Lidocaine Toxicity and Drug Interactions
Lidocaine toxicity is dosage related and directly proportional to its plasma concentration. Lidocaine for cardiac conditions has a narrow therapeutic index, with only a small difference between therapeutic and potentially toxic concentrations.
When intravenous (IV) lidocaine is given to treat ventricular arrhythmias (dysrhythmias), the therapeutic range for plasma concentrations is 1 to 5 mg/L, or 1 to 5 μg/ml. The potential for lidocaine toxicity is considered to be clinically significant at plasma concentrations greater than 6.0 mg/L. The metabolites of lidocaine have both pharmacologic and potential toxic effects; the threshold concentration for lidocaine-metabolite toxicity has not been established.
The safe use of lidocaine requires knowledge of lidocaine toxicology. This is especially important when using tumescent local anesthesia for large-volume liposuction.
Toxic Effects and Treatment
Lidocaine toxicity typically occurs in two settings: (1) slow systemic absorption with a slow sustained IV infusion and (2) rapid systemic absorption, such as an excessive IV bolus dose. With slow systemic absorption of lidocaine, the onset of toxic symptoms is progressive. With a toxic IV bolus dose of lidocaine, seizures, loss of consciousness, and rarely cardiovascular collapse may occur without any of the milder central nervous system (CNS) symptoms. Respiratory acidosis and hypoxia exacerbate lidocaine toxicity.
Tumescent lidocaine at 35 mg/kg has proved to be exceedingly safe. In my experience a tumescent dosage of 55 mg/kg is associated with a small (2% or less) incidence of mild lidocaine toxicity manifested by nausea and vomiting. When this nausea has occurred, the corresponding blood lidocaine concentrations have all been less than 3 μg/ml. Above 60 mg/kg the incidence of nausea is 10% or greater. A few liposuction surgeons have reported more than a 30% incidence of nausea or vomiting among patients given 70 to 100 mg/kg of tumescent lidocaine; the corresponding blood levels were not reported.
Occasionally, tumescent liposuction patients report nausea and vomiting at lidocaine plasma concentrations well below the toxic threshold of 6 mg/L. Nausea may also result from antibiotics, however, as well as trauma-induced inflammatory effects of liposuction. Nausea and vomiting might also be caused by narcotic analgesics used in the perioperative period.
It is easier to prevent than to treat nausea and vomiting. Limiting the dosage of tumescent lidocaine to 50 mg/kg or less and avoiding the use of narcotic analgesics is the simplest approach to avoiding gastrointestinal toxicity from lidocaine.
Central Nervous System
Lidocaine toxicity develops progressively with increasing plasma concentrations. “Typical” clinical signs and symptoms of lidocaine toxicity, however, may appear at very safe, low therapeutic plasma concentrations. These typical symptoms are also produced by other drugs often used together with tumescent local anesthesia.
Mild drowsiness is a common symptom experienced by nearly all patients who have received tumescent local anesthesia with resulting plasma concentrations of 1 to 3 mg/L, well below the threshold for toxicity. Drowsiness is so common that it cannot be considered a sign of impending toxicity. At high plasma concentrations, however, drowsiness can be expected to precede unconsciousness and coma.
Lightheadedness is less common but not rare. Localized muscle fasciculations typically occur, especially in muscle groups immediately subjacent to the fat infiltrated with tumescent anesthesia. Such CNS and neuromuscular symptoms are more appropriately referred to as pharmacologic side effects rather than toxic events.
Early signs of true lidocaine toxicity include nervousness, apprehension, euphoria, confusion, dizziness, and blurred or double vision (see later discussion). These same symptoms are manifestations of benzodiazepine toxicity, which may confuse the situation.
Certain premonitory CNS symptoms, including tinnitus, nausea, vomiting, lightheadedness, and generalized muscle twitching, have been reported to precede lidocaine-induced seizures, unconsciousness, and coma. The onset of various signs and symptoms of CNS toxicity from lidocaine is progressive and sequential. The surgeon must recognize that CNS toxicity occurs before potentially fatal lidocaine-induced cardiovascular collapse.
Respiratory depression and respiratory arrest are definite signs of serious toxicity. Respiratory depression with respiratory acidosis can significantly worsen the toxicity of lidocaine. Respiratory acidosis and hypercarbia cause an exponential increase in lidocaine toxicity.1
Cardiovascular lidocaine toxicity is more dangerous than CNS toxicity. The plasma concentration of lidocaine that causes cardiovascular toxicity is several times greater than the threshold for CNS toxicity.
Direct cardiac toxicity of lidocaine causes bradycardia, peripheral vasodilation, hypotension, depressed myocardial contractility, and depressed conduction through the cardiac conduction system, which can lead to cardiovascular collapse and death.
Initial Treatment Measures
Dependable ventilation is necessary to prevent respiratory acidosis, and oxygen should be administered at the first signs of systemic toxicity. Based on animal studies, lidocaineinduced dysrhythmias and cardiac depression are best treated with bretylium.
Although diazepam (Valium) and midazolam (Versed) are the drugs of choice to treat lidocaine-induced seizures, no evidence shows that benzodiazepines can be safely used to prevent seizures in an outpatient setting. The use of diazepam to treat a seizure presumes that the patient has adequate respiratory support. The high doses required to terminate a lidocaine-induced seizure can depress ventilations. When diazepam is administered to treat a grand mal seizure, the physician must be prepared to assist respiration with an Ambu bag or other means of artificial respirations.
If a lidocaine-induced seizure does occur, initial interventions must be to prevent physical injury and to provide hyperventilation and good oxygen delivery.
Midazolam, a water-soluble benzodiazepine, is the drug of choice for treating lidocaine-induced seizures. After an initial bolus of 5 to 7 mg, additional 1-mg to 2-mg increments of midazolam are given until the seizure is controlled.
Postoperative Diazepam Contraindicated. In experimental animals given convulsant doses of a local anesthetic, pretreatment with a benzodiazepine prevents seizures in a dose-related manner.2-4 Preoperative use of benzodiazepines, such as oral lorazepam or IV midazolam, is reasonable for anxiolysis and sedation. Routine postoperative use of benzodiazepines, however, should be avoided.
Some surgeons have proposed that patients receive diazepam 8 to 10 hours after surgery to prevent lidocaineinduced seizures, which are most likely to occur during peak plasma lidocaine concentrations. Despite the plausibility of this conjecture, I do not recommend preemptive treatment with diazepam for the following reasons:
- A surgeon should never give so much lidocaine that concern exists about a lidocaine-induced seizure. The fact that diazepam will protect against a lidocaineinduced seizure is no reason to administer higher and higher doses of lidocaine.
- A benzodiazepine such as diazepam may predispose to lidocaine toxicity by causing respiratory depression and respiratory acidosis.
- Benzodiazepines may slow lidocaine metabolism by inhibiting cytochrome P450 3A4 (CYP3A4), thus increasing plasma lidocaine levels and the risks of nonseizure-related lidocaine toxicity.
- If the surgeon believes that seizures from tumescent lidocaine are a significant risk, the patient should be admitted to an intensive care unit (ICU) for observation. In an ICU, benzodiazepines are appropriate for seizure prophylaxis but require close patient observation, since the first evidence of toxicity might be cardiac arrest without premonitory seizure activity.
- It is not appropriate to send a patient home with oral diazepam if the surgeon is concerned about a lidocaine-induced seizure. If seizures are unlikely, however, peremptory benzodiazepines are unnecessary and may cause symptoms such as confusion, nausea, and ataxia, which can be mistaken for early lidocaine toxicity.
Bretylium is preferred to lidocaine for the treatment of ventricular dysrhythmias from high doses of local anesthesia. Plasma lidocaine concentrations resulting from tumescent anesthesia rarely approach the threshold for toxicity. However, giving IV lidocaine to treat ventricular fibrillation in a patient who has already received a high dose of lidocaine might precipitate toxicity.
Direct Tissue Effects
Although muscle toxicity induced by tumescent local anesthetic has not been noted clinically, muscle lysis and ischemic necrosis associated with lidocaine and epinephrine have been reported in experimental models using much higher doses.5
High concentrations of lidocaine can have a toxic effect on peripheral nerves. Peripheral nerve toxicity involving the cauda equina may have been caused by repeated or continuous infusions of 5% lidocaine during spinal anesthesia.6,7 A solution of 5% lidocaine caused irreversible conduction block in desheathed amphibian nerves.8
Rapid Absorption Toxicity
An excessive IV bolus dose of lidocaine can result from the following:
- Appropriate dose of lidocaine for a regional nerve block that is inadvertently injected intravascularly.
- Regional IV anesthesia (Bier’s block) that is released too rapidly into the systemic circulation.
- Excessive IV loading dose of lidocaine for initiating treatment of ventricular tachycardia.
A moderately excessive IV bolus dose of lidocaine produces brief peak plasma concentrations above the toxic threshold. The short duration is the result of the rapid α-phase redistribution of lidocaine out of the vascular space and into the peripheral tissues (see Chapter 19). The lung temporarily binds large amounts of lidocaine on its first pass through the pulmonary circulation. Within 20 seconds of an 0.5-mg/kg IV bolus dose of lidocaine, about 60% is absorbed into lung tissue.9 This pulmonary reservoir effect is saturable and insignificant in the setting of a prolonged lidocaine infusion.
Therefore, except for massively excessive doses, lidocaine toxicity after an IV bolus dose is brief and self-limited.
Slow Absorption Toxicity
Toxicity after a sustained infusion of lidocaine is more prolonged and more ominous. With extended infusion the threshold for toxicity is gradually exceeded after lidocaine has saturated all the peripheral fatty tissues. Rapid redistribution of lidocaine out of the vascular space, as occurs after an IV bolus dose, cannot occur because the peripheral storage sites are already saturated with lidocaine. Instead, plasma lidocaine concentrations decrease only as fast as hepatic metabolism will allow. Thus toxicity associated with sustained infusion or prolonged absorption, such as with tumescent anesthesia, is more long lasting and therefore potentially more dangerous than toxicity after an IV bolus dose.
A typical setting in which a physician might encounter lidocaine toxicity involves the treatment of ventricular ectopy (ectopia) in an intensive cardiac care unit. Toxicity occurs when standard doses are administered to patients with decreased ability to metabolize lidocaine. Examples include patients with decreased hepatic blood flow caused by congestive heart failure, with greatly impaired hepatic function caused by advanced cirrhosis, or with drug interactions caused by lidocaine analogs or other drugs that impair lidocaine metabolism.10
Prevention: Avoiding Human Error
To my knowledge, no deaths have resulted from lidocaine toxicity with true tumescent liposuction totally by local anesthesia. However, fatal cases of lidocaine overdose have occurred in other clinical settings. The increasing popularity and more frequent use of tumescent anesthesia guarantee an increased incidence of adverse pharmacologic and toxic reactions.
The surgeon can minimize the probability of a negligent or careless error by insisting on written operating room (OR) policies and procedures for the use of lidocaine with tumescent anesthesia for liposuction. The most important safeguard against careless or inadvertent errors in lidocaine dosing is a requirement for written lidocaine orders. The surgeon must insist on the most fastidious records of the exact total milligram doses actually administered. Physician and staff must double-check the orders for accuracy. Lidocaine orders must be expressed in terms of total dose in milligrams (mg) and total dosage (mg/kg).
The most likely causes of lidocaine toxicity with tumescent liposuction result from errors by the physician, nurse, or patient. In my experience, preventable mistakes in lidocaine dosage have been associated with the human errors listed next.
- Casual or indifferent attitude regarding the maximum safe lidocaine dosage (mg/kg) proved to be fatal in one case. The surgeon apparently disregarded or was ignorant about the recommended maximum safe dosage of tumescent lidocaine. One cannot assume that tumescent anesthesia is safe at any dosage.
- Dosage miscalculations must be expected to occur, even with the most fastidious attention to detail.11 Surgeons, nurses, and anesthesiologists should double-check each other’s calculations of the total allowable dosage.
- Poor communication among staff, as a result of verbal orders, ambiguous or imprecise written orders, and illegible written orders, has been associated with critical misinterpretation and has had serious consequences. Oral orders are dangerous. Lidocaine orders must be written and signed by the surgeon before a nurse is permitted to prepare the tumescent anesthetic solutions (see Box 20-1).
- Inaccurate or nonexistent records of the cumulative lidocaine dose (mg) and dosage (mg/kg) have been associated with lidocaine toxicity during tumescent liposuction when more than 110 mg/kg was given inadvertently. The result was temporary neurologic toxicity (see Box 20-2).
- Inadequately trained staff is the fault of the surgeon. Poorly trained OR staff resulted in a fatality when lidocaine was mistakenly added to an IV infusion without the clinician’s knowledge.12
- Inadvertent double dose of lidocaine has occurred when the anesthesia orders were written in terms of “ml” of lidocaine instead of mg of lidocaine. A medical assistant used 2% lidocaine when the surgeon had intended 1% lidocaine. No dermatologic surgical procedure requires 2% lidocaine. It may be advisable not to permit 2% lidocaine in an office or surgical facility where tumescent liposuction is performed. Medical assistants are not as well trained as registered nurses for mixing medications.
- False or inaccurate clinical history may result in errors. Patients do lie, and others forget to inform the surgeon of important clinical information. When one patient neglected to inform the surgeon of a preexisting seizure disorder, the result was an unexpected intraoperative seizure, with aspiration, asphyxia, and death. Even with standard “safe” dosages, propofol and lidocaine can lower the seizure threshold.
- Use of unreported medications places patients at risk for unexpected drug interactions. Clinical experience demands the assumption that every patient is taking medication(s) without reporting this to the surgeon. For this reason alone, total lidocaine dosage should be moderate. Pushing lidocaine dosages to their limit to avoid the inconvenience of serial liposuction procedures on separate days does not meet any prudent standard of care.
- Unawareness of adverse drug interactions with lidocaine or epinephrine is always a risk. Although they cannot reasonably expect to have knowledge of every reported or conceivable drug interaction, surgeons should at least know about published accounts of the most dangerous or the most common adverse interactions. The hepatic isoenzyme CYP3A4 is critical for the metabolism of lidocaine. Any physician who uses lidocaine should have an understanding of the role of cytochrome P450 isoenzymes in the occurrence of drug interactions with lidocaine (see Chapter 18).
- Expressing lidocaine doses in terms of milliliters per kilogram is dangerous. It is much safer simply to express lidocaine doses in terms of total milligrams per kilogram (mg/kg) rather than total volume of lidocaine solution times concentration of lidocaine solution per kilogram, (mL) · (mg/ml)/(kg). Expressing lidocaine doses in terms of milliliters of 1% or 2% lidocaine is more susceptible to error and has been associated with at least one death. An order for “100 cc of lidocaine per liter” with the intention of ordering “100 ml of 1% lidocaine placed in a liter of solution” can easily result in the patient receiving 100 ml of 2% lidocaine per liter.
The risk of lidocaine toxicity is known to be closely correlated with mg/kg dosage. Thus it is reasonable to express a lidocaine order in terms of the milligrams of lidocaine. It is easier to calculate the total lidocaine dose (3000 mg) when the order is written as “four liters of solution at 750 mg of lidocaine per liter” versus “four liters of solution, each containing 37.5 ml of 2% lidocaine per liter.”
Symptoms of True Toxicity
Earliest symptoms of true lidocaine toxicity are not pathognomonic. Symptoms of lidocaine toxicity overlap with signs and symptoms of side effects from other drugs taken by tumescent liposuction patients. For example, lightheadedness, anxiety, confusion, disorientation, tremors, dysarthria, and unsteady gait are early signs of toxicity for both benzodiazepines and lidocaine. Similarly, nausea and vomiting are often associated with antibiotics, benzodiazepines, and elevated lidocaine plasma concentrations.
If a patient has nausea and vomiting as well as the other signs just listed, true lidocaine toxicity might be suspected. Such a situation might justify an examination in an emergency room (ER) and obtaining plasma lidocaine levels. If the lidocaine levels are elevated, observation overnight in a hospital is appropriate.
I have encountered only one patient with true lidocaine toxicity. This obese female patient had a plasma lidocaine concentration of 6.1 mg/L after having received 58 mg/kg of tumescent lidocaine. She was also taking 200 mg of sertraline (Zoloft) daily for an anxiety disorder. Sertraline, as with other selective serotonin reuptake inhibitors (SSRIs), is a competitive inhibitor of CYP3A4, the same enzyme responsible for metabolic elimination of lidocaine. She was taken to a local ER 12 hours after completion of tumescent infiltration, complaining of nausea, vomiting, confusion, memory impairment, and anxiety (see Case Report 18-1).
Mild Toxicity: Case Examples
Virtually all patients who have tumescent anesthesia without sedation experience a mild degree of somnolence. Patients typically feel slightly sleepy when reclining and listening to quiet music. They often take a brief nap on returning home or to a hotel room. I estimate that a serum lidocaine concentration less than 1 mg/L (1 μg/ml) is sufficient to produce this subjective sleepiness.
Having treated more than 1000 tumescent liposuction patients with lidocaine doses in the range of 45 to 60 mg/kg without any serious lidocaine toxicity, I am confident that a dosage of less than 50 mg/kg is safe. Careful questioning postoperatively, however, has revealed an apparent 1% to 2% incidence of mild, transient CNS effects in patients receiving tumescent lidocaine dosages of 50 to 60 mg/kg. Typically the symptoms are noticed within 8 to 16 hours after the infiltration of the tumescent anesthetic. Often the patients have just awakened from a nap when they first notice the symptoms.
Usually the symptoms are minimal, and patients do not bother to inform me by telephone. When I do receive telephone calls about these symptoms, they are typically mild but worrisome to the patient and always have been transient, lasting 1 to 4 hours. Mild nausea is occasionally described. Some patients describe a degree of mild dysarthria, mild confusion, and slight memory impairment.
For example, a patient might have difficulty pronouncing words or have a slightly unsteady gait, as if mildly drunk. One patient had difficulty remembering her telephone and apartment numbers. Another patient, who had taken no sedatives, experienced mild nausea and brief mild dysarthria approximately 8 hours after receiving 51 mg/kg of tumescent lidocaine. One surgeon inappropriately gave more than 70 mg/kg to a patient, who had a similar experience. The onset of symptoms occurred approximately 12 hours after surgery, on awakening from a nap. Serum lidocaine concentrations were not obtained.
On receiving a telephone call from a patient with these symptoms, the surgeon should take a careful history and perform a rapid evaluation. Patients may admit self-medication with a sedative or a codeine-type narcotic analgesic from a prescription written by another physician. One patient admitted taking a “bushel-full” of a health food store version of Ephedra (ephedrine) to “cleanse her system of the lidocaine.”
The symptoms listed are known to occur with reactions associated with benzodiazepines or hydrocodone. For some patients the subjective symptoms have been consistent with a hyperventilation syndrome, with perioral and digital tingling and mild to moderate anxiety.
Once the mild nature of the complaint is determined, I speak to the patient by telephone every 1 to 2 hours or until the symptoms improve. I tell the patient that if the symptoms worsen, evaluation in a local ER will be necessary. The symptoms usually begin to improve noticeably within an hour or two. Having the patient drink fluids, relax in a semirecumbent position, watch television as a distraction, or breathe into a paper bag has been helpful.
Ten to 12 hours after tumescent infiltration of almost 60 mg/kg of lidocaine for liposuction, two of my patients awoke after a brief nap with disorientation, memory impairment, slightly slurred speech, and anxiety. They were sufficiently anxious to warrant more than a telephone evaluation. Plasma lidocaine levels, obtained as part of an ER examination, were 2.8 and 3.1 mg/L, well below the 6.0 mg/L threshold for lidocaine toxicity. These patients likely had much lower thresholds for subjective symptoms.
Subjective CNS toxicity is most likely to occur with relatively high doses of tumescent lidocaine. Serious consequences have not been reported. Nevertheless, I rarely allow the lidocaine dosage to exceed 55 mg/kg.
It is theoretically impossible to define precisely the maximum safe dose of tumescent lidocaine. A scientific attempt to determine a maximum safe dose of tumescent lidocaine is, at best, a sophisticated process of biostatistical estimation (see Chapters 6 and 21).
As noted elsewhere, a proposal that a higher dosage limit for tumescent liposuction is safe is merely a clinical hypothesis. The surgeon who makes such a proposal has a strong ethical obligation to make a concerted statistical effort to disprove the hypothesis. Presenting an untested hypothesis as if it were an “established, scientifically validated fact” is unethical and dangerous.
In one report, 59.1 mg/kg resulted in a serum lidocaine concentration of 6.1 μg/ml (6 μg/ml = 6 mg/L).13 In addition, I have been told of two fatalities in liposuction patients who were mistakenly given approximately 105 mg/kg. This information allows one to estimate the level at which toxic and fatal reactions to tumescent lidocaine might occur, 60 mg/kg and 105 mg/kg, respectively.
Local Anesthetic Allergic Reactions
In the late 1940s and early 1950s, procainamide (Novacaine), now procaine (Novocain), was virtually the only local anesthetic used in the United States. By 1960, lidocaine had become the most widely used local anesthetic because of its superior safety and efficacy and the exceedingly low incidence of allergy. Patients and some clinicians still tend to use “novacaine” as a generic term referring to all local anesthetics.
Procain is an ester-type local anesthetic that is metabolized in the blood by plasma esterases. Lidocaine is an amide-type local anesthetic that is metabolized by CYP3A4. The general population has a 10% prevalence of allergy to procaine. True allergic reactions to lidocaine are extremely rare, but a history of allergy to any local anesthesia cannot be ignored.
Most patients are not aware of the distinction between adverse drug reaction and allergic drug reaction. Many dental patients and some dentists use the words “allergic reaction” to describe the alarming tachycardia that is a common sequela of a rapid systemic absorption of epinephrine after injection into the highly vascular buccal mucosa. They make no distinction between an allergic reaction and the predictable pharmacologic event following rapid systemic absorption of epinephrine. Questions during the preliposuction history generally provide enough information to distinguish between a potentially serious anaphylactic or anaphylactoid drug reaction and a benign pharmacologic response.
If a true adverse reaction to a local anesthetic cannot be excluded by the history, or if the patient insists that a reaction was truly allergic, the patient should be referred to a specialist for consultation, allergy testing, and a written report documenting the findings and recommendations.
Most “adverse” reactions to local anesthesia are not truly allergic but rather pharmacologic events, anxiety reactions, or vasovagal reactions (syncope). Chemically mediated reactions are most likely related to a preservative such as sodium bisulfite.14 Preservative-free lidocaine without epinephrine is available in single-use ampules. Epinephrine, 1 mg/ml, containing no bisulfite and no preservatives, is commercially available in 1.0-ml ampules (American Regent Laboratories, Shirley, NY).
Adverse Drug Interactions
Other local anesthetics have adverse interactions with lidocaine. The pharmacologic or toxic effects of lidocaine and any other local anesthetic are additive.15 Lidocaine is displaced from plasma binding proteins by bupivacaine at therapeutic doses of each drug.16
Drug that share CYP3A4 as the important metabolic enzyme may have adverse interactions with lidocaine.
General anesthesia with halothane plus nitrous oxide causes an elevation in lidocaine plasma concentrations.17 Systemic anesthesia can have two dangerous effects in the setting of tumescent liposuction, as follows:
- General anesthesia can lower the maximum safe dose of lidocaine. Such a potentially dangerous drug interaction is likely to result from competition and inhibition of hepatic CYP3A4, as well as decreased hepatic blood flow.
- General anesthesia can suppress lidocaine-induced seizures, which might otherwise act as premonitory signs of impending cardiac toxicity, including fatal cardiovascular collapse.
Sinus bradycardia was seen in a patient taking the oral antiarrhythmic drug amiodarone after being given lidocaine as local anesthesia. Amiodarone competes with lidocaine for binding to CYP3A4.18 A seizure was reported in a patient given these drugs intravenously.19
Dilute bupivacaine and high-dose dilute epinephrine have been associated with a death during liposuction by local anesthesia in a patient taking phentermine (Fastin).
Cocaine and lidocaine interact adversely. In a rat study, the overall toxicity of cocaine was significantly increased with simultaneous exposure to lidocaine.20 At doses of 30 or 40 mg/kg, intraperitoneal lidocaine does not induce seizures or death; the pharmacokinetic absorption characteristics of intraperitoneal injections are similar to IV injections. In animals receiving 35 mg/kg of cocaine alone, the incidence of seizure was 10%, with no deaths. With the addition of 30 and 40 mg/kg of lidocaine, the incidence of seizures increased to 50% and 80%, respectively, with death occurring in 30% and 60%.
At sufficiently high doses, beta blockers decrease cardiac output, thus decreasing hepatic blood flow and rate of lidocaine extraction by the liver. Propranolol, in moderate therapeutic doses, decreases the systemic clearance of lidocaine by up to 50%.21,22 Many liposuction patients take beta blockers for treatment of hypertension or migraine headaches. To avoid preoperative hypertension or recurrent severe headaches, patients should continue these drugs during liposuction surgery. By reducing the maximum lidocaine dose to less than 40 mg/kg, no evidence of lidocaine toxicity has been reported during tumescent liposuction.
A study using rat liver microsomes showed that lidocaine 3-hydroxylation and propranolol ring hydroxylations are mediated by the same cytochrome P450 2D isoenzymes.23
Phenytoin and lidocaine have been reported to have additive cardiac depressant effects.24
Using high-dose lidocaine in patients with seizure disorders probably carries a risk of lowering the seizure threshold.
Lack of communication between anesthesiologist and surgeon has contributed to deaths of patients not being treated totally by local anesthesia. Both surgeon and anesthesiologist should be aware of the total parenteral (IV and subcutaneous) fluid dosage. If either clinician is unaware of the fluids administered to the patient by the other, a fluid overload is highly probable. Excessive parenteral isotonic fluids can result in hemodilution, leading to disseminated intravascular coagulation (DIC), pulmonary edema, and adult respiratory distress syndrome (ARDS).
Similarly, both the surgeon and the anesthesiologist should constantly know the exact mg/kg dosage of tumescent lidocaine that the patient has received; this is an absolute standard of care. A physician must be continually aware of the precise dosage of a potentially toxic anesthetic that is administered to a patient under the physician’s supervision. This requirement demands compulsively accurate record keeping, using an efficient intraoperative anesthesia flow sheet that is specifically designed for tumescent anesthesia.
Surgical Orders and Flow Sheets
I know of two superwet liposuction–related deaths resulting from pulmonary edema and lidocaine toxicity (see Chapter 9). In both cases, no explicit orders were written for lidocaine. Surgeons should know that local anesthetics are toxic and that explicit orders must be written before the preparation or mixture of parenteral medications.
Surgeons and anesthesiologists must be in complete agreement regarding the exact type and dosage of drug and fluids used during liposuction. Besides excessive volumes of liposuction, lack of knowledge about IV fluid toxicity, and careless surgical technique, the greatest risk of surgical mortality with the tumescent technique is lack of precise communication between the surgeon and staff.
The intended total mg/kg dosage of tumescent lidocaine must be written before preparation of the anesthetic solution. Surgeons, anesthesiologists, and OR staff are not accustomed to written orders for local anesthesia, but written orders are an absolute necessity for safe tumescent anesthesia. The OR staff should be instructed not to mix any tumescent anesthesia unless explicit written orders have been completed by the surgeon (Box 20-1).
The orders must specify the following:
- Patient’s weight in kilograms
- Maximum allowable total mg/kg dosage of lidocaine individualized for patient
- Total milligrams of lidocaine and epinephrine in each liter bag of solution
- Milliequivalents of sodium bicarbonate in each liter of physiologic saline
The surgeon and staff are responsible for documenting the true dose of lidocaine and epinephrine that the patient actually has received. This is accomplished by means of a special intraoperative anesthesia flow sheet, which all surgeons performing tumescent techniques are encouraged to use (Box 20-2).
Treatment of Lidocaine Overdose
As discussed, human error is the most likely cause of lidocaine overdose and serious toxicity. The goal is to minimize the possibility of error through training of staff and fastidious written policies and procedures; for example, staff should have Advanced Cardiac Life Support (ACLS) training. The person responsible for preparing the tumescent anesthetic solution should be specifically trained in the proper procedure of following written orders specified in terms of “mg of lidocaine per liter of solution.” Also, 2% lidocaine should be either eliminated from inventory or stored separately from the lidocaine used for tumescent anesthetic solutions.
If there is a significant risk that a toxic overdose has been given, the patient should not be managed in an outpatient facility. Appropriate clinical observation in an ICU, with cardiac monitoring, secure IV access, and oxygen supplementation, is necessary with a suspected or a recognized overdose of tumescent lidocaine.
A patient who has received too much lidocaine should not be treated for a seizure before it occurs. For example, preemptive treatment with a benzodiazepine such as diazepam may actually impair lidocaine metabolism by inhibiting CYP3A4, thereby increasing the risk of a seizure. By impairing ventilation, benzodiazepines can also increase the risk of seizures. The most prudent approach is to observe the patient closely in the ICU for a potential seizure. Plasma lidocaine concentrations should be obtained every 4 to 6 hours. The patient should be discharged only after two consecutive levels indicate that (1) the peak concentration has been achieved and (2) the subsequent levels are definitely on a downward course.
When a serious lidocaine toxicity is encountered, the principal therapeutic intervention is treating seizures and maintaining adequate ventilation and oxygenation. Treatment with oxygen alone is insufficient to prevent hypoventilation and respiratory acidosis. Good ventilation and protection of the airway are crucial. After initial administration of oxygen by mask, maintaining a patent airway may require endotracheal intubation.
When a lidocaine seizure does occur, the two most important aspects of treatment involve the following:
- Ensuring adequate ventilation and protecting the airway
- Treating the seizure with IV antiseizure medications (e.g., midazolam, diazepam, propofol) or an ultrashort-acting barbiturate (e.g., thiopental)
Treatment of hypotension may require IV fluids, a vasopressor drug such as dopamine, or another appropriate sympathomimetic agent. Dialysis is of no significant benefit for overdoses with amide-type local anesthetic agents.
- Englesson S: The influence of acid base changes on central nervous system toxicity of local anesthetic agents, Acta Anaesth Scand 18:88-103, 1974.
- Wesseling H, Bovenhorst GH, Wiers JW: Effects of diazepam and pentobarbitone on convulsions induced by local anesthetics in mice, Eur J Pharmacol 13:150-154, 1971.
- de Jong RH, Heavner JE: Diazepam prevents and aborts lidocaine convulsions in monkeys, Anesthesiology 41:226-230, 1974.
- de Jong RH, Heavner JE: Diazepam prevents local anesthetic seizures, Anesthesiology 34:523-531, 1971.
- Foster AH, Carlson BM: Myotoxicity of local anesthetics and regeneration of the damaged muscle fibers, Anesth Analg 59:727-736, 1980.
- Rigler ML, Drasner K, Krejcie TC, et al: Cauda equina syndrome after continuous spinal anesthesia, Anesth Analg 72: 275-281, 1991.
- Schell RM, Brauer FS, Cole DJ, Applegate RL II: Persistent spinal nerve root deficits after continuous spinal anesthesia, Can J Anaesth 38:908-911, 1991.
- Lambert LA, Lambert DH, Strichartz GR: Irreversible conduction block in isolated nerve by high concentration of local anesthetics, Anesthesiology 80:1082-1093, 1994.
- Jorfeldt L, Lewis DH, Löfström B, Post C: Lung uptake of lidocaine in healthy volunteers, Acta Anaesthesiol Scand 23: 567, 1979.
- Sharma SC, Rama PR, Miller GL, et al: Systemic absorption and toxicity from topically administered lidocaine during transesophageal echocardiography, J Am Soc Echocardiogr 9:710-711, 1996.
- Douglas JH III, Ross JD, Bruce DL: Delayed awakening due to lidocaine overdose, J Clin Anesth 2:126-128, 1990.
- Edgren B, Tilelli J, Gehrz R: Intravenous lidocaine overdosage in a child, J Toxicol Clin Toxicol 24:51-58, 1986.
- Klein JA, Kassardjian N: Lidocaine toxicity with tumescent liposuction, Derm Surg J 23:1169, 1997.
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- Kyttä J, Heavner JE, Badgwell JM, Rosenberg PH: Cardiovascular and central nervous system effects of coadministered lidocaine and bupivacaine, Reg Anesth 16:89, 1991.
- Goolkasian DL, Slaughter RL, Edwards DJ, Lalka D: Displacement of lidocaine from serum alpha1-acid glycoprotein binding sites by basic drugs, Eur J Clin Pharmacol 25:413, 1983.
- Bentley JB, Glass S, Gandolfi AJ: The influence of halothane on lidocaine pharmacokinetics in man, Anesthesiology 59:A246, 1983.
- Ha HR, Candinas R, Stieger B, et al: Interactions between amiodarone and lidocaine, J Cardiovasc Pharmacol 28:533-539, 1966.
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|BOX 20-1 Orders for Tumescent Local Anesthesia|
|Patient’s preoperative weight today: _______ kg|
|Maximum allowable lidocaine dosage: _______ mg/kg|
|Bag #_______:||Lidocaine _______ mg||Epi _______ mg|
|Bag #_______:||Lidocaine _______ mg||Epi _______ mg|
|Bag #_______:||Lidocaine _______ mg||Epi _______ mg|
|Bag #_______:||Lidocaine _______ mg||Epi _______ mg|
|Bag #_______:||Lidocaine _______ mg||Epi _______ mg|
|BOX 20-2 Sample Entry from Flow Sheet Documenting Amount of Infiltrated Anesthetics|
|Bag # (drugs + 0.9% NaCl):||1||2||3||etc.||totals|
|Lidocaine (mg put in bag) [A]:|
|ml of bag infiltrated [B]:|
|Initial ml in bag [C]:|
|Lidocaine mg infiltrated [A × (B/C)]:|
|Total mg/kg lidocaine actually infiltrated: _________________|