Impact of CYP2D6 and CYP2B6 phenotypes on the response to tramadol in patients with acute post-surgical pain.

Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized ß coefficients = 0.386 and 0.346, R2 = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized ß coefficient = 0.224, R2 = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response.

The effect of immediate postoperative Boussignac CPAP on adverse pulmonary events after thoracic surgery: A multicentre, randomised controlled trial.

BACKGROUND: The effectiveness of prophylactic continuous positive pressure ventilation (CPAP) after thoracic surgery is not clearly established. OBJECTIVE: The aim of this study was to assess the effectiveness of CPAP immediately after lung resection either by thoracotomy or thoracoscopy in preventing atelectasis and pneumonia. DESIGN: A multicentre, randomised, controlled, open-label trial. SETTINGS: Four large University hospitals at Madrid (Spain) from March 2014 to December 2016. PATIENTS: Immunocompetent patients scheduled for lung resection, without previous diagnosis of sleep-apnoea syndrome or severe bullous emphysema. Four hundred and sixty-four patients were assessed, 426 were randomised and 422 were finally analysed. INTERVENTION: Six hours of continuous CPAP through a Boussignac system versus standard care. MAIN OUTCOME MEASURES: Primary outcome: incidence of the composite endpoint 'atelectasis + pneumonia'. Secondary outcome: incidence of the composite endpoint 'persistent air leak + pneumothorax'. RESULTS: The primary outcome occurred in 35 patients (17%) of the CPAP group and in 58 (27%) of the control group [adjusted relative risk (ARR) 0.53, 95% CI 0.30 to 0.93]. The secondary outcome occurred in 33 patients (16%) of the CPAP group and in 29 (14%) of the control group [ARR 0.92, 95% CI 0.51 to 1.65]. CONCLUSION: Prophylactic CPAP decreased the incidence of the composite endpoint 'postoperative atelectasis + pneumonia' without increasing the incidence of the endpoint 'postoperative persistent air leaks + pneumothorax'.

Oxygen Reserve Index Predicts Hypoxemia During One-Lung Ventilation: An Observational Diagnostic Study.

OBJECTIVE: To determine the accuracy of the Oxygen Reserve Index (ORi) to predict hypoxemia during one-lung ventilation (OLV). DESIGN: An observational diagnostic test study. SETTING: A tertiary care teaching hospital. PARTICIPANTS: Forty consecutive patients scheduled for thoracic surgery with OLV. MEASUREMENTS AND MAIN RESULTS: Patients were ventilated with tidal volumes of 8 mL/kg ideal body weight during two-sided ventilation and 6 mL/kg during OLV, and with fraction of inspired oxygen (FIO2) of 60%. ORi was measured continuously. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and accuracy were calculated for ORi = 0 in different phases of anesthesia. Hypoxemia during OLV was defined as SpO2 < 90%. Hypoxemia owing to malpositioning of the double lumen tube was an exclusion criterion. ORi = 0 five minutes after tracheal intubation in the supine position showed a sensitivity of 63.6% (confidence interval [CI] 95% 31.6-87.6), specificity of 93.1% (95% CI 75.8-98.8), and an accuracy of 85.0% (95% CI 69.5-93.8). The rate of hypoxemia was 27.5% (95% CI 15.14-44.14). CONCLUSIONS: An ORi value equal to zero, 5 minutes after the onset of mechanical ventilation in the supine position, predicts the development of hypoxemia during OLV. These findings may be helpful to adjust FIO2 individually in patients undergoing OLV and to avoid unnecessary high concentrations of oxygen.

Effects of oxygen on post-surgical infections during an individualised perioperative open-lung ventilatory strategy: a randomised controlled trial.

BACKGROUND: We aimed to examine whether using a high fraction of inspired oxygen (FIO2) in the context of an individualised intra- and postoperative open-lung ventilation approach could decrease surgical site infection (SSI) in patients scheduled for abdominal surgery. METHODS: We performed a multicentre, randomised controlled clinical trial in a network of 21 university hospitals from June 6, 2017 to July 19, 2018. Patients undergoing abdominal surgery were randomly assigned to receive a high (0.80) or conventional (0.3) FIO2 during the intraoperative period and during the first 3 postoperative hours. All patients were mechanically ventilated with an open-lung strategy, which included recruitment manoeuvres and individualised positive end-expiratory pressure for the best respiratory-system compliance, and individualised continuous postoperative airway pressure for adequate peripheral oxyhaemoglobin saturation. The primary outcome was the prevalence of SSI within the first 7 postoperative days. The secondary outcomes were composites of systemic complications, length of intensive care and hospital stay, and 6-month mortality. RESULTS: We enrolled 740 subjects: 371 in the high FIO2 group and 369 in the low FIO2 group. Data from 717 subjects were available for final analysis. The rate of SSI during the first postoperative week did not differ between high (8.9%) and low (9.4%) FIO2 groups (relative risk [RR]: 0.94; 95% confidence interval [CI]: 0.59-1.50; P=0.90]). Secondary outcomes, such as atelectasis (7.7% vs 9.8%; RR: 0.77; 95% CI: 0.48-1.25; P=0.38) and myocardial ischaemia (0.6% [n=2] vs 0% [n=0]; P=0.47) did not differ between groups. CONCLUSIONS: An oxygenation strategy using high FIO2 compared with conventional FIO2 did not reduce postoperative SSIs in abdominal surgery. No differences in secondary outcomes or adverse events were found. CLINICAL TRIAL REGISTRATION: NCT02776046.

Effects of neuromuscular block reversal with sugammadex versus neostigmine on postoperative respiratory outcomes after major abdominal surgery: a randomized-controlled trial.

PURPOSE: Postoperative pulmonary complications may be better reduced by reversal of neuromuscular block with sugammadex than by reversal with neostigmine because the incidence of residual block after sugammadex application is lower and diaphragm function is less impaired than after neostigmine administration. The aim of the study was to compare the effect of reversal of neuromuscular block with sugammadex or neostigmine on lung function after major abdominal surgery. METHODS: One hundred and thirty adults scheduled for major abdominal surgery under combined general and epidural anesthesia were randomly allocated to receive 40 µg of neostigmine or 4 mg·kg-1 of sugammadex to reverse neuromuscular block. Two blinded researchers performed spirometry and lung ultrasound before the surgery, as well as 1 hr and 24 hr postoperatively. Differences in mean changes from baseline were analyzed with repeated measures analysis of variance. Forced vital capacity (FVC) loss one hour after surgery was the main outcome. Secondary outcomes were differences in rate and size of atelectasis one hour and 24 hr after surgery. RESULTS: One hundred twenty-six patients were included in the main analysis. In the neostigmine group (n = 64), mean (95% confidence interval [95% CI]) reduction in FVC after one hour was 0.5 (0.4 to 0.6) L. In the sugammadex group (n = 62), the mean (95% CI) reduction in FVC during the first hour was 0.5 (95% CI, 0.3 to 0.6) L. Thirty-nine percent of patients in the neostigmine group and 29% in the sugammadex group had visible atelectasis. Median [interquartile range (IQR)] atelectasis area was 9.7 [4.7-13.1] cm2 and 6.8 [3.6-12.5] cm2, respectively. CONCLUSION: We found no differences in pulmonary function in patients reversed with sugammadex or neostigmine in a high-risk population. TRIAL REGISTRATION: EudraCT 2014-005156-26; registered 27 May, 2015.

Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects.

Fentanyl is an agonist of the µ-opioid receptor commonly used in the treatment of moderate-severe pain. In order to study whether pharmacogenetics explains some of the variability in the response to fentanyl, several genes related to fentanyl receptors, transporters and metabolic enzymes have been analysed. Thirty-five healthy volunteers (19 men and 16 women) receiving a single 300 µg oral dose of fentanyl were genotyped for 9 polymorphisms in cytochrome P450 (CYP) enzymes (CYP3A4 and CYP3A5), ATP-binding cassette subfamily B member 1 (ABCB1), opioid receptor mu 1 (OPRM1), catechol-O-methyltransferase (COMT) and adrenoceptor beta 2 (ADRB2) by real-time PCR. Fentanyl concentrations were measured by ultra-performance liquid chromatography combined with tandem mass spectrometry (UPLC-MS/MS). Fentanyl pharmacokinetics is affected by sex. Carriers of the CYP3A4*22 allele, which is known to reduce the mRNA expression, showed higher area under the concentration-time curve (AUC) and lower clearance (Cl) values. Although this finding might be of importance, its validity needs to be confirmed in other similar settings. Furthermore, carriers of the ABCB1 C1236T T/T genotype presented a lower AUC and higher Cl, as well as lower half-life (T1/2 ). As volunteers were blocked with naltrexone, the effect of fentanyl on pharmacodynamics might be biased; however, we could observe that fentanyl had a hypotensive effect. Moreover, ADRB2 C523A A allele carriers showed a tendency towards reducing systolic blood pressure. Likewise, OPRM1 and COMT minor allele variants were risk factors for the development of somnolence. CYP3A5*3, ABCB1 C3435T and ABCB1 G2677T/A were not associated with fentanyl's pharmacokinetics, pharmacodynamics and safety profile.

Characterization of occupational sensitization by multiallergen immunoblotting in workers exposed to laboratory animals.

BACKGROUND: Studies have estimated that 10% to 23% of workers exposed to laboratory animals report symptoms of laboratory animal allergy. OBJECTIVES: To determine the level of occupational sensitization in workers exposed to laboratory animals and to develop a diagnosis system based on a multiallergen IgE immunoblot. METHODS: A total of 75 workers exposed to laboratory animals were initially studied with skin prick tests performed with animal epithelia extracts. The workers with suspected occupational disease and positive skin prick test results were further studied with the ImmunoCAP system to determine specific IgE levels to urine and epithelia allergens and with multiallergen IgE immunoblotting to detect specific IgE levels to epithelia allergens and bovine serum albumin. RESULTS: Twenty of the 75 workers were studied with ImmunoCAP and multiallergen IgE immunoblotting. Nine were polysensitized and 3 were sensitized to only one animal. The results obtained by ImmunoCAP and multiallergen IgE immunoblotting were concordant except for in 3 workers, who had low or negative values of specific IgE determined by ImmunoCAP but positive allergen detections by immunoblotting. On the basis of the results of the study and the clinical symptoms related by workers, 16% were diagnosed as having occupational allergy. CONCLUSIONS: Multiallergen immunoblotting by means of a unique test offers a graphic representation of sensitization to the different animals to which workers are exposed, providing additional information on the clinical symptoms caused by the involved allergens. The results presented suggest that this system can improve the diagnosis of laboratory animal allergy by obtaining a sensitization profile for each exposed worker.

Occupational sensitization to fungal enzymes used in animal feed industry.

BACKGROUND: Industrial enzymes cause the increasing prevalence of occupational hypersensitivity. Our objective was to study workers occupationally exposed to fungal enzymes in 2 animal feed factories to determine if the sensitization originated in the enzymes or was caused by the microorganism used to produce the enzymes. METHODS: Eighty-six consenting workers were studied by skin prick tests with extracts from the enzymatic products handled in their factories. Positive workers were then studied by IgE immunoblotting and basophil activation was measured by flow cytometry. RESULTS: Eight of the 86 workers analysed (9%) tested positive and were more frequently sensitized to phytase from Trichoderma and Peniophora. Glucanase and alpha-amylase from Bacillus amyloliquefaciens did not cause sensitization in any worker. No cross-reactions were observed between Trichoderma and Peniophora sp. phytases. Workers were sensitized to the product that they handled. CONCLUSIONS: Fungal enzymes cause occupational hypersensitivity in animal feed industries. Immunoblotting and basophil activation are useful to evaluate the effects of handling enzymes as part of the medical surveillance of enzyme-exposed workers. We describe Peniophora sp. 6-phytase as a new allergen and enzymes from Trichoderma as strong sensitizers.