Daily Anesthesiology Research Analysis

BACKGROUND: The use of the first in class proteasome inhibitor bortezomib (BTZ) is highly effective in the treatment of multiple myeloma. However, its long-term use is limited by the fact that most treated patients develop painful polyneuropathy. In some of the treated patients, pain resolves with time; in others, it persists, with the underlying mechanisms poorly understood. One prerequisite for neural toxicity is the ability of a drug to penetrate the blood-nerve barrier. METHODS: Here, we analysed the pathways involved in early BTZ-induced polyneuropathy development and its resolution in rats and in myeloma patients using pain behaviour, barrier analysis, transcriptomics, immunohistochemistry, and clinical data. RESULTS: One cycle of BTZ elicited transient tactile and cold allodynia in rats. Transcriptomic signature and network analysis revealed regulation of circadian, extracellular matrix, and immune genes within the nerve and modest changes in the dorsal root ganglia. Recovery processes resealed the small molecule leakiness of the perineurial barrier, reversed axonal swelling, and normalised fibre density in the skin. Expression of the microtubule-associated cytoskeletal protein cortactin matched this process in the perineurium. Netrin-1 as a known barrier sealer was also upregulated in pain resolution in nerve and skin. In patients with painful BTZ-induced polyneuropathy, skin innervation was reduced and netrin-1 was unchanged, compatible with the persistence of pain. CONCLUSIONS: In summary, our data demonstrate that early bortezomib toxicity targets mainly peripheral nerves and indicate that pain resolution could be supported by protective growth factors such as netrin-1 for remodelling of the extracellular matrix and neuronal barriers. CLINICAL TRIAL REGISTRATION: DRKS00025422.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) can improve outcomes in refractory out-of-hospital cardiac arrest (OHCA), but access is limited by geographic and system constraints. We aimed to compare the potential impact of different ECPR delivery strategies in an urban setting using simulation modeling. METHODS: We performed a Monte Carlo simulation using historical OHCA data (2015-2019) from Montreal's sole EMS. Each of 2000 iterations simulated 1240 annual OHCA cases using geospatial heatmaps. Patients meeting ECPR criteria (witnessed arrest, bystander CPR, age ≤ 70 years old) were included. We tested in-hospital models (2-, 3-, and 4-hospital), a rendezvous model, and two prehospital strategies: hospital-based deployment and an optimally located mobile team. Transport times were estimated using a machine learning model trained on real operational data. Outcomes included survival with favorable neurological outcome, proportion of patients achieving flow recovery at 60 min and low-flow time. RESULTS: On average, 255 patients were included per iteration. With in-hospital ECPR delivery, increasing from 2 to 4 hospitals modestly improved CPC 1-2 survival (25.3% vs 28.0%), flow recovery at 60 min (69.2% vs 75.1%), and low-flow interval (-2.4 min. Rendezvous yielded 28.8% CPC 1-2 survival, 77.3% flow-recovery at 60 min and -2.9 min low-flow time. Prehospital strategies had the greatest impact, improving CPC 1-2 survival (39.5% and 42.0%), flow-recovery at 60 min (99.7% and 100%), and low-flow time (-7.8 and -12 min) for hospital-based and optimally placed teams respectively. CONCLUSION: In this simulation, prehospital ECPR strategies showed the potential to increase survival, improve flow recovery at 60 min, and reduce low-flow times in urban OHCA.

Perioperative neurocognitive disorder (PND) is a prevalent postoperative complication of the central nervous system (CNS) in elderly patients. Advanced age is an independent risk factor for developing PND. Microglia are essential immune cells in the CNS and play a critical role in neuroinflammation. The activation of microglia is closely linked to PND, although the precise mechanism remains unclear. Gamma oscillations (30-100 Hz) are associated with higher cognitive functions, including attention. The aim of this study was to investigate the mechanism by which microglial activation in PND disrupts gamma oscillations. The study utilized 18-month-old male C57BL/6 J mice and established a PND model through exploratory laparotomy. The results of both Contextual Fear Conditioning (CFC) and Morris Water Maze (MWM) experiments demonstrated that exploratory laparotomy could lead to hippocampus-dependent neurocognitive dysfunction in aged mice. We observed that exploratory laparotomy induced the transformation of microglia in the hippocampus of aged mice into an activated phenotype characterized by enlarged cell bodies and shortened processes. This transformation was accompanied by a significant increase in the expression levels of pro-inflammatory factors in hippocampal tissue, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Specific depletion of microglia in aged mice, achieved by drinking water supplemented with the colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 for seven consecutive days, resulted in a reduction of postoperative hippocampal neuroinflammation and a significant improvement in cognitive dysfunction. Similarly, perioperative inhibition of microglial activation with minocycline resulted in cognitive improvement. Additionally, we found that the expression levels of hippocampal parvalbumin (PV) and glutamate decarboxylase 67 (GAD67) were significantly reduced following exploratory laparotomy, which was accompanied by disturbed gamma oscillations. Depletion of microglia restored the expression levels of PV and GAD67 and significantly improved the disturbances in gamma oscillations. These findings suggest that the activation of hippocampal microglia and the associated neuroinflammatory response following surgery play a crucial role in PND. The underlying mechanism may be related to disturbed gamma oscillations and a reduction in the inhibitory function of PV interneurons.