The bispectral index (BIS) and a sedation score were used to determine and compare the effect of propofol in the presence of fentanyl, alfentanil, remifentanil and sufentanil. Seventy-five non-premedicated patients were assigned randomly into five groups (15 in each) to receive fentanyl, alfentanil, remifentanil, sufentanil or placebo. Opioids were administered using a target-con-trolled infusion device, to obtain the following predicted effect-site concentrations: fentanyl, 1.5 ng ml(-1); alfentanil, 100 ng ml(-1); remifentanil, 6 ng ml(-1); and sufentanil, 0.2 ng ml(-1). After this, a target-controlled infusion of propofol (Diprifusor) was started to increase concentration gradually, to achieve predicted effect-site concentrations of 1, 2, and 4 microg ml(-1). At baseline and at each successive target effect-site concentration of propofol, the BIS, sedation score and haemodynamic variables were recorded. At the moment of loss of consciousness (LOC), the BIS and the effect-site concentration of propofol were noted. The relationship between propofol effect-site concentration and BIS was preserved with or without opioids. In the presence of an opioid, LOC occurred at a lower effect-site concentration of propofol and at a higher BIS50 (i.e. the BIS value associated with 50% probability of LOC), compared with placebo. Although clinically the hypnotic effect of propofol is enhanced by analgesic concentrations of mu-agonist opioids, the BIS does not show this increased hypnotic effect.

Background: Recent laboratory studies showed that exposure to supraclinical concentrations of propofol can induce cell death of immature neurons. However, no data are available regarding the effects of clinically relevant concentrations of this agent on neuronal development. The authors addressed this issue by evaluating the effect of propofol on dendritic growth and arbor expansion of developing gamma-aminobutyric acid-positive (GABAergic) interneurons. Methods: Immature neuroblasts were isolated from the newborn rat subventricular zone and differentiated into GABAergic interneurons in culture. In addition to cell death, the effects of increasing concentrations and durations of propofol exposure on neuronal dendritic development were evaluated using the following morphologic parameters: total dendritic length, primary dendrites, branching point, and Scholl analysis. Results: The authors demonstrate that propofol induced cell death of GABAergic neurons at concentrations of 50 microg/ml or greater. As little as 1 microg/ml propofol significantly altered several aspects of dendritic development, and as little as 4 h of exposure to this agent resulted in a persistent decrease in dendritic growth. In contrast, application of midazolam did not affect neuronal development. Conclusion: Short-term exposure of immature developing GABAergic neurons to clinically relevant concentrations of propofol can induce long-term changes in dendritic arbor development. These results suggest that propofol anesthesia during central nervous system development could interfere with the molecular mechanisms driving the differentiation of GABAergic neurons and thus could potentially lead to impairment of neural networks.

Background: Altered central nervous system sensory processing (neuroplasticity) is a basic mechanism underlying postoperative pain that can be made visible using quantitative sensory testing. Using quantitative sensory testing, the authors investigated how perioperative analgesia affects postoperative neuroplasticity and how this relates to clinical pain measures. Methods: Patients undergoing back surgery received placebo, fentanyl, or ketorolac (n = 15 per group) before isoflurane-nitrous oxide anesthesia. Preoperatively to 5 days postoperatively, we measured thresholds to electrical skin stimulation at the incision site, arm, and leg; pain scores; and morphine patient-controlled analgesia consumption. Results: Decreased pain thresholds versus preoperatively were seen 5 days postoperatively, with decreases greater for ketorolac (-63%; P = 0.00005 vs. preoperatively) than placebo (-45%; P = 0.008 vs. preoperatively) but nonsignificant for fentanyl (-36%; P = 0.9 vs. preoperatively). Mainly nonnociceptive thresholds were increased up to 24 h postoperatively. Postoperative clinical pain measures were similar across drug groups. Postoperative pain tolerance threshold changes did not correlate with preoperative clinical pain measures but were inversely related to preoperative thresholds for placebo and ketorolac but not fentanyl. Conclusions: Without analgesia, neuroplasticity after surgery was inhibitory the first 24 h and followed at 5 days by excitation. Fentanyl efficiently preempted this hyperalgesia, but hyperalgesia was greater with ketorolac than with placebo. Clinical pain measures neither reflected the different effects of ketorolac and fentanyl on postoperative neuroplasticity nor permitted prediction of postoperative neuroplasticity. The information obtained by perioperative quantitative sensory testing is separate from and additional to that from clinical pain measures and may enable more mechanism-based approaches to surgical analgesia management in the future.

Ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate type of glutamate receptors, was reported to induce neuronal cell death when administered to produce anesthesia in young rodents and monkeys. Subanesthetic doses of ketamine, as adjuvant to postoperative sedation and pain control, are also frequently administered to young children. However, the effects of these low concentrations of ketamine on neuronal development remain unknown. The present study was designed to evaluate the effects of increasing concentrations (0.01–40 μg/ml) and durations (1–96 h) of ketamine exposure on the differentiation and survival of immature γ-aminobutyric acidergic (GABAergic) interneurons in culture. In line with previous studies (Scallet et al., 2004), we found that a 1-h-long exposure to ketamine at concentrations ≥ 10 μg/ml was sufficient to trigger cell death. At lower concentrations of ketamine, cell loss was only observed when this drug was chronically (> 48 h) present in the culture medium. Most importantly, we found that a single episode of 4-h-long treatment with 5 μg/ml ketamine induced long-term alterations in dendritic growth, including a significant (p < 0.05) reduction in total dendritic length and in the number of branching points compared to control groups. Finally, long-term exposure (> 24 h) of neurons to ketamine at concentrations as low as 0.01 μg/ml also severely impaired dendritic arbor development. These results suggest that, in addition to its dose-dependent ability to induce cell death, even very low concentrations of ketamine could interfere with dendritic arbor development of immature GABAergic neurons and thus could potentially interfere with the development neural networks.

We have investigated the interaction between magnesium sulphate 40 mg kg⁻¹ i.v. and vecuronium. First, we determined the effect of pretreatment with magnesium on the potency of vecuronium using a single bolus dose-response technique. In addition, we compared the time course of vecuronium-induced neuromuscular block (vecuronium 100 μg kg⁻¹) with and without magnesium pretreatment. For both parts, neuromuscular block was assessed by electromyography. In addition, the effect of magnesium pretreatment on vecuronium-induced neuromuscular block was investigated in the context of rapid sequence induction of anaesthesia. We found that the neuromuscular potency of vecuronium was increased by pretreatment with magnesium sul phate. The ED₅₀ and ED₉₀ of vecuronium with MgSO₄ were 25% lower than without MgSO₄ (ED₅₀ 21.3 vs 26.9 μg kg⁻¹ ED₉₀ 34.2 vs 45.7 μg kg⁻¹P < 0.05 for both). Mean onset time was 147.3 (SD 22.2) s in the MgSO₄ group vs 297.3 (122) s for controls (P < 0.05). Clinical duration was prolonged (MgSO₄-vecuronium 43.3 (9) min vs 25.2 (5.1) min for controls; P < 0.05). This was also true for the recovery index (20.1 (6.6) mm vs 10.6 (3.4) min; P < 0.05) and duration to 75% recovery (63.4 (9.9) min vs 35.8 (6.9) min; < 0.05). In the context of rapid sequence induction, pretreatment with MgSO₄ improved the intubating score of vecuronium compared with vecuronium without MgSO₄ reach ing the same quality as that with suxamethonium 1 mg kg⁻¹. We conclude that magnesium pretreat ment increased the neuromuscular potency of vecuronium, in addition to modifying the time course of its neuromuscular block.