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Background: Breast cancer is the most common malignancy in women. Surgery remains the most effective treatment. Several perioperative factors, including the surgical stress response, many anesthetics and opioids, adversely affect immune function. Regional anesthesia-analgesia attenuates perioperative immunosuppression. We tested the hypothesis that patients who receive combined propofol/paravertebral anesthesia-analgesia (propofol/paravertebral) exhibited reduced levels of protumorigenic cytokines and matrix metalloproteinases (MMPs) and elevated levels of antitumorigenic cytokines compared with patients receiving sevoflurane anesthesia with opioid analgesia (sevoflurane/opioid). Methods: Primary breast cancer surgery patients were randomized to propofol/paravertebral (n = 15) or sevoflurane/opioid (n = 17) and preoperative and postoperative serum concentrations of 11 cytokines (interleukin 1β [IL-1β], IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon γ, and tumor necrosis factor α) and 3 MMPs (MMP-1, MMP-3, and MMP-9) were measured. Results: Treatment groups were well balanced for age, weight, surgical procedure, and cancer pathologic diagnosis. Pain scores were lower at 1 and 2 hrs with paravertebral analgesia compared with morphine but similar at 24 hrs. Patients in the propofol/paravertebral group showed a greater percentage decrease in postoperative compared with preoperative IL-1β (median [quartiles], −26% [−15% to −52%] versus −4% [−14% to 2%], P = 0.003), a significant attenuation in elevated MMP-3 (2% [−39% to 12%] versus 29% [23%-59%], P = 0.011) and MMP-9 (26% [13%-54%] versus 74% [50%-108%], P = 0.02), and a significant increase in IL-10 (10% [5%-33%] versus −15% [20% to −2%], P = 0.001) compared with sevoflurane/opioid group. No significantly different changes in IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13, interferon γ, tumor necrosis factor α, or MMP-1 were observed between the 2 groups. Conclusions: Propofol/paravertebral anesthesia-analgesia for breast cancer surgery alters a minority of cytokines influential in regulating perioperative cancer immunity. Further evaluation is required to determine the significance of these observations.

Background Regional anesthesia and analgesia attenuate or prevent perioperative factors that favor minimal residual disease after removal of the primary carcinoma. Therefore, the authors evaluated prostate cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia or general anesthesia with postoperative opioid analgesia. Methods In a retrospective review of medical records, patients with invasive prostatic carcinoma who underwent open radical prostatectomy between January 1994 and December 2003 and had either general anesthesia-epidural analgesia or general anesthesia-opioid analgesia were evaluated through October 2006. The endpoint was an increase in postoperative prostate-specific antigen. Results After adjusting for tumor size, Gleason score, preoperative prostate-specific antigen, margin, and date of surgery, the epidural plus general anesthesia group had an estimated 57% (95% confidence interval, 17-78%) lower risk of recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.43 (95% confidence interval, 0.22-0.83; P = 0.012) in a multivariable Cox regression model. Gleason score and tumor size (percent of prostate involved) were also independent predictors of recurrence (hazards ratios of 1.19 [1.08, 1.52], P = 0.004, and 1.17 [1.03, 1.34] for 10% size difference, P = 0.01, respectively). A similar association between epidural use and recurrence was obtained by comparing patients matched on the propensity to receive epidural versus general anesthesia. Conclusions Open prostatectomy surgery with general anesthesia, substituting epidural analgesia for postoperative opioids, was associated with substantially less risk of biochemical cancer recurrence. Prospective randomized trials to evaluate this association seem warranted.

Background and Objectives: There is little knowledge of the pharmacokinetics of local anesthetics and adjunctive analgesics after paravertebral blockade. We evaluated the pharmacokinetics of low-dose levobupivacaine, fentanyl, and clonidine after paravertebral analgesia for breast surgery. Methods: Thirty-eight patients receiving paravertebral analgesia for breast surgery received a 19-mL paravertebral bolus of levobupivacaine 0.25% combined with a 1-mL volume of saline (group L, 13 patients), fentanyl 50 μg (group LF, 13 patients), or clonidine 150 μg (group LC, 12 patients) followed 1 hour later by infusion of levobupivacaine 0.1% (L), levobupivacaine 0.05% with fentanyl 4 μg/mL (LF), or levobupivacaine 0.05% with clonidine 3 μg/mL (LC), respectively. Plasma concentrations of study drugs were determined at intervals up to 24 hours after bolus injection. Results: There was rapid absorption of levobupivacaine after bolus with mean (standard deviation) maximum plasma concentration (Cpmax) of 0.51(0.24) μg/mL in a median time to maximum concentration tCpmax of 15 minutes. Mean Cpmax fentanyl and clonidine after bolus were 0.62 (0.37) and 0.79 (0.23) ng/mL, in a median tCpmax of 15 and 22.5 minutes, respectively. Mean Cpmax levobupivacaine after infusion was 0.47 (0.41) μg/mL in a median tCpmax of 24 hours. There was progressive accumulation of fentanyl and clonidine at 24 hours with a mean Cpmax of 0.72 (0.33) and 1.74 (0.70) ng/mL, respectively. Conclusions: After paravertebral bolus and infusion administration, Cpmax levobupivacaine was within the safe range. Cpmax fentanyl and clonidine were less than the effective levels after IV administration, suggesting that their analgesic effect may be partly attributed to a peripheral mechanism of action.

The addition of fentanyl or clonidine to levobupivacaine was evaluated in patients undergoing breast surgery under general anaesthesia with intra- and postoperative paravertebral analgesia. Patients were randomly allocated to four groups: Group L received 19 ml bolus levobupivacaine 0.25% plus 1 ml saline followed by an infusion of levobupivacaine 0.1%; Group LF received 19 ml bolus levobupivacaine 0.25% plus fentanyl 50 microg followed by an infusion of levobupivacaine 0.05% with fentanyl 4 microg x ml(-1); Group LC received 19 ml bolus levobupivacaine 0.25% plus clonidine 150 microg followed by an infusion of levobupivacaine 0.05% with clonidine 3 microg x ml(-1); Group C (control) received general anaesthesia without paravertebral analgesia. All groups received postoperative i.v. morphine patient controlled analgesia (PCA). Although mean (SD) postoperative PCA morphine consumption was decreased in LF [7.9 (4.1) mg] and LC [5.9 (3.5) mg]vs L [27.7 (8.6) mg] or C patients [21.7 (5.5) mg], p < 0.01, paravertebral fentanyl and clonidine were associated with significantly increased vomiting and hypotension, respectively.

Postoperative nausea and vomiting is common after cardiac surgery and may contribute to significant morbidity. Gastric decompression during anesthesia has been used for postoperative nausea and vomiting prophylaxis in shorter duration noncardiac surgery with conflicting results. We tested the hypothesis that gastric decompression during elective coronary revascularization surgery with cardiopulmonary bypass and continued afterwards until tracheal extubation would reduce the incidence of vomiting or retching and nausea. In a prospective, randomized, cohort study, 104 patients with at least 2 Apfel's risk factors for postoperative nausea and vomiting were allocated to receive a gastric tube on free gravity drainage after induction of anesthesia (n = 52) or to a control group (n = 52). The gastric tube was removed simultaneously with tracheal extubation postoperatively. The primary outcome measure was the incidence of vomiting or retching. Secondary outcomes included the incidence and severity of nausea measured on a visual analog scale. The incidence of vomiting or retching was 13.4% in patients with gastric decompression, compared with 11.5% in the control group (P = 0.7). Similarly, there was no statistically significant difference between the two groups in the incidence of nausea (32.7% versus 25.0%, P = 0.6), median severity of nausea on a visual analog scale at 12 h (25; range, 0-55 mm versus 30; range, 0-60 mm, P = 0.4), or antiemetics administration (38.5% versus 28.8%, P = 0.3). Continuous gastric decompression during coronary revascularization surgery and afterwards until tracheal extubation did not reduce the incidence of vomiting or retching or the incidence and severity of nausea in these patients.

Postoperative cognitive dysfunction (POCD) is evident in 26% of elderly patients seven days after major non-cardiac surgery. Despite the growing popularity of day surgery, the influence of anesthetic techniques on next day POCD has not been investigated. Therefore, we evaluated the incidence of POCD and changes in serum markers of neuronal damage (S-100ss protein and Neuron-Specific Enolase), 24 hr after single-agent propofol or sevoflurane anesthesia in elderly patients undergoing minor surgery.Patients (n = 30, mean age 73, range 65-86 yr) coming for cystoscopy or hysteroscopy, were randomized, in an observer-blind design, to receive either single-agent propofol or sevoflurane anesthesia. Changes in neuropsychological tests (the Stroop test and the modified Word-Recall Test), 24 hr postoperatively were compared with age-matched control subjects (n = 15) using Z-score analysis. Changes in S-100beta protein and Neuron-Specific Enolase levels were also documented.POCD was present in 7/15 [47% (95% confidence interval (CI) 21 to 72%)] patients who received propofol and 7/15 [47% (95% CI 21 to 72%)] patients who received sevoflurane, compared with 1/15 [7% (95% CI 6 to 19%)] control patients, P = 0.03. S-100beta protein and Neuron-Specific Enolase levels were not significantly different in anesthetized patients postoperatively compared with preoperative values.The incidence of POCD in elderly patients on the first day after minor surgery is higher than previously reported for seven days after major surgery, and is increased after both propofol and sevoflurane anesthesia, compared with age-matched controls. S-100beta protein and Neuron-Specific Enolase levels were unaffected by anesthetic technique.

UNLABELLED Halothane affects synaptic transmission in the rat hippocampus with a 50% effective dose (ED50) correlating with clinical figures for minimum alveolar anesthetic concentration (MAC). Halothane dose-dependently suppresses glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs) in the rat hippocampus. It also inhibits voltage-gated Na+ channels. The anticonvulsant lamotrigine acts as a Na+ channel antagonist and inhibits glutamate release after Na+ channel activation. Given their known similar sites of action, the combination of halothane and lamotrigine may alter the inhibition produced by either drug alone. Extracellular recordings of field EPSPs were obtained from the dentate gyrus in the presence of 100 microM picrotoxin (to block GABAA receptors). Stimulation at 30 Hz (200 ms, pulse duration 0.1 ms, six pulses) allowed us to investigate use-dependent block (UDB). Once a stable equilibrium was established, halothane and lamotrigine were administered via the perfusate, and recordings were collected. Both halothane (n = 12) and lamotrigine (n = 6) exhibited reversible inhibition of the EPSP (ED50 0.28 mM [1.2%] and 100 microM, respectively) at low-frequency stimulation. Slices (n = 6) exposed to halothane 0.2 mM (0.75%), then to lamotrigine, showed reduced sensitivity compared with lamotrigine alone. Halothane 0.2 mM potentiated the control UDB (Pulse 6:31% +/- 11% control versus 20.5% +/- 2.5% halothane 0.75%; P < 0.05; n = 6). Lamotrigine had no effect on control UDB. The combination (n = 6) did not alter UDB effects compared with controls or lamotrigine alone. Halothane may reduce the effect of lamotrigine on glutamate release, either at the receptor or via effects at the inactivated Na+ channel. The site of interaction requires further examination. IMPLICATIONS The general and local anesthetic drugs halothane and lamotrigine act at both the glutamate receptor and the Na+ channels and, in our experiments, independently inhibited synaptic transmission at low-frequency stimulation. Although halothane potentiated control use-dependent block, lamotrigine had no effect. Halothane attenuated the inhibitory dose-dependent effects of lamotrigine on synaptic transmission at a low frequency. The clinical importance of this interaction in patients presenting for anesthesia remains unanswered.

Background Propofol is a short-acting intravenous anesthetic agent. However, cognitive function remains depressed for several hours thereafter. We have evaluated the ability of nefiracetam, a novel cognition-enhancing agent, to alleviate propofol-induced amnesia in a rodent model of learning. Methods Rats were trained in a one-trial, step-through, light-dark passive avoidance paradigm. Propofol (10 and 75 mg/kg) was administered by the intraperitoneal route at 15 min before training and separately at increasing times in the immediate 0-6 h post-training period (100 and 150 mg/kg). Nefiracetam, 9 mg/kg, was administered by the intraperitoneal route 1 h before training. Animals were tested for recall at the 12 h post-training time, and after their killing, immunocytochemistry was used to determine the increase in hippocampal neuronal polysialylation, an event associated with memory consolidation. Induction and duration of anesthesia induced by propofol was determined using tail pinch and pedal withdrawal reflexes. Results Propofol-induced anterograde amnesia occurred in a dose-dependent manner. Induction of retrograde amnesia required a higher dose of propofol, which anesthetized the animals and was effective only in the immediate 3-h post-training period. In the absence of any evident effect on the onset or duration of anesthesia, nefiracetam prevented both forms of propofol-induced amnesia and preserved the learning-associated changes of neuronal polysialylation state. Conclusions The ability of nefiracetam to prevent propofol-induced anterograde and retrograde amnesia is proposed to be indirect and to result from modulation of gene transcription in a manner that initiates a cascade of events involving protein synthesis leading to synaptic growth associated with the formation of the long-term memory trace.

The Mallampati classification is a commonly used means of preoperatively predicting a difficult endotracheal intubation.As the laryngeal portion of the laryngeal mask airway (LMA) must sit over the larynx, we wondered whether the Mallampati classification also predicts difficulty in achieving adequate seating of the LMA. LMA positioning was assessed prospectively in 100 adult patients by fiberoptic bronchoscopy to determine whether there was a relationship between the ease of seating of the LMA and the Mallampati classification. In 72 patients, optimal seating of the LMA was achieved on the first attempt at insertion, and all these patients were classified as Mallampati class 1 or 2. In all 28 cases of difficulty with LMA insertion, the patients were Mallampati class 2 or 3. In two cases the LMA was abandoned, and in these cases both patients were Mallampati class 3, (P = 0.0001 by chi squared analysis). We conclude that the Mallampati classification indicates difficulty not only in tracheal intubation but also in achieving an adequate airway with the LMA. (Anesth Analg 1995;81:1001-4)

Background Metastatic recurrence is the main cause of breast cancer-related deaths. Tumour cell proliferation and migration are crucial steps in the metastatic process. Several perioperative factors, including general anaesthesia and opioid analgesia, adversely affect immune function, potentially increasing metastatic recurrence. Regional anaesthesia–analgesia has been consistently shown to attenuate the stress response to surgery, and also reduce opioid and general anaesthesia requirements, thereby attenuating this perioperative immunosuppression. We investigated the effect of serum from breast cancer surgery patients who received different anaesthetic techniques on breast cancer cell function in vitro . Methods Patients were randomized to receive propofol/paravertebral anaesthesia–analgesia (propofol/paravertebral, n =11) or sevoflurane general anaesthesia with opioid analgesia (sevoflurane/opioid, n =11). The ER-negative MDA-MB-231 cell line was treated with patient serum from both groups. The effects on proliferation and migration were measured. Results Treatment groups were well balanced for age, weight, surgical procedure, and cancer pathology. Pain scores were lower at 1 and 2 h in the propofol/paravertebral analgesia group. Compared with preoperative values, proliferation of MDA-MB-231 cells treated with postoperative patient serum at 10% concentration from the propofol/paravertebral group was significantly reduced compared with the sevoflurane/opioid group (−24% vs 73%, P =0.01). There was no significant change in MDA-MB-231 cell migration after treatment with patient serum between the two groups. Conclusions Serum from patients receiving propofol/paravertebral anaesthesia for breast cancer surgery inhibited proliferation, but not migration, of ER-MDA-MB-231 cells in vitro , to a greater extent than that from patients receiving sevoflurane/opioid anaesthesia–analgesia. This implies that anaesthetic technique alters the serum molecular milieu in ways that may affect breast cancer cell function, possibly by altering anaesthetic and opioid drug administration and resultant pain scores.

Regional anesthesia and analgesia attenuate or prevent perioperative factors that favor minimal residual disease after removal of the primary carcinoma. Therefore, the authors evaluated prostate cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia or general anesthesia with postoperative opioid analgesia.In a retrospective review of medical records, patients with invasive prostatic carcinoma who underwent open radical prostatectomy between January 1994 and December 2003 and had either general anesthesia-epidural analgesia or general anesthesia-opioid analgesia were evaluated through October 2006. The endpoint was an increase in postoperative prostate-specific antigen.After adjusting for tumor size, Gleason score, preoperative prostate-specific antigen, margin, and date of surgery, the epidural plus general anesthesia group had an estimated 57% (95% confidence interval, 17-78%) lower risk of recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.43 (95% confidence interval, 0.22-0.83; P = 0.012) in a multivariable Cox regression model. Gleason score and tumor size (percent of prostate involved) were also independent predictors of recurrence (hazards ratios of 1.19 [1.08, 1.52], P = 0.004, and 1.17 [1.03, 1.34] for 10% size difference, P = 0.01, respectively). A similar association between epidural use and recurrence was obtained by comparing patients matched on the propensity to receive epidural versus general anesthesia.Open prostatectomy surgery with general anesthesia, substituting epidural analgesia for postoperative opioids, was associated with substantially less risk of biochemical cancer recurrence. Prospective randomized trials to evaluate this association seem warranted.

BACKGROUND Paravertebral analgesia is useful for breast surgery. Patient controlled analgesia by IV or epidural routes is well established for delivering postoperative analgesia. Our objective was to apply patient control to paravertebral analgesia and evaluate the efficacy and tolerability of two distinct dosing regimens. METHODS Patients undergoing major breast cancer surgery were recruited for this prospective, double-blind, randomized trial of two patient-controlled paravertebral analgesia regimens: 19 patients received levobupivacaine 0.2% at 8 mL/h with 3-mL bolus and 15-min lockout (15-min lockout group); 18 received levobupivacaine 0.2% at 4 mL/h with 8-mL bolus and 30-min lockout (30-min lockout group). Our primary outcome was dynamic pain scores (visual analog scale) at 4-hourly intervals for 36 h. Secondary outcomes were resting pain scores, rescue analgesia requirements, volume of levobupivacaine administered, demands for levobupivacaine, levobupivacaine boluses received, and patient satisfaction. RESULTS Resting and dynamic pain scores were comparable in the groups. Two 15-min lockout patients and five 30-min lockout patients required rescue analgesia (P = 0.23). Patients received 400 +/- 95 mL and 330 +/- 130 mL levobupivacaine in 15-min and 30-min lockout groups, respectively (P = 0.012). The 15-min lockout group requested a bolus 75 +/- 16 times; the 30-min lockout group requested it 69 +/- 14 times (P = 0.40). However, the 15-min lockout group received 39 +/- 22 boluses and the 30-min lockout group only 24 +/- 16 (P = 0.02). Systolic pressure, heart rate, respiratory rate, sedation scores, nausea, antiemetic requirement, and satisfaction scores were similar in each group. CONCLUSIONS Patient-controlled paravertebral analgesia for breast cancer surgery, with either regimen, provided satisfactory analgesia and was well tolerated.

Although the exact basis of their action remains unknown, volatile agents affect noradrenergic and serotoninergic systems. Imipramine and fluoxetine have documented effects on these neurotransmitter transmission systems. Given the common sites of action of these antidepressants and halothane, we examined their individual and combined effects on tonic excitatory post-synaptic potentials (EPSPs) and frequency dependent blockade in the rat dentate gyrus in vitro. Extracellular recordings of field EPSPs were maintained from the dentate gyrus, in the presence of picrotoxin (100 microM). Stimulation at 30 Hz (200 ms) allowed investigation of frequency dependent blockade. Once a stable equilibrium was established, halothane, imipramine and fluoxetine were administered via the perfusate and recordings were made. Halothane produced a dose dependent reduction in EPSP amplitude (EC50 0.28 mM; n = 12). Imipramine (1-10 microM) potentiated the EPSP amplitude (148.2 +/- 8.2%; imipramine 1 microM; n = 6). Fluoxetine (0.5-10 microM) reduced EPSP amplitude to 83.7 +/- 22.1% of control (n = 6). In the presence of halothane 0.2 mM, imipramine reduced the EPSP amplitude to 56.5 +/- 9.9% of control (imipramine 10 microM; n = 6; p < 0.05 compared with imipramine alone). Halothane (0.2 mM) demonstrated frequency dependent blockade. However, neither imipramine nor fluoxetine showed use dependent inhibition at the doses investigated. When combined with halothane 0.2 mM, fluoxetine 10 microM demonstrated frequency dependent blockade at the sixth pulse in the train compared with controls (13.8 +/- 4.7% vs 38.1 +/- 8.3%; n = 6; p < 0.05). The halothane-imipramine combination did not exhibit use dependent blockade greater than controls. The reversal of imipramine-induced EPSP potentiation by the preapplication of halothane has not been previously reported. It may be due to modulation of noradrenergic transmission by halothane. The frequency dependent blockade produced by the combination of fluoxetine 10 microM and halothane may be mediated by a nonspecific membrane effect on 5-HT uptake. These differing effects underline the broad action of volatile agents on synaptic mechanisms.

The antiproliferative potential of the volatile anesthetics isoflurane, enflurane and sevoflurane was determined and compared to the valproate teratogen. The in vitro system employed, a G1 phase proliferative arrest endpoint in C6 glioma, has served previously to discriminate agents with known teratogenic potential in vivo. Based on estimated IC50 values that were within twice the estimated minimum aveolar concentration value, the rank antiproliferative potency of the inhalational anesthetics employed was isoflurane=enflurane≫sevoflurane. Flow cytometric analysis of growth-arrested cell populations failed to reveal specific accumulation in any cell cycle phase and the lack of a G1 phase-specific effect was confirmed by the absence of a transient, time-dependent sialylation event in synchronized cells. The antiproliferative mechanism of volatile anesthetics, and valproate, was mediated at hydrophobic binding sites, as increasing the hydration sphere of the drug-micelle complex, using the hygroscopic qualities of the dimethylsulfoxide vehicle, completely reversed this effect. Our findings suggest inhalational anesthetics lack the specific in vitro characteristics of the valproate teratogen.

Background: Patients who are undergoing laparoscopic procedures can present with a number of ventilatory and circulatory problems. The use of a gasless technique for performing a laparoscopy by using a mechanical lifting device may potentially avoid such problems. Objective: To compare the cardiorespiratory effects of laparoscopy with and without gas insufflation. Methods: Twelve adult pigs were randomized to undergo a laparoscopy by using either carbon dioxide insufflation or mechanical elevation. Full invasive monitoring was performed preoperatively and at 10-minute intervals throughout the operative period. Parameters that were measured included blood gas determinations, mean arterial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, central venous pressure, cardiac output, stroke volume, and total peripheral resistance. Results: Carbon dioxide insufflation unlike mechanical elevation led to a fall in Po2and absorption of a significant quantity of CO2, resulting in hypercapnia, acidosis, and a consequent hyperdynamic circulation. Conclusion: These findings have significant implications for the use of CO2insufflation for laparoscopy in patients with a compromised respiratory or cardiac status. (Arch Surg. 1995;130:984-988)