The alpha2-adrenergic receptor antagonist yohimbine improves endotoxin-induced inhibition of gastrointestinal motility in mice.

BACKGROUND: Sepsis inhibits gastrointestinal motility. Although the exact mechanism of this is unclear, lipopolysaccharide is known to activate macrophages in the gastrointestinal wall, which upregulate their expression of inducible nitric oxide synthase (iNOS). This leads to an increased production of nitric oxide, which relaxes the gastrointestinal muscles. We studied endotoxaemic mice to determine whether yohimbine improved delayed gastric emptying and gastrointestinal transit. METHODS: Male Balb/c mice (n = 49) were randomly allocated to two groups, and either yohimbine 25 microg or saline was injected s.c. Four hours later, mice in each group were further randomly allocated to two groups, and either lipopolysaccharide 100 microg or saline was injected intraperitoneally. Eight hours later, liquid containing fluorescent microbeads was infused into the stomach, and 30 min later, gastric emptying and gastrointestinal transit were measured using flow cytometry. We also studied whether yohimbine given after injection of lipopolysaccharide was effective (n = 22). In another group of mice (n = 32), iNOS in the gastrointestinal tract was measured using western blotting. RESULTS: Lipopolysaccharide significantly inhibited gastric emptying and gastrointestinal transit. Yohimbine, given before or after lipopolysaccharide, significantly attenuated the inhibitory effects of lipopolysaccharide. Lipopolysaccharide increased the expression of iNOS in the small intestine and yohimbine suppressed the effects of lipopolysaccharide. CONCLUSIONS: In endotoxaemic mice, yohimbine improved delayed gastric emptying and gastrointestinal transit, possibly by downregulating lipopolysaccharide-induced increased expression of iNOS.

Intrathecal betamethasone pain relief in cancer patients with vertebral metastasis: a pilot study.

BACKGROUND: We have reported previously the usefulness of intrathecal betamethasone for pain relief in cancer patients who suffer from intractable pain caused by vertebral metastasis. The mechanism by which betamethasone relieves pain may be related to alterations in cerebrospinal fluid (CSF) concentrations of pro-inflammatory cytokines and prostanoids. METHODS: Thirteen cancer patients with intractable pain caused by vertebral metastasis received 2-3 mg betamethasone in the lumbar subarachnoid space. CSF concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-8 and prostaglandin E(2) (PGE(2)) were measured with an enzyme-linked immunosorbent assay (ELISA) and a chemiluminescence enzyme immunoassay. Pain was measured using a numerical pain score (range, 0-10; 0, no pain; 10, worst pain imaginable). RESULTS: Intrathecal betamethasone was associated with a significant decrease in the pain score in six patients. In these cases, the pain score decreased from 6.7 +/- 0.5 (mean +/- standard error of the mean) to 3.3 +/- 0.3 (P < 0.05), and the CSF concentrations of IL-8 and PGE(2) decreased significantly compared with pre-treatment levels (IL-8, 183.3 +/- 21.2 to 116.5 +/- 10.6 pg/ml; PGE(2), 43.8 +/- 10.3 to 14.7 +/- 3.0 pg/ml). There were no significant changes in the CSF concentrations of cytokines and PGE(2) in the remaining seven patients. CONCLUSION: Pain relief with intrathecal betamethasone is related to decreases in the CSF concentration of IL-8 and PGE(2).

Intrathecal betamethasone for cancer pain in the lower half of the body: a study of its analgesic efficacy and safety.

BACKGROUND: Sufficient analgesia for cancer pain is sometimes difficult to achieve with conventional treatments. We aimed at investigating the analgesic efficacy and safety of intrathecal betamethasone in patients with uncontrollable cancer pain. METHODS: Betamethasone 1 mg mixed with saline was injected into the lumbar intrathecal space once a week in 10 patients with persistent cancer pain in the lower half of the body. During the 4-week study period, the analgesic efficacy and adverse effects related to intrathecal betamethasone were observed. RESULTS: Long-lasting analgesia (mean numerical pain score < or = 5) for 7 days, after immediate analgesia within 10 min, was obtained without the need to increase the morphine dose in 5 of 10 patients. In almost all of the patients, not only pain, but also uncomfortable symptoms were improved. Adverse effects related to neurotoxicity of intrathecal betamethasone, such as sensory and motor dysfunctions, were not observed in any patients. CONCLUSION: When conventional cancer pain treatments are not successful, intrathecal betamethasone may be useful, as it probably induces long-lasting analgesia without adverse effects and improves activities of daily living, especially in patients with vertebral bone metastases.

Inducible nitric oxide synthase and tumor necrosis factor-alpha in delayed gastric emptying and gastrointestinal transit induced by lipopolysaccharide in mice.

Gastrointestinal motility disturbances during endotoxemia are probably caused by lipopolysaccharide (LPS)-induced factors: candidates include nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1ss, and interleukin-6. Flow cytometry was used to determine the effects of LPS and these factors on gastric emptying (evaluated indirectly by determining percent gastric retention; %GR) and gastrointestinal transit (GIT) in male BALB/c mice (23-28 g). NO (300 microg/mouse, N = 8) and TNF-alpha (2 microg/mouse, N = 7) increased (P < 0.01) GR and delayed GIT, mimicking the effect of LPS (50 microg/mouse). During early endotoxemia (1.5 h after LPS), inhibition of inducible NO synthase (iNOS) by a selective inhibitor, 1400 W (150 microg/mouse, N = 11), but not antibody neutralization of TNF-alpha (200 microg/mouse, N = 11), reversed the increase of GR (%GR 78.8 +/- 3.3 vs 47.2 +/- 7.5%) and the delay of GIT (geometric center 3.7 +/- 0.4 vs 5.6 +/- 0.2). During late endotoxemia (8 h after LPS), both iNOS inhibition (N = 9) and TNF-alpha neutralization (N = 9) reversed the increase of GR (%GR 33.7 +/- 2.0 vs 19.1 +/- 2.6% (1400 W) and 20.1 +/- 2.0% (anti-TNF-alpha)), but only TNF-alpha neutralization reversed the delay of GIT (geometric center 3.9 +/- 0.4 vs 5.9 +/- 0.2). These findings suggest that iNOS, but not TNF-alpha, is associated with delayed gastric emptying and GIT during early endotoxemia and that during late endotoxemia, both factors are associated with delayed gastric emptying, but only TNF-alpha is associated with delayed GIT.

Inducible nitric oxide synthase and tumor necrosis factor-alpha in delayed gastric emptying and gastrointestinal transit induced by lipopolysaccharide in mice

Gastrointestinal motility disturbances during endotoxemia are probably caused by lipopolysaccharide (LPS)-induced factors: candidates include nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1ß, and interleukin-6. Flow cytometry was used to determine the effects of LPS and these factors on gastric emptying (evaluated indirectly by determining percent gastric retention; percentGR) and gastrointestinal transit (GIT) in male BALB/c mice (23-28 g). NO (300 æg/mouse, N = 8) and TNF-alpha (2 æg/mouse, N = 7) increased (P < 0.01) GR and delayed GIT, mimicking the effect of LPS (50 æg/mouse). During early endotoxemia (1.5 h after LPS), inhibition of inducible NO synthase (iNOS) by a selective inhibitor, 1400 W (150 æg/mouse, N = 11), but not antibody neutralization of TNF-alpha (200 æg/mouse, N = 11), reversed the increase of GR ( percentGR 78.8 ± 3.3 vs 47.2 ± 7.5 percent) and the delay of GIT (geometric center 3.7 ± 0.4 vs 5.6 ± 0.2). During late endotoxemia (8 h after LPS), both iNOS inhibition (N = 9) and TNF-alpha neutralization (N = 9) reversed the increase of GR ( percentGR 33.7 ± 2.0 vs 19.1 ± 2.6 percent (1400 W) and 20.1 ± 2.0 percent (anti-TNF-alpha)), but only TNF-alpha neutralization reversed the delay of GIT (geometric center 3.9 ± 0.4 vs 5.9 ± 0.2). These findings suggest that iNOS, but not TNF-alpha, is associated with delayed gastric emptying and GIT during early endotoxemia and that during late endotoxemia, both factors are associated with delayed gastric emptying, but only TNF-alpha is associated with delayed GIT.

Propofol acts at the sigma-1 receptor and inhibits pentazocine-induced c-Fos expression in the mouse posterior cingulate and retrosplenial cortices.

BACKGROUND: The sigma-1 receptor is functionally linked with psychotomimetic effects of various drugs. A sigma-1 receptor agonist enhances bradykinin-induced intracellular Ca(2+) concentration ([Ca(2+)]i) increase and induces c-Fos expression in a part of the brain. The aim of this study was to investigate the effects of several intravenous anaesthetics on the sigma-1 receptor. METHODS: First, using Wistar rat brains, (+)[(3)H]SKF-10,047, a selective sigma-1 receptor agonist was displaced by propofol, dexmedetomidine, droperidol, and thiopental. Second, Fura-2 loaded NG-108 cells were incubated with (+)pentazocine, a selective sigma-1 receptor agonist, and propofol and then its fluorescence was observed after stimulation with bradykinin. Third, male ICR mice received Intrafat or propofol intraperitoneally (i.p.), followed by pentazocine i.p. Brain slices were prepared and Fos-like immunoreactivity was detected using an immunohistochemical method. results: Propofol, droperidol, and dexmedetomidine displaced (+)[(3)H]SKF-10,047 binding in a concentration-dependent manner with Ki50s of 10.2 +/- 0.6, 0.17 +/- 0.03, 5.73 +/- 1.2 microM, respectively. Thiopental sodium was practically ineffective. Propofol produced a statistically significant reduction in the maximal binding capacity (Bmax) but did not affect the dissociation constant (K(d)). (+)Pentazocine significantly enhanced bradykinin-induced [Ca(2+)]i increases, but propofol did not affect it. Pentazocine induced marked Fos-LI positive cells in the posterior cingulate and retrosplenial cortices (PC/RS), which was significantly reduced by propofol. CONCLUSIONS: These results suggest that propofol may be a sigma-1 receptor antagonist, and that various effects of propofol on the brain may be mediated, at least partly, by the sigma-1 receptor.

The laryngeal tube.

The laryngeal tube (VBM Medizintechnik, Sulz, Germany) is a relatively new extraglottic airway, designed to secure a patent airway during either spontaneous breathing or controlled ventilation. In this review article, we have assessed the potential role of the laryngeal tube during anaesthesia and during cardiopulmonary resuscitation. There are four variations of the laryngeal tube: standard laryngeal tube, disposable laryngeal tube, laryngeal tube-Suction II and disposable laryngeal tube-Suction II. The design of the device has been revised several times. Insertion of the standard laryngeal tube is as easy as with the laryngeal mask airway classic. The laryngeal tube may provide a better sealing effect than the laryngeal mask. The incidence of complications with the two devices is similar, although the laryngeal tube may require more re-adjustments of its position to obtain a clear airway. Compared with the ProSeal laryngeal mask, the laryngeal tube may be less effective. The efficacy of the standard laryngeal tube is unclear, particularly in patients breathing spontaneously or in children. The efficacy of the laryngeal tube Suction-II and disposable devices is also not clear. From the limited number of studies and reports available, it can be concluded that the laryngeal tube is potentially useful in maintaining a clear airway during anaesthesia and cardiopulmonary resuscitation. In addition, the device may be useful as an aid to tracheal intubation.

Appropriate cuff volumes of the Laryngeal Tube.

The manufacturer of the Laryngeal Tube (VBM, Germany) states that the cuffs should be inflated until the intracuff pressure reaches 60 cmH(2)O or with a certain volume of air (60 ml for the size 3 and 80 ml for size 4). We studied 100 patients to investigate this. In addition, we examined whether the patient's height or weight could be a predictor of the required volume. Following insertion of a laryngeal tube, the cuff volume at the intracuff pressure 60 cmH(2)O was measured. The mean (SD) volume was 62 (7.2) ml for size 3 and 84 (11.2) ml for size 4. There was a correlation between the height of the patient and the cuff volume (correlation coefficient = 0.64; p < 0.01; volume (ml) = -86.5 + 1.02 height (cm)), and between the patient's weight and the cuff volume (correlation coefficient = 0.37; p < 0.01; volume (ml) = 45.3 + 0.558 weight (kg)). The required volume for size 3 was < 60 ml in nine of 27 patients (33%), and for size, 4 < 80 ml in 20 of 73 patients (27%). Our results support the manufacturer's recommended cuff volumes, but if the cuff is inflated with these fixed volumes (60 ml and 80 ml), the cuff would be overinflated in one-third of patients, increasing the theoretical risk of ischaemic changes to the oropharynx. Since the cuff volume is correlated with the patient's height or weight, the cuff volume should be adjusted to the patients' stature.

Ease of insertion of the laryngeal tube during manual-in-line neck stabilisation.

The laryngeal tube has a potential role in airway management during anaesthesia or cardiopulmonary resuscitation. In patients with unstable necks, the head and neck may need to be stabilised manually (manual in-line stabilisation), but it is not known whether this procedure affects the ease of insertion of the laryngeal tube. We studied, in a cross-over study, 21 adult patients to compare the success rate of ventilation through the laryngeal tube between the Magill position (a pillow under the occiput and the head extended) or the manual in-line position of the head and neck (without a pillow under the occiput). After induction of anaesthesia and neuromuscular blockade, the laryngeal tube was inserted in turn in the two positions. The ease of insertion was scored with four categories (easy, moderately difficult, difficult and impossible), and adequacy of ventilation through the device was assessed. Ventilation was adequate in all 21 patients in the Magill position, but only in two of 21 patients during manual in-line positioning (p < 0.01; 95%CI for difference: 68-94%). In the Magill position, insertion of the laryngeal tube was easy in 16 patients and moderately difficult in the remaining five patients; in the manual in-line stabilisation position, insertion was moderately difficult in two patients and impossible in the remaining 19 patients. Stabilisation of the patient's head and neck by the manual in-line method made insertion of the laryngeal tube either difficult or impossible.

Effect of propofol and isoflurane anaesthesia on the immune response to surgery.

There are two major subpopulations of peripheral helper T lymphocytes: T helper 1 (Th1) and T helper 2 (Th2) cells. Surgical stress increases the number of Th2 cells, and decreases that of Th1 cells, resulting in a decrease in the Th1/Th2 ratio, and, consequently, in suppressed cell-mediated immunity. Since anaesthesia can suppress the stress response to surgery, it may inhibit the decrease in the Th1/Th2 ratio. Using flow cytometry, we studied whether propofol anaesthesia (n = 9) or isoflurane anaesthesia (n = 9) had more effect on the decrease in the Th1/Th2 ratio after surgery in patients undergoing craniotomy. The Th1/Th2 ratio decreased significantly after isoflurane anaesthesia (p = 0.011), while it did not change after propofol anaesthesia. The ratio was significantly lower with isoflurane than propofol (p = 0.009). Propofol anaesthesia attenuated the surgical stress-induced adverse immune response better than isoflurane anaesthesia.