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 key secondary outcomes were 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 key 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.).

Observed differences in nutrition management at two time points spanning a decade in critically ill trauma patients with and without head injury.

BACKGROUND: Nutritional needs of trauma patients admitted to the intensive care unit may differ from general critically ill patients, but most current evidence is based on large clinical trials recruiting mixed populations. OBJECTIVE: The aim of the study was to investigate nutrition practices at two time points that span a decade in trauma patients with and without head injury. METHODS: This observational study recruited adult trauma patients receiving mechanical ventilation and artificial nutrition from a single-centre intensive care unit between February 2005 to December 2006 (cohort 1), and December 2018 to September 2020 (cohort 2). Patients were categorised into head injury and non-head injury subgroups. Data regarding energy and protein prescription and delivery were collected. Data are presented as median [interquartile range]. Wilcoxon rank-sum test assessed the differences between cohorts and subgroups, with a P value ≤ 0.05. The protocol was registered with the Australian and New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001816246). RESULTS: Cohort 1 included 109 patients, and 112 patients were included in cohort 2 (age: 46 ± 19 vs 50 ± 19 y; 80 vs 79% M). Overall, nutrition practice did not differ between head-injured and non-head-injured subgroups (all P > 0.05). Energy prescription and delivery decreased from time point one to time point two, regardless of subgroup (Prescription: 9824 [8820-10 581] vs 8318 [7694-9071] kJ; Delivery: 6138 [5130-7188] vs 4715 [3059-5996] kJ; all P < 0.05). Protein prescription did not change from time point one to time point two. Although protein delivery remained constant from time point one to time point two in the head injury group, protein delivery reduced in the non-head injury subgroup (70 [56-82] vs 45 [26-64] g/d, P < 0.05). CONCLUSION: In this single-centre study, energy prescription and delivery in critically ill trauma patients reduced from time point one to time point two. Protein prescription did not change, but protein delivery reduced from time point one to time point two in non-head injury patients. Reasons for these differing trajectories require exploration. STUDY REGISTRATION: Trial registered at www.anzctr.org.au. TRIAL ID: ACTRN12618001816246.

Muscle Protein Synthesis after Protein Administration in Critical Illness.

Rationale: Dietary protein may attenuate the muscle atrophy experienced by patients in the ICU, yet protein handling is poorly understood. Objectives: To quantify protein digestion and amino acid absorption and fasting and postprandial myofibrillar protein synthesis during critical illness. Methods: Fifteen mechanically ventilated adults (12 male; aged 50 ± 17 yr; body mass index, 27 ± 5 kg⋅m-2) and 10 healthy control subjects (6 male; 54 ± 23 yr; body mass index, 27 ± 4 kg⋅m-2) received a primed intravenous L-[ring-2H5]-phenylalanine, L-[3,5-2H2]-tyrosine, and L-[1-13C]-leucine infusion over 9.5 hours and a duodenal bolus of intrinsically labeled (L-[1-13C]-phenylalanine and L-[1-13C]-leucine) intact milk protein (20 g protein) over 60 minutes. Arterial blood and muscle samples were taken at baseline (fasting) and for 6 hours following duodenal protein administration. Data are mean ± SD, analyzed with two-way repeated measures ANOVA and independent samples t test. Measurements and Main Results: Fasting myofibrillar protein synthesis rates did not differ between ICU patients and healthy control subjects (0.023 ± 0.013% h-1 vs. 0.034 ± 0.016% h-1; P = 0.077). After protein administration, plasma amino acid availability did not differ between groups (ICU patients, 54.2 ± 9.1%, vs. healthy control subjects, 61.8 ± 13.1%; P = 0.12), and myofibrillar protein synthesis rates increased in both groups (0.028 ± 0.010% h-1 vs. 0.043 ± 0.018% h-1; main time effect P = 0.046; P-interaction = 0.584) with lower rates in ICU patients than in healthy control subjects (main group effect P = 0.001). Incorporation of protein-derived phenylalanine into myofibrillar protein was ∼60% lower in ICU patients (0.007 ± 0.007 mol percent excess vs. 0.017 ± 0.009 mol percent excess; P = 0.007). Conclusions: The capacity for critically ill patients to use ingested protein for muscle protein synthesis is markedly blunted despite relatively normal protein digestion and amino acid absorption.

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

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

Mixed-mode versus paper surveys for patient-reported outcomes after critical illness: A randomised controlled trial.

OBJECTIVE: The aim of the study was to determine the response rate to a mixed-mode survey using email compared with that to a paper survey in survivors of critical illness. DESIGN: This is a prospective randomised controlled trial. SETTING: The study was conducted at a single-centre quaternary intensive care unit (ICU) in Adelaide, Australia. PARTICIPANTS: Study participants were patients admitted to the ICU for ≥48 h and discharged from the hospital. INTERVENTIONS: The participants were randomised to receive a survey by paper (via mail) or via online (via email, or if a non-email user, via a letter with a website address). Patients who did not respond to the initial survey received a reminder paper survey after 14 days. The survey included quality of life (EuroQol-5D-5L), anxiety and depression (Hospital Anxiety and Depression Scale), and post-traumatic symptom (Impact of Event Scale-Revised) assessment. MAIN OUTCOME MEASURES: Survey response rate, extent of survey completion, clinical outcomes at different time points after discharge, and survey cost analysis were the main outcome measures. Outcomes were stratified based on follow-up time after ICU discharge (3, 6, and 12 months). RESULTS: A total of 239 patients were randomised. The response rate was similar between the groups (mixed-mode: 78% [92/118 patients] vs. paper: 80% [97/121 patients], p = 0.751) and did not differ between time points of follow-up. Incomplete surveys were more prevalent in the paper group (10% vs 18%). The median EuroQol-5D-5L index value was 0.83 [0.71-0.92]. Depressive symptoms were reported by 25% of patients (46/187), anxiety symptoms were reported by 27% (50/187), and probable post-traumatic stress disorder was reported by 14% (25/184). Patient outcomes did not differ between the groups or time points of follow-up. The cost per reply was AU$ 16.60 (mixed-mode) vs AU$ 19.78 (paper). CONCLUSION: The response rate of a mixed-mode survey is similar to that of a paper survey and may provide modest cost savings.

Energy-Dense versus Routine Enteral Nutrition in the Critically Ill.

BACKGROUND: The effect of delivering nutrition at different calorie levels during critical illness is uncertain, and patients typically receive less than the recommended amount. METHODS: We conducted a multicenter, double-blind, randomized trial, involving adults undergoing mechanical ventilation in 46 Australian and New Zealand intensive care units (ICUs), to evaluate energy-dense (1.5 kcal per milliliter) as compared with routine (1.0 kcal per milliliter) enteral nutrition at a dose of 1 ml per kilogram of ideal body weight per hour, commencing at or within 12 hours of the initiation of nutrition support and continuing for up to 28 days while the patient was in the ICU. The primary outcome was all-cause mortality within 90 days. RESULTS: There were 3957 patients included in the modified intention-to-treat analysis (1971 in the 1.5-kcal group and 1986 in the 1.0-kcal group). The volume of enteral nutrition delivered during the trial was similar in the two groups; however, patients in the 1.5-kcal group received a mean (±SD) of 1863±478 kcal per day as compared with 1262±313 kcal per day in the 1.0-kcal group (mean difference, 601 kcal per day; 95% confidence interval [CI], 576 to 626). By day 90, a total of 523 of 1948 patients (26.8%) in the 1.5-kcal group and 505 of 1966 patients (25.7%) in the 1.0-kcal group had died (relative risk, 1.05; 95% CI, 0.94 to 1.16; P=0.41). The results were similar in seven predefined subgroups. Higher calorie delivery did not affect survival time, receipt of organ support, number of days alive and out of the ICU and hospital or free of organ support, or the incidence of infective complications or adverse events. CONCLUSIONS: In patients undergoing mechanical ventilation, the rate of survival at 90 days associated with the use of an energy-dense formulation for enteral delivery of nutrition was not higher than that with routine enteral nutrition. (Funded by National Health and Medical Research Institute of Australia and the Health Research Council of New Zealand; TARGET ClinicalTrials.gov number, NCT02306746 .).

Enteral nutrition in circulatory shock: friend or foe?

PURPOSE OF REVIEW: Circulatory shock is associated with reduced splanchnic blood flow and impaired gut epithelial barrier function (EBF). Early enteral nutrition (EN) has been shown in animal models to preserve EBF. There are limited human data informing early EN in circulatory shock and critical care nutrition guidelines provide disparate recommendations regarding the optimal timing and dose. The purpose of this review is to describe the harms and benefits of early EN in circulatory shock by identifying and appraising recent human data. RECENT FINDINGS: The cumulative risk of nonocclusive bowel ischemia and necrosis in patients with circulatory shock is no higher than 0.3% across observational and randomized controlled trial-level data, and whether the risk is increased by EN delivery remains uncertain. Observational data suggest that early EN in circulatory shock is associated with improved clinical outcomes but data from robust randomized controlled trials remain equivocal, so the optimal timing and dose remain unknown. SUMMARY: Based on the best available data, initiating restrictive dose EN into the stomach after initial resuscitation in patients with circulatory shock does not appear to be harmful. In fact, early EN may preserve EBF and improve clinical outcomes.

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 Six Months after Delivering 100% or 70% of Enteral Calorie Requirements during Critical Illness (TARGET). A Randomized Controlled Trial.

Rationale: The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared with a lesser amount of calories are unknown.Objectives: Our hypotheses were that achieving approximately 100% of recommended calorie intake during critical illness would increase quality-of-life scores, return to work, and key life activities and reduce death and disability 6 months later.Methods: We conducted a multicenter, blinded, parallel group, randomized clinical trial, with 3,957 mechanically ventilated critically ill adults allocated to energy-dense (1.5 kcal/ml) or routine (1.0 kcal/ml) enteral nutrition.Measurements and Main Results: Participants assigned energy-dense nutrition received more calories (percent recommended energy intake, mean [SD]; energy-dense: 103% [28] vs. usual: 69% [18]). Mortality at Day 180 was similar (560/1,895 [29.6%] vs. 539/1,920 [28.1%]; relative risk 1.05 [95% confidence interval, 0.95-1.16]). At a median (interquartile range) of 185 (182-193) days after randomization, 2,492 survivors were surveyed and reported similar quality of life (EuroQol five dimensions five-level quality-of-life questionnaire visual analog scale, median [interquartile range]: 75 [60-85]; group difference: 0 [95% confidence interval, 0-0]). Similar numbers of participants returned to work with no difference in hours worked or effectiveness at work (n = 818). There was no observed difference in disability (n = 1,208) or participation in key life activities (n = 705).Conclusions: The delivery of approximately 100% compared with 70% of recommended calorie intake during critical illness does not improve quality of life or functional outcomes or increase the number of survivors 6 months later.

Early anthropometry, strength, and function in survivors of critical illness.

BACKGROUND: Critically ill patients experience acute muscle wasting and long-term functional impairments, yet this has been inadequately categorised early in recovery. OBJECTIVE: This observational study aimed to evaluate anthropometry, strength, and muscle function after intensive care unit discharge. METHODS: Adult patients able to complete study measures after prolonged intensive care unit stay (≥5 d) were eligible. Demographic and clinical data were collected, and bodyweight, height, triceps skinfold, trunk length, handgrip strength, 6-minute walk test, whole-body dual-energy x-ray absorptiometry, and mid-thigh, knee, and above-ankle circumferences were measured. Body cell mass was calculated from these data. Data are presented as mean (standard deviation) or median [interquartile range]. RESULTS: Fourteen patients (50% male; 57 [10.5] years) were assessed 11.1 (6.9) d after intensive care unit discharge. Patients lost 4.76 (6.66) kg in the intensive care unit. Triceps skinfold thickness (17.00 [8.65] mm) and handgrip strength (12.60 [8.57] kg) were lower than normative data. No patient could commence the 6-minute walk test. Dual-energy x-ray absorptiometry-derived muscle mass correlated with handgrip strength (R = 0.57; 95% confidence interval = 0.06-0.85; p = 0.03), but body cell mass did not. CONCLUSIONS: Anthropometry and strength in intensive care unit survivors are below normal. Muscle mass derived from dual-energy x-ray absorptiometry correlates with handgrip strength but body cell mass does not.

Nutrition intake in the post-ICU hospitalization period.

PURPOSE OF REVIEW: The care of critically ill patients has evolved over recent years, resulting in significant reductions in mortality in developed countries; sometimes with prolonged issues with recovery. Nutrition research has focused on the early, acute period of critical illness, until more recently, where the post-ICU hospitalization period in critical care survivors has become a focus for nutrition rehabilitation. In this period, nutrition rehabilitation may be a vital component of recovery. RECENT FINDINGS: Overall, oral nutrition is the most common mode of nutrition provision in the post-ICU period. Compared with oral intake alone, calorie and protein requirements can be better met with the addition of oral supplements and/or enteral nutrition to oral intake. However, calorie and protein intake remains below predicted targets in the post-ICU hospitalization period. Achieving nutrition targets are complex and multifactorial, but can primarily be grouped into three main areas: patient factors; clinician factors; and system factors. SUMMARY: A nutrition intervention in the post-ICU hospitalization period may provide an opportunity to improve survival and functional recovery. However, there are multiple barriers to the delivery of calculated nutrition requirements in this period, a limited understanding of how this can be improved and how this translates into clinical benefit.

Any news from the prokinetic front?

PURPOSE OF REVIEW: This review provides an update of recently conducted studies and randomized controlled trials evaluating prokinetic drugs. RECENT FINDINGS: Prokinetic drugs accelerate gastric emptying and, particularly in patients with gastric dysmotility and enteral feed intolerance, their use increases the delivery of enteral nutrition. However, prokinetic drugs have not been shown to improve patient-centered outcomes in trials but benefit is assumed on the basis of observational studies, which report close associations between gastric dysmotility, enteral feed intolerance and poor outcomes, and improvement in surrogate physiological outcomes when prokinetic drugs are administered. SUMMARY: It may not be feasible to establish superiority of a prokinetic drug within a randomized controlled trial with a patient-centered event as the primary outcome. The use of metoclopramide and erythromycin as prokinetic drugs is based on observations from trials measuring surrogate physiological outcomes. Randomized controlled trials of alternative drug regimens and novel prokinetic drugs have recently been completed and results outlined.

A retrospective evaluation of nutrition support in relation to clinical outcomes in critically ill patients with an open abdomen.

BACKGROUND: Optimising nutrition support in critically ill patients with an open abdomen is challenging. OBJECTIVES: The aims of this study were to (i) quantify the amount and adequacy of nutrition support administered and (ii) determine any relationships that exist between mode of nutrition support delivery and clinical outcomes in critically ill patients with an open abdomen. METHODS: A retrospective review of critically ill patients mechanically ventilated for at least 48 h with an open abdomen in a mixed quaternary referral intensive care unit. Enteral and parenteral nutrition (ml) administered daily to patients was recorded for up to 21 days. Length of stay in the intensive care unit and hospital and duration of mechanical ventilation (days) were reported. RESULTS: Thirty patients were studied [14 male, 68 y (15-90 y), body mass index 25 kg/m2 (11-51 kg/m2), Acute Physiology and Chronic Health Evaluation II score 20 (7-41), energy goal 1860 kcal/d (1250-2712 kcal/d)]. Patients received 55% (0-117%) of energy goal and 56% (0-105%) protein goal from either enteral or parenteral nutrition. When enteral nutrition was delivered alone or in combination with parenteral nutrition, patients received 48% (0-146%) of their energy and 59% (19-105%) of their protein goal. Patients fed parenteral nutrition, either alone or as supplementary to enteral nutrition (n = 18), received more energy when compared with those who only received enteral nutrition (n = 9) [65 (27-117) vs 49 (15-89) % energy goal, P = 0.025]. Parenteral nutrition was associated with an increased length of stay in hospital [63 (45-156) vs 45 (17-93) d, P = 0.037]. CONCLUSION: Patients with an open abdomen receive about half of their nutrition requirements when fed exclusively via the enteral route. Providing combination enteral and parenteral nutrition to reach nutritional goals may not result in better clinical outcomes for patients with an open abdomen.

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.

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

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

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.

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

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

The insulinotropic effect of pulsatile compared with continuous intravenous delivery of GLP-1.

AIMS/HYPOTHESIS: In healthy individuals, both insulin and glucagon-like peptide 1 (GLP-1) are secreted in a pulsatile fashion. Insulin has greater glucose-lowering properties when administered in pulses compared with a constant i.v. infusion. The primary aim of this randomised double-dummy cross-over study was to compare the insulinotropic response to pulsatile and continuous i.v. infusions of equivalent doses of GLP-1. METHODS: Twelve healthy participants aged 18-35 years were randomised to three different treatments on separate days: a continuous infusion day (GLP-1 at 0.6 pmol kg(-1) min(-1) [1 ml/min] and a 1 ml placebo bolus every 6 min); a pulsatile infusion day (placebo at 1 ml/min and a 3.6 pmol/kg GLP-1 bolus every 6 min); and a placebo day (placebo at 1 ml/min and a 1 ml placebo bolus every 6 min). Between 45 and 120 min, a hyperglycaemic clamp was used to maintain blood glucose at 9 mmol/l. Venous blood glucose and plasma insulin concentrations were measured every 5 min from 0 to 45 min and every 1 min from 45 to 120 min; plasma glucagon was measured every 15 min. The order of treatment was randomised by the Pharmacy Department and both study investigators and participants were blinded to the treatment arm. The dextrose requirement and glucagon data were analysed using repeated measures ANOVA and insulin data were analysed with a linear mixed effects maximum likelihood model. RESULTS: Continuous and pulsatile infusions of GLP-1 increased the dextrose requirement by ~threefold (p < 0.001) and increased insulin secretion by ~ninefold (p < 0.001). There was no difference in the effect of both treatments. Although hyperglycaemia reduced plasma glucagon concentrations, there was no difference between the treatment days. CONCLUSIONS/INTERPRETATION: In healthy individuals, pulsatile and continuous administration of i.v. GLP-1 appears to have comparable insulinotropic effects. TRIAL REGISTRATION: ACTRN12612001040853 FUNDING: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia.

Liberal Glycemic Control in Critically Ill Patients With Type 2 Diabetes: An Exploratory Study.

OBJECTIVES: The optimal blood glucose target in critically ill patients with preexisting diabetes and chronic hyperglycemia is unknown. In such patients, we aimed to determine whether a " liberal" approach to glycemic control would reduce hypoglycemia and glycemic variability and appear safe. DESIGN: Prospective, open-label, sequential-period exploratory study. SETTING: Medical-surgical ICU. PATIENTS: During sequential 6-month periods, we studied 83 patients with preexisting type 2 diabetes and chronic hyperglycemia (glycated hemoglobin, ≥ 7.0% at ICU admission). INTERVENTION: During the "standard care" period, 52 patients received insulin to treat blood glucose concentrations greater than 10 mmol/L whereas during the "liberal" period, 31 patients received insulin to treat blood glucose concentrations greater than 14 mmol/L. MEASUREMENTS AND MAIN RESULTS: Time-weighted mean glucose concentrations and the number and duration of moderate (< 4.0 mmol/L) and severe (≤ 2.2 mmol/L) hypoglycemic episodes were recorded, with moderate and severe hypoglycemic episodes grouped together. Glycemic variability was assessed by calculating the coefficient of variability for each patient. Safety was evaluated using clinical outcomes and plasma concentrations of markers of inflammation, glucose-turnover, and oxidative stress. Mean glucose (TWglucoseday 0-7, standard care: 9.3 [1.8] vs liberal: 10.3 [2.1] mmol/L; p = 0.02) and nadir blood glucose (4.4 [1.5] vs 5.5 [1.6] mmol/L; p < 0.01) were increased during the liberal period. There was a signal toward reduced risk of moderate-severe hypoglycemia (relative risk: liberal compared with standard care: 0.47 [95% CI, 0.19-1.13]; p = 0.09). Ten patients (19%) during the standard period and one patient (3%) during the liberal period had recurrent episodes of moderate-severe hypoglycemia. Liberal therapy reduced glycemic variability (coefficient of variability, 33.2% [12.9%] vs 23.8% [7.7%]; p < 0.01). Biomarker data and clinical outcomes were similar. CONCLUSIONS: In critically ill patients with type 2 diabetes and chronic hyperglycaemia, liberal glycemic control appears to attenuate glycemic variability and may reduce the prevalence of moderate-severe hypoglycemia.