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.

Reversal of cerebral ischaemia and hypoxia and of sickness behaviour by megadose sodium ascorbate in ovine Gram-negative sepsis.

BACKGROUND: The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis. METHODS: Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg-1 over 30 min+0.5 g kg-1 h-1 for 6.5 h) or vehicle (n=6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70-80 mm Hg. RESULTS: At 23 h of sepsis, MAP (mean [sem]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] µM) decreased (both P<0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P<0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all PTreatment<0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both PGroupxTime<0.01), and increased plasma ascorbate (20 000 [300] µM; PGroup<0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate. CONCLUSIONS: Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load.

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.

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.

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.

Gut dysfunction in the ICU: diagnosis and management.

PURPOSE OF REVIEW: Progress has been made in our understanding of gut dysfunction in critical illness. This review will outline new findings and give perspectives based on previous knowledge and concurrent advances in nutrition. RECENT FINDINGS: The relationship between gut dysfunction and poor outcomes in critical illness has received considerable interest. It remains uncertain whether gut dysfunction is merely a marker of illness severity or if it is directly responsible for prolonged critical illness and increased mortality. This relationship is difficult to ascertain given there is no agreed method for identification and quantification; biomarkers such as intestinal fatty acid binding protein and citrulline show promise but require further study. Recent studies have investigated strategies to deliver enteral nutrition targets with impacts on gut function, including high calorie or protein formulae, intermittent regimes and novel prokinetics. SUMMARY: Gut dysfunction is associated with poor outcomes, but it remains uncertain whether strategies to improve gut function will influence survival and recovery.

Outcomes for patients with COVID-19 admitted to Australian intensive care units during the first four months of the pandemic.

OBJECTIVES: To describe the characteristics and outcomes of patients with COVID-19 admitted to intensive care units (ICUs) during the initial months of the pandemic in Australia. DESIGN, SETTING: Prospective, observational cohort study in 77 ICUs across Australia. PARTICIPANTS: Patients admitted to participating ICUs with laboratory-confirmed COVID-19 during 27 February - 30 June 2020. MAIN OUTCOME MEASURES: ICU mortality and resource use (ICU length of stay, peak bed occupancy). RESULTS: The median age of the 204 patients with COVID-19 admitted to intensive care was 63.5 years (IQR, 53-72 years); 140 were men (69%). The most frequent comorbid conditions were obesity (40% of patients), diabetes (28%), hypertension treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (24%), and chronic cardiac disease (20%); 73 patients (36%) reported no comorbidity. The most frequent source of infection was overseas travel (114 patients, 56%). Median peak ICU bed occupancy was 14% (IQR, 9-16%). Invasive ventilation was provided for 119 patients (58%). Median length of ICU stay was greater for invasively ventilated patients than for non-ventilated patients (16 days; IQR, 9-28 days v 3 days; IQR, 2-5 days), as was ICU mortality (26 deaths, 22%; 95% CI, 15-31% v four deaths, 5%; 95% CI, 1-12%). Higher Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores on ICU day 1 (adjusted hazard ratio [aHR], 1.15; 95% CI, 1.09-1.21) and chronic cardiac disease (aHR, 3.38; 95% CI, 1.46-7.83) were each associated with higher ICU mortality. CONCLUSION: Until the end of June 2020, mortality among patients with COVID-19 who required invasive ventilation in Australian ICUs was lower and their ICU stay longer than reported overseas. Our findings highlight the importance of ensuring adequate local ICU capacity, particularly as the pandemic has not yet ended.

Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients.

Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum-derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient-stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high-lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient-stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.

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.

Gut dysmotility in the ICU: diagnosis and therapeutic options.

PURPOSE OF REVIEW: To provide a comprehensive update of diagnosis and treatment of gastrointestinal dysmotility in the critically ill, with a focus on work published in the last 5 years. RECENT FINDINGS: Symptoms and clinical features consistent with upper and/or lower gastrointestinal dysmotility occur frequently. Although features of gastrointestinal dysmotility are strongly associated with adverse outcomes, these associations may be because of unmeasured confounders. The use of ultrasonography to identify upper gastrointestinal dysmotility appears promising. Both nonpharmacological and pharmacological approaches to treat gastrointestinal dysmotility have recently been evaluated. These approaches include modification of macronutrient content and administration of promotility drugs, stool softeners or laxatives. Although these approaches may reduce features of gastrointestinal dysmotility, none have translated to patient-centred benefit. SUMMARY: 'Off-label' metoclopramide and/or erythromycin administration are effective for upper gastrointestinal dysmotility but have adverse effects. Trials of alternative or novel promotility drugs have not demonstrated superiority over current pharmacotherapies. Prophylactic laxative regimens to prevent non-defecation have been infrequently studied and there is no recent evidence to further inform treatment of established pseudo-obstruction. Further trials of nonpharmacological and pharmacological therapies to treat upper and lower gastrointestinal dysmotility are required and challenges in designing such trials are explored.

Systematic review of incretin therapy during peri-operative and intensive care.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are incretin hormones. By lowering blood glucose in a glucose-dependent manner, incretin-based therapies represent a novel and promising intervention to treat hyperglycaemia in hospital settings. We performed a systematic review of the literature for all current applications of incretin-based therapies in the peri-operative and critical care settings. METHODS: We searched MEDLINE, the Cochrane Library, and Embase databases for all randomised controlled trials using exogenous GLP-1, GLP-1 receptor agonists, exogenous GIP and dipeptidyl peptidase IV inhibitors in the setting of adult peri-operative care or intensive care. We defined no comparator treatment. Outcomes of interest included blood glucose, frequency of hypoglycaemia and insulin administration. RESULTS: Of the 1190 articles identified during the initial literature search, 38 fulfilled criteria for full-text review, and 19 single-centre studies were subsequently included in the qualitative review. Of the 18 studies reporting glycaemic control, improvement was reported in 15, defined as lower glucose concentrations in 12 and as reduced insulin administration (with similar glucose concentrations) in 3. Owing to heterogeneity, meta-analysis was possible only for the outcome of hypoglycaemia. This revealed an incidence of 7.4% in those receiving incretin-based therapies and 6.8% in comparator groups (P = 0.94). CONCLUSIONS: In small, single-centre studies, incretin-based therapies lowered blood glucose and reduced insulin administration without increasing the incidence of hypoglycaemia. TRIAL REGISTRATION: PROSPERO, CRD42017071926.

Glycaemic control targets after traumatic brain injury: a systematic review and meta-analysis.

BACKGROUND: Optimal glycaemic targets in traumatic brain injury (TBI) remain unclear. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing intensive with conventional glycaemic control in TBI requiring admission to an intensive care unit (ICU). METHODS: We systematically searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to November 2016. Outcomes of interest included ICU and in-hospital mortality, poor neurological outcome, the incidence of hypoglycaemia and infective complications. Data were analysed by pairwise random effects models with secondary analysis of differing levels of conventional glycaemic control. RESULTS: Ten RCTs, involving 1066 TBI patients were included. Three studies were conducted exclusively in a TBI population, whereas in seven trials, the TBI population was a sub-cohort of a mixed neurocritical or general ICU population. Glycaemic targets with intensive control ranged from 4.4 to 6.7 mmol/L, while conventional targets aimed to keep glucose levels below thresholds of 8.4-12 mmol/L. Conventional versus intensive control showed no association with ICU or hospital mortality (relative risk (RR) (95% CI) 0.93 (0.68-1.27), P = 0.64 and 1.07 (0.84-1.36), P = 0.62, respectively). The risk of a poor neurological outcome was higher with conventional control (RR (95% CI) = 1.10 (1.001-1.24), P = 0.047). However, severe hypoglycaemia occurred less frequently with conventional control (RR (95% CI) = 0.22 (0.09-0.52), P = 0.001). CONCLUSIONS: This meta-analysis of intensive glycaemic control shows no association with reduced mortality in TBI. Intensive glucose control showed a borderline significant reduction in the risk of poor neurological outcome, but markedly increased the risk of hypoglycaemia. These contradictory findings should motivate further research.

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.

Probable Catastrophic Antiphospholipid Syndrome with Intracerebral Hemorrhage Secondary to Epstein-Barr Viral Infection.

BACKGROUND: Catastrophic antiphospholipid syndrome (CAPS) is a rare, severe variant of antiphospholipid syndrome with a high mortality rate. We report a unique case of CAPS secondary to Epstein-Barr viral (EBV) infection complicated by pulmonary and intracerebral hemorrhage. A review of the CAPS literature relevant to intensive care practice is used to outline a rational approach to diagnosis and management. METHODS: All data are from a single patient admitted to the Neurosciences Critical Care Unit in Addenbrooke's Hospital, Cambridge, in March 2016. Medline, Web of Science, PubMed, and the Cochrane Library were searched through September 2016 without restrictions for cases of CAPS, management of CAPS in the intensive care unit, and hemorrhage complicating CAPS. The patient gave express written consent to access and publish these data. RESULTS: This is only the second reported case of probable CAPS secondary to EBV infection. Furthermore, pulmonary and intracerebral hemorrhage is rare manifestations of this multisystem prothrombotic state which provided unique challenges to the management. CONCLUSIONS: While rare, CAPS should be considered in any patient presenting with rapidly progressive multiorgan failure, evidence of thrombotic microangiopathy, and antiphospholipid antibodies. A high index of suspicion is required as early, aggressive, multimodal treatment with anticoagulation, and immunosuppression improves outcomes.