British Journal of Anaesthesia - current issue

Advances in pharmacology and therapeutics

Hopkins, P. M., Hardman, J. G. — 2009-06-22

Advances in patient comfort: awake, delirious, or restrained

Trivedi, M., Shelly, M., Park, G. — 2009-06-22

Neurokinin-1 antagonists: a step change in prevention of postoperative nausea and vomiting?

Rowbotham, D. J. — 2009-06-22

Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting

Diemunsch, P., Joshi, G. P., Brichant, J.-F. — 2009-06-22

Despite major advances, emesis remains a major problem in the context of cancer chemotherapy and in the postoperative period. A better understanding of the relevant neurocircuitry, especially the central pattern generator responsible for emesis and the central role of substance P, led to the development of a new class of antiemetics: the neurokinin-1 (NK1) receptor antagonists. Aprepitant is the first NK1 receptor antagonist approved for use in postoperative nausea and vomiting, but several other compounds are currently being investigated for their potential as antiemetics in the postoperative and cancer chemotherapy settings.

Pharmacogenomic variability and anaesthesia

Searle, R., Hopkins, P. M. — 2009-06-22

The concept of ‘personalized medicine’ in which a knowledge of genetic factors guides prescribing tailored to the individual is popularly considered to be an inevitable consequence of completion of the International Human Genome Project. We should not forget, however, that a personal or family history of one of several uncommon pharmacogenetic conditions has influenced the use of the implicated drug(s) during anaesthesia for the past 50 yr. Although this has been important for those affected, pharmacogenomics heralds the prospect of an individual's genetic profile informing every prescription. Progress has been rapid in some areas, notably cancer chemotherapy where response to treatment can be predicted on the basis of the genetic profile of the tumour cells. The situation is different for most currently available drugs, including those used by anaesthetists, where genetic variability to drug response is presumed to be the result of a complex interaction of multiple factors. We review the nature and investigation of pharmacogenomic variability and contrast the progress made with research into opioid variability with the more limited literature concerning i.v. and inhalation anaesthetics.

Pharmacokinetic models for propofol--defining and illuminating the devil in the detail

Absalom, A. R., Mani, V., De Smet, T., Struys, M. M. R. F. — 2009-06-22

The recently introduced open-target-controlled infusion (TCI) systems can be programmed with any pharmacokinetic model, and allow either plasma- or effect-site targeting. With effect-site targeting the goal is to achieve a user-defined target effect-site concentration as rapidly as possible, by manipulating the plasma concentration around the target. Currently systems are pre-programmed with the Marsh and Schnider pharmacokinetic models for propofol. The former is an adapted version of the Gepts model, in which the rate constants are fixed, whereas compartment volumes and clearances are weight proportional. The Schnider model was developed during combined pharmacokinetic–pharmacodynamic modelling studies. It has fixed values for V1, V3, k₁₃, and k₃₁, adjusts V2, k₁₂, and k₂₁ for age, and adjusts k₁₀ according to total weight, lean body mass (LBM), and height. In plasma targeting mode, the small, fixed V1 results in very small initial doses on starting the system or on increasing the target concentration in comparison with the Marsh model. The Schnider model should thus always be used in effect-site targeting mode, in which larger initial doses are administered, albeit still smaller than for the Marsh model. Users of the Schnider model should be aware that in the morbidly obese the LBM equation can generate paradoxical values resulting in excessive increases in maintenance infusion rates. Finally, the two currently available open TCI systems implement different methods of effect-site targeting for the Schnider model, and in a small subset of patients the induction doses generated by the two methods can differ significantly.

Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile

2009-06-22

Opioid receptors are currently classified as µ (mu: mOP), (delta: dOP), (kappa: kOP) with a fourth related non-classical opioid receptor for nociceptin/orphainin FQ, NOP. Morphine is the current gold standard analgesic acting at MOP receptors but produces a range of variably troublesome side-effects, in particular tolerance. There is now good laboratory evidence to suggest that blocking DOP while activating MOP produces analgesia (or antinociception) without the development of tolerance. Simultaneous targeting of MOP and DOP can be accomplished by: (i) co-administering two selective drugs, (ii) administering one non-selective drug, or (iii) designing a single drug that specifically targets both receptors; a bivalent ligand. Bivalent ligands generally contain two active centres or pharmacophores that are variably separated by a chemical spacer and there are several interesting examples in the literature. For example linking the MOP agonist oxymorphone to the DOP antagonist naltrindole produces a MOP/DOP bivalent ligand that should produce analgesia with reduced tolerance. The type of response/selectivity produced depends on the pharmacophore combination (e.g. oxymorphone and naltrindole as above) and the space between them. Production and evaluation of bivalent ligands is an emerging field in drug design and for anaesthesia, analgesics that are designed not to be highly selective morphine-like (MOP) ligands represents a new avenue for the production of useful drugs for chronic (and in particular cancer) pain.

What makes a molecule an anaesthetic? Studies on the mechanisms of anaesthesia using a physicochemical approach

Sear, J. W. — 2009-06-22

Recent studies of mechanisms of anaesthesia have been mainly ‘target orientated’, investigating the activity of both volatile and i.v. agents at putative sites of action. An alternative approach is one that is ‘ligand orientated’, focusing on the properties of molecules that define their immobilizing ability and secondly define their potency. The use of conventional descriptors (such as non-polar solubility or the octanol–water partition coefficient [Log P]) are limited in their utility as predictors of potency as they represent three-dimensional molecular properties as a one-dimensional parameter. Using different computer-based molecular modelling methods (molecular similarity studies and comparative molecular field analysis [CoMFA]), we have identified the molecular bases of the activity of structurally diverse anaesthetics, such that they can be described as a single model based on the spatial distribution of molecular bulk and electrostatic potential. The same approach can also be used to model other properties of anaesthetic agents, such as cardiovascular depression. The present data suggest that, for the i.v. agents, it may be difficult to separate immobilizing (anaesthetic) activity and cardiovascular depression within a single molecule.

Sodium channels and the synaptic mechanisms of inhaled anaesthetics

Hemmings, H. C. — 2009-06-22

General anaesthetics act in an agent-specific manner on synaptic transmission in the central nervous system by enhancing inhibitory transmission and reducing excitatory transmission. The synaptic mechanisms of general anaesthetics involve both presynaptic effects on transmitter release and postsynaptic effects on receptor function. The halogenated volatile anaesthetics inhibit neuronal voltage-gated Na⁺ channels at clinical concentrations. Reductions in neurotransmitter release by volatile anaesthetics involve inhibition of presynaptic action potentials as a result of Na⁺ channel blockade. Although voltage-gated ion channels have been assumed to be insensitive to general anaesthetics, it is now evident that clinical concentrations of volatile anaesthetics inhibit Na⁺ channels in isolated rat nerve terminals and neurons, as well as heterologously expressed mammalian Na⁺ channel subunits. Voltage-gated Na⁺ channels have emerged as promising targets for some of the effects of the inhaled anaesthetics. Knowledge of the synaptic mechanisms of general anaesthetics is essential for optimization of anaesthetic techniques for advanced surgical procedures and for the development of improved anaesthetics.

Immunomodulation in the critically ill

Webster, N. R., Galley, H. F. — 2009-06-22

Immunotherapy in the critically ill is an appealing notion because of the apparent abnormal immune and inflammatory responses seen in so many patients. The administration of a medication that could alter immune responses and decrease mortality in patients with sepsis could represent a ‘magic bullet’. Various approaches have been tried over the last 20 yr: steroids; anti-endotoxin or anti-cytokine antibodies; cytokine receptor antagonists; and other agents with immune-modulating side-effects. However, in some respects, research along these lines has been unsuccessful or disappointing at best. The current state of knowledge is summarized with particular reference to sepsis and the acute respiratory distress syndrome.

Pharmacological optimization of tissue perfusion

Mongardon, N., Dyson, A., Singer, M. — 2009-06-22

After fluid resuscitation, vasoactive drug treatment represents the major cornerstone for correcting any major impairment of the circulation. However, debate still rages as to the choice of agent, dose, timing, targets, and monitoring modalities that should optimally be used to benefit the patient yet, at the same time, minimize harm. This review highlights these areas and some new pharmacological agents that broaden our therapeutic options.

Anaesthesia and myocardial ischaemia/reperfusion injury

Frassdorf, J., De Hert, S., Schlack, W. — 2009-06-22

Anaesthetists are confronted on a daily basis with patients with coronary artery disease, myocardial ischaemia, or both during the perioperative period. Therefore, prevention and ultimately adequate therapy of perioperative myocardial ischaemia and its consequences are the major challenges in current anaesthetic practice. This review will focus on the translation of the laboratory evidence of anaesthetic-induced cardioprotection into daily clinical practice.

Statins for all: the new premed?

Brookes, Z. L. S., McGown, C. C., Reilly, C. S. — 2009-06-22

The use of statins is widespread and many patients presenting for surgery are regularly taking them. There is evidence that statins have beneficial effects beyond those of lipid lowering, including reducing the perioperative risk of cardiac complications and sepsis. This review addresses the cellular mechanisms by which statins may produce these effects. Statins appear to have actions on vascular nitric oxide through the balance of inducible and endothelial nitric oxide synthase. The clinical evidence for these benefits is also briefly reviewed with the objective of clarifying the current status of statin use in the perioperative period. There is reasonably strong evidence that patients already taking statins should continue on them perioperatively. However, the evidence for the prophylactic use of statins perioperatively is weak and lacks prospective controlled studies.

Current concepts in neuromuscular transmission

Fagerlund, M. J., Eriksson, L. I. — 2009-06-22

The neuromuscular junction (NMJ) is structured and powered to transduce electrical activity from the distal nerve terminal of a motor neurone via the neuromuscular cleft to the post-junctional muscle membrane to ultimately generate muscle contraction. Our understanding of this complex function has expanded over many years, and the NMJ has served as a prototype for how different synapses operate in the peripheral and central nervous systems. The NMJ has a presynaptic part which is synonymous with the distal nerve ending, being responsible for neurotransmitter synthesis, packaging into vesicles, and subsequent vesicle transportation to active release sites where vesicle docking, fusion, and release of acetylcholine and other co-released transmitters finally take place. The synaptic cleft, filled with large molecular complexes that guarantee ultrastructural NMJ arrangement and signal transduction, allows for rapid diffusion and degradation of the neurotransmitter. The postsynaptic part consists of a folded muscle membrane into which nicotinic acetylcholine receptors (nAChRs) directly opposite the presynaptic active release sites are mounted and fixed by a cytoskeleton. This specialized postsynaptic region is closely associated with the perijunctional zone where a high density of sodium channels promote and amplify the signal in order to guarantee the propagation of the electrical activity to generate muscle contraction. The transduction process is maintained at load (i.e. high stimulus frequency) by a presynaptic mechanism allowing for sustained transmitter release over time at high demand. This positive feedback mechanism relies on neuronal nAChRs present on the distal nerve terminal, whereas the continuation of the transduction process at the postsynaptic part relies on the classical muscle type nAChR. In this review, we will focus on recent findings of potential clinical importance that will advance our understanding of the effects of neuromuscular blocking agents and neuromuscular monitoring and also our management of disorders of the neuromuscular system within anaesthesia and intensive care.

Reversal of neuromuscular block

Srivastava, A., Hunter, J. M. — 2009-06-22

The use of anticholinesterases to reverse residual neuromuscular block is efficacious only if recovery is already established. It was originally advised that at least the second twitch (T2) of the train-of-four response should be detectable before neostigmine is administered. Even in these circumstances, the full effect of anticholinesterases takes up to 10 min to achieve. Anticholinesterases also have muscarinic side-effects that require an antimuscarinic to be administered concomitantly. An ideal reversal agent could be given at any time after the administration of a neuromuscular blocking agent (NMBA), and should have no muscarinic side-effects. The gamma cyclodextrin, sugammadex, has been demonstrated to effectively antagonize even profound block produced by the aminosteroid NMBAs, rocuronium and vecuronium, by chelating them. The complex is then excreted in the urine. Sugammadex is ineffective in antagonizing the benzylisoquinolinium NMBAs. The dose should be adjusted according to the degree of residual block: sugammadex 16 mg kg^–1 for immediate reversal; 4–8 mg kg^–1 for antagonizing profound block (post-tetanic count 1–2); and 2 mg kg^–1 to antagonize moderate block (when T2 is detectable). As yet, the extent of any side-effects that may occur with this new antagonist is not fully known, although rarely adverse cardiovascular effects (hypotension, hypertension, prolonged QT interval) have already been reported.

Major complications of central neuraxial block: the Third National Audit Project: some comments and questions

2009-06-22

Bupivacaine chondrotoxicity

White, S. M., Turner, R., McNaught, A. F., McCartney, C., Webb, S. T., Ghosh, S. — 2009-06-22

Bispectral index sensor as a possible cause of postoperative visual loss after frontal craniotomy

Yamashita, S., Takahashi, H., Tanaka, M. — 2009-06-22

Video laryngoscopy and external laryngeal manipulation

2009-06-22

Response entropy-state entropy difference and nociception: a matter of context

Mathews, D. M., Aho, A. J., Yli-Hankala, A., Lyytikainen, L.-P., Jantti, V. — 2009-06-22

Diagnosis of vertebral canal haematoma by myelography and spiral computer tomography in a patient with an implantable cardioverter-defibrillator contraindicating magnetic resonance imaging

Boye, S., Schumacher, J. — 2009-06-22

Incidental recognition of an aspirated tablet in an oesophagectomized patient

2009-06-22

Familial Mediterranean fever abdominal pain during spinal anaesthesia

Sert, H., Muslu, B., Usta, B., Gozdemir, M. — 2009-06-22

A Practical Approach to Pediatric Anesthesia

Barker, I. — 2009-06-22

Stewart's Textbook of Acid-Base

Soni, N. — 2009-06-22

Clinical Pain Management--Practice and Procedures

Chambers, W. A. — 2009-06-22

Ultrasound in Anesthetic Practice

Dowling, M., Bedforth, N. — 2009-06-22

Clinical Anesthesia--Near Misses and Lessons Learned

Sirian, R., Hardman, J. G. — 2009-06-22