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

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

Relationship of blood thiamine pyrophosphate to plasma phosphate and the response to enteral nutrition plus co-administration of intravenous thiamine during critical illness.

BACKGROUND: Hypovitamin B1 occurs frequently during critical illness but is challenging to predict or rapidly diagnose. The aim of this study was to evaluate whether plasma phosphate concentrations predict hypovitamin B1, enteral nutrition prevents hypovitamin B1 and intravenous thiamine supplementation achieves supraphysiological concentrations in critically ill patients. METHODS: Thirty-two enterally fed critically ill patients, with a plasma phosphate concentration ≤0.65 mmol/L, formed a nested cohort within a larger randomised clinical trial. Patients were assigned to receive intravenous thiamine (200 mg) twice daily, and controls were not administered intravenous thiamine. Thiamine pyrophosphate concentrations were measured at four time points (pre- and post-infusion and 4- and 6-h post-infusion) on days 1 and 3 in those allocated to thiamine and once in the control group. RESULTS: Baseline thiamine pyrophosphate concentrations were similar (intervention 88 [67, 93] vs. control 89 [62, 110] nmol/L, p = 0.49). Eight (25%) patients had hypovitamin B1 (intervention 3 vs. control 5), with two patients in the control group remaining insufficient at day 3. There was no association between baseline phosphate and thiamine pyrophosphate concentrations. Intravenous thiamine achieved supraphysiological concentrations 6 h post first infusion, with concentrations increasing to day 3. In the control group, thiamine pyrophosphate concentrations were not statistically different between baseline and day 3 (mean change: 8.6 [-6.0, 23.1] nmol/L, p = 0.25). CONCLUSIONS: Phosphate concentrations did not predict hypovitamin B1, which was observed in 25% of the participants. Enteral nutrition alone prevented the development of new hypovitamin B1. Administration of a single 200-mg dose of intravenous thiamine achieved supraphysiological concentrations of thiamine pyrophosphate, with repeated dosing sustaining this effect.

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

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

The use of smartphone-derived location data to evaluate participation following critical illness: A pilot observational cohort study.

BACKGROUND: Disability is common following critical illness, impacting the quality of life of survivors, and is difficult to measure. 'Participation' can be quantified as involvement in life outside of their home requiring movement from their home to other locations. Participation restriction is a key element of disability, and following critical illness, participation may be diminished. It may be possible to quantify this change using pre-existing smartphone data. OBJECTIVES: The feasibility of extracting location data from smartphones of survivors of intensive care unit (ICU) admission and assessing participation, using location-based outcomes, during recovery from critical illness was evaluated. METHODS: Fifty consecutively admitted, consenting adult survivors of non-elective admission to ICU of greater than 48-h duration were recruited to a prospective observational cohort study where they were followed up at 3 and 6 months following discharge. The feasibility of extracting location data from survivors' smartphones and creating location-derived outcomes assessing participation was investigated over three 28-d study periods: pre-ICU admission and at 3 and 6 months following discharge. The following were calculated: time spent at home; the number of destinations visited; linear distance travelled; and two 'activity spaces', a minimum convex polygon and standard deviation ellipse. RESULTS: Results are median [interquartile range] or n (%). The number of successful extractions was 9/50 (18%), 12/39 (31%), and 13/33 (39%); the percentage of time spent at home was 61 [56-68]%, 77 [66-87]%, and 67 [58-77]% (P = 0.16); the number of destinations visited was 34 [18-64], 38 [22-63], and 65 [46-88] (P = 0.02); linear distance travelled was 367 [56-788], 251 [114-323], and 747 [326-933] km over 28 d (P = 0.02), pre-ICU admission and at 3 and 6 months following ICU discharge, respectively. Activity spaces were successfully created. CONCLUSION: Limited smartphone ownership, missing data, and time-consuming data extraction limit current implementation of mass extraction of location data from patients' smartphones to aid prognostication or measure outcomes. The number of journeys taken and the linear distance travelled increased between 3 and 6 months, suggesting participation may improve over time.

Frailty is not independently associated with intensive care unit length of stay: An observational study.

BACKGROUND: Frailty is independently associated with morbidity and mortality in critically ill patients. However, the association between preadmission frailty and the degree of treatment received in the intensive care unit (ICU) remains unclear. OBJECTIVE: To describe patient length of stay in an ICU and the treatments provided according to the extent of patient frailty. METHODS: Single-centre retrospective cohort study of adult patients admitted to a tertiary ICU between January 2018 and December 2019. Frailty was assessed using the Clinical Frailty Scale (CFS). The primary outcome was ICU length of stay stratified by CFS score (1-8). Secondary outcomes were the proportion of patients with each CFS score treated with vasoactive agents, invasive ventilation, noninvasive ventilation, renal replacement therapy, and tracheostomy. Poisson regression and competing risks regression was used to analyse associations between ICU length of stay and potential confounders. RESULTS: The study cohort comprised 2743 patients, with CFS scores known for 2272 (83%). Length of stay in the ICU increased with each increment in the CFS up to a score of 5, beyond which it decreased with higher frailty scores. After adjusting for age, illness severity, admission type, and treatment limitation, CFS scores were not independently associated with length of stay in the ICU (P = 0.31). The proportion of patients receiving specific ICU treatments peaked at different CFS scores, being highest for vasoactive agents at CFS 5 (47%), invasive ventilation CFS 3 (51%), noninvasive ventilation CFS 6 (11%), renal replacement therapy CFS 6 (8.2%), and tracheostomy CFS 5 (2.2%). Increasing frailty was associated with increased mortality and discharge to a destination other than home. CONCLUSIONS: The extent of frailty is not independently associated with length of stay in the ICU. The proportion of patients receiving specific ICU treatments peaked at different CFS scores.

Incident Diabetes in Survivors of Critical Illness and Mechanisms Underlying Persistent Glucose Intolerance: A Prospective Cohort Study.

OBJECTIVES: Stress hyperglycemia occurs in critically ill patients and may be a risk factor for subsequent diabetes. The aims of this study were to determine incident diabetes and prevalent prediabetes in survivors of critical illness experiencing stress hyperglycemia and to explore underlying mechanisms. DESIGN: This was a prospective, single center, cohort study. At admission to ICU, hemoglobin A1c was measured in eligible patients. Participants returned at 3 and 12 months after ICU admission and underwent hemoglobin A1c testing and an oral glucose tolerance test. Blood was also collected for hormone concentrations, whereas gastric emptying was measured via an isotope breath test. ß-cell function was modeled using standard techniques. SETTING: Tertiary-referral, mixed medical-surgical ICU. PATIENTS: Consecutively admitted patients who developed stress hyperglycemia and survived to hospital discharge were eligible. MEASUREMENTS AND MAIN RESULTS: Consent was obtained from 40 patients (mean age, 58 yr [SD, 10], hemoglobin A1c 36.8 mmol/mol [4.9 mmol/mol]) with 35 attending the 3-month and 26 the 12-month visits. At 3 months, 13 (37%) had diabetes and 15 (43%) had prediabetes. At 12 months, seven (27%) participants had diabetes, whereas 11 (42%) had prediabetes. Mean hemoglobin A1c increased from baseline during the study: +0.7 mmol/mol (-1.2 to 2.5 mmol/mol) at 3 months and +3.3 mmol/mol (0.98-5.59 mmol/mol) at 12 months (p = 0.02). Gastric emptying was not significantly different across groups at either 3 or 12 months. CONCLUSIONS: Diabetes and prediabetes occur frequently in survivors of ICU experiencing stress hyperglycemia. Based on the occurrence rate observed in this cohort, structured screening and intervention programs appear warranted.

Are point-of-care measurements of glycated haemoglobin accurate in the critically ill?

INTRODUCTION: Critically ill patients with type 2 diabetes mellitus (T2DM) and chronic hyperglycaemia may benefit from a more liberal approach to glucose control than patients with previously normal glucose tolerance. It may therefore be useful to rapidly determine HbA1c concentrations. Point-of-care (POC) analysers offer rapid results but may be less accurate than laboratory analysis. AIM(S): The aim of this study was to determine agreement between POC and laboratory HbA1c testing in critically ill patients with T2DM. METHODS: Critically ill patients with T2DM had concurrent laboratory, capillary-, and arterial-POC HbA1c measurements performed. Data are presented as mean (standard deviation) or median [interquartile range]. Measurement agreement was assessed by Lin's concordance correlation coefficient, Bland-Altman 95% limits of agreement, and classification by Cohen's kappa statistic. RESULTS: HbA1c analysis was performed for 26 patients. The time to obtain a result from POC analysis took a median of 9 [7, 10] minutes. Laboratory analysis took a median of 328 [257, 522] minutes from the time of test request to the time of report. Lin's correlation coefficient showed almost perfect agreement (0.99%) for arterial- vs capillary-POC and both POC methods vs arterial laboratory analysis. Bland-Altman plots showed a mean difference of 2.0 (3.7) with 95% limits of agreement of -5.4 to 9.3 for capillary vs laboratory, 1.6 (3.4) and -5.1 to 8.4 for arterial vs laboratory, and -0.137 (2.6) and -5.2 to 4.9 for capillary vs arterial. Patient classification as having inadequately controlled diabetes (>53 mmol/mol) showed 100% agreement across all tests. CONCLUSIONS: HbA1c values can be accurately and rapidly obtained using POC testing in the critically ill.

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

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

Cerebral metabolic effects of strict versus conventional glycaemic targets following severe traumatic brain injury.

BACKGROUND: Optimal glycaemic targets for patients with severe traumatic brain injury remain unclear. The primary objective of this microdialysis study was to compare cerebral metabolism with strict versus conventional glycaemic control. METHODS: We performed a prospective single-centre randomised controlled within-subject crossover study of 20 adult patients admitted to an academic neurointensive care unit with severe traumatic brain injury. Patients underwent randomised, consecutive 24-h periods of strict (4-7 mmol/L; 72-126 mg/dl) and conventional (<10 mmol/L; 180 mg/dl) glycaemic control with microdialysis measurements performed hourly. The first 12 h of each study period was designated as a 'washout' period, with the subsequent 12 h being the period of interest. RESULTS: Cerebral glucose was lower during strict glycaemia than with conventional control (mean 1.05 [95% CI 0.58-1.51] mmol/L versus 1.28 [0.81-1.74] mmol/L; P = 0.03), as was lactate (3.07 [2.44-3.70] versus 3.56 [2.81-4.30]; P < 0.001). There were no significant differences in pyruvate or the lactate/pyruvate ratio between treatment phases. Strict glycaemia increased the frequency of low cerebral glucose (< 0.8 mmol/L; OR 1.91 [95% CI 1.01-3.65]; P < 0.05); however, there were no differences in the frequency of critically low glucose (< 0.2 mmol/L) or critically elevated lactate/pyruvate ratio between phases. CONCLUSIONS: Compared with conventional glycaemic targets, strict blood glucose control was associated with lower mean levels of cerebral glucose and an increased frequency of abnormally low glucose levels. These data support conventional glycaemic targets following traumatic brain injury. TRIAL REGISTRATION: ISRCTN, ISRCTN19146279 . Retrospectively registered on 2 May 2014.

Haemoglobin concentration and volume of intravenous fluids in septic shock in the ARISE trial.

BACKGROUND: Intravenous fluids may contribute to lower haemoglobin levels in patients with septic shock. We sought to determine the relationship between the changes in haemoglobin concentration and the volume of intravenous fluids administered during resuscitation from septic shock. METHODS: We performed a retrospective cohort study of patients enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial who were not transfused red blood cells (N = 1275). We determined the relationship between haemoglobin concentration, its change over time and volume of intravenous fluids administered over 6, 24 and 72 h using univariate and multivariate analysis. RESULTS: Median (IQR) haemoglobin concentration at baseline was 133 (118-146) g/L and decreased to 115 (102-127) g/L within the first 6 h of resuscitation (P < 0.001), 110 (99-122) g/L after 24 h, and 109 (97-121) g/L after 72 h. At the corresponding time points, the cumulative volume of intravenous fluid administered was 1.3 (0.7-2.2) L, 2.9 (1.8-4.3) L and 4.6 (2.7-7.1) L. Haemoglobin concentration and its change from baseline had an independent but weak association with intravenous fluid volume at each time point (R2 < 20%, P < 0.001). After adjusting for covariates, each litre of intravenous fluid administered was associated with a change in haemoglobin concentration of - 1.0 g/L (95% CI -1.5 to -0.6, P < 0.001) at 24 h and - 1.3 g/L (- 1.6 to - 0.9, P < 0.001) at 72 h. CONCLUSIONS: Haemoglobin concentration decreases during resuscitation from septic shock, and has a significant but weak association with the volume of intravenous fluids administered.

A Quality Control Study of the Adherence to Recommended Physiological Targets for the Management of Brain-Dead Organ Donors in South Australian Intensive Care Units.

BACKGROUND: The Australian and New Zealand Intensive Care Society and the Australasian Transplant Coordinators Association provide recommendations on the physiological management of brain-dead donors. PROBLEM STATEMENT: How often physiological targets are prescribed for brain-dead donors in Australian intensive care units (ICUs), and how well these compare to recommended targets is unknown. It is also unknown how often recommended targets are achieved, irrespective of prescribed targets. METHODS: We performed a retrospective, observational quality control study in 81 adult (>18 years) brain-dead donors to describe how often physiological targets were prescribed, comparing these to current guidelines. We determined the proportion of observations within the recommended target range, irrespective of any prescribed target. We aimed to identify poor adherence to recommended targets to guide future quality improvement initiatives. OUTCOMES: Seventy-four (91%) donors had at least 1 prescribed physiological target written on the ICU chart, with a median of 2 (range 2-5), and a maximum of 13 targets. Prescribed targets appeared to adhere well with recommended targets. Most recommended physiological targets were met irrespective of any prescribed target. However, one-quarter of serum sodium observations and one-third of blood glucose levels were above the recommended target. IMPLICATIONS FOR PRACTICE: Quality improvement initiatives are required to improve the prescription of physiological targets in brain-dead donors in South Australia. Serum sodium and serum glucose targets were not met. However, this most likely reflects the need for current guidelines to be updated in line with current evidence.

Structure and Function of the Kidney in Septic Shock. A Prospective Controlled Experimental Study.

RATIONALE: It is unclear how septic shock causes acute kidney injury (AKI) and whether this is associated with histological change. OBJECTIVES: We aimed to determine the nature and extent of changes in renal structure and function over time in an ovine model of septic shock. METHODS: Fifteen sheep were instrumented with a renal artery flow probe and renal vein cannula. Ten were given intravenous Escherichia coli to induce septic shock, and five acted as controls. Animals were mechanically ventilated for 48 hours, while receiving protocol-guided parenteral fluids and a norepinephrine infusion to maintain mean arterial pressure. Renal biopsies were taken every 24 hours or whenever animals were oliguric for 2 hours. A renal pathologist, blinded to tissue source, systematically quantified histological appearance by light and electron microscopy for 31 prespecified structural changes. MEASUREMENTS AND MAIN RESULTS: Sheep given E. coli developed septic shock, oliguria, increased serum creatinine, and reduced creatinine clearance (AKI), but there were no changes over time in renal blood flow between groups (P > 0.30) or over time within groups (P > 0.50). Renal oxygen consumption increased only in nonseptic animals (P = 0.01), but there was no between-group difference in renal lactate flux (P > 0.50). There was little structural disturbance in all biopsies and, although some cellular appearances changed over time, the only difference between septic and nonseptic animals was mesangial expansion on electron microscopy. CONCLUSIONS: In an intensive care-supported model of gram-negative septic shock, early AKI was not associated with changes in renal blood flow, oxygen delivery, or histological appearance. Other mechanisms must contribute to septic AKI.

Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study.

OBJECTIVES: Pantoprazole is frequently administered to critically ill patients for prophylaxis against gastrointestinal bleeding. However, comparison to placebo has been inadequately evaluated, and pantoprazole has the potential to cause harm. Our objective was to evaluate benefit or harm associated with pantoprazole administration. DESIGN: Prospective randomized double-blind parallel-group study. SETTING: University-affiliated mixed medical-surgical ICU. PATIENTS: Mechanically ventilated critically ill patients suitable for enteral nutrition. INTERVENTIONS: We randomly assigned patients to receive either daily IV placebo or pantoprazole. MEASUREMENTS AND MAIN RESULTS: Major outcomes were clinically significant gastrointestinal bleeding, infective ventilator-associated complication or pneumonia, and Clostridium difficile infection; minor outcomes included overt bleeding, hemoglobin concentration profiles, and mortality. None of the 214 patients randomized had an episode of clinically significant gastrointestinal bleeding, three patients met the criteria for either an infective ventilator-associated complication or pneumonia (placebo: 1 vs pantoprazole: 2), and one patient was diagnosed with Clostridium difficile infection (0 vs 1). Administration of pantoprazole was not associated with any difference in rates of overt bleeding (6 vs 3; p = 0.50) or daily hemoglobin concentrations when adjusted for transfusion rates of packed red cells (p = 0.66). Mortality was similar between groups (log-rank p = 0.33: adjusted hazard ratio for pantoprazole: 1.68 [95% CI, 0.97-2.90]; p = 0.06). CONCLUSIONS: We found no evidence of benefit or harm with the prophylactic administration of pantoprazole to mechanically ventilated critically ill patients anticipated to receive enteral nutrition. The practice of routine administration of acid-suppressive drugs to critically ill patients for stress ulcer prophylaxis warrants further evaluation.

Stress hyperglycaemia in critically ill patients and the subsequent risk of diabetes: a systematic review and meta-analysis.

BACKGROUND: Hyperglycaemia occurs frequently in critically ill patients without diabetes. We conducted a systematic review and meta-analysis to evaluate whether this 'stress hyperglycaemia' identifies survivors of critical illness at increased risk of subsequently developing diabetes. METHODS: We searched the MEDLINE and Embase databases from their inception to February 2016. We included observational studies evaluating adults admitted to the intensive care unit (ICU) who developed stress hyperglycaemia if the researchers reported incident diabetes or prediabetes diagnosed ≥3 months after hospital discharge. Two reviewers independently screened the titles and abstracts of identified studies and evaluated the full text of relevant studies. Data were extracted using pre-defined data fields, and risk of bias was assessed using the Newcastle-Ottawa Scale. Pooled ORs with 95 % CIs for the occurrence of diabetes were calculated using a random-effects model. RESULTS: Four cohort studies provided 2923 participants, including 698 with stress hyperglycaemia and 131 cases of newly diagnosed diabetes. Stress hyperglycaemia was associated with increased risk of incident diabetes (OR 3.48; 95 % CI 2.02-5.98; I 2 = 36.5 %). Studies differed with regard to definitions of stress hyperglycaemia, follow-up and cohorts studied. CONCLUSIONS: Stress hyperglycaemia during ICU admission is associated with increased risk of incident diabetes. The strength of this association remains uncertain because of statistical and clinical heterogeneity among the included studies.

Cerebrospinal fluid and plasma ascorbate concentrations following subarachnoid haemorrhage.

Background: Ascorbate, the biologically active form of vitamin C, is the primary neural anti-oxidant. Ascorbate concentrations have never been quantified following aneurysmal subarachnoid haemorrhage (aSAH). Objective: To quantify plasma and cerebrospinal fluid (CSF) ascorbate concentrations in patients following SAH. Design Setting Participants Main Outcome Measures: Cohort study in which plasma and CSF ascorbate concentrations were measured longitudinally in 12 aSAH patients admitted to a quaternary referral intensive care unit and compared to one-off samples obtained from 20 pregnant women prior to delivery in a co-located obstetric hospital. Data are median [interquartile range] or median (95 % confidence intervals). Results: Forty-eight plasma samples were obtained from the 12 aSAH patients (eight females, age 62 [53-68] years). Eight participants with extra-ventricular drains provided 31 paired CSF-plasma samples. Single plasma and CSF samples were obtained from 20 pregnant women (age 35 [31-37] years). Initial plasma and CSF ascorbate concentrations post aSAH were less than half those in pregnant controls (plasma: aSAH: 31 [25-39] µmol/L vs. comparator: 64 [59-77] µmol/L; P < 0.001 and CSF: 116 [80-142] µmol/L vs. 252 [240-288] µmol/L; P < 0.001). Post aSAH there was a gradual reduction in the CSF:plasma ascorbate ratio from ∼4:1 to ∼1:1. Six (50 %) patients developed vasospasm and CSF ascorbate concentrations were lower in these patients (vasospasm: 61 (25, 97) vs. no vasospasm: 110 (96, 125) µmol/L; P = 0.01). Conclusion: Post aSAH there is a marked reduction in CSF ascorbate concentration that is most prominent in those who develop vasospasm.

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

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

Venous blood for the analysis of acid-base status in a model of septic shock.

OBJECTIVE: To determine the relationship between arterial and venous acid-base status in a model of septic shock. METHODS: Paired samples (n = 435) of arterial and femoral venous blood from 57 sheep (47 septic, 10 non-septic) managed with protocol-guided ventilation, sedation, parenteral fluids and inotropic support. RESULTS: The arterial-venous difference in acid-base parameters was similar with and without sepsis. There was a consistent arterio-venous relationship for metabolic (pH, lactate, bicarbonate, base excess), but not respiratory parameters (partial pressures of oxygen, carbon dioxide, and haemoglobin-oxygen saturation), independent of sepsis. CONCLUSIONS: Venous blood provides a reliable measure of metabolic but not respiratory disturbance.

The impact of bereavement support on psychological distress in family members: a systematic review and meta-analysis.

Background: Persistent psychological distress occurs frequently in family members of patients who die in an intensive care unit (ICU). Objective: To determine the effectiveness of bereavement interventions in reducing persisting psychological distress in bereaved family members after death in an adult ICU. Design: Systematic review and meta-analysis of studies that assessed the effect of bereavement interventions on persisting psychological distress in bereaved family members of ICU patients. Data sources: MEDLINE and APA PsycInfo databases were searched until April 2020. Review methods: Two of us independently screened titles and abstracts of identified studies, and then completed full text evaluation of selected studies. We assessed risk of bias using version 2 of the Cochrane risk-of-bias tool for randomised trials and the Newcastle-Ottawa Scale, which is designed to assess the quality of non-randomised studies in meta-analyses. We also used random effects meta-analysis to assess the effect of various interventions on total Hospital Anxiety and Depression Scale (HADS) scores. Results: From 664 citations, five studies were included - three multicentre randomised clinical trials and two single centre observational studies. Three studies tested the intervention of written bereavement support materials and two studies used narration of family members' experiences in the ICU. All studies reported HADS scores. Scores for Impact of Event Scale, Impact of Event Scale-Revised and Inventory of Complicated Grief were measured in some but not all studies. There was no effect of an intervention on HADS scores (weighted mean difference, -0.79 [95% confidence interval, -3.81 to 2.23]; I2 = 65.8%). Conclusions: Owing to limited data, and clinical and statistical heterogeneity, there is considerable uncertainty regarding whether bereavement support strategies reduce, increase or have no effect on psychological distress in bereaved family members.

Long-term outcomes of patients admitted to an intensive care unit with intentional self-harm.

Self-harm is one of the most common reasons for admission to an intensive care unit (ICU). While most patients with self-harm survive the ICU admission, little is known about their outcomes after hospital discharge. We conducted a retrospective cohort study of patients in the Barwon region in Victoria admitted to the ICU with self-harm (between 1998 and 2018) who survived to hospital discharge. The primary objective was to determine mortality after hospital discharge, and secondarily estimate relative survival, years of potential life lost, cause of death and factors associated with death. Over the 20-year study period, there were 710 patients in the cohort. The median patient age was 37 years (interquartile range (IQR) 26-48 years). A total of 406 (57%) were female, and 527 (74%) had a prior psychiatric diagnosis. The incidence of ICU admission increased over time (incidence rate ratio 1.05; 95% confidence interval (CI) 1.03-1.06 per annum). There were 105 (15%) patients who died after hospital discharge. Relative survival decreased each year after discharge, with the greatest decrement during the first 12 months. At ten years, relative survival was 0.85 (95% CI 0.81-0.88). The median years of potential life lost was 35 (IQR 22-45). Cause of death was self-harm in 27%, possible self-harm in 32% and medical disease in 41%. The only factors associated with mortality were male sex, older age and re-admission to ICU with self-harm. Further population studies are required to confirm these findings, and to understand what interventions may improve long-term survival in this relatively young group of critically ill patients.

Urinary and renal oxygenation during dexmedetomidine infusion in critically ill adults with mechanistic insights from an ovine model.

PURPOSE: Examine effects of dexmedetomidine on bladder urinary oxygen tension (PuO2) in critically ill patients and delineate mechanisms in an ovine model. MATERIALS AND METHODS: In 12 critically ill patients: oxygen-sensing probe inserted in the bladder catheter and dexmedetomidine infusion at a mean (SD) rate of 0.9 ± 0.3 µg/kg/h for 24-h. In 9 sheep: implantation of flow probes around the renal and pulmonary arteries, and oxygen-sensing probes in the renal cortex, renal medulla and bladder catheter; dexmedetomidine infusion at 0.5 µg/kg/h for 4-h and 1.0 µg/kg/h for 4-h then 16 h observation. RESULTS: In patients, dexmedetomidine decreased bladder PuO2at 2 (-Δ11 (95% CI 7-16)mmHg), 8 (-Δ 7 (0.1-13)mmHg) and 24 h (-Δ 11 (0.4-21)mmHg). In sheep, dexmedetomidine at 1 µg/kg/h reduced renal medullary oxygenation (-Δ 19 (14-24)mmHg) and bladder PuO2 (-Δ 12 (7-17)mmHg). There was moderate correlation between renal medullary oxygenation and bladder PuO2; intraclass correlation co-efficient 0.59 (0.34-0.80). Reductions in renal medullary oxygenation were associated with reductions in blood pressure, cardiac output and renal blood flow (P < 0.01). CONCLUSIONS: Dexmedetomidine decreases PuO2in critically ill patients and in sheep. In sheep this reflects a decrease in renal medullary oxygenation, associated with reductions in cardiac output, blood pressure and renal blood flow.