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).