Postoperative Opioid Consumption After Scheduled Compared With Unscheduled Cesarean Delivery.

OBJECTIVE: To identify characteristics associated with high inpatient daily opioid consumption after cesarean delivery. METHODS: This is a retrospective cohort study of all cesarean deliveries performed under neuraxial anesthesia with neuraxial morphine, at a single institution from January 1, 2015, to December 31, 2015. Women with preoperative opioid use disorder or chronic opioid use were excluded. Sociodemographic data, medical comorbidities, use of anxiolytics or antidepressants, smoking history, nonopioid substance use, intrapartum and cesarean delivery characteristics, and opioid consumption data (converted to morphine milligram equivalents) were abstracted. We defined high opioid use as a mean daily opioid consumption, standardized to the postoperative length of stay (excluding the first 24 postoperative hours to account for neuraxial morphine), greater than the 75th percentile of all opioid consumption. We used multivariable Poisson regression, stratified by whether or not cesarean delivery was scheduled, to identify characteristics associated with high opioid consumption. RESULTS: Among 949 women who underwent cesarean delivery, the mean (SD) and median (interquartile range) daily opioid consumption was 48.6 (22.8) and 44.6 (36.6-66.6) morphine milligram equivalents, respectively. Among those women with high opioid consumption, the mean (SD) and median (interquartile range) daily opioid consumption was 78.8 (8.5) and 78.3 (72.9-83.5) morphine milligram equivalents, respectively. Daily opioid consumption among those with high consumption was similar among women with scheduled compared with unscheduled cesarean delivery. Sociodemographic characteristics were similar among women with and without high opioid consumption. No sociodemographic, antepartum, or intrapartum characteristics were associated with high opioid consumption for either women having unscheduled or scheduled cesarean deliveries. CONCLUSION: For a quarter of women undergoing cesarean delivery, daily consumption of opioids is equivalent to 10 tablets of oxycodone 5 mg daily. No characteristics were associated with high opioid use for women having a scheduled or unscheduled cesarean delivery. Understanding opioid consumption after cesarean delivery is critical to managing women's postoperative pain while decreasing opioid exposure and risks of long-term opioid use disorder.

The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction. METHODS: To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy. RESULTS: Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival. CONCLUSIONS: Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.