Hemodynamic Effects of Ketamine Compared With Propofol or Dexmedetomidine as Continuous ICU Sedation.

BACKGROUND: Ketamine has seen increased use for sedation in the intensive care unit. In contrast to propofol or dexmedetomidine, ketamine may provide a positive effect on hemodynamics. OBJECTIVE: The objective of this study was to compare the development of clinically significant hypotension or bradycardia (ie, negative hemodynamic event) between critically ill adults receiving sedation with ketamine and either propofol or dexmedetomidine. METHODS: This was a retrospective cohort study of adults admitted to an intensive care unit at an academic medical center between January 2016 and January 2021. RESULTS: Patients in the ketamine group (n = 78) had significantly less clinically significant hypotension or bradycardia compared with those receiving propofol or dexmedetomidine (n = 156) (34.6% vs 63.5%; P < 0.001). Patients receiving ketamine also experienced smaller degree of hypotension observed by percent decrease in mean arterial pressure (25.3% [17.4] vs 33.8% [14.5]; P < 0.001) and absolute reduction in systolic blood pressure (26.5 [23.8] vs 42.0 [37.8] mm Hg; P < 0.001) and bradycardia (15.5 [24.3] vs 32.0 [23.0] reduction in beats per minute; P < 0.001). In multivariate logistic regression modeling, receipt of propofol or dexmedetomidine was the only independent predictor of a negative hemodynamic event (odds ratio [OR]: 3.3, 95% confidence interval [CI], 1.7 to 6.1; P < 0.001). CONCLUSION AND RELEVANCE: Ketamine was associated with less clinically relevant hypotension or bradycardia when compared with propofol or dexmedetomidine, in addition to a smaller absolute decrease in hemodynamic parameters. The clinical significance of these findings requires further investigation.

Functional differences in the mu opioid receptor SNP 118A>G are dependent on receptor splice-variant and agonist-specific recruitment of ß-arrestin.

The OPRM1 gene codes for the mu opioid receptor (MOR) and polymorphisms are associated with complex patient clinical responses. The most studied single nucleotide polymorphism (SNP) in OPRM1 is adenine (A) substituted by guanine (G) at position 118 (118A>G, rs1799971) leading to a substitution of asparagine (Asn) for aspartic acid (Asp) at position 40 in the N terminus of the resulting protein. To date, no structural explanation for the associated clinical responses resulting from the 118A>G polymorphism has been proposed. We utilized computational modeling paired with functional cellular assays to predict unstructured N- and C-terminal regions of MOR-1. Using molecular docking and post-docking energy minimizations with morphine, we show that the extracellular substitution of Asn at position 40 alters the cytoplasmic C-terminal conformation, while leaving the G-protein binding interface unaffected. A real-time BRET assay measuring G-protein and ß-arrestin association with MOR r generated data that tested this prediction. Consistent with this in silico prediction, we show changes in morphine-mediated ß-arrestin association with receptor variants with little change in morphine-mediated G-protein association comparing MOR-1 wild type (WT) to MOR-1118A>G. We tested the system with different opioid agonists, the OPRM1 118A>G SNP, and different MOR splice variants (MOR-1 and MOR-1O). These results are consistent with the observation that patients with the 118A>G OPRM1 allele respond more readily to fentanyl than to morphine. In conclusion, the 118A>G substitution alters receptor responses to opioids through variable C-terminal domain movements that are agonist and splice variant dependent.

Outcomes with high dose cytarabine and mitoxantrone induction for adults with mixed phenotype acute leukemia.

The optimal induction strategy for mixed phenotype acute leukemia (MPAL) is unknown, though retrospective data has shown improved remission rates and overall survival with acute lymphoblastic leukemia (ALL)-based regimens. At Memorial Sloan Kettering Cancer Center (MSKCC), the most utilized induction regimen for MPAL is high dose cytarabine plus mitoxantrone ("ALL-2"), though outcomes with this regimen are not well described. In this study, outcomes to first-line induction chemotherapy in 24 patients at MSKCC with MPAL classified by 2016 World Health Organization criteria are reported. The overall response rate was 94 % (16 of 17) in patients receiving ALL-2, including 86 % (6 of 7) in patients with extramedullary disease. Thirteen patients who received ALL-2 induction proceeded to allogeneic hematopoietic cell transplant (allo-HCT). The most common toxicity associated with ALL-2 was febrile neutropenia, documented in 12 patients. With a median follow-up of 37 months, median overall survival was not reached in the ALL-2 cohort, and 3-year overall survival was 62 %. In multivariate analysis, age ≥ 60 years and MPAL with isolated extramedullary disease were associated with significantly worse overall survival (P = .009 and P = .01, respectively). These results support further prospective investigation of ALL-2 as a front-line induction regimen for adults with MPAL.