An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study.

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

Preload Dependence Is Associated with Reduced Sublingual Microcirculation during Major Abdominal Surgery.

BACKGROUND: Dynamic indices, such as pulse pressure variation, detect preload dependence and are used to predict fluid responsiveness. The behavior of sublingual microcirculation during preload dependence is unknown during major abdominal surgery. The purpose of this study was to test the hypothesis that during abdominal surgery, microvascular perfusion is impaired during preload dependence and recovers after fluid administration. METHODS: This prospective observational study included patients having major abdominal surgery. Pulse pressure variation was used to identify preload dependence. A fluid challenge was performed when pulse pressure variation was greater than 13%. Macrocirculation variables (mean arterial pressure, heart rate, stroke volume index, and pulse pressure variation) and sublingual microcirculation variables (perfused vessel density, microvascular flow index, proportion of perfused vessels, and flow heterogeneity index) were recorded every 10 min. RESULTS: In 17 patients, who contributed 32 preload dependence episodes, the occurrence of preload dependence during major abdominal surgery was associated with a decrease in mean arterial pressure (72 ± 9 vs. 83 ± 15 mmHg [mean ± SD]; P = 0.016) and stroke volume index (36 ± 8 vs. 43 ± 8 ml/m; P < 0.001) with a concomitant decrease in microvascular flow index (median [interquartile range], 2.33 [1.81, 2.75] vs. 2.84 [2.56, 2.88]; P = 0.009) and perfused vessel density (14.9 [12.0, 16.4] vs. 16.1 mm/mm [14.7, 21.4], P = 0.009), while heterogeneity index was increased from 0.2 (0.2, 0.4) to 0.5 (0.4, 0.7; P = 0.001). After fluid challenge, all microvascular parameters and the stroke volume index improved, while mean arterial pressure and heart rate remained unchanged. CONCLUSIONS: Preload dependence was associated with reduced sublingual microcirculation during major abdominal surgery. Fluid administration successfully restored microvascular perfusion.

Plethysmographic variability index (PVI) accuracy in predicting fluid responsiveness in anesthetized children.

INTRODUCTION: Plethysmographic Variability Index (PVI) has been shown to accurately predict responsiveness to fluid loads in adults. The goal of this study was to evaluate PVI accuracy when predicting fluid responsiveness during noncardiac surgery in children. MATERIAL AND METHODS: Children aged 2-10 years scheduled for noncardiac surgery under general anesthesia were included. PVI was assessed concomitantly with stroke volume index (SVI). A response to fluid load was defined by an SVI increase of more than 15%. A 10 ml·kg(-1) normal saline intravenous fluid challenge was administered before surgical incision and after anesthetic induction. After incision, fluid challenges were administered when SVI values decreased by more than 15% or where judged necessary by the anesthesiologist. Statistical analyses include receiving operator characteristics (ROC) analysis and the determination of gray zone method with an error tolerance of 10%. RESULTS: Fifty-four patients were included, 97 fluid challenges administered and 45 responses recorded. Area under the curve of ROC curves was 0.85 [0.77-0.93] and 0.8 [0.7-0.89] for baseline PVI and SVI values, respectively. Corresponding gray zone limits were [10-17%] and [22-31 ml·m(-2)], respectively. PVI values exhibited different gray zone limits for pre-incision and postincision fluid challenges, whereas SVI values were comparable. PVI value percentages in the gray zone were 34% overall and 44% for challenges performed after surgical incision. DISCUSSION: This study found both PVI and prechallenge SVI to be accurate when used to predict fluid load response during anesthetized noncardiac surgery in children. However, a third of recorded PVI values were inconclusive.