Daily Anesthesiology Research Analysis
A double-blind pilot RCT shows a multi-drug anti-inflammatory bundle markedly reduces postoperative delirium after hip fracture surgery. A multicenter ICU study quantifies that 10.7% of prepared IV medications are discarded, highlighting sustainability and cost targets. Preclinical work identifies GDF15-driven microglial activation as a mechanistic driver of sepsis-associated cognitive impairment, with anti-GDF15 therapy improving cognition in mice.
Summary
A double-blind pilot RCT shows a multi-drug anti-inflammatory bundle markedly reduces postoperative delirium after hip fracture surgery. A multicenter ICU study quantifies that 10.7% of prepared IV medications are discarded, highlighting sustainability and cost targets. Preclinical work identifies GDF15-driven microglial activation as a mechanistic driver of sepsis-associated cognitive impairment, with anti-GDF15 therapy improving cognition in mice.
Research Themes
- Delirium prevention via multi-target anti-inflammatory modulation
- Sustainable critical care and medication waste reduction
- Neuroinflammation mechanisms in sepsis-associated encephalopathy
Selected Articles
1. Effect of combination of multiple anti-inflammatory drugs strategy on postoperative delirium among older patients undergoing hip fracture surgery: a pilot randomized controlled trial.
In a dual-center, double-blind pilot RCT (n=132 randomized; 123 analyzed), a perioperative anti-inflammatory bundle (dexmedetomidine, glucocorticoid, ulinastatin, NSAIDs) reduced postoperative delirium from 44% to 15% (RR 0.33; P=0.001) without major adverse events. Lower postoperative CRP partially mediated the effect, supporting inflammation as a causal pathway.
Impact: This rigorously blinded pilot RCT demonstrates a substantial reduction in postoperative delirium using a pragmatic, multi-target anti-inflammatory strategy, a leading cause of morbidity in older surgical patients.
Clinical Implications: If replicated, anesthesiologists could adopt protocolized anti-inflammatory bundles to prevent delirium in high-risk geriatric fracture surgery, integrating dexmedetomidine sedation, a single perioperative steroid dose, ulinastatin, and NSAIDs with careful patient selection and monitoring.
Key Findings
- Postoperative delirium was reduced from 44% (27/61) to 15% (9/62) with the anti-inflammatory bundle (RR 0.33; 95% CI 0.17–0.64; P=0.001).
- No major adverse events occurred in either group, supporting safety of the bundled approach.
- Postoperative CRP levels were significantly lower with the bundle, and mediation analysis implicated systemic inflammation in the protective effect.
Methodological Strengths
- Dual-center, double-blind, placebo-controlled randomized design
- Predefined primary outcome with mediation analysis linking CRP to clinical effect
Limitations
- Pilot sample size and two-center setting limit generalizability
- Bundle design precludes disentangling the contribution of individual drugs; short (3-day) delirium follow-up
Future Directions: Conduct adequately powered, multicenter RCTs to confirm efficacy, optimize dosing/timing, assess long-term cognitive and functional outcomes, and evaluate cost-effectiveness and safety in broader populations.
BACKGROUND: Postoperative delirium is the most common complication in older patients and is associated with surgery-induced inflammation. Although inflammation plays a key role in delirium, the potential benefits of a comprehensive anti-inflammatory approach to managing perioperative systemic inflammation remain underexplored. This study evaluated whether a perioperative anti-inflammatory bundle strategy, combining dexmedetomidine, glucocorticoids, ulinastatin, and nonsteroidal anti-inflammatory drugs, reduces the risk of postoperative delirium in older patients undergoing hip fracture surgery. METHODS: This dual-center, double-blind, placebo-controlled, parallel-group, pilot study was conducted from August 2023 to January 2024 at two tertiary university hospitals. A total of 132 patients aged ≥ 65 years with an American Society of Anesthesiologists physical status of 2 or 3 scheduled for elective hip fracture surgery were screened and randomized to receive either an anti-inflammatory drug bundle or a placebo. The primary outcome was postoperative delirium, identified within the first three postoperative days. Postoperative blood inflammatory markers and acute pain were measured for mediation analysis. RESULTS: Of the 132 patients randomized, 123 (93%) completed the trial (mean age, 82 years; 75% women). The prevalence of postoperative delirium was significantly lower in the anti-inflammatory bundle group (15%, 9/62) compared to the placebo group (44%, 27/61) (risk difference, - 30 percentage points [95% CI, - 45 to - 15]; relative risk [RR], 0.33 [95% CI, 0.17 to 0.64]; P = 0.001). No major adverse events were reported in either group. The postoperative CRP level in the anti-inflammatory bundle group was significantly lower (predicted mean difference: - 29.4 [95% CI: - 46.5, - 12.2] mg·L
2. Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.
In LPS-induced murine sepsis, CSF GDF15 rose markedly; intracerebroventricular anti-GDF15 (ponsegromab) mitigated cognitive and memory deficits, reduced microglial activation/phagocytosis, and prevented synaptic loss. In vitro, GDF15 enhanced microglial inflammatory cytokines and phagocytic activity, supporting a causal role.
Impact: Identifies GDF15 as a mechanistic driver of neuroinflammation and cognitive impairment in sepsis and demonstrates target engagement with a therapeutic antibody, opening a translational pathway for SAE.
Clinical Implications: While preclinical, these data suggest GDF15 blockade could become a therapeutic strategy for sepsis-associated encephalopathy. Future clinical translation will need systemic delivery approaches, safety evaluation, and biomarker-guided patient selection.
Key Findings
- CSF GDF15 levels increased significantly after LPS-induced sepsis in mice.
- Intracerebroventricular anti-GDF15 (ponsegromab) improved fear-conditioning and novel object recognition performance.
- GDF15 promoted microglial inflammatory cytokine production and phagocytosis; antibody treatment reduced microglial activation and protected synapses.
Methodological Strengths
- Convergent in vivo behavioral, histological, and in vitro mechanistic assays
- Target engagement using a clinically developed monoclonal antibody
Limitations
- LPS model may not capture the full complexity of polymicrobial sepsis
- Intracerebroventricular delivery limits immediate clinical translatability; sample sizes not detailed in abstract
Future Directions: Evaluate systemic anti-GDF15 strategies, validate in polymicrobial sepsis models, define dosing windows, and assess interaction with sedation/analgesia regimens and long-term cognitive outcomes.
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe neurological condition caused by sepsis, and presents with symptoms ranging from delirium and coma to long-term cognitive dysfunction. SAE is acknowledged as a widespread brain impairment characterized by the activation of microglia. However, the specific pathological mechanisms that drive this activation are still not clearly understood. Growth differentiation factor 15 (GDF15) levels have been noted to be considerably increased in patients with sepsis, where they are linked to disease severity and can independently predict short- and long-term mortality risk. Serum levels of GDF15 have also been negatively associated with gray matter volume and predict cognitive impairment in older individuals. However, the impact of GDF15 on sepsis-induced cognitive and memory impairments, as well as the mechanisms behind these effects, are poorly understood. METHODS: To examine the role of GDF15 in SAE, a sepsis model was created in adult C57BL/6J mice using intraperitoneal administration of lipopolysaccharide (LPS). GDF15 levels in plasma and cerebrospinal fluid were measured by ELISA. The anti-GDF15 monoclonal antibody ponsegromab was injected intracerebroventricularly before modeling, and cognitive and memory functions of the septic mice were assessed using fear-conditioning and novel object recognition tests. Microglial activation and phagocytosis were evaluated using immunofluorescence and Golgi staining. Additionally, an in vitro investigation of LPS-stimulated microglia was conducted to evaluate the impacts of GDF15 on inflammatory cytokine productions and microglial phagocytic activity. Mechanisms were explored using RNA sequencing, qPCR, western blotting, flow cytometry, and immunofluorescence assays. RESULTS: In the cerebrospinal fluid of septic mice, levels of GDF15 were notably elevated after intraperitoneal injection of LPS. Lateral ventricular injection of the anti-GDF15 antibody alleviated both cognitive and memory impairment in the septic mice, together with microglial activation and phagocytosis in the hippocampus, thereby protecting against synaptic loss. CONCLUSION: The levels of GDF15 were elevated in the brains of septic mice. Targeting GDF15 with an anti-GDF15 antibody was found to improve sepsis-induced cognitive and memory impairment by reducing the microglial inflammatory response and phagocytosis. These results indicate that GDF15 could serve as an important therapeutic target for treating SAE.
3. Discarded intravenous medication in the ICU: the GAME-OVER multicenter prospective observational study.
Across 81 ICUs and 1,076 patients, 10.7% of prepared IV medication volume was discarded during a 24-hour snapshot, with 90% of waste concentrated in 25 drugs and an estimated national annual cost of €2.74 million. Patient/flow factors (admissions/discharges, SOFA≥7, intubation, RRT, BMI) were associated with waste, underscoring system-level interventions.
Impact: Provides the first large-scale, prospective quantification of ICU IV medication waste with cost attribution and risk factors, enabling targeted sustainability and stewardship strategies.
Clinical Implications: Hospitals can prioritize high-yield interventions: ready-to-administer dosing, unit-dose preparation, on-demand compounding, pharmacy-ICU workflow redesign, and analytics to target the 25 key drugs driving 90% of waste.
Key Findings
- 10.7% (95% CI 9.9–11.5) of prepared IV medication volume was discarded across 81 ICUs and 1,076 patients.
- Ninety percent of waste was attributable to 25 drugs; estimated national annual cost €2,737,163.
- Admission/discharge volume, elective surgery admission, SOFA≥7, intubation, renal replacement therapy, and BMI were independently associated with increased waste.
Methodological Strengths
- Prospective multicenter design with pre-registered protocol
- Large sample capturing diverse ICU settings and standardized primary metric
Limitations
- Single 24-hour snapshot per ICU may miss temporal variability
- Conducted in France; generalizability to other health systems may vary; no linkage to patient outcomes
Future Directions: Test targeted stewardship interventions (e.g., ready-to-administer formats, predictive preparation) in pragmatic trials, incorporate environmental life-cycle assessment, and integrate waste metrics into quality dashboards.
BACKGROUND: Medication waste is a contributor to the healthcare environmental footprint and impacts ecosystems. Data on medication waste in the intensive care unit (ICU) are scarce, and therefore are essential to develop new sustainable strategies. METHODS: The GAME-OVER French multicenter prospective observational study was conducted from November 2022 to March 2023, over a 24-h period of choice, at the discretion of each participating center. Adult ICUs were enrolled in the study on a voluntary basis and hospitalized patients who did not express opposition were included in the analysis. The primary endpoint was the percentage of discarded intravenous (IV) medication in the ICU, defined as the ratio of the discarded volume to the total volume of IV medication prepared. Secondary endpoints included identifying risk factors and main reasons for medication waste and estimating its related healthcare cost. RESULTS: Among the 81 ICUs and the 1076 enrolled patients, 408.9 L of 130 IV medications were prepared. The discarded volume was 43.8 L, resulting in a 10.7% discarded IV medication (95% Confidence Interval (CI), 9.9-11.5). Number of daily admissions/discharges in the ICU, as admission for elective surgery, Sequential Organ Failure Assessment score ≥ 7, endotracheal intubation, renal replacement therapy and body mass index were independently associated with increased discarded IV medication. Ninety percent of pharmaceutical waste was attributed to 25 key drugs, with an estimated national annual cost of 2,737,163€. CONCLUSIONS: Discarded intravenous medication in the ICU is considerable and results in significant costs for the health care system, without obvious patient-centered value. Risk factors associated with medication waste were largely nonmodifiable, emphasizing the need for sustainable practices in patient care and resource management. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05553054 . September 23, 2022.