Pharmaceutical Information

XYLOCAINE Parenteral Solutions 0.5, 1, 1.5 and 2% contain lidocaine hydrochloride 5, 10, 15 and 20 mg/mL, respectively. Solutions with epinephrine contain 0.010 mg/mL (1:100,000) or 0.005 mg/mL (1:200,000) epinephrine.

Non-medicinal Ingredients

Plain Solutions: Sodium chloride (for isotonicity), water for injection, sodium hydroxide and/or hydrochloric acid to adjust pH 5.0-7.0.

Solutions with Epinephrine: Sodium chloride (for isotonicity), sodium metabisulfite (as an antioxidant), water for injection, sodium hydroxide and/or hydrochloric acid to adjust pH 3.3-5.5. Certain vial presentations may contain citric acid which acts as a stabilizer for epinephrine. Please refer to the product label.

Multidose Vials: As above and methylparaben (as a preservative) 1 mg/mL.

Last updated on RxList: 5/7/2008

XYLOCAINE Parenteral Solutions (lidocaine hydrochloride) are indicated for production of local or regional anesthesia by infiltration techniques including percutaneous injection, by peripheral nerve block techniques such as brachial plexus and intercostal blocks, and by central neural techniques including epidural and caudal blocks, when the accepted procedures for these techniques, as described in standard textbooks, are observed.

Adults: Table 2 (Recommended Dosages) summarizes the recommended volumes and concentrations of XYLOCAINE Parenteral Solutions (lidocaine hydrochloride) for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated.

These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient. In all cases the lowest concentration and smallest dose that will produce the desired result should be given. Dosages should be reduced for children, elderly and debilitated patients, and patients with cardiac and/or liver disease.

Children: In children the dosage should be calculated on a weight basis up to 5 mg/kg. With the addition of epinephrine, up to 7 mg/kg can be used. Individual variations occur. In children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.

The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (i.e. total dose) of local anesthetic used. Thus, an increase in volume and concentration of XYLOCAINE will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia. However, increasing the volume and concentration of XYLOCAINE may result in a more profound fall in blood pressure when used in epidural anesthesia. Although the incidence of side effects with lidocaine is quite low, caution should be exercised when employing large volumes and concentrations since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected. The risk of reaching a toxic plasma concentration or inducing a local neural injury must be considered when prolonged blocks and/or repeated administration are employed.

In general, complete block of all nerve fibres in large nerves requires the higher concentrations of drug. In smaller nerves, or when a less intense block is required (e.g., in the relief of labour pain), the lower concentrations are indicated. The volume of drug used will affect the extent of spread of anesthesia.

The duration of effect can be increased by using solutions containing epinephrine (see Table 2). The risk of epinephrine systemic effects with solutions containing large volumes of epinephrine should be considered.

Epidural Anesthesia

The lowest dosage that will produce the desired effect should be given. The amount varies with the number of dermatomes to be anesthetized (generally 2-3 mL of the indicated concentration per dermatome). Solutions with preservatives (methylparaben) should not be used since their safety has not been established.

Caudal and Lumbar Epidural Block

Test Dose: As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 3-5 mL of 1.5% lidocaine should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. During the administration of a test dose, it is recommended that constant electrocardiographic (ECG) monitoring occur. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10-15 μg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.

Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of XYLOCAINE through the catheter should be avoided and when feasible, fractional doses should be administered.

The main dose should be injected slowly at a rate of 100-200 mg/min, or in incremental doses, while keeping in constant verbal contact with the patient. If toxic symptoms occur, the injection should be stopped immediately.

In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

Table 2: Dosage Recommendations In Adults.

Availability Of Dosage Forms

XYLOCAINE Parenteral Solutions are available in Polyamp® Duofit® (plastic ampoules suitable for Luer fit and Luer lock syringes), single use and multidose glass vials, and glass ampoules (see Table 3).

Table 3: Availability

Sterilization, Storage and Technical Procedures

Adequate precautions should be taken to avoid prolonged contact between local anesthetic solutions containing epinephrine (low pH) and metal surfaces (e.g. needles or metal parts of syringes), since dissolved metal ions, particularly copper ions, may cause severe local irritation (swelling, edema) at the site of injection and accelerate the degradation of epinephrine.

When chemical disinfection of multidose vials is desired, either isopropyl alcohol (70%) or ethyl alcohol (70%) is recommended. Many commercially available brands of rubbing alcohol, as well as solutions of ethyl alcohol not of USP grade, contain denaturants which are injurious to rubber and therefore are not to be used.

The solubility of lidocaine is limited at pH > 6.5. This must be taken into consideration when alkaline solutions, i.e. carbonates, are added, since precipitation might occur. In the case of epinephrine-containing solutions, mixing with alkaline solutions may cause rapid degradation of epinephrine.

XYLOCAINE plain solutions in glass vials may be autoclaved for 15-20 minutes at 121°C. Due to the nature of the Polyamp® system, the plastic ampoules must not be autoclaved. Due to the heat sensitivity of epinephrine, products containing epinephrine should not be autoclaved.

All solutions should be stored at controlled room temperature (15-30ºC). XYLOCAINE Parenteral Solutions containing epinephrine should be protected from light.

Do not use if solution is pinkish or darker than slightly yellow or if it contains a precipitate.

XYLOCAINE Parenteral Solutions without preservative are for single use only. Discard unused portion. The multidose vials should not be used for more than three days after the container has been opened for the first time.

There is a greater risk of microbial contamination with multidose vials than with single dose vials. Single-dose vials should therefore be used whenever possible. If a multidose vial is used, appropriate control procedures to prevent contamination should be employed, including the following:

• use of single-use sterile injecting equipment;
• use of a sterile needle and syringe for each insertion into the vial;
• rule out the introduction of contaminated material or fluid into a multidose vial.

Polyamp® Duofit® are trademarks of the AstraZeneca group of companies.
AstraZeneca Canada Inc. 1004 Middlegate Road., Mississauga.

Last updated on RxList: 5/7/2008

Adverse experiences following the administration of lidocaine are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by overdosage, rapid absorption, or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient.

Table 1: Adverse Drug Reaction Frequencies

Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported:

Central Nervous System

CNS manifestations are excitatory and/or depressant and may be characterized by circumoral paresthesia, lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, hyperacusis, tinnitus, blurred vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest.

Drowsiness following the administration of lidocaine is usually an early sign of a high lidocaine plasma level and may occur as a consequence of rapid absorption.

Cardiovascular System

Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, arrhythmia, and cardiovascular collapse, which may lead to cardiac arrest.

Allergic

Allergic reactions are characterized by cutaneous lesions, urticaria, edema or, in the most severe instances, anaphylactic shock. Allergic reactions of the amide type are rare and may occur as a result of sensitivity either to the local anesthetic agent or to other components in the formulation.

Neurologic

The incidences of adverse reactions may be related to the total dose of local anesthetic administered but is also dependent upon the particular drug used, the route of administration and the physical status of the patient. Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome), have been associated with regional anesthesia. Neurological effects may be related to local anesthetic techniques, with or without a contribution from the drug.

In the practice of lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. For example, a high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis and bradycardia.

Neurologic effects following unintentional subarachnoid administration during epidural anesthesia may include spinal block by varying magnitude (including total or high spinal block), hypotension secondary to spinal block, urinary retention, fecal and urinary incontinence, loss of perineal sensation and sexual function, persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control, all of which may have slow, incomplete or no recovery; headache, backache, septic meningitis, meningismus, slowing of labour, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid.

Preclinical safety data

In animal studies, the signs and symptoms of toxicity noted after high doses of lidocaine are the results of the effects on the central nervous and cardiovascular systems. No drug related adverse effects were seen in the reproduction toxicity studies, neither did lidocaine show any mutagenic potential in either in vitro or in vivo mutagenicity tests. Cancer studies have not been performed with lidocaine, due to the area and duration of therapeutic use for this drug.

Lidocaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics (e.g. certain anti-arrhythmics, such as mexilitine) since the toxic effects are additive. Specific interaction studies with lidocaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised.

XYLOCAINE with Epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur and cerebrovascular and cardiac accidents are possible. Likewise, XYLOCAINE with Epinephrine or solutions containing XYLOCAINE and another vasoconstrictor should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAO) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Phenothiazines and butyrophenones may oppose the vasoconstrictor effects of epinephrine giving rise to hypotensive responses and tachycardia.

If sedatives are employed to reduce patient apprehension, they should be used in reduced doses, since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect.

Solutions containing epinephrine should be used with caution in patients undergoing general anesthesia with inhalation agents such as halothane and enflurane, due to the risk of serious cardiac arrhythmias.

Non-cardioselective betablockers such as propranolol enhance the pressor effects of epinephrine, which may lead to severe hypertension and bradycardia.

Drug/Laboratory Test Interactions

The intramuscular injection of lidocaine may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine.

Last updated on RxList: 5/7/2008

LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY EQUIPMENT AND THE PERSONNEL NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (see also ADVERSE REACTIONS and PRECAUTIONS). DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND POSSIBLY, DEATH.

It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetics, both the original and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.

Local anesthetic solutions containing antimicrobial preservatives (e.g. methylparaben) should not be used for epidural or spinal anesthesia because the safety of these agents has not been established with regard to intrathecal injection, either intentional or accidental.

XYLOCAINE with epinephrine solutions contain sodium metabisulfite, a sulfite that may cause allergic reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

The safety and effectiveness of XYLOCAINE Parenteral Solutions (lidocaine hydrochloride) depend on proper dosage, correct technique, adequate precautions and readiness for emergencies. Standard textbooks should be consulted for specific techniques and precautions for various regional anesthetic procedures.

Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and SYMPTOMS AND TREATMENT OF OVERDOSAGE). During major regional nerve blocks or using large doses, the patient should have i.v. fluids running via an indwelling catheter to assure a functioning intravenous pathway. THE LOWEST DOSAGE THAT RESULTS IN EFFECTIVE ANESTHESIA SHOULD BE USED TO AVOID HIGH PLASMA LEVELS AND SERIOUS ADVERSE EFFECTS. INJECTIONS SHOULD BE MADE SLOWLY, WITH FREQUENT ASPIRATIONS BEFORE AND DURING THE INJECTION TO AVOID INTRAVASCULAR INJECTION.

During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and that the patient be monitored for central nervous system toxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding (see DOSAGE AND ADMINISTRATION). When clinical conditions permit, consideration should be given to employing local anesthetic solutions that contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative.

Repeated doses of XYLOCAINE may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients and children should be given reduced doses commensurate with their age and physical condition. Patients in poor general condition due to aging or other compromising factors such as partial or complete heart conduction block, bradycardia, epilepsy, advanced liver disease, severe renal dysfunction or severe shock will also require special attention.

Because amide-type local anesthetics such as lidocaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease.

Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations.

Lidocaine should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.

Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive (see DRUG INTERACTIONS).

Lumbar and caudal epidural anesthesia should be used with extreme caution in persons with the following conditions: existing neurological disease, spinal deformities, septicemia and severe hypertension.

Central nerve blocks may cause cardiovascular depression, especially in the presence of hypovolemia. Epidural anesthesia should be used with caution in patients with impaired cardiovascular function.

Paracervical block can sometimes cause fetal bradycardia/tachycardia, and careful monitoring of the fetal heart rate is necessary.

Epidural anesthesia may lead to hypotension and bradycardia. This risk can be reduced by preloading the circulation with crystalloidal or colloidal solutions. Hypotension should be treated promptly with e.g., ephedrine 5-10 mg intravenously and repeating as necessary.

Local anesthetic procedures should not be used when there is inflammation and/or sepsis in the region of the proposed injection.

Solutions containing epinephrine should be used with caution in patients whose medical history and physical evaluation suggest the existence of untreated hypertension, poorly controlled hyperthyroidism, diabetes, ischemic heart disease, heart block, cerebral vascular insufficiency and peripheral vascular disorder. These solutions should also be used cautiously in areas of the body supplied by end arteries, such as digits, or otherwise having a compromised blood supply (see also DRUG INTERACTIONS).

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression or drowsiness may be early warning signs of central nervous system toxicity.

Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. It has been shown that the use of amide local anesthetics in malignant hyperthermia patients is safe. However, there is no guarantee that neural blockade will prevent the development of malignant hyperthermia during surgery. It is also difficult to predict the need for supplemental general anesthesia. Therefore, a standard protocol for the management of malignant hyperthermia should be available.

Lidocaine should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine.

Besides the direct anesthetic effect, local anesthetics may have a very mild effect on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

Use in the Head and Neck Area

Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions caused by inadvertent injection to an artery. These reactions may be similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Inadvertent injections into an artery can cause cerebral symptoms even at low doses. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression leading to cardiac arrest have been reported. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed.

Retrobulbar injections may very occasionally reach the cranial subarachnoid space causing temporary blindness, cardiovascular collapse, apnea, convulsions, etc. These reactions, which may be due to intra-arterial injection or direct injection into the central nervous system via the sheaths of the optic nerve, must be diagnosed and treated promptly.

Retrobulbar and peribulbar injections of local anesthetics carry a low risk of persistent ocular muscle dysfunction. The primary causes include trauma and/or local toxic effects on muscles and/or nerves. The severity of such tissue reactions is related to the degree of trauma, the concentration of the local anesthetic and the duration of exposure of the tissue to the local anesthetic. For this reason, as with all local anesthetics, the lowest effective concentration and dose of local anesthetic should be used. Vasoconstrictors and other additives may aggravate tissue reactions and should be used only when indicated.

Use in Pregnancy

It is reasonable to assume that a large number of pregnant women and women of child-bearing age have been given lidocaine. No specific disturbances to the reproductive process have so far been reported, e.g. no increased incidence of malformations. However, care should be given during early pregnancy when maximum organogenesis takes place.

The addition of epinephrine may potentially decrease uterine blood flow and contractility, especially after inadvertent injection into maternal blood vessels.

There are no adequate and well-controlled studies in pregnant women of the effect of lidocaine on the developing fetus.

Labour and Delivery

Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity. The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. A vasopressor, such as ephedrine, may be indicated (see PRECAUTIONS). The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable.

Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labour and facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labour by removing the parturient's reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance.

Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected, present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication.

Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides.

Nursing Mothers

Lidocaine is excreted in the breast milk, but in such small quantities that there is generally no risk of affecting the infant at therapeutic dose levels. It is not known whether epinephrine enters breast milk, but is unlikely to affect the breast-fed infant.

Use in Children

In children, the dosage should be calculated on a weight basis up to 5 mg/kg. With the addition of epinephrine, up to 7 mg/kg can be used (see DOSAGE AND ADMINISTRATION).

Last updated on RxList: 5/7/2008

Symptoms And Treatment Of Overdosage

Acute systemic toxicity from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics and originate mainly in the central nervous and the cardiovascular systems (see ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS).

Symptoms

With accidental intravascular injections, the toxic effect will be obvious within 1-3 min, while with overdosage, peak plasma concentrations may not be reached for 20-30 min depending on the site of injection, with signs of toxicity thus being delayed.

Central nervous system toxicity is a graded response, with symptoms and signs of escalating severity. The first symptoms are circumoral paresthesia, numbness of the tongue, lightheadedness, hyperacusis and tinnitus. Visual disturbance and muscular tremors are more serious and precede the onset of generalized convulsions. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity, together with the interference with normal respiration. In severe cases apnea may occur. Acidosis increases the toxic effects of local anesthetics.

Recovery is due to redistribution and metabolism of the local anesthetic drug. Recovery may be rapid unless large amounts of the drug have been administered.

Cardiovascular effects may be seen in cases with high systemic concentrations. Severe hypotension, bradycardia, arrhythmia and cardiovascular collapse may be the result in such cases.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anesthetic or is heavily sedated with drugs such as a benzodiazepine or barbiturate.

Treatment

The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anesthetic administration. At the first sign of change, oxygen should be administered. If signs of acute systemic toxicity appear, injection of the local anesthetic should be immediately stopped.

The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection consists of immediate attention to the establishment and maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred.

If convulsions occur, the objective of the treatment is to maintain ventilation and oxygenation and support the circulation. Oxygen must be given and ventilation assisted if necessary (mask and bag or tracheal intubation). Should convulsions not stop spontaneously after 15-20 seconds, an anticonvulsant should be given i.v. to facilitate adequate ventilation and oxygenation. Thiopental sodium 1-3 mg/kg i.v. is the first choice. Alternatively diazepam 0.1 mg/kg bw i.v. may be used, although its action will be slow. Prolonged convulsions may jeopardise the patient's ventilation and oxygenation. If so, injection of a muscle relaxant (e.g. succinylcholine 1 mg/kg bw) will facilitate ventilation, and oxygenation can be controlled. Early endotracheal intubation must be considered in such situations.

If cardiovascular depression is evident (hypotension, bradycardia), ephedrine 5-10 mg i.v. should be given and may be repeated, if necessary, after 2-3 minutes.

Should circulatory arrest occur, immediate cardiopulmonary resuscitation should be instituted. Continual oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

Children should be given doses commensurate with their age and weight.

XYLOCAINE Parenteral Solutions (lidocaine hydrochloride) are contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to other components of the solution i.e. methylparaben (multidose solutions) or sodium metabisulfite and/or citric acid in solutions containing epinephrine.

Last updated on RxList: 5/7/2008

Mechanism of Action

Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. The sodium channels of the nerve membrane are considered a receptor for local anesthetic molecules.

Onset of Action

The onset of action is 1-5 minutes following infiltration and 5-15 minutes following other types of administration. The duration of anesthesia depends on the concentration of lidocaine used, the dose, and the type of block. The 2% solution will last 1½-2 h when given epidurally, and up to 5 hours with peripheral nerve blocks. With the 1% concentration, there is less effect on motor nerve fibres and the duration of action is shorter. The addition of epinephrine decreases the rate of absorption, reducing toxicity and increasing the duration of effect.

Hemodynamics

Lidocaine, like other local anesthetics, may also have effects on other excitable membranes (e.g. brain and myocardium). If excessive amounts of drug reach systemic circulation, symptoms and signs of toxicity may appear, emanating from the central nervous and cardiovascular systems.

Central nervous system toxicity (see SYMPTOMS AND TREATMENT OF OVERDOSAGE) usually precedes the cardiovascular effects since it occurs at lower plasma concentrations. Direct effects of local anesthetics on the heart include slow conduction, negative inotropism and eventually cardiac arrest. Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration depending on the extent of the concomitant sympathetic block.

Pharmacokinetics and Metabolism

Lidocaine is completely absorbed following parenteral administration. The rate of absorption depends on the dose, route of administration, and the vascularity of the injection site. The highest peak plasma levels are obtained following intercostal nerve block (approximately 1.5 μg/mL per 100 mg injected) while abdominal subcutaneous injections give the lowest (approximately 0.5 μg/mL per 100 mg injected). Epidural and major nerve blocks are intermediate.

Absorption is considerably slowed by the addition of epinephrine, although it also depends on the site of injection. Peak plasma concentrations are reduced by 50% following subcutaneous injection, by 30% following epidural injection and by 20% following intercostal block if epinephrine 5 μg/mL is added.

Lidocaine shows complete and biphasic absorption from the epidural space with half lives of the two phases in the order of 9.3 min and 82 min respectively. The slow absorption is the rate limiting factor in the elimination of lidocaine, which explains why the apparent terminal half-life is longer after epidural administration. Absorption of lidocaine from the subarachnoid space is monophasic with an absorption half-life of 71 min.

Lidocaine has a total plasma clearance of 0.95 L/min, a volume of distribution at steady state of 91 L, a terminal half-life of 1.6 h and an estimated hepatic extraction ratio of 0.65. The clearance of lidocaine is almost entirely due to liver metabolism, and depends both on liver blood flow and the activity of metabolizing enzymes.

The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 μg of free base per mL, 60 to 80 percent of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein.

Lidocaine readily crosses the placenta, and equilibrium with regard to the unbound concentration is rapidly reached. The degree of plasma protein binding in the fetus is less than in the mother, which results in lower total plasma concentrations in the fetus.

Lidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. The main metabolites formed from lidocaine are monoethylglycine xylidide (MEGX), glycinexylidide (GX), 2,6-xylidine and 4-hydroxy-2,6-xylidine. The N-dealkylation to MEGX, is considered to be mediated by both CYP1A2 and CYP3A4. The metabolite 2,6-xylidine is converted to 4-hydroxy-2,6-xylidine by CYP2A6, and the latter is the major urinary metabolite in man. Only 3% of lidocaine is excreted unchanged. About 70% appears in the urine as 4-hydroxy-2,6-xylidine.

MEGX has a convulsant activity similar to that of lidocaine and a somewhat longer half-life. GX lacks convulsant activity and has a half-life of about 10 h. The elimination half-life of lidocaine following intravenous bolus injection is typically 1.5 to 2.0 hours. The terminal half-life in neonates (3.2 h) is approximately twice that of adults, whereas clearance is similar (10.2 mL/min kg). The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites.

Acidosis increases the systemic toxicity of lidocaine while the use of CNS depressants may increase the levels of lidocaine required to produce overt CNS effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 μg free base per mL.

Last updated on RxList: 5/7/2008

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of epidural anesthesia.

Last updated on RxList: 5/7/2008