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.

Individualized Fluid Management Using the Pleth Variability Index: A Randomized Clinical Trial.

BACKGROUND: The present trial was designed to assess whether individualized strategies of fluid administration using a noninvasive plethysmographic variability index could reduce the postoperative hospital length of stay and morbidity after intermediate-risk surgery. METHODS: This was a multicenter, randomized, nonblinded parallel-group clinical trial conducted in five hospitals. Adult patients in sinus rhythm having elective orthopedic surgery (knee or hip arthroplasty) under general anesthesia were enrolled. Individualized hemodynamic management aimed to achieve a plethysmographic variability index under 13%, and the standard management strategy aimed to maintain a mean arterial pressure above 65 mmHg during general anesthesia. The primary outcome was the postoperative hospital length of stay decided by surgeons blinded to the group allocation of the patient. RESULTS: In total, 447 patients were randomized, and 438 were included in the analysis. The mean hospital length of stay ± SD was 6 ± 3 days for the plethysmographic variability index group and 6 ± 3 days for the control group (adjusted difference, 0.0 days; 95% CI, -0.6 to 0.5; P = 0.860); the theoretical postoperative hospital length of stay was 4 ± 2 days for the plethysmographic variability index group and 4 ± 1 days for the control group (P = 0.238). In the plethysmographic variability index and control groups, serious postoperative cardiac complications occurred in 3 of 217 (1%) and 2 of 224 (1%) patients (P = 0.681), acute postoperative renal failure occurred in 9 (4%) and 8 (4%) patients (P = 0.808), the troponin Ic concentration was more than 0.06 µg/l within 5 days postoperatively for 6 (3%) and 5 (2%) patients (P = 0.768), and the postoperative arterial lactate measurements were 1.44 ± 1.01 and 1.43 ± 0.95 mmol/l (P = 0.974), respectively. CONCLUSIONS: Among intermediate-risk patients having orthopedic surgery with general anesthesia, fluid administration guided by the plethysmographic variability index did not shorten the duration of hospitalization or reduce complications.

Tolerance and efficacy of a polyamine-deficient diet for the treatment of perioperative pain.

BACKGROUND: Polyamines have been identified as pain agonists and interact with N-methyl-D-aspartate receptors. A prospective, randomized, multicenter, and blinded phase II clinical trial was conducted to evaluate a polyamine-deficient diet for the treatment of perioperative pain in patients during spinal surgery. METHODS: All analyses followed the intention-to-treat principle. The trial was designed to evaluate the dose-ranging effect of a low polyamine diet with respect to a total (group 1) or partial (group 2) polyamine diet on perioperative pain (7 d before and 5 d after surgery). Pain (numerical scale at rest and motion), quality of life questionnaires (Brief Pain Inventory, EIFEL questionnaire, and Short Form-12 acute questionnaire), and tolerance of and compliance with the nutritional program were measured. RESULTS: Compliance (preoperatively: 100% in group 1 and 83% in group 2; postoperatively: 83% in group 1 and 71% in group 2) and tolerance were good. After 7 d following the diet before surgery, decreased pain was observed in group 1 whereas no effect was observed in group 2 (P = 0.144). This analgesic effect became significant in group 1 in the subgroup of patients with initial high levels of pain (NS ≥ 4) at rest (P = 0.03) and during motion (P = 0.011). Quality of life was significantly improved in group 1 (P = 0.0465). In the postoperative period, pain was significantly decreased in group 1 compared to group 2 at rest (P = 0.022) and during motion (P = 0.029). The effect was significantly better on patients with higher initial pain both at rest (P = 0.013) and during motion (P = 0.005) in group 1 compared to group 2. CONCLUSION: Suppression of polyamines from the diet offers a nutrition-based treatment option for perioperative pain reduction independent of and complementary to typical analgesic approaches.

A targeted remifentanil administration protocol based on the analgesia nociception index during vascular surgery.

BACKGROUND: The intraoperative modulation of opioids continues to be based on clinical signs. This may result in adverse events such as sympathetic reactivity or opioid-induced hyperalgesia. Recently, the Analgesia/Nociception Index (ANI), a non-invasive 0-100 index derived from heart rate variability analysis, has been proposed for nociception assessment. However, the ability of the ANI to adequately guide intraoperative opioid administration has never been demonstrated. We designed a prospective study to evaluate the ability of the ANI to guide remifentanil administration in vascular surgery. METHODS: One hundred and eighty adults presenting for elective surgery were included. All received total intravenous anaesthesia with propofol adjusted to entropy and remifentanil adjusted to the ANI. The primary endpoint was the number of patients without any episode of reactivity defined as a 20% increase in heart rate or arterial pressure or the occurrence of movement. Secondary endpoints included opioid use and maximal pain rate in the first postoperative day. RESULTS: Anaesthesia was achieved without any episode of reactivity in 160 (89%) patients. Twenty-five episodes of reactivity occurred in 20 (11%) patients. The median remifentanil dose was 0.042 [0.040-0.044]µg.kg-1.min-1. At 24hours, the maximal NRS pain score was 2 [2,3]. One hundred and fifty-five patients (86%) did not receive any postoperative opioids, whereas 25 (14%) received a median dose of 5[5-10] mg of oxycodone. CONCLUSION: This prospective study demonstrated that the ANI can be used to adequately guide intraoperative remifentanil administration during vascular surgery. Such guidance resulted in low remifentanil consumption, low postoperative pain rates and low opioid rescue analgesia.

The OPVI trial - perioperative hemodynamic optimization using the plethysmographic variability index in orthopedic surgery: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Hemodynamic optimization during surgery is of major importance to decrease postoperative morbidity and length of hospital stay. However, conventional cardiac output monitoring is rarely used at the bedside. Recently, the plethysmographic variability index (PVI) was described as a simplified alternative, using plug-and-play noninvasive technology, but its clinical utility remains to be established. METHODS/DESIGN: The hemodynamic optimization using the PVI (OPVI) trial is a multicenter randomized controlled two-arm trial, randomizing 440 patients at intermediate risk of postoperative complications after orthopedic surgery. Hemodynamic optimization was conducted using either the PVI (PVI group) or conventional mean arterial pressure (control group). The anesthesiologist performed the randomization the day before surgery using an interactive web response system, available 24 hours a day, 7 days a week. The randomization sequence was generated using permutated blocks and stratified by center and type of surgery (knee or hip arthoplasty). Patients and surgeons, but not anesthesiology staff, were blinded to the allocation group. The primary outcome measure is the length of hospital stay following surgery. The attending surgeon, who was blinded to group assessment, determined hospital discharge. Secondary outcome measures are theoretical length of hospital stay, determined using a dedicated discharge-from-hospital checklist, postoperative arterial lactate level in the recovery room, postoperative troponin level, presence of serious postoperative cardiac complications, and postoperative acute kidney insufficiency. DISCUSSION: The OPVI trial is the first multicenter randomized controlled study to investigate whether perioperative hemodynamic optimization using PVI during orthopedic surgery could decrease the length of hospital stay and postoperative morbidity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02207296 .

Hemodynamic effects of positive end-expiratory pressure during abdominal hyperpression: a preliminary study in healthy volunteers.

PURPOSE: An increase in abdominal pressure induces an increase in left ventricular afterload under clinical conditions. We tested the hypothesis that positive end-expiratory pressure (PEEP) could reverse the hemodynamic consequences of abdominal hyperpression by opposing the increase in left ventricular afterload. MATERIALS AND METHODS: Eight healthy volunteers were investigated during 3 experimental conditions: (1) baseline, (2) increase in abdominal pressure by means of medical antishock trousers (MAST) inflation, and (3) addition of PEEP +10 cm H(2)O. Heart loading conditions and left ventricular systolic and diastolic function were assessed by transthoracic echocardiography. RESULTS: The application of PEEP significantly reduced the prior increase in end-systolic wall stress: 45 ± 11 vs 55 ± 14 kdyn/cm(2), P < .05. Medical antishock trousers inflation significantly altered the deceleration time of mitral E wave: 199 ± 23 vs 156 ± 38 milliseconds, P < .05. Left ventricular preload and global systolic performance were unaffected by MAST and PEEP applications. CONCLUSIONS: The increase in left ventricular afterload induced by MAST inflation can be efficiently reduced by the use of a moderate PEEP. Potential clinical applications in the abdominal compartment syndrome or in the setting of laparoscopic surgery should be developed.

The prognostic value of B-type natriuretic peptide after cardiac surgery: a comparative study between coronary artery bypass graft surgery and aortic valve replacement.

OBJECTIVES: The influence of the cardiac surgical procedure on B-type natriuretic peptide (BNP) for the identification of high-risk patients has not been evaluated. This study aimed to compare the prognostic utility of pre- and postoperative BNP in predicting adverse long-term outcome after coronary artery bypass graft (CABG) surgery and aortic valve replacement (AVR). DESIGN: A retrospective study. SETTING: A university teaching hospital. PARTICIPANTS: One hundred eighty-nine patients. MEASUREMENTS AND MAIN RESULTS: Preoperative, early postoperative (24 hours), and late postoperative (day 5) BNP levels were measured. Major adverse cardiac events (MACEs) within 12 months after surgery were chosen as study endpoints. The predictive abilities of BNP measurements were compared using receiver operating characteristic (ROC) curves. Patients were stratified by CABG surgery (n = 100) and AVR (n = 89). Thirty-four (18%) patients experienced 44 MACEs over the study period. Preoperative BNP values were significantly different between groups. Postoperative BNP gradually increased by 431% on day 5 after CABG surgery and by 100% after AVR (both p < 0.001 v preoperative values). Pre- and early postoperative BNP values were accurate in predicting MACEs after AVR (areas under the ROC curves: 0.78 [95% confidence interval, 0.66-0.90] and 0.76 [95% confidence interval, 0.62-0.89], respectively) and inaccurate after CABG surgery (0.54 [95% confidence interval, 0.38-0.70] and 0.54 [95% confidence interval, 0.36-0.73], respectively). The late postoperative BNP value was of limited value. CONCLUSIONS: BNP measurements should take into account the type of cardiac surgery. Whatever the time of measurement, BNP accurately predicts long-term adverse outcome in valve surgery patients. A late postoperative BNP measurement is useless after cardiac surgery.

Combination of EuroSCORE and cardiac troponin I improves the prediction of adverse outcome after cardiac surgery.

BACKGROUND: Reclassification tables have never been used to compare concentrations of cardiac troponin I (cTnI) with predictive models of risk in the perioperative setting. The current study aimed to evaluate the prognostic value of pre- and/or postoperative serum cTnI when combined with The European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting adverse outcome after cardiac surgery. METHODS: Nine hundred five consecutive patients were included. Standard EuroSCORE as well as preoperative and 24-h postoperative cTnI were measured in all patients. Major adverse cardiac events and in-hospital mortality were chosen as study endpoints. The performance of EuroSCORE with and without pre- and/or postoperative cTnI were assessed by means of receiver operating characteristic curves, net reclassification index, and integrated discrimination improvement analyses. Data are expressed as ±SD. RESULTS: Death occurred in 28 of 905 (3%) patients and major adverse cardiac events in 202/905 (22%) patients. Models including EuroSCORE alone were characterized by a low discriminative power (c-index = 0.60 ± 0.05) in predicting major adverse cardiac events. The c-index increased to 0.61 ± 0.05 (P = 0.46), 0.70 ± 0.04 (P < 0.001), and 0.71 ± 0.04 (P < 0.001) when preoperative, postoperative, and pre/postoperative cTnI were included, respectively. The better predictive ability was confirmed by net reclassification index (0.41 ± 0.08, P < 0.001; 0.67 ± 0.08, P < 0.001; and 0.68 ± 0.08, P < 0.001, respectively) and integrated discrimination improvement (0.003 ± 0.002, P = 0.12; 0.099 ± 0.015, P < 0.001; and 0.094 ± 0.016, P < 0.001, respectively). Similar results were observed for in-hospital mortality. CONCLUSIONS: The combination of EuroSCORE and postoperative cTnI provides the best discriminative power and performance in predicting adverse outcome after cardiac surgery and is suggested as being an effective model that improves early identification of high-risk patients.

Does preoperative B-type natriuretic peptide better predict adverse outcome and prolonged length of stay than the standard European System for Cardiac Operative Risk Evaluation after cardiac surgery?

OBJECTIVES: Although B-type natriuretic peptide (BNP) strongly predicts cardiac morbidity and mortality, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) has a modest predictive value to identify a composite operative risk after cardiac surgery. The authors tested the hypothesis that a single preoperative BNP measurement would be superior to standard EuroSCORE in predicting composite adverse outcomes after cardiac surgery. DESIGN: A prospective observational study. SETTING: A teaching university hospital. PARTICIPANTS: Two hundred eight adult patients. INTERVENTIONS: Conventional cardiac surgery with cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: The preoperative additive EuroSCORE and BNP measurement were performed in all patients. Postoperative nonfatal major adverse cardiac events (malignant ventricular arrhythmia, myocardial infarction, and cardiac dysfunction), all-cause mortality, and prolonged lengths of stay were chosen as study endpoints. Predictive abilities of both EuroSCORE and BNP were assessed using logistic regression and compared with receiver operating characteristic (ROC) curves. Thirty-six (17%, 95% confidence interval [CI], 12%-22%) patients experienced 49 events over the study period. The areas under the ROC curves assessing the utility of EuroSCORE and BNP in predicting adverse outcome and prolonged in-hospital stay were 0.59 (95% CI, 0.48-0.69) versus 0.76 (95% CI, 0.68-0.85; p < 0.001) and 0.65 (95% CI, 0.57-0.74) versus 0.71 (95% CI, 0.63-0.80; p = 0.147), respectively. Using logistic regression, BNP considered as a dichotomized variable was the only independent predictor of adverse cardiac outcome (adjusted odds ratio = 10.7; 95% CI, 4.1-27.8; p < 0.001). CONCLUSIONS: Preoperative BNP measurement is a strong, independent, and more accurate predictor of adverse outcome than EuroSCORE in patients undergoing cardiac surgery. BNP could be considered as a simple and objective tool for the detection of high-risk patients after cardiac surgery.

Comparison of minithoracotomy and conventional sternotomy approaches for valve surgery.

OBJECTIVE: To compare patients undergoing valve surgery through a minithoracotomy approach with a matched group undergoing conventional valve surgery. DESIGN: Control study. SETTING: University hospital, single center. PARTICIPANTS: Forty-one consecutive patients scheduled for valve surgery by minithoracotomy approach were matched with a similar group of patients operated on by the sternotomy approach. INTERVENTIONS: Criteria for matching included type of valve procedure (aortic valve replacement or mitral valve repair), age, surgeons, and left ventricular function. Two surgeons performed the surgical procedures. Perioperative care was standardized for all patients. Operative and postoperative data were recorded. MEASUREMENTS AND MAIN RESULTS: The 41 pairs of patients were correctly matched, except for left ventricular function (n = 1). Twenty patients underwent mitral valve repair and 62 aortic valve replacement. Preoperative demographic data and clinical characteristics were similar in both groups. Cardiopulmonary bypass, aortic clamping, and surgery times were longer in the minithoracotomy group (p < 0.05). In 3 patients, the minithoracotomy approach had to be converted into a sternotomy during the surgical procedure for better visualization. Minithoracotomy patients had significantly increased postoperative total blood loss (p < 0.05). No difference was found between the groups for extubation time and intensive care or in-hospital lengths of stay. CONCLUSION: These results suggest that valve surgery is feasible in many cases through minithoracotomy. Nevertheless, this approach increases surgical complexity and in this comparative study no significant benefit was shown.