Neutrophil extracellular trapping and angiogenesis biomarkers after intravenous or inhalation anaesthesia with or without intravenous lidocaine for breast cancer surgery: a prospective, randomised trial.

BACKGROUND: Experimental and, retrospective, clinical data indicate that anaesthetic technique might influence the risk of metastasis after cancer surgery. Neutrophil extracellular trapping (NETosis) is an immunological mechanism strongly linked with increased metastatic risk. Similarly, vascular endothelial growth factor A is linked to angiogenesis implicated in recurrence. Therefore, we investigated the effect of four anaesthetic techniques on NETosis and angiogenic factors expression in women undergoing breast cancer resection. METHODS: Women (n=120) undergoing primary breast tumour resection were randomly assigned to receive one of four anaesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Venous blood was collected before induction and 20-28 h after operation. Neutrophil myeloperoxidase and citrullinated histone H3, biomarkers of NETosis, and biomarkers of angiogenesis were measured by enzyme-linked immunosorbent assay. RESULTS: Patient characteristic data and perioperative management did not differ between study groups. The anaesthetic technique including lidocaine decreased expression of citrullinated histone H3 compared with no lidocaine (109 [23] vs 125 [22] ng ml-1, P=0.01 for SL and S and 98 [14] vs 130 [32] mg ml-1, P=0.007, for PL and P, respectively). Similarly, myeloperoxidase was decreased by lidocaine (8.5 [3.4] vs 10.8 [1.8] ng ml-1, P=0.03 for SL and S and 8.6 [3.1] vs 11.6 [2.5] ng ml-1, P=0.01 for PL and P, respectively). Lidocaine also decreased expression of matrix metalloproteinase 3 (MMP3) but not MMP9, whichever anaesthetic was used. Vascular endothelial growth factor A concentrations were not significantly influenced by the anaesthetic technique. CONCLUSIONS: I.V. perioperative lidocaine decreased postoperative expression of NETosis and MMP3, regardless of general anaesthetic technique. This supports the hypothesis that i.v. lidocaine during cancer surgery of curative intent might reduce recurrence. CLINICAL TRIAL REGISTRATION: NCT02839668.

Pain distress: the negative emotion associated with procedures in ICU patients.

PURPOSE: The intensity of procedural pain in intensive care unit (ICU) patients is well documented. However, little is known about procedural pain distress, the psychological response to pain. METHODS: Post hoc analysis of a multicenter, multinational study of procedural pain. Pain distress was measured before and during procedures (0-10 numeric rating scale). Factors that influenced procedural pain distress were identified by multivariable analyses using a hierarchical model with ICU and country as random effects. RESULTS: A total of 4812 procedures were recorded (3851 patients, 192 ICUs, 28 countries). Pain distress scores were highest for endotracheal suctioning (ETS) and tracheal suctioning, chest tube removal (CTR), and wound drain removal (median [IQRs] = 4 [1.6, 1.7]). Significant relative risks (RR) for a higher degree of pain distress included certain procedures: turning (RR = 1.18), ETS (RR = 1.45), tracheal suctioning (RR = 1.38), CTR (RR = 1.39), wound drain removal (RR = 1.56), and arterial line insertion (RR = 1.41); certain pain behaviors (RR = 1.19-1.28); pre-procedural pain intensity (RR = 1.15); and use of opioids (RR = 1.15-1.22). Patient-related variables that significantly increased the odds of patients having higher procedural pain distress than pain intensity were pre-procedural pain intensity (odds ratio [OR] = 1.05); pre-hospital anxiety (OR = 1.76); receiving pethidine/meperidine (OR = 4.11); or receiving haloperidol (OR = 1.77) prior to the procedure. CONCLUSIONS: Procedural pain has both sensory and emotional dimensions. We found that, although procedural pain intensity (the sensory dimension) and distress (the emotional dimension) may closely covary, there are certain factors than can preferentially influence each of the dimensions. Clinicians are encouraged to appreciate the multidimensionality of pain when they perform procedures and use this knowledge to minimize the patient's pain experience.

Antiproliferative and Apoptotic Effects of Lidocaine on Human Hepatocarcinoma Cells. A preliminary study.

BACKGROUND AND AIMS: It is now well documented that certain anesthetic techniques may influence long term outcome in cancer patients undergoing surgery. More recently, local anesthetics proved certain antiproliferative effects in cancer cells. In our study, we aimed to investigate if lidocaine has antiproliferative effects in human hepatocarcinoma cells and to identify possible mechanisms of these effects. METHODS: We investigated the inhibitory effect of different concentrations of lidocaine on the proliferation of cultured HepG2 human hepatocarcinoma cells and LX2 normal liver fibroblasts. Cells were exposed to nine different concentrations of lidocaine for 72h. MTT assay was used to investigate HepG2 and LX2 proliferation while Western blotting was used for detection of p53 expression level. RESULTS: Our data showed that lidocaine inhibited cell proliferation in a concentration-dependent manner in both HepG2 and LX2. The antiproliferative effects of lidocaine in LX2 were significantly diminished as compared with those in HepG2 (p< 0.001). Similarly, the expression level of p53 was significant decreased in HepG2 lines treated with lidocaine as compared with control and LX2 (p = 0.0241). CONCLUSIONS: In clinically relevant concentrations, lidocaine had significant antiproliferative effects on human hepatocarcinoma cells. These effects were time and dose-dependent. One of the possible mechanisms of these effects is by modifying the P53 expression level. The relevance of these findings in clinical practice is limited; clinical impact of these effects on the outcome of patients with hepatocarcinoma undergoing surgery or minimal invasive procedures needs to be demonstrated in future animal models and clinical studies.

The influence of total intravenous anaesthesia and isoflurane anaesthesia on plasma interleukin-6 and interleukin-10 concentrations after colorectal surgery for cancer: a randomised controlled trial.

BACKGROUND: Although it has been demonstrated that both surgery and anaesthesia induce immune suppression, it remains unclear whether there are differences between anaesthetic techniques in inducing immune suppression in cancer patients. OBJECTIVE: The aim of this present study was to compare the effects of total intravenous anaesthesia (TIVA) and isoflurane anaesthesia on plasma concentrations of interleukins IL-6 and IL-10 in patients undergoing surgery for colorectal cancer. DESIGN: A randomised, controlled, open-label study. SETTING: University hospital. PATIENTS: Seventy patients undergoing open colorectal surgery with tumour resection were randomised prospectively into one of two groups; 60 patients completed the study. INTERVENTIONS: Group 1 (n = 30) received TIVA and group 2 (n = 30) received isoflurane. Propofol infusion rate and inspired concentration of isoflurane were titrated to achieve bispectral index values of 40 to 55. MAIN OUTCOME MEASURES: Plasma concentrations of IL-6 and IL-10 were measured preoperatively, before surgical incision and at 2 and 24 h postoperatively. The area under the curve (AUC) for IL-6 and IL-10 over 24 h and plasma interleukin concentrations at each time point were compared between the groups. RESULTS: Median (range) AUC for IL-6 was 4657 (1219 to 8427) pg h ml in the TIVA group and 5349 (839 to 8126) pg h ml in the isoflurane group. For IL-10, AUC was 1165 (344 to 5258) pg h ml in the TIVA group and 1405 (463 to 8161) pg h ml in the isoflurane group. When comparing interleukin concentrations between study groups at different time intervals, there were no significant differences in plasma concentrations of IL-6 or IL-10. Intragroup comparisons revealed that IL-6 and IL-10 concentrations were significantly increased 2 and 24 h postoperatively in both groups when compared with their baseline values (P < 0.01 and P < 0.01 at 2 and 24 h for the TIVA group and isoflurane group, respectively). CONCLUSION: We found no significant differences between the effects of TIVA and isoflurane anaesthesia on plasma concentrations of IL-6 and IL-10 after colorectal cancer surgery during the first 24 h postoperatively. Further studies are needed to determine differences in long-term outcome of these patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01902849. The study was registered retrospectively.

Determinants of procedural pain intensity in the intensive care unit. The Europain® study.

RATIONALE: Intensive care unit (ICU) patients undergo several diagnostic and therapeutic procedures every day. The prevalence, intensity, and risk factors of pain related to these procedures are not well known. OBJECTIVES: To assess self-reported procedural pain intensity versus baseline pain, examine pain intensity differences across procedures, and identify risk factors for procedural pain intensity. METHODS: Prospective, cross-sectional, multicenter, multinational study of pain intensity associated with 12 procedures. Data were obtained from 3,851 patients who underwent 4,812 procedures in 192 ICUs in 28 countries. MEASUREMENTS AND MAIN RESULTS: Pain intensity on a 0-10 numeric rating scale increased significantly from baseline pain during all procedures (P < 0.001). Chest tube removal, wound drain removal, and arterial line insertion were the three most painful procedures, with median pain scores of 5 (3-7), 4.5 (2-7), and 4 (2-6), respectively. By multivariate analysis, risk factors independently associated with greater procedural pain intensity were the specific procedure; opioid administration specifically for the procedure; preprocedural pain intensity; preprocedural pain distress; intensity of the worst pain on the same day, before the procedure; and procedure not performed by a nurse. A significant ICU effect was observed, with no visible effect of country because of its absorption by the ICU effect. Some of the risk factors became nonsignificant when each procedure was examined separately. CONCLUSIONS: Knowledge of risk factors for greater procedural pain intensity identified in this study may help clinicians select interventions that are needed to minimize procedural pain. Clinical trial registered with www.clinicaltrials.gov (NCT 01070082).

The influence of a prophylactic dose of dexamethasone for postoperative nausea and vomiting on plasma interleukin concentrations after laparoscopic cholecystectomy: a randomised trial.

BACKGROUND: Little is known about the effects of small doses of dexamethasone used for the prophylaxis of postoperative nausea and vomiting on the innate host response. OBJECTIVES: We studied the influence of dexamethasone 4 mg on the perioperative plasma concentrations of interleukins after laparoscopic cholecystectomy. We hypothesised that there would be differences in pro-inflammatory interleukin concentrations in patients who received dexamethasone. DESIGN: A randomised controlled study. SETTING: University hospital. PATIENTS: Forty-six patients undergoing laparoscopic cholecystectomy under total intravenous anaesthesia were allocated randomly into one of two study groups; 42 patients completed the study. INTERVENTIONS: Patients in group 1 (dexamethasone, n = 22) received dexamethasone 4 mg and group 2 (n = 20) acted as controls. MAIN OUTCOME MEASURES: Plasma levels of tumour necrosis factor alpha and interleukins 1ß, 6, 8, 10 and 13 were measured before anaesthesia, before surgery and 2 and 24 h after surgery. The frequency and number of episodes of postoperative nausea and vomiting were recorded. RESULTS: Areas under the curve of the percentage variation of interleukins 6 and 8 were significantly lower in the dexamethasone group. There were no significant differences between groups in the areas under the curve for tumour necrosis factor alpha and interleukins 1ß, 10 and 13. The greatest variation in interleukin concentrations was 2 h postoperatively, when the concentration of interleukin 6 was greater in the control group, whereas the concentration of interleukin 10 was higher in the dexamethasone group. Twenty-four hours after surgery, only the concentration of interleukin 6 remained significantly increased in both groups (P = 0.001 and P = 0.002, respectively). There were no significant differences between groups in respect of postoperative nausea and vomiting. CONCLUSION: Prophylactic dexamethasone given before laparoscopic cholecystectomy produced a significant decrease in concentrations of interleukins 6 and 8. Further studies are needed to investigate the clinical implications of these findings.

Choice of anesthetic technique on plasma concentrations of interleukins and cell adhesion molecules.

BACKGROUND: Whether inflammatory responses to surgery are comparably activated during total intravenous anesthesia (TIVA) and during volatile anesthesia remains unclear. We thus compared the perioperative effects of TIVA and isoflurane anesthesia on plasma concentrations of proinflammatory and anti-inflammatory interleukins and cell adhesion molecules. METHODS: Patients having laparoscopic cholecystectomies were randomly allocated to two groups: 44 were assigned to TIVA and 44 to isoflurane anesthesia. IL-1ß, IL-6, IL-8, IL-10, IL-13, and the cellular adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were determined preoperatively, before incision, and at 2 and 24 hours postoperatively. Our primary outcomes were area-under-the-curve cytokine and adhesion molecule concentrations over 24 postoperative hours. RESULTS: The only statistically significant difference in area-under-the-curve concentrations was for IL-6, which was greater in patients given isoflurane:78 (95% confidence interval (CI): 52 to 109) pg/ml versus 33 (22 to 50) pg/ml, P= 0.006. Two hours after surgery, IL-6 was significantly greater than baseline in patients assigned to isoflurane: 47 (95% CI: 4 to 216, P<0.001) pg/ml versus 18 (95%CI: 4 to 374, P<0.001) pg/ml in the TIVA group. In contrast, IL-10 was significantly greater in patients assigned to TIVA: 20 (95% CI: 2 to 140, P<0.001) pg/ml versus 12 (95% CI: 3 to 126, P<0.001) pg/ml. By 24 hours after surgery, concentrations were generally similar between study groups and similar to baseline values. CONCLUSION: The only biomarker whose postoperative area-under-the-curve concentrations differed significantly as a function of anesthetic management was IL-6. Two hours after surgery, IL-6 concentrations were significantly greater in patients given isoflurane than TIVA. However, the differences were modest and seem unlikely to prove clinically important. Further studies are needed.