Lidocaine (lignocaine)

Observational studies

Lidocaine has been used to treat some of the symptoms of multiple sclerosis in 30 patients with painful tonic seizures, attacks of neuralgia, paroxysmal itching, and Lhermitte’s sign [ ]. Lidocaine was given by intravenous infusion for 5.5 hours in a maintenance dose of 2.0–2.8 mg/kg/hour after a loading dose, and the mean steady-state concentration was 2.4 μg/ml. Lidocaine almost completely abolished the paroxysmal symptoms and markedly alleviated the persistent symptoms of multiple sclerosis. Adverse reactions were not specifically mentioned, but in one case, when the plasma concentration of lidocaine rose above 3.5 μg/ml, weakness of the left leg became marked and was associated with an extensor plantar response; this disappeared when the lidocaine was replaced by saline single-blind, but subsequently the positive symptoms recurred.

Intravenous lidocaine has been used to treat severe chronic daily headache in 19 patients (three men, median age 37 years) [ ]. There were adverse reactions during four infusions of lidocaine: hyperkalemia (6.4 mmol/l), which did not resolve after withdrawal of lidocaine; transient hypotension (75/50 mmHg), which was attributed to concomitant droperidol; an unspecified abnormality of cardiac rhythm and on another occasion a transient bradycardia; and chest pain with a normal electrocardiogram, fever, and intractable nausea. The study was neither randomized nor placebo-controlled, and in no case was the adverse event strongly associated with the administration of lidocaine.

Placebo-controlled studies

In a double-blind, placebo-controlled study of the use of intravenous lidocaine for neuropathic pain, 16 patients were given 5 ml/kg intravenously over 30 minutes [ ]. Lidocaine was better than placebo in relieving pain. The major adverse reaction was light-headedness, which occurred in seven patients given lidocaine and none given saline. Other adverse reactions included somnolence, nausea and vomiting, dysarthria or garbled speech, blurred vision, and malaise. In two patients the rate of infusion had to be reduced because of adverse reactions.

Cardiovascular

Lidocaine can cause dysrhythmias and hypotension. The dysrhythmias that have been reported include sinus bradycardia, supraventricular tachycardia [ ], and rarely torsade de pointes [ ]. There have also been rare reports of cardiac arrest (2) and worsening heart failure [ ]. Lidocaine can also cause an increased risk of asystole after repeated attempts at defibrillation [ ]. Lidocaine may increase mortality after acute myocardial infarction, and it should be used only in patients with specific so-called warning dysrhythmias (that is frequent or multifocal ventricular extra beats, or salvos) [ ].

Sinus bradycardia has been seen after a bolus injection of 50 mg, atrioventricular block after a dose of 800 mg given over 12 hours, and left bundle branch block after a mere subconjunctival injection of 2% lidocaine.

• High-grade atrioventricular block has been reported in a 14-day-old infant who was given lidocaine 2 mg/kg intravenously [ ].

A death due to ventricular fibrillation after 50 mg and another due to sinus arrest after 100 mg have been reported [ ]. Two cases of ventricular fibrillation and cardiopulmonary arrest occurred after local infiltration of lidocaine for cardiac catheterization [ ].

Lidocaine does not usually cause conduction disturbances, but cases have been reported in the presence of hyperkalemia [ ].

• A 57-year-old man with a wide-complex tachycardia was given lidocaine 100 mg intravenously and immediately became asystolic. Resuscitation was unsuccessful.

• A 31-year-old woman had a cardiac arrest and was resuscitated to a wide-complex tachycardia, which was treated with intravenous lidocaine 100 mg. She immediately became asystolic but responded to calcium chloride.

In both cases there was severe hyperkalemia, and the authors suggested that hyperkalemia-induced resting membrane depolarization had increased the number of inactivated sodium channels, thus increasing the binding of lidocaine and potentiating its effects.

The degree of hypotension occurring after epidural anesthesia with alkalinized lidocaine (with adrenaline) was greater than with a standard commercial solution [ ].

In 23 patients there was a significant dose-dependent reduction in blood pressure following submucosal infiltration of lidocaine plus adrenaline compared with saline plus adrenaline for orthognathic surgery [ ]. The study was randomized but small; larger studies are needed to confirm effects that could easily have been due to multifactorial causes in patients undergoing general anesthesia.

Respiratory

Topical anesthesia of the airways is commonly used to facilitate endoscopy and sometimes manipulation of the airways. This can result in an increase in airway flow resistance, possibly due to laryngeal dysfunction [ ]. Lidocaine spray 10%, used for upper airways anesthesia for fiberoptic intubation in a grossly obese patient, caused acute airway obstruction. The patient went on to have a percutaneous tracheotomy, and it was postulated that the local anesthetic had abolished laryngeal receptors responsible for airway maintenance, or that laryngospasm and reduced muscle tone due to the lidocaine might have been the cause [ ].

Life-threatening bronchospasm can occur after either spinal or topical use of lidocaine. In one series of patients being treated with lidocaine spray 40 mg for persistent cough, there was an increase of airway resistance [ ].

Ear, nose, throat

Local anesthesia to the larynx, for example with 4% lidocaine, is generally safe. Laryngeal edema has been reported in a few cases and could be due to the propellant rather than to lidocaine itself [ ].

Intranasal 4% lidocaine has been used for migraine and cluster headaches with success and few serious adverse effects: a bitter taste was common and some patients complained of nasal burning and oropharyngeal numbness [ ].

Lidocaine gel is not recommended for lubrication of laryngeal masks. It confers no benefits and increases the incidence of adverse reactions such as intraoperative hiccups, postoperative hoarseness, nausea, vomiting, and tongue paresthesia [ ].

Nervous system

Nervous system toxicity is most often seen with rapid intravenous infusion [ , , ]. The effects include headache, dizziness, tremor, confusion, tinnitus, dysarthria, paresthesia, respiratory depression, altered level of consciousness (from drowsiness to coma), and convulsions.

Two cases have illustrated the effects of lidocaine in precipitating partial seizures in patients with a previous history of epilepsy [ ].

• A 36-year-old woman developed chest pain and ventricular tachycardia. She had a 14-year history of focal motor seizures controlled with phenytoin. After receiving intravenous lidocaine 100 mg to treat the dysrhythmias, she developed a typical seizure involving the right side of her face and arm. She was given a loading dose of phenytoin and the seizure abated. However, the ventricular tachycardia persisted and was treated with additional lidocaine 50 mg followed by an infusion of 3.3 mg/minute; 6 hours later she had a generalized seizure with a venous blood lidocaine concentration of 21 μg/ml. The infusion was stopped and the seizure was treated with intravenous diazepam 10 mg.

• A 41-year-old woman with a long-standing history of focal and secondarily generalized seizures controlled with carbamazepine underwent cerebral arteriography, during which she was inadvertently given lidocaine 20 mg via an intra-arterial catheter in the right internal carotid artery; within 20 seconds she had a focal seizure.

These two patients had their typical partial seizures triggered by high doses of lidocaine. In both cases the serum concentrations of their usual anticonvulsants were initially low. The first patient received a loading dose of phenytoin after the partial seizure, was then given a second bolus of lidocaine and an infusion, and then had a second seizure, which was generalized. There was no evidence that this second seizure evolved from the left seizure focus. The authors concluded that lidocaine can activate seizure foci in patients with a history of partial seizures and that this may be more likely if the serum concentrations of anticonvulsants are low. However, therapeutic concentrations of antiepileptic drugs may not prevent generalized seizures that result from the widespread lowering of seizure threshold caused by high concentrations of lidocaine.

A tonic-clonic seizure occurred after the application of 400 mg of lidocaine jelly to traumatized ureteric mucosa [ ].

• A 54-year-old woman who was given lidocaine, 200 mg intravenously, for ventricular fibrillation during cardiopulmonary bypass, had a tonic–clonic seizure [ ]. The seizure occurred immediately after the administration of lidocaine and was relieved by the intravenous administration of thiopental and midazolam. Her ventricular fibrillation responded to procainamide 1 g intravenously over 10 minutes.

• Seizures in a 3-month old boy occurred after an overdose of lidocaine for circumcision [ ].

The pharmacokinetics of lidocaine are altered by cardiopulmonary bypass, because of hemodilution, changed protein binding, the exclusion of the lungs as an organ for first-pass elimination, altered acid–base balance, and sometimes drug interactions. In particular, reduced protein binding may have contributed in this case to the risk of seizure, but plasma lidocaine concentrations were not measured.

• A 30-year-old woman received two 5 g applications of 40% lidocaine cream with occlusion by plastic wrap during and after laser therapy to areas of her skin [ ]. She developed dizziness and headache postoperatively, followed 45 minutes later by light-headedness, increasing dizziness, and confusion. The dressings were removed. The lidocaine concentration was 2.7 μg/ml 7 hours later.

It is recommended that repeat applications of lidocaine, especially in high-concentration formulations, be avoided and the area of application limited.

• A 16-year-old woman had had an adverse reaction after administration of an unknown local anesthetic agent for a dental procedure. Patch testing had elicited similar symptoms with lidocaine only, and 20 minutes after subcutaneous lidocaine 0.05 mg she developed perioral paresthesia, nausea, vomiting, vertigo, dizziness, mild agitation, drowsiness, and euphoria. Hemodynamic parameters remained stable but her symptoms were thought to be part of a genuine non-allergic, neuropsychiatric reaction, as the patch testing was double-blind and placebo-controlled [ ].

Transient and permanent nerve damage can occur after regional anesthesia, particularly neuraxial anesthesia. The mechanism of this nerve damage is unclear. Some studies have shown an indirect effect. However, in crayfish giant axon, lidocaine had a dose- and time-dependent effect on isolated nerve function in vitro [ ]. At high concentrations lidocaine caused irreversible conduction block and total loss of resting membrane potential. These results in an isolated nerve suggest a direct neurotoxic effect of lidocaine.

Accidental overdose of intravenous lidocaine has been described in a patient under general anesthesia [ ].

• A 79-year-old woman had general anesthesia with propofol induction and sevoflurane maintenance for a gynecological operation under bispectral index monitoring for depth of anesthesia. Owing to an inadvertent programming error lidocaine 800 mg was infused over 8 minutes. The bispectral index fell to 0 (flat line EEG) and remained so for about 10 minutes before gradually increasing to 60. The patient developed hypotension, atrial dysrhythmias, and prolonged weakness, despite reversal, the cause of which was not clear.

The effects of local anesthetics on bispectral index monitoring have not been investigated before, but in this case lidocaine suppressed it completely at high doses.

Sensory systems

Tinnitus and visual disturbances are early components of a systemic toxic reaction to lidocaine.

Metabolism

High systemic doses of lidocaine can cause transient hypoglycemia [ ].

Electrolyte balance

There has been one report of hypokalemia (2.2 mmol/l), probably due to potassium channel blockade, after administration of high-dose intravenous lidocaine (8 mg/l) for raised intracranial pressure [ ].

Hematologic

Severe thrombocytopenic purpura with a lidocaine-mediated antiplatelet IgM antibody has been reported [ ].

Methemoglobinemia is a common adverse effect of prilocaine (see also benzocaine above). In a retrospective cohort study of 50 children aged 3–31 months undergoing infiltration anesthesia of the scalp before craniofacial surgery, lidocaine 1% with adrenaline caused this complication in 10 children [ ]. The methemoglobin concentrations were low and in the range 2.2–18% (median 6%). In eight children, the methemoglobinemia resolved spontaneously within 12 hours. Only two children were given methylthioninium chloride (methylene blue). No cause other than lidocaine could be identified. There was no correlation between the dose of lidocaine and the occurrence of methemoglobinemia.

Three cases of lidocaine-induced methemoglobinemia have been reported in patients undergoing topical anesthesia of the airway and oropharynx [ ].

• A 26-year-old woman undergoing bronchoscopy received lidocaine jelly 2% to each nostril, lidocaine solution 2% sprayed on the throat, and 10 ml of lidocaine solution 2% into the trachea. She was also given intravenous diazepam 5 mg and pethidine 75 mg and intramuscular atropine 0.6 mg. She developed dyspnea and cyanosis after the procedure and despite 100% oxygen, her SpO ₂ was 85%. Her methemoglobin concentration was 14%.

• A 61-year-old woman was given 15 ml of lidocaine solution 2% and lidocaine spray 4% for topical anesthesia of the throat and oropharynx before upper gastrointestinal endoscopy. She was also sedated with intravenous midazolam 2 mg and pethidine 75 mg. She became cyanosed and desaturated (SpO ₂ 78%) immediately after the procedure. Her SpO ₂ did not recover, despite 100% oxygen. Her methemoglobin concentration was 37%.

• In preparation for transesophageal echocardiogram, a 73-year-old woman was given 15 ml of lidocaine solution 2% and lidocaine spray 4% to anesthetize the oropharynx, plus intravenous midazolam 1 mg and pethidine 12.5 mg. She very rapidly became cyanosed, but remained asymptomatic. Her SpO ₂ was 85% on oxygen 2 l/minute and her methemoglobin concentration was 25%.

Liver

Liver damage due to lidocaine has rarely been reported. However, severe liver damage has been reported shortly after the withdrawal of mexiletine 300 mg/day and the introduction of lidocaine 1000 mg/day, although lidocaine in the same dose had been used during the previous week [ ]. The lidocaine was withdrawn and the liver enzymes normalized after treatment with prednisolone.