Clinical manifestations

Presentation and course

Neurologic adverse effects of local anesthetics are shown in Table 1 and may be followed by involvement of the cardiovascular system. Other adverse effects, such as those involving the respiratory systems and allergic reactions, may occur concomitantly.

Table 1. Adverse Effects of Local Anesthetics Involving the Nervous System

Local manifestations related to cranial nerves. An analysis of 108 ophthalmologic complications following intraoral local anesthesia for dental procedures in 65 cases showed that the most common were those involving cranial nerves (49). The most common complication was diplopia (39.8%), mostly resulting from paralysis of the lateral rectus muscle; others were ptosis, dilated pupil, and loss of vision. Most of these resolved within a few hours as the effect of anesthetic wore off.

Temporary blindness has been reported after an inadvertent overdosage of lidocaine during a regional anesthetic procedure.

Diplopia, transient unilateral loss of vision, and strabismus due to paralysis of the extrinsic muscles of the eye have been reported following block of inferior dental nerve or posterior superior alveolar nerve with local anesthetic for dental procedures (01). The pathomechanism of visual loss due to oral nerve block is not known but there was partial recovery of visual function in a reported case (22). Transient blurred vision and diplopia has been reported following a Gow-Gates mandibular block injection in dentistry, and the possible mechanisms are inadvertent intravenous injection, or diffusion through tissue planes from the site of injection to the orbit (11).

Diplopia, loss of vision, or ophthalmoplegia can rarely occur following inferior alveolar nerve block, which is one of the common procedures in dentistry. Cases of drooping eyelid due to paralysis of the levator palpebrae superioris muscle with acute pain and numbness in the infraorbital area on the same side as infiltration of a local anesthetic in buccal vestibule have been explained by inadvertent injection of the anesthetic solutions in the extraosseous branch of posterior superior alveolar artery through to the infraorbital artery (38). In another case, transient diplopia was considered to be due to retro flow of local anesthetic agent through the inferior alveolar artery and indirectly to the ophthalmic artery paralyzing the lateral rectus muscle with recovery after 1 hour (37). In such cases recovery takes place spontaneously without any sequelae. Cranial nerve palsies can occur after procedures involving local anesthetic blocks, eg, of branches of trigeminal nerve. Ptosis has been reported after stellate ganglion block. Facial nerve paralysis has been reported after a superficial cervical plexus blocks.

Other cranial nerve manifestations that have been reported are facial nerve palsy, Horner syndrome (10), transient glossopharyngeal nerve palsy (34), and trigeminal neuralgia.

Local manifestations related to peripheral nerves. Phantom-limb pain can occur following a continuous popliteal nerve block after foot surgery with alleviation and recurrence corresponding to cessation and resumption of the local anesthetic infusion.

Carotid endarterectomy performed under local anesthesia may cause temporary ipsilateral vocal cord paralysis. There were no significant differences in operating time or volume or frequency of anesthetic administration in patients with temporary vocal cord paralysis compared with those without.

Though peripheral nerve injury/damage is rare due to nerve blocks and decreases over time, some blocks are relatively higher risk than others, such as interscalene block (25).

Effect of local anesthetics on muscles. Local anesthetics injections in muscles for relief of muscle pain have a detrimental effect on mesenchymal stem cells, which have an important role in the treatment of degenerative disorders of muscles (53). These were in vitro studies, and in vivo studies are needed to confirm these findings.

Manifestations of CNS toxicity of local anesthetics. Central nervous system symptoms are often part of local anesthetic systemic toxicity (LAST), which can lead to CNS toxicity besides cardiac toxicity. Initial symptoms of local anesthetic CNS toxicity are those of excitation, which may be manifested by restlessness and dizziness. Other manifestations are tremors, slurring of speech, and irrational conversation. This may proceed to a seizure or CNS depression. Ropivacaine is considered safer for the central nervous system, but a few published reports still implicate ropivacaine as being associated with convulsions.

Local anesthetics can lead to myotoxicity, which can be dose/concentration dependent and can worsen with longer exposure to anesthetic agent (56).

Seizures. Seizures are an adverse effect of an overdosage of local anesthetics and are likely to occur if the injection is made inadvertently into a blood vessel (08). Unfortunately, it can also lead to status epilepticus and nonconvulsive status epilepticus (04). Seizure activity following the administration of local anesthetic in pediatric dentistry is the most common adverse event, suggesting intravascular administration or a toxic dose, but there were no cases of permanent damage or fatal outcomes (45). A direct correlation exists between clinical symptoms and blood levels of lidocaine: as the level increases to 8 to 12 mg/L, the probability of seizure also increases. Central nervous system toxicity can develop even after accidental intraarterial injection of low concentrations of local anesthetics into peripheral arteries during peripheral nerve block. Convulsions have been reported after left superior laryngeal nerve block to facilitate endotracheal intubation. The possible cause may be accidental injection of the local anesthetic into the vertebral artery. Seizures may also occur as a complication of peripheral nerve block with a local anesthetic without inadvertent blood vessel puncture. Neonatal seizures have been reported following lidocaine administration for circumcision.

Apart from infiltration, local anesthetics may be given intravenously for regional anesthesia. According to a review of publications on intravenous regional anesthesia, the lowest dose of local anesthetic associated with a seizure is 1.4 mg/kg for lidocaine; 4 mg/kg for prilocaine, and 1.3 mg/kg for bupivacaine (16).

Miscellaneous manifestations. Initiation excitation may be followed by depression of the CNS with drowsiness, respiratory arrest, and coma. Concomitant myocardial depression may produce hypotension, disturbances of cardiac rhythm, and cardiac arrest. It can also cause DWI and FLAIR changes on MRI, which could mimic stroke, but no clear large vessel occlusion is identified (41).

Neurologic complications of spinal and epidural anesthesia. The most frequent complication of spinal anesthesia is spinal nerve root irritation. Cases have been reported of transient radicular irritation following intrathecal anesthesia with mepivacaine. This complication manifests from several hours to 1 day following the procedure and is characterized by sharp and bilateral radiating pain, usually involving the lower extremities. Usually no neurologic deficits arise, and the pain resolves within 1 week. Cauda equina syndrome is rare and is likely to occur with continuous spinal anesthesia through a microspinal catheter. Other complications of spinal anesthesia are due to leakage of spinal fluid through the lumbar puncture site with intracranial hypotension. These include headache, diplopia, and transient hearing loss. Sixth cranial nerve palsy may occur due to ischemic or traction injury (06). The risk of developing transient neurologic symptoms after spinal anesthesia with lidocaine is significantly higher than when bupivacaine, prilocaine, or procaine is used. Other complications may include lumbosacral radiculopathy, polyradiculopathy, and thoracic myelopathy after epidural injections (55).

Prognosis and complications

The prognosis of recovery from complications of local anesthesia is generally good. Recovery from seizures and transient neurologic deficits occurs within a matter of hours or days. Prognosis of neurologic deficits following spinal anesthesia is guarded, particularly in rare cases of paraplegia due to spinal cord ischemic infarction. Prompt identification and treatment can improve the prognosis in grave cases. Awareness about the myriad of neurologic symptoms among nurses and physicians can hopefully contribute to the timely diagnosis and treatment of such complications.

Biological basis

Etiology and pathogenesis

Neurologic complications have been reported with all currently used local anesthetics. Complications may result from the local effect on nerves, the neurotoxic effect of systemic absorption, overdosage, or inadvertent injection into the circulation. Some of the complications are due to injection, which may injure the nerve directly or compress it due to the formation of a hematoma. The causes of neurologic damage associated with spinal anesthesia include the following:

Because local anesthetics act through reversible binding at sodium channels, manifestations of toxicity include central nervous system as well as cardiovascular effects. Cumulative toxicity of local anesthetics depends directly on the concentration achieved in plasma, whereas CNS toxicity depends largely on the membrane-stabilizing effect of the drug. Factors affecting plasma concentration and, thus, toxicity, include the site and rate of injection, concentration and total administered dose, absorption, degree of tissue binding, and rate of metabolism and excretion. The extent of absorption depends on tissue vascularity, sites and techniques of application, and the patient's disease state. Lidocaine is eliminated mainly by the liver, and both the drug, as well as its toxic metabolite, can accumulate in congestive heart failure and liver disorders, producing neurotoxicity at low drug concentrations.

Absorption from mucous membranes is usually more rapid than from subcutaneous tissues. Seizures are associated with lidocaine after topical administration for airway anesthesia for bronchoscopy. Seizures have been reported following local application of lidocaine to the oropharyngeal region and following ureteral stone manipulation with lidocaine.

Complication of procedures. Examples of technical factors leading to neurologic complications are:

Risk factors. Patients with a history of epilepsy are predisposed to seizures as an adverse effect of local anesthetics. Patients with underlying mechanical, ischemic, or metabolic neurologic derangements are considered to be at increased risk of progressive neural injury following peripheral nerve block, but axillary blockade in patients with ulnar neuropathy undergoing ulnar nerve transposition is considered to be a safe procedure. Patients with prior nerve demyelination changes and prior existing neuropathies may be at relatively high risk for post nerve block peripheral nerve injuries (PNI). A retrospective study evaluated documented PNI in Charcot Marie Tooth neuropathy patients receiving peripheral nerve blocks but did not find any higher incidence of PNI in such patients. Age greater than 65 years could also be a patient-related risk factor (29).

Drug interactions. Complications of local anesthetics may be enhanced by interactions with other drugs. These interactions may be pharmacokinetic or pharmacodynamic. The following pharmacokinetic interactions increase the toxicity of local anesthetics:

The following pharmacodynamic interactions increase the neurotoxicity of local anesthetics:

Most of the studies reported in the literature have used lidocaine as the prototype for examining the effects of local anesthetics on the nervous system. The main action of local anesthetics on neural tissues is a depressant effect on the conduction of nerve impulse, due to the blocking of sodium channels. Lidocaine can also close the chloride channels at the synaptic cleft; the resultant chloride ion flow hyperpolarizes the membrane and enhances synaptic transmission.

Pathomechanism of local anesthetic-induced seizures. CNS toxicity of local anesthetics may be due to the depression of subcortical inhibitory control of gamma-aminobutyric acid over normally occurring excitatory activity. The convulsant effect of local anesthetics is due to an imbalance in brain activity because excitatory pathways are more resistant than are inhibitory pathways. The course of events, ie, initial excitation of the CNS followed by depression, is explained by selective blockade of inhibitory cortical synapses by local anesthetics.

One explanation of local anesthetic-induced seizures is blocking of sodium channels, which is for achieving local anesthesia, but can lead to neurotoxicity when spread to the systemic circulation and central nervous system, particularly in children (27). One theory of pathomechanisms of neurotoxicity of local anesthetics is based on Twik-related, pH-sensitive K+ channels, which generate neuronal potassium "leak" currents, membrane depolarization, and increased neuronal excitability (30). As these channels are expressed throughout the brain, this is the suggested mechanism for seizures in this setting.

Seizures have been reported after transversus abdominis plane block, which is commonly used for postcesarean section analgesia due to systemic absorption of the large amount of local anesthetic required for a successful block (51).

Pathomechanism of neurotoxicity. The toxic effect of local anesthetics on nerves has been studied. Local anesthetics precipitate nerve edema, increase endoneural nerve pressure, reduce nerve blood flow, and lead to nerve ischemia. Bupivacaine, ropivacaine, and mepivacaine are the least neurotoxic, whereas lidocaine is moderately toxic and procaine is the most damaging to the nerves. Increased caspase has been reported at molecular levels with local anesthetic agents, which may contribute to tissue damage (Verlinde at al 2016).

Ropivacaine promoted cell death in an in vitro study on PC12 cells as well as in animal spinal cords in a treatment group compared with a sham-operated group (42). This study showed that ropivacaine neurotoxicity in vivo and in vitro is mediated by the Akt (protein kinase B) signaling pathway and that may explain its adverse neurologic effects.

Amitriptyline, an antidepressant sodium ion channel blocker with prolonged local anesthetic effect, produces Wallerian degeneration with destruction of nerve fibers and a hyperalgesic pain state following application to peripheral nerves. In clinical use, it has no advantage over bupivacaine regarding efficacy and should not be used as a local anesthetic.

An overload of intracellular calcium is involved in the neurotoxic effect of some anesthetics. Results of a study suggest that T-type calcium channels, which lower the threshold of action potentials, may be involved in bupivacaine neurotoxicity, but specific subtypes of these channels have not yet been identified (52).

An experimental study on SH-SY5Y cells has shown that nicotinamide adenine dinucleotide (NAD+) depletion contributes to bupivacaine-induced neurotoxicity, which is attenuated by NAD+ repletion (58). An experimental study has shown that bupivacaine-induced neurotoxicity involves reactive oxygen species-induced mitochondrial damage and endoplasmic reticulum stress leading to apoptosis, which can be attenuated by ginkgolide B, an active component of Ginkgo biloba through its antioxidant property (26).

Epidemiology

The exact frequency of occurrence of adverse reactions to local anesthetics is difficult to determine, as only a small fraction of these are reported to health authorities. Those published are even fewer. Local anesthetics comprised 5% to 10% of the cases reported to the National Adverse Anesthetics Reactions Advisory Service in the United Kingdom. More than one fourth of all adverse reactions reported to the United Kingdom Medicines Control Agency were due to local anesthetics. An analysis of 1157 adverse reactions of local anesthetics in 721 patients, reported to the French Pharmacovigilance System, showed that 21.1% involved the nervous system (14). Seizures were the most frequent neurologic complications, leading to death in four cases.

In the United States, systemic toxicity from the injection or overdose of local anesthetics is a rare but potentially fatal complication that occurs in less than 1 in 1000 patients (50).

The reported risk of permanent neurologic injury with local anesthesia is less than 5 per 10,000 cases and systemic toxicity to 1 in 10,000 cases. The most common complication of procedures performed as outpatient with local anesthesia is syncope, which occurs in 1 in 160 patients.

Perineural catheters with administration of local anesthetics are used widely for the treatment of postoperative pain. If performed carefully, this procedure has a low rate of neurologic complications – less than 1 in 2000 cases.

A study found 7% risk of neurologic injury due to regional anesthesia in upper limb surgeries (02).

Prevention

Use of local anesthetics with lower risk of CNS toxicity. Levobupivacaine has similar potency to bupivacaine, but a relatively lower risk of CNS complications. A prospective randomized study has shown that ropivacaine is an alternative for deep topical anesthesia, as it has a better safety margin and lesser toxicity effect than other comparable local anesthetic agents (21).

Ultrasound-guided nerve blocks. It is generally recognized that real-time, needle-nerve visualization during ultrasound guided nerve block can prevent nerve injury. A review of cases of neuropathy as a complication of peripheral nerve block indicates that half of these complications can be prevented by use of ultrasound-guided nerve block (17). Despite this precaution, a severe brachial plexus injury has been reported after combined ultrasound and nerve stimulator-guided supraclavicular brachial plexus block (35). Intraneural injection during ultrasound-guided interscalene block resulted in a neurologic complication manifested by weakness and dysesthesias in the arm, which took 2 weeks to resolve (09). In a case of ultrasound-guided stellate ganglion block, inadvertent intra-arterial injection of a local anesthetic agent led to a tonic-clonic seizure, which could be minimized under the ultrasound guidance with various protective strategies, including the determination of any prior variation, optimizing the block route, maintaining a constant probe pressure, and using saline for the test dosage (28). This case resulted in the implementation of new protocols of the ultrasound-guided stellate ganglion block in the authors’ institution.

In an open study, for ultrasound-guided stellate ganglion block for patients with postherpetic neuralgia and complex regional pain syndrome of the upper extremity, a 2 mL dosage of 0.5% mepivacaine was found to be sufficient for block, which was as successful as that achieved by conventional larger volumes of local anesthetic, but produced fewer adverse effects such as dysphagia and upper arm weakness due to a less extensive spread of the anesthetic solution (24).

The American Society of Regional Anesthesia and Pain Medicine’s Practice Advisory on Neurologic Complications Associated with Regional Anesthesia and Pain Medicine offers recommendations to aid in the understanding and potential limitation of complications associated with mechanical, ischemic, or neurotoxic injury of the neuraxis or peripheral nervous system, which may arise during the practice of regional anesthesia and/or interventional pain medicine (33). It focuses on the preventive role of various monitoring technologies such as ultrasound guidance and injection pressure monitoring. New clinical recommendations focus on emerging concerns including nerve blocks in deeply sedated patients or those with preexisting neurologic disease, and inflammatory neuropathies.

A study by Xu and colleagues found that more experienced providers have lower risk of neurologic complications with peripheral nerve blocks in orthopedic surgeries (54).

Replacing general by local anesthesia for neurosurgical procedures. Several neurosurgical procedures such as craniotomies, laminectomies, and peripheral nerve procedures can now be done under local anesthesia. A retrospective study on 50 consecutive patients with single-level L5/S1 disc herniation underwent percutaneous endoscopic lumbar discectomy via the interlaminar approach under gradient local anesthesia to assess efficacy as well as safety as an alternative to general anesthesia because sinuvertebral nerve and the spinal nerve root can be irritated during shearing of the ligamentum flavum and manipulation of the annulus fibrosis, inducing intolerable back and leg pain (13). Different concentrations of local anesthetic compound were injected into different tissues inside and outside the ligamentum flavum to complete gradient local anesthesia. Results showed control of intraoperative pain. Gradient local anesthesia not only improved intraoperative satisfaction but also reduced local anesthesia-related adverse reactions and surgery-related complications.

Differential diagnosis

Confusing conditions

Complications need to be differentiated from other causes of similar complaints. Differential diagnosis of peripheral neuropathy following local anesthesia should include consideration of other causes, although the history of local anesthetic makes the diagnosis straightforward.

In the case of seizures, other causes that may have predisposed the patient to a seizure should be considered. These may include intracranial lesions, a history of epilepsy, or other drugs that may interact with local anesthetics to cause seizures.

Associated or underlying disorders

The risk of severe postoperative neurologic dysfunction in patients with preexisting peripheral sensorimotor neuropathy, Guillian Barre syndrome, multiple sclerosis, diabetic polyneuropathy, or spinal canal pathology who undergo neuraxial anesthesia or analgesia is higher than the risk in the general population.

In the case of patients presenting with cranial nerve lesions, the possibility of a previous local anesthetic should be considered in the differential diagnosis, and the patient should be questioned regarding any procedure that may have been carried out previously. This is particularly relevant in minor procedures on the head and neck with local anesthetic infiltration. However, the possibility of a cranial nerve lesion as a complication of spinal anesthetic should also be kept in mind.

Diagnostic workup

A patient with neurologic complications of local anesthetics should have a blood sample examined for serum concentration of the suspected anesthetic, as well as a normal hematological examination to assess the effects of local anesthetics on platelets, leukocytes, and the morphology of erythrocytes. Blood gas analysis should be done for detection, and correction of acidosis is important in management. Cardiovascular complications may require monitoring of blood pressure and electrocardiography. An electroencephalogram may be performed as a part of the investigation of a seizure, but it does not have any value in predicting the onset of neurotoxicity prior to a seizure. Peripheral neuropathy may require electromyography and nerve conduction studies.

Management

Control of seizures is the most important part of the neurologic management of adverse reactions to local anesthetics.

The patient should receive 100% oxygen. Diazepam or barbiturates should be used for the control of seizures. Intravenous suxamethonium (succinylcholine) 2 mg/kg is used to facilitate intubation. Acidosis increases the amount of unbound drug, thus, increasing its toxicity. Hypoxia and hypercapnia increase cerebral blood flow and, therefore, carry more lidocaine to the brain. Correcting the acidosis and hypoxia in cases of lidocaine overdosage is important for seizure control. Although low-dose propofol has been recommended for the control of seizures, it should be noted that propofol has also been implicated in seizures due to general anesthetics. Lipid emulsions have been infused to reverse systemic toxicity, including seizures and cardiac arrest resulting from the administration of levobupivacaine, ropivacaine, bupivacaine, or mepivacaine. The optimal dose has not been established and risks of administering too high a dose are uncertain.

Neurologic and cardiovascular symptoms associated with systemic toxicity of local anesthetics usually resolves following infusion of a lipid emulsion. Intravenous lipid infusion was also used successfully with full recovery in a case of ropivacaine-induced neurotoxicity manifested by restlessness and limb-twitching during emergence from anesthesia (32). A metaanalysis showed improvement in perioperative peripheral nerve injuries with help of hyperbaric oxygen therapy (02).

Clinical trials have shown that phentolamine mesylate injection can accelerate reversal of soft-tissue anesthesia and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor used for dental procedures (18).

The American Society of Regional Anesthesia and Pain Medicine has updated its algorithm on management of systemic toxicity of local anesthetics and commented that lipid emulsions may currently be underutilized (47).

Special considerations

Local anesthesia in patients with neurologic disorders. Peripheral regional anesthesia can be safely used in patients with spinal cord injury, multiple sclerosis, Guillain-Barré disease, neurofibromatosis, diseases of the neuromuscular junction, and Charcot-Marie-Tooth disease without neurologic complications (31). In a single-blind study on patients undergoing transforaminal lumbar surgery, no significant difference in neurologic complications was observed between the epidural anesthesia and the local anesthesia groups (12).

A patient with postpolio syndrome developed cauda equina syndrome after combined spinal anesthesia and postoperative epidural analgesia (46). Needle- or catheter-induced trauma, spinal hematoma, spinal ischemia, intraneural anesthetic injection, or infection were ruled out, leading to suspicion of neurotoxicity of bupivacaine and ropivacaine. There has been successive use of local anesthesia in patients with amyotrophic lateral sclerosis based on a case report (36).

Pregnancy

Local anesthetics can cross the placenta by diffusion and may cause fetal CNS and respiratory depression. Hypotension due to spinal anesthesia for caesarian section may reduce the uteroplacental flow and contribute to fetal hypoxia. Generally, local and regional anesthesia in pregnancy is safe and has a good safety record. However, neonatal lidocaine intoxication, with manifestations including seizures, may occur following maternal pudendal block during delivery. No evidence shows that local anesthetics have any teratogenic effect when used during the first trimester of pregnancy.

Inadvertent intrathecal injection of local anesthetic has been reported in a patient undergoing epidural block for delivery and resulted in motor block of lower extremities and shortness of breath (44). This was successfully managed with cerebrospinal lavage using CSF exchange for an equal volume of normal saline resulting in successful delivery.

Immunocompromised patients. There may be enhanced risk of neurotoxicity in patients with underlying compromised immunity due to HIV, cancer, immunotherapy, or diabetes. There is increased incidence of meningitis and epidural abscess as complication of spinal anesthesia in patients with underlying compromised immunity. There is also a chance of worsened peripheral nerve injury due to preexisting neuropathy due to use of chemotherapy (19).

Pediatrics. Local anesthetic systemic toxicity has the highest incidence in infants less than 6 months of age and is associated with bolus dosing and penile nerve blocks (05). It is treated by securing the airway, control of seizure activity, and cardiopulmonary resuscitation if required. Administration of intralipid (intravenous lipid emulsion) should be started at the first sign of toxicity. In contrast to reports of adverse effects in individual pediatric patients, analysis of results of large series of cases has shown a level of safety in pediatric regional anesthesia that is comparable to that in adult patients and is a useful and safe modality (07).

Anesthesia

This article deals with complications of local anesthesia.