Summary

We do not know how general anaesthetics cause their desired effects. Contrary to what has been thought until relatively recently, the clinical state of anaesthesia consists of multiple components that are mediated via interaction of the anaesthetic drugs with different targets on the molecular, the cellular, the network and the structural–anatomical levels. The mechanisms by which some of these drugs induce the different components of ‘anaesthesia’ may be rather specific: discrete mutations of single amino acids in specific proteins profoundly affect the ability of certain anaesthetics to achieve specific endpoints. Despite this potential specificity, inhalational anaesthetics are present in the body at very high concentrations during surgical anaesthesia. Due to their lipid solubility, general anaesthetics dissolve in every membrane, penetrate into organelles and interact with numerous cellular structures in multiple ways. A priori, it is therefore not unreasonable to assume that these drugs have the potential to cause insidious changes in the body other than those acute and readily apparent ones that we routinely monitor for. Some changes may wane within a short time after removal of the drug (e.g. the suppression of immune cell function). Others may persist after complete removal of the drug and even become self-propagating (e.g. spread of malignant cells, the β-oligomerization of proteins), still others may be irreversible (e.g. the induction of apoptosis in the central nervous system) but of unclear significance. This article will focus on evidence for anaesthetic toxicity in the central nervous system, which appears to be susceptible to anaesthetic neurotoxicity primarily at the extremes of ages but via different pathways: in the neonate, during the period of most intense synaptogenesis, anaesthetics can induce excessive apoptosis; in the aging brain subtle cognitive dysfunction can persist long after clearance of the drug and processes resembling neurodegenerative disorders may be accelerated. At all ages, anaesthetics affect gene expression regulating protein synthesis in poorly understood ways. While it seems reasonable to assume that the vast majority of our patients completely restore homeostasis after general anaesthesia, exposure to these drugs probably has more profound and longer-lasting effects on the brain than heretofore imagined.

Background and objective In the present study, we investigated the combination of etomidate and s-ketamine with regard to its suitability for modified rapid-sequence induction using rocuronium for muscle relaxation.

Methods In a prospective, randomized and double-blinded study, 90 patients were assigned to one of three groups for induction of anaesthesia in combination with etomidate (0.3 mg kg−1) and muscle relaxation with rocuronium (0.6 mg kg−1). The groups were as follows: (a) control, i.e. placebo; (b) fentanyl, fentanyl (1.5 μg kg−1); (c) ketamine, s-ketamine (0.5 mg kg−1). Tracheal-intubating conditions after 1 min were classified as excellent, good or poor. During the induction of anaesthesia, arterial pressure and heart rate were measured every 60 s.

Results Intubating conditions were best using etomidate and s-ketamine (23 excellent, 7 good, 0 poor) compared with the control (8, 16, 6 respectively) and fentanyl groups (7, 21, 2 respectively) (P < 0.01). While heart rate and arterial pressure remained stable in the control and fentanyl groups during induction, both significantly increased in the ketamine group (P < 0.01).

Conclusions The combination of etomidate and s-ketamine for anaesthesia induction produces mostly excellent intubating conditions after 60 s using only 0.6 mg kg−1 of rocuronium. This combination of drugs may be a useful alternative, if succinylcholine needs to be avoided, for modified rapid-sequence induction.

Background and objective The objective of this study was to determine the dose as well as the duration of exposure–dependent effects of methohexital on neutrophil [polymorphonuclear leucocyte (PMN)] free amino acid profiles and, in a parallel study, on PMN immune functions.

Methods Whole blood samples were taken from 20 volunteers and incubated with methohexital [0 (control), 3.6, 26, 130 and 260 μgmL−1] for 10, 30, 60 or 120 min. PMN amino acid profiles were documented using advanced PMN separation and highperformance liquid chromatography procedures. Superoxide anion (O2−) and hydrogen peroxide production (H2O2), and activity of released myeloperoxidase (MPO), were determined photometrically.

Results After methohexital, significant dose (≥26 μg mL−1) as well as duration of exposure–dependent (≥30 min) increases in histidine, isoleucine, leucine, valine, methionine, serine, glycine, threonine, and decreases in glutamine, glutamate, aspartate, asparagine, arginine, ornithine, citrulline, alanine and taurine were observed (P ≤0.05). Concerning PMN immune functions, methohexital significantly decreased O2−, H2O2 formation and MPO (≥26 μgmL−1, ≥30 min, P≤0.05).

Conclusions Altogether, there is significant relevance to the pharmacological regimens which enhance the supply of methohexital in whole blood. In regards to our results, we suggest that considerable changes in PMN ‘dynamic free amino acid pool’, for example induced by methohexital, may be one of the determinants in cell nutrition adversely affecting PMN metabolism. It is partially through its effect on the PMN free amino acid pool that maleficent pharmacological stress may have an unintentional influence on PMN immune functions.

We studied the direct effect of intravenous anaesthetics, local anaesthetics and premedication drugs in common use for major surgery, on the spontaneous versus lectin induced proliferation of cultured normal rat peripheral blood mononuclear cells, not exposed to surgical or any other trauma prior to culture. Peripheral blood mononuclear cells were incubated in cell-culture medium in the presence or in the absence of propofol, ketamine, fentanyl, midazolam, thiopental sodium, lidocaine or etomidate. The cells proliferated either spontaneously or under stimulation with a lectin phytohaemagglutinine P for 72 h. The proliferation rate was evaluated by 2H-Thymidine incorporation. Fentanyl, thiopental sodium, lidocaine and etomidate significantly inhibited phytohaemagglutinine P induced 3H-Thymidine incorporation in cultured rat peripheral blood mononuclear cells. Counts per minute of the cultures treated with these drugs were 1667.80±745.72, 1614.1±615.00, 1688.0±615.0 and 1549±560.41, respectively, compared with the phytohaemagglutinine P stimulated positive control counts per minute, 13488±4305.6 (P<0.001 in each comparison). Propofol, ketamine and midazolam inhibited the lectin-induced cell proliferation to levels not statistically different from the baseline. Counts per minute of these cultures were 1361.90±745.73; 1108.90±751.33 and 1518.10±848.88, respectively. Compared either with the baseline 972.57±356.73 counts per minute or to the positive control culture counts per minute, 13488±4305.6 the difference was statistically significant (P<0.001) in each comparison. All the substances tested in this study proved capable of exerting direct inhibitory effect on circulating immunocompetent cells, because the latter were not subjected to any other immunosuppressive factor, be it operative trauma, blood transfusion, malnutrition, drug abuse, prior to culture. The possible theoretical and practical implications are discussed in this study.

The physical compatibility of thiopentone and propofol mixtures was investigated. The investigations used were macroscopic and microscopic observations, zeta potential and oil droplet size measurements. There was no evidence of instability in the mixtures. The thiopentone–propofol mixture has the potential advantage of reducing the pain on injection, provides synergistic interaction, does not prolong recovery when used for induction of anaesthesia, may reduce the incidence of convulsions and is cost-effective.

We have used eltanolone and propofol to induce anaesthesia and by intermittent injection to supplement nitrous oxide during maintenance in 67 patients undergoing minor gynaecological surgery. This study was a controlled randomized phase III with two parallel groups and a blinded assessment of post-operative recovery. Complications during induction and maintenance were few. Urticaria occurred in two patients given eltanolone and in none of those given propofol. Time to orientation and time to eye opening were significantly shorter in the propofol group (P < 0.001). Systolic and diastolic blood pressure decreased in both groups but the decrease was significantly greater in the propofol group (P < 0.005 systolic blood pressure; P < 0.001 diastolic blood pressure). Heart rate decreased significantly in the propofol group (P < 0.002). We conclude that eltanolone anaesthesia is associated with a greater haemodynamic stability than propofol anaesthesia but that early recovery occurs more slowly.

Reports about post-operative infections associated with the use of propofol prompted us to investigate the in-use contamination of lipid-formulated intravenous (i.v.) anaesthetics used for general anaesthesia or for sedation of intensive care patients in this department. The level and incidence of extrinsic contamination of propofol (‘Diprivan’) and of another intravenous anaesthetic, etomidate, formulated in lipid solution (‘Etomidat-lipuro’) was found to be low during two study periods. However, the need to observe strict aseptic precautions in handling these intravenous drugs must be emphasized.

Abnormalities of platelet haemostasis pose increased risk to patients undergoing anaesthesia and surgery. We have investigated the effect of propofol on platelet aggregation in 12 patients undergoing upper and lower abdominal surgery. Propofol 2.5 mg kg−1 was administered via a cannula in the antecubital vein. Venous blood samples were obtained before induction and 10 min after administration of propofol. Platelet aggregation measurements were made for adenosine diphosphate (ADP), collagen and adrenaline. The results show that propofol does not affect platelet aggregation in the concentrations used.