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Original article
Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing
  1. Marcel P H van den Broek1,
  2. Carin M A Rademaker1,
  3. Henrica L M van Straaten2,
  4. Alwin D R Huitema3,
  5. Mona C Toet4,
  6. Linda S de Vries4,
  7. Antoine C G Egberts1,5,
  8. Floris Groenendaal4
  1. 1Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands
  2. 2Department of Neonatology, Isala Clinics, Zwolle, The Netherlands
  3. 3Department of Pharmacy and Pharmacology, Slotervaart Hospital/the Netherlands Cancer Institute, Amsterdam, The Netherlands
  4. 4Department of Neonatology, Wilhelmina Childrens’ Hospital/UMCU, Utrecht, The Netherlands
  5. 5Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  1. Correspondence to Marcel P H van den Broek, Department of Clinical Pharmacy, University Medical Centre Utrecht, P.O. Box 85500, Utrecht 3508 GA, The Netherlands; m.p.h.vandenbroek{at}umcutrecht.nl

Abstract

Background Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therpeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients.

Objective To study the efficacy and safety of lidocaine in newborns with perinatal asphyxia during moderate hypothermia, and to develop an effective and safe dosing regimen.

Methods Hypothermic newborns with perinatal asphyxia and lidocaine for seizure control were included. Efficacy was studied using continuous amplitude-integrated electroencephalography. Safety was assessed using continuous cardiac monitoring. An optimal dosing regimen was developed with simulations using data from a pharmacokinetic model. Plasma samples were collected during hypothermia on consecutive mornings.

Results A total of 22 hypothermic and 26 historical normothermic asphyxiated newborns with lidocaine were included. A response of 91% on epileptiform activity on the amplitude-integrated EEG was observed for lidocaine add-on therapy. No relationship between lidocaine or MEGX plasma concentrations and heart frequency could be identified. None of the newborns experienced cardiac arrythmias. Hypothermia reduced lidocaine clearance by 24% compared with normothermia. A novel dosing regimen was developed an initial bolus loading dose of 2 mg/kg, for patients with body weight 2.0–2.5 kg followed by consecutive continuous infusions of 6 mg/kg/h (for 3.5 h), 3 mg/kg/h (for 12 h), 1.5 mg/kg/h (for 12 h), or for patients with bodyweights 2.5–4.5 kg 7 mg/kg/h (for 3.5 h), 3.5 mg/kg/h (for 12 h), 1.75 mg/kg/h (for 12 h), before stopping.

Conclusions Lidocaine can be assumed to be an effective antiepileptic drug during hypothermia in asphyxiated neonates.

  • Neonatology
  • Pharmacology
  • Neurology

https://doi.org/10.1136/archdischild-2012-302678

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    What is already known on this topic

    • Lidocaine is an effective anticonvulsant for seizure control in asphyxiated newborns under normothermia.

    • Therapeutic hypothermia is a neuroprotective strategy for asphyxiated newborns.

    • Therapeutic hypothermia may alter drug disposition and efficacy/safety of drugs.

    What this study adds

    • Evidence of efficacy of lidocaine for seizure control in asphyxiated newborns under/during therapeutic hypothermia.

    • Providing a novel dosing regimen to be used during therapeutic hypothermia in neonates.

    Introduction

    Perinatal asphyxia is the most common cause of neonatal seizures. Moderate hypothermia (33.5°C) has proven to be an effective neuroprotective strategy for newborns suffering from hypoxic ischemic encephalopathy related to perinatal asphyxia.1 Suppression of cerebral metabolism is thought to be one of the mechanisms for this neuroprotective effect. However, whole body hypothermia does not only suppress cerebral metabolism, it also suppresses systemic processes that are responsible for drug distribution and elimination.2 Changes in these processes can require adjusted dosing regimens in order to achieve drug effects similar to normothermia: thermopharmacology.

    Lidocaine has been shown to be an effective anticonvulsant in neonatal seizures that persist despite first-line (and second-line) anticonvulsant therapy.3 ,4 The physicochemical properties of lidocaine enable passage of the blood-brain barrier, and in the central nervous system it acts as a depressant.5 A dosing regimen for both preterm and term neonates with seizures under normothermic conditions has been developed.6 The main safety issues, with regards to lidocaine, relate to cardiotoxicity—in particular, proarrhythmias and bradycardia.4 ,7–9 Cardiac adverse events have been reported in normothermic neonates receiving lidocaine for anticonvulsive treatment.4 These adverse events may be more pronounced during hypothermia when the dose is not properly adjusted.

    The aim of this study was to evaluate the efficacy and safety (heart frequency and rhythm) of lidocaine in hypothermic newborns, to quantify the impact of hypothermia on pharmacokinetics, and to develop an effective and safe dosing algorithm.

    Methods

    Setting and study population

    The study was performed in two tertiary NICUs. Term newborns were eligible for inclusion if they had severe perinatal asphyxia followed by neonatal encephalopathy, qualifying for treatment with hypothermia.10 Exclusion criteria were congenital abnormalities, or encephalopathy due to other causes. Therapeutic hypothermia (rectal temperature 33.5°C) was started within 6 h after birth and was maintained during 72 h. The study was approved by the local ethics committees of the two participating centres. For all participants, informed consent was provided by the parents.

    To study the effect of hypothermia on lidocaine pharmacokinetics, the hypothermic group was compared using pharmacokinetic modelling to a historical control group that consisted of asphyxiated normothermic newborns with neonatal convulsions.

    Patient inclusion, lidocaine dosing and the bioanalytical assays of the control group have been published previously.6 ,11

    Lidocaine dosing and bioanalysis

    Neonatal seizures were treated according to a Dutch protocol. Lidocaine was started when epileptiform activity on the amplitude-integrated EEG persisted despite phenobarbital and midazolam therapy. Because a clinical-relevant effect of hypothermia on lidocaine clearance (CL) was expected, the lidocaine dose was a priori decreased compared with the dosing guidelines under normothermic conditions.3 This reduced dosing regimen consisted of an initial dose of 2 mg/kg over 10 min, followed by an infusion of 4 mg/kg/h during 6 h.11 After 6 h, the infusion was reduced to 2 mg/kg/h during 12 h. Subsequently, dosing was stopped, resulting in a cumulative dose of 70% compared with the normothermic regimen.

    Blood samples were drawn once a day from an arterial line on consecutive mornings during the hypothermic phase. Concentrations were determined in plasma using LC-MS/MS.12

    Efficacy

    Clinical efficacy of lidocaine was monitored using amplitude-integrated EEG. Responsiveness was defined as a reduction of electrographic seizure burden of >80% within 4 h of commencing lidocaine.

    Safety

    Safety was assessed using cardiac monitoring (heart frequency), which was performed using a Philips IntelliVue MP70 Neonatal Monitor (Philips Medical Systems, Boeblingen, Germany). Clinical monitoring of cardiac arrhythmias is based on observation of sudden deviations in heart frequency.

    The influence of lidocaine and MEGX on heart frequency was visually tested by relating the lidocaine dosing regimen to the heart frequency.

    Dosing regimen development

    A dosing advice was developed by dose simulations after assessment of a lidocaine population pharmacokinetic model.

    Pharmacokinetic analysis was performed using non-linear mixed-effect modelling (NONMEM).13 ,14 More detailed information about the pharmacokinetic modelling strategy and model evaluation is included in the online supplementary appendix.

    To study the effect of hypothermia on pharmacokinetics, body temperature was tested as a dichotomous variable on each pharmacokinetic parameter.

    Simulations were used to evaluate different lidocaine-dosing strategies under hypothermia.

    Results

    Twenty-two asphyxiated full-term hypothermic newborns received lidocaine . A total of 83 lidocaine plasma samples were collected. Characteristics of the study groups are displayed in table 1.

    View this table:
    Table 1

    Characteristics of the study groups*

    The observed lidocaine plasma concentration under hypothermia (n=75) are displayed in figure 1. The highest observed lidocaine plasma concentration was 8.8 mg/l at the end of the initial 6 h loading infusion step.

    Figure 1
    Figure 1

    Observed lidocaine plasma concentrations under hypothermia.

    Efficacy

    In 91% (20/22) of all neonates, seizures did respond to lidocaine add-on therapy under hypothermia. One patient with recurring epileptiform activity on the amplitude-integrated EEG shortly after lidocaine had finished received a second course of lidocaine treatment, after which epileptiform activity was stopped again. Additional anticonvulsants (midazolam and/or clonazepam) and pyridoxine were administered to newborns who did not respond to lidocaine therapy (n=2). Newborns that did not responsd to lidocaine had very severe structural brain damage on their cranial MRI.

    Safety

    Figure 2 illustrates the observed time-course of heart rate change from baseline during lidocaine therapy under hypothermia. No effect of lidocaine plasma concentrations on heart frequency was observed. None of the newborns in our study population experienced cardiac arrhythmias during lidocaine therapy.

    Figure 2
    Figure 2

    Relationships between lidocaine and heart frequency. Time-course of the heart frequency (HF, upper) and the heart frequency change from baseline (dHF, lower) during lidocaine infusion under hypothermia. Lines represent the median and the minimum and maximum observed values.

    Dosing algorithm

    A population pharmacokinetics model for lidocaine was developed for both hypothermic neonates and normothermic asphyxiated newborns. A significant effect of hypothermia on CL could be identified (p<0.01), but no effect of hypothermia on MEGX pharmacokinetic parameters was noted. CL was reduced by 24% during hypothermia compared with normothermia.

    More detailed information on parameter estimates, model evaluation and simulations are included in the online supplementary appendix.

    The simulated population concentration-time curves of the currently applied hypothermic dosing regimen are displayed in figure 3A. With this regimen, 1.1% of the simulated newborns would have a lidocaine plasma concentration exceeding 9 mg/l at the end of the 6 h infusion, whereas 16.4% would have a plasma concentration below 4 mg/l.

    Figure 3
    Figure 3

    Population concentration-time profiles of the applied hypothermic regimen (left window), the unadjusted normothermic regimen (middle window) and the proposed novel hypothermic regimen (right window) for lidocaine under hypothermia; 10% and 90% percentiles with medians are shown for lidocaine (solid grey area) and MEGX (dashed transparant area). Avoidable lidocaine concentration: >9 mg/l.

    According to the simulations, implementation of the unadjusted normothermic dosing regimen under hypothermia would result in a lidocaine plasma concentration of >9 mg/l in 13% of the individuals (figure 3B).

    A novel dosing strategy for therapeutic hypothermia was developed using simulations (figure 3C). The strategy consisted (figure 4) of a shortened loading infusion duration of 3.5 h instead of 4 h. (6) At the end of the 3.5 h loading infusion, an acceptable number of 5.9% of the simulated newborns had a lidocaine plasma concentration exceeding 9 mg/l, with 2.2% of the simulated newborns with concentrations exceeding 10 mg/l. Only 2.5% had a plasma concentration below 4 mg/l (figure 3C).

    Figure 4
    Figure 4

    Suggested lidocaine dosing regimens in term-asphyxiated newborns.

    Discussion

    A response of 91% was observed during hypothermia for lidocaine add-on therapy in our population. This percentage is in agreement with observed response rates in normothermic newborns (70–92%).

    Moderate therapeutic hypothermia reduced CL by 24% compared with normothermia. Lidocaine is classified as a ‘high-clearance’ drug, which implicates that hepatic clearance of lidocaine is especially determined by the hepatic blood flow.15 During hypothermia, a decreased hepatic blood flow due to a decreased cardiac output and stroke volume has been observed.16–19 We expect that the reduced observed metabolism of lidocaine during moderate hypothermia is primarily caused by an impaired hepatic blood flow, which is in accordance with the high-clearance pharmacokinetic principle.

    By contrast, for phenobarbital, a drug classified as a ‘low-clearance’ drug, no effect of moderate therapeutic hypothermia on phenobarbital clearance could be identified.20

    Based on the mechanism of action of lidocaine on the heart, we hypothesize that the cardiac effect of lidocaine is less pronounced during hypothermia. Under normal physiological conditions, the binding sites of lidocaine on the cardiomyocytes are not continuously available.7 Inhibition of sodium channels by lidocaine increases during systole when the drug-binding sites are available, and decreases during diastole.21 Thus, the effect of lidocaine on heart frequency does not only depend on the drug concentration at the receptor site, but also on the frequency of the heart itself. We expect that lidocaine has less cardiotoxicity in hypothermic neonates compared with normothermic neonates, because the baseline heart frequency is already reduced by hypothermia itself.22 Median baseline heart rate under hypothermia in our population was 116 bpm which is in agreement with observations from other authors.18 ,23

    Therefore, we aimed at equivalent lidocaine plasma concentrations in hypothermic neonates as in normothermic neonates, in order to optimise seizure control. To account for the reduced clearance of lidocaine under hypothermia, we developed a novel hypothermic dosing regimen. A reduction in loading-dose duration (same mg/kg/h) was chosen from a patient safety point of view rather than adjusting the dose (in mg/kg/h) to avoid dosing errors (figure 4).

    Since the highest observed lidocaine plasma concentration in the hypothermic groups was 8.8 mg/l, and in our patients no relationship between lidocaine dosing and heart frequency was identified, we consider that it is safe to administer lidocaine with regimens that maintain plasma concentration below about 9 mg/l, although taking into account that our dataset only included 22 infants.

    Based on extensive clinical experience with lidocaine, a prolonged lidocaine exposure is advised due to observation of reoccurrence of seizures after lidocaine cessation in some normothermic (term) newborns, and in one hypothermic (term) newborn. Lidocaine exposure could be prolonged by extending the duration of the first dose-reduction step to 12 h. The novel regimen is a slight modification of the normothermic regimen that is easy to implement, with the difference that the duration of the initial infusion step is reduced by half an hour. Therapeutic drug monitoring remains crucial in case of cardiac toxicity or failure of seizure control.

    A precaution that should be taken into account to reduce the occurrence of cardiac adverse events, is to avoid administering lidocaine to patients with congenital heart disease, or to patients who already received phenytoin.4

    Prospective evaluation of the pharmacokinetic model and the proposed novel dosing regimen will be performed under the multicentre PharmaCool study.24

    Conclusion

    A response of 91% on epileptiform activity on the amplitude-integrated EEG was observed under hypothermia for lidocaine add-on therapy in our population, which is better than the effect of other antiepileptic drugs. No relationship between lidocaine or MEGX plasma concentrations and heart frequency could be identified. No infants experienced cardiac arrhythmias. A novel hypothermic dosing regimen was developed to account for the reduced clearance of lidocaine by 24% under hypothermia. Lidocaine can be assumed to be an effective antiepileptic drug during hypothermia.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors Every coauthor contributed equally to the preparation of this manuscript (study design, patient inclusion, patient follow-up, writing, and so on).

    • Funding None.

    • Competing interests None.

    • Ethics approval Medical Ethics Committees Utrecht and Zwolle.

    • Provenance and peer review Not commissioned; externally peer reviewed.