Highlight
- Early restrictive versus liberal fluid resuscitation in sepsis-induced hypotension showed no significant difference in survivors’ long-term cognitive and physical function.
- Assessments at 6 and 12 months post-randomization demonstrated comparable disability, mobility, and quality of life across groups.
- Findings suggest that fluid resuscitation volume strategy may not impact long-term patient-centered outcomes in sepsis survivors.
Study Background
Sepsis-induced hypotension is a critical condition frequently managed in intensive care units (ICUs). Adequate fluid resuscitation is a cornerstone of early sepsis treatment to restore tissue perfusion and prevent organ failure. However, the optimal volume of intravenous fluids remains controversial. Liberal fluid strategies provide larger volumes aiming for rapid hemodynamic stabilization, but may increase risks such as fluid overload and tissue edema. Conversely, restrictive strategies limit fluid volume to minimize harm but might compromise perfusion.
While prior trials have evaluated short-term mortality and organ function, the impact of fluid volume strategies on survivors’ long-term cognitive and physical function, disability, and health-related quality of life (HRQoL) remains inadequately understood. Given the increasing recognition of post-sepsis morbidity affecting survivors’ quality of life, research on interventions that influence long-term outcomes is urgently needed.
Study Design
This article reports on SHAMROC (Sepsis-induced Hypotension: Assessing effect of Method of Resuscitation On Patient-centered Outcomes), a pre-specified long-term follow-up study embedded within the NIH NHLBI PETAL Network’s CLOVERS trial (NCT03434028). CLOVERS was an open-label, randomized controlled trial enrolling 1563 patients presenting with sepsis-induced hypotension to evaluate early restrictive versus liberal fluid resuscitation strategies.
Participants in CLOVERS were randomized to either a restrictive fluid strategy, which limited intravenous fluid administration, or a liberal fluid strategy, which permitted greater fluid volumes. SHAMROC prospectively assessed functional outcomes at 6 and 12 months after randomization in a subset of 898 patients, constituting 57% of the original trial cohort. To address potential bias from informative censoring due to mortality, analyses used trimmed means at 50%, which truncate extremes of the data distribution to equitably incorporate survivors and non-survivors.
Primary endpoints included cognitive function assessed by the Montreal Cognitive Assessment-Blind (MoCA-Blind) score, executive function measured by the Hayling Sentence Completion Test, and physical function evaluated by Activities of Daily Living (ADL) score and PROMIS Mobility score. Health-related quality of life was assessed by the EQ-5D-5L instrument.
Key Findings
Out of the 898 SHAMROC participants, 196 were lost to follow-up, leading to the analysis of 702 patients at 6 months, of whom 431 were survivors and 271 non-survivors at that timepoint. Baseline demographic and clinical characteristics were balanced between groups, supporting comparability.
At 6 months, no significant differences were observed between the restrictive and liberal fluid groups across multiple outcome measures. Specifically, the trimmed mean difference for MoCA-Blind score was 0.11 (95% CI -1.44 to 1.70), indicating minimal variance in cognitive function. Similarly, executive function differences (Hayling Test) had a trimmed mean difference of 0.38 (95% CI -0.97 to 1.76), and disability status differences measured by ADL score were 0.03 (95% CI -0.84 to 0.90).
Mobility, assessed by PROMIS Mobility score, showed no significant advantage (trimmed mean difference 0.72, 95% CI -2.20 to 3.64), and HRQoL measured by EQ-5D-5L also showed negligible difference (-0.01, 95% CI -0.07 to 0.06). These findings were consistent at 12 months, demonstrating stability of outcomes over time.
No safety concerns or unexpected adverse effects were reported in relation to fluid volume strategies regarding long-term function. The comprehensive follow-up underscores that initial fluid resuscitation volume does not appear to modify the trajectory of recovery in cognitive or physical domains in sepsis-induced hypotension survivors.
Expert Commentary
The SHAMROC analysis contributes critical evidence to ongoing debates regarding fluid management in sepsis. While earlier investigations focused predominantly on short-term survival and organ support metrics, this study expands understanding to patient-centered outcomes that resonate most with survivors’ lived experiences.
The absence of differences suggests that the physiological trade-offs between restrictive and liberal fluid approaches during early sepsis resuscitation may have less effect on long-term neurological and functional status than hypothesized. This may reflect the multifactorial nature of sepsis recovery, wherein late complications, ongoing organ dysfunction, inflammation, and rehabilitation practices influence outcomes more profoundly than fluid volume in the initial phase.
Limitations include the open-label study design, potential selection bias given not all CLOVERS participants were included in SHAMROC, and loss to follow-up. However, the use of trimmed means to reduce bias from death-associated censoring strengthens confidence in results. Future research could explore individualized fluid strategies targeting specific subpopulations or pathophysiological phenotypes.
Conclusion
SHAMROC’s robust long-term follow-up demonstrates that early restrictive fluid resuscitation in sepsis-induced hypotension does not compromise survivors’ cognitive, executive, physical function, or quality of life compared to a liberal strategy. These findings provide reassurance supporting judicious fluid management tailored to clinical context without adversely impacting meaningful patient-centered recovery parameters up to one year.
Clinicians should continue to emphasize comprehensive sepsis care beyond fluid volume optimization, including early rehabilitation and multidisciplinary support to enhance long-term outcomes.
Funding and ClinicalTrials.gov
The SHAMROC and CLOVERS trials were supported by the NIH NHLBI PETAL Network. The CLOVERS trial is registered under ClinicalTrials.gov Identifier NCT03434028.
References
1. Jorda A, Gelbenegger G, Shapiro NI, et al. Effects of an early restrictive versus liberal fluid strategy on long-term patient-centered outcomes in sepsis-induced hypotension: an open-label, randomized controlled trial. Am J Respir Crit Care Med. 2026;212(7):1510-1521. PMID: 42093058.
2. National Heart, Lung, and Blood Institute PETAL Network. CLOVERS Trial (NCT03434028). Available at clinicaltrials.gov. Accessed 2026.
3. Prescott HC, Angus DC. Enhancing recovery from sepsis: A review. JAMA. 2018;319(1):62-75.
4. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304-377.
5. Needham DM, Davidson J, Cohen H, et al. Improving long-term outcomes after discharge from intensive care unit: Report from a stakeholders’ conference. Crit Care Med. 2012;40(2):502-509.
