Local Anesthetic Systemic Toxicity

Description

Local anesthetic (LA) toxicity can range from mild symptoms to severe central nervous system (CNS) and cardiovascular (CV) toxicity that can result in death.
The severity of LA systemic toxicity is based on a variety of factors:
- Regional block technique
- Location
- Type of local anesthetic utilized
- Total dosage
- Timeliness of detection and appropriate treatment
- Individual patient risk factors
In addition to LA toxicity, local anesthetics, can also result in other adverse reactions:
- Allergic reaction
- Methemoglobinemia
- Neurotoxicity (cauda equina syndrome, transient neurologic symptoms)

Epidemiology

Incidence

Epidural injection: 1.2–11 per 10,000 blocks
Caudal injection: 1.3–69 per 10,000 blocks
Peripheral nerve blocks: 7.5–20 per 10,000 blocks

Morbidity

Severe cardiovascular and neurologic compromise

Mortality

According to the ASA Closed Claims review of peripheral nerve blocks from 1980 to 2000, 7 of 19 claims associated with death or brain damage were attributed to LA systemic toxicity.

Etiology/Risk Factors

Risk factors for LA toxicity:
- Location of regional block: Areas with high vascularity favor uptake of local anesthetic and result in higher blood levels. Intercostal > Caudal > Epidural > Brachial plexus > Sciatic > Spinal.
- Type of local anesthetic:
  - More potent, longer-acting LAs tend to be more toxic.
  - The S(–) isomers (levobupivacaine and ropivacaine) seem to be less toxic than R(+) isomers or racemic bupivacaine.
- Technique and dosage
  - Dose = volume × concentration
  - Unnecessarily high dosing can increase the risk of serious toxicity if intravascular uptake occurs.
  - Studies on ultrasound-guided regional blockade have indicated that with proper placement, smaller doses can provide adequate blockade.
Individual patient risk factors:
- Patients at extremes of age (<4 months or >70 years)
- History of cardiac conduction defects or ischemic heart disease
- Cardiac, renal, and hepatic dysfunction are important predictors of local anesthetic plasma levels after a specific dose rather than body weight or BMI.

Physiology/Pathophysiology

The mechanism of LA toxicity is highly controversial. Due to ethical concerns, no human randomized controlled trials exist. Data on this topic relies on animal studies and case reports.
In general, the CNS is more sensitive to LA toxicity than the CV system. for most local anesthetics, CV toxicity does not occur until 3 times the concentration necessary to produce seizures. This CV/CNS ratio tends to be lower with bupivacaine.
Hypoxia and hypercarbia can decrease the convulsive threshold and predispose to myocardial toxicity.
CNS toxicity: 2-phase pathophysiologic process:
- First, preferential blockade of the inhibitory CNS pathways leaves the excitatory pathways unopposed. This can manifest as shivering/muscle tremors and proceed to tonic–clonic seizures.
- With increasing plasma levels, both inhibitory and excitatory pathways are blocked. Generalized CNS depression ensues with potential respiratory arrest.
CV toxicity: One of the primary mechanisms of CV toxicity is thought to be from binding and inhibition of Na⁺ channels by LAs. At higher concentrations, it is believed that cardiac Ca²⁺ and K⁺ channels are also inhibited. LAs are also thought to antagonize beta-adrenergic receptors. 2-phase pathophysiologic process:
- In the CNS excitatory phase, activation of the sympathetic nervous system results in tachycardia and hypertension.
- With increasing plasma levels, bradycardia, hypotension, and ventricular arrhythmias occur.

Prevantative Measures

According to the 2010 American Society of Regional Anesthesia (ASRA) practice advisory:

Use lowest effective dose of LA
Incremental dosing: Pause 15–30 seconds between each 3–5 mL dosing.
Aspirate for blood prior to each injection.
Consider using a pharmacologic marker/test dose to identify inadvertent intravascular injection:
- Epinephrine 15 µg produces a greater than 10 beat increase in heart rate or a greater than 15 mm Hg increase in systolic blood pressure.
- Note that beta-blockers, advanced age, labor, and general/neuraxial anesthesia may inhibit this response.
- Fentanyl 100 µg produces sedation in laboring patients.
Ultrasound guidance: Reportedly decreases the incidence of intravascular injection. Whether it decreases actual incidence of LA systemic toxicity still remains to be answered.

Diagnosis ⬆ ⬇

Classically in LA systemic toxicity, CNS symptoms are followed by CV symptoms. However, in review of case reports, there is extreme variability in presentation.
Particularly with potent local anesthetics, cardiac toxicity may occur simultaneously or precede seizures. Sometimes CV toxicity is the only manifestation.
CNS toxicity:
- Classic early symptoms: Circumoral numbness, metallic taste, lightheadedness, visual/auditory disturbances, agitation/tremors
- Later symptoms: Seizure, coma, respiratory arrest
CV toxicity:
- First, cardiac excitation: Tachycardia, hypertension, ventricular arrhythmias
- Later, CV depression: Bradycardia, hypotension, decreased contractility, asystole

Differential Diagnosis

Pain during uterine contraction may also produce increased heart rate.

Treatment ⬆ ⬇

Airway management is of utmost importance. Prevention of hypoxia and hypercarbia/acidosis can halt progression of LA toxicity to seizures and/or CV collapse, as well as aid in successful resuscitation.
for seizures, the first-line therapy is benzodiazepines. Small doses of thiopental or propofol may also be used, realizing this may worsen hypotension/CV depression. Avoid propofol when there are signs of CV compromise. Future studies may support lipid infusion as the initial treatment.
If seizures persist, consider small doses of neuromuscular blockers to halt muscle contractures, thus preventing further oxygen consumption and CO₂ production. Seizures (electrical function) may continue despite a lack of tonic–clonic muscle activity.
for cardiac arrest, perform standard ACLS with the following modifications:
- Small doses of epinephrine (<1 µg/kg) if needed
- Avoid vasopressin
- Avoid calcium channel blockers and beta-blockers
- for ventricular arrhythmias, amiodarone is preferred. Avoid local anesthetics (i.e., lidocaine, procainamide).
20% Lipid emulsion therapy
- Consider starting the infusion immediately after airway management. Lipid emulsion can be a significant aid in resuscitation, acting as a "lipid sink," drawing lipophilic local anesthetic from within cardiac tissues.
- Dosing
  - Bolus 1.5 mL/kg over 1 minute
  - Infusion of 0.25 mL/kg/min for at least 10 minutes after circulatory stability is achieved.
  - If the patient is still unstable, re-bolus and increase the infusion to 0.5 mL/kg/min.
  - Recommended upper limit: 10 mL/kg over 30 minutes
- Note: Propofol is not a substitute for lipid emulsion.
Consider cardiopulmonary bypass (CPB) if inadequate responses to lipid emulsion and vasopressor therapy.

Follow-Up ⬆ ⬇

Delayed re-occurrence of LA systemic toxicity has been reported.
- Continue close monitoring of patients for 12 hours after severe episodes.
- Maintain oxygenation and ventilation.
- Once the patient is stabilized from the initial episode of LA systemic toxicity, consider consultation with a cardiologist or intensivist.
- Recommend stay in a monitored setting/ICU setting to observe for signs of recurrent cardiac or central nervous system toxicity.
There are concerns of possible adverse effects following lipid therapy.
- Lipid emulsion for TPN is associated with pancreatitis; however, there have been no reported cases associated with lipid infusion for LA toxicity.
- Further observation and studies are needed to fully elucidate the possible adverse effects of lipid therapy for LA toxicity.

Closed Claims Data

LA systemic toxicity accounts for 1/3^rd of claims for death or brain damage associated with regional anesthesia.

References ⬆ ⬇

Butterworth JF. Local anesthetics: Mechanisms, toxicities, and controversies from a clinical perspective. American Society of Anesthesiologists Annual Meeting, San Diego, CA, 2010.
Drasner K. Local anesthetic systemic toxicity: A historical perspective. Reg Anesth Pain Med. 2010;35:160–164.
Groban L. Central nervous system and cardiac effects from long-acting amide local anesthetic toxicity in the intact animal model. Reg Anesth Pain Med. 2003;28(1):3–11.
Lee LA , Posner KL , Cheney FW , et al. Complications associated with eye blocks and peripheral nerve blocks: An American Society of Anesthesiologists Closed Claims Analysis. Reg Anesth Pain Med. 2008;33(5):416–422.
Mulroy MF. Systemic toxicity and cardiotoxicity from local anesthetics: Incidence and preventive measures. Reg Anesth Pain Med. 2002;27(6):556–561.
Neal JM , Bernards CM , Butterworth JF 4th, et al. ASRA practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35(2):152–161.
Weinberg GL , Ripper R , Murphy P , et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31:296–303.

Additional Reading ⬆ ⬇

See Also (Topic, Algorithm, Electronic Media Element)

Codes ⬆ ⬇

ICD9

968.9 Poisoning by other and unspecified local anesthetics

ICD10

T41.3X1A Poisoning by local anesthetics, accidental, init

Clinical Pearls ⬆ ⬇

Be prepared to handle severe LA systemic toxicity by preparing a LA toxicity kit, including lipid emulsion therapy and posting instructions on its use.
When performing a regional or neuraxial anesthetic technique, use the smallest dose of local anesthetic necessary.
Use a pharmacologic marker/test dose to aid with identification of vascular injection.
Inject 3–5 mL aliquots followed by aspiration to assess for blood. Pause for 15–30 seconds prior to resuming injection to ask the patient if they are experiencing symptoms of toxicity and observe for signs.
Be vigilant. Monitor patient during and after the injection, noting that toxicity can present >30 minutes after injection.
Consider LA toxicity in any patient with altered mental status, neurologic symptoms, or CV instability following a regional anesthetic.
Note that >40% of cases do not follow the classic presentation of local anesthetic systemic toxicity. Cardiovascular signs may be the only manifestation in severe cases.

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Basics ⬇