Neurotoxicity: Local anesthetics are potentially neurotoxic; and in clinical practice injected doses are frequently much greater than those thought capable of producing neurotoxicity. It is the presence of the perineurium acting as a diffusion barrier which prevents excessively high concentrations of local anesthetic from reaching the intraneural structures. Neurotoxicity is likely to occur only with intraneural injection, and is accompanied by intense pain. Pain may be the only initial indication of trouble to come and many conservative practitioners will avoid performing nerve blocks on patients who are excessively sedated, or otherwise uncommunicative and who may not be able to give warning of the intraneural injection. For similar reasons, care should be exercised when supplementing pre-existing nerve block.

Allergy: As noted above, allergic reactions to amide local anesthetics are rare; careful history elicited from those with a history of an allergic reaction to amides quite often reveals symptoms of tachycardia, chest tightness and lightheadedness - the consequence of intravascular injection of epinephrine, a common additive to a local anesthetic mixture. True allergies to ester local anesthetics are also not common, but do occur; ester local anesthetics should certainly be avoided in individuals with allergies to PABA. If signs or symptoms of allergic response occur then standard medical interventions need to be implemented immediately, get assistance, support the airway, administer fluids and don't delay giving epinephrine in the event of hypovolemic shock and/or severe bronchospasm.

Systemic Toxicity: Most systemic reactions occur as a result of inadvertent intravascular injection or injection into a highly vascular tissue bed with resultant rapid local anesthetic uptake into the circulating system; the danger sites are the brain and the heart. Incorporation of epinephrine 5 mg/mL into the local anesthetic dose (1:200,000 dilution) both delays systemic absorption and, more significantly, when used as a test-dose can warn of intravascular injection by eliciting tachycardia.11 Central nervous and cardiovascular system toxicity are dose and time dependent. The faster plasma levels of local anesthetic rise, the more likely that an adverse reaction will occur. Prevent high blood levels by always using the lowest dose/weakest concentration compatible with desired effect, and by injecting slowly or in divided doses; minimize redistribution by incorporating epinephrine or phenylephrine in the mix.

Initial symptoms of CNS toxicity are tinnitus, metallic taste, difficulty focusing, lightheadedness, circum-oral numbness and intellectual confusion; note that these responses can only be detected in an awake, alert patient, as a consequence performing regional blocks on comatose subjects takes away one level of safety. If brain tissue levels continue to rise the patient will experience muscle twitching, tremors and then generalized tonic-clonic convulsions resulting in loss of consciousness, generalized CNS depression and respiratory arrest. If seizures occur, the airway should be protected and the patient mask ventilated with oxygen until the seizure abates. If necessary, the seizure can be aborted with diazepam or sodium pentothal and the patient intubated and ventilated.

Cardiovascular toxicity is most frequently associated with the use of bupivacaine, however, all local anesthetics affect the cardiac electrical conducting system, depress the myocardium and peripheral vascular smooth muscle. As in nerve, they reduce the action potential in the heart by limiting the inward flow of sodium current. Lidocaine is a "fast-in, fast-out" sodium channel blocker that reaches steady-state block in one or two beats. Bupivacaine, conversely is "fast-in, slow-out" and channel inhibition increases with successive beats and with faster heart rates. The reason for this is that several local anesthetics, bupivacaine included, will only penetrate the ion channel when it is in the "open" conformation.

Local anesthetics prolong conduction time in the heart (prolonged PR and QRS intervals). Increasing plasma levels will suppress the sino-atrial and atrio-ventricular nodes causing sinus bradycardia, conduction block, electrical inexcitability and cardiac arrest. Bupivacaine's "fast-in, slow-out" action makes the heart vulnerable to malignant re-entry cardiac arrhythmias. The ratio of the dosage required for irreversible cardiovascular collapse and the dosage that will produce CNS toxicity, CC/CNS ratio, is approximately 7:1 for lidocaine and 4:1 for bupivacaine indicating that bupivacaine has greater cardiovascular toxicity that lidocaine; (the heart is further sensitized to bupivacaine during pregnancy). Commercially available bupivacaine is the racemic mixture of its r and s enantiomers. The pure s isomeric form of bupivacaine is now commercially available (as chirocaine), and it complements ropivacaine, a relatively new homologue of s-bupivacaine. Early studies with ropivacaine suggested that it might be significantly less cardiotoxic than bupivacaine; however, adjusting for ropivacaine's lesser potency, equipotent doses seem to confer approximately the same degree of cardiotoxicity as bupivacaine. Similar, preliminary, data has now been obtained with chirocaine although clinical trials with this drug are in their infancy.

Little is known about the most appropriate anti-arrhythmic to use during local anesthetic induced cardiac arrest. High doses of epinephrine and atropine may be appropriate, bretylium may be of benefit in cases of bupivacaine toxicity. In the cardiac arrest situation one must pay particular attention to oxygenation and ventilation and be prepared to perform cardiopulmonary resuscitation for an indefinite period of time. In extreme situations, cardiopulmonary bypass may have to be implemented until the effects of the local anesthetic have dissipated. Understand that if organ oxygenation and perfusion can be maintained effectively until local anesthetic levels diminish the patient will recover fully.

One final note on toxicity; both benzocaine and prilocaine (more correctly its o-toluidine metabolite) produce methemoglobinemia which both reduces the oxygen-carrying capacity of hemoglobin and impairs oxygen release, and promotes a noticeable cyanosis when present in high doses. In patients monitored by pulse oximetry probes methemoglobinemia causes the probe to read 85%, regardless of the actual SaO2 (i.e. a falsely low saturation reading when SaO2 is actually >85%, and a falsely high reading when it is actually <85%). Treatment of this complication involves administration of methylene blue or ascorbic acid. Prilocaine is no longer available in the US as the pure drug, but is present in the topical anesthetic mixture EMLA (see above).