Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain. Objective: To determine whether SDD reduces in-hospital mortality in critically ill adults. Design, Setting, and Participants: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021. Interventions: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care. Main Outcomes and Measures: The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs. Results: Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, -1.7% [95% CI, -4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, -11.0%; 95% CI, -14.7% to -7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, -1.95%; 95% CI, -3.5% to -0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, -0.24%; 95% CI, -0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (-3.3% vs -1.59%; mean difference, -1.71% [1-sided 97.5% CI, -∞ to 4.31%] and 0.88% vs 0.55%; mean difference, -0.32% [1-sided 97.5% CI, -∞ to 5.47%]) in the first and second periods, respectively. Conclusions and Relevance: Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT02389036.

An international comparison of the cost of fluid resuscitation therapies.

OBJECTIVE: Fluid resuscitation is a ubiquitous intervention in the management of patients treated in the intensive care unit, which has implications for intensive care unit resourcing and budgets. Our objective was to calculate the relative cost of resuscitation fluids in several countries to inform future economic evaluations. METHODS: We collected site-level data regarding the availability and cost of fluids as part of an international survey. We normalised costs to net present values using purchasing power parities and published inflation figures. Costs were also adjusted for equi-effective dosing based on intravascular volume expansion effectiveness and expressed as US dollars (USD) per 100 mL crystalloid equivalent. RESULTS: A total of 187 sites had access to cost data. Between countries, there was an approximate six fold variation in the cost of crystalloids and colloids overall. The average cost for crystalloids overall was less than 1 USD per 100 mL. In contrast, colloid fluids had higher average costs (59 USD per 100 mL). After adjusting for equi-effective dosing, saline was ∼27 times less costly than albumin (saline: 0.6 USD per 100 mL crystalloid equivalent; albumin 4-5%: 16.4 USD; albumin 20-25%: 15.8 USD) and ∼4 times less costly than hydroxyethyl starch solution (saline: 0.6 USD; hydroxyethyl starch solution: 2.5 USD). Buffered salt solutions, such as compound sodium acetate solutions (e.g., Plasmalyte®), had the highest average cost of crystalloid fluids, costing between 3 and 4 USD per 100 mL. CONCLUSION: The cost of fluid varies substantially between fluid types and between countries, although normal (0.9%) saline is consistently less costly than colloid preparations and some buffered salt solutions. These data can be used to inform future economic evaluations of fluid preparations.

Protocol summary and statistical analysis plan for the Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients (SuDDICU) crossover, cluster randomised controlled trial.

Background: It is unclear whether the use of selective decontamination of the digestive tract (SDD) improves outcomes in ventilated patients in intensive care units (ICUs) and whether SDD is associated with the development of antibiotic resistance. Objective: To describe the study protocol and statistical analysis plan for the Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients (SuDDICU) trial. Design, setting, participants and intervention: SuDDICU is an international, crossover, cluster randomised controlled trial of mechanically ventilated patients in ICUs using two 12-month trial periods. For each period, participating ICUs will implement SDD plus standard care or standard care alone. The SuDDICU drug intervention is an oral paste and gastric suspension of three antibiotics combined with a 4-day course of intravenous antibiotics. Observational ecological assessments will be conducted during five surveillance periods. The trial will be conducted in 19 ICUs in Australia and ten ICUs in Canada and the United Kingdom, and will recruit 15 000-17 000 patients. Recruitment commenced in Australia in 2017. Main outcome measures: The primary outcome is all-cause hospital mortality. Secondary outcomes include: duration of ventilation, ICU stay and hospital stay; incidence of new antibiotic-resistant organisms during the index ICU admission; changes in antibiotic-resistant organism rates; incidence of new Clostridioides difficile infections; and total use of antibiotics. Results and conclusions: SuDDICU will determine whether the use of SDD plus standard care is associated with a reduction in hospital mortality in ventilated ICU patients compared with standard care alone. It will also quantify the impact of the use of SDD on the development of antibiotic resistance. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12615000411549) and ClinicalTrials.gov (NCT02389036).

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock.

BACKGROUND: Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS: We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS: From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. CONCLUSIONS: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).

Statistical analysis plan for the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial.

BACKGROUND: The Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial, a 3800-patient, multicentre, randomised controlled trial, will be the largest study to date of corticosteroid therapy in patients with septic shock. OBJECTIVE: To describe a statistical analysis plan (SAP) and make it public before completion of patient recruitment and data collection. The SAP will be adhered to for the final data analysis of this trial, to avoid analysis bias arising from knowledge of study findings. METHODS: The SAP was designed by the chief investigators and statisticians and approved by the ADRENAL management committee. All authors were blind to treatment allocation and to the unblinded data produced during two interim analyses conducted by the Data Safety and Monitoring Committee. The data shells were produced from a previously published protocol. Statistical analyses are described in broad detail. Trial outcomes were selected and categorised into primary, secondary and tertiary outcomes, and appropriate statistical comparisons between groups are planned and described in a way that is transparent, available to the public, verifiable and determined before completion of data collection. RESULTS: We developed a standard SAP for the ADRENAL trial, and have produced a trial profile outline and list of mock tables. We describe analyses of baseline characteristics, processes of care, measures of efficacy and outcomes. Six pre-specified subgroups were defined, and statistical comparisons between groups in these subgroups are described. CONCLUSION: We have developed an SAP for the ADRENAL trial. This plan accords with high-quality standards of internal validity to minimise analysis bias.

Patterns of intravenous fluid resuscitation use in adult intensive care patients between 2007 and 2014: An international cross-sectional study.

BACKGROUND: In 2007, the Saline versus Albumin Fluid Evaluation-Translation of Research Into Practice Study (SAFE-TRIPS) reported that 0.9% sodium chloride (saline) and hydroxyethyl starch (HES) were the most commonly used resuscitation fluids in intensive care unit (ICU) patients. Evidence has emerged since 2007 that these fluids are associated with adverse patient-centred outcomes. Based on the published evidence since 2007, we sought to determine the current type of fluid resuscitation used in clinical practice and the predictors of fluid choice and determine whether these have changed between 2007 and 2014. METHODS: In 2014, an international, cross-sectional study was conducted (Fluid-TRIPS) to document current patterns of intravenous resuscitation fluid use and determine factors associated with fluid choice. We examined univariate and multivariate associations between patients and prescriber characteristics, geographical region and fluid type. Additionally, we report secular trends of resuscitation fluid use in a cohort of ICUs that participated in both the 2007 and 2014 studies. Regression analysis were conducted to determine changes in the administration of crystalloid or colloid between 2007 and 2014. FINDINGS: In 2014, a total of 426 ICUs in 27 countries participated. Over the 24 hour study day, 1456/6707 (21.7%) patients received resuscitation fluid during 2716 resuscitation episodes. Crystalloids were administered to 1227/1456 (84.3%) patients during 2208/2716 (81.3%) episodes and colloids to 394/1456 (27.1%) patients during 581/2716 (21.4%) episodes. In multivariate analyses, practice significantly varied between geographical regions. Additionally, patients with a traumatic brain injury were less likely to receive colloid when compared to patients with no trauma (adjusted OR 0.24; 95% CI 0.1 to 0.62; p = 0.003). Patients in the ICU for one or more days where more likely to receive colloid compared to patients in the ICU on their admission date (adjusted OR 1.75; 95% CI 1.27 to 2.41; p = <0.001). For secular trends in fluid resuscitation, 84 ICUs in 17 countries contributed data. In 2007, 527/1663 (31.7%) patients received fluid resuscitation during 1167 episodes compared to 491/1763 (27.9%) patients during 960 episodes in 2014. The use of crystalloids increased from 498/1167 (42.7%) in 2007 to 694/960 (72.3%) in 2014 (odds ratio (OR) 3.75, 95% confidence interval (CI) 2.95 to 4.77; p = <0.001), primarily due to a significant increase in the use of buffered salt solutions. The use of colloids decreased from 724/1167 (62.0%) in 2007 to 297/960 (30.9%) in 2014 (OR 0.29, 95% CI 0.19 to 0.43; p = <0.001), primarily due to a decrease in the use of HES, but an overall increase in the use of albumin. CONCLUSIONS: Clinical practices of intravenous fluid resuscitation have changed between 2007 and 2014. Geographical location remains a strong predictor of the type of fluid administered for fluid resuscitation. Overall, there is a preferential use of crystalloids, specifically buffered salt solutions, over colloids. There is now an imperative to conduct a trial determining the safety and efficacy of these fluids on patient-centred outcomes. TRIAL REGISTRATION: Clinicaltrials.gov: Fluid-Translation of research into practice study (Fluid-TRIPS) NCT02002013.

Reduced taste function and taste papillae density in children with chronic kidney disease.

BACKGROUND: Taste loss may contribute to the loss of appetite in children with chronic kidney disease (CKD) and other serious medical conditions that result in malnutrition. Traditional methods for measurement of taste loss commonly use aqueous tastant solutions that can induce nausea, vomiting, or even pain in the mouth. An alternative is to measure fungiform papillae density on the anterior tongue since this correlates with taste sensitivity. Here we aimed to develop a non-invasive method for assessing papillae density on the anterior tongue and to use the method to determine if CKD patients [estimated glomerular filtrate (eGFR < 60 ml/min/1.73 m(2))] have a lower density than clinical controls (CC)(eGFR > 89 ml/min/1.73 m(2)). METHODS: Thirty-five healthy adults participated in the development of a method, which was assessed by 24 children, 12 of whom were CKD patients and 12 were clinical controls. RESULTS: Similar papillae densities were found using invasive and non-invasive methods (F(1,34) = 0.647, p = 0.427). The CKD group had a significantly lower papillae density (X(2) = 7.17, p = 0.007) and poorer taste sensitivity than the CC group (p = 0.0272), and the density correlated significantly with eGFR (r = 0.56, p < 0.01). CONCLUSIONS: Loss of taste in children with CKD is due to the reduced number of papillae and their taste-sensing receptor cells.

Changes in fungiform papillae density during development in humans.

The anterior region of the human tongue ceases to grow by 8-10 years of age and the posterior region at 15-16 years. This study was conducted with 30 adults and 85 children (7-12 year olds) to determine whether the cessation of growth in the anterior tongue coincides with the stabilization of the number and distribution of fungiform papillae (FP) on this region of the tongue. This is important for understanding when the human sense of taste becomes adult in function. This study also aimed to determine whether a small subpopulation of papillae could be used to predict the total number of papillae. FP were photographed and analyzed using a digital camera. The results indicated that the number of papillae stabilized at 9-10 years of age, whereas the distribution and growth of papillae stabilized at 11-12 years of age. One subpopulation of papillae predicted the density of papillae on the whole anterior tongue of 7-10 year olds, whereas another was the best predictor for the older children and adults. Overall, the population, size, and distribution of FP stabilized by 11-12 years of age, which is very close to the age that cessation of growth of the anterior tongue occurs.