Metabolomic Impact of Lidocaine on a Triple Negative Breast Cancer Cell Line.

Background: Metabolomics and onco-anesthesia are two emerging research fields in oncology. Metabolomics (metabolites analysis) is a new diagnostic and prognostic tool that can also be used for predicting the therapeutic or toxic responses to anticancer treatments. Onco-anesthesia studies assess the impact of anesthesia on disease-free and overall survival after cancer surgery. It has been shown that local anesthetics (LA), particularly lidocaine (LIDO), exert antitumor properties both in vitro and in vivo and may alter the biologic fingerprints of cancer cells. As LA are known to impair mitochondrial bioenergetics and byproducts, the aim of the present study was to assess the impact of LIDO on metabolomic profile of a breast cancer cell line. Methods: Breast cancer MDA-MB-231 cells were exposed for 4 h to 0.5 mM LIDO or vehicle (n = 4). The metabolomic fingerprint was characterized by high resolution magic angle spinning NMR spectroscopy (HRMAS). The multivariate technique using the Algorithm to Determine Expected Metabolite Level Alteration (ADEMA) (Cicek et al., PLoS Comput. Biol., 2013, 9, e1002859), based on mutual information to identify expected metabolite level changes with respect to a specific condition, was used to determine the metabolites variations caused by LIDO. Results: LIDO modulates cell metabolites levels. Several pathways, including glutaminolysis, choline, phosphocholine and total choline syntheses were significantly downregulated in the LIDO group. Discussion: This is the first study assessing the impact of LIDO on metabolomic fingerprint of breast cancer cells. Among pathways downregulated by LIDO, many metabolites are reported to be associated with adverse prognosis when present at a high titer in breast cancer patients. These results fit with the antitumor properties of LIDO and suggest its impact on metabolomics profile of cancer cells. These effects of LIDO are of clinical significance because it is widely used for local anesthesia with cutaneous infiltration during percutaneous tumor biopsy. Future in vitro and preclinical studies are necessary to assess whether metabolomics analysis requires modification of local anesthetic techniques during tumor biopsy.

Aspirin in Patients With Previous Percutaneous Coronary Intervention Undergoing Noncardiac Surgery.

Background: Uncertainty remains about the effects of aspirin in patients with prior percutaneous coronary intervention (PCI) having noncardiac surgery. Objective: To evaluate benefits and harms of perioperative aspirin in patients with prior PCI. Design: Nonprespecified subgroup analysis of a multicenter factorial trial. Computerized Internet randomization was done between 2010 and 2013. Patients, clinicians, data collectors, and outcome adjudicators were blinded to treatment assignment. (ClinicalTrials.gov: NCT01082874). Setting: 135 centers in 23 countries. Patients: Adults aged 45 years or older who had or were at risk for atherosclerotic disease and were having noncardiac surgery. Exclusions were placement of a bare-metal stent within 6 weeks, placement of a drug-eluting stent within 1 year, or receipt of nonstudy aspirin within 72 hours before surgery. Intervention: Aspirin therapy (overall trial, n = 4998; subgroup, n = 234) or placebo (overall trial, n = 5012; subgroup, n = 236) initiated within 4 hours before surgery and continued throughout the perioperative period. Of the 470 subgroup patients, 99.9% completed follow-up. Measurements: The 30-day primary outcome was death or nonfatal myocardial infarction; bleeding was a secondary outcome. Results: In patients with prior PCI, aspirin reduced the risk for the primary outcome (absolute risk reduction, 5.5% [95% CI, 0.4% to 10.5%]; hazard ratio [HR], 0.50 [CI, 0.26 to 0.95]; P for interaction = 0.036) and for myocardial infarction (absolute risk reduction, 5.9% [CI, 1.0% to 10.8%]; HR, 0.44 [CI, 0.22 to 0.87]; P for interaction = 0.021). The effect on the composite of major and life-threatening bleeding in patients with prior PCI was uncertain (absolute risk increase, 1.3% [CI, -2.6% to 5.2%]). In the overall population, aspirin increased the risk for major bleeding (absolute risk increase, 0.8% [CI, 0.1% to 1.6%]; HR, 1.22 [CI, 1.01 to 1.48]; P for interaction = 0.50). Limitation: Nonprespecified subgroup analysis with small sample. Conclusion: Perioperative aspirin may be more likely to benefit rather than harm patients with prior PCI. Primary Funding Source: Canadian Institutes of Health Research.

Impact of nitrous oxide on the haemodynamic consequences of venous carbon dioxide embolism: An experimental study.

BACKGROUND: Nitrous oxide (N2O) is still considered an important component of general anaesthesia. However, should gas embolisation occur as result of carbon dioxide (CO2) pneumoperitoneum, N2O may compromise safety, as the consequences of a gas embolus consisting of a combination of CO2 and N2O may be more severe than CO2 alone. OBJECTIVE: This experimental study was designed to compare the cardiopulmonary consequences of gas embolisation with a N2O/CO2 mixture, or CO2 alone. DESIGN: Experimental study. SETTING: Research Institute Against Digestive Cancer laboratory, Strasbourg, France. ANIMALS: Seven Large-White pigs receiving standardised inhalation anaesthesia. INTERVENTIONS: Each animal, acting as its own control, was studied in two successive experimental conditions - intravenous gas injections of 2 ml kg of 100% CO2 and 2 ml kg of a gas mixture consisting of 10% N2O and 90% CO2. MAIN OUTCOMES MEASURES: Haemodynamic and ventilatory consequences of embolisation with the gases. RESULTS: We found that the haemodynamic (heart rate, mean arterial blood pressure, central venous pressure, mean pulmonary artery pressure, pulmonary artery occlusion pressure and transoesophageal echocardiography parameters) and ventilatory (arterial oxygen saturation, end-tidal CO2 concentration and mixed venous oxygen saturation) consequences of embolisation with either 100% CO2 or 10% N2O with 90% CO2 were similar. CONCLUSION: The findings of this study may alleviate concerns that the use of N2O, as a part of a balanced general anaesthesia technique, may have greater adverse consequences should embolisation of pneumoperitoneal gas containing N2O occur.

Should the wheel be reinvented in a human study?

Recently, Zimmer and colleagues reported a lack of analgesic efficacy from intraperitoneal nebulization of bupivacaine using the Insuflow device for patients undergoing laparoscopic cholecystectomy. This is not surprising. An in vitro study in 2008 showed that hot evaporation-based devices, similar to Insuflow, are unable to transport drug molecules dissolved in a water solvent. These results are in keeping with the physical principle that hot evaporation enables only evaporation of the solvent (e.g., water) and not of the solute (e.g., bupivacaine). Although this well-conducted human study has a defendable medical justification and a high theoretical interest, it is not acceptable to choose a human model for an experimental study that attempts to explore a question whose answer has already been published years before in a bench setting.

Changes in core temperature during peritoneal insufflation: comparison of two CO2 humidification devices in pigs.

BACKGROUND: Various modifications of the physical status of CO2 have been used to reduce hypothermia caused by flow of insufflating gas. This animal study aimed to investigate the effects on core temperature, of insufflation with CO2 using two different humidification devices: unheated, humidified CO2 using the Modified-Aeroneb system (Nektar, San Carlos, CA) and warmed, humidified CO2 using the HME-Booster (Medisize, Hillegom, The Netherlands). METHODS: We undertook a prospective four-session study on a homogeneous group of four pigs. After general anesthesia, all animals were treated successively with the following protocols in a randomized order at 8-d intervals: Control (no pneumoperitoneum), Standard (unheated, unhumidified CO2), Modified-Aeroneb (unheated, humidified CO2 by cold nebulization), HME-Booster (heated, humidified CO2). The core temperature of the animals was recorded every 10 min. RESULTS: The temperature decrease is significantly influenced by time (P=0.0001; ANOVA), by the insufflation method (P=0.01), and by the interaction between time and the insufflation method (P=0.0001). The method of contrasts showed the following results:--The temperature decrease in the Standard group and HME-Booster group became greater than in the Control group after 40 min (P=0.02)--The temperature decrease in the Modified-Aeroneb group became greater than in the Control group after 100 min (P=0.04)--The temperature decrease in the Modified-Aeroneb group was less than in the HME-Booster group after 40 min (P=0.04) and less than in the Standard group after 60 min (P=0.01)--The temperature decrease in the Standard group was greater than in the HME-Booster group after 160 min (P=0.005). CONCLUSIONS: Compared with the HME-Booster system, the Modified-Aeroneb is at least as effective in limiting the drop in core temperature during laparoscopic insufflation.

An evaluation of gas humidifying devices as a means of intraperitoneal local anesthetic administration for laparoscopic surgery.

BACKGROUND: Intraperitoneal local anesthetic administration has been reported to provide perioperative analgesia during laparoscopic procedures. The aim of this in vitro study was to assess the efficiency of commercially available humidification devices to deliver ropivacaine and to determine the effects of modifying the device's position between the insufflator and the Veress needle on the amount of ropivacaine delivered. METHODS: In the first experiment, four humidification devices filled with ropivacaine (0.20% and 0.75%) were placed at the outlet of a laparoscopic insufflation system delivering a constant carbon dioxide flow. A catheter was connected to the humidifier's outlet and the other end submerged in a calibrated vial containing 25 mL of 50% methanol in water. The concentration of ropivacaine collected in the methanol-water solution was measured using high performance liquid chromatography. In the second experiment, the clinical situation was imitated by placing 3 m of silicone tubing between the humidifier and the collection vial to evaluate its influence on the amount of ropivacaine delivered. Only one humidifier was tested in the second experiment because the other three tested humidification devices did not efficiently deliver ropivacaine. RESULTS: The evaporation-based humidifiers delivered very small or nonmeasurable quantities of ropivacaine. In contrast, the microvibration-based aerosol humidification device delivered significant amounts (89.1%-94.3%) of the drug. The insertion of silicone tubing between the humidifier and the collecting vial reduced the amount of delivered ropivacaine to 62.3%. CONCLUSIONS: The microvibration-based aerosol humidification device may be used to deliver local anesthetics during laparoscopic procedures. Further research is necessary to confirm these results in clinical practice and to provide effective humidification that does not blur the surgeon's view.

Calibrated pneumoperitoneal venting to prevent N2O accumulation in the CO2 pneumoperitoneum during laparoscopy with inhaled anesthesia: an experimental study in pigs.

UNLABELLED: Nitrous oxide (N2O) accumulates in the CO2 pneumoperitoneum during laparoscopy when N2O is used as an adjuvant for inhaled anesthesia. This may worsen the consequences of gas embolism and introduce a fire risk. In this study, we quantified the pneumoperitoneal gas venting necessary to prevent significant contamination by inhaled N2O. Four domestic pigs (26-30 kg) were anesthetized and ventilated with 66% N2O in oxygen. A CO2 pneumoperitoneum was insufflated and maintained at a pressure of 12 mm Hg. Each animal underwent three experimental conditions, in random sequence, for 70 min each: 1) no pneumoperitoneal leak, 2) leak of 2 L every 10 min (12 L/h), and 3) leak of 4 L every 10 min (24 L/h). Every 10 min, pneumoperitoneal gas samples were analyzed for fractions (FPn) of N2O and CO2. Without leaks, FPnN2O increased continually and reached 29.58% +/- 3.15% at 70 min. With leaks of 2 and 4 L every 10 min (12 and 24 L/h), FPnN2O reached a plateau of <10% after 30 min. We conclude that calibrated pneumoperitoneal venting of 12 or 24 L/h is enough to prevent the constitution of potentially dangerous pneumoperitoneal gas mixtures if venting is constant. IMPLICATIONS: External venting calibrated at four or eight initial pneumoperitoneal volumes per hour with compensation by fresh CO2 is sufficient to prevent nitrous oxide buildup of more than 10% in the pneumoperitoneum during laparoscopy with inhaled general anesthesia if venting is constant.