Learning Objectives: After participating in this CME activity, the physician should be better able to:
1. Manage the 4 primary symptoms of local anesthetic systemic toxicity (LAST).
2. Assess the role of lipid emulsion therapy (Intralipid) in treating LAST.
3. Implement the suggested modifications to Advanced Cardiac Life Support guidelines in patients with LAST.
Local anesthetics are an essential ingredient of interventional pain medicine. It is extremely rare for patients to manifest serious adverse effects or experience complications secondary to local anesthetic injection. But dramatic adverse events can occur. These adverse effects range from the mild symptoms that may appear after systemic absorption of local anesthetic from a correctly sited and appropriately dosed regional anesthetic procedure to major central nervous system (CNS) or cardiac toxicity that can result in major morbidity or mortality.
A variety of factors influence the incidence and severity of local anesthetic systemic toxicity (LAST), including individual patient risk factors, concurrent medications, location and technique of the nerve block performed, the specific local anesthetic agent, total local anesthetic dose (ie, the product of concentration × volume), speed of detection of the signs and symptoms, and adequacy and speed of rescue therapy.
Interest in local anesthetic toxicity has followed 3 waves: The first wave arrived with the initial discovery of local anesthetic toxicity soon after the introduction of cocaine in 1884. A second wave of interest occurred after a number of fatalities from the use of bupivacaine and etidocaine in the 1970s. And, finally, in the late 1980s, a third wave of interest followed the introduction of ropivacaine and levobupivacaine and continues through the present.
Researchers and practitioners now have improved understanding of LAST pathophysiology, and new treatment modalities, including use of lipid emulsion therapy, have recently emerged. The American Society of Regional Anesthesia and Pain Medicine (ASRA) commissioned a panel of experts to update and expand recommendations that were originally published after the 2001 ASRA Conference on Local Anesthetic Toxicity. The recent practice advisory
1 focuses on LAST, which includes cardiac and CNS toxicity as a result of unintended intravascular injection or delayed tissue uptake.
History of LAST
Soon after the introduction of cocaine, systemic toxicity was observed manifesting as seizures and respiratory failure.
2 Direct cardiac toxicity was also gradually recognized as a major issue in systemic toxicity, rather than just an associated adverse effect. The systemic toxic effects of cocaine led to Einhorn's development of procaine in 1904.
Unfortunately, LAST continued to be a significant problem with cocaine, and the American Medical Association (AMA) formed the Committee for the Study of Toxic Effects of Local Anesthetics
3 in the early 1920s. It noted that local anesthetics could cause death by sudden cardiac arrest, and this phenomenon could precede seizures or even occur in the total absence of seizures. The AMA committee emphasized the importance of establishing an airway to optimize oxygenation and ventilation, a theme that Moore and Bridenbaugh
4continue to emphasize until today.
Soon after the potent lipid-soluble local anesthetics bupivacaine and etidocaine were introduced into clinical practice, they were linked to fetal death in 1:900 pregnant women who received a paracervical block. Ten years later, bupivacaine was linked to fatal cardiac arrest in otherwise healthy adult patients. With the report of Prentice
5 and Albright's editorial,
6 the FDA issued a “Dear Doctor” letter withdrawing obstetric analgesia as an indication for the use of 0.75% bupivacaine. The FDA also warned against further use of bupivacaine in paracervical block and IV regional anesthesia. Less cardiotoxic single enantiomers—ropivacaine and levobupivacaine—were introduced in the late 1980s. Serious morbidity and mortality from cardiac toxicity has continued, however. The first case reports
7 of successful rescue of humans experiencing refractory cardiac toxicity came in 2006.
Prevention
The ASRA Practice Advisory
1 emphasizes “the primacy of prevention in reducing the frequency and severity of LAST, yet no single intervention has been identified that can reliably eliminate risk.”
The key to prevention is to reduce the amount of local anesthetic that is intravascularly injected and to decrease tissue uptake of local anesthetic. This can best be accomplished by the early detection of an intravascular block needle or catheter placement. If an intravascular injection is administered at all, it should ideally contain the lowest possible dose of local anesthetic. To these ends, various intravascular identification methods have been proposed since the description of the epinephrine test dose by Moore and Batra
8 in 1981.
Local anesthetic dose can be limited by several methods. The calculated total dose (the product of volume × concentration) should be tailored to the minimum mass of local anesthetic molecules necessary to achieve a solid nerve block. It has been suggested that most peripheral nerve blocks are performed with significantly larger doses than are necessary. This concept is further supported by excellent clinical results obtained using smaller doses placed in close proximity to the nerve with ultrasound-guided regional anesthesia and continuous perineural catheters.
Risk Factors
Risk factors for the development of LAST include: extremes of age (<4 months or >70 years) or those with preexisting atrioventricular conduction blocks or a history of ischemic heart disease. It is interesting to note that body weight and body mass index (BMI) do not correlate well with local anesthetic plasma levels after a specific dose in adults; there is, however, a better correlation in children. It is important to remember that nerve block site, use of a vasoconstrictor like epinephrine, and patient-related factors such as cardiac, renal, or hepatic dysfunction are more important predictors of local anesthetic plasma levels than either body weight or BMI.
When the above-noted factors that may predispose to LAST are present, reduction of local anesthetic dose seems to be the appropriate action, but there are no established practice parameters to guide dose reduction. Incremental injection of 3 to 5 mL of local anesthetic, with a concomitant pause for at least 1 circulation time, before further injection is a time-honored recommendation with great intuitive appeal, but with absolutely no objective efficacy data.
It is important to realize that any potential benefit from this approach may be outweighed by increasing the total time of injection, which brings with it an attendant risk of needle movement and puncture of a vessel that might not have happened had the block been conducted quickly. Even in the steadiest hands, the tip of the needle will move over time. It has been estimated by Pan et al
9 that aspiration of needles and catheters, although recommended, may fail to identify intravascular placement in at least 2% of patients.
Substituting ropivacaine or levobupivacaine might reduce the potential for systemic toxicity. Nonetheless, these drugs are still potentially toxic when administered as an IV bolus, and the theoretical benefit of chirality becomes less important with increasing doses, particularly among patients already at higher risk for local anesthetic toxicity.
The use of an intravascular test dose remains the most reliable marker of intravascular injection. Only fentanyl and epinephrine
10 meet suggested standards for reliability and applicability. IV fentanyl 100 mcg has been shown to produce drowsiness or sedation reliably in laboring patients.
With regard to epinephrine, 10 to 15 mcg/mL epinephrine has a positive predictive value and 80% sensitivity in detecting intravascular injection in adults if heart rate increases by 10 or more beats per minute, or systolic blood pressure increases by 15 mm Hg or higher. However, epinephrine test doses are unreliable in elderly patients, or in patients who are deeply sedated, taking beta-blockers, or anesthetized with general or neuraxial anesthesia.
Epinephrine is also controversial with regard to its role causing nerve injury. Although epinephrine has been shown in animal models to worsen local anesthetic-induced neurotoxicity, it is unclear
11 whether the additive injury in humans is clinically distinguishable from that caused primarily by the local anesthetic itself. The frequency of seizures during performance of peripheral nerve block was similar to the frequency of permanent nerve injury in one major study (1.2 versus 2.4 in 10,000, respectively). However, it is important to keep in mind that LAST, but not nerve injury, has the potential to produce mortality.
Clinical Diagnosis of Systemic Toxicity
The classic description of LAST includes subjective symptoms of CNS excitement, such as auditory changes including tinnitus or a siren sound, circumoral numbness, metallic taste, and agitation. Symptoms then progress to seizures and/or CNS depression (coma, respiratory arrest).
Cardiac Toxicity Can Precede Seizure Activity
In the classic descriptions of LAST, cardiac toxicity does not occur without preceding CNS toxicity. However, when LAST occurs secondary to direct intravascular injection—particularly with injection into the carotid or vertebral arteries during a stellate ganglion block—early warning symptoms can be bypassed, and the patient can rapidly develop seizure activity that may progress to cardiac toxicity (hypertension, tachycardia, ventricular arrhythmias). With greatly elevated concentrations of local anesthetic, the hypertensive, tachycardic reaction may be rapidly followed by cardiac depression (bradycardia, asystole, decreased contractility, and hypotension). It is important to recognize that with potent amide anesthetics, cardiac toxicity may occur simultaneously with seizure activity or even precede it.
Although the classic description is useful for teaching purposes, case reports of LAST demonstrate the extreme variability of its presentation, including timing of onset, initial manifestations, and duration. An atypical presentation was reported in approximately 40% of published cases of LAST. In these instances, symptoms were delayed by 5 minutes or more or occurred with only cardiovascular signs of toxicity. The practitioner's vigilance is of critical importance in recognizing these early signs of LAST, appreciating their variable presentation, and having a low threshold for considering LAST in patients who have received potentially toxic doses of local anesthetics and manifest atypical or unexpected signs and symptoms.
Most reports
12,
13 noted the first onset of symptoms between 1 and 5 minutes after injection, suggesting some intravascular injection, lower extremity injection, or decreased tissue uptake. Importantly, approximately 25% of cases described symptoms first appearing more than 5 minutes after injection, with one report describing a 60-minute delay, which emphasizes the importance of prolonged observation of patients receiving potentially toxic doses of local anesthetic.
The ASRA panel
1 suggested that although LAST tended to follow classic presentations, variations were very common. Although seizure was the most common presenting symptom, less than 20% of cases involved any of the classic prodromal symptoms such as auditory changes, metallic taste, or disinhibition. Furthermore, the panel concluded that LAST does not always manifest itself as obvious seizure or cardiac arrhythmias in close temporal relationship to local anesthetic injection. Practitioners should consider the diagnosis of impending LAST in patients who develop unexplained agitation or CNS depression, or unexplained signs of cardiovascular compromise, for example, progressive hypotension, bradycardia, or ventricular arrhythmia, even if more than 15 minutes have elapsed since local anesthetic injection.
Treatment
The treatment regimen for LAST includes airway management, circulatory support, and promoting the resolution of the systemic effects of local anesthetics (
Figure 1). Unlike the treatment of “conventional” cardiac arrest, the key to successful care of patients with LAST is recognizing the primacy of airway management.
As reported by Moore et al
14 50 years ago, prevention of hypoxia and acidosis by immediate restoration of oxygenation and ventilation can either halt progression to cardiovascular collapse and seizure or facilitate resuscitation. If seizures occur, they should be rapidly suppressed to prevent injury to the patient and the development of acidosis. A benzodiazepine (eg, diazepam or midazolam) is the first-line therapy to treat LAST-related seizures. If tonic-clonic movements persist despite these measures, a small dose of succinylcholine may be considered to stop muscular activity rapidly, as continued seizure activity exacerbates hypoxia and systemic acidosis.
Local anesthetic-induced cardiac arrest requires rapid restoration of coronary perfusion pressure to improve myocardial contractility and to displace local anesthetics from cardiac tissues by improved tissue perfusion. Maintenance of adequate cardiac output and oxygen delivery to tissues is crucial for prevention and treatment of acidosis.
It is important to recognize that cardiac arrest or arrhythmia associated with LAST represents a substantially different medical problem from the more typical out-of-hospital scenarios addressed by the American Heart Association Advanced Cardiac Life Support (ACLS) guidelines. Although a standard dose (1 mg) of epinephrine may restore circulation and initially improve blood pressure, it is also highly arrhythmogenic.
Furthermore, in animal studies
15 of local anesthetic–induced cardiac arrest, epinephrine resulted in poorer outcomes from bupivacaine-induced asystole than did lipid emulsion, while vasopressin (the other ACLS drug recommended for cardiac arrest) also showed very poor outcomes and was associated with pulmonary hemorrhage.
Therefore, the ASRA panel advises that if epinephrine is used in treating LAST, lower than the standard ACLS initial doses of epinephrine are suggested (<1 mcg/kg). On the basis of animal studies, consideration should be given to avoiding vasopressin. In recalcitrant cases of LAST in which there is inadequate response to epinephrine and other standard therapies, cardiopulmonary bypass should be considered as a bridging therapy until tissue levels of local anesthetic have cleared.
Lipid Emulsion Therapy
Lipid emulsion therapy (Intralipid) can be instrumental in facilitating resuscitation, most probably by acting as a “lipid sink” that draws down the content of lipid-soluble local anesthetics from within cardiac tissue, thereby improving cardiac conduction, contractility, and coronary perfusion.
The ASRA panel recommends an initial bolus of 1.5 mL/kg (lean body mass, not total body weight) of 20% lipid emulsion, followed by an infusion of 0.25 mL/kg per minute continued for 10 minutes after hemodynamic stability is attained. Failure to achieve stability should prompt an additional bolus and increase of infusion rate to 0.5 mL/kg per minute. Approximately 10 mL/kg of lipid emulsion for 30 minutes is recommended as an upper limit for initial administration.
Because tissue depots of local anesthetic can redistribute to the circulation over time, and delayed recurrence of severe toxicity has been reported, it is recommend that any patient with significant LAST be observed for at least 12 hours.
There is no evidence that one formulation of lipid emulsion is superior to another for the treatment of LAST. However, it is important to note that propofol is absolutely not an acceptable substitute for lipid emulsion therapy because of its low lipid content (10%), the large volumes required for the benefit of lipid in resuscitation (equivalent to hundreds of milliliters), and the direct cardiac depressant effects of propofol administration (
Figure 1).
Conclusion
Local anesthetics are wonderful tools for the diagnosis and treatment of pain, but there is a real risk of toxicity even in the best of hands. It is important to recognize that with potent amide anesthetics, cardiac toxicity may occur simultaneously with seizure activity or even precede it. Case reports of LAST demonstrate the extreme variability of its presentation, including timing of onset, initial manifestations, and duration. Airway management is the key to successful care of LAST patients, which also includes circulatory support, and promoting the resolution of the systemic effects of local anesthetics.
Lipid emulsion therapy, such as Intralipid, can be instrumental in facilitating resuscitation, drawing down the content of lipid-soluble local anesthetics from within cardiac tissue, thereby improving cardiac conduction, contractility, and coronary perfusion.
Having a supply of Intralipid available on all block carts is a reasonable and attainable goal to treat LAST.
References
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3. Mayer E. The toxic effects following the use of local anesthetics. JAMA. 1924;82:876–885.
4. Moore DC, Bridenbaugh LD. Oxygen: the antidote for systemic toxic reactions from local anesthetic drugs. JAMA. 1960;174:102–107.
5. Prentice JE. Cardiac arrest following caudal anesthesia. Anesthesiology. 1979;50:51–53.
6. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology. 1979;51:285–287.
7. Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. 2006;105:217–218.
8. Moore DC, Batra MS. The components of an effective test dose prior to epidural block. Anesthesiology. 1981;55:693–696.
9. Pan PH, Bogard TD, Owen MD. Incidence and characteristics of failures in obstetric neuraxial analgesia and anesthesia: a retrospective analysis of 19,259 deliveries. Int J Obstet Anesth. 2004;13:1073–1076.
10. Guay J. The epidural test dose: a review. Anesth Analg. 2006;102: 921–929.
11. Neal JM. Effects of epinephrine in local anesthetics on the central and peripheral nervous systems: neurotoxicity and neural blood flow. Reg Anesth Pain Med. 2003;28:124–134.
12. Drasner K. Local anesthetic systemic toxicity: a historical perspective. Reg Anesth Pain Med. 2010;35:160–164.
13. Barrington MJ, Watts SA, Gledhill SR, et al. Preliminary results of the Australasian Regional Anaesthesia Collaboration: a prospective audit of over 7000 peripheral nerve and plexus blocks for neurological and other complications. Reg Anesth Pain Med. 2009;34: 534–541.
14. Moore DC, Crawford RD, Scurlock JE. Severe hypoxia and acidosis following local anesthetic-induced convulsions. Anesthesiology. 1980;53:259–260.
15. Weinberg GL, Di Gregorio G, Ripper R, et al. Resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose. Anesthesiology. 2008;108:907–913.
© 2012 Lippincott Williams & Wilkins, Inc.
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