTS:About 55 patients (sex: 73% male, age: 66 ± 10 years, BMI: 28 ± 4 kg/m2, empagliflozin n = 25, control n = 30) were included in this study and analyzed according to the intention-to-treat principle. Empagliflozin was associated with increased diuresis, mean difference 549 mL (95% CI 258-839, p < 0.001), and less positive fluid balance postoperatively, mean difference -1217 mL (95% CI -2373- -61, p = 0.039). Empagliflozin did not increase the amount of intravenous fluid administered. In the empagliflozin group, norepinephrine was infused for 11.8 ± 11.5 h compared to 19.3 ± 19.3 h in the control group (p = 0.080). No significant between-group differences were observed in postoperative blood pressure and heart rate. CONCLUSIONS:Perioperative SGLT2 inhibition was associated with increased diuresis and lesser fluid accumulation without an increase in vasopressor requirement. These data warrant validation and further evaluation in a larger-scale, double-blind, placebo-controlled trial. EDITORIAL COMMENT:In this sub-study of the randomized MERCURI-2 trial of perioperative empagliflozin for nondiabetics in cardiac surgery, the authors describe the hemodynamic outcomes and fluid status of the patients. The authors noted a higher urine output and a more negative fluid balance in the intervention group compared to the placebo group. An interesting observation is the trend towards lower noradrenaline usage, although this cannot be concluded with confidence based on this data. The findings support considering and further studying the use of these medications for patients with cardiovascular disease undergoing surgery. TRIAL REGISTRATION:https://onderzoekmetmensen.nl/en/trial/26563 Identifier: NL9561.

Megadose sodium ascorbate has shown promise as a treatment to reverse the pathophysiological effects of ovine Gram-negative sepsis. In human septic shock, lower doses of sodium ascorbate improved urine output and reduced vasopressor requirements compared with placebo. We sought to determine the minimum therapeutic dose of sodium ascorbate required to reverse sepsis-induced cardiovascular and renal dysfunction in sheep. Healthy young adult sheep were instrumented with renal artery flow probes, and oxygen-sensing and laser Doppler probes in the kidneys. Non-anaesthetised animals were infused with live Escherichia coli for 31-h. At 23.5-h of sepsis, four groups (n = 7–8/group) received fluid resuscitation (30 mL/kg Hartmann’s solution) and were randomized to intravenous sodium ascorbate (1.0, 2.0, or 3.0 g/kg) or vehicle, delivered as a bolus followed by 7-h infusion. Norepinephrine was titrated to maintain mean arterial pressure (MAP) at 70 mmHg. At 23-h of sepsis, animals developed hypotension, hyperlactatemia, acute kidney injury, and renal medullary hypoxia. Vehicle-treated sheep required escalating doses of norepinephrine (from 0.4 to 0.8 ± 0.2 µg/kg/min) to restore MAP. Sodium ascorbate at 3.0 g/kg (achieving plasma ascorbate levels of 10 mmol/L) rapidly restored MAP, allowing withdrawal of norepinephrine in half the animals (P = 0.007). Lower doses of sodium ascorbate (1.0 and 2.0 g/kg) had no significant effect on vasopressor requirements. The improvements in renal medullary oxygenation (25.2 ± 3.3 to 43.4 ± 4.5 mmHg, P = 0.04) and urine flow (from 0.5 ± 0.2 to 6.9 ± 2.4 ml/kg/h, P < 0.0001) were dose-dependent. Renal medullary tissue protein expression of nuclear factor kappa-light chain-enhancer B was significantly reduced with 3.0 g/kg of sodium ascorbate (to -52.9 ± 13.3

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce chronic kidney disease progression in people with type 2 diabetes mellitus. Sepsis is the leading cause of acute kidney injury (AKI). This study investigated whether GLP-1 is renoprotective in an ovine model of gram-negative septic AKI. Sixteen healthy merino ewes were surgically instrumented to measure mean arterial pressure, cardiac output, renal blood flow, renal cortical and medullary perfusion and oxygenation, and renal function. After a 5-day recovery period, sepsis was induced via continuous intravenous infusion of live Escherichia coli for 30 h. After 24 h, the sheep were randomized to receive an intravenous infusion of 3.6 pmol/kg/min GLP-1 (n = 8) or a fluid-matched vehicle (n = 8) for 6 h. After 24 h of sepsis, 7/8 sheep in each group developed AKI. GLP-1 treatment increased renal blood flow compared to placebo + 13 vs. − 3.4 ml/min difference (95% CI) = 16 (− 7–40) P = 0.0054), and maintained renal cortical oxygenation + 2.5 mmHg vs. = − 7.2 mmHg, difference (95% CI) = 9.7 (5.2–14.4) P < 0.001. GLP-1 maintained renal medullary perfusion + 1.7 vs. vehicle − 213 perfusion units, difference (95% CI) = 214 (− 21–450) P = 0.07. However, GLP-1 did not significantly improve the primary endpoint of renal medullary oxygenation − 1.6 vs. − 11.5, difference (95% CI) = 9.9 (− 6.8–26.7) P = 0.21. In an ovine model of gram-negative sepsis-associated AKI, GLP-1 infusion supported global renal perfusion, renal oxygen delivery, and cortical oxygenation but failed to improve renal medullary oxygenation and kidney function.

Patients with aneurysmal subarachnoid haemorrhage (aSAH) often receive multiple radiation based diagnostic studies. Cumulative radiation exposure has been associated with long term health consequences from both dose dependent deterministic harm and increased risk of developing adverse events in a non-dose dependant manner i.e. stochastic harm. The objective was to calculate cumulative radiation exposure in the acute phase after aSAH. Single centre retrospective, observational study of consecutive adult patients admitted to the ICU for management of aSAH over five years. Organ and effective radiation doses were determined using institution specific conversion coefficients based on scanner radiation output metrics for all computed tomography imaging and fluoroscopy examinations. Calculated patient doses for the duration of the hospital admission were determined using National Cancer Institute radiation dosimetry tools. A total of 276 patients met the inclusion criteria; 180 females (65