Dr. Gevirtz is Associate Professor of Anesthesiology, Louisiana State University Health Sciences Center, New Orleans, LA, and Medical Director, Somnia Pain Management, 627 W St, Harrison, New York, NY 10528; E-mail: firstname.lastname@example.org.
All faculty and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity.
Dr. Gevirtz has disclosed that use of Intralipid for treatment of local anesthetic systemic toxicity as discussed in this article has not been approved by the U.S. Food and Drug Administration.
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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 advisory1 focuses on LAST, which includes cardiac and CNS toxicity as a result of unintended intravascular injection or delayed tissue uptake.
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 Anesthetics3 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 Bridenbaugh4continue 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 Prentice5 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 reports7 of successful rescue of humans experiencing refractory cardiac toxicity came in 2006.
The ASRA Practice Advisory1 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 Batra8 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 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 al9 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 epinephrine10 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 unclear11 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.
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).
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 reports12,13 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 panel1 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.
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 al14 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 studies15 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 (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).
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.
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.
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.
A subspecialty is being born. As of April, 11 of the nation’s three dozen obstetric anesthesiology fellowships have received official recognition from the Accreditation Council for Graduate Medical Education. The fellowships received initial accreditation at a meeting of the council’s Residency Review Committee in anesthesiology, making obstetric anesthesia the fifth subspecialty.
Obstetric anesthesiology training has been available without accreditation for decades. The program at Brigham and Women’s Hospital, in Boston, for instance, which is applying for 2013 accreditation, has been in place for more than 25 years. But over the past 10 years the push for accreditation has taken place, said McCallum Hoyt, MD, MBA, assistant professor of anesthesiology at the Brigham and president of the Society for Obstetric Anesthesia and Perinatology (SOAP), which led the effort.
“Choosing to become accredited was based on the recognition that we did have a unique body of knowledge,” she said. “Now we can standardize what it is we’re offering when we say ‘OB fellowship.’”
Michael G. Richardson, MD, who directs the obstetric anesthesiology fellowship at Vanderbilt University in Nashville, Tenn., called obstetrics a legitimate subspecialty of anesthesia with a wealth of skills. “A lot of people think it’s about time,” he said. “We’ve been due for this.”
Some Pushing Required
Not everyone agreed on the subspecialization. Some SOAP members were reluctant to push for accreditation, recalled John Sullivan, MD, MBA, who directs the anesthesiology residency at Northwestern University, in Evanston, Ill., and who served as a member of SOAP’s Ad Hoc Committee on Accreditation. (Northwestern’s obstetric fellowship was among the ones to receive accreditation this spring.)
“That school of thought believed that the additional administrative work, costs and lost flexibility would make seeking fellowship accreditation not worthwhile,” Dr. Sullivan told Anesthesiology News. Some existing obstetric fellowships, for instance, are structured as a hybrid fellow/faculty position, which allows for higher pay and may be a recruitment advantage. That would not be allowed in an accredited fellowship. Maintaining accreditation also carries costs, and programs are already under financial pressure.
These factors compound the fact that subspecialization within anesthesiology practices can, in itself, complicate call schedules and staffing as well as rob generalists of valuable experience. “We watched the pediatric anesthesia community also wrestle with this,” Dr. Sullivan said.
Prospective fellows, however, seem to value accredited fellowships, he added. “Would you like an oversight agency to ensure that the quality of your training is good? Of course. It’s a great thing for a resident. It creates a lot of work, though, for all of us.”
Indeed, just applying for accredited status was a challenge. Having received the program requirements near the end of 2011, fellowship directors faced a tight Feb. 29, 2012, application deadline. Some directors said that they had to do far more description than overhaul.
“I don’t think we are drastically changing the way we train our fellows” upon accreditation, Dr. Richardson said. However, he added, the new program—at least at Vanderbilt—will carry more rigorous provisions for assessment and feedback.
New to some programs are two interdisciplinary requirements. Fellows must spend two weeks in a neonatal intensive care unit and two weeks with specialists in maternal and fetal medicine. Each one-year program also will include three months of protected research time.
Obstetric anesthesiology is the fifth subspecialty of anesthesiology to receive accreditation from the graduate education group, after cardiothoracic anesthesia, critical care anesthesia, pain medicine and pediatric anesthesia. The subspecialty has come into its own in part because of increased morbidity in pregnant patients compared with 20 years ago, said Michaela K. Farber, MD, fellowship director at the Brigham.
“Women who wouldn’t have been well enough to reproduce, are now able to—and they still have a lot of risk,” Dr. Farber said. “So to have centers with people trained with the expertise required to have them safely deliver is increasingly important.”
Advanced maternal age is one culprit: Older mothers have more comorbidities and are at higher risk for complications during delivery. Obesity and diabetes place many pregnant women in the high-risk category; obesity as well as repeat cesarean deliveries also may be contributing to rising rates of postpartum hemorrhage.
Many women also owe their chance at motherhood to advances in neonatal cardiac surgery. “Now most children born with congenital heart disease make it to adulthood and want to have children,” Dr. Hoyt said. “That’s a whole new body of medicine we weren’t even looking at 20 years ago.”
Multiple pregnancies resulting from in vitro fertilization mean higher physiologic stress on the mother, which can unmask underlying comorbidities, said Mark Zakowski, MD, director of the fellowship at Cedars-Sinai Medical Center in Los Angeles, which received accreditation. Other knowledge central to obstetric anesthesia includes the management of chronic pain after cesarean surgery, the use of drugs like suboxone to aid in the management of opiate-dependent mothers and any number of approaches to labor analgesia.
In the long run, the next step for obstetric anesthesiology could be certification. Physicians training in three of the four accredited anesthesia subspecialties, as well as in hospice and palliative care, can seek certification from the American Board of Anesthesiology. But no such option exists yet for obstetric anesthesiologists. “Whether we want to go down that pathway of an actual exam comes with a whole different set of questions and issues,” Dr. Hoyt noted.
In the meantime, standardizing the curriculum will help both patients and obstetric anesthesiologists, she said. “Around the country, whether you’re on the East Coast or the West Coast or the center part of the country, you can be assured that people coming out of accredited programs will have roughly the same body of knowledge,” she said. “I’m very excited about the whole thing.”
Dr. Richardson, too, is enthusiastic about the development. “I think any profession that self-regulates needs to do it rigorously, and that’s what accreditation helps us to achieve,” he said. “It can only be good for our profession. It can only be good for patient care.”