Status epilepticus (SE) and refractory status epilepticus (RSE) can be difficult to manage in the pediatric and neonatal populations. Concerns over drug reactions and interactions in the developing child pose potential limitations to antiepileptic drug (AED) selection in the setting of SE and RSE.Reference Bath and Scharfman 1 - Reference Ikonomidou and Turski 3
Current management options for SE and RSE in the pediatric/neonatal patient population include, but are not limited to: benzodiazepines, barbiturates, phenytoin, levetiracetam, carbamazepine, and lidocaineReference Vento, de Vries, Alberola, Blennow, Steggerda and Greisen 4 —all of which have displayed varying efficacy at seizure control in SE and RSE.Reference Vento, de Vries, Alberola, Blennow, Steggerda and Greisen 4 - Reference Brophy, Bell, Claassen, Alldredge, Bleck and Glauser 7
Lidocaine, a class Ib antiarrhythmic agent, has known sodium channel–based AED properties in both the adult and pediatric populations stemming back to the 1950s. 8 - Reference De Giorgio, Altman, Hamilton-Byrd and Rabinowicz 11 Its potential summative benefit in the presence of other sodium channel–mediated AEDs seem to be mediated by its amine chain motif and external sodium channel binding site.Reference Yang, Huang and Kuo 12 - Reference Kuo, Lou and Huang 14 Using lidocaine to treat seizures is common in the pediatric literature. Of interest within a recent survey, the third commonly prescribed AED for neonatal seizures was lidocaine.Reference Vento, de Vries, Alberola, Blennow, Steggerda and Greisen 4
Given the use of lidocaine as an AED in the pediatric and neonatal populations as reported in the literature to date,Reference Aggarwal and Wali 15 - Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 we decided to perform a systematic review to determine the effectiveness of lidocaine in controlling pediatric/neonatal SE and RSE.
Methods
A systematic review using the methodology outlined in the Cochrane Handbook for Systematic ReviewersReference Higgins and Green 36 was conducted. The data were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Reference Moher, Liberati, Tetzlaff, Altman and Group 37 The review questions and search strategy were decided upon by the primary author (FAZ) and supervisor (MW).
Search Question, Population, Inclusion, and Exclusion Criteria
The question posed for systematic review was: What is the effectiveness of lidocaine for control of SE in human children? All studies, prospective and retrospective of any size based on human subjects, were included. The reason for an all-inclusive search was based on the small number of studies of any type identified by the primary author during a preliminary search of MEDLINE.
The primary outcome measure was electrographic seizure control. Secondary outcome measures were patient outcome (if reported) and adverse effects of lidocaine treatment. Inclusion criteria were: all studies including human subjects whether prospective or retrospective, all study sizes, pediatric patients (age younger than 18 years), any language, and the use of lidocaine for seizure control in SE. Exclusion criteria were adult and animal studies. Any non-English studies were translated.
Search Strategy
MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to October 2014 were searched using individualized search strategies for each database. The search strategy for MEDLINE can be seen in supplementary Appendix A, with a similar search strategy used for the other databases. In addition, the World Health Organization’s International Clinical Trials Registry Platform was searched looking for studies planned or underway.
As well, meeting proceedings for the past 5 years looking for ongoing and unpublished work based on lidocaine use for seizures were examined. The meeting proceedings of the following professional societies were searched: Canadian Neurological Sciences Federation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, European Neurosurgical Society, World Federation of Neurological Surgeons, American Neurology Association, American Academy of Neurology, American Epilepsy Society, European Federation of Neurological Science, World Congress of Neurology, Society of Critical Care Medicine, Neurocritical Care Society, and the World Federation of Societies of Intensive and Critical Care Medicine, American Society for Anesthesiologists, World Federation of Societies of Anesthesiologist, Australian Society of Anesthesiologists, International Anesthesia Research Society, Society of Neurosurgical Anesthesiology and Critical Care, Society for Neuroscience in Anesthesiology and Critical Care, and the Japanese Society of Neuroanesthesia and Critical Care.
Finally, reference lists of any review articles or systematic reviews on seizure management were reviewed for relevant studies on lidocaine usage for seizure control.
Study Selection
Using two reviewers (FAZ and KJZ), a two-step review of all articles returned by our search strategies was performed. First, the reviewers independently screened all titles and abstracts of the returned articles to decide if they met the inclusion criteria. Second, full text of the chosen articles was then assessed to confirm if the articles met the inclusion criteria and that the primary outcome of seizure control was reported in the study. Any discrepancies between the two reviewers were resolved by a third independent reviewer (MW).
Data Collection
Data were extracted from the selected articles and stored in an electronic database. Data fields included: patient demographics, type of study (prospective or retrospective), number of patients, dose and route of lidocaine administration used, timing to administration of drug, duration of drug administration, time to effect of drug, how many other AEDs were used before lidocaine, degree of seizure control, adverse effects, and patient outcome.
Quality of Evidence Assessment
Assessment of the level of evidence for each included study was conducted by two independent reviewers (FAZ and MW) using the Oxford criteriaReference Phillips, Ball, Sackett, Straus, Haynes and Dawes 38 and the Grading of Recommendation Assessment Development and Education (GRADE) criteriaReference Guyatt, Oxman, Vist, Kunz, Falck-Ytter and Alonso-Coello 39 - Reference Jaeschke, Guyatt, Dellinger, Schünemann, Levy and Kunz 44 for level of evidence.
The Oxford criteria consist of a five-level grading system for literature. Level 1 is split into subcategories 1a, 1b, and 1c, which represent a systematic review of randomized control trials with homogeneity, individual randomized control trials with narrow confidence interval, and all or none studies, respectively. Oxford level 2 is split into 2a, 2b, and 2c, representing systematic review of cohort studies with homogeneity of data, individual cohort study or low-quality randomized control trials, and outcomes research, respectively. Oxford level 3 is split into 3a and 3b, representing systematic review of case-control studies with homogeneity of data and individual case-control study respectively. Oxford level 4 represents case-series and poor cohort studies. Finally, Oxford level 5 represents expert opinion.
The GRADE level of evidence is split into 4 levels: A, B, C, and D. GRADE level A represents high evidence with multiple high-quality studies having consistent results. GRADE level B represents moderate evidence with one high-quality study or multiple low-quality studies. GRADE level C evidence represents low evidence with one or more studies with severe limitations. Finally, GRADE level D represents very low evidence based on either expert opinion or few studies with severe limitations.
Any discrepancies between the grading of the two reviewers were resolved via discussion and a third reviewer when required (CJK).
Statistical Analysis
A meta-analysis was not performed in this study because of the heterogeneity of data within the articles and the small number of low-quality studies.
Results
The results of the search strategy across all databases and other sources are summarized in Figure 1. Overall, a total of 727 articles were identified, with 718 from the database search and nine from the search of published meeting proceedings. Seventy-two duplicate references were removed, leaving 655 for analysis. By applying the inclusion/exclusion criteria to the title and abstract of the articles, we identified 54 articles that fit these criteria. Of the 54 identified, 45 were from the database search and nine were from published meeting proceedings. Applying the inclusion/exclusion criteria to the full-text documents, only 21 articles were eligible for inclusion in the systematic review, with 19 from the database and two from meeting proceeding sources. The 33 articles that were excluded were done so because they either did not report details around the administration of lidocaine for seizure control, were based on adult patients only, were nonrelevant studies, or because they were review articles. Upon review of the reference sections of relevant review articles, no additional articles were added.
Figure 1 Flow diagram of search results.
Of the 21 articles included in the review, 20 were original studies,Reference Aggarwal and Wali 15 - Reference Lin, Lin, Wang, Hsia and Wu 26 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 - Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 with one companion abstract publication identified.Reference Lin, Lin and Wang 27 The companion abstract was included for completenessReference Lin, Lin and Wang 27 and was not included for the rest of the review to avoid duplication of patient data. There were 15 original retrospective studiesReference Aggarwal and Wali 15 , Reference Bernhard, Bohm and Hojeberg 16 , Reference Dan and Boyd 18 , Reference Hamano, Sugiyama, Yamashita, Tanaka, Hayakawa and Minamitani 20 , Reference Hellström-Westas, Westgren, Rosén and Svenningsen 21 , Reference Kobayashi, Ito, Miyajima, Fujii and Okuno 23 - Reference Lin, Lin, Wang, Hsia and Wu 26 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 , Reference Okumura, Komatsu, Abe, Kitamura, Matsui and Ikeno 30 , Reference Shany, Benzaqen and Watemberg 32 - Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 and five prospective studies.Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19 , Reference Hellström-Westas, Svenningsen, Westgren, Rosén and Lagerström 22 , Reference Malingré, Van Rooij, Rademaker, Toet, Ververs and van Kesteren 29 , Reference Rey, Radvayani-Bouvet, Bodiou, Richard, Torricelli and Walti 31 Within the retrospective studies, 12 were retrospective case seriesReference Aggarwal and Wali 15 , Reference Bernhard, Bohm and Hojeberg 16 , Reference Dan and Boyd 18 , Reference Hamano, Sugiyama, Yamashita, Tanaka, Hayakawa and Minamitani 20 , Reference Hellström-Westas, Westgren, Rosén and Svenningsen 21 , Reference Kwon, Seo and Hwang 24 , Reference Lin, Lin, Wang, Hsia and Wu 26 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 , Reference Okumura, Komatsu, Abe, Kitamura, Matsui and Ikeno 30 , Reference Shany, Benzaqen and Watemberg 32 , Reference Wallin, Nergårdh and Hynning 34 , Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 and the remaining three were retrospective case reports.Reference Kobayashi, Ito, Miyajima, Fujii and Okuno 23 , Reference Lago, Boniver, Casara, Laverda, Fiore and Salvadori 25 , Reference Wakamoto, Takahashi, Ebihara, Okamoto, Hayashi and Ichiyama 33 All studies were based in single centers. The five prospective studies included three prospective single-arm studiesReference Hellström-Westas, Svenningsen, Westgren, Rosén and Lagerström 22 , Reference Malingré, Van Rooij, Rademaker, Toet, Ververs and van Kesteren 29 , Reference Rey, Radvayani-Bouvet, Bodiou, Richard, Torricelli and Walti 31 and two randomized control trials.Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19 The two randomized control trials compared lidocaine to benzodiazepine (midazolam or clonazepam) in the setting of RSE.
Across all studies, 235 patients were studied using lidocaine for control of their SE/RSE (mean: 11.8 patients/study; range: 1-46 patients/study), with a total of 252 separate episodes of SE/RSE treated with lidocaine documented. Sixteen patients were studied as controls, using benzodiazepine-based therapies in the setting of RSE.Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19 The age of patients studied ranged from 25 weeks’ gestational age to 16 years. Study demographics and patient characteristics for the pediatric studies can be seen in Table 1, whereas treatment characteristics and seizure outcome are reported in Table 2.
Table 1 Pediatric study characteristics and patient demographics
AERRPS, acute encephalitis with refractory repetitive partial seizures; benzo, benzodiazepine; clonaz, clonazepam; GA, gestational age; GTC, generalized tonic clonic; lido, lidocaine; midaz, midazolam; NYD, not yet diagnosed; phenobarb, phenobarbital; TS, tuberous sclerosis; Tx, treatment.
* Lin et alReference Lin, Lin, Wang, Hsia and Wu 26 and Lin et alReference Lin, Lin and Wang 27 contain duplicate data, with only the data from Lin et alReference Lin, Lin, Wang, Hsia and Wu 26 included in the final summary of data. Lin et alReference Lin, Lin and Wang 27 is the published meeting abstract of Lin et al.Reference Lin, Lin, Wang, Hsia and Wu 26
Table 2 Pediatric articles: lidocaine treatment characteristics, seizure response, and outcome
BP, blood pressure; IV, intravenous; midaz, midazolam; rehab, rehabilitation center; Tx, treatment.
* Lin et alReference Lin, Lin, Wang, Hsia and Wu 26 and Lin et alReference Lin, Lin and Wang 27 contain duplicate data, with only the data from Lin et alReference Lin, Lin, Wang, Hsia and Wu 26 included in the final summary of data. Lin et alReference Lin, Lin and Wang 27 is the published meeting abstract of Lin et al.Reference Lin, Lin, Wang, Hsia and Wu 26
A variety of underlying pathology leading to SE/RSE was reported within the 234 cases treated with lidocaine. The most commonly reported pathology was hypoxia/anoxia, primary epilepsy, encephalitis, and intracerebral hemorrhage. A large number of studies failed to specify the underlying cause of SE/RSE.
Pre-Lidocaine Treatment Characteristics
Duration of treatment before lidocaine administration was documented in five studies, ranging from 35 minutes to 10 days. Patients were on various numbers of AEDs before lidocaine, with the mean number of AEDs ranging from two to eight with most patient treatments typically consisting of a combination of oral AED and intravenous anesthetic agents. Of note, in 20 of the 234 (8.5%) SE/RSE episodes described, phenytoin was on board during lidocaine administration. All AEDs reported as being used in management were typically on board during the lidocaine treatment. Similarly, the duration of lidocaine treatment was described in 10 of the 20 studies, with treatment duration ranging from one time bolus dosing, up to 36 days of continuous intravenous infusion. One patient was discharged with lidocaine transdermal patches, eventually being transitioned to mexilitine.Reference Kobayashi, Ito, Miyajima, Fujii and Okuno 23
Lidocaine Treatment Characteristics
The Retrospective Studies
The literature on lidocaine use for control of SE/RSE in the pediatric population yielded 15 retrospective studies.Reference Aggarwal and Wali 15 , Reference Bernhard, Bohm and Hojeberg 16 , Reference Dan and Boyd 18 , Reference Hamano, Sugiyama, Yamashita, Tanaka, Hayakawa and Minamitani 20 , Reference Hellström-Westas, Westgren, Rosén and Svenningsen 21 , Reference Kobayashi, Ito, Miyajima, Fujii and Okuno 23 - Reference Lin, Lin, Wang, Hsia and Wu 26 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 , Reference Okumura, Komatsu, Abe, Kitamura, Matsui and Ikeno 30 , Reference Shany, Benzaqen and Watemberg 32 - Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 Within these 15 studies, one used bolus dosing of lidocaine in isolation,Reference Aggarwal and Wali 15 with a dose of 100 mg intravenously once.
Four studies used continuous infusions of lidocaine only,Reference Kobayashi, Ito, Miyajima, Fujii and Okuno 23 , Reference Lin, Lin, Wang, Hsia and Wu 26 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 , Reference Wallin, Nergårdh and Hynning 34 with dosing ranging from 1 to 8 mg/kg/hour. Of note, one of these studiesReference Kobayashi, Ito, Miyajima, Fujii and Okuno 23 transitioned from continuos infusion to lidocaine transdermal patch for maintenance therapy in a single patient. Duration of the lidocaine infusion was documented in only one study from this group, with duration ranging from 0.5 to 2.5 days.Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28
Six studies used bolus dosing of lidocaine, followed by continuous infusions.Reference Bernhard, Bohm and Hojeberg 16 , Reference Hamano, Sugiyama, Yamashita, Tanaka, Hayakawa and Minamitani 20 , Reference Hellström-Westas, Westgren, Rosén and Svenningsen 21 , Reference Kwon, Seo and Hwang 24 , Reference Lago, Boniver, Casara, Laverda, Fiore and Salvadori 25 , Reference Shany, Benzaqen and Watemberg 32 The initial bolus ranged from 0.91 mg/kg to 4 mg/kg intravenously, typically given over 20 minutes (when documented). The infusion rates ranged up to 2 to 6 mg/kg/hour. The duration of the lidocaine infusions in this group of studies varied from 1 to 36 days, with three manuscripts failing to document duration of therapy.Reference Hamano, Sugiyama, Yamashita, Tanaka, Hayakawa and Minamitani 20 , Reference Kwon, Seo and Hwang 24 , Reference Shany, Benzaqen and Watemberg 32
Finally, four studies failed to document the details of lidocaine dosing and administration.Reference Dan and Boyd 18 , Reference Okumura, Komatsu, Abe, Kitamura, Matsui and Ikeno 30 , Reference Wakamoto, Takahashi, Ebihara, Okamoto, Hayashi and Ichiyama 33 , Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 Lidocaine treatment characteristics can be seen in Table 2.
The Prospective Studies
The literature on lidocaine use for control of SE/RSE in the pediatric population yielded five prospective studies.Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19 , Reference Hellström-Westas, Svenningsen, Westgren, Rosén and Lagerström 22 , Reference Malingré, Van Rooij, Rademaker, Toet, Ververs and van Kesteren 29 , Reference Rey, Radvayani-Bouvet, Bodiou, Richard, Torricelli and Walti 31 Within these, three were prospective single-arm studies. The first study was a prospective study of 24 patients with unspecified underlying etiology, treated with a 1.6 to 2.2 mg/kg bolus, followed by a continuous infusion at 4.7 to 6.3 mg/kg/hour, for a duration of 0.1 to 9.3 days.Reference Hellström-Westas, Svenningsen, Westgren, Rosén and Lagerström 22 The second study was a prospective study of 20 patients with unspecified underlying etiology, treated with 2 mg/kg intravenous bolus of lidocaine over 10 minutes, followed by continuous infusion for 36 hours.Reference Malingré, Van Rooij, Rademaker, Toet, Ververs and van Kesteren 29 The infusion protocol was as follows: 6 mg/kg/hour for 12 hours, then 4 mg/kg/hour for 12 hours, and finally 2 mg/kg/hour for 12 hours. The final prospective single-arm study followed 13 patients with hypoxia as the predominant underlying etiology.Reference Rey, Radvayani-Bouvet, Bodiou, Richard, Torricelli and Walti 31 These patients were administered continuous lidocaine infusions via the following protocol: 4 mg/kg/hour for 1 day, then 2 mg/kg/hour for 1 day, and finally 1 mg/kg/hour for 1 day for a total treatment duration of 3 days.
The two remaining prospective studies identified in this review were randomized control trials comparing lidocaine to benzodiazepine-based therapy.Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19
The first study was a randomized control trial of 11 patients with hypoxia as the predominant etiology of their SE. These patients had all received phenobarbitone as the first-line AED, and if failure of seizure control was noted at 12 hours they were randomized to one of three groups. One group (n=5) received lidocaine bolus of 4 mg/kg over 20 minutes, followed by a continuous infusion at 2 mg/kg/hour for an unspecified duration. If failure of lidocaine occurred at this point, the infusion dose was escalated to 4 mg/kg/hour for 12 hours. If the seizures still failed to respond at this point the patient was removed from the trial. Another group (n=3) received a midazolam bolus of 60 mcg/kg followed by an infusion of 150 mcg/kg/hour for 12 hours. If failure of midazolam occurred at this point, the infusion dose was escalated to 300 mcg/kg/hour for 12 hours. If the seizures still failed to respond at this point, the patient was removed from the trial. The final group (n=3) received clonazepam at an unspecified dose and duration.
The second randomized trial followed 20 patients with primary epilepsy as predominant etiology of their SE.Reference Fallah and Gofrani 19 These patients all received diazepam (0.2-0.3 mg/kg intravenous load twice), phenytoin (15-20 mg/kg intravenous load), and phenobarbitone (10 mg/kg intravenous load over 10 minutes). If failure of these three AEDs occurred, patients were enrolled and randomized to receive either midazolam or lidocaine therapy. The midazolam group (n=10) received 0.15 mg/kg bolus followed by a continuous infusion of 1 to 6 mcg/kg/hour, titrated to effect, for a treatment duration of 24 hours. The lidocaine group (n=10) received a 1 mg/kg bolus; if no response, then a second dose was given after 15 minutes followed by a continuous infusion at 5 mg/kg/hour for 12 hours. The infusion was then titrated off by 0.5 mg/kg/hour on an hourly basis. If a patient from either group failed, then therapy was stopped and pentobarbital was started.
Seizure Response
Overall, 174 of the 252 (69.0%) SE/RSE episodes studied displayed seizure response to lidocaine administration. Complete seizure control upon lidocaine administration occurred in 143 of the 252 (57.6%) SE/RSE episodes documented. A greater than 50% reduction in seizure frequency occurred in 31 of the 252 (12.3%) SE/RSE episodes described. Failure of lidocaine treatment occurred in 78 of 252 (30.9%) episodes.
In those patients with phenytoin on board during lidocaine administration, there were 20 discrete SE/RSE episodes recorded. Lidocaine administration resulted in seizure reduction in 12 of these 20 (60.0%) episodes, with all resulting in complete seizure control. Eight of these 20 (40.0%) SE/RSE episodes failed lidocaine administration when phenytoin was already on board.
In comparison, analyzing those patients treated with lidocaine without phenytoin on board recorded a total of 232 discrete SE/RSE episodes. Complete seizure response to lidocaine administration occurred in 131 of the 232 (56.5%) of the SE/RSE episodes. Failure of lidocaine therapy occurred in 70 of the 232 (30.1%) of the SE/RSE episodes described.
Focusing on the randomized trialsReference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19 comparing lidocaine treatment to benzodiazepine-based therapy for SE/RSE, one study displayed a 60.0% seizure response rate to lidocaine (either cessation or >50% reduction in seizures), with the benzodiazepine groups failing to demonstrate seizure response.Reference Boylan, Rennie, Chorley, Pressler and Fox 17 The second randomized trial displayed a 50% seizure response rate to lidocaine in the setting of RSE, with only a 20% response rate in the midazolam group.Reference Fallah and Gofrani 19
Recurrence of seizures upon withdrawal of lidocaine occurred in six of the 78 (7.7%) responsive SE/RSE episodes. Recurrence rates were unspecified in 174 of the SE/RSE episodes.
Adverse Effects of Lidocaine
Only six studies documented adverse events related to lidocaine administration.Reference Fallah and Gofrani 19 - Reference Hellström-Westas, Svenningsen, Westgren, Rosén and Lagerström 22 , Reference Lago, Boniver, Casara, Laverda, Fiore and Salvadori 25 , Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 Bradycardia and hypotension were noted in 30 and 11 patients, respectively. Other less commonly reported complications were: tachycardia (two), metabolic acidosis (one), and decreased oxygen saturations (one).
Outcome
Patient outcome was reported sparingly in most studies because the main focus of these reports was the success/failure of lidocaine treatment. In those studies that reported such data, outcomes were as follows: dead (13), major morbidity (14), moderate morbidity (4), and minor/no morbidity (13). These data can be seen in Table 2.
Level of Evidence for Lidocaine
Based on two independent reviewers, there were a total of 20 original studies reviewed with five representing Oxford level 2b evidence for the administration of lidocaine in pediatric SE/RSE.Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19 , Reference Hellström-Westas, Svenningsen, Westgren, Rosén and Lagerström 22 , Reference Malingré, Van Rooij, Rademaker, Toet, Ververs and van Kesteren 29 , Reference Rey, Radvayani-Bouvet, Bodiou, Richard, Torricelli and Walti 31 Fifteen studies represented Oxford level 4 evidence for lidocaine administration in pediatric SE/RSE.Reference Aggarwal and Wali 15 , Reference Bernhard, Bohm and Hojeberg 16 , Reference Dan and Boyd 18 , Reference Hamano, Sugiyama, Yamashita, Tanaka, Hayakawa and Minamitani 20 , Reference Bath and Scharfman 1 , Reference Kobayashi, Ito, Miyajima, Fujii and Okuno 23 - Reference Lin, Lin, Wang, Hsia and Wu 26 , Reference Lin, Lin and Wang 27 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 , Reference Okumura, Komatsu, Abe, Kitamura, Matsui and Ikeno 30 , Reference Shany, Benzaqen and Watemberg 32 - Reference Yamamoto, Aihara, Niijima and Yamanouchi 35
Two of the 20 studies met GRADE B level of evidence,Reference Fallah and Gofrani 19 , Reference Malingré, Van Rooij, Rademaker, Toet, Ververs and van Kesteren 29 three met GRADE C evidence,Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Hellström-Westas, Svenningsen, Westgren, Rosén and Lagerström 22 , Reference Rey, Radvayani-Bouvet, Bodiou, Richard, Torricelli and Walti 31 whereas the remaining 15 met GRADE D level of evidence.Reference Aggarwal and Wali 15 , Reference Bernhard, Bohm and Hojeberg 16 , Reference Dan and Boyd 18 , Reference Hamano, Sugiyama, Yamashita, Tanaka, Hayakawa and Minamitani 20 , Reference Bath and Scharfman 1 , Reference Kobayashi, Ito, Miyajima, Fujii and Okuno 23 - Reference Lin, Lin, Wang, Hsia and Wu 26 , Reference Lin, Lin and Wang 27 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 , Reference Okumura, Komatsu, Abe, Kitamura, Matsui and Ikeno 30 , Reference Shany, Benzaqen and Watemberg 32 - Reference Yamamoto, Aihara, Niijima and Yamanouchi 35 Summary of the level of evidence can be seen in Table 3.
Table 3 Pediatric studies: Oxford and GRADE level of evidence
* Lin et alReference Lin, Lin, Wang, Hsia and Wu 26 and Lin et alReference Lin, Lin and Wang 27 contain duplicate data, with only the data from Lin et alReference Lin, Lin, Wang, Hsia and Wu 26 included in the final summary of data. Lin et alReference Lin, Lin and Wang 27 is the published meeting abstract of Lin et al.Reference Lin, Lin, Wang, Hsia and Wu 26
Discussion
Lidocaine is a type Ib antiarrhythmic agent and sodium channel antagonist commonly used in the cardiac and pain literature. It is through its sodium channel blockage that neural conduction is reduced and impeded, leading to its antiarrhythmic and anesthetic properties. Given these effects at the neuronal sodium channel, lidocaine’s role as an AED has been investigated.Reference Yang, Huang and Kuo 12 , Reference Kuo, Lou and Huang 14 - Reference Lin, Lin, Wang, Hsia and Wu 26
Unlike other sodium channel–blocking AEDs, such as phenytoin (also a class Ib antiarrhythmic), its structure includes an aromatic and amine chain motif allowing for binding to the sodium channel via both the channels’ pore-lining phenyl-binding site,Reference Lin, Lin and Wang 27 , Reference Lundqvist, Ågren, Hellström-Westas, Flink and Wickström 28 or via the external amine chain site, both of which lead to the reduction of ion transport across the cellular membrane. Other sodium channel–based AEDs typically only carry a diphenyl motif, solely allowing binding at the pore-lining phenyl sites,Reference Kuo 13 blocking sodium ion transport. Thus, lidocaine can potentially add further sodium channel blockade in the setting of refractory seizures where other sodium channel antagonists are on board because of interaction with the external amine binding site.
To date, small case series have appeared since the 1950s describing the use of lidocaine as an AED, with the majority of the literature focused on the pediatric population. Given the success of lidocaine as an AED in the setting of neonatal and pediatric seizures,Reference Cervenka, Hartman, Venkatesan, Geocadin and Kossoff 10 - Reference Yang, Huang and Kuo 12 we elected to perform a systematic review of the literature to determine its effect on SE and RSE in the adult population.
Through our review, we identified 20 original articles pertaining to the reported usage of lidocaine for control of SE/RSE in the pediatric population. Nineteen were published manuscripts, whereas one was a published meeting abstract. A total of 235 patients were described in these articles with 252 discrete episodes of SE/RSE treated with lidocaine therapy. Sixteen patients were identified as prospectively enrolled control subjects, receiving benzodiazepine-based therapy in comparison to lidocaine. The majority of the studies were retrospective case reports/series, with only five being prospective in nature. Looking at the primary outcome of our study (seizure control), 69.0% of the SE/RSE episodes responded to lidocaine therapy via seizure cessation or greater than 50% reduction in seizures. Complete seizure cessation was noted in 57.6%, greater than 50% reduction in 12.3%, and failure of lidocaine therapy was noted in 30.9%. Comparing those patients with and without phenytoin on board during lidocaine administration, seizure cessation occurred in 60.0% and 56.6%, respectively. In the secondary outcomes, bradycardia and hypotension were commonly reported. Unfortunately, patient outcome data were too sparingly documented for any strong conclusion on the impact of lidocaine therapy in pediatric SE/RSE. A meta-analysis was not possible given the heterogeneous, retrospective nature of the studies available. Based on this review, we can currently provide Oxford level 2b, GRADE C, recommendations for the use of lidocaine for pediatric SE/RSE.
Some important points have arisen from our review. First, the seizure response rate of 69.0% with lidocaine administration in a population of medically refractory cases is quite high compared with other therapies for RSE.Reference Shorvon and Ferlisi 45 This may represent a significant publication bias, focused on publishing only positive results with lidocaine for SE/RSE. Second, the seizure cessation rate of 60.0% to lidocaine whereas phenytoin has already been administered highlights the effectiveness of this medication in the presence of another sodium channel agent, as further emphasized by the 56.5% cessation rate for those patients not on phenytoin during lidocaine therapy. The effect of the external sodium channel binding motif of lidocaine, not possessed by phenytoin, is the likely reason for the seemingly “additive” benefit of lidocaine in the presence of another sodium channel based AED. Third, the two randomized trials,Reference Boylan, Rennie, Chorley, Pressler and Fox 17 , Reference Fallah and Gofrani 19 though small, did demonstrate superior seizure control with lidocaine therapy compared to benzodiazepines when utilized as a secondReference Boylan, Rennie, Chorley, Pressler and Fox 17 or fourthReference Fallah and Gofrani 19 line agent in SE/RSE. Fourth, the seizure recurrence following withdrawal of lidocaine therapy was scarcely described, likely secondary to publication bias or underreporting. Lidocaine treatment is not a long-term solution, but an option during crisis. Seizure response to lidocaine should be met with ongoing adjustment of oral AEDs with the goal of discontinuing intravenous anesthetic agents. Fifth, there did not appear to be a trend to increased efficacy in any particular underlying etiology treated within the studies. Finally, the number of complications described was not insignificant. Hypotension and bradycardia with lidocaine administration likely stems from the class Ib antiarrhythmic effects of lidocaine. It was not clear from the studies included in this review as to whether these side effects occurred during bolus dosing or continuous administration. Similarly, the dose of lidocaine therapy was likely to correlate with these side effects, though not commented on in the studies.
Our review has significant limitations. First, the small number of studies identified, all with small patient populations, makes it difficult to generalize to all pediatric SE/RSE patients. Second, the predominantly retrospective heterogeneous nature of the data makes it difficult to perform a meaningful meta-analysis, resulting in a strictly descriptive analysis. Third, the heterogeneity of prior treatments, time to lidocaine administration, and lidocaine dosage and duration leave the data on seizure responsiveness difficult to interpret. It is even more difficult, on the basis of these data, to recommend a treatment regimen based on lidocaine. Fourth, the outcome data were poorly recorded in the majority of the studies identified. As such, formal comments on the impact of lidocaine therapy on patient outcome during SE/RSE cannot be made at this time. Finally, as previously mentioned, there is likely a significant publication bias in the literature favoring the publication of only positive results with lidocaine therapy for pediatric SE/RSE. Despite these significant limitations, we believe the data provide evidence for the potential benefit of lidocaine therapy in the setting of pediatric SE/RSE.
Future prospective analysis of lidocaine treatment during SE/RSE should be conducted. Formal comparison between phenytoin and lidocaine in a randomized fashion may prove interesting. Furthermore, prospective evaluation of lidocaine as the third-line agent in adult SE/RSE, in comparison to other commonly used agents also should be conducted.
Conclusions
There currently is Oxford level 2b, GRADE C, evidence to support the use of lidocaine for SE and RSE in the pediatric population. Further prospective studies of lidocaine administration in this setting are warranted.
Disclosures
The authors have nothing to disclose.
Supplementary Material
To view supplementary material for this article, please visit http://dx.doi.org/10.1017/cjn.2015.278.
