Cerebral Glucose Metabolism following TBI: Changes in Plasma Glucose, Glucose Transport and Alternative Pathways of Glycolysis-A Translational Narrative Review.

Traumatic brain injury (TBI) is a major public health concern with significant consequences across various domains. Following the primary event, secondary injuries compound the outcome after TBI, with disrupted glucose metabolism emerging as a relevant factor. This narrative review summarises the existing literature on post-TBI alterations in glucose metabolism. After TBI, the brain undergoes dynamic changes in brain glucose transport, including alterations in glucose transporters and kinetics, and disruptions in the blood-brain barrier (BBB). In addition, cerebral glucose metabolism transitions from a phase of hyperglycolysis to hypometabolism, with upregulation of alternative pathways of glycolysis. Future research should further explore optimal, and possibly personalised, glycaemic control targets in TBI patients, with GLP-1 analogues as promising therapeutic candidates. Furthermore, a more fundamental understanding of alterations in the activation of various pathways, such as the polyol and lactate pathway, could hold the key to improving outcomes following TBI.

PRECISION-TBI: a study protocol for a vanguard prospective cohort study to enhance understanding and management of moderate to severe traumatic brain injury in Australia.

INTRODUCTION: Traumatic brain injury (TBI) is a heterogeneous condition in terms of pathophysiology and clinical course. Outcomes from moderate to severe TBI (msTBI) remain poor despite concerted research efforts. The heterogeneity of clinical management represents a barrier to progress in this area. PRECISION-TBI is a prospective, observational, cohort study that will establish a clinical research network across major neurotrauma centres in Australia. This network will enable the ongoing collection of injury and clinical management data from patients with msTBI, to quantify variations in processes of care between sites. It will also pilot high-frequency data collection and analysis techniques, novel clinical interventions, and comparative effectiveness methodology. METHODS AND ANALYSIS: PRECISION-TBI will initially enrol 300 patients with msTBI with Glasgow Coma Scale (GCS) <13 requiring intensive care unit (ICU) admission for invasive neuromonitoring from 10 Australian neurotrauma centres. Demographic data and process of care data (eg, prehospital, emergency and surgical intervention variables) will be collected. Clinical data will include prehospital and emergency department vital signs, and ICU physiological variables in the form of high frequency neuromonitoring data. ICU treatment data will also be collected for specific aspects of msTBI care. Six-month extended Glasgow Outcome Scores (GOSE) will be collected as the key outcome. Statistical analysis will focus on measures of between and within-site variation. Reports documenting performance on selected key quality indicators will be provided to participating sites. ETHICS AND DISSEMINATION: Ethics approval has been obtained from The Alfred Human Research Ethics Committee (Alfred Health, Melbourne, Australia). All eligible participants will be included in the study under a waiver of consent (hospital data collection) and opt-out (6 months follow-up). Brochures explaining the rationale of the study will be provided to all participants and/or an appropriate medical treatment decision-maker, who can act on the patient's behalf if they lack capacity. Study findings will be disseminated by peer-review publications. TRIAL REGISTRATION NUMBER: NCT05855252.

Perioperative management of long-acting glucagon-like peptide-1 (GLP-1) receptor agonists: concerns for delayed gastric emptying and pulmonary aspiration.

Prescriptions and use of glucagon-like peptide-1 (GLP-1) receptor agonists are increasing dramatically, as indications are expanding from the treatment of diabetes mellitus to weight loss for people with obesity. As GLP-1 receptor agonists delay gastric emptying, perioperative healthcare practitioners could be concerned about an increased risk for pulmonary aspiration during general anaesthesia. We summarise relevant medical literature and provide evidence-based recommendations for perioperative care for people taking GLP-1 receptor agonists. GLP-1 receptor agonists delay gastric emptying; however, ongoing treatment attenuates this effect. The risk of aspiration during general anaesthesia is unknown. However, we advise caution in patients who recently commenced on GLP-1 receptor agonists. After over 12 weeks of treatment, standard fasting times likely suffice to manage the risk of pulmonary aspiration for most otherwise low-risk patients.

Nutrition practices in critically ill adults receiving noninvasive ventilation: A quantitative survey of Australian and New Zealand intensive care clinicians.

BACKGROUND: Noninvasive ventilation (NIV) is frequently used in the intensive care unit (ICU), yet there is a paucity of evidence to guide nutrition management during this therapy. Understanding clinicians' views on nutrition practices during NIV will inform research to address this knowledge gap. OBJECTIVE: The objective of this study was to describe Australian and New Zealand clinicians' views and perceptions of nutrition management during NIV in critically ill adults. METHODS: A cross-sectional quantitative online survey of Australian and New Zealand medical and nursing staff with ≥12 months ICU experience was disseminated through professional organisations via purposive snowball sampling from 29 August to 9 October 2022. Data collection included demographics, current practices, and views and perceptions of nutrition during NIV. Surveys <50% complete were excluded. Data are represented in number (%). RESULTS: A total of 152 surveys were analysed; 71 (47%) nursing, 69 (45%) medical, and 12 (8%) not specified. There was limited consensus on nutrition management during NIV; however, most clinicians (n = 108, 79%) reported that nutrition during NIV was 'important or very important'. Oral intake was perceived to be the most common route (n = 83, 55%), and 29 (21%) respondents viewed this as the safest. Most respondents (n = 106, 78%) reported that ≤50% of energy targets were met, with gastric enteral nutrition considered most likely to meet targets (n = 55, 40%). Reported nutrition barriers were aspiration risk (n = 87, 64%), fasting for intubation (n = 84, 62%), and nutrition perceived as a lower priority (n = 73, 54%). Reported facilitators were evidence-based guidelines (n = 77, 57%) and an NIV interface compatible with enteral nutrition tube (n = 77, 57%). CONCLUSION: ICU medical and nursing staff reported nutrition during NIV to be important; however, there was a lack of consensus on the route of feeding considered to be the safest and most likely to achieve nutrition targets. Interventions to minimise aspiration and fasting, including an interface with nasoenteric tube compatibility, should be explored.

Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial.

BACKGROUND: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. METHODS: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score. RESULTS: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes. CONCLUSION: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.

The prognostic value of elevated neutrophil-lymphocyte ratio for cardiac surgery-associated acute kidney injury: A systematic review and meta-analysis.

BACKGROUND: Patients undergoing cardiac surgery are at significant risk of developing postoperative acute kidney injury (AKI). Neutrophil-lymphocyte ratio (NLR) is a widely available inflammatory biomarker which may be of prognostic value in this setting. METHODS: We conducted a systematic review and meta-analysis of studies reporting associations between perioperative NLR with postoperative AKI. We searched Medline, Embase and the Cochrane Library, without language restriction, from inception to May 2022 for relevant studies. We meta-analysed the reported odds ratios (ORs) with 95% confidence intervals (CIs) for both elevated preoperative and postoperative NLR with risk of postoperative AKI and need for renal replacement therapy (RRT). We conducted a meta-regression to explore inter-study statistical heterogeneity. RESULTS: Twelve studies involving 10,724 participants undergoing cardiac surgery were included, with eight studies being deemed at high risk of bias using PROBAST modelling. We found statistically significant associations between elevated preoperative NLR and postoperative AKI (OR 1.45, 95% CI 1.18-1.77), as well as postoperative need for RRT (OR 2.37, 95% CI 1.50-3.72). Postoperative NLR measurements were not of prognostic significance. CONCLUSIONS: Elevated preoperative NLR is a reliable inflammatory biomarker for predicting AKI following cardiac surgery.

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.

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.

Machine learning predicts the short-term requirement for invasive ventilation among Australian critically ill COVID-19 patients.

OBJECTIVE(S): To use machine learning (ML) to predict short-term requirements for invasive ventilation in patients with COVID-19 admitted to Australian intensive care units (ICUs). DESIGN: A machine learning study within a national ICU COVID-19 registry in Australia. PARTICIPANTS: Adult patients who were spontaneously breathing and admitted to participating ICUs with laboratory-confirmed COVID-19 from 20 February 2020 to 7 March 2021. Patients intubated on day one of their ICU admission were excluded. MAIN OUTCOME MEASURES: Six machine learning models predicted the requirement for invasive ventilation by day three of ICU admission from variables recorded on the first calendar day of ICU admission; (1) random forest classifier (RF), (2) decision tree classifier (DT), (3) logistic regression (LR), (4) K neighbours classifier (KNN), (5) support vector machine (SVM), and (6) gradient boosted machine (GBM). Cross-validation was used to assess the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of machine learning models. RESULTS: 300 ICU admissions collected from 53 ICUs across Australia were included. The median [IQR] age of patients was 59 [50-69] years, 109 (36%) were female and 60 (20%) required invasive ventilation on day two or three. Random forest and Gradient boosted machine were the best performing algorithms, achieving mean (SD) AUCs of 0.69 (0.06) and 0.68 (0.07), and mean sensitivities of 77 (19%) and 81 (17%), respectively. CONCLUSION: Machine learning can be used to predict subsequent ventilation in patients with COVID-19 who were spontaneously breathing and admitted to Australian ICUs.

Higher versus lower enteral calorie delivery and gastrointestinal dysfunction in critical illness: A systematic review and meta-analysis.

BACKGROUND AND AIMS: In critical illness, enteral nutrition (EN) is frequently limited by gastrointestinal (GI) dysfunction. The aim of this systematic review and meta-analysis was to determine relationships between enteral calorie delivery and GI dysfunction in critically ill adults. METHODS: MEDLINE, EMCARE, EMBASE, and CINAHL databases were searched from 1 January 2000 to 11 August 2021 to identify parallel group randomised controlled trials of an EN intervention that resulted in a significant difference in calorie delivery between groups and reported at least one outcome relating to GI dysfunction. Study groups were categorised as 'higher' or 'lower' calorie delivery and data were extracted on study interventions, GI dysfunction and clinical outcomes. Extracted data were aggregated using a random effects model and presented as risk ratio with 95% confidence intervals. A P-value <0.05 was considered significant. The risk of publication bias was assessed graphically using a funnel plot. RESULTS: From 13 studies involving 6824 patients the mean calorie delivery in the higher calorie group was 1673 ± 468 kcal/day compared to 1121 ± 312 kcal/day in the lower calorie group. The higher calorie group had an increased risk of a large (any volume ≥300 ml) gastric residual volume (GRV) (RR 1.40; 95% CI 1.09, 1.80; P = 0.009) and prokinetic administration (RR 1.18; 95% CI 1.11, 1.27; P < 0.00001). There were no between group differences in the presence of vomiting/regurgitation (RR 0.93; 95% CI 0.58, 1.49; P = 0.76), diarrhoea (RR 1.12; 95% CI 0.93, 1.35; P = 0.22) or abdominal distension (RR 0.71; 95% CI 0.49, 1.04; P = 0.08). There was no evidence of publication bias. CONCLUSION: Higher calorie delivery is associated with increased rates of GRV≥300 ml and prokinetic administration, but not vomiting/regurgitation, diarrhoea or abdominal distension. OTHER: No funding was received for the conduct of this systematic review and meta-analysis. The protocol was prospectively registered with PROSPERO (CRD42021268876).

Is it time to personalise glucose targets during critical illness?

PURPOSE OF REVIEW: Dysglycaemia complicates most critical care admissions and is associated with harm, yet glucose targets, particularly in those with preexisting diabetes, remain controversial. This review will summarise advances in the literature regarding personalised glucose targets in the critically ill. RECENT FINDINGS: Observational data suggest that the degree of chronic hyperglycaemia in critically ill patients with diabetes attenuates the relationship between mortality and several metrics of dysglycaemia, including blood glucose on admission, and mean blood glucose, glycaemic variability and hypoglycaemia in the intensive care unit. The interaction between acute and chronic hyperglycaemia has recently been quantified with novel metrics of relative glycaemia including the glycaemic gap and stress hyperglycaemia ratio. Small pilot studies provided preliminary data that higher blood glucose thresholds in critically ill patients with chronic hyperglycaemia may reduce complications of intravenous insulin therapy as assessed with biomakers. Although personalising glycaemic targets based on preexisting metabolic state is an appealing concept, the recently published CONTROLLING trial did not identify a mortality benefit with individualised glucose targets, and the effect of personalised glucose targets on patient-centred outcomes remains unknown. SUMMARY: There is inadequate data to support adoption of personalised glucose targets into care of critically ill patients. However, there is a strong rationale empowering future trials utilising such an approach for patients with chronic hyperglycaemia.

Update on glucose control during and after critical illness.

PURPOSE OF REVIEW: There is a complex bidirectional relationship between critical illness and disordered glucose metabolism. This review aims to provide a comprehensive summary of the recent evidence focused on the relationship between critical illness and disordered glucose metabolism through the distinct phases of prior to, during, and after an acute illness that requires admission to the intensive care unit (ICU). RECENT FINDINGS: Recent data suggest that preexisting glucose metabolism affects the optimal blood glucose target during critical illness, with preliminary data suggesting that glucose targets should be 'personalized' based on preexisting glycemia. Because of the close association between critical illness and disordered glucose metabolism, there is a need to optimize glucose monitoring in the ICU with rapid, precise, and cost-efficient measurements at the bedside. Recent studies have evaluated the use of various methodologies, with a focus on the use of near-continuous glucose monitoring. For those patients with preexisting diabetes who survive ICU, nocturnal hypoglycemia may be an unrecognized and important issue when discharged to the ward. There is increasing evidence that patients with high blood glucose during their acute illness, so called 'stress hyperglycemia', are at increased risk of developing diabetes in the years following recovery from the inciting event. Critically ill patients with COVID-19 appear at greater risk. SUMMARY: There have been important recent insights in the approach to glucose monitoring and glucose targets during critical illness, monitoring and administration of glucose-lowering drugs on discharge from the ICU, and longitudinal follow-up of patients with stress hyperglycemia.

People in intensive care with COVID-19: demographic and clinical features during the first, second, and third pandemic waves in Australia.

OBJECTIVE: To compare the demographic and clinical features, management, and outcomes for patients admitted with COVID-19 to intensive care units (ICUs) during the first, second, and third waves of the pandemic in Australia. DESIGN, SETTING, AND PARTICIPANTS: People aged 16 years or more admitted with polymerase chain reaction-confirmed COVID-19 to the 78 Australian ICUs participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project during the first (27 February - 30 June 2020), second (1 July 2020 - 25 June 2021), and third COVID-19 waves (26 June - 1 November 2021). MAIN OUTCOME MEASURES: Primary outcome: in-hospital mortality. SECONDARY OUTCOMES: ICU mortality; ICU and hospital lengths of stay; supportive and disease-specific therapies. RESULTS: 2493 people (1535 men, 62%) were admitted to 59 ICUs: 214 during the first (9%), 296 during the second (12%), and 1983 during the third wave (80%). The median age was 64 (IQR, 54-72) years during the first wave, 58 (IQR, 49-68) years during the second, and 54 (IQR, 41-65) years during the third. The proportion without co-existing illnesses was largest during the third wave (41%; first wave, 32%; second wave, 29%). The proportion of ICU beds occupied by patients with COVID-19 was 2.8% (95% CI, 2.7-2.9%) during the first, 4.6% (95% CI, 4.3-5.1%) during the second, and 19.1% (95% CI, 17.9-20.2%) during the third wave. Non-invasive (42% v 15%) and prone ventilation strategies (63% v 15%) were used more frequently during the third wave than during the first two waves. Thirty patients (14%) died in hospital during the first wave, 35 (12%) during the second, and 281 (17%) during the third. After adjusting for age, illness severity, and other covariates, the risk of in-hospital mortality was similar for the first and second waves, but 9.60 (95% CI, 3.52-16.7) percentage points higher during the third than the first wave. CONCLUSION: The demographic characteristics of patients in intensive care with COVID-19 and the treatments they received during the third pandemic wave differed from those of the first two waves. Adjusted in-hospital mortality was highest during the third wave.

One-hour plasma glucose level after a 75 g oral glucose load and its relationship to gastric emptying in survivors of critical illness and stress hyperglycaemia.

Objective: A 1-hour plasma glucose level ≥ 8.6 mmol/L in a 75 g oral glucose tolerance test has been strongly associated with increased morbidity and mortality in outpatients without diabetes. Our primary aim was to evaluate the 1-hour plasma glucose level in a 75 g glucose tolerance test in survivors of critical illness with stress hyperglycaemia at 3 months after intensive care unit (ICU) discharge, with the secondary aims to evaluate the 2-hour plasma glucose level, glycated haemoglobin (HbA1c), and gastric emptying. Design:Post hoc analysis of a single-centre, prospective cohort study. Setting: Single-centre, tertiary referral, mixed medical-surgical ICU. Participants: Consecutively admitted patients aged ≥ 18 years who developed stress hyperglycaemia and survived to hospital discharge were eligible. Interventions: Participants returned at 3 months after ICU discharge and underwent a 75 g oral glucose tolerance test. Main outcome measures: One- and 2-hour post load plasma glucose level, HbA1c, and assessment of gastric emptying via an isotope breath test. Results: Thirty-five patients (12 females; mean age, 58.5 years [SD, 10.5]; mean HbA1c, 37.4 mmol/mol [SD, 7.0]) attended the followup. In 32/35 patients (91%) the 1-hour post load plasma glucose level was ≥ 8.6 mmol/L. There was a positive correlation between the plasma glucose level at 1 hour (r2 = 0.21; P = 0.006), but no correlation between the 2-hour glucose level (r2 = 0.006; P = 0.63) and gastric emptying. Conclusion: Glucose intolerance, when defined as 1-hour glucose level ≥ 8.6 mmol/L following a 75 g oral glucose load, persists at 3 months in most survivors of stress hyperglycaemia and is dependent on the rate of gastric emptying. Longitudinal studies to characterise mechanisms underlying dysglycaemia and progression to diabetes in individuals with stress hyperglycaemia are indicated.

A multicenter randomized clinical trial of pharmacological vitamin B1 administration to critically ill patients who develop hypophosphatemia during enteral nutrition (The THIAMINE 4 HYPOPHOSPHATEMIA trial).

BACKGROUND: Hypophosphatemia may be a useful biomarker to identify thiamine deficiency in critically ill enterally-fed patients. The objective was to determine whether intravenous thiamine affects blood lactate, biochemical and clinical outcomes in this group. METHOD: This randomized clinical trial was conducted across 5 Intensive Care Units. Ninety critically ill adult patients with a serum phosphate ≤0.65 mmol/L within 72 h of commencing enteral nutrition were randomized to intravenous thiamine (200 mg every 12 h for up to 14 doses) or usual care (control). The primary outcome was blood lactate over time and data are median [IQR] unless specified. RESULTS: Baseline variables were well balanced (thiamine: lactate 1.2 [1.0, 1.6] mmol/L, phosphate 0.56 [0.44, 0.64] mmol/L vs. control: lactate 1.0 [0.8, 1.3], phosphate 0.54 [0.44, 0.61]). Patients randomized to the intervention received a median of 11 [7.5, 13.5] doses for a total of 2200 [1500, 2700] mg of thiamine. Blood lactate over the entire 7 days of treatment was similar between groups (mean difference = -0.1 (95 % CI -0.2 to 0.1) mmol/L; P = 0.55). The percentage change from lactate pre-randomization to T = 24 h was not statistically different (thiamine: -32 (-39, -26) vs. control: -24 (-31, -16) percent, P = 0.09). Clinical outcomes were not statistically different (days of vasopressor administration: thiamine 2 [1, 4] vs. control 2 [0, 5.5] days; P = 0.37, and deaths 9 (21 %) vs. 5 (11 %); P = 0.25). CONCLUSIONS: In critically ill enterally-fed patients who developed hypophosphatemia, intravenous thiamine did not cause measurable differences in blood lactate or clinical outcomes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12619000121167).

Pharmacological Management of Paroxysmal Sympathetic Hyperactivity: A Scoping Review.

Paroxysmal sympathetic hyperactivity (PSH) occurs in ∼10% of patients following acute severe brain injury. While PSH is associated with worse outcomes, there are no clinical practice guidelines to inform treatment. We aimed to systematically review the literature on the pharmacological management of PSH. MEDLINE, Embase, and Cochrane library databases were searched from inception to August 2020. Eligible studies met the following criteria: 1) randomized controlled trials, non-randomized controlled trials (case control or controlled cohort), observational studies, case series, and case reports; 2) study population of adult and pediatric patients; 3) exposure to an acute neurological insult complicated by PSH (or historic synonym); 4) description of pharmacological treatment of PSH. Our search retrieved 2729 citations with 83 articles assessed for inclusion. After full text extraction, 56 manuscripts inclusive of 459 patients met eligibility criteria. We identified 31 case reports, 15 case series (152 patients), seven retrospective case control or cohort studies (212 patients), and three prospective observational studies (52 patients). Traumatic brain injury was the most common precipitating insult (407 patients), followed by hypoxic encephalopathy (72 patients) and intracranial hemorrhage (10 patients). There were 48 drugs from 22 classes prescribed for the management of PSH. The most frequently prescribed agents were benzodiazepines, ß-blockers, opioids, α-2 agonists, and baclofen. However, route and dose of drug and subsequent outcome were inconsistently reported, such that no summary was possible. While a wide variety of drugs have been reported to treat PSH, there is a lack of even moderate-quality evidence to inform clinical decision making.

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.