The introduction of the new long acting local anaesthetics, bupivacaine and etidocaine, has stimulated an expansion of interest in regional anaesthesia, particularly for obstetrical applications and pain therapy. System toxicity following injection of local anesthetics occurs albeit infrequently, and tentative correlations have been made between the onset of CNS and cardiovascular effects and circulating drug concentrations in both adults and neonates. Amongst other factors, interpretation of these relationships depends upon blood distribution and plasma binding of the agents, sampling sites and acid-base balance. The disposition kinetics and placental transfer of the amide type agents have been well characterised. In adults their clearance is almost entirely hepatic but in neonates an increase in the renal component is, in part, a reflection of the immaturity of some of the enzymes responsible for their metabolism. Ester type agents are rapidly hydrolysed by plasma pseudocholinesterase and this has led to a preference for chloroprocaine in some obstetric procedures. Major determinants of the systemic absorption of the agents after perineural administration include their physicochemical and vasoactive properties, perfusion and tissue binding at the site of injection and whether or not adrenaline has been added. In respect of blood drug concentrations achieved after various regional anaesthetic procedures, the margin of systemic safety appears to favour bupivacaine and etidocaine compared to shorter acting analogues such as lignocaine and mepivacaine. The time course of local anaesthetic remaining at the site of injection has been calculated following intravenous regional anaesthesia and peridural block. This has allowed prediction of the local and systemic accumulation of the drugs following contined dosage. Blood concentrations of local anaesthetics after perineural injection are not closely related to age, weight or pregnancy but may be influenced by diseases associated with haemodynamic changes and by other drugs given at or around the time of regional blockade.

Fentanyl, a synthetic opiate with a (clinical) potency of 50 to 100 times that of morphine, was introduced into clinical practice in the early 1960s. Usually administered by single intravenous doses, it developed a reputation for having a short duration of action and it was assumed that this was a consequence of rapid removal from the body. However, as clinical experience increased, it was realised that administration of multiple doses or large doses during narcotic-based anaesthesia sometimes led to delayed recovery and prolonged respiratory depression, suggesting that the duration of action was limited by redistribution within the body rather than removal from the body. Recent developments in analytical techniques have allowed pharmacokinetic studies and these have confirmed this opinion; fentanyl is rightly regarded as having a redistribution-limited duration of action after single or infrequent doses (analogous to thiopentone). However, the magnitude of the pharmacokinetic constants reported for fentanyl are remarkably inconsistent even in healthy volunteers, for reasons apparently only explainable by assay differences. Hence, estimates of apparent volume of distribution (area) range from around 60L to over 300L, estimates of terminal half-life range from about 1.5 to 6 hours (15 hours in geriatric patients) and total body clearance ranges from 0.4 to over 1.5 L/min. Renal excretion accounts for up to 10% of the dose; the remainder of the clearance would appear to be predominantly hepatic, but with contributions from other tissues. Continued clinical developments of narcotic-based anaesthetic techniques have resulted in high doses of narcotic being used, with oxygen, as the sole anaesthetic agents. At present these techniques are usually based on fentanyl, and the technique is frequently called 'stress-free anaesthesia' because of the effects in obtunding the 'stress response' caused by surgery (elevation of plasma concentrations of cortisol, glucose, ADH, etc. in the intra- and post-operative period) and the lack of deleterious effects on the cardiovascular system.(ABSTRACT TRUNCATED AT 400 WORDS)

Levobupivacaine comprises 50% of commercially available bupivacaine and is being considered for use in its own right. Local anesthetics can cause toxicity to the cardiovascular and central nervous systems. As a part of a preclinical evaluation of levobupivacaine, this study compared the toxic effects of levobupivacaine and bupivacaine in sheep.

We performed a double-blinded, randomized, controlled trial in 15 patients to determine the efficacy of intrathecal morphine or clonidine, alone or combined, in the treatment of neuropathic pain after spinal cord injury. The combination of morphine and clonidine produced significantly more pain relief than placebo 4 h after administration; either morphine or clonidine alone did not produce as much pain relief. In addition, lumbar and cervical cerebrospinal fluid (CSF) concentrations, sampled at these levels at different times after administration were examined for a relationship between pain relief and CSF drug concentration. Lumbar CSF drug concentrations were initially several orders of magnitude larger than those in cervical CSF. After 1-2 h, the concentrations of morphine in cervical CSF markedly exceeded those of clonidine. The concentration of morphine in the cervical CSF and the degree of pain relief correlated significantly. We conclude that intrathecal administration of a mixture of clonidine and morphine is more effective than either drug administered alone and is related to the CSF-borne drug concentration above the level of spinal cord injury. If there is pathology that may restrict CSF flow, consideration should be given to intrathecal administration above the level of spinal cord damage to provide an adequate drug concentration in this region.

PDRM 3Outcome Hyperkalaemia (potassium level of at least 5.5mmol/L) Process of care Use of an ACE inhibitor without monitoring the potassium level before starting therapy, within six weeks of commencement and at least annually thereafter (n=44) PDRM 4Outcome Fall or broken bone Process of care: Uuse of a long half-life hypnotic-anxiolytic (n=41) ■ Few approaches to the assessment of quality of medicines use have focussed on the evidence base for treatment ■ A valid instrument (medication assessment tool -MAT) was developed from the Scottish intercollegiate guidelines network heart failure guideline ■ The MAT was found to be sensitive to change in prescribing using hospital admission and discharge data ■ The MAT demonstrated very good inter-rater agreement when applied to patient data from a heart failure clinic ■ The MAT offers a novel in-process approach to the assessment of medication use in practice and may provide a means to establish acceptable standards of medication adherence to national guidelines

The incidence of pain in 170 children recovering from surgery was surveyed in two major teaching hospitals along with an analysis of analgesic medication prescribed and administered. Analgesic medication was not ordered for 16% of the patients and narcotic analgesic medication ordered was not given for 39% of the patients. In 29% of the patients, where an order for "narcotic or non-narcotic analgesic medication' was written, the non-narcotic drug was given exclusively. Irrespective of the treatments received, only 25% of the patients were pain free on the day of surgery and 13% reported severe pain. By the first postoperative day, 53% reported no pain but 17% still reported severe pain. There appeared to be no relationship between ages of patients and severity of pain reported. Analysis of orders written for postoperative analgesics revealed extremely variable prescribing habits of the medical staff and that doses frequently were too small and/or too infrequent. The majority of orders were written "PRN' which often was interpreted by nursing staff as "as little as possible.' Nursing staff also preferred not to give narcotic medications but substituted non-narcotic analgesics, even soon after surgery. Many of the children surveyed became withdrawn and this was interpreted as coping with pain. Others expressed a dread of "the needle' as a way of administering analgesics and preferred to suffer pain to an injection. We have concluded that there is considerable scope to improve pain management in children after surgery. This improvement must be based on improved education of medical and nursing staff in contemporary clinical pharmacology and on improved communication between staff, parents and patients.

The recognition that long-acting local anaesthetics, particularly bupivacaine the de facto standard long-acting local anaesthetic, were disproportionately more cardiotoxic than their shorter-acting counterparts stimulated the development of the bupivacaine congeners, ropivacaine and levobupivacaine. These agents, like all local anaesthetics, can produce cardiotoxic sequelae by direct and indirect mechanisms that derive from their mode of local anaesthetic actions, i.e. inhibition of voltage-gated ion channels. While all local anaesthetics can cause direct negative inotropic effects, ropivacaine and levobupivacaine are less cardiotoxic than bupivacaine judging by the larger doses tolerated in laboratory animal preparations before the onset of serious cardiotoxicity (particularly electro-mechanical dissociation or malignant ventricular arrhythmias). Additionally, they are less toxic to the CNS than bupivacaine judging by the larger doses tolerated before the onset of seizures. This may be clinically important because CNS effects may be involved in the production of serious cardiotoxicity. Preclinical studies in humans are a 'blunt instrument' in their ability to distinguish significant differences between these drugs because of the relatively small doses that can be used. Nevertheless, available evidence from human studies corroborates the preclinical laboratory animal studies. Because clinically significant differences between these drugs are more quantitative than qualitative, i.e. toleration of a larger dose before manifestation of toxicity, we have concluded that these newer agents have a lower risk of causing serious cardiotoxicity than bupivacaine. Thus, compared with bupivacaine, the newer agents may be seen as 'safer', but they must not be regarded as 'safe'.

The risk of accidental intravascular injection and consequent acute toxicity is ever-present with most neural blockade techniques. The severity of cardiovascular and central nervous system (respectively, CVS and CNS) toxicity is directly related to the local anesthetic potency, dose, and rate of administration. Nonetheless, although the anesthetic potency of ropivacaine and levobupivacaine is similar to that of bupivacaine, at usual clinical doses, ropivacaine and levobupivacaine are less likely than bupivacaine to cause convulsions or lethal dysrhythmias. Signs of CNS stimulation, ranging from tremors to convulsions and perhaps cardiac dysrhythmias, can be described in terms of a chaos-derived state change in which the local anesthetic appears to act as an initiator. Both CNS and CVS effects are rather poorly correlated with arterial drug concentrations but better correlated with concentrations in the respective regional venous drainage. Lung uptake reduces the maximum drug concentration by approximately 40%. Prolonging intravenous administration from 1 to 3 minutes results in a similar decrease in maximum concentration. This is an underlying tenet of dose fractionation, but the main advantage of dose fractionation is that the anesthesiologist is able to cease administration with less of the dose given if signs or symptoms of toxicity occur. Overall, it appears that the gains in safety from ropivacaine and levobupivacaine are due more to favorable pharmacodynamic enantioselectivity than to pharmacokinetic factors. This essay presents some pharmacokinetic aspects relevant to acute toxicity of local anesthetics, mainly using data from the authors' studies in a sheep model of simulated accidental intravenous administration.