Perioperative Regional Anesthesia Pain Outcomes in Children: A Retrospective Study of 3160 Regional Anesthetics in Routine Practice.

OBJECTIVE: Randomized controlled trials indicate regional anesthesia (RA) improves postoperative outcomes with reduced pain and opioid consumption. Therefore, we hypothesized children who received RA, regardless of technique, would have reduced pain/opioid use in routine practice. METHODS: Using a retrospective cohort, we assessed the association of RA with perioperative outcomes in everyday practice at our academic pediatric hospital. Patients 18 years or below undergoing orthopedic, urologic, or general surgeries with and without RA from May 2014 to September 2021 were categorized as single shot, catheter based, or no block. Outcomes included intraoperative opioid exposure and dose, preincision anesthesia time, postanesthesia care unit (PACU) opioid exposure and dose, PACU antiemetic/antipruritic administration, PACU/inpatient pain scores, PACU/inpatient lengths of stay, and cumulative opioid exposure. Regression models estimated the adjusted association of RA with outcomes, controlling for multiple variables. RESULTS: A total of 11,292 procedures with 3160 RAs were included. Compared with no-block group, single-shot and catheter-based blocks were associated with opioid-free intraoperative anesthesia and opioid-free PACU stays. Post-PACU (ie, while inpatient), single-shot blocks were not associated with improved pain scores or reduced opioid use. Catheter-based blocks were associated with reduced PACU and inpatient opioid use until 24 hours postop, no difference in opioid use from 24 to 36 hours, and a higher probability of use from 36 to 72 hours. RA was not associated with reduced cumulative opioid consumption. DISCUSSION: Despite adjustment for confounders, the association of RA with pediatric pain/opioid use outcomes was mixed. Further investigation is necessary to maximize the benefits of RA.

CNS Repopulation by Hematopoietic-Derived Microglia-Like Cells Corrects Progranulin deficiency.

Hematopoietic stem cell transplantation can deliver therapeutic proteins to the CNS through donor-derived hematopoietic cells that become microglia-like cells. However, using standard conditioning approaches, hematopoietic stem cell transplantation is currently limited by low and slow engraftment of microglia-like cells. We report an efficient conditioning regimen based on Busulfan and a six-day course of microglia depletion using the colony-stimulating factor receptor 1 inhibitor PLX3397. Combining Busulfan-myeloablation and transient microglia depletion results in robust, rapid, and persistent microglia replacement by bone marrow-derived microglia-like cells throughout the CNS. Adding PLX3397 does not affect neurobehavior or has adverse effects on hematopoietic reconstitution. Through single-cell RNA sequencing and high-dimensional CyTOF mass cytometry, we show that microglia-like cells are a heterogeneous population and describe six distinct subpopulations. Though most bone-marrow-derived microglia-like cells can be classified as homeostatic microglia, their gene signature is a hybrid of homeostatic/embryonic microglia and border associated-macrophages. Busulfan-myeloablation and transient microglia depletion induce specific cytokines in the brain, ultimately combining myeloid proliferative and chemo-attractive signals that act locally to repopulate microglia from outside the niche. Importantly, this conditioning approach demonstrates therapeutic efficacy in a mouse model of GRN deficiency. Transplanting wild-type bone marrow into Grn-/- mice conditioned with Busulfan plus PLX3397 results in high engraftment of microglia-like cells in the brain and retina, restoring GRN levels and normalizing lipid metabolism.