A 5-month-old girl weighing 7.5 kg presented with an imperforate hymen for incision, drainage, and vaginoscopy. The patient had a history of laryngomalacia and an upper respiratory tract infection with fever, which was treated with antibiotics until a few days before; she was asymptomatic. After discussion with the surgical team and family, the decision was made to perform the procedure under caudal block only. In the OR, the caudal block was successfully performed using 6.5 mL of 0.25% bupivacaine, after negative aspiration to blood and cerebrospinal fluid and following a negative response to a test dose.
Shortly after the injection of local anesthetic (LA), the patient started having convulsions. Accidental intravascular injection of the LA was suspected. Ventricular fibrillation was noted on the monitor and the pediatric advanced cardiac life support protocol was initiated, with high-quality chest compressions, IV epinephrine, intralipid (3 doses of 12-mL 20% fat emulsion), calcium, sodium bicarbonate, and atropine administration. The airway was secured with an endotracheal tube. After the first defibrillation, the patient returned to spontaneous circulation. A hypothermia protocol was initiated for 24 hours and the patient was sent to the pediatric ICU, intubated and sedated, and was hemodynamically stable. After 24 hours, the patient was slowly warmed. There was no evidence of any ischemic encephalopathy. The next day, the patient was extubated, neurologically intact, and discharged from the hospital.
Local anesthetic systemic toxicity (LAST) is a rare complication after administration of LA. It occurs when LAs are accidentally injected or abruptly absorbed into the systemic circulation at a rate exceeding their clearance. Toxicity is caused by extensive accumulation of LA in plasma and subsequent blockage of voltage-gated sodium channels in the heart (eg, ventricular fibrillation) or central nervous system (CNS; eg, convulsions). Since it is a rare event, incidence data on LAST originates mainly from retrospective reviews of large data registries. MÖrwald et al, in a retrospective cohort study including 238,437 orthopedic patients receiving peripheral nerve block (PNB) between 2006 and 2014, reported an incidence of 0.18%, as defined by occurrence of cardiac arrest and/or seizures and/or administration of lipid emulsion.1
Typically, the clinical signs are progressive; in 26% of cases, the symptoms occur immediately (<60 seconds) after LA injection.3 The classic presentation of LAST includes CNS symptoms appearing first, followed by cardiovascular collapse. However, this classic presentation is only seen in 60% of patients.3,4 As reported by Vasques et al, the most common neurologic manifestations are prodromal symptoms (eg, dysarthria, perioral numbness, metallic taste, anxiety, visual changes, muscle twitching, etc), which present in 40% of patients with LAST.4Prodromal symptoms can progress to seizures. Seizures occur in 25% of cases of LAST, whereas 45% of LAST cases show only CNS signs, 11% show only cardiovascular signs, and 44% show both CNS and cardiovascular signs. Cardiovascular signs and symptoms usually occur after or along with CNS symptoms during LAST, presenting as bradycardia, hypotension, and shock in 41% of cases, or ventricular tachycardia/ventricular fibrillation in 15% of cases.3,4
Late onset of LAST is increasingly reported, especially after continuous infusion of LAs. Indeed, 10% of cases of LAST can develop as late as 60 minutes after single-shot regional anesthesia.4
Injection of LA in highly vascular areas significantly increases the risk for accidental intravascular injection. PNBs for shoulder arthroplasty have a significantly higher risk for LAST than PNBs for hip or knee arthroplasty due to the proximity of the vasculature to the CNS.2
Blocks requiring large volumes and doses of LA significantly increase the risk for LAST. Free LA in plasma may be increased by low alpha-1-acid glycoprotein (AAG) levels (eg, in pregnancy, extremes of age, small patient size, etc). During pregnancy, the increased cardiac output can further raise the risk for LAST. Impaired hepatic and/or renal clearance and extremes of age (especially after repeated dosing or administration of an LA as a continuous infusion) can significantly delay clearance of the LA. Acidosis, hypoxia, and hypercarbia also can augment the systemic effects of LAs. Pure isomer LAs (eg, ropivacaine and levobupivacaine) are less cardiotoxic and less neurotoxic than racemic mixture LAs (eg, bupivacaine).5
The recently published third practice advisory on LAST by the American Society of Regional Anesthesia and Pain Medicine (ASRA) recommends using ultrasound guidance for PNBs.6 In a meta-analysis including 946 patients in 13 studies of PNBs, ultrasound guidance significantly decreased the risk for vascular puncture compared with electrical neurostimulation.7 The lowest volume and concentration of LA required for the extent and duration of a specific block should be incrementally injected after negative aspiration through the needle or catheter. Adding epinephrine to the test dose helps identify inadvertent IV injection by monitoring an abrupt increase in heart rate.
The practice advisory emphasizes the additive effect of LA and the importance of prolonged monitoring for at least 30 to 45 minutes, especially after truncal blocks (eg, transversus abdominis plane block, quadratus lumborum block).6 Heavy sedation should be avoided during injection of LA for early detection of CNS symptoms. The maximum recommended doses should not be exceeded (eg, without/with epinephrine, the maximum dose for lidocaine is 4.5/7 mg/kg, for bupivacaine is 2.5/3 mg/kg, and for ropivacaine is 3/3.5 mg/kg).
The treatment of cardiac arrest caused by LAST differs from conventional advanced cardiac life support in 2 aspects: First, priority is given to airway management to avoid factors aggravating LAST, such as hypoxia, hypercapnia, and acidosis; second, small initial doses of epinephrine (≤1 mcg/kg) are administered. Medications to be avoided include vasopressin, calcium channel blockers, beta-blockers, and lidocaine. The preferred first-line antiarrhythmic should be amiodarone.
Lipid emulsion therapy should be initiated immediately after securing the airway. The recommended doses of 20% lipid emulsion for adults weighing more than 70 kg are bolus, 100 mL IV over 2 to 3 minutes, followed by infusion of 200 to 250 mL over 15 to 20 minutes. For children or adults weighing less than 70 kg: bolus, 1.5 mL/kg ideal body weight IV over 2 to 3 minutes, followed by infusion at 0.25 mL/kg per minute. The dose can be repeated as needed, but the maximum dose of lipid emulsion is 12 mL/kg.6 The mechanism of action of the lipid emulsion is multifaceted. Recent evidence shows that lipid emulsion works by moving the LA out of cardiac tissue and the brain (via the so-called scavenging effect). In addition, the emulsion has inotropic qualities, activating cardioprotective pathways and affecting mitochondrial metabolism and fa tty acid metabolism.8 Seizures should be preferentially treated with benzodiazepines. An updated checklist for treating LAST is available on the ASRA website.9
- Mörwald EE, Zubizarreta N, Cozowicz C, et al. Incidence of local anesthetic systemic toxicity in orthopedic patients receiving peripheral nerve blocks. Reg Anesth Pain Med. 2017;42(4):442-445.
- Rubin DS, Matsumoto MM, Weinberg G, et al. Local anesthetic systemic toxicity in total joint arthroplasty: incidence and risk factors in the United States from the National Inpatient Sample 1998-2013. Reg Anesth Pain Med. 2018;43(2):131-137.
- Di Gregorio G, Neal JM, Rosenquist RW, et al. Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009. Reg Anesth Pain Med. 2010;35(2):181-187.
- Vasques F, Behr AU, Weinberg G, et al. A review of local anesthetic systemic toxicity cases since publication of the American Society of Regional Anesthesia recommendations: to whom it may concern. Reg Anesth Pain Med.2015;40(6):698-705.
- 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.
- Neal JM, Barrington MJ, Fettiplace MR, et al. The third American Society of Regional Anesthesia and Pain Medicine practice advisory on local anesthetic systemic toxicity: executive summary 2017. Reg Anesth Pain Med. 2018;43(2):113-123.
- Abrahams MS, Aziz MF, Fu RF, et al. Ultrasound guidance compared with electrical neurostimulation for peripheral nerve block: a systematic review and meta-analysis of randomized controlled trials. Br J Anaesth. 2009;102(3):408-417.
- Fettiplace MR, Weinberg G. The mechanisms underlying lipid resuscitation therapy. Reg Anesth Pain Med. 2018;43(2):138-149.
- American Society of Regional Anesthesia and Pain Medicine. Checklist for treatment of local anesthetic systemic toxicity. www.asra.com/ advisory-guidelines/ article/ 3/ checklist-for-treatment-of-local-anesthetic-systemic-toxicity. Accessed September 24, 2018.