Extra Topic 4.6 -- Local Anesthetic Toxicity

Question 1

What do you think is going on?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 1

While I could consider several potential causes of these symptoms, such as –

• hypoxia,
• acidosis,
• myocardial ischemia,
• alcohol withdrawal, and
• a seizure disorder,
• the timing of the event and the progression of his symptomatology are most consistent with local anesthetic toxicity.

Recognizing that the presentation of local anesthetic toxicity is extremely variable in onset and initial symptomatology, I would consider this possibility in any situation where a patient experienced an altered mental state, neurologic symptoms, or cardiovascular instability following the administration of local anesthetic for regional anesthesia.

Question 2

What are the signs and symptoms associated with local anesthetic toxicity?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 2

Initially, the patient developing local anesthetic toxicity may experience nonspecific neurologic symptoms such as –

• metallic taste,
• circumoral paresthesias,
• tongue numbness,
• visual disturbances (i.e. blurred vision and difficulty focusing),
• auditory disturbances (i.e. tinnitus),
• lightheadedness,
• dizziness, and
• a feeling of “impending doom”.

In the classical description, these subjective symptoms are followed by symptoms of central nervous system (CNS) excitation, such as –

• agitation,
• shivering,
• muscle twitching,
• tremors of the face and distal extremities, and
• tonic-clonic seizures (CNS excitation is thought to occur secondary to an initial blockade of inhibitory pathways in the cerebral cortex).

As toxicity increases, the patient experiences CNS depression, with subsequent resolution of seizure activity, respiratory depression, loss of consciousness, coma, and respiratory arrest (as plasma levels of local anesthetic increase, both inhibitory and excitatory CNS pathways are blocked, resulting in CNS depression).

With very high levels of toxicity, the patient may experience hypertension, tachycardia, and ventricular arrhythmias (cardiac excitation) followed by bradycardia, decreased contractility, hypotension, conduction block, and asystole (cardiac depression).

When administering local anesthetics, it is important to keep in mind that patients may progress rapidly to seizure activity and cardiac toxicity without experiencing any of the initial nonspecific neurologic symptoms, as may occur following a direct arterial injection.

Likewise, the onset of symptoms may be significantly delayed, as may be the case following tumescent procedures (delayed for over 15 minutes in some reports).

Clinical Notes:

• Direct arterial injection (especially into the carotid or vertebral arteries) may result in the rapid progression of symptoms because toxic levels of local anesthetic may be delivered to the brain before undergoing significant extraction in the lungs (which would occur following intravenous injection).
• The symptoms of local anesthetic toxicity are delayed with –
  
  • intermittent intravascular injection,
  • lower extremity injection (longer circulation time),
  • low cardiac output states (longer circulation time), and
  • delayed tissue absorption (such as may occur following a tumescent procedure).

Question 3

Are there any advantages to using ropivacaine rather than bupivacaine?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 3

Single enantiomer derivatives of bupivacaine, such as ropivacaine and levo-bupivacaine (S stereoisomer) have been developed and utilized in an attempt to achieve lasting regional anesthesia, while avoiding the significant cardiovascular toxicity associated with racemic bupivacaine (S and R stereoisomers).

The reduced cardiotoxicity associated with these single enantiomer drugs may be due to reduced affinity for brain and myocardial tissue.

In the case of ropivacaine, the reduced cardiac depression of its propyl side chain, as compared to the butyl side chain of bupivacaine, may also play a role.

Another potential advantage of ropivacaine is the provision of similar sensory blockade in association with less extensive motor blockade, as compared to an equal dose of bupivacaine.

• Clinical Notes:*
• Cardiac Toxicity: Lidocaine < Ropivacaine < Bupivacaine

Question 4

Does the addition of epinephrine reduce the risk of local anesthetic toxicity?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 4

The addition of epinephrine may reduce the risk of local anesthetic toxicity by –

• reducing systemic absorption (secondary to vasoconstriction) and/or
• helping to identify unintended intravascular injection (i.e. an increase in heart rate of 10 beats/minute or an increase in systolic pressure of > 15 mmHg).

However, there is some evidence that this may be accompanied by – an undesirable reduction in the seizure threshold for intravenous local anesthetics (rat studies).

This reduction in the seizure threshold may be due to –

• vasoconstrictor-induced hyperdynamic circulatory changes that lead to increased delivery of local anesthetic to the brain (increased cerebral blood flow),
• disruption of the blood-brain barrier, and
• decreased clearance of local anesthetics (blood flow redistribution away from the liver).

Question 5

How do local anesthetics affect the heart?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 5

The inhibition of voltage-gated sodium channels results in the following direct cardiac effects:

1. slowed cardiac conduction (increased PR-interval and widened QRS complex),
2. decreased rate of depolarization (secondary to a reduction in availability of the fast sodium channels that allow the rapid sodium influx required for membrane depolarization),
3. a dose-dependent reduction in cardiac contractility (potentially contributing to hypotension, metabolic acidosis, and reduced clearance of local anesthetic), and
4. depressed spontaneous pacemaker activity in the sinus node (potentially leading to bradycardia and cardiac arrest).

Peripheral vascular effects vary depending on the amount of local anesthetics in the plasma, with – –

1. low concentrations resulting in vasoconstriction and
2. high concentrations causing vasodilation.

Question 6

The patient’s blood pressure is stable, but he continues to experience seizure activity and develops stable monomorphic ventricular tachycardia.

Assuming his condition is the result of local anesthetic toxicity, what will you do?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 6

In treating this complication, I would:

1. stop injecting local anesthetic;
2. call for help and a lipid rescue kit;
3. ensure adequate ventilation and oxygenation to correct and/or avoid factors that enhance the systemic toxicity of local anesthetics, such as –
   
   • hypercarbia
     
     • (increased cerebral blood flow, intra-neuronal ion trapping of the drug, and decreased plasma protein binding of local anesthetics),
   • acidosis
     
     • (reduces the seizure threshold and decreases plasma protein binding of local anesthetics), and
   • hypoxemia;
4. administer a benzodiazepine to treat his seizure
   
   • (seizure activity increases metabolism, which may lead to hypoxemia, hypercarbia, and acidosis);
5. administer succinylcholine and intubate the patient if –
   
   • ventilation were inadequate,
   • the risk of aspiration was significant (history of GERD or hiatal hernia), or
   • if tonic-clonic movements persisted despite benzodiazepine administration (while succinylcholine would minimize the metabolic acidosis associated with seizure-induced muscle activity, it would not affect the acidosis that develops secondary to seizure-induced increases in cerebral metabolism;
6. initiate lipid emulsion therapy with a bolus of 1.5 mL/kg of 20% lipid solution (roughly 100 mL in adults) and a continuous infusion at 0.25 mL/kg/minute, with plans to discontinue the infusion only after establishing hemodynamic stability for at least 10 minutes
   
   • (repeat bolus and double infusion rate every 5 minutes as necessary,
   • keeping in mind that the recommended upper limit for initial dosing is 10 mL/kg for 30 minutes);
7. administer adenosine and/or amiodarone for additional treatment of his ventricular dysrhythmia
   
   • (procainamide, lidocaine, B-blockers, calcium channel blockers, and vasopressin should be avoided when treating bupivacaine-induced ventricular arrhythmias);
8. perform immediate synchronized cardioversion if the patient became unstable (assuming he remained in monomorphic VT-polymorphic VT usually requires unsynchronized shock); and
9. consider cardiopulmonary bypass if the patient’s response to these therapies was inadequate (cardiopulmonary bypass may serve as “bridging therapy” until tissue levels of local anesthetic have diminished).

Clinical Notes:

• Resuscitation drugs that deserve special consideration in association with local anesthetic toxicity include:
  
  • Epinephrine – Standard resuscitation doses of epinephrine (1 mg) are not recommended during resuscitation of a patient experiencing local anesthetic toxicity because epinephrine is highly arrhythmogenic and can reduce the efficacy of lipid rescue. Therefore, it is recommended to utilize smaller doses in this setting (< 1 mcg/kg or 10-100 mcg boluses).
  • Vasopressin – Animal studies have associated the use of vasopressin in the treatment of local anesthetic toxicity with poor outcomes and pulmonary hemorrhage. Therefore, practitioners should consider avoiding this drug in this setting.
  • Local Anesthetics – Drugs like procainamide and lidocaine should be avoided in the resuscitation of patients experiencing local anesthetic toxicity since they would exacerbate the primary cause of cardiovascular instability.
  • Calcium Channel Blockers – Calcium channel blockers should be avoided in the treatment of local anesthetic toxicity due to their effects on the cardiovascular system, such as slowed cardiac conduction, negative inotropy, and vasodilation.
  • B-blockers – B-blockers should be avoided in the treatment of local anesthetic toxicity due to the reduced blood flow to the liver (potentially reducing the metabolism of amide local anesthetics), negative inotropic effects, and negative chronotropic effects associated with their use.

Question 7

The nurse runs to get some versed.

In the meantime, you realize you have propofol at the bedside.

Could you just administer propofol to stop his seizure?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 7

GIven the potential for cardiovascular instability in this situation,

I would NOT administer propofol.

While propofol and thiopental are acceptable alternatives to quickly stop seizure activity, they should be avoided in the setting of cardiovascular instability because of their direct cardiodepressant effects.

Furthermore, the low lipid content of propofol makes it an inappropriate substitute for lipid emulsion therapy.

Question 8

When is the appropriate time to initiate lipid emulsion therapy?

(A 64-year-old man scheduled for total knee arthroplasty receives a femoral and sciatic nerve block pre-operatively to facilitate post-operative pain control. During placement of the blocks, he becomes agitated, develops a tonic-clonic seizure, and loses consciousness.)

Answer 8

The appropriate time to initiate lipid emulsion therapy is controversial.

Since early treatment may prevent cardiovascular collapse, many practitioners believe that waiting until standard therapy has failed to initiate lipid emulsion therapy is unreasonable.

On the other hand, administering lipids at the first sign of local anesthetic toxicity would result in unnecessary treatment, since only a fraction of patients progress from the initial premonitory symptoms to severe toxicity.

Therefore, I would initiate therapy when the signs and symptoms of local anesthetic toxicity appeared to be rapidly progressing or when a patient experienced prolonged seizure activity or signs of cardiac toxicity (i.e. bradycardia, heart block, hypotension, asystole, or ventricular arrhythmia).

Clinical Note:

• Patients should be monitored for at least 30 minutes following the administration of potentially toxic doses of local anesthetic because toxicity has been reported to present longer than 15 minutes after injection (this recommendation refers to patients who have yet to develop any signs or symptoms of toxicity).
  
  • (More likely to happen in tumescent procedure)
• Patients should be monitored very closely for at least 12 hours following significant local anesthetic toxicity because local anesthetic can continue to redistribute to the circulation from tissue depots, potentially resulting in delayed recurrence of severe toxicity.