Local anesthetic systemic toxicity

Mepivacaine is an aminoamide local anesthetic. Systemic toxicity is its major complication and can prove fatal. Vasoconstrictors are not warranted, as they do not alter the rate of systemic reactions. 

The authors point out that even though dura irrigation and infiltration with local anesthetics is commonly per-formed/ one has to be aware of fhe risk of local anesthetic systemic toxicity (LAST) with this route of adminisfration. 

Sites BD, Taenzer AH, Herrick MD, Gflloon C, Antonakakis J, Richins J, et al. Inddence of local anesthetic systemic toxicity and postoperative neurologic symptoms associated with 12,668 ultrasound-guided nerve blocks an analysis from a prospective clinical registry. Reg Anesth Pain Med 2012 37(5) 478-82. 

EMLA cream (lidocaine 2.5% and prilocaine 2.5%) consists of a eutectic mixture of focal anesthetics. It is used to provide topical anesthetic to intact skin. Other topical preparations are effective only on mucosal surfaces. EMLA has been shown to reduce pain on venipuncture and provide substantial anesthesia for skin graft donor sites. No significant local or systemic toxicity has been demonstrated. 

The efficacy of topical ocular anesthetics is usually determined by their ability to suppress corneal sensitivity When a dose-response relationship is determined for various anesthetics, a concentration for each drug is obtained beyond which no further increase in activity occurs. The concentration at which this maximum efficacy occurs is termed the maximum effective concentra-tion.Uhns, increasing the concentration of the anesthetic beyond the maximum effective concentration serves no useful purpose but increases the risk of local and systemic toxicity... 

Systemic hypersensitivity reactions are not a frequent problem in local anesthesia. Systemic toxicity or allergy to additives (hyaluronidase, bisulfate, parabens) has sometimes been mistakenly classified as hypersensitivity to local anesthetics (SEDA-17,135) (29). WeU-documented case reports are very few, relating particularly to the older aminoesters this appears to be because these agents have the highly antigenic para-aminobenzoic acid as a metabolite (SEDA-13, 98). The incidence of true allergy is actually very low, probably less than 1% of all the adverse effects attributable to these substances (SEDA-20, 123). 

Administration of a local anesthetic in a carbonic acid-carbon dioxide aqueous solution rather than the usual solution of a hydrochloride salt appreciably improves the time of onset and duration of action. This change in solution form is apparently not associated with local or systemic toxicity. 

Specific Local Anesthetic Agents. Clinically used local anesthetics and the methods of appHcation are summarized in Table 5. Procaine hydrochloride [51-05-8] (Novocain), introduced in 1905, is a relatively weak anesthetic having along onset and short duration of action. Its primary use is in infiltration anesthesia and differential spinal blocks. The low potency and low systemic toxicity result from rapid hydrolysis. The 4-arninobenzoic acid... 

An important property of the ideal local anesthetic is low systemic toxicity at an effective concentration. Onset of action should be quick, and duration of action should be sufficient to allow time for the surgical procedure. The local anesthetic should be soluble in water and stable in solution. It should not deteriorate by the heat of sterilization, and it should be effective both when injected into tissue and when applied topically to mucous membranes. Its effects should be completely reversible. 

Excellent and rapid anesthetization of an extremity can be obtained easily. Following insertion of an intravenous catheter in the limb of interest, a rubber bandage is used to force blood out of the limb, and a tourniquet is applied to prevent the blood from reentering a dilute solution of local anesthetic, most commonly lido-caine, is then injected intravenously. This technique fills the limb s vasculature and carries the anesthetic solution to the nerve by means of the blood supply. Because of the pain produced by a tourniquet after some time, this procedure usually is limited to less than 1 hour. The systemic blood levels of drug achieved after tourniquet release generally remain below toxic levels. 

The most commonly used vasoconstrictors, the sympathomimetic drugs, are often added to local anesthetics to delay absorption of the anesthetic from its injection site. By slowing absorption, these drugs reduce the anesthetic s systemic toxicity and keep it in contact with nerve fibers longer, thereby increasing the drug s duration of action. Administration of lidocaine 1% with epinephrine results in the same degree of blockade as that produced by lidocaine 2% without the vasoconstrictor. 

Local anesthetics are frequently coadministered with vasoconstrictor molecules such as epinephrine. Normally, they are applied or injected locally and then taken up by local blood vessels into the systemic circulation, ultimately leading to their metabolic breakdown. The co-administration of a vasoconstrictor decreases the systemic absorption of the local anesthetic, thereby increasing its effective half-life in the area of administration and decreasing the probability of systemic toxicity (i.e., cardiac toxicity) secondary to systemic distribution. 

Combining agonists with some local anesthetics greatly prolongs the duration of infiltration nerve block the total dose of local anesthetic (and the probability of toxicity) can therefore be reduced. Epinephrine, 1 200,000, is the favored agent for this application, but norepinephrine, phenylephrine, and other agonists have also been used. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal. 

Since blood levels are lowered up to 30% when vasoconstrictors are added to local anesthetics, localized neuronal uptake is enhanced because of higher local tissue concentrations in the region of drug administration, and the risks of systemic toxic effects are reduced. Furthermore, when used in spinal anesthesia, epinephrine acts directly on the cord to both enhance and prolong local anesthetic-induced spinal anesthesia by acting on a2 adrenoceptors, which inhibit release of... 

The two major forms of local anesthetic toxicity are (1) systemic effects following absorption of the local anesthetic from their site of administration and (2) direct neurotoxicity from the local effects of these drugs when high concentrations are administered in close proximity to the spinal cord and other major nerve trunks. When blood levels of local anesthetics rise rapidly, adverse effects on several major organ systems may be observed. 

Benzocaine is an ester local anesthetic with a moderate onset of action and short duration. It is minimally absorbed and therfore relatively free from systemic adverse effects (toxic range of total dose 200 to 300 mg Tetzlaff, 2000). 

Systemic effects are more likely to occur with long-acting anesthetics if an excessive dose is used, if absorption into the blood stream is accelerated for some reason, or if the drug is accidentally injected into the systemic circulation rather than into extravascular tissues.17 40 Other factors that can predispose a patient to systemic effects include the type of local anesthetic administered, as well as the route and method of administration.3 Therapists and other health care professionals should always be alert for signs of the systemic effects of local anesthetics in patients. Early symptoms of CNS toxicity include ringing/buzzing... 

Many substances of widely different chemical structure abolish the excitability of nerve fibers on local application in concentrations that do not cause permanent injury and that may not affect other tissues. Sensory nerve fibers are most susceptible, so that these agents produce a selective sensory paralysis, which is utilized especially to suppress the pain of surgical operation. This property was first discovered in cocaine, but because of its toxicity and addiction liability, it has been largely displaced by synthetic chemicals. The oldest of these, procaine (novocaine), is still the most widely used. Its relatively low toxicity renders it especially useful for injections, but it is not readily absorbed from intact mucous membranes and is therefore not very effective for them. Many of its chemical derivatives are also used. They differ in penetration, toxicity, irritation, and local injury as well as in duration of action and potency. Absolute potency is not so important for practical use as is its balance with the other qualities. If cocaine is absorbed in sufficient quantity, it produces complex systemic actions, involving stimulation and paralysis of various parts of the CNS. These are mainly of toxicological and scientific interest. Its continued use leads to the formation of a habit, resembling morphinism. This is not the case with the other local anesthetics. 

As the anesthetic agent is absorbed and thus removed from the site of application, its local action ceases, and its systemic and toxic effects start. Because most of these drugs, especially cocaine, are rapidly destroyed in the body, the systemic toxicity increases with the rapidity of absorption. It is therefore desirable and often necessary to delay the absorption. This may be done by restricting the local circulation. Cocaine itself tends to do this by producing a local vasoconstriction, an action that is not shared by its substitutes. This vasoconstriction should be reinforced by the addition of epinephrine. More dilute solution may thus be used, and the anesthetic effect is much more prolonged. With intracutaneous infiltration, the pressure and edema also result in ischemia. In suitable situations, the circulation may be slowed by bandages, or arrested by temporarily clamping the arterial blood supply. 

Two major forms of local anesthetic toxicity are recognized direct neurotoxicity from the local effects of certain agents administered around the cord or other major nerve trunks, and systemic... 

The only other anesthetic to cause serious toxicity for which a metabolic drug interaction has been reasonably well characterized is the local anesthetic and antiarrhythmic agent lidocaine. Amiodarone decreased lidocaine systemic clearance in a patient (primarily by inhibition of CYP3A4 N-dealkylation of lidocaine) and yielded concentrations of lidocaine that led to seizures (78,79). 

This test has been used since then many times each with slight variations. For instance, exposure of only one eye to the test substance and no exposure of the other eye or exposure of the other eye to the vehicle. To minimize discomfort to the animal, a local anesthetic is sometimes instilled before use of the test substance. The qualitative scoring system hasbeen extended using also measures of eye blinks or wipes. Examinations can also include magnifying glasses, slit lamp examination, fluorescein staining and photodocumentation. After observed toxicity, animals are sacrificed, the eyes removed and subjected to microscopic and histological examinations. 

Cocaine was also the first aminoester local anesthetic, and its adverse effects differ from those of other local anesthetics. Owing to its rapid absorption by mucous membranes, cocaine applied topically can cause systemic toxic effects. There is a wide variation in the rate and amount of cocaine that is systemically absorbed. This variability can be affected by the type and concentration of vasoconstrictor used with cocaine and also accounts for the differences in cocaine pharmacokinetics in cocaine abusers (SEDA-20,128). 

Marsch SC, Schaefer HG, Castelli I. Unusual psychological manifestation of systemic local anesthetic toxicity. Anesthesiology 1998 88(2) 531-3. 

---