Summary

Ion channels regulate a diversity of physiological functions such as neuronal signalling, cardiac excitability and immune cell response. All of these systems may be affected during the conduct of general as well as local anaesthesia. Thus, the investigation of anaesthetic action on ion channels has become the focus of an increasing number of laboratory studies. Consequently, the concepts of ion channel physiology are becoming important for understanding the scientific and pharmacological basis of clinical anaesthesia. This brief guide is intended to help in understanding the increasing number of studies concerned with the effects of anaesthetic agents on ionic currents. The generation of ionic currents requires a complex molecular interplay of ions, ion channel proteins and lipid membranes. Anaesthetic agents frequently exhibit more than a single effect on ion channel function. Their effects can be described by quantifying the pharmacological alteration of ion channel activation, conductance and inactivation. Many physiological functions are directly influenced by ion channels. Pharmacological action on ion channels is thus fundamental to effects as well as side-effects of anaesthetic agents. The alteration of ion channel function by anaesthetic agents consequently determines their clinical effects.

Summary

Background and objective: To investigate the effects of barbiturates on batrachotoxin-modified sodium channels from different regions of the human heart. Single sodium channels from human atria were studied and compared with existing data from the human ventricle and from the central nervous system.

Methods: Sodium channels from preparations of human atrial muscle were incorporated into planar lipid bilayers in the presence of batrachotoxin, a sodium channel activator. The steady-state behaviour of single sodium channels was recorded in symmetrical 500 mmol NaCl before and after the addition of pentobarbital 0.34–1.34 mmol.

Results: The batrachotoxin-treated human atrial sodium channel had an average single-channel conductance of 23.8 ± 1.6 pS in symmetrical 500 mmol NaCl and a channel fractional open time of 0.83 ± 0.06. The activation mid-point potential was −98.0 ± 2.3 mV. Extracellular tetrodotoxin (a specific sodium channel blocking agent) blocked these channels with a k1/2 = 0.53 μmol at 0 mV. Pentobarbital reduced the time average conductance of single atrial sodium channels in a concentration-dependent manner (ID50 = 0.71 mmol). In the same way, the steady-state activation was shifted to more hyperpolarized potentials (−10.6 mV at 0.67 mmol pentobarbital).

Conclusions: The properties of batrachotoxin-modified sodium channels from human atrial tissue did not differ greatly from those described for ventricular sodium channels in the literature. Our data yielded no explanation for the observed functional diversity. However, cardiac sodium channels differ from those found in the central nervous system.

Summary

Background and objective: For total intravenous anaesthesia an opioid is often combined with a hypnotic. A supra-additive interaction has been reported for clinical signs such as loss of consciousness or loss of the eyelash reflex. This study investigated the type of interaction of alfentanil and propofol on the electroencephalogram.

Methods: Twenty patients scheduled for abdominal surgery were enrolled in the study. Anaesthesia was induced and maintained with alfentanil and propofol. Each patient received a target-controlled infusion of alfentanil. Three target concentrations of 150, 225 and 300 ng mL−1 were applied to each patient in random order. Propofol was added to the alfentanil infusion by a feedback system. The set point was the range of 1.5–2.5 Hz median frequency of the electroencephalogram. Four arterial blood samples were taken within the last 20 min of each period. The mean drug concentrations were used to determine the type of interaction and an isobole was estimated by fitting Bernstein spline functions to the data.

Results: In 17 patients, all three alfentanil target concentrations could be administered. The test for supra-additivity as well as the isobole construction resulted in an additive type of interaction. The line of additivity cA/cA0 + cP/cP0 = 1 was best fitted for the values (standard deviation) cA0 = 1240 (51) ng mL−1 and cP0 = 5.21 (0.36) μg mL−1.

Conclusions: The type of interaction between alfentanil and propofol on the electroencephalogram in the investigated dose range is additive. This gives the freedom and need to select the appropriate dosing ratio of alfentanil and propofol by other considerations.

Summary

Background and objective: Knowledge of the pharmacodynamic interaction between remifentanil and propofol is important to permit optimal dosage strategies. We studied this pharmacodynamic interaction using the median power frequency of the processed electroencephalogram as a control parameter for feedback-controlled dosing of propofol.

Methods: Twenty-one patients were given total intravenous anaesthesia with remifentanil and propofol. During three target-controlled infusion regimens, the target concentrations of remifentanil (5, 10, 15 ng mL−1) and propofol dosing were automatically adjusted to keep the median power frequency in the range 2 ± 0.5 Hz. In each patient and during each remifentanil target concentration, four arterial propofol/remifentanil concentration pairs were measured. The type of interaction was tested using the relative distance from the line of additivity and the isobole was modelled using Bernstein splines.

Results: The results from 13 patients were used for data analysis. The measured remifentanil concentrations during the three targets were (mean ± SD): 3.6 ± 0.9, 8.1 ± 2.5 and 12.4 ± 2.8 ng mL−1. The corresponding propofol concentrations were 2.64 ± 0.86, 2.13 ± 0.58 and 2.09 ± 0.58 μg mL−1. The data were best described with an additive type of interaction and the isobole was estimated using:

Conclusions: Within the studied concentration range, remifentanil and propofol showed an additive type of pharmacodynamic interaction on the electroencephalogram.

Summary

Background and objective: Sevoflurane has been used for the induction and maintenance of anaesthesia during cardiac surgery owing to its favourable haemodynamic effects. It has been suggested that it offers protection against myocardial ischaemia–reperfusion injury.

Methods: We investigated the effect of sevoflurane on plasma concentrations of tumour necrosis factor-α (TNF-α) after ex vivo stimulation of whole-blood leukocytes by lipopolysaccharide from 20 patients undergoing coronary artery bypass surgery. The patients were randomized to two groups. Group 1 patients were induced and maintained with sevoflurane; those in Group 2 were anaesthetized with moderate doses of midazolam–sufentanil. Blood samples were drawn from the patients on seven occasions from before induction of anaesthesia until 24 h after skin closure.

Results: Plasma concentrations of TNF-α were lower in Group 1 than in Group 2 after cessation of cardiopulmonary bypass (median (interquartiles): 25 (21–30) versus 37 (28–79) pg mL−1; P < 0.05) and 24 h after skin closure (196 (100–355) versus 382 (233–718) pg mL−1; P < 0.05). Postoperatively, two cases of myocardial infarction were recorded, one in each group. Six patients in Group 2 needed continued inotropic support after the first morning to maintain haemodynamic stability versus one patient in Group 1 (P < 0.05). The length of stay in the intensive care unit was significantly lower in Group 1 than in Group 2 (mean ± SD: 25 ± 16 versus 54 ± 30 h; P < 0.05).

Conclusions: Sevoflurane reduces production of TNF-α more than total intravenous anaesthesia with midazolam–sufentanil during cardiac surgery. This may reduce cardiac morbidity and the length of stay in the intensive care unit.

Summary

Background and objective: We investigated the following aspects of pharmacokinetic-guided total intravenous anaesthesia with remifentanil and propofol in patients undergoing surgical myocardial revascularization: anaesthetic efficacy, haemodynamic effects, impact on extubation of the trachea and analgesia after operation.

Methods: Thirty-two patients undergoing on-pump coronary bypass surgery received intravenous anaesthesia with remifentanil and propofol. Both drugs were dosed and titrated based on computer-assisted pharmacokinetic models to maintain constant plasma concentrations. The propofol target plasma concentration was 1.2 μg mL−1 throughout the procedure. A remifentanil target plasma concentration of 8 ng mL−1 was achieved over 2 min for induction. After tracheal intubation, the opioid plasma concentration was reduced to 4 ng mL−1, and then titrated up to 8 ng mL−1 during surgery. Postoperative analgesia was managed with remifentanil infusion until 4 h after tracheal extubation, and a continuous infusion of tramadol was started 1 h before the remifentanil was stopped.

Results: After induction of anaesthesia, heart rate (−20%) and cardiac index (−6%) decreased significantly. No hypotensive episodes (mean arterial pressure <60 mmHg) occurred. Intraoperative haemodynamics were stable. Three cases of myocardial ischaemia were detected: two by transoesophageal echocardiography and one with ST-segment monitoring. The duration of postoperative mechanical ventilation of the lungs was 95 ± 13 min and the time to extubation was 150 ± 18 min. Postoperative analgesia was satisfactory in all patients.

Conclusions: Pharmacokinetic-based total intravenous anaesthesia with remifentanil and propofol provides adequate anaesthesia during coronary surgery with cardiopulmonary bypass and allows safe early extubation after operation.

Summary

Background and objective: The mechanism underlying stable cuff pressure in the Brandt rediffusion endotracheal tube during anaesthesia with nitrous oxide is not fully understood. The present study assessed changes in gas concentrations in the cuff during and after nitrous oxide anaesthesia.

Methods: The pressure of an air-filled Brandt endotracheal tube cuff was measured; anaesthesia was maintained with nitrous oxide 67% and oxygen 33% for 6 h in the Continuous Group; oxygen was substituted for nitrous oxide after 3 h of nitrous oxide anaesthesia in the Discontinuous Group (n = 8 for each). In some other patients, the study was terminated at 90, 180, 270 and 360 min (n = 8 for each). Gas concentrations in the cuff were measured at the end of the study.

Results: Cuff pressures increased slightly during the first 180 min of anaesthesia (P < 0.001). Thereafter, the cuff pressure did not change significantly in the Control Group but decreased in the Discontinuous Group (P < 0.001); there was a significant difference between the two groups (P < 0.0001). Cuff pressure never exceeded 22 mmHg and there were no air leaks in either group during the 6 h anaesthesia. Nitrous oxide concentrations in the cuff were 11.3 ± 2.6% and 2.6 ± 0.8% in the Control Group and Discontinuous Groups, respectively; however, changes in carbon dioxide and oxygen concentrations in the cuff were within approximately 1%.

Conclusions: Small changes in the nitrous oxide concentration in the cuff contribute to a stable cuff pressure in the Brandt rediffusion system, but changes in carbon dioxide or oxygen concentrations have little effect.

Summary

Background and objective: The bispectral index, a parameter derived from the electroencephalograph, has been shown to correlate with the loss of consciousness and sedation. This study was designed to assess the effects of bispectral index monitoring on sevoflurane and its recovery profiles.

Methods: Sixty ASA I and II patients undergoing open abdominal surgery were randomized into two groups: one monitored using the bispectral index (Group BIS) and the other without its use (controls). After a standardized induction, anaesthesia was maintained with sevoflurane in both groups. In Group BIS, sevoflurane was titrated to maintain the bispectral index in the range 40–60. In the control group, the administered sevoflurane concentration was adjusted according to the signs of anaesthesia. The end-tidal sevoflurane concentration, bispectral index and routine haemodynamic variables were noted every 5 min during surgery. The consumption of sevoflurane was computed. At the conclusion of surgery operations, the time to ‘open eyes on verbal command’, ‘motor response to verbal command’ and Aldrete's score were recorded by a blinded anaesthesiologist.

Results: The difference in the consumption of sevoflurane was not significant between the groups. Bispectral index monitoring was associated with a reduction of 4.73% in sevoflurane usage and 2.19 mL h−1 was saved.

Conclusions: Bispectral index monitoring during anaesthesia provides only a small advantage related to the need to monitor the depth of anaesthesia.

Summary

Background and objective: Headache is a common and distressing morbidity associated with day case surgery. We undertook a prospective, observational study to identify risk factors associated with perioperative headache in a modern, day case surgery setting.

Methods: Two hundred-and-thirty consecutive patients presenting for day case surgery were invited to complete a questionnaire about their previous experience of headache and various associated risk factors. Questionnaires were completed by 90% of patients. The presence of headache in the pre- or postoperative period was also documented. We used multivariate logistic regression to model perioperative headache.

Results: Increased frequency of previous headache, odds ratio (95% confidence interval) 1.9 (1.2–2.8) (P = 0.004) and low alcohol consumption 0.90 (0.87–0.98) (P = 0.019) were significant predictors. A history of migraine showed a trend towards being predictive 1.9 (0.9–4.0) (P = 0.055). Some risk factors thought to be important such as caffeine withdrawal and duration of starvation and fluid deprivation were not associated with perioperative headache in this setting.

Conclusions: In this study of risk factors associated with perioperative headache in day case surgery, increased frequency of headache and low alcohol consumption were independent risk factors.

Summary

Background and objective: In recent human and animal studies, intrathecal administration of various doses of neostigmine produces analgesia without neurotoxicity. The aim was to examine the effects of intrathecal neostigmine and bupivacaine in patients undergoing perianal surgery under spinal anaesthesia.

Methods: The patients were randomly allocated into three groups of 15: Group 1 (controls) received hyperbaric bupivacaine 10 mg + dextrose 5%, 1 mL, to a total volume of 3 mL; Group 2 received hyperbaric bupivacaine 10 mg + neostigmine 25 μg in dextrose 5%, 1 mL, to a total volume of 3 mL; and Group 3 received hyperbaric bupivacaine 10 mg + neostigmine 50 μg in dextrose 5%, 1 mL, to a total volume of 3 mL.

Results: The onset of sensory block was significantly earlier for Group 2 and 3 patients compared with Group 1 patients (P < 0.05). The full time to recovery of motor block and sensory block was significantly longer in Group 3 compared with Group 1 (P < 0.05). In Group 3, the average time until the first dose of tramadol was longer than Group 1 (P < 0.05). The incidence rate of nausea and vomiting was significantly higher in Groups 2 and 3 than in Group 1 (P < 0.05).

Conclusions: The use of intrathecal neostigmine as an analgesic drug in perianal surgery is unsatisfactory because of prolonged motor blockade and nausea.

Summary

Background and objective: Trazodone hydrochloride is used in the treatment of neuropathic pain. However, the analgesic effects of trazodone on neuropathic pain are controversial. The study was undertaken to determine the analgesic effect of trazodone on a chronic constriction injury model.

Methods: We tested the effect of trazodone on thermal hyperalgesia due to a chronic constriction injury of the sciatic nerve in rats and examined the effects of lesions in the descending and ascending serotonergic system induced by 5,7-dihydroxytriptamine (5,7-DHT).

Results: The analgesic effects of trazodone showed a clear dose dependency. Furthermore, the analgesic effect of trazodone was observed in rats injected with 5,7-DHT into the dorsal raphe nucleus and medial raphe nucleus.

Conclusions: The results suggest that a mainly serotonergic descending pain control pathway mediates the analgesic effects of trazodone.

Summary

Background and objective: This double-blind randomized study tested whether the addition of magnesium or ketamine to morphine for intravenous patient-controlled analgesia resulted in improved analgesic efficacy and lower pain scores compared with morphine patient-controlled analgesia alone after major abdominal surgery.

Methods: Ninety patients (3 × 30) were randomly allocated to receive either morphine 0.4 mg mL−1 (Group M) by patient-controlled analgesia, morphine 0.4 mg mL−1 + MgSO4 30 mg mL−1 (Group MM) or morphine 0.4 mg mL−1 + ketamine 1 mg mL−1 (Group MK). Postoperative analgesia was started when the verbal rating scale was ≥2. Patients were first given a standardized loading dose (0.05 mg kg−1) of the study solution. They were then allowed to use bolus doses of this solution (0.0125 mg kg−1 every 20 min without time limit). Discomfort, sedation, pain scores, cumulative morphine consumption and adverse effects were recorded up to 24 h after the start of the patient-controlled analgesia.

Results: The level of discomfort, level of sedation and verbal rating scores decreased significantly with time in all groups (P < 0.05). Both verbal rating and discomfort scores were significantly lower in Groups MM and MK at 15, 30 and 60 min compared with Group M (P < 0.001). Cumulative morphine consumption after 12 and 24 h was significantly higher in Group M alone (median 26 and 49 mg, respectively) compared with Group MM (24.2 and 45.7 mg) and Group MK (24.4 and 46.5 mg).

Conclusions: In the immediate postoperative period, the addition of magnesium or ketamine to morphine for intravenous patient-controlled analgesia led to a significantly lower consumption of morphine. However, these differences are unlikely to be of any clinical relevance.