Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

BACKGROUND: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. METHODS: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding. RESULTS: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis.

BACKGROUND: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. OBJECTIVE: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. METHODS: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. RESULTS: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. CONCLUSION: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial.

BACKGROUND: The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients. OBJECTIVE: To outline the statistical analysis plan for the REVISE trial. METHODS: REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated. RESULTS: The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment. CONCLUSIONS: This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT03374800. November 21, 2017.

REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol.

INTRODUCTION: The Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE. METHODS AND ANALYSIS: REVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial. ETHICS AND DISSEMINATION: All participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to - Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION NUMBER: NCT03374800.

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).

Preparedness and response to COVID-19 in a quaternary intensive care unit in Australia: perspectives and insights from frontline critical care clinicians.

OBJECTIVES: This study was conducted to explore the perspectives and opinions of intensive care unit (ICU) nurses and doctors at a COVID-19-designated pandemic hospital concerning the preparedness and response to COVID-19 and to consolidate the lessons learnt for crisis/disaster management in the future. DESIGN: A qualitative study using in-depth interviews (IDIs) and focus group discussions (FGDs). Purposeful sampling was conducted to identify participants. A semistructured guide was used to facilitate IDIs with individual participants. Two FGDs were conducted, one with the ICU doctors and another with the ICU nurses. Thematic analysis identified themes and subthemes informing about the level of preparedness, response measures, processes, and factors that were either facilitators or those that triggered challenges. SETTING: ICU in a quaternary referral centre affiliated to a university teaching COVID-19-designated pandemic hospital, in Adelaide, South Australia. PARTICIPANTS: The participants included eight ICU doctors and eight ICU nurses for the IDIs. Another 16 clinicians participated in FGDs. RESULTS: The study identified six themes relevant to preparedness for, and responses to, COVID-19. The themes included: (1) staff competence and planning, (2) information transfer and communication, (3) education and skills for the safe use of personal protective equipment, (4) team dynamics and clinical practice, (5) leadership, and (6) managing end-of-life situations and expectations of caregivers. CONCLUSION: Findings highlight that preparedness and response to the COVID-19 crisis were proportionate to the situation's gravity. More enablers than barriers were identified. However, opportunities for improvement were recognised in the domains of planning, logistics, self-sufficiency with equipment, operational and strategic oversight, communication and managing end-of-life care.

Perceptions held by healthcare professionals concerning organ donation after circulatory death in an Australian intensive care unit without a local thoracic transplant service: A descriptive exploratory study.

BACKGROUND AND OBJECTIVE: Organ donation rates continue to be low in Australia compared with demand. Donation after circulatory death (DCD) has been an important strategy to increase donation rates, facilitated by advances in cardiopulmonary support in intensive care units (ICUs). However, DCD may harbour greater logistical challenges and unfavourable perceptions amongst some ICU healthcare professionals. The aim of this study was to evaluate and understand DCD perceptions at an Australian tertiary hospital. METHODS: This descriptive exploratory study was conducted at an Australian tertiary hospital. Participants were recruited voluntarily for interview via email and word-of-mouth through the hospital's ICU network. The study used a mixed-methods approach; five close-ended questions were included in the form of Likert scales followed by a semistructured interview with open-ended questions designed to understand participants' perceptions of DCD. Interviews were recorded, transcribed, and thematically analysed. RESULTS: Sixteen participants were interviewed including eight intensive care doctors, four donation specialist nursing coordinators (DSNCs), and four bedside nurses. Likert responses demonstrated clinicians' support for both DCD and donation after brain death (DBD). Thematic analysis of the transcripts yielded three overarching themes including 'Contextual and environmental influences on DCD decision-making', 'Personal difficulties faced by clinicians in DCD decision-making', and 'Family influences on DCD decision-making'. Significant geographical separation between donation and organ retrieval teams, incurring significant resource utilisation, impacted the donation team's decision-making around DCD, as did a perceived disruption of ICU care to facilitate donation especially for cases where successful DCD was identified to be unlikely. CONCLUSIONS: Overall, DCD was as acceptable to participants as DBD. However, the geographical separation of this centre meant that logistical barriers potentially impacted the DCD process. Open lines of communication with transplant centres, local resourcing, and a culture of education, experience, and leadership may facilitate the DCD programs where distant retrieval is commonplace.

Effects of Standard vs Energy-Dense Formulae on Gastric Retention, Energy Delivery, and Glycemia in Critically Ill Patients.

BACKGROUND: Energy-dense formulae are often provided to critically ill patients with enteral feed intolerance with the aim of increasing energy delivery, yet the effect on gastric emptying is unknown. The rate of gastric emptying of a standard compared with an energy-dense formula was quantified in critically ill patients. METHODS: Mechanically ventilated adults were randomized to receive radiolabeled intragastric infusions of 200 mL standard (1 kcal/mL) or 100 mL energy-dense (2 kcal/mL) enteral formulae on consecutive days in this noninferiority, blinded, crossover trial. The primary outcome was scintigraphic measurement of gastric retention (percentage at 120 minutes). Other measures included area under the curve (AUC) for gastric retention and intestinal energy delivery (calculated from gastric retention of formulae over time), blood glucose (peak and AUC), and intestinal glucose absorption (using 3-O-methyl-D-gluco-pyranose [3-OMG] concentrations). Comparisons were undertaken using paired mixed-effects models. Data presented are mean ± SE. RESULTS: Eighteen patients were studied (male/female, 14:4; age, 55.2 ± 5.3 years). Gastric retention at 120 minutes was greater with the energy-dense formula (standard, 17.0 ± 5.9 vs energy-dense, 32.5 ± 7.1; difference, 12.7% [90% confidence interval, 0.8%-30.1%]). Energy delivery (AUC120 , 13,038 ± 1119 vs 9763 ± 1346 kcal/120 minutes; P = 0.057), glucose control (peak glucose, 10.1 ± 0.3 vs 9.7 ± 0.3 mmol/L, P = 0.362; and glucose AUC120 8.7 ± 0.3 vs 8.5 ± 0.3 mmol/L.120 minutes, P = 0.661), and absorption (3-OMG AUC120 , 38.5 ± 4.0 vs 35.7 ± 4.0 mmol/L.120 minutes; P = .508) were not improved with the energy-dense formula. CONCLUSION: In critical illness, administration of an energy-dense formula does not reduce gastric retention, increase energy delivery to the small intestine, or improve glucose absorption or glucose control; instead, there is a signal for delayed gastric emptying.

Study protocol and statistical analysis plan for the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial.

BACKGROUND: Contemporary glucose management of intensive care unit (ICU) patients with type 2 diabetes is based on trial data derived predominantly from patients without type 2 diabetes. This is despite the recognition that patients with type 2 diabetes may be relatively more tolerant of hyperglycaemia and more susceptible to hypoglycaemia. It is uncertain whether glucose targets should be more liberal in patients with type 2 diabetes. OBJECTIVE: To detail the protocol, analysis and reporting plans for a randomised clinical trial - the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial - which will evaluate the risks and benefits of targeting a higher blood glucose range in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A multicentre, parallel group, open label phase 2B randomised controlled clinical trial of 450 critically ill patients with type 2 diabetes. Patients will be randomised 1:1 to liberal blood glucose (target 10.0-14.0 mmol/L) or usual care (target 6.0-10.0 mmol/L). MAIN OUTCOME MEASURES: The primary endpoint is incident hypoglycaemia (< 4.0 mmol/L) during the study intervention. Secondary endpoints include biochemical and feasibility outcomes. RESULTS AND CONCLUSION: The study protocol and statistical analysis plan described will delineate conduct and analysis of the trial, such that analytical and reporting bias are minimised. TRIAL REGISTRATION: This trial has been registered on the Australian New Zealand Clinical Trials Registry (ACTRN No. 12616001135404) and has been endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group.

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.

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.

The impact on new-onset stress and PTSD in relatives of critically ill patients explored by diaries study (The "INSPIRED" study).

BACKGROUND: There is rising prevalence of post-traumatic-stress-disorder (PTSD) in patients and their relatives after ICU discharge. The impact of ICU diaries on PTSD in relatives of critically ill patients in Australia has not been fully evaluated. OBJECTIVES: To determine if relatives of an Australian critically ill population were interested in using ICU diaries. To determine the prevalence and impact of ICU diaries upon symptoms of PTSD, depression and anxiety in relatives of an Australian critically ill population. METHODS DESIGN: Prospective, observational, exploratory study. SETTING: Royal Adelaide Hospital (RAH), Adelaide, Australia. PARTICIPANTS: One hundred and eight consecutive patients, staying >48h in a level 3 ICU were identified. A survey using DASS-21, IES-R questionnaires was performed on admission followed by a repeat survey 90days post discharge from ICU. An IES-R score >33 was used to define severe PTSD symptoms. A comparison between subjects who did and did not complete their diaries was performed. RESULTS: Forty subjects refused to participate, eight were excluded, and sixty family members were included for analysis, thirty-six of whom completed diaries. There was no statistically significant difference between PTSD symptom scores at follow-up controlling for useful diary completion (complete - see methods) and PTSD at baseline. There was a statistically significant association between PTSD and unemployment, controlling for PTSD at baseline (P value=0.0045). Family members had significantly higher odds of PTSD at baseline compared to 3 month follow up (P value=0.0092, Odds Ratio=3.3, 95% CI: 1.3, 8.2). This was independent of the completeness of the diaries and adjusted for clustering on subject. Family members with incomplete diaries were less likely to report depressive symptoms at baseline (P value=0.0218, estimate=-4.6, 95% CI: -8.5, -0.7). Diary completion was not indicative of the likelihood of family members to report PTSD symptoms (P value=0.5468, estimate=-1.6, 95% CI: -6.8, 3.6). CONCLUSION: ICU diaries were often not completed and completion did not appear to be related to the incidence of stress, anxiety, depression and PTSD symptoms in the families of patients in the ICU. This may be because Australian families are generally not interested in maintaining a diary.

The relationship between fasting plasma citrulline concentration and small intestinal function in the critically ill.

INTRODUCTION: In this study, we aimed to evaluate whether fasting plasma citrulline concentration predicts subsequent glucose absorption in critically ill patients. METHODS: In a prospective observational study involving 15 healthy and 20 critically ill subjects, fasting plasma citrulline concentrations were assayed in blood samples immediately prior to the administration of a liquid test meal (1 kcal/ml; containing 3 g of 3-O-methylglucose (3-OMG)) that was infused directly into the small intestine. Serum 3-OMG concentrations were measured over the following 4 hours, with the area under the 3-OMG concentration curve (AUC) calculated as an index of glucose absorption. RESULTS: The groups were well matched in terms of age, sex and body mass index (BMI) (healthy subjects versus patients, mean (range) values: age, 47 (18 to 88) versus 49 (21 to 77) years; sex ratio, 60% versus 80% male; BMI, 25.2 (18.8 to 30.0) versus 25.5 (19.4 to 32.2) kg/m(2)). Compared to the healthy subjects, patients who were critically ill had reduced fasting citrulline concentration (26.5 (13.9 to 43.0) versus 15.2 (5.7 to 28.6) µmol/L; P < 0.01) and glucose absorption (3-OMG AUC, 79.7 (28.6 to 117.8) versus 61.0 (4.5 to 97.1) mmol/L/240 min; P = 0.05). There was no relationship between fasting citrulline concentration and subsequent glucose absorption (r = 0.28; P = 0.12). CONCLUSIONS: Whereas both plasma citrulline concentrations and glucose absorption were reduced in critical illness, fasting plasma citrulline concentrations were not predictive of subsequent glucose absorption. These data suggest that fasting citrulline concentration does not appear to be a marker of small intestinal absorptive function in patients who are critically ill.