Case Study
A 29-year-old 70-kg para 1, gravida 1 woman requested an epidural for labor pain relief at 5 cm of cervical dilatation. An epidural was inserted, and patient-controlled epidural analgesia (PCEA) was established using a low-dose epidural mixture of 0.1% bupivacaine with 2 µg/ml fentanyl.
The patient eventually delivered her healthy baby spontaneously but suffered a third-degree perineal tear that required repair in the OR. The patient was taken to the OR, and an epidural top-up of 15 ml 0.5% bupivacaine (75 mg) was administered after a negative aspiration test through the epidural catheter.
Moments after the injection, the patient became agitated and had a tonic-clonic seizure. Shortly after this, the ECG monitor showed runs of irregular rhythm with a noninvasive blood pressure monitoring system reading of 150/100 mmHg with a heart rate of 120 beats/min. Because of the clinical presentation and temporal association with the injection, local anesthetic systemic toxicity (LAST) was suspected.
An emergency (code blue) call for help was put out immediately. High-flow 100% oxygen via a bag-valve-mask system was administered, and 3 mg midazolam was given intravenously in increments, which stopped the seizure. A decision was made to intubate the patient’s trachea to permit controlled ventilation, with a plan for expedited surgery. Thiopental 250 mg was given cautiously to prevent awareness, and succinylcholine 100 mg was given to facilitate intubation of the trachea using a rapid-sequence technique. Lipid rescue – treatment with an IV lipid emulsion – was initiated, using Intralipid 20% with a bolus dose of 1.5 ml/kg (105 ml) and an infusion starting at 15 ml/kg per hour (105 ml/h). Within 5 minutes, the patient’s ECG showed sinus rhythm at a normal heart rate. Later aspiration of the epidural catheter showed free flow of blood, suggesting venous placement.
Surgery was performed under general anesthesia, and the patient was woken and her trachea extubated at the end of the procedure. No further seizures occurred, and the patient remained cardiovascularly stable postoperatively. She was discharged home 24 hours later.
Key Points
This patient became unconscious and had a tonic-clonic seizure following an epidural top-up.
A presumptive diagnosis of LAST was made.
Venous blood was later aspirated through her epidural catheter, supporting IV placement or migration as a cause.
Supportive resuscitation measures were instituted immediately.
The early intervention with lipid emulsion could have possibly prevented the progression from cardiac toxicity to cardiac arrest.
Discussion
Local anesthetic systemic toxicity (LAST) is a potentially lethal complication of regional anesthesia and analgesia. A third of cases relate to epidural anesthesia, according to a large retrospective review of cases of LAST reported in the literature between 1979 and 2009.1 After a single IV injection of a toxic local anesthetic (LA) dose, LAST occurs very rapidly, in less than 1 minute in 50 percent of cases and less than 5 minutes in 75 percent of cases. During a continuous infusion of local anesthetic solution, LAST can be delayed; it can occur days after initiation of the infusion.1
Normal Action and Toxic Action of Local Anesthetics
Anesthetists usually intend local anesthetic drugs (LAs) to act solely on peripheral neuronal tissue. LAs exist in both ionized acid and nonionized base forms. The nonionized form has the ability to cross the myelin sheath barrier and reach the axon. The low pH inside the cell facilitates the dissociation of the nonionized local anesthetic to the ionized form. It is the ionized fraction that has the ability to contact the sodium channels from the inside of the cells and consequently block them.2 However, being sodium channel inhibitors, LAs can act in multiple locations in the CNS and the cardiovascular system, where sodium channels are widespread, causing undesirable effects. In excess, these undesirable effects may be regarded as toxicity. The development of symptoms and signs of LA toxicity relates directly to the concentration of the drug in the plasma. LAST is caused by a high circulating plasma concentration of LA, generally occurring as a result of either IV entrainment of LA or delayed absorption from the anesthetic depot at an injection site. The plasma concentration will depend on the rate of absorption from the injected site as well as inadvertent IV injection.3
Features of LAST
Most cases of LAST follow a broadly typical pattern of presentation, with a combination of CNS and cardiovascular system (CVS) signs and symptoms. The first signs or symptoms of LAST are often related to the CNS, with seizures being the most common sign.1 The “classic” prodromal signs of agitation, metallic taste, circumoral numbness, and auditory changes occur in less than 20 percent of patients.1
The most frequent signs of CVS toxicity, occurring in about 50 percent of patients, are ECG abnormalities, including tachyarrhythmia, bradyarrhythmia, ventricular ectopics, conduction defects, or QRS complex widening. More ominous signs, such as malignant arrhythmia including ventricular tachycardia and fibrillation or asystole, occur in about 10 percent of patients.
Clinicians should note that in only 11 percent of cases of LAST do cardiovascular symptoms occur in the absence of CNS toxicity.1 Because of the wide spectrum of presenting signs and symptoms and the fact that a “classic” presentation is uncommon in reality, vigilance and an index of suspicion of LAST should always be maintained.
CNS Toxicity
CNS toxicity is thought to occur in two stages, with initial blockade of sodium channels in inhibitory neurons, allowing the excitatory neurons to act unopposed, resulting in seizures. Increasing concentration of local anesthetic then depresses all CNS neurons, manifesting ultimately as unconsciousness and coma. Electroencephalogram (EEG) recordings usually show slowing of activity and ultimately “silence” (inactivity). CNS depression in the brainstem can cause eventual collapse of the cardiovascular system. In most cases, convulsions can be managed successfully.2
Cardiovascular System Toxicity
Although the major pharmacologic effects of local anesthetics are mediated via blockade of sodium channels, they also can block potassium and calcium channels, contributing to cardiovascular toxicity. The enantiomers of LAs show differential ion channel blockade, the R-isomer having double the potency at sodium channels, 70 times the potency at potassium channels, and three times the potency at calcium channels.4
The channel blockade described has direct and indirect effects on the myocardium. Direct effects include negative inotropy and impaired conduction through cardiac conduction tissue. Abnormal conduction predisposes to reentry phenomena and dysrhythmias. Indirect effects may result from disruption to the autonomic outflow and direct effect on the cardiac center in the brain.4
Finally, LAs can also have effects on oxidative phosphorylation in the mitochondria and on intracellular cyclic AMP levels, both of which can disrupt cellular function4 (Table 38.1).
| Progression of CNS toxicity | Progression of CVS toxicity |
|---|---|
| Circumoral paresthesia | Hypertension |
| Tinnitus | Tachycardia (CNS excitation phase) |
| Confusion | Myocardial depression |
| Convulsions | Reduced cardiac output |
| Loss of consciousness | Hypotension |
| Coma | Peripheral vasodilatation |
| Respiratory depression | Severe hypotension |
| Sinus bradycardia | |
| Conduction defects | |
| Dysrhythmias | |
| Cardiac arrest |
Note: Patients may not exhibit all steps.
LAST in Obstetrics
In obstetrics, the absolute and relative risk of LAST may be increased. Pregnant women form a large proportion of the patient population, and a disproportionately large number of them are subject to a regional anesthetic technique with potentially toxic LA doses. Hence the absolute risk is increased. Furthermore, it is accepted that obstetric care is increasingly complicated by rising maternal age, obesity, and other comorbidities.
Relative risk may be increased because there may be real differences in susceptibility to LA toxicity in the pregnant state. Several mechanisms may account for this. Epidural vein distension is said to make entrainment of local anesthetic and catheter migration more likely. Increased cardiac output may increase uptake of local anesthetic from the epidural space and increase delivery to target sites. Pregnancy-related decreases in protein binding may increase the availability of free drug in the vascular compartment.5, 6 The hormonal effects of estradiol6 and progesterone7 appear detrimentally to alter cardiomyocyte electrophysiology. Neurons may demonstrate increased susceptibility to local anesthetics during pregnancy, reducing the threshold for seizures.8
Cardiac arrest secondary to LAST remains a serious potential problem in obstetrics despite the use of low concentration LAs for labor analgesia and increased awareness of toxicity.9,10 Clinicians would do well to remind themselves of the large dose of LA contained in an epidural top-up used to provide anesthesia (as opposed to analgesia) for surgery, whenever they administer one.
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