Steven Shafer

Background: Anesthetic agents are well known for their effects on memory and pain; however, previous studies quantifying anesthetic modulation of memory have not included experimental noxious stimulation. This study used functional magnetic resonance imaging to determine how low doses of propofol, dexmedetomidine, and fentanyl affect the brain systems for memory encoding and pain perception. Methods: This was a single-blind, 1:1:1, randomized, placebo-controlled crossover study of 92 healthy volunteers ages 18 to 40 yr. Effect-site concentrations were targeted for propofol (1.0 mcg/ml), dexmedetomidine (0.15 ng/ml), or fentanyl (0.9 ng/ml). Participants listened to a series of 80 words creating a mental picture. Thirty were accompanied by a 2-s painful shock. Blood oxygen–weighted images were obtained at 7 T using a custom head coil. The primary outcome was next-day memory performance, measured by d′, a normalized measure of correct identifications versus false positives. Mixed models were fit to test outcome differences between drug groups. Only statistically significant ( P < 0.05) changes are reported, after adjustment for multiple comparisons. Results: Recollection, reported as mean d′ (95% CI), was 1.16 (95% CI, 0.97 to 1.34) under no drug. This was reduced under propofol (0.51; 95% CI, 0.182 to 0.842; P = 0.006) but not under dexmedetomidine (1.04; 95% CI, 0.73 to 1.35; P = 0.99) or fentanyl (0.98; 95% CI, 0.68 to 1.28; P = 0.99). Propofol decreased memory-encoding activation of the hippocampus and amygdala. Propofol reduced pain-related activation in the insula, anterior cingulate, hippocampus, and amygdala. Dexmedetomidine showed decreased memory-related activation in the hippocampus but did not change pain ratings or show activation differences in pain-processing areas. Fentanyl showed decreased memory activation in the hippocampus and amygdala. During painful stimulation, fentanyl decreased activation in the primary somatosensory cortex and insula and increased activation in the anterior cingulate, hippocampus, and amygdala. Conclusions: These findings add important details to the complex framework of how these distinct anesthetics affect different aspects of cognition through diverse neuroanatomic targets in the brain.

Background: Few studies have assessed the dose ratio of calcium gluconate to calcium chloride or defined the time course of change in serum ionized calcium concentration after intravenous injection. Methods: In a bioequivalence (dose ratio) trial, parturients undergoing cesarean delivery were randomly assigned to receive calcium chloride (0.5 g) or calcium gluconate (1.5 or 2 g) by 10-min intravenous infusion. Venous serum ionized calcium concentration was measured before calcium infusion and approximately 5, 10, 15, 30, and 60 min after infusion start. These data were combined with serum ionized calcium concentration measurements in parturients who received 1 g calcium chloride or saline placebo in two recent clinical trials to define the pharmacokinetics of intravenous calcium over the first hour during and after drug administration. Results: The bioequivalence study enrolled 34 participants, from whom were collected 181 serum ionized calcium concentration measurements. The dose ratio of calcium gluconate to calcium chloride was 3.11 (95% CI, 2.77 to 3.48). Population pharmacokinetics of calcium were determined using 311 serum ionized calcium concentration measurements from 70 parturients. The pharmacokinetics of intravenous calcium were described by a two-compartment model with systemic clearance of 0.18 (95% CI, 0.07 to 0.27) l/min, distributional clearance of 1.25 (95% CI, 1.03 to 1.56) l/min, central volume of 10.9 (95% CI, 9.3 to 12.6) l, and peripheral volume of 16.5 (95% CI, 12.5 to 24.7) l. After adjusting for the dose ratio, calcium gluconate and calcium chloride had identical time courses. A 1-g infusion of calcium chloride resulted in a peak increase in serum ionized calcium concentration of 0.39 (0.38 to 0.42 mM), which decreased by half (29 [23 to 40] min) after initiation of the 10-min infusion. Conclusions: This study confirmed a 3:1 dose ratio of calcium gluconate to calcium chloride and estimated the pharmacokinetics over the first hour after intravenous delivery. These data inform clinical care and may guide future trials assessing calcium efficacy to reduce bleeding in obstetric patients.

Background: Nonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated transient receptor potential vanilloid subfamily member 1 agonists for analgesia after surgery. This study examines intraoperative vocacapsaicin, a novel prodrug of the transient receptor potential vanilloid subfamily member 1 agonist capsaicin, in a validated model of postsurgical pain. Methods: This was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. Patients were randomized 1:1:1:1 to surgical site administration of 14 ml of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/ml. The prespecified primary endpoint was the area-under-the-curve of the numerical rating scale pain score at rest through 96 h for the 0.30 mg/ml group. Prespecified ordered, secondary endpoints for the 0.30 mg/ml group included the percentage of patients who did not require opioids from 0 to 96 h, total opioid consumption through 96 h, and the area-under-the-curve of the numerical rating scale pain score for the first week. Results: The 147 patients were randomized. During the first 96 h, vocacapsaicin (0.30 mg/ml) reduced pain at rest by 33% versus placebo (primary endpoint, 95% CI [10%, 52%], effect size [Cohen’s d] = 0.61, P = 0.005). Of patients receiving vocacapsaicin (0.30 mg/ml), 26% did not require postoperative opioids for analgesia (P = 0.025) versus 5% of patients receiving placebo. Vocacapsaicin (0.30 mg/ml) reduced opioid consumption over the first 96 h by 50% versus placebo (95% CI [26%, 67%], effect size = 0.76, P = 0.002). Vocacapsaicin (0.30 mg/ml) reduced pain over the first week by 37% versus placebo (95% CI [12%, 57%], effect size = 0.62, P = 0.004). The treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration-versus-response relationship. Vocacapsaicin was well tolerated with no differences between groups in any safety parameter. Conclusions: A single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 h after surgery compared to control. Editor’s Perspective: What We Already Know about This Topic: What This Article Tells Us That Is New:

In their Perspective article, Bhattacharyya and Hanage (Feb. 17 issue)¹ observe that “viruses don’t inevitably evolve toward being less virulent; evolution simply selects those that excel at multiplying.” This statement assumes that the B.1.1.529 (omicron) variant evolved through natural selection as the virus passed from host to host.