It has been nearly 4 years since 4 dramatic case reports1–4 of lipid reversal of local anesthetic toxicity were published in Anesthesia & Analgesia with 3 accompanying editorials.5–7 Since then, IV lipid emulsion (ILE) infusion has been included in practice advisories of the Association of Anesthetists of Great Britain and Ireland, the American Society of Regional Anesthesia and Pain Medicine, and endorsed by the American Heart Association Advanced Cardiac Life Support recommendations. Moreover, ILE has also been reported to reverse acute toxicity from a variety of lipophilic drug overdoses. As a result, the utility of this therapy is becoming more widely recognized by practitioners in other medical subspecialties, particularly emergency medicine and critical care.
A group of 4 papers in this issue of Anesthesia & Analgesia focuses on ILE: 1 case report, 2 laboratory investigations, and 1 highly novel blend of the two, a study attempting to identify the cause of sudden, postoperative fatal cardiovascular collapse in a wounded soldier. The medical literature generally weighs clinical trials as providing a higher level of evidence than either case reports or animal studies. However, we believe randomized trials are no longer ethically defensible in studying lipid infusion for local anesthetic toxicity and are probably not feasible in many other cases. These facts place the burden for proof of principle and establishing overall efficacy of lipid emulsion–based resuscitation on case reports, laboratory studies, and systematic analyses of both. The current group of papers reflects this reality. One paper8 is the subject of a separate Special Article that addresses the suitability of pigs as a model for studying ILE. The others are each unique and add substantial value to the ILE experience and literature.
KOCH'S POSTULATES, CROSSOVERS, AND CONTROLS?
A letter to the editor by Yurtlu et al.9 in this issue provides an example of the potential usefulness of lipid in treating psychotropic medication overdose. In this case, central nervous system depression associated with olanzapine overdose was rapidly reversed by lipid infusion: the Glasgow Coma Scale score increasing during the lipid infusion from 7 to 15. Olanzapine is a thienobenzodiazepine antipsychotic, and this case is similar to a case report by McAllister et al.10 in which a 4-year-old boy with depressed mental status after an overdose of olanzapine rapidly regained consciousness after a lipid infusion. Interestingly, both cases had subsequent recurrence of obtundation and repeat reversal of the stupor with a second infusion of lipid. Aside from the implications for postevent monitoring and treatment of recurrent toxicity, both of these case reports address the efficacy of lipid emulsion infusion in an interesting way. It was very common in the early days of lipid resuscitation for skeptics to point out that reversal of toxicity could not be ascribed specifically to lipid when the patients had also received a variety of other resuscitation drugs; hence, we often heard statements along the lines, “The patient probably recovered because the epinephrine finally ‘kicked in.'” However, in these cases of olanzapine toxicity, each patient experienced 2 reversals of clinical toxicity temporally associated with lipid infusion and no other treatment. Although not exactly fulfilling a “toxicologic equivalent” of Koch's postulates, this nearly identical sequence of reversal-recurrence-reversal in 2 patients does support a causal relationship of clinical recovery with lipid emulsion infusion. Moreover, in both cases, the patients seem to have avoided more significant morbidity or death.
IN ISOLATED HEART
The superb study by Liu et al.11 in this issue used an isolated rat heart model to compare lipid and epinephrine alone and in combination for treatment of bupivacaine-induced asystole. The isolated heart has several advantages for comparing treatments for toxic cardiomyopathy as extracardiac confounders are removed from the analysis. Moreover, as the authors demonstrate, the system provides data that encompass every major metric of cardiac function. After a high-concentration challenge to induce asystole, Liu et al. continued to infuse bupivacaine at low concentrations throughout recovery to mimic accurately the clinical setting where local anesthetic continues to linger at low concentrations in the blood long after an initial intravascular injection. A previous study by the same group confirmed that during bupivacaine infusion, lipid emulsion reduces cardiac bupivacaine content and dose dependently improves cardiac performance.12 They further identified an optimal infusing concentration of lipid in this model (2%) that achieved the highest rate pressure product (RPP) and reduced cardiac bupivacaine content most effectively.
The current study continues in the same vein, as they first identify an optimal epinephrine infusing concentration (balancing the inotropic and arrhythmogenic effects) then compare the recovery dynamics among 4 treatment groups: lipid only, epinephrine only, lipid and epinephrine combined, and control. In terms of recovering RPP as a percent of baseline, there is a clear advantage in combining epinephrine with lipid emulsion, and the authors' key conclusion is that the combination is superior to either agent alone. However, interpreting and translating the data to a clinical setting is not so clearcut, particularly because deciding on “optimal” epinephrine dosing in a patient during cardiac arrest is suspect at best and certainly not reliably or precisely achievable. Moreover, there is no difference in time to recovery between the lipid-only and combination treatments (P = 0.995), so one can ask, “Why add epinephrine?” The authors will point to the superior RPP in the combined group but we counter, “At what cost?” No hearts given only lipid developed arrhythmias whereas 3 of 12 hearts in the combination group had bouts of ventricular tachycardia, presumably with a loss of intraventricular pressure as described in the epinephrine-only group. Moreover, adding epinephrine had no benefit for reducing cardiac bupivacaine content, the ultimate goal in reversing toxicity. Lipid-only reversal (without epinephrine) has been described in patients. Nevertheless, improved metrics of cardiac performance are generally desirable in this setting, so it is reasonable to consider adding epinephrine during resuscitation if this does not either interfere with lipid resuscitation as described by Hiller et al.13 or produce malignant arrhythmias that would similarly impair resuscitative efforts. The take-home here, supported by data from Liu et al.,11 is that adding epinephrine is reasonable in small doses. This approach is reflected in the American Society of Regional Anesthesia practice guidelines that now recommend keeping epinephrine boluses <1 μg/kg.
SOLDIERS AND HEROES
Since the first days of our military involvement in Iraq, Dr. Buckenmaier and colleagues14 have established protocols and employed state-of-the-art tools in the management of pain in our troops suffering combat-related injuries. These encompass multimodal and continuous catheter techniques, the latter including both epidural and peripheral nerve blocks. Real-life situations make this all the more remarkable because care is delivered routinely in harrowing circumstances, combat hospitals, and during long flights in airborne critical care units.
The case report by Buckenmaier et al.14 in this issue of Anesthesia & Analgesia is another example of pathfinding insofar as it models a specific event in the tragic, postoperative death of a soldier. This young hero had experienced penetrating injuries to both legs, left arm, and the abdomen. He was stabilized at an army hospital in Germany where lumbar epidural and brachial plexus catheters were placed allowing successful pain management during his transport stateside to Walter Reed Army Hospital. There his wounds were further débrided under an uneventful general anesthetic. However, in the recovery room, he emerged from anesthesia complaining of pain on a scale of 10 of 10. Shortly after the catheters were redosed with ropivacaine, the young man experienced sudden cardiovascular collapse (their Fig. 1) that resisted a maximal team effort for more than 80 minutes of resuscitation including ILE infusion. The temporal association with catheter infusion pointed to local anesthetic systemic toxicity as the cause of the cardiac arrest, and the postmortem blood ropivacaine level of 7.9 μg/mL seemed to substantiate this diagnosis. However, Dr. Buckenmaier and colleagues asked an entirely novel question: “How does lipid emulsion infusion alter postmortem blood levels of local anesthetic?”
They infused ropivacaine in pigs to the point of cardiovascular collapse and treated 1 group with a modest dose of lipid emulsion (1 mL/kg) whereas a control group received no additional treatment. They then measured serial postmortem ropivacaine concentrations in blood and key organs. Notwithstanding the limitations of the pig as a model of ILE resuscitation,15 and this is not a resuscitation study, the report by Buckenmaier et al. clearly shows that ILE causes postmortem plasma concentration of local anesthetic to increase over time while tissue content decreases reciprocally in key organs. This suggests that the ropivacaine concentration found at postmortem examination was likely much lower at the time of death, conforming with the 2.6 μg/mL blood level drawn before the event. We now ask, “Why did our young solder die? Why was a state-of-the-art resuscitation including antidotal therapy ineffective?” It is clear that even with optimal treatment, ILE is not infallible. This leads to more questions than we have answers. Was there an undetected comorbidity associated with the blast injuries that reduced the efficacy of resuscitation or was this young man among the subgroup of asymptomatic patients with a lowered threshold for local anesthetic toxicity (e.g., as found among those with mitochondrial or other metabolic derangements)? These questions leave us in the uneasy position of uncertainty as to the cause of this tragic event.
Lacking randomized, prospective clinical trials, we will continue to rely for the foreseeable future on laboratory studies and case reports to evaluate the efficacy and parameters of clinical utility for lipid emulsion infusion in treating lipophilic drugs and other potential indications.16 Although not rising to the evidence level of well-designed clinical trials, case reports nonetheless can offer much in terms of providing clinical insights and generalized understanding from single, outlier-type experiences,17 and we should continue to give consideration to the best examples. Laboratory studies of lipid resuscitation must similarly use models that are suitable in that they mimic the clinical event, use relevant metrics and properly scaled doses, and minimize experimental confounders. Finally, as leaders in resuscitation, it is incumbent on anesthesiologists to inform colleagues in other specialties of the dangers of local anesthetic toxicity and its proper treatment. This is particularly true given the antidotal efficacy of lipid in this setting and the lack of published reports of complications related to its use. The next time you recognize the indiscriminate use or questionable dosing of local anesthetics, remember that it is our responsibility to intervene and educate.
Name: Guy Weinberg, MD.
Contribution: This author helped write the manuscript.
Attestation: Guy Weinberg approved the final manuscript.
Conflicts of Interest: Guy Weinberg is cofounder of ResQ Pharma, LLC and manages the website www.lipidrescue.org.
Name: Lisa Warren, MD.
Contribution: This author helped write the manuscript.
Attestation: Lisa Warren approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
This manuscript was handled by: Terese T. Horlocker, MD.
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