Selective digestive tract decontamination in critically ill adults with acute brain injuries: a Post-Hoc analysis of a Randomized Clinical Trial.

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Paul Young, Anthony Devaux, Qiang Li, Laurent Billot, Joshua Davis, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3412001/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Nov, 2023 Read the published version in Intensive Care Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Purpose: To determine whether Selective Decontamination of the Digestive Tract (SDD) reduces in-hospital mortality in mechanically ventilated critically ill adults admitted to the Intensive Care Unit (ICU) with acute brain injuries or conditions. Methods: A post-hoc analysis from a crossover, cluster-randomized clinical trial. ICUs were randomly assigned to adopt or not to adopt a SDD strategy for two alternating 12-month periods, separated by a 3-month inter-period gap. Patients in the SDD group (n=2791; 968 admitted to the ICU with an acute brain injury) 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; 1093 admitted to the ICU with an acute brain injury) received standard care. The primary outcome was in-hospital mortality within 90 days. There were four secondary clinical outcomes: death in ICU, ventilator-, ICU- and hospital-free days to day 90. Results Of 2061 patients with acute brain injuries (mean age, 55.8 years; 36.4% women), all completed the trial. In patients with acute brain injuries, there were 313/968 (32.3%) and 415/1093 (38.0%) in-hospital deaths in the SDD and standard care groups (unadjusted odds ratio [OR], 0.76, 95% confidence interval [CI] 0.63 to 0.92; p = 0.004). The use of SDD was associated with statistically significant improvements in the four clinical secondary outcomes compared to standard care. There was no statistical difference in the heterogeneity of treatment effect between patients with and without acute brain injuries (interaction p=0.22). Conclusions: In this post-hoc analysis of a randomized clinical trial in critically ill patients with acute brain injuries receiving mechanical ventilation, the use of SDD significantly reduced in-hospital mortality in patients compared to standard care without SDD. These findings require confirmation. Trial Registration: Clinical Trials.gov registration number: NCT02389036 Selective Decontamination of the Digestive Tract acute brain injury mechanical ventilation mortality. Figures Figure 1 Figure 2 Figure 3 Take home message Improved in clinically important outcomes associated with Selective Decontamination of the Digestive Tract, such as reduced mortality and duration of mechanical ventilation, may be restricted to specific high-risk populations such as those with acute brain injuries. Introduction Selective decontamination of the digestive tract (SDD), consisting of an oral antibiotic paste and a gastric antibiotic suspension, combined with a short course of intravenous antibiotics has been extensively studied in critically ill patients [ 1 ]. In the recently published Selective Decontamination of the Digestive Tract in the Intensive Care Unit (SuDDICU) trial, hospital mortality was not significantly different for patients allocated to SDD and standard care without SDD [ 2 ]. When data from this and other randomized clinical trials were combined in a Bayesian meta-analysis, there was a 99.3% posterior probability that SDD was associated with reduced hospital mortality compared to standard care [ 1 ]. It remains uncertain whether the reduction in mortality associated with SDD [ 2 ] was driven by a benefit in a particular subgroup or subgroups. Patients with acute brain injuries or conditions with reduced levels of consciousness and impaired airway reflexes are at risk of aspiration events that may progress to lower respiratory tract infections or ventilator-associated pneumonia [ 1 , 3 , 4 ]. Ventilator-associated pneumonia may result in fever, hypoxaemia and impaired ventilation that are recognized causes of secondary brain injury [ 4 ], potentially resulting in additional deaths. As SDD is an infection control strategy designed to prevent ventilator-associated pneumonia, it may be of particular benefit in this group of patients. To evaluate the possibility that SDD benefits patients admitted to the ICU with acute brain injuries, a post-hoc subgroup analysis using data from the SuDDICU trial was conducted. Methods Consent Ethical approval for the SuDDICU Australia trial was obtained from Human Research Ethics Committees and Research Governance Offices at each site. As SDD was implemented as an ICU-wide intervention, a waiver of individual patient consent was obtained from each Lead Human Research Ethics Committee according to jurisdictional requirements. For patients in the standard care group, a waiver of consent was obtained as no intervention was provided. As no new data were obtained for this subgroup analysis, additional ethical approval was not required. Study design and oversight The study protocol and statistical analysis plan [ 5 ] and the primary manuscript [ 2 ] for the SuDDICU crossover, cluster randomized clinical trial have been published previously. The SuDDICU trial was reported according to the CONSORT 2010 reporting guidelines [ 6 ]. (Supplementary Appendix). Data were entered into an encrypted database for statistical analyses conducted at The George Institute for Global Health, Australia. Details of the trial management, sponsorship, collaborations and committees and a full list of investigators is provided in the Supplementary Appendix. Trial participants The SuDDICU Australia trial was conducted in 19 ICUs in 17 hospitals in Australia from May 2017 to November 2021. Eligible ICUs were general medical and surgical ICUs capable of treating mechanically ventilated adults and able to implement SDD in all eligible patients. Eligible patients were mechanically ventilated (either on ICU admission or during ICU admission) and expected to remain ventilated until at least the second day after enrollment. Patients who were not initially expected to require two days of ventilation were rescreened and enrolled if eligibility criteria were subsequently met. SuDDICU trial site and participant eligibility criteria are shown in Supplementary Appendix. For this post hoc subgroup analysis, patients with an acute brain injury at ICU admission were identified using the Acute Physiological And Chronic Health Assessment (APACHE)-III ICU admission diagnosis [ 7 ]. Patients with the following admission diagnoses were defined as having an acute brain injury: cardiac arrest; intracerebral hemorrhage; subarachnoid hemorrhage; stroke; brain infection; neurologic neoplasm; seizure; subdural haematoma; coma; traumatic brain injury; and epidural haematoma. All other patients were defined as not having an acute brain injury. Randomization ICUs were randomly assigned to adopt a SDD strategy or to continue standard care for two alternating 12-month periods, separated by a 3-month inter-period gap. Full details of randomization, that was stratified by the number of ICU beds in the study site, is outlined in the protocol5 and the SuDDICU trial manuscript [ 2 ]. Interventions SDD comprised i.) a six-hourly topical application of 0.5g of oral paste containing 10mg colistin, 10mg tobramycin and 125,000 international units of nystatin applied to the buccal mucosa and oropharynx; ii.) a six-hourly administration of 10mL of gastric suspension containing 100mg colistin, 80mg tobramycin and 2x106 international units of nystatin to the upper gastrointestinal tract via a gastric or post-pyloric tube; iii.) a four-day course of an intravenous SDD-compliant antibiotic that included a third-generation cephalosporin or ciprofloxacin, unless already treated with specified antibiotics with activity against Gram-negative bacteria during the first four days after enrollment, in which case additional antibiotics were not administered. The SDD paste and suspension were manufactured by Verita Pharma® (Sydney, Australia) under licence from The George Institute for Global Health in accordance with the standards for Good Manufacturing Practice approved by the Therapeutic Goods Administration of Australia. Details of the SDD drug preparations have been described previously [ 2 ]. The SDD oral paste and gastric suspension were administered as soon as possible after eligibility criteria were met and were continued until extubation or day 90, whichever came first. All other treatments, including use of prophylactic or therapeutic antibiotics, were at the discretion of treating clinicians in accordance with respective institutional microbiological prescription policies. Data and Study Management Data collected at baseline included demographics, ICU admission diagnosis, APACHE score (a severity of illness score ranging from 0 to 71 [APACHE-II] [ 8 ] or 0 to 299 [APACHE-III] [ 9 ], with higher scores indicating an increased risk of death) and specific risk factors for infection including prior receipt of oral chlorhexidine and intravenous antibiotics. For patients treated in ICUs during the SDD intervention period, daily data documenting the delivery of SDD oral paste and gastric suspension were collected for the duration of mechanical ventilation up to 90 days and administration of SDD-compliant antibiotics for 5 days. Adherence in administering the topical components of SDD was reported as the proportion of patients receiving at least one eligible dose of SDD on a daily basis for the duration of mechanical ventilation. Doses of all intravenous antibiotics were collected for 28 days, presented as daily defined doses, as defined by the World Health Organisation [ 10 ]. Data recorded daily for 90 days included the duration of mechanical ventilation, ICU and hospital admission, all new organisms isolated from blood and non-blood cultures, any new positive test for Clostridioides difficile and new antibiotic resistant organisms from all cultures, as described previously [ 2 ]. Details of source data verification and monitoring are provided in the Supplementary Appendix. Outcome Measures The primary outcome was all-cause in-hospital mortality within 90 days of enrollment during the index hospital admission. Clinical secondary outcomes were ICU mortality and days alive and free of mechanical ventilation, ICU admission and hospitalization through 90 days. Microbiological secondary outcomes were the results from all new blood cultures; the incidence of new positive Clostridioides difficile tests; the incidence of new pre-defined antibiotic resistant organisms from all blood, non-blood surveillance and clinical cultures, and total antibiotic use, defined in daily defined doses. Statistical Analysis Although not pre-specified, this subgroup analysis was conducted using the same statistical analysis plan used in the main SuDDICU analysis [ 2 ]. Patients were analyzed in their randomization group, regardless of adherence, using all available data without imputation. The primary outcome of death in the hospital within 90 days was analyzed using an individual-level hierarchical logistic regression model, including both a random cluster effect and a random cluster-period effect. The effect of the intervention was estimated as the odds ratio (OR) for death and the 95% confidence interval (CI) with degrees of freedom adjusted by the Kenward-Roger correction [ 11 ]. Absolute difference of event rate was also estimated from a linear regression at cluster level weighted proportionally to the inverse of the binomial variance for each cluster-period. ICU mortality was evaluated in a similar fashion. The number of days alive and free of mechanical ventilation, ICU, and hospitalisation within 90 days were analyzed using a hierarchical linear regression model with the Kenward-Roger correction. Intervention effects were reported as adjusted mean differences and 95% CIs. Time to discharge alive from the ICU and the hospital was summarized by subgroup using cumulative incidence functions treating mortality as a competing risk, censored at day 90. Intervention effects were estimated as hazard ratios (HR) and 95% CIs obtained from a cause-specific Cox model, with a fixed effect of treatment and a random site effect. In all analyses, heterogeneity in treatment response for patients with and without an acute brain injury was assessed by adding the subgroup variable as well as its interaction with the intervention to the main analysis model. To evaluate for the possibility of heterogeneity of treatment effect on in-hospital mortality within the subgroup of patients with acute brain injuries, the subgroup was divided group into three mutually exclusive categories and fitted an interaction between treatment allocation and category. These categories were: (i) traumatic brain injury (defined as APACHE-III ICU admission diagnoses of head trauma, subdural hematoma and subdural/epidural hematoma; (ii) subarachnoid hemorrhage and stroke (defined as APACHE-III ICU admission diagnoses of intracerebral hemorrhage; subarachnoid hemorrhage; stroke; intracerebral hemorrhage and (iii) other brain injuries (defined as APACHE-III ICU admission diagnoses of cardiac arrest; brain infection; neurologic neoplasm; seizure; other neurologic disease; coma). An additional within brain injury subgroup analysis compared heterogeneity of treatment effect on in-hospital mortality was based on whether or not patients were receiving intravenous antibiotics at baseline. Microbiological outcomes were analyzed using the proportions of patients with at least one event in each cluster-period. These proportions were modelled using weighted linear regression where the weights are computed using the inverse of variance for each cluster-period. All these analyses were performed without any adjustment. All statistical tests were performed using a 2-sided level of 0.05. As all analyses conducted in this study are post-hoc, they were be considered to be exploratory. Statistical analyses were conducted using SAS software (version 9.4) (Cary NC, USA) Results Study sites and patients A total of 5982 mechanically ventilated adults were included with 2061 (mean age 55.8 years; 36.4% women) defined as having an acute brain injury or condition. In the first intervention period, 1019 patients with an acute brain injury were recruited into the trial with 388 (38.1%) in the SDD group and 631 (61.9%) in standard care group. In the second intervention period, 1042 patients with an acute brain injury were recruited with 580 (55.7%) in the SDD group and 462 (44.3%) in standard care group. The primary outcome was available for all 968 patients in the SDD group and all 1093 patients in the standard care group (Figure 1). Baseline characteristics of patients with acute brain injuries allocated to SDD and standard care groups were similar (Table 1) except that the time from ICU admission to enrollment was a median of 11.6 hours (interquartile range [IQR] 1.3-29.6 hours) in the SDD group and a median of 1.9 hours (IQR 0.0-17.5 hours) in the standard care group; oral chlorhexidine was used in 261/968 (27.0%) of patients in the SDD group and 198/1093 (18.1%) in the standard care group and systemic steroids were used in 51/968 (5.3%) in the SDD group and 103/1093 (9.4%) in standard care group. Study treatments and process measures Among patients with acute brain injuries in the SDD group, the proportion of days of mechanical ventilation where patients received both the SDD oral paste and gastric suspension was 93.1% (eFigure 1, Supplementary Appendix). Data on administration of each component of SDD are shown in eTable 1, Supplementary Appendix and the proportions of patients receiving SDD-compliant antibiotics in the SDD and standard care groups are shown in eFigure2, Supplement Appendix. Primary outcome At hospital discharge within 90 days of enrollment, in patients with acute brain injuries, 313 (32.3%) of 968 allocated to the SDD group and 415 (38.0%) of 1093 allocated to the standard care group had died (mean difference -6.2%, 95% CI -8.9% to -3.5%; OR 0.76, 95% CI 0.63 to 0.92; p=0.004). Findings were similar after adjusting for age at baseline, sex, APACHE II/III score and diagnosis (OR 0.74; 95% CI 0.57 to 0.97; p=0.03) but not significant after adding time from ICU admission to enrolment, systemic steroids, oral chlorhexidine and receipt of intravenous antibiotics at the time of enrolment (OR 0.78; 95% CI 0.59 to1.04; p=0.08). (Table 2). The respective hazard ratios for time to death with SDD vs. standard care were 0.83 (95% CI, 0.71 to 0.96) and 1.01 (95% CI 0.89 to 1.15) for patients with and without acute brain injuries respectively (Figure 2a and 2b). There was no significant heterogeneity in the effect of SDD on mortality for patients with (OR 0.78, 95% CI 0.63 to 0.99, p=0.04) and without (OR 0.92, 95% CI 0.76 to 1.11, p=0.36) acute brain injuries respectively (interaction p=0.22) (Figure 3, eTable2 Supplementary Appendix). There was no significant difference in mortality between the SDD and standard care groups between patients with traumatic brain injury vs. subarachnoid hemorrhage or between stroke vs. other brain injuries (eTable 3, Supplementary Appendix); or based on receipt or not of intravenous antibiotics at baseline (eTable 3, Supplementary Appendix). Causes of death in patients with acute brain injuries by treatment group are shown in eTable 4, Supplementary Appendix. Clinical secondary outcomes Of four clinical secondary outcomes (death in ICU, days alive and free of mechanical ventilation, days alive and free of ICU admission and days alive and free of hospital admission), there were statistically significant differences in favor of the SDD group in patients with acute brain injuries (Table 2). The respective hazard ratios for days alive and free of mechanical ventilation with SDD vs. standard care were 1.11 (95% CI 1.01 to 1.22) and 1.10 (95% CI 1.03 to 1.18) for patients with and without acute brain injuries respectively (eFigure 3a and 3b, Supplementary Appendix). The respective hazard ratios for alive and free of ICU with SDD vs. standard care were 1.10 (95% CI, 0.99 to 1.22) and 1.03 (95% CI 0.96 to 1.11) for patients with and without acute brain injuries respectively (eFigure 4a and 4b, Supplementary Appendix). The respective hazard ratios for alive and free of hospital with SDD vs. standard care were 1.06 (95% CI, 0.94 to 1.18) and 1.00 (95% CI 0.93 to 1.07) for patients with and without acute brain injuries respectively (eFigure 5a and 5b, Supplementary Appendix). There was no significant heterogeneity in the effect of SDD on the four secondary clinical outcomes for patients with and without acute brain injuries (eTable2 and eFigure 3, Supplementary Appendix). Microbiological secondary outcomes For the SDD group compared to the standard care group, there was a statistically significant reduction in the proportion of patients from whom new antibiotic resistant organisms were cultured (20.5% vs 34.2%; absolute difference -13.9 percentage points; 95% CI -17.5 to -10.3); for new positive blood cultures excluding coagulase negative Staphylococcus aureus (2.8% vs 5.5%; absolute difference -1.90 percentage points, 95% CI -3.5 to -0.4) and for new positive Clostridioides difficile tests (0.1% vs 0.8%; absolute difference -0.6 percentage points, 95% CI –1.0 to -0.1) (eTable 5, Supplementary Appendix). Among the patients with acute brain injuries in the SDD and standard care groups respectively, the number of patients with blood cultures collected was 552 (57.0%) vs. 713 (65.2%) and the number of patients with non-blood cultures collected was 229 (23.7%) vs. 411 (37.6%). Data on specific organisms cultured from blood specimens and for new antibiotic resistant organisms cultured from non-blood specimens from the SDD and standard care groups are shown in the eTable 6, Supplementary Appendix. New antibiotic resistant organisms were cultured from the respiratory tract in 115 of 968 (11.9%) and 275 of 1093 (25.2%) of patients allocated to SDD and standard care groups respectively. The mean cumulative daily defined doses over the first 28 days of all intravenous antibiotics and of intravenous antibiotics not administered as part of the SDD treatment regimen are shown in the eFigure 6, Supplementary Appendix. The cumulative daily doses of each antibiotic class are also shown in the eFigure 7, Supplementary Appendix. Among patients with acute brain injuries, daily defined doses of antibiotics administered over the first seven days following enrollment were significantly higher in the SDD group compared to the standard care group (eFigure 8, Supplementary Appendix) although daily defined doses over the first 28 days following enrollment were not significantly different between the two groups (eFigure 9, Supplementary Appendix). Adverse events and protocol deviations New positive Clostridioides difficile infections occurred in 1 of 968 (0.1%) patients in the SDD group and 9 of 1093 (0.8%) patients in the standard care group. Other adverse and serious adverse events were rare (eTable 7, Supplementary Appendix). Discussion In this post-hoc analysis using data from a cross-over, cluster randomized clinical trial, the use of SDD in the subgroup of mechanically ventilated critically ill adults with acute brain injuries or conditions was associated with a clinically and statistically significantly reduced in-hospital mortality compared with standard care without SDD. The use of SDD was associated with significantly reduced ICU mortality, duration of mechanical ventilation and duration of ICU and hospital admission and with lower rates of new blood stream infections and new cultures of antibiotic resistant organisms. In patients without acute brain injuries or conditions, who made up around two thirds of SuDDICU trial population, no significant differences in any clinical outcome between SDD and standard care groups were observed. Apart from one small trial [ 12 ], patients with acute brain injuries have not been a focus of clinical trials evaluating SDD [ 1 ]. Prior randomized clinical trials have suggested that intravenous antibiotic prophylaxis may reduce rates of ventilator-associated pneumonia in patients after cardiac arrest [ 13 , 14 ] and with other brain injuries in the ICU [ 15 , 16 ]. These trials of prophylactic antibiotics did not focus on patient-important outcomes such as mortality. In this large subgroup of nearly 2000 patients with acute brain injuries from a pragmatic randomized clinical trial, SDD was associated with improvements in several patient-centred outcomes. The 5.7 percentage point reduction in mortality corresponds to a number need to treat of 18 to avoid one death. This is a clinically important effect size in a population of patients with a control mortality rate of 38 percentage points. Excellent protocol adherence was achieved with over 90 percentage points of eligible doses of commercial-standard SDD drug preparations administered for the duration of mechanical ventilation. In contrast to the overall SuDDICU trial population [ 2 ], patients with acute brain injuries who were allocated to SDD received significantly more daily defined doses of antibiotics in the first seven days compared patients allocated to standard care. Although SDD was associated with lower rates of new infections that may have mitigated potential contributors to secondary brain injury, data about brain process measures, such as intracranial pressure, types, duration and intensity of brain-specific therapies or assessments of longer-term functional brain outcome, were not available to confirm or refute putative mechanisms of benefit. While ventilator-associated pneumonia is a common cause of ICU-acquired infection [ 17 ], specific data on the diagnosis or source of infection or the impact of ventilator-associated pneumonia on respiratory function were not available for analysis, although lower rates of new antibiotic resistant organisms were cultured from the respiratory tract in patients allocated to SDD. This subgroup analysis has some limitations. First, the intervention was unblinded and therefore subject to ascertainment bias, although this was mitigated by the objective primary outcome and the adoption of SDD as standard care administered to all eligible patients during the intervention period. Second, we reported the primary ICU admission diagnoses defining the presence of an acute brain injuries may have miscategorized some patients. Third, while the primary outcome was reported using pre-specified unadjusted analyses, adjusted analyses accounting for baseline imbalances are equally important for a post hoc analysis, both in the interpretation of the primary outcome and the heterogeneity of treatment effect between patients with and without acute brain injury, where statistical significance was lost after adjustments. Fourth, although the modest reduction in mortality with SDD observed in patients with acute brain injuries is consistent with our study hypothesis and with the beneficial effects from SDD observed in the clinical secondary outcomes, the differential mortality treatment effect is larger than we observed and is likely to be implausible. Accordingly, the absence of statistically significant heterogeneity of treatment effect in our study may be due to low statistical power. Fifth, this analysis was hypothesis-driven and was not pre-specified before the primary trial. While the cumulative evidence suggests that the use of SDD is associated with reduced hospital mortality [ 1 ], this post hoc analysis of data from the SuDDICU study suggests that this effect may be primarily driven by a benefit in patients with acute brain injuries and that other patients may have little or no benefit from SDD. Before implementation into clinical practice, these findings must be confirmed through analysis of patient-level data from other trials or through new randomized clinical trials. Conclusion Among critically ill patients receiving mechanical ventilation, SDD significantly reduced in-hospital mortality in patients with acute brain injuries compared to standard care without SDD. However, the findings from this post-hoc analysis in this patient population require confirmation. Declarations Acknowledgments The authors and investigators wish to acknowledge the patients who were enrolled in our study and their families; the health care workers who cared for these patients; the research co-ordinators at each participating hospital; members and executive of the Australian and New Zealand Intensive Care Society Clinical Trials Group; the international independent Data and Safety Monitoring Committee; manufacturing and support staff at Verita® Pharma, Sydney, who provided the SDD drug preparations; international collaborators in Canada and the United Kingdom; and the research and support teams at The George Institute for Global Health, Sydney. This paper was endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group. Access to Data Statement Dr Myburgh and Dr Billot had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Data sharing statement See Supplementary Appendix. Role of the Sponsor and Funders The George Institute for Global Health, Australia was the Principal Sponsor for this trial. This trial was supported by a Project Grant from the National Health and Medical Research Council of Australia (Project Grant number 1084244). SDD drug preparations were purchased and manufactured under contract with the George Institute for Global Health by Verita Pharma® (Sydney, Australia). The sponsor, funders and drug manufacturer had no input into the design and conduct of the study, collection, management, analysis and interpretation of data; preparation, review or approval of the manuscript; and the decision to submit the manuscript for publication. The Sponsor had no right of veto to publish this trial or to control the decision regarding to which journal the paper was submitted. Funding statement: No specific funding for this post hoc analysis was obtained. The SuDDICU Australia trial was supported by a Project Grant from the National Health and Medical Research Council of Australia (Project Grant number 1084244); by a Leadership Fellowship from National Health and Medical Research Council of Australia (to Dr. Myburgh); by Practitioner Fellowships from the National Health and Medical Research Council of Australia (to Drs. Finfer); by a Career Development Fellowship from National Health and Medical Research Council (to Dr. Davis); by an Emerging Leader Investigator Grant from the National Health and Medical Research Council of Australia (to Dr. Hammond);by a Clinical Practitioner Research Fellowship from the Health Research Council of New Zealand (to Dr. Young). Competing interests: The George Institute for Global Health holds all intellectual property rights related to the SuDDICU study drugs, including component drug acquisition, manufacturing, packaging and distribution. None of the SuDDICU investigators have any direct or indirect financial or commercial interests relating to the development of the SuDDICU study drugs. Author contributions Non-author collaborators: Presented in Supplementary Appendix. Concept and design: Billot, Davis, Delaney, Devaux, Finfer, Hammond, Li, Myburgh, Seppelt, Venkatesh, Young. Acquisition, analysis and interpretation of data: Billot, Delaney, Devaux, Finfer, Hammond, Li, Micallef, Myburgh, Seppelt, Young. Drafting of the manuscript: Young (wrote the first draft of the manuscript); Billot, Devaux, Finfer, Li, Micallef, Myburgh, Seppelt Critical revision of the manuscript for important intellectual content: Billot, Davis, Devaux, Delaney, Finfer, Hammond, Li, Micallef, Myburgh, Seppelt, Venkatesh, Young. Statistical analysis: Billot, Devaux, Li. Obtained funding: Davis, Finfer, Myburgh, Seppelt, Young. Administrative, technical or material support: Billot, Devaux, Finfer, Hammond, Li, Micallef, Myburgh. Supervision: Billot, Finfer, Hammond, Li, Myburgh. References Hammond NE, Myburgh J, Seppelt I, et al. Association Between Selective Decontamination of the Digestive Tract and In-Hospital Mortality in Intensive Care Unit Patients Receiving Mechanical Ventilation: A Systematic Review and Meta-analysis. JAMA. 2022;328(19):1922-1934. doi:10.1001/jama.2022.19709 The SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2022;328(19):1911-1921. doi:10.1001/jama.2022.17927 Bonten MJ, Kollef MH, Hall JB. Risk factors for ventilator-associated pneumonia: from epidemiology to patient management. Clin Infect Dis. 2004;38(8):1141-9. doi:10.1086/383039 Ewig S, Torres A, El-Ebiary M, et al. 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International study of the prevalence and outcomes of infection in intensive care units. JAMA. Dec 2 2009;302(21):2323-9. doi:10.1001/jama.2009.1754 Tables Table 1: Characteristics of patients with acute brain injuries at ICU admission Characteristic SDD (n=968) Standard care (n=1093) Age, years 54.9±18.04 56.6±17.60 Male, no. (%) 625 (64.6) 686 (62.8) ICU admission source, no. (%) Emergency department 522 (53.9) 513 (46.9) Admitted following emergency surgery 199 (20.6) 223 (20.4) Hospital floor (wards) 121 (12.5) 177 (16.2) Transfer from another hospital 74 (7.6) 112 (10.2) Transfer from another ICU 39 (4.0) 62 (5.7) Admitted following elective surgery 13 (1.3) 6 (0.5) Time from ICU admission to enrollment, median (IQR), h 11.6 (1.3-29.6) 1.9 (0.0-17.5) Severity of illness score a , median (IQR) APACHE II 22.0 (17.0-28.0) [n=471] 22.0 (16.0- 27.0) [n=702] APACHE III 66.0 (47.0-90.0) [n=497] 78.0 (56.0- 99.0) [n=373] Comorbidities, no. (%) Diabetes 167 (17.3) 203 (18.6) Systemic steroids 51 (5.3) 103 (9.4) Immunosuppression 41 (4.2) 70 (6.4) Prior treatments, no. (%) Receiving intravenous antibiotics at enrollment 569 (58.8) 582 (53.2) Receiving intravenous antibiotics for >48h prior to enrollment 124 (21.8) 113 (19.4) Use of oral chlorhexidine 261 (27.0) 198 (18.1) ICU admission diagnosis, no. (%) Cardiac arrest 316 (32.6) 336 (30.7) Traumatic brain injury 220 (22.7) 233 (21.3) Intracerebral hemorrhage 120 (12.4) 119 (10.9) Subarachnoid hemorrhage 100 (10.3) 118 (10.8) Seizure 61 (6.3) 85 (7.8) Brain infection 50 (5.2) 48 (4.4) Stroke 37 (3.8) 44 (4.0) Coma 33 (3.4) 41 (3.8) Subdural/epidural haematoma 15 (1.5) 28 (2.6) Brain neoplasm 4 (0.4) 13 (1.2) Other 12 (1.2) 28 (2.6) ± values are mean±SD a Severity of illness was determined by the Acute Physiology and Chronic Health Evaluation (APACHE) scores, ranging from 0 to 71 (APACHE II) 7 or 0 to 299 (APACHE III) 8 , with higher scores indicating an increased risk of death. Abbreviations: APACHE: Acute Physiology And Chronic Health Evaluation; ICU: intensive care unit; IQR: interquartile range; SD: standard deviation; SDD: selective decontamination of the digestive tract Table 2: Clinical outcomes for patients with acute brain injuries at ICU admission Characteristic SDD (N=968) Standard care (N=1093) Difference % (95% CI) Odds ratio (95% CI) P value Primary outcome: in-hospital death within 90 d, no. (%) Primary analysis 313 (32.3) 415 (38.0) -6.2% (-8.9% to -3.5%) 0.76 (0.63 to 0.92) 0.004 Adjusted analysis a 0.74 (0.57 to 0.97) 0.02 Adjusted analysis b 0.78 (0.59 to1.04) 0.082 Clinical secondary outcomes Death in the ICU, no. (%) 247 (25.5) 323 (29.6) -5.0% (-8.4% to -1.5%) 0.79 (0.65 to 0.97) 0.02 Days alive and free of mechanical ventilation Mean±SD 57.2±38.3 52.1±39.5 5.60 (2.17 to 9.03) 0.001 Median (IQR) 81.0 (3.0 to 87.0) 78.0 (1.0 to 87.0) Days alive and free of ICU admission Mean±SD 54.0±37.3 49.2±38.4 5.18 (1.85 to 8.50) 0.002 Median (IQR) 76.0 (0.0 to 84.0) 72.0 (0.0 to 83.0) Days alive and free of hospital admission Mean±SD 39.8±34.2 36.3±34.5 3.72 (0.70 to 6.75) 0.02 Median (IQR) 50.0 (0.0 to 72.0) 38.0 (0.0 to 72.0) a Adjusted for baseline Age, Sex, APACHE II/III score and diagnosis (operative vs non-operative) b Adjusted for time from ICU admission to enrollment, systemic steroids, oral chlorhexidine, and on intravenous antibiotics at time of enrollment in addition to the other variables from the previous model Abbreviations: ICU: intensive care unit; IQR: interquartile range; SD: standard deviations; SDD: selective decontamination of the digestive tract Supplementary Files CONSORTCHECKLIST060723.pdf SuDDICUBrainRepsonsetoJAMAReviewersR2toICM041023JM.pdf SuDDICUBrainRepsonsetoReviewersR1submitted150923docx.pdf SuDDICUNeuroSuppAppendixICMsubmitted041023.pdf Cite Share Download PDF Status: Published Journal Publication published 20 Nov, 2023 Read the published version in Intensive Care Medicine → Version 1 posted Reviewers agreed at journal 08 Oct, 2023 Reviewers invited by journal 08 Oct, 2023 Editor assigned by journal 08 Oct, 2023 First submitted to journal 06 Oct, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3412001","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":238588066,"identity":"8c311d4e-63dd-491a-92d4-511332140443","order_by":0,"name":"Paul Young","email":"","orcid":"","institution":"Medical Research Institute of New Zealand","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"Young","suffix":""},{"id":238588067,"identity":"3e1fe4fc-6963-4fb0-a732-9176cfdc20a9","order_by":1,"name":"Anthony Devaux","email":"","orcid":"","institution":"The George Institute for Global Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Devaux","suffix":""},{"id":238588068,"identity":"1609cc5b-d82b-44c3-89d8-0c8440af6843","order_by":2,"name":"Qiang Li","email":"","orcid":"","institution":"The George Institute for Global Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Li","suffix":""},{"id":238588069,"identity":"a99b2548-67c4-4b56-8161-e67783e479c4","order_by":3,"name":"Laurent Billot","email":"","orcid":"","institution":"The George Institute for Global Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Laurent","middleName":"","lastName":"Billot","suffix":""},{"id":238588070,"identity":"8a51dbbc-d31d-4e8f-aeb5-1c4a784172ef","order_by":4,"name":"Joshua Davis","email":"","orcid":"","institution":"Menzies School of Health Research","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Davis","suffix":""},{"id":238588071,"identity":"d4aeb3bb-f466-431b-b815-6dbd0c093b4c","order_by":5,"name":"Anthony Delaney","email":"","orcid":"","institution":"The George Institute for Global Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Delaney","suffix":""},{"id":238588072,"identity":"1868ac73-fe64-4756-9a9e-943fe08c53b4","order_by":6,"name":"Simon Finfer","email":"","orcid":"","institution":"The George Institute for Global Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Simon","middleName":"","lastName":"Finfer","suffix":""},{"id":238588073,"identity":"b34f791f-eacb-4136-9026-548089196092","order_by":7,"name":"Naomi Hammond","email":"","orcid":"","institution":"The George Institute for Global 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Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Balasubramanian","middleName":"","lastName":"Venkatesh","suffix":""},{"id":238588077,"identity":"f8860c99-72bf-41e6-9a03-f2ed0890b271","order_by":11,"name":"John A Myburgh","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-4088-7016","institution":"The George Institute for Global Health","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"John","middleName":"A","lastName":"Myburgh","suffix":""}],"badges":[],"createdAt":"2023-10-05 03:55:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3412001/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3412001/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00134-023-07261-y","type":"published","date":"2023-11-20T15:01:43+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44466475,"identity":"d46f725f-a360-4a18-a18a-9f60bd14a7aa","added_by":"auto","created_at":"2023-10-11 21:03:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":86785,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant flow for patients with acute brain injuries in the SuDDICU trial.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/d666db382cf26191aadaa138.jpg"},{"id":44465855,"identity":"8281e92c-6b4e-4c85-ab56-38404c0ed894","added_by":"auto","created_at":"2023-10-11 20:55:04","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":132118,"visible":true,"origin":"","legend":"\u003cp\u003eProbability of survival within 90 days\u003c/p\u003e\n\u003cp\u003eFigure 2A: Patients with acute brain injuries\u003c/p\u003e\n\u003cp\u003eFigure 2B Patients without acute brain injuries\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/e91b994a6fb0625a71d6312b.jpg"},{"id":44466669,"identity":"98d5bc46-daf7-4828-815d-a8db4824be11","added_by":"auto","created_at":"2023-10-11 21:11:04","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":94170,"visible":true,"origin":"","legend":"\u003cp\u003eClinical outcomes for patients with and without acute brain injuries at ICU admission\u003c/p\u003e\n\u003cp\u003eAll analysis are adjusted for baseline Age, Sex, APACHE II/III score, diagnosis (operative vs non-operative), time from ICU admission to enrolment, systemic steroids, oral chlorhexidine, IV antibiotics at time of enrolment, acute neurological injuries and interaction between treatment and acute neurological injuries.\u003c/p\u003e\n\u003cp\u003eAbbreviations: SDD: selective decontamination of the digestive tract.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/c485e7e4dad88a1415bfdf5f.jpg"},{"id":47146469,"identity":"f93146e5-6ecf-4de9-890b-91c731d04ea8","added_by":"auto","created_at":"2023-11-27 15:08:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":635692,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/b90b1ae0-e27f-4cbe-bb84-4d8e610e5f8b.pdf"},{"id":44465860,"identity":"f86feea8-2d91-4ec6-91f9-8aaabaebe5dc","added_by":"auto","created_at":"2023-10-11 20:55:04","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":87705,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORTCHECKLIST060723.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/85722a5d07fd80923c362b5e.pdf"},{"id":44465858,"identity":"d2fa7f3e-4a6b-41f7-8891-a9d063a2e600","added_by":"auto","created_at":"2023-10-11 20:55:04","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":139156,"visible":true,"origin":"","legend":"","description":"","filename":"SuDDICUBrainRepsonsetoJAMAReviewersR2toICM041023JM.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/27acd8f4328e919faa90efc7.pdf"},{"id":44466476,"identity":"a0be9641-e240-4c50-95e2-b3044954a289","added_by":"auto","created_at":"2023-10-11 21:03:04","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":240409,"visible":true,"origin":"","legend":"","description":"","filename":"SuDDICUBrainRepsonsetoReviewersR1submitted150923docx.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/1490c2a940cb9fc54fdcbae1.pdf"},{"id":44465859,"identity":"ad29b930-33a6-4d0c-a823-e754a735c6da","added_by":"auto","created_at":"2023-10-11 20:55:04","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":907299,"visible":true,"origin":"","legend":"","description":"","filename":"SuDDICUNeuroSuppAppendixICMsubmitted041023.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3412001/v1/8fe6cac39aa1a02ea9a09e0a.pdf"}],"financialInterests":"","formattedTitle":"Selective digestive tract decontamination in critically ill adults with acute brain injuries: a Post-Hoc analysis of a Randomized Clinical Trial.","fulltext":[{"header":"Take home message","content":"\u003cp\u003eImproved in clinically important outcomes associated with Selective Decontamination of the Digestive Tract, such as reduced mortality and duration of mechanical ventilation, may be restricted to specific high-risk populations such as those with acute brain injuries. \u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eSelective decontamination of the digestive tract (SDD), consisting of an oral antibiotic paste and a gastric antibiotic suspension, combined with a short course of intravenous antibiotics has been extensively studied in critically ill patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In the recently published Selective Decontamination of the Digestive Tract in the Intensive Care Unit (SuDDICU) trial, hospital mortality was not significantly different for patients allocated to SDD and standard care without SDD [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. When data from this and other randomized clinical trials were combined in a Bayesian meta-analysis, there was a 99.3% posterior probability that SDD was associated with reduced hospital mortality compared to standard care [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It remains uncertain whether the reduction in mortality associated with SDD [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] was driven by a benefit in a particular subgroup or subgroups.\u003c/p\u003e \u003cp\u003ePatients with acute brain injuries or conditions with reduced levels of consciousness and impaired airway reflexes are at risk of aspiration events that may progress to lower respiratory tract infections or ventilator-associated pneumonia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Ventilator-associated pneumonia may result in fever, hypoxaemia and impaired ventilation that are recognized causes of secondary brain injury [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], potentially resulting in additional deaths. As SDD is an infection control strategy designed to prevent ventilator-associated pneumonia, it may be of particular benefit in this group of patients.\u003c/p\u003e \u003cp\u003eTo evaluate the possibility that SDD benefits patients admitted to the ICU with acute brain injuries, a post-hoc subgroup analysis using data from the SuDDICU trial was conducted.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eConsent\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eEthical approval\u003c/strong\u003e \u003cp\u003efor the SuDDICU Australia trial was obtained from Human Research Ethics Committees and Research Governance Offices at each site. As SDD was implemented as an ICU-wide intervention, a waiver of individual patient consent was obtained from each Lead Human Research Ethics Committee according to jurisdictional requirements. For patients in the standard care group, a waiver of consent was obtained as no intervention was provided. As no new data were obtained for this subgroup analysis, additional ethical approval was not required.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and oversight\u003c/h2\u003e \u003cp\u003eThe study protocol and statistical analysis plan [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and the primary manuscript [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] for the SuDDICU crossover, cluster randomized clinical trial have been published previously.\u003c/p\u003e \u003cp\u003eThe SuDDICU trial was reported according to the CONSORT 2010 reporting guidelines [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. (Supplementary Appendix).\u003c/p\u003e \u003cp\u003eData were entered into an encrypted database for statistical analyses conducted at The George Institute for Global Health, Australia.\u003c/p\u003e \u003cp\u003eDetails of the trial management, sponsorship, collaborations and committees and a full list of investigators is provided in the Supplementary Appendix.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTrial participants\u003c/h2\u003e \u003cp\u003eThe SuDDICU Australia trial was conducted in 19 ICUs in 17 hospitals in Australia from May 2017 to November 2021.\u003c/p\u003e \u003cp\u003eEligible ICUs were general medical and surgical ICUs capable of treating mechanically ventilated adults and able to implement SDD in all eligible patients.\u003c/p\u003e \u003cp\u003eEligible patients were mechanically ventilated (either on ICU admission or during ICU admission) and expected to remain ventilated until at least the second day after enrollment. Patients who were not initially expected to require two days of ventilation were rescreened and enrolled if eligibility criteria were subsequently met. SuDDICU trial site and participant eligibility criteria are shown in Supplementary Appendix.\u003c/p\u003e \u003cp\u003eFor this post hoc subgroup analysis, patients with an acute brain injury at ICU admission were identified using the Acute Physiological And Chronic Health Assessment (APACHE)-III ICU admission diagnosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Patients with the following admission diagnoses were defined as having an acute brain injury: cardiac arrest; intracerebral hemorrhage; subarachnoid hemorrhage; stroke; brain infection; neurologic neoplasm; seizure; subdural haematoma; coma; traumatic brain injury; and epidural haematoma. All other patients were defined as not having an acute brain injury.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eRandomization\u003c/h2\u003e \u003cp\u003eICUs were randomly assigned to adopt a SDD strategy or to continue standard care for two alternating 12-month periods, separated by a 3-month inter-period gap. Full details of randomization, that was stratified by the number of ICU beds in the study site, is outlined in the protocol5 and the SuDDICU trial manuscript [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eSDD comprised i.) a six-hourly topical application of 0.5g of oral paste containing 10mg colistin, 10mg tobramycin and 125,000 international units of nystatin applied to the buccal mucosa and oropharynx; ii.) a six-hourly administration of 10mL of gastric suspension containing 100mg colistin, 80mg tobramycin and 2x106 international units of nystatin to the upper gastrointestinal tract via a gastric or post-pyloric tube; iii.) a four-day course of an intravenous SDD-compliant antibiotic that included a third-generation cephalosporin or ciprofloxacin, unless already treated with specified antibiotics with activity against Gram-negative bacteria during the first four days after enrollment, in which case additional antibiotics were not administered.\u003c/p\u003e \u003cp\u003e The SDD paste and suspension were manufactured by Verita Pharma\u0026reg; (Sydney, Australia) under licence from The George Institute for Global Health in accordance with the standards for Good Manufacturing Practice approved by the Therapeutic Goods Administration of Australia. Details of the SDD drug preparations have been described previously [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe SDD oral paste and gastric suspension were administered as soon as possible after eligibility criteria were met and were continued until extubation or day 90, whichever came first.\u003c/p\u003e \u003cp\u003eAll other treatments, including use of prophylactic or therapeutic antibiotics, were at the discretion of treating clinicians in accordance with respective institutional microbiological prescription policies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData and Study Management\u003c/h2\u003e \u003cp\u003eData collected at baseline included demographics, ICU admission diagnosis, APACHE score (a severity of illness score ranging from 0 to 71 [APACHE-II] [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] or 0 to 299 [APACHE-III] [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], with higher scores indicating an increased risk of death) and specific risk factors for infection including prior receipt of oral chlorhexidine and intravenous antibiotics.\u003c/p\u003e \u003cp\u003eFor patients treated in ICUs during the SDD intervention period, daily data documenting the delivery of SDD oral paste and gastric suspension were collected for the duration of mechanical ventilation up to 90 days and administration of SDD-compliant antibiotics for 5 days. Adherence in administering the topical components of SDD was reported as the proportion of patients receiving at least one eligible dose of SDD on a daily basis for the duration of mechanical ventilation.\u003c/p\u003e \u003cp\u003eDoses of all intravenous antibiotics were collected for 28 days, presented as daily defined doses, as defined by the World Health Organisation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Data recorded daily for 90 days included the duration of mechanical ventilation, ICU and hospital admission, all new organisms isolated from blood and non-blood cultures, any new positive test for Clostridioides difficile and new antibiotic resistant organisms from all cultures, as described previously [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDetails of source data verification and monitoring are provided in the Supplementary Appendix.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures\u003c/h2\u003e \u003cp\u003eThe primary outcome was all-cause in-hospital mortality within 90 days of enrollment during the index hospital admission.\u003c/p\u003e \u003cp\u003eClinical secondary outcomes were ICU mortality and days alive and free of mechanical ventilation, ICU admission and hospitalization through 90 days.\u003c/p\u003e \u003cp\u003eMicrobiological secondary outcomes were the results from all new blood cultures; the incidence of new positive Clostridioides difficile tests; the incidence of new pre-defined antibiotic resistant organisms from all blood, non-blood surveillance and clinical cultures, and total antibiotic use, defined in daily defined doses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAlthough not pre-specified, this subgroup analysis was conducted using the same statistical analysis plan used in the main SuDDICU analysis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Patients were analyzed in their randomization group, regardless of adherence, using all available data without imputation.\u003c/p\u003e \u003cp\u003eThe primary outcome of death in the hospital within 90 days was analyzed using an individual-level hierarchical logistic regression model, including both a random cluster effect and a random cluster-period effect. The effect of the intervention was estimated as the odds ratio (OR) for death and the 95% confidence interval (CI) with degrees of freedom adjusted by the Kenward-Roger correction [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Absolute difference of event rate was also estimated from a linear regression at cluster level weighted proportionally to the inverse of the binomial variance for each cluster-period. ICU mortality was evaluated in a similar fashion.\u003c/p\u003e \u003cp\u003eThe number of days alive and free of mechanical ventilation, ICU, and hospitalisation within 90 days were analyzed using a hierarchical linear regression model with the Kenward-Roger correction. Intervention effects were reported as adjusted mean differences and 95% CIs. Time to discharge alive from the ICU and the hospital was summarized by subgroup using cumulative incidence functions treating mortality as a competing risk, censored at day 90. Intervention effects were estimated as hazard ratios (HR) and 95% CIs obtained from a cause-specific Cox model, with a fixed effect of treatment and a random site effect.\u003c/p\u003e \u003cp\u003eIn all analyses, heterogeneity in treatment response for patients with and without an acute brain injury was assessed by adding the subgroup variable as well as its interaction with the intervention to the main analysis model.\u003c/p\u003e \u003cp\u003eTo evaluate for the possibility of heterogeneity of treatment effect on in-hospital mortality within the subgroup of patients with acute brain injuries, the subgroup was divided group into three mutually exclusive categories and fitted an interaction between treatment allocation and category. These categories were: (i) traumatic brain injury (defined as APACHE-III ICU admission diagnoses of head trauma, subdural hematoma and subdural/epidural hematoma; (ii) subarachnoid hemorrhage and stroke (defined as APACHE-III ICU admission diagnoses of intracerebral hemorrhage; subarachnoid hemorrhage; stroke; intracerebral hemorrhage and (iii) other brain injuries (defined as APACHE-III ICU admission diagnoses of cardiac arrest; brain infection; neurologic neoplasm; seizure; other neurologic disease; coma). An additional within brain injury subgroup analysis compared heterogeneity of treatment effect on in-hospital mortality was based on whether or not patients were receiving intravenous antibiotics at baseline.\u003c/p\u003e \u003cp\u003eMicrobiological outcomes were analyzed using the proportions of patients with at least one event in each cluster-period. These proportions were modelled using weighted linear regression where the weights are computed using the inverse of variance for each cluster-period. All these analyses were performed without any adjustment.\u003c/p\u003e \u003cp\u003eAll statistical tests were performed using a 2-sided level of 0.05.\u003c/p\u003e \u003cp\u003eAs all analyses conducted in this study are post-hoc, they were be considered to be exploratory.\u003c/p\u003e \u003cp\u003eStatistical analyses were conducted using SAS software (version 9.4) (Cary NC, USA)\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy sites and patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 5982 mechanically ventilated adults were included with 2061 (mean age 55.8 years; 36.4% women) defined as having an acute brain injury or condition. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the first intervention period, 1019 patients with an acute brain injury were recruited into the trial with 388 (38.1%) in the SDD group and 631 (61.9%) in standard care group. \u0026nbsp;In the second intervention period, 1042 patients with an acute brain injury were recruited with 580 (55.7%) in the SDD group and 462 (44.3%) in standard care group. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary outcome was available for all 968 patients in the SDD group and all 1093 patients in the standard care group (Figure 1). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBaseline characteristics of patients with acute brain injuries allocated to SDD and standard care groups were similar (Table 1) except that the time from ICU admission to enrollment was a median of 11.6 hours (interquartile range [IQR] 1.3-29.6 hours) in the SDD group and a median of 1.9 hours (IQR 0.0-17.5 hours) in the standard care group; oral chlorhexidine was used in 261/968 (27.0%) of patients in the SDD group and 198/1093 (18.1%) in the standard care group and systemic steroids were used in 51/968 (5.3%) in the SDD group and 103/1093 (9.4%) in standard care group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy treatments and process measures\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong patients with acute brain injuries in the SDD group, the proportion of days of mechanical ventilation where patients received both the SDD oral paste and gastric suspension was 93.1% (eFigure 1, Supplementary Appendix).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData on administration of each component of SDD are shown in eTable 1, Supplementary Appendix and the proportions of patients receiving SDD-compliant antibiotics in the SDD and standard care groups are shown in eFigure2, Supplement Appendix. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt hospital discharge within 90 days of enrollment, in patients with acute brain injuries, 313 (32.3%) of 968 allocated to the SDD group and 415 (38.0%) of 1093 allocated to the standard care group had died (mean difference -6.2%, 95% CI -8.9% to -3.5%; OR 0.76, 95% CI 0.63 to 0.92; p=0.004).\u0026nbsp;Findings were similar after adjusting for age at baseline, sex, APACHE II/III score and diagnosis (OR 0.74; 95% CI 0.57 to 0.97; p=0.03) but not significant after adding time from ICU admission to enrolment, systemic steroids, oral chlorhexidine and receipt of intravenous antibiotics at the time of enrolment (OR 0.78; 95% CI 0.59 to1.04; p=0.08). (Table 2). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe respective hazard ratios for time to death with SDD vs. standard care were 0.83 (95% CI, 0.71 to 0.96) and 1.01 (95% CI 0.89 to 1.15) for patients with and without acute brain injuries respectively (Figure 2a and 2b). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was no significant heterogeneity in the effect of SDD on mortality for patients with (OR 0.78, 95% CI 0.63 to 0.99, p=0.04) and without (OR 0.92, 95% CI 0.76 to 1.11, p=0.36) acute brain injuries respectively (interaction p=0.22) (Figure 3, eTable2 Supplementary Appendix).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in mortality between the SDD and standard care groups between patients with traumatic brain injury vs. subarachnoid hemorrhage or between stroke vs. other brain injuries (eTable 3, Supplementary Appendix); or based on receipt or not of intravenous antibiotics at baseline (eTable 3, Supplementary Appendix). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCauses of death in patients with acute brain injuries by treatment group are shown in eTable 4, Supplementary Appendix.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical secondary outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf four clinical secondary outcomes (death in ICU, days alive and free of mechanical ventilation, days alive and free of ICU admission and days alive and free of hospital admission), there were statistically significant differences in favor of the SDD group in patients with acute brain injuries (Table 2). \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe respective hazard ratios for days alive and free of mechanical ventilation with SDD vs. standard care were 1.11 (95% CI 1.01 to 1.22) and 1.10 (95% CI 1.03 to 1.18) for patients with and without acute brain injuries respectively (eFigure 3a and 3b, Supplementary Appendix). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe respective hazard ratios for alive and free of ICU with SDD vs. standard care were 1.10 (95% CI, 0.99 to 1.22) and 1.03 (95% CI 0.96 to 1.11) for patients with and without acute brain injuries respectively (eFigure 4a and 4b, Supplementary Appendix). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe respective hazard ratios for alive and free of hospital with SDD vs. standard care were 1.06 (95% CI, 0.94 to 1.18) and 1.00 (95% CI 0.93 to 1.07) for patients with and without acute brain injuries respectively (eFigure 5a and 5b, Supplementary Appendix). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was no significant heterogeneity in the effect of SDD on the four secondary clinical outcomes for patients with and without acute brain injuries (eTable2 and eFigure 3, Supplementary Appendix).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMicrobiological secondary outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the SDD group compared to the standard care group, there was a statistically significant reduction in the proportion of patients from whom new antibiotic resistant organisms were cultured (20.5% vs 34.2%; absolute difference -13.9 percentage points; 95% CI -17.5 to -10.3); for new positive blood cultures excluding coagulase negative Staphylococcus aureus (2.8% vs 5.5%; \u0026nbsp;absolute difference -1.90 percentage points, 95% CI -3.5 to -0.4) and for new positive Clostridioides difficile tests (0.1% vs 0.8%; absolute difference -0.6 percentage points, 95% CI \u0026ndash;1.0 to -0.1) (eTable 5, Supplementary Appendix).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the patients with acute brain injuries in the SDD and standard care groups respectively, the number of patients with blood cultures collected was 552 (57.0%) vs. 713 (65.2%) and the number of patients with non-blood cultures collected was 229 (23.7%) vs. 411 (37.6%). \u0026nbsp;Data on specific organisms cultured from blood specimens and for new antibiotic resistant organisms cultured from non-blood specimens from the SDD and standard care groups are shown in the eTable 6, Supplementary Appendix. \u0026nbsp;New antibiotic resistant organisms were cultured from the respiratory tract in 115 of 968 (11.9%) and 275 of 1093 (25.2%) of patients allocated to SDD and standard care groups respectively.\u003c/p\u003e\n\u003cp\u003eThe mean cumulative daily defined doses over the first 28 days of all intravenous antibiotics and of intravenous antibiotics not administered as part of the SDD treatment regimen are shown in the eFigure 6, Supplementary Appendix. \u0026nbsp;The cumulative daily doses of each antibiotic class are also shown in the eFigure 7, Supplementary Appendix. \u0026nbsp;Among patients with acute brain injuries, daily defined doses of antibiotics administered over the first seven days following enrollment were significantly higher in the SDD group compared to the standard care group (eFigure 8, Supplementary Appendix) although daily defined doses over the first 28 days following enrollment were not significantly different between the two groups (eFigure 9, Supplementary Appendix).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events and protocol deviations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNew positive Clostridioides difficile infections occurred in 1 of 968 (0.1%) patients in the SDD group and 9 of 1093 (0.8%) patients in the standard care group. \u0026nbsp;Other adverse and serious adverse events were rare (eTable 7, Supplementary Appendix).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this post-hoc analysis using data from a cross-over, cluster randomized clinical trial, the use of SDD in the subgroup of mechanically ventilated critically ill adults with acute brain injuries or conditions was associated with a clinically and statistically significantly reduced in-hospital mortality compared with standard care without SDD. The use of SDD was associated with significantly reduced ICU mortality, duration of mechanical ventilation and duration of ICU and hospital admission and with lower rates of new blood stream infections and new cultures of antibiotic resistant organisms. In patients without acute brain injuries or conditions, who made up around two thirds of SuDDICU trial population, no significant differences in any clinical outcome between SDD and standard care groups were observed.\u003c/p\u003e \u003cp\u003eApart from one small trial [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], patients with acute brain injuries have not been a focus of clinical trials evaluating SDD [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Prior randomized clinical trials have suggested that intravenous antibiotic prophylaxis may reduce rates of ventilator-associated pneumonia in patients after cardiac arrest [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and with other brain injuries in the ICU [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These trials of prophylactic antibiotics did not focus on patient-important outcomes such as mortality.\u003c/p\u003e \u003cp\u003eIn this large subgroup of nearly 2000 patients with acute brain injuries from a pragmatic randomized clinical trial, SDD was associated with improvements in several patient-centred outcomes. The 5.7 percentage point reduction in mortality corresponds to a number need to treat of 18 to avoid one death. This is a clinically important effect size in a population of patients with a control mortality rate of 38 percentage points. Excellent protocol adherence was achieved with over 90 percentage points of eligible doses of commercial-standard SDD drug preparations administered for the duration of mechanical ventilation. In contrast to the overall SuDDICU trial population [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], patients with acute brain injuries who were allocated to SDD received significantly more daily defined doses of antibiotics in the first seven days compared patients allocated to standard care.\u003c/p\u003e \u003cp\u003eAlthough SDD was associated with lower rates of new infections that may have mitigated potential contributors to secondary brain injury, data about brain process measures, such as intracranial pressure, types, duration and intensity of brain-specific therapies or assessments of longer-term functional brain outcome, were not available to confirm or refute putative mechanisms of benefit. While ventilator-associated pneumonia is a common cause of ICU-acquired infection [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], specific data on the diagnosis or source of infection or the impact of ventilator-associated pneumonia on respiratory function were not available for analysis, although lower rates of new antibiotic resistant organisms were cultured from the respiratory tract in patients allocated to SDD.\u003c/p\u003e \u003cp\u003eThis subgroup analysis has some limitations. First, the intervention was unblinded and therefore subject to ascertainment bias, although this was mitigated by the objective primary outcome and the adoption of SDD as standard care administered to all eligible patients during the intervention period. Second, we reported the primary ICU admission diagnoses defining the presence of an acute brain injuries may have miscategorized some patients. Third, while the primary outcome was reported using pre-specified unadjusted analyses, adjusted analyses accounting for baseline imbalances are equally important for a post hoc analysis, both in the interpretation of the primary outcome and the heterogeneity of treatment effect between patients with and without acute brain injury, where statistical significance was lost after adjustments. Fourth, although the modest reduction in mortality with SDD observed in patients with acute brain injuries is consistent with our study hypothesis and with the beneficial effects from SDD observed in the clinical secondary outcomes, the differential mortality treatment effect is larger than we observed and is likely to be implausible. Accordingly, the absence of statistically significant heterogeneity of treatment effect in our study may be due to low statistical power. Fifth, this analysis was hypothesis-driven and was not pre-specified before the primary trial.\u003c/p\u003e \u003cp\u003eWhile the cumulative evidence suggests that the use of SDD is associated with reduced hospital mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], this post hoc analysis of data from the SuDDICU study suggests that this effect may be primarily driven by a benefit in patients with acute brain injuries and that other patients may have little or no benefit from SDD. Before implementation into clinical practice, these findings must be confirmed through analysis of patient-level data from other trials or through new randomized clinical trials.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAmong critically ill patients receiving mechanical ventilation, SDD significantly reduced in-hospital mortality in patients with acute brain injuries compared to standard care without SDD. However, the findings from this post-hoc analysis in this patient population require confirmation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors and investigators wish to acknowledge the patients who were enrolled in our study and their families; the health care workers who cared for these patients; the research co-ordinators at each participating hospital; members and executive of the Australian and New Zealand Intensive Care Society Clinical Trials Group; the international independent Data and Safety Monitoring Committee; manufacturing and support staff at Verita\u0026reg; Pharma, Sydney, who provided the SDD drug preparations; international collaborators in Canada and the United Kingdom; and the research and support teams at The George Institute for Global Health, Sydney.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis paper was endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAccess to Data Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Myburgh and Dr Billot had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sharing statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSee Supplementary Appendix.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of the Sponsor and Funders\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe George Institute for Global Health, Australia was the Principal Sponsor for this trial. This trial was supported by a Project Grant from the National Health and Medical Research Council of Australia (Project Grant number 1084244). SDD drug preparations were purchased and manufactured under contract with the George Institute for Global Health by Verita Pharma\u0026reg; (Sydney, Australia).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe sponsor, funders and drug manufacturer had no input into the design and conduct of the study, collection, management, analysis and interpretation of data; preparation, review or approval of the manuscript; and the decision to submit the manuscript for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Sponsor had no right of veto to publish this trial or to control the decision regarding to which journal the paper was submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific funding for this post hoc analysis was obtained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe SuDDICU Australia trial was supported by a Project Grant from the National Health and Medical Research Council of Australia (Project Grant number 1084244); by a Leadership Fellowship from National Health and Medical Research Council of Australia (to Dr. Myburgh); by Practitioner Fellowships from the National Health and Medical Research Council of Australia (to Drs. Finfer); by a Career Development Fellowship from National Health and Medical Research Council (to Dr. Davis); by an Emerging Leader Investigator Grant from the National Health and Medical Research Council of Australia (to Dr. Hammond);by a Clinical Practitioner Research Fellowship from the Health Research Council of New Zealand (to Dr. Young).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe George Institute for Global Health holds all intellectual property rights related to the SuDDICU study drugs, including component drug acquisition, manufacturing, packaging and distribution. None of the SuDDICU investigators have any direct or indirect financial or commercial interests relating to the development of the SuDDICU study drugs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNon-author collaborators:\u0026nbsp;\u003c/em\u003e Presented in Supplementary Appendix.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConcept and design:\u0026nbsp;\u003c/em\u003eBillot, Davis, Delaney, Devaux, Finfer, Hammond, Li, Myburgh, Seppelt, Venkatesh, Young.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcquisition, analysis and interpretation of data:\u0026nbsp;\u003c/em\u003eBillot, Delaney, Devaux,\u0026nbsp;Finfer, Hammond, Li, Micallef, Myburgh, Seppelt, Young.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDrafting of the manuscript:\u0026nbsp;\u003c/em\u003eYoung (wrote the first draft of the manuscript); Billot, Devaux, Finfer, Li, Micallef, Myburgh, Seppelt\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCritical revision of the manuscript for important intellectual content:\u0026nbsp;\u003c/em\u003eBillot, Davis, Devaux, Delaney, Finfer, Hammond, Li, Micallef, Myburgh, Seppelt, Venkatesh, Young.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis:\u0026nbsp;\u003c/em\u003eBillot, Devaux, Li.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eObtained funding:\u003c/em\u003e Davis, Finfer, Myburgh, Seppelt, Young.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAdministrative, technical or material support:\u0026nbsp;\u003c/em\u003eBillot, Devaux, Finfer, Hammond, Li, Micallef, Myburgh.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSupervision:\u0026nbsp;\u003c/em\u003eBillot, Finfer, Hammond, Li, Myburgh.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHammond NE, Myburgh J, Seppelt I, et al. 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April 2022 https://www.anzics.com.au/wp-content/uploads/2021/03/ANZICS-APD-Data-Dictionary.pdf \u003c/li\u003e\n\u003cli\u003eKnaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818-29. \u003c/li\u003e\n\u003cli\u003eKnaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest. 1991;100(6):1619-36. doi:10.1378/chest.100.6.1619\u003c/li\u003e\n\u003cli\u003eOrganization WH. Defined daily dose (DDD). Accessed 3rd July, 2023. https://www.who.int/tools/atc-ddd-toolkit/about-ddd\u003c/li\u003e\n\u003cli\u003eKenward M.G. RJH. An improved approximation to the precision of fixed effects from restricted maximum likelihood. Computational statistics and data analysis. 2009;53:2583-2595. \u003c/li\u003e\n\u003cli\u003eKorinek AM, Laisne MJ, Nicolas MH, Raskine L, Deroin V, Sanson-Lepors MJ. Selective decontamination of the digestive tract in neurosurgical intensive care unit patients: a double-blind, randomized, placebo-controlled study. Crit Care Med. 1993;21(10):1466-73. doi:10.1097/00003246-199310000-00013\u003c/li\u003e\n\u003cli\u003eRibaric SF, Turel M, Knafelj R, et al. Prophylactic versus clinically-driven antibiotics in comatose survivors of out-of-hospital cardiac arrest-A randomized pilot study. Resuscitation. 2017;111:103-109. doi:10.1016/j.resuscitation.2016.11.025\u003c/li\u003e\n\u003cli\u003eFrancois B, Cariou A, Clere-Jehl R, et al. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. N Engl J Med. 2019;381(19):1831-1842. doi:10.1056/NEJMoa1812379\u003c/li\u003e\n\u003cli\u003eSirvent JM, Torres A, El-Ebiary M, Castro P, de Batlle J, Bonet A. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respiratory and Crit Care Med. 1997;155(5):1729-1734. doi:10.1164/ajrccm.155.5.9154884\u003c/li\u003e\n\u003cli\u003eAcquarolo A, Urli T, Perone G, Giannotti C, Candiani A, Latronico N. Antibiotic prophylaxis of early onset pneumonia in critically ill comatose patients. A randomized study. Int Care Med. 2005;31(4):510-516. doi: I: 10.1007/s00134-005-2585-5\u003c/li\u003e\n\u003cli\u003eVincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. Dec 2 2009;302(21):2323-9. doi:10.1001/jama.2009.1754\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"631\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"3\"\u003e\u003cbr\u003e\u003cstrong\u003eTable 1:\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCharacteristics of patients with acute brain injuries at ICU admission\u003c/strong\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=968)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandard care\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1093)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e54.9\u0026plusmn;18.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e56.6\u0026plusmn;17.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eMale, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e625 (64.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e686 (62.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eICU admission source, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Emergency department\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e522 (53.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e513 (46.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eAdmitted following emergency surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e199 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e223 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eHospital floor (wards)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e121 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e177 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eTransfer from another hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e74 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e112 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eTransfer from another ICU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e39 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e62 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eAdmitted following elective surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e13 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e6 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eTime from ICU admission to\u003c/p\u003e\n \u003cp\u003eenrollment, median (IQR), h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e11.6 (1.3-29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e1.9 (0.0-17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eSeverity of illness score\u003csup\u003ea\u003c/sup\u003e, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eAPACHE II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e22.0 (17.0-28.0)\u003c/p\u003e\n \u003cp\u003e[n=471]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e22.0 (16.0- 27.0) [n=702]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eAPACHE III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e66.0 (47.0-90.0)\u003c/p\u003e\n \u003cp\u003e[n=497]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e78.0 (56.0- 99.0)\u003c/p\u003e\n \u003cp\u003e[n=373]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eComorbidities, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eDiabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e167 (17.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e203 (18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eSystemic steroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e51 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e103 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eImmunosuppression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e41 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e70 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003ePrior treatments, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eReceiving intravenous antibiotics at enrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e569 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e582 (53.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eReceiving intravenous antibiotics for \u0026gt;48h prior to enrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e124 (21.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e113 (19.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003e\u0026nbsp;Use of oral chlorhexidine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e261 (27.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e198 (18.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eICU admission diagnosis, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eCardiac arrest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e316 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e336 (30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eTraumatic brain injury \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e220 (22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e233 (21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eIntracerebral hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e120 (12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e119 (10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eSubarachnoid hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e100 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e118 (10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eSeizure\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e61 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e85 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eBrain infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e50 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e48 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eStroke\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e37 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e44 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eComa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e33 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e41 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eSubdural/epidural haematoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e15 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e28 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eBrain neoplasm\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e4 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e13 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.96988906497623%\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e12 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.515055467511885%\"\u003e\n \u003cp\u003e28 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u0026plusmn; values are mean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Severity of illness was determined by the Acute Physiology and Chronic Health Evaluation (APACHE) scores, ranging from 0 to 71 (APACHE II)\u003csup\u003e7\u003c/sup\u003e or 0 to 299 (APACHE III)\u003csup\u003e8\u003c/sup\u003e, with higher scores indicating an increased risk of death.\u003c/p\u003e\n \u003cp\u003eAbbreviations: APACHE: Acute Physiology And Chronic Health Evaluation; ICU: intensive care unit; IQR: interquartile range; SD: standard deviation; SDD: selective decontamination of the digestive tract\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"924\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eClinical outcomes for patients with acute brain injuries at ICU admission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N=968)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandard care (N=1093)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDifference %\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOdds ratio\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003ePrimary outcome: in-hospital death within 90 d, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003ePrimary analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e313 (32.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e415 (38.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e-6.2%\u003c/p\u003e\n \u003cp\u003e(-8.9% to -3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e0.76 (0.63 to 0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eAdjusted analysis\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e0.74 (0.57 to 0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eAdjusted analysis\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.78 (0.59 to1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.082\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eClinical secondary outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eDeath in the ICU, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e247 (25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e323 (29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e-5.0% (-8.4% to -1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e0.79 (0.65 to 0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eDays alive and free of mechanical ventilation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e57.2\u0026plusmn;38.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e52.1\u0026plusmn;39.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e5.60 (2.17 to 9.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e81.0 (3.0 to 87.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e78.0 (1.0 to 87.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eDays alive and free of ICU admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e54.0\u0026plusmn;37.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e49.2\u0026plusmn;38.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e5.18 (1.85 to 8.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e76.0 (0.0 to 84.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e72.0 (0.0 to 83.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eDays alive and free of hospital admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e39.8\u0026plusmn;34.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e36.3\u0026plusmn;34.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e3.72 (0.70 to 6.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.32900432900433%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e50.0 (0.0 to 72.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e38.0 (0.0 to 72.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.341991341991342%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.367965367965368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.225108225108226%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Adjusted for baseline Age, Sex, APACHE II/III score and diagnosis (operative vs non-operative)\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Adjusted for time from ICU admission to enrollment, systemic steroids, oral chlorhexidine, and on intravenous antibiotics at time of enrollment in addition to the other variables from the previous model\u003c/p\u003e\n\u003cp\u003eAbbreviations: ICU: intensive care unit; IQR: interquartile range; SD: standard deviations; SDD: selective decontamination of the digestive tract\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"intensive-care-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"icme","sideBox":"Learn more about [Intensive Care Medicine](http://link.springer.com/journal/134)","snPcode":"134","submissionUrl":"https://www.editorialmanager.com/icme/default2.aspx","title":"Intensive Care Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Selective Decontamination of the Digestive Tract, acute brain injury, mechanical ventilation, mortality.","lastPublishedDoi":"10.21203/rs.3.rs-3412001/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3412001/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo determine whether Selective Decontamination of the Digestive Tract (SDD) reduces in-hospital mortality in mechanically ventilated critically ill adults admitted to the Intensive Care Unit (ICU) with acute brain injuries or conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA post-hoc analysis from a crossover, cluster-randomized clinical trial. ICUs were randomly assigned to adopt or not to adopt a SDD strategy for two alternating 12-month periods, separated by a 3-month inter-period gap. Patients in the SDD group (n=2791; 968 admitted to the ICU with an acute brain injury) 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; 1093 admitted to the ICU with an acute brain injury) received standard care.\u003cstrong\u003e \u003c/strong\u003eThe primary outcome was in-hospital mortality within 90 days. There were four secondary clinical outcomes: death in ICU, ventilator-, ICU- and hospital-free days to day 90.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e Of 2061 patients with acute brain injuries (mean age, 55.8 years; 36.4% women), all completed the trial. In patients with acute brain injuries, there were 313/968 (32.3%) and 415/1093 (38.0%) in-hospital deaths in the SDD and standard care groups (unadjusted odds ratio [OR], 0.76, 95% confidence interval [CI] 0.63 to 0.92; p = 0.004). The use of SDD was associated with statistically significant improvements in the four clinical secondary outcomes compared to standard care. There was no statistical difference in the heterogeneity of treatment effect between patients with and without acute brain injuries (interaction p=0.22).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eIn this post-hoc analysis of a randomized clinical trial in critically ill patients with acute brain injuries receiving mechanical ventilation, the use of SDD significantly reduced in-hospital mortality in patients compared to standard care without SDD. These findings require confirmation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eClinical Trials.gov registration number: NCT02389036\u003c/p\u003e","manuscriptTitle":"Selective digestive tract decontamination in critically ill adults with acute brain injuries: a Post-Hoc analysis of a Randomized Clinical Trial.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-11 20:54:59","doi":"10.21203/rs.3.rs-3412001/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2023-10-08T10:47:13+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-08T09:10:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-08T08:45:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Intensive Care Medicine","date":"2023-10-06T23:14:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"intensive-care-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"icme","sideBox":"Learn more about [Intensive Care Medicine](http://link.springer.com/journal/134)","snPcode":"134","submissionUrl":"https://www.editorialmanager.com/icme/default2.aspx","title":"Intensive Care Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5f44e232-7a9a-4918-b525-77e30cd4c973","owner":[],"postedDate":"October 11th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-11-27T15:06:42+00:00","versionOfRecord":{"articleIdentity":"rs-3412001","link":"https://doi.org/10.1007/s00134-023-07261-y","journal":{"identity":"intensive-care-medicine","isVorOnly":false,"title":"Intensive Care Medicine"},"publishedOn":"2023-11-20 15:01:43","publishedOnDateReadable":"November 20th, 2023"},"versionCreatedAt":"2023-10-11 20:54:59","video":"","vorDoi":"10.1007/s00134-023-07261-y","vorDoiUrl":"https://doi.org/10.1007/s00134-023-07261-y","workflowStages":[]},"version":"v1","identity":"rs-3412001","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3412001","identity":"rs-3412001","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}