Local anesthetics systemic toxicity in children: analysis of the French pharmacovigilance database

Local anesthetics can cause severe systemic toxicity after intravenous absorption from injection site (topical, or subcutaneous), particularly in the pediatric population. However, the factors associated with these systemic reactions are poorly known.

Local anesthetics systemic toxicity can lead to severe systemic reactions, up to death. The majority of these reactions occurred within one hour of administration, some occurred several hours later. Doses used were below or above the maximum recommended doses. Children should be carefully monitored at least during one hour after LA administration. The use of recommended doses does not prevent to onset of systemic toxicity. Lipid emulsion was administered in very few cases, which may underline a lack of awareness of its indication as an antidote in case of systemic toxicity. In case of transdermal application in ambulatory settings, particular attention should be drawn to ensure that parents appropriately follow the prescription of local anaesthetics.

Local anesthetics (LA) are used in several medical conditions, from stitches to surgeries. Since the first use of cocaine for eye surgery in 1884, several molecules have been synthesized the most common being lidocaine [1]. LA bind to voltage-gated sodium channels of nerve cells, preventing the entry of sodium ions. This results in further blocking nerve depolarization and therefore pain transmission [2]. According to their administration site, LA are intended to be used for a local or regional action (topical or subcutaneous administration), or for epidural or spinal anesthesia.

LA are drugs having an overall very good safety profile. In some cases, they are associated with benign injection site reactions, such as rash. However, severe adverse drug reactions (ADRs) may occur after systemic absorption or inadvertent intravascular injection [3, 4]. Systemic toxicity of LA being concentration-dependent, characteristics of the injection site as well as administration method play a crucial role in their absorption and transfer to systematic blood circulation [5]. Local anesthetics systemic toxicity (LAST) is characterized by neurological and cardio-pulmonary adverse drug reactions that may be serious and even life-threatening [6, 7]. Early management, and if necessary administration of a non-specific antidote such as lipid emulsion, leads to favorable outcome in most cases [8, 9].

To date, LAST cases have been reported in adults and children after local or regional uses [10‐13]. However, in relation with specific pharmacokinetics characteristics, LAST in children may be different from adults and toxic doses or clinical outcome are poorly known [14, 15].

In this study, we aimed to describe the characteristics of the LAST pediatric cases reported to the French Pharmacovigilance Network and to identify determinants associated with life-threatening consequences.

To our knowledge, we report here one of the largest retrospective series of 64 LAST cases in children, at a national level [13]. Neurological reactions were the most frequently reported, followed by combined neurological and cardiac reactions, in line with the literature [11, 13, 19, 20]. All patients recovered except two infants with fatal outcome. Our multivariate model showed that the use of lidocaine, and a context of general and orthopedic surgery were significantly associated with the occurrence of a life-threatening reaction. However, interestingly neither patient age nor patient sex, nor local anesthetic dosages were significantly associated with the occurrence of a life-threatening condition.

LAST characteristics are related to neurological and cardio-pulmonary injuries. The first symptoms described in the literature are usually neurological, including prodromal symptoms like dizziness, confusion, dysarthria, tinnitus and metallic taste, followed by seizures up to seizures with loss of consciousness [21]. They are the result of active diffusion, involving a proton-antiporter flux as well as passive diffusion [22]. As dose increase, cardiovascular toxicity appears with symptoms like bradycardia, hypotension, ST-segment changes, arrhythmia or tachycardia that may lead to cardiorespiratory arrest. LAST diagnosis is based on clinical symptoms. Given the profile of this rapidly evolving intoxication, LA plasma assay is rarely performed during the first moments in clinical practice. Hence, as illustrated by the cases described here, plasma level is generally poorly informative.

To date, most reports have been related to long acting LA such as bupivacaine [13]. In our retrospective study, lidocaine was the most frequently involved in pediatric LAST cases. Although it is a short-acting LA, theoretically leading to less risk of systemic intoxication compared to long-acting LA, lidocaine is probably the most commonly used LA in children [23]. It is available in a wide variety of dosage forms (injectable, patch, gel for skin application, spray, etc.). Furthermore, it is used in children in a wide variety of clinical situations by pediatricians and is not restricted to anesthesiologists as are bupivacaine or ropivacaine. Hence, this common use associated with a trivialization of the dose limits and administration precautions may increase the number of LAST cases overall.

In the literature, symptoms of intoxication are generally described as occurring within a few minutes following administration. Some authors even describe cases occurring more than five minutes after administration as "atypical" [11]. However, in our study, a majority of cases occurred 10 to 60 min after administration, and sometimes later, as described in previous studies [20]. This underlines the need to closely monitor patients during at least one hour following the administration of LA. In children, this monitoring may for instance imply the parents. Indeed, the majority of the reactions being non-specific, the parents are probably the most likely to detect an unusual behavior of their child. However, this involvement requires an appropriate explanation of the potential risks by healthcare professional without creating excessive anxiety. In addition, most of the warning minor signs commonly described in LA overdose (metallic taste, tinnitus, paresthesia…) were not found in our cases series. This may be related with a lack of verbalization and/or of knowledge of these sensations by infants or children. Indeed, particularly in newborns and young children, warning signs consist mainly of crying, which is not specific enough to alert to potential toxicity. One could also hypothesize that there may be fewer warning signs in the pediatric population, compared to adults, preventing healthcare provider from early detection of a LAST. Moreover, our cases series based on reports from the French pharmacovigilance network are mostly serious. Therefore, minor signs may not be clearly mentioned in the case commentary.

Our findings as previous cases found that LAST cases were disproportionately reported in infants. For instance, infants and children show a higher total body-surface area to body mass ratio than adults, resulting in a higher exposure to topical LA [24]. In terms of distribution, lower quantity of total plasma protein is seen in the neonate and young infant, especially alpha-1-acid glycoprotein, the major binding protein for LA, therefore increasing the free concentration of drugs [25]. Concerning drug metabolism, drug-metabolizing enzyme levels like cytochrome P450 gradually increase during childhood. Finally, concerning elimination there is a maturation of the renal function in a dynamic way, starting from fetal life to early childhood. This development is related with an increase in the glomerular filtration rate during childhood, and thus may altered the plasma level of drugs [24]. In line with these pediatric characteristics, reduced pediatric doses have been proposed [26]. However, our findings highlight that about half of the LAST cases occurred with the use of recommended doses, as shown by other studies [13, 20]. This observation emphasizes the fact that even when using recommended doses, vigilance must be maintained for early identification of LAST and an appropriate administration technique must be used, especially when administered by injection (subcutaneous or epidural) [27].

LAST management is essentially based on symptomatic cares. It includes the discontinuation of administration of LA, the use of an anti-seizure agent (usually benzodiazepine) and management of cardiac reactions if necessary [6, 28]. In life-threatening conditions, 20% lipid emulsion is recommended [8, 29]. The mechanism of lipid emulsion is not fully understood, and several theories have been proposed [30]. Lipid emulsion could work as a “lipid sink”, by forming a lipid phase in the plasma and attract free lipophilic drugs like LA from the plasma. Efficiency of lipid emulsion could also have a metabolic origin, by acting as fatty acid substrate and increasing the production of adenosine triphosphate by mitochondria in the heart. In addition, triglycerides contained in the lipid emulsion could activate myocardial calcium and potassium channels to increase cardiac function [8, 31]. The use of this lipid emulsion in LAST management has been recommended by the American Society of Regional Anesthesia and Pain Medicine (ASRA) in 2010 [32]. In this case series over 40 years, of 11 life-threatening cases occurring after those recommendations, lipid emulsion have been administered in 4 cases (36%). Consistently, a recent literature review found a similar rate of lipid emulsion use overall [13]. This under-use may be related to a lack of knowledge of the recommendations for the management of these poisonings [19, 20]. Furthermore, in order to ensure the earliest possible use in the diagnosis of intoxication,, efforts must be performed for lipid emulsion availability in all clinical departments using LA.

Finally, several cases involved patches or cream containing lidocaine and prilocaine, mainly prior a vaccination or minor skin surgery. LAST was a consequence of the application of whole tubes (up to 8) used for dermatological biopsies, of whole patches in newborns, or of patches applied during a whole night on a newborn. In addition to the risk of LAST, the misuse of eutectic mixture of lidocaine and prilocaine can lead to methemoglobinemia (MetHb). MetHb is the oxidized form of hemoglobin, when the iron moiety is oxidized from its ferrous state Fe²⁺ to its ferric state Fe³⁺. This oxidized MetHb has a poor oxygen affinity reducing the oxygen delivery to tissue leading to hypoxia. When massively exposed to an exogenous oxidizing agent, such as chemicals (pesticides, nitrates…) or drugs (LA, dapsone, chloroquine…) protective pathways are overwhelmed leading to symptoms of hypoxia and requiring the administration of an antidote such as methylene blue [33]. Among LA, MetHb is a specific side effect of the use of prilocaine due to their oxidative properties [34], reported here in 7 cases (Table 1) and in several case reports in the literature [10]. These cases show the need to not trivialize the use of these drugs, particularly in outpatient settings where post-procedure monitoring will not be optimal, and where crying will be the main warning sign. Furthermore, newborns exhibit thinner and more permeable skin, increasing the risk of systemic reactions and requiring extra caution.

LAST in children appear to be a rare event according to the relatively low number of cases reported over more than 30 years at a national level. The pediatric population has specific pharmacokinetic characteristics, evolving with age, making it at higher risk, particularly in infants [36, 37]. It can lead to severe ADRs in more than a third of cases life-threatening. LAST occur in majority less than one hour after LA administration. Early management is essential, and requires specialized cares, including intravenous lipid emulsion in life threatening cases. Finally, the large number of cases that occurred in the absence of identified overdosage emphasizes the need to respect the administration procedures and patient monitoring. In ambulatory settings, the correct explanation and understanding of the prescription is essential, as well as the caution to not trivialize the use of LA.