Though surgical administrators often don't deal directly with the pharmacodynamics and pharmacokinetics of local anesthetics, it wouldn't hurt to gain an understanding of these complexities from an anesthesia provider's perspective. Doing so will give you the ability to discuss with your providers the way local anesthesia is used in your facility and will help you set standards of care, enhancing safety. To aid your understanding, let's look at the myths surrounding dosing and the issues surrounding local anesthetic side effects.

The myth of the maximal safe dose
Why do books and journal articles persist in defining a maximal drug dose? Many factors influence the ability of a given local anesthetic to produce adequate regional anesthesia, including the dose, site of administration and additives - and these factors aren't independent of one another. So it's illogical to speak of one maximal dose of local anesthetic that will be safe regardless of where and how it's administered.1 By looking at the components of local anesthetics - including the myths within the myth - we can better understand why we can't assume a safe dose.

• Potency and duration. The nerve-blocking potency of local anesthetics increases in correlation with molecular weight and lipid solubility.2,3 Larger, more lipophilic local anesthetics permeate nerve membranes - a huge percentage of which are composed of lipids - more readily and bind sodium ion-channels with greater affinity. More lipid-soluble local anesthetics (such as bupivacaine or ropivacaine) are relatively water-insoluble, highly protein-bound in blood, less readily removed by the blood stream from nerve membranes and more slowly "washed out" from isolated nerves in vitro. The greater the lipid solubility of a local anesthetic, the more tightly it tends to bind to the sodium channel (the protein-rich site of action), increasing potency, lengthening the duration of action (and unfortunately also increasing the tendency for severe cardiac toxicity).
• Speed of onset. While higher lipid solubility makes for a more potent and long-lasting anesthetic, it also decreases the speed of onset. This has to do with there being an increased number of places where lipid-soluble local anesthetics might be led astray on their way to their binding sites. The textbooks tend to emphasize an unrelated factor: Local anesthetics with a higher pKa (the pH at which there are an equal number of charged and uncharged anesthetic molecules on either side of a nerve's membrane) tend to have a slower onset time. However, despite what the books say, this is not a consistent finding. Of the two local anesthetics of fastest onset, etidocaine is highly lipid-soluble and chloroprocaine has a high pKa, minimizing the value of generalizations about pKa and speed of onset. So much for that rule.
• Differential sensory nerve block. You usually can't obtain sensory anesthesia sufficient for skin incision without motor impairment.4,5,6 All local anesthetics will block smaller-diameter fibers at lower concentrations than are required to block larger fibers of the same type.7 Some are more selective than others: Bupivacaine and ropivacaine, for example, are relatively selective for sensory fibers. Bupivacaine produces more rapid onset of sensory than motor block, whereas the closely related chemical mepivacaine demonstrates no differential onset during regional nerve blocks.8 Could sensory and motor nerves have different local anesthetic binding sites? In fact, there are differing sodium channel forms in unmyelinated nerves, motor nerves and dorsal root ganglia, offering the tantalizing possibility that specific antagonists may someday be produced that can produce sensory anesthesia without any motor nerve block at all.9,10 A more specific drug could have fewer side effects. For example, if the drug bound to channels in sensory nerves but not to channels in the heart, it's possible that the drug might be incapable of producing cardiac toxicity.
• Site of administration. As the local anesthetic dose increases, so do the likelihood of success and the duration of anesthesia, while the delay of onset and tendency for differential block decrease. In general, the fastest onset and shortest duration of anesthesia occurs with spinal or subcutaneous injections; a slow onset and long duration are obtained with plexus blocks.11 The difference between local anesthetic concentrations in the blood after injection of the same dose in different sites is quite sizable; intercostal blocks produce the greatest concentration, while sciatic-femoral and other plexus blocks produce the lowest. (Epidural and caudal blocks fall between these two extremes). Further, the maximal tolerable dose for any local anesthetic is infinitesimally small when given into any artery that feeds the brain. But with the same dose, intercostal blocks consistently produce greater peak local anesthetic concentrations than plexus or epidural blocks.5,11,12,13 Again, it's illogical to try to pin a maximum dose with this kind of variation.
• Additives. The additives in your local anesthetic can change its potency, duration and speed of onset. Epinephrine, which is frequently added to local anesthetic solutions to cause vasoconstriction and serve as a marker for intravascular injection, increases local anesthetic duration largely by prolonging and increasing intra-neural concentrations of anesthetic.5,12,14 Other popular additives include clonidine, NaHCO3, opioids and hyaluronidase. Local anesthetics have greater apparent potency at basic pH than at a more acidic one.15 Not surprisingly, then, some clinical studies show that the addition of sodium bicarbonate speeds the onset of nerve blocks.5,12

The many faces of toxicity
Though adverse reactions to local anesthetics generally are the result of too much anesthetic, there are many mechanisms of action by which they can occur. It's not safe to assume, as many providers do, that side effects arise only from sodium-ion channel inhibition - this may not even be the case for cardiovascular toxicity. There's more to it, and you have to be prepared to recognize and handle each form of toxicity.

Aside from sodium-ion channels, local anesthetics will bind to - and inhibit - many other targets, including voltage-gated potassium and calcium channels, enzymes, NMDA receptors, b-adrenergic receptors, G-protein-mediated modulation of potassium and calcium channels and nicotinic acetylcholine receptors.6,17,18 Local anesthetics' binding to these other sites could not only underlie the production of spinal or epidural analgesia, but could also contribute to toxic side effects.6,19,20 Let's look at the types of side effects that can occur, why they happen and how to deal with them.

• Central nervous system side effects. This kind of toxicity results from inhibition of excitatory pathways in the CNS, producing a stereotypical sequence of signs and symptoms.4,5,11,12 As the local anesthetic dose increases, patients may experience light-headedness, tinnitus, numbness of the mouth and face, a metallic taste, double vision and slurred speech. Seizures may also arise due to this CNS excitation.4,5 If for some reason dosing continued beyond that which produced seizures, CNS excitation progresses to CNS depression and eventual respiratory arrest. More potent local anesthetics (such as bupivacaine) produce seizures at lower blood concentrations and lower doses than less potent drugs (such as lidocaine). Both metabolic and respiratory acidosis can decrease the dose that can trigger these effects.21
• Cardiovascular toxicity. Local anesthetics bind to and inhibit cardiac sodium-ion channels, inhibiting conduction in the heart with the same rank order of potency as for nerve block.4,19,22,23 Local anesthetics will produce dose-dependent myocardial depression, possibly from interference with calcium-signaling mechanisms within cardiac muscle.24 (In the heart, local anesthetics such as levobupivacaine and ropivacaine less potently bind and inhibit sodium-ion channels than bupivacaine.6,19,25 Bupivacaine binds channels more avidly and longer than lidocaine does.26)

In animal studies, most local anesthetics will not produce CV toxicity until the blood concentration exceeds three times the amount that produces seizures; however, there are clinical reports of simultaneous CNS and CV toxicity with bupivacaine at doses below that threshold.4,5,12 These studies also appear to show that bupivacaine is more likely to induce cardiac toxicity than levobupivacaine, lidocaine or ropivacaine.27-32 Further, these drugs, despite their being in the same class, appear to act differently in the body, which raises this question: Does CV toxicity arise from the same mechanism? Consider this evidence:

• The potent local anesthetics (such as bupivacaine) seem much more prone to produce arrhythmias.
• The less potent agents (such as lidocaine) more likely produce left-ventricular depression.
• Resuscitation drug failure occurs most often with bupivacaine.

The likely answer is that the mechanism - and, thus, the treatment - depends on which local anesthetic has been administered.

• Treatment of local anesthetic toxicity. Treatment of adverse local anesthetic reactions depends on their severity. Minor reactions can be allowed to terminate spontaneously. Local-anesthetic-induced seizures should be managed by maintaining the airway and providing oxygen. Seizures may be terminated with intravenous thiopental (1-2 mg/kg), midazolam (0.05-0.10 mg/kg) or propofol (0.5-1.5 mg/kg).5 If local anesthetic intoxication produces CV depression, hypotension may be treated by infusion of intravenous fluids and vasopressors (phenylephrine 0.5-5 mg/kg/min, norepinephrine 0.02-0.2 mg/kg/min or vasopressin 2-20 units IV). If myocardial failure is present, epinephrine (1-15 mg/kg IV bolus) may be required.

When toxicity progresses to cardiac arrest, the guidelines for advanced cardiac life support are reasonable.33 However, you could substitute amiodarone and vasopressin for lidocaine and epinephrine, respectively.34-36 With unresponsive bupivacaine cardiac toxicity, considered intravenous lipid or cardiopulmonary bypass.37 Recent animal experiments demonstrate the remarkable ability of lipid infusion to resuscitate animals from bupivacaine overdosage, even after 10 minutes of unsuccessful conventional resuscitative efforts.38-40 The first reports of lipid being used for human resuscitation from local anesthetic toxicity are only now emerging.

Known and unknown
Local anesthetics have come a long way from the days when cocaine was used to produce spinal and epidural anesthesia. As the range of options has increased, so has our appreciation for the myriad toxic effects of these drugs.41

After 120 years of medical use, some features of local anesthesia are well understood: Peripheral nerve blocks are almost certainly the result of inhibition of sodium-ion channels in neuronal membranes. Conversely, the mechanisms of spinal and epidural anesthesia remain poorly defined.

In addition, the mechanisms by which local anesthetics produce CV toxicity likely vary with the more potent agents (such as bupivacaine) producing arrhythmias through (likely) sodium-ion-channel action, and with the less potent agents (such as lidocaine) producing myocardial depression via other pathways.