Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing

Broek, Marcel P. H. van den; Rademaker, Carin M. A.; Straaten, H.L.M. van; Huitema, Alwin D. R.; Toet, Mona C.; Vries, Linda S. de; Egberts, Toine C. G.; Groenendaal, Floris

doi:10.1136/archdischild-2012-302678

Cited by 39 publications

(50 citation statements)

References 24 publications

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“…>66%) or the third-line add-on drug lidocaine (91%) [7,20]. In table 3, the efficacy of clinical studies investigating the second-line effectiveness of midazolam after phenobarbital in newborns is summarized.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant Effectiveness and Hemodynamic Safety of Midazolam in Full-Term Infants Treated with Hypothermia

et al. 2015

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Background: Midazolam is used as an anticonvulsant in neonatology, including newborns with perinatal asphyxia treated with hypothermia. Hypothermia may affect the safety and effectiveness of midazolam in these patients. Objectives: The objective was to evaluate the anticonvulsant effectiveness and hemodynamic safety of midazolam in hypothermic newborns and to provide dosing guidance. Methods: Hypothermic newborns with perinatal asphyxia and treated with midazolam were included. Effectiveness was studied using continuous amplitude-integrated electroencephalography. Hemodynamic safety was assessed using pharmacokinetic-pharmacodynamic modeling with plasma samples and blood pressure recordings (mean arterial blood pressure) under hypothermia. Results: No effect of therapeutic hypothermia on pharmacokinetics could be identified. Add-on seizure control with midazolam was limited (23% seizure control). An inverse relationship between the midazolam plasma concentration and mean arterial blood pressure could be identified. At least one hypotensive episode was experienced in 64%. The concomitant use of inotropes decreased midazolam clearance by 33%. Conclusions: Under therapeutic hypothermia, midazolam has limited add-on clinical anticonvulsant effectiveness after phenobarbital administration. Due to occurrence of hypotension requiring inotropic support, midazolam is less suitable as a second-line anticonvulsant drug under hypothermia.

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Section: Discussionmentioning

confidence: 99%

Anticonvulsant Effectiveness and Hemodynamic Safety of Midazolam in Full-Term Infants Treated with Hypothermia

et al. 2015

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“…Lidocaine undergoes hepatic metabolism through CYP1A2, and is classified as a high-clearance drug, therefore, its hepatic CI is predominately impacted by changes in hepatic blood flow. Van den Broek et al (2013) investigated the effects of TTM on the PK and efficacy of lidocaine in neonates with encephalopathy. A total of 22 asphyxiated neonates underwent hypothermia to 33.5°C for 72 hours.…”

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confidence: 99%

Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations

Anderson

Poloyac

Kochanek

et al. 2016

Therapeutic Hypothermia and Temperature Management

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Targeted temperature management (TTM) has been shown to reduce mortality and improve neurological outcomes in out-of-hospital cardiac arrest (CA) patients and in neonates with hypoxic-ischemic encephalopathy (HIE). TTM has also been associated with adverse drug events in the critically ill patient due to its effect on drug pharmacokinetics (PKs) and pharmacodynamics (PDs). We aim to evaluate the current literature on the effect of TTM on drug PKs and PDs following CA. MEDLINE/PubMed databases were searched for publications, which include the MeSH terms hypothermia, drug metabolism, drug transport, P450, critical care, cardiac arrest, hypoxic-ischemic encephalopathy, pharmacokinetics, and pharmacodynamics between July 2006 and October 2015. Twenty-three studies were included in this review. The studies demonstrate that hypothermia impacts PK parameters and increases concentrations of cytochrome-P450-metabolized drugs in the cooling and rewarming phase. Furthermore, the current data demonstrate a combined effect of CA and hypothermia on drug PK. Importantly, these effects can last greater than 4-5 days post-treatment. Limited evidence suggests hypothermia-mediated changes in the Phase II metabolism and the Phase III transport of drugs. Hypothermia also has been shown to potentially decrease the effect of specific drugs at the receptor level. Therapeutic hypothermia, as commonly deployed/applied during TTM, alters PK, and elevates concentrations of several commonly used medications. Hypothermia-mediated effects are an important factor when dosing and monitoring patients undergoing TTM treatment.

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“…Lidocaine-associated cardiac events have been reported in several studies [1][2][3][4][6][7][8][9][10] , but most had a limited number of infants. Incidence rates ranged from 0 to 4.8%.…”

Section: Discussionmentioning

confidence: 99%

“…Lidocaine promises to be an effective therapy for neonatal seizures persisting despite first-and second-line therapy [1][2][3][4] ; however, it is not widely used [5] , presumably due to the risk of cardiac events. Cardiac events have been reported in studies with neonates receiving lidocaine for seizures, with incidences ranging from 0 to 4.8% [1][2][3][4][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

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Lidocaine-Associated Cardiac Events in Newborns with Seizures: Incidence, Symptoms and Contributing Factors

Weeke

Schalkwijk²,

Toet³

et al. 2015

Neonatology

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Background: Lidocaine is an effective therapy for neonatal seizures; however, it is not widely used, presumably due to the risk of cardiac events. Objective: To investigate the incidence of cardiac events in full-term and preterm infants receiving lidocaine for seizures. Methods: Full-term (n = 368) and preterm (n = 153) infants, admitted to a level 3 neonatal intensive care unit from 1992 to 2012, who received lidocaine for seizures were retrospectively studied. The causal relation between reported cardiac events and lidocaine administration was evaluated based on expected plasma concentrations, symptoms and relevant interactions during cardiac events. Results: Cardiac events were reported in 11/521 infants (2.1%; 9 full-term, 2 preterm). In 7/11 infants the causal relation was considered plausible, in 3/11 questionable and in 1/11 implausible. The incidence was calculated to be 1.3-1.9% (n = 7-10/521), but was only 0.4% (n = 1/246, p = 0.02) when using reduced-dose regimens. Important risk factors for cardiac events were unstable potassium, (congenital) cardiac dysfunction and concurrent phenytoin use. Conclusions: Lidocaine-associated cardiac events were rare in our cohort, especially since the introduction of new reduced-dose regimens. This indicates that lidocaine is safe to use as an antiepileptic drug in full-term and preterm infants.

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Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing

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

Cited by 39 publications

References 24 publications

Anticonvulsant Effectiveness and Hemodynamic Safety of Midazolam in Full-Term Infants Treated with Hypothermia

Anticonvulsant Effectiveness and Hemodynamic Safety of Midazolam in Full-Term Infants Treated with Hypothermia

Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations

Lidocaine-Associated Cardiac Events in Newborns with Seizures: Incidence, Symptoms and Contributing Factors

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