1. szöveg

Toxicity of local anaesthetic agents

Local anaesthetic agents can cause neurotoxicity, myotoxicity and systemic toxicity. The mechanisms of direct neurotoxicity and myotoxicity are similar and independent of sodium channel blockade. Systemic local anaesthetic toxicity can cause serious morbidity and mortality, the incidence appears to be stable despite the hope that widespread use of ultrasound for regional anaesthesia would reduce its incidence. Occurrence of systemic local anaesthetic toxicity is reliant on the interaction between patient characteristics, the rate of rise and the plasma level of local anaesthetic achieved.  The most significant advancement in the treatment of local anaesthetic toxicity is the introduction of lipid emulsion. However, there still have been few case reports of successful use and the mechanism of action is yet to be clarified.

Direct neurotoxicity

Neurotoxicity from local anaesthetic agents manifests as persistent neurological injury that is unrelated to needle trauma. It has been closely linked to both the intrathecal administration of high concentration lignocaine (5% solution) and the use of spinal microcatheters. The provoking factor in this neurotoxicity is thought to be the exposure of the cauda equina to a high concentration of local anaesthetic. This occurs with the use of a spinal micro catheter due to the inability to cause a turbulent flow due to the small diameter of the catheter and subsequent pooling of the local anaesthetic around the nerve roots. Exposure of nerves with minimal connective tissue protection to high concentrations of local anaesthetic is probably not possible outside the subarachnoid space and hence this phenomenon has only been described in clinical practice in association with spinal anaesthesia.

The exact cellular mechanism is unknown but it is probably unrelated to direct Na⁺ channel blockade. It is postulated that cellular damage occurs due to mitochondrial damage through depletion of ATP, the uncoupling of oxidative phosphorylation and the production of oxygen free radical species.

 Myotoxicity

Several studies have been aimed at elucidating the mechanism of local anaesthetic myotoxicity which seems to affect striated and smooth muscle fibres in a dose dependent manner. Ropivacaine in vitro seems to cause smooth muscle fibre damage through hypercontraction of the myocyte triggered by increased Ca²⁺ influx from the extracellular space and increasing Ca²⁺ release from the sarcoplasmic reticulum. The pattern of damage to striated muscle fibres seems to be similar with triggering of hypercontraction followed by lytic degeneration of the sarcoplasmic reticulum, cellular oedema and necrosis.

The pathological release of Ca²⁺ is agent specific and is related to high concentrations of local anaesthetics. At concentrations >1 mmol/l most local anaesthetics activate the RyR receptor, leading to the release of significant amounts of Ca²⁺ from the sarcoplasmic reticulum. Conversely, at low concentrations these channels are inhibited. While these findings have been repeatedly found in vitro, it has been hard to correlate this with myotoxicity in the clinical setting. It is possible that only low concentrations of local anaesthetic occur after peripheral nerve blocks, or other more significant causes of muscle damage such as surgical injury occur. Additionally, it is possible that low levels of myotoxicity frequently occur, but the symptoms of pain and weakness are attributed to surgical causes.

Systemic toxicity

Only small amounts of injected local anaesthetic are taken up into the nerve. The remainder of the dose given is taken up into the systemic circulation. The rate at which it is taken up is dependent on the proximity of blood vessels, the concentration gradient for its uptake and the diffusion characteristics of the drug. The plasma concentration will depend on the rate of absorption and the rate of clearance from the body.

It is the plasma which is the vehicle for delivery of drugs to their effect sites, and while dependent on a number of physicochemical characteristics of the drug, it is expected that there is a consistent relationship between the plasma level and the effect site concentration. Many textbooks reiterate a fairly constant plasma level concentration at which neurological and then cardiovascular symptoms occur. However, if one examines the literature on which this is based, it becomes evident that it is difficult to draw such firm conclusions about the plasma levels that cause toxicity from the available evidence. No dose of local anaesthetic is potentially safe if administered in the incorrect position. Slowly rising plasma levels are much better tolerated than rapidly rising levels and in general, plasma levels cannot be predicted from the dose that is used during peripheral nerve block, both unexpectedly high and low levels may occur for a given dose.

Since the initial paper by Weinberg et al. suggesting that intravenous lipid emulsion could treat local anaesthetic toxicity, there has been a fairly rapid incorporation of lipid emulsion into algorithms for treatment of local anaesthetic toxicity.

This rapid incorporation has occurred despite only 20 case reports in the literature of successful lipid emulsion use in local anaesthetic toxicity.  This rapid incorporation perhaps reflects the lack of satisfactory alternative measures and the perception that there are few, if any side effects from lipid emulsion treatment. There has not yet been a case report of an unsuccessful resuscitation from local anaesthetic toxicity with the appropriate use of lipid emulsion, although this may reflect publication bias.

 

Kelly Byrne, Conrad Engelbrecht 

Trends in Anaesthesia and Critical Care, 29 August, 2012