Daily Sepsis Research Analysis
A multicenter RCT (OPTPRESS) shows that targeting higher mean arterial pressure (80–85 mmHg) in older patients with septic shock significantly increases 90-day mortality versus standard targets (65–70 mmHg). Complementing this, a multicenter target trial emulation suggests early adjunctive vasopressin may reduce ICU mortality, particularly at lower norepinephrine doses, while large database analyses link hyperosmolality trajectories to higher in-hospital mortality, highlighting an accessible pro
Summary
A multicenter RCT (OPTPRESS) shows that targeting higher mean arterial pressure (80–85 mmHg) in older patients with septic shock significantly increases 90-day mortality versus standard targets (65–70 mmHg). Complementing this, a multicenter target trial emulation suggests early adjunctive vasopressin may reduce ICU mortality, particularly at lower norepinephrine doses, while large database analyses link hyperosmolality trajectories to higher in-hospital mortality, highlighting an accessible prognostic marker.
Research Themes
- Hemodynamic targets and vasoactive strategies in septic shock
- Trajectory-based biomarkers for prognosis in sepsis
- Advanced causal inference (target trial emulation) in critical care research
Selected Articles
1. Efficacy of targeting high mean arterial pressure for older patients with septic shock (OPTPRESS): a multicentre, pragmatic, open-label, randomised controlled trial.
In a multicenter pragmatic RCT of 518 patients ≥65 years with septic shock, targeting MAP 80–85 mmHg increased 90-day mortality versus 65–70 mmHg (39.3% vs 28.6%; risk difference 10.7%). No subgroup benefited, including those with chronic hypertension; renal replacement therapy–free days were fewer with the high-MAP strategy.
Impact: This trial provides definitive evidence that higher MAP targets harm elderly septic shock patients, directly informing hemodynamic targets in guidelines.
Clinical Implications: Avoid targeting MAP 80–85 mmHg in elderly septic shock; standard targets of 65–70 mmHg should be preferred. Monitor for potential renal support needs when higher vasopressor targets are considered.
Key Findings
- 90-day all-cause mortality was higher with MAP 80–85 mmHg vs 65–70 mmHg (39.3% vs 28.6%; risk difference 10.7%; 95% CI 2.6–18.9).
- Renal replacement therapy–free days at 28 days were fewer in the high-target group.
- No subgroup, including patients with chronic hypertension, derived benefit from a higher MAP target.
- Trial was stopped early for harm based on interim analysis.
Methodological Strengths
- Multicenter pragmatic randomized controlled design with prespecified outcomes
- Early termination for harm with clear mortality signal
Limitations
- Open-label design may introduce performance bias
- Generalizability primarily to older Japanese ICU population; target maintained for first 72 hours
Future Directions: Assess individualized MAP targets integrating frailty, vascular stiffness, and microcirculatory endpoints; evaluate downstream renal and cardiovascular adverse effects of higher vasopressor exposure.
PURPOSE: We examined the effect of a high-target mean arterial pressure (MAP) on septic shock in a previously underrepresented region. METHODS: A multicentre, pragmatic, open-label, randomised controlled trial was conducted in 29 hospitals in Japan, where the prevalence of chronic hypertension among older individuals is 66.9%. Patients who were diagnosed with septic shock, aged ≥ 65 years, and admitted to an intensive care unit were randomised 1:1 to the high (target MAP = 80-85 mmHg) or control (target MAP = 65-70 mmHg) groups from 1 July 2021 to 12 December 2023. The target MAP was maintained for 72 h or until vasopressors were no longer required. The primary outcome was the 90-day all-cause mortality. Secondary outcomes included organ support-free days and adverse events. RESULTS: The trial was terminated early on the basis of the interim analysis results, suggesting the harm of the high-target strategy. Of the 518 patients, 258 were in the high-target group, and 260 were in the control group. By 90 days after randomisation, 101 patients (39.3%) in the high-target group and 74 (28.6%) in the control group had died from any cause (risk difference = 10.7; 95% confidence interval, 2.6-18.9). Renal replacement therapy-free days at 28 days were shorter in the high-target group. No clinical benefits for any outcome were observed in any subpopulation, including those with known chronic hypertension. CONCLUSION: Among older patients with septic shock, high-target MAP significantly increased mortality compared with standard care. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000041775; 13 September 2020.
2. Effect of early adjunctive vasopressin initiation for septic shock patients: a target trial emulation.
In a multicenter target trial emulation of 3,105 septic shock patients, initiating vasopressin within 6 hours was associated with lower estimated 30-day ICU mortality (18.45% vs 19.34%; RR 0.95, 95% CI 0.93–0.98). Benefits were strongest when norepinephrine doses were below ~0.25 µg/kg/min.
Impact: This study leverages advanced causal inference to address timing of vasopressin, suggesting earlier use may improve outcomes and guiding the design of definitive RCTs.
Clinical Implications: Consider earlier adjunctive vasopressin when escalating vasopressors, particularly before norepinephrine exceeds ~0.25 µg/kg/min, while awaiting RCT confirmation.
Key Findings
- Early (≤6 h) vasopressin start was associated with lower estimated 30-day ICU mortality versus usual care (18.45% vs 19.34%; RR 0.95, 95% CI 0.93–0.98).
- Effect modification suggested stronger benefit at lower norepinephrine-equivalent doses (<~0.25 µg/kg/min).
- Parametric g-formula target trial emulation reduced immortal time and time-varying confounding biases.
Methodological Strengths
- Multicenter target trial emulation with parametric g-formula to address time-varying confounding
- Predefined subgroup interactions (norepinephrine dose, APACHE, lactate, ventilation) enhance interpretability
Limitations
- Observational emulation remains susceptible to residual confounding and measurement bias
- Details of vasopressin dosing strategies and adherence may vary across centers
Future Directions: Conduct prospective randomized trials testing early adjunctive vasopressin initiation thresholds based on norepinephrine dose and shock severity.
BACKGROUND: In septic shock, the optimal timing of adjunctive vasopressin initiation shock is unknown. We aimed to assess the effect of its early initiation for patients with septic shock. METHODS: We conducted a multicenter target trial emulation to estimate the intensive care unit (ICU) mortality effect of early (≤ 6 h) adjunctive vasopressin compared with usual care. Eligible patients had septic shock diagnosed within 6 h of ICU admission. The primary outcome of this study was 30-day ICU mortality. Subgroup analyses were conducted to test the interaction of early vasopressin start with peak norepinephrine-equivalent dose (NED) at 6 h, APACHE score, peak lactate at 6 h and invasive mechanical ventilation. Secondary outcomes were the impact of delayed vasopressin introduction on 30-day ICU mortality and effect of NED at vasopressin start on 30-day ICU mortality. We used the parametric g-formula to emulate a target trial. RESULTS: Overall, 3,105 patients fulfilled the inclusion criteria. Mean age was 62 years and mean APACHE III score was 83. In the first six hours of vasopressor therapy, 1,864 (60%) patients were invasively ventilated. Estimated 30-day ICU mortality was 19.34% (95%CI, 17.0 to 21.68) in the no vasopressin group and 18.45% (95%CI, 16.26 to 20.63) in the early vasopressin group; relative risk 0.95 (95%CI, 0.93 to 0.98). The estimated 30-day ICU mortality effect of starting vasopressin was particularly strong at lower norepinephrine doses (< 0.25 µg.kg CONCLUSIONS: In this emulation of a hypothetical target trial, patients with septic shock benefited from early vasopressin administration. These findings can help design prospective randomised-control trials of early adjunctive vasopressin use in septic shock.
3. Association between osmolality trajectories and mortality in patients with sepsis: a group-based trajectory model in large ICU open access databases.
Across 19,502 sepsis ICU admissions in MIMIC-IV and eICU-CRD, five osmolality trajectories were identified. Persistent hyperosmolality conferred markedly higher in-hospital mortality (OR 3.33 in MIMIC; 2.50 in eICU), while maintaining 290–300 mOsm/L was associated with lower risk; findings were robust across IPWRA and subgroups.
Impact: Demonstrates an easily measurable, trajectory-based biomarker that stratifies mortality risk across two large independent ICU datasets.
Clinical Implications: Routine monitoring and avoidance of persistent or rising hyperosmolality (targeting ~290–300 mOsm/L) may inform fluid and electrolyte management to mitigate risk.
Key Findings
- Identified five distinct osmolality trajectories in 19,502 sepsis ICU patients across MIMIC-IV and eICU-CRD.
- Persistent hyperosmolality increased in-hospital mortality risk (OR 3.33 [2.71–4.09] in MIMIC; OR 2.50 [1.97–3.17] in eICU).
- Dynamic increases in osmolality were also associated with higher mortality (OR 1.68 in both datasets).
- Maintaining osmolality within 290–300 mOsm/L was associated with lower mortality risk; results were robust to IPWRA and subgroup analyses.
Methodological Strengths
- Large sample size across two independent ICU databases with external replication
- Use of group-based trajectory modeling with adjusted analyses and IPWRA sensitivity checks
Limitations
- Retrospective design limits causal inference; unmeasured confounding possible
- Variability in osmolality measurement timing and methods across centers
Future Directions: Prospective interventional studies targeting osmolality ranges and mechanisms linking hyperosmolality to organ dysfunction in sepsis.
OBJECTIVE: The regulation of osmolality levels is controlled by the endocrine system, reflecting the body's water and electrolyte balance. However, the relationship between dynamic osmolality trajectories and the prognosis of septic patients has not yet been reported. This study aims to investigate the predictive value of dynamic osmolality trajectories on mortality among patients with sepsis. METHODS: A retrospective analysis was performed using the MIMIC IV and eICU-CRD databases. A total of 19,502 patients were included, 10,263 from MIMIC IV and 9,239 from eICU-CRD. Group-based trajectory modeling (GBTM) analysis was performed to identify distinct osmolality trajectories. The association between these trajectories and in-hospital mortality was assessed by logistic regression analysis and further adjusted for potential confounders. Subgroup analysis was used to identify potential interactive factors and to assess the robustness of the present findings. RESULTS: Five distinct osmolality trajectories were identified. Patients in the persistent hyperosmolality trajectory (Trajectory-5) had significantly higher in-hospital mortality compared to other trajectories, with an increased risk of in-hospital mortality of 233% (OR 3.33, 95% CI 2.71-4.09) and 150% (OR 2.50, 95% CI 1.97-3.17) in MIMIC IV and eICU-CRD respectively, with Trajectory-2 as reference. A dynamic increase in osmolality (Trajectory-4) was also associated with a 68% (OR 1.68, 95% CI 1.39-2.03) and a 68% (OR 1.68, 95% CI 1.44-1.97) increase in the risk of death, compared with Trajectory-2. Conversely, maintaining osmolality in the range of 290-300 mOsm/L (Trajectory-1 and Trajectory-2) was associated with a lower risk of death. Our results remained stable in the IPWRA and subgroup analyses. CONCLUSION: Our findings suggest that dynamic changes in plasma osmolality are significantly associated with in-hospital mortality in septic patients. Osmolality trajectory model provides a potentially effective, easily accessible and cost-effective biomarker for the prognostic assessment and clinical management of sepsis.