Daily Anesthesiology Research Analysis
Three studies shape perioperative neuroscience and critical care systems: a mechanistic BJA study links bortezomib neuropathy to blood-nerve barrier dysfunction and identifies netrin-1/cortactin as recovery correlates; an aged-mouse study shows microglia-driven disruption of gamma oscillations underlies perioperative neurocognitive disorder; and a Resuscitation Monte Carlo model finds prehospital ECPR strategies could markedly boost neurologically intact survival in urban OHCA.
Summary
Three studies shape perioperative neuroscience and critical care systems: a mechanistic BJA study links bortezomib neuropathy to blood-nerve barrier dysfunction and identifies netrin-1/cortactin as recovery correlates; an aged-mouse study shows microglia-driven disruption of gamma oscillations underlies perioperative neurocognitive disorder; and a Resuscitation Monte Carlo model finds prehospital ECPR strategies could markedly boost neurologically intact survival in urban OHCA.
Research Themes
- Peripheral neurotoxicity mechanisms and barrier biology in chemotherapy-induced neuropathy
- Microglia–interneuron circuitry and gamma oscillations in perioperative neurocognitive disorder
- Systems modeling to optimize prehospital ECPR delivery in urban out-of-hospital cardiac arrest
Selected Articles
1. Neuronal toxicity and recovery from early bortezomib-induced neuropathy: blood-nerve barrier dysfunction without dorsal root ganglion damage.
In rats, a single bortezomib cycle caused transient tactile/cold allodynia with blood-nerve barrier leakiness and ECM/circadian/immune gene changes in nerve but only modest DRG changes. Recovery resealed the perineurial barrier, normalized axonal morphology and skin innervation, and paralleled cortactin upregulation and netrin-1 increases. In patients with persistent neuropathic pain, skin innervation was reduced and netrin-1 did not increase, implicating barrier remodeling pathways in resolution.
Impact: This translational study reveals barrier biology as a key driver of bortezomib neuropathy and identifies netrin-1/cortactin–linked perineurial sealing as a recovery correlate, opening mechanistically grounded therapeutic avenues.
Clinical Implications: Monitoring small-fiber loss and targeting perineurial barrier repair (e.g., netrin-1 pathways or ECM remodeling) may help prevent or reverse chemotherapy-induced neuropathy; anesthesiologists and pain specialists could incorporate barrier-protective strategies alongside dose management.
Key Findings
- Early bortezomib produced transient tactile and cold allodynia in rats with perineurial small-molecule leakiness that resealed during recovery.
- Nerve transcriptomics highlighted circadian, extracellular matrix, and immune gene regulation; DRG changes were modest.
- Cortactin expression in perineurium and netrin-1 levels increased with pain resolution; patients with persistent pain showed reduced skin innervation without netrin-1 increase.
Methodological Strengths
- Multisystem translational approach (rat behavior, barrier assays, transcriptomics, IHC, and patient skin data).
- Concordant structural-functional readouts linking barrier integrity, molecular markers (cortactin, netrin-1), and behavioral outcomes.
Limitations
- Human data were correlative and limited in sample depth; causal validation in patients is lacking.
- Temporal window focused on early toxicity; long-term remodeling and dosing regimens were not evaluated.
Future Directions: Test barrier-sealing biologics (e.g., netrin-1 agonism) and ECM-modulatory strategies in preclinical models and early-phase trials; develop biomarkers of perineurial leakiness for patient stratification.
2. Optimizing extracorporeal cardiopulmonary resuscitation delivery for out-of-hospital cardiac arrest: a Monte Carlo simulation study.
Using geospatial Monte Carlo simulations of Montreal OHCA, prehospital ECPR strategies outperformed in-hospital models, increasing CPC 1–2 survival to 39.5–42.0%, achieving 99.7–100% flow recovery at 60 minutes, and reducing low-flow times by 7.8–12 minutes. Expanding in-hospital centers yielded modest gains, while a rendezvous model was intermediate.
Impact: This systems-level analysis quantifies the potential survival benefit of deploying mobile ECPR teams, informing urban EMS design and resource allocation for maximum neurological outcomes.
Clinical Implications: Urban EMS systems considering ECPR should prioritize prehospital deployment models to minimize low-flow time and improve neurologically intact survival; planning must address staffing, training, and logistics for mobile ECMO teams.
Key Findings
- Prehospital ECPR strategies achieved the highest modeled CPC 1–2 survival (39.5–42.0%) and 60-minute flow recovery (99.7–100%).
- Low-flow time was substantially reduced with prehospital teams (−7.8 to −12 minutes) versus in-hospital strategies.
- Increasing in-hospital ECPR centers from 2 to 4 yielded only modest improvements (CPC 1–2: 25.3% to 28.0%).
Methodological Strengths
- Large-scale Monte Carlo simulation with 2000 iterations grounded in real OHCA geospatial and operational data.
- Machine-learning–derived transport time estimates and comparison of multiple deployment strategies.
Limitations
- Simulation-based outcomes may not capture real-world implementation barriers (team availability, cannulation times, patient selection).
- Single-EMS urban setting limits generalizability; no cost-effectiveness analysis included.
Future Directions: Prospective pragmatic trials or stepped-wedge implementations comparing in-hospital versus prehospital ECPR, with cost, safety, and equity outcomes; refine criteria integrating real-time prediction.
3. Gamma Oscillation Disruption Induced By Microglial Activation Contributes to Perioperative Neurocognitive Disorders in Aged Mice.
In aged mice undergoing exploratory laparotomy, hippocampal microglia became activated, proinflammatory cytokines increased, PV interneuron markers (PV, GAD67) decreased, and gamma oscillations were disrupted, yielding hippocampus-dependent cognitive deficits. Microglial depletion (PLX3397) or inhibition (minocycline) restored PV/GAD67 expression, improved gamma oscillations, and rescued cognition.
Impact: This work mechanistically links microglial activation to cortical network dysfunction (gamma oscillations) and identifies actionable targets (microglia, PV interneuron preservation) for PND mitigation.
Clinical Implications: Perioperative neuroinflammation is a modifiable driver of PND; anti-inflammatory microglial modulators and interventions preserving PV interneuron function warrant clinical exploration in older surgical patients.
Key Findings
- Exploratory laparotomy in aged mice activated hippocampal microglia and increased TNF-α, IL-1β, and IL-6, causing hippocampus-dependent cognitive deficits.
- PV and GAD67 expression decreased with disrupted gamma oscillations; microglial depletion restored PV/GAD67 and normalized gamma rhythms.
- Perioperative minocycline improved cognition, supporting microglia-targeted strategies for PND.
Methodological Strengths
- Use of aged mice with behavioral assays (CFC, MWM), molecular profiling, and electrophysiological readouts.
- Pharmacologic manipulations (PLX3397, minocycline) to test causality of microglial activation.
Limitations
- Findings are preclinical; translational relevance to human PND requires validation.
- Timing and dosing paradigms for microglial modulation were limited to perioperative windows.
Future Directions: Pilot trials testing microglia-targeted anti-inflammatories and gamma-modulating interventions in older surgical patients; biomarker development (EEG gamma, cytokines) for risk stratification.