Pharmacotherapy for Seizures in Neonates with Hypoxic Ischemic Encephalopathy

Yozawitz, Elissa; Stacey, Arthur; Pressler, Ronit

doi:10.1007/s40272-017-0250-4

Cited by 24 publications

(20 citation statements)

References 147 publications

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“…Thus in the absence of oxygen and glucose, neither primary nor secondary transport will be effective, and neither will blockade of secondary transporters . During reperfusion after hypoxia and ischemia, or after prolonged episodes of status epilepticus, seizures often do not respond to GABAergic anticonvulsants . One possible etiology is the increase in neuronal chloride observed in this study, and the consequent positive shift in GABA reversal potential.…”

Section: Discussionmentioning

confidence: 72%

Transient ischemia facilitates neuronal chloride accumulation and severity of seizures

Blauwblomme

Dzhala

Staley

2018

Ann Clin Transl Neurol

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ObjectivePreceding oxygen glucose deprivation (OGD) and ongoing seizures have both been reported to increase neuronal chloride concentration ([Cl−]i), which may contribute to anticonvulsant failure by reversing the direction of chloride currents at inhibitory GABAA synapses.MethodsThe effects of OGD on [Cl−]i, seizure activity, and anticonvulsant efficacy were studied in a chronically epileptic in vitro preparation.ResultsSeizures initially increased during OGD, followed by suppression. On reperfusion, seizure frequency and [Cl−]i progressively increased, and phenobarbital efficacy was reduced. Bumetanide (10 μmol/L) and furosemide (1 mmol/L) prevented or reduced the OGD induced [Cl−]i increase. Phenobarbital efficacy was enhanced by bumetanide (10 μmol/L). Furosemide (1 mmol/L) suppressed recurrent seizures.Interpretation[Cl−]i increases after OGD and is associated with worsened seizure activity, reduced efficacy of GABAergic anticonvulsants, and amelioration by antagonists of secondary chloride transport.

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Section: Discussionmentioning

confidence: 72%

Transient ischemia facilitates neuronal chloride accumulation and severity of seizures

Blauwblomme

Dzhala

Staley

2018

Ann Clin Transl Neurol

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“…During TH, the heart frequency is reduced compared to normothermia, thereby reducing the potential for cardiotoxicity. However, to minimise the chance of cardiac toxicity, lidocaine should not be co‐administered with phenytoin or to neonates with congenital heart disease …”

Section: Discussionmentioning

confidence: 99%

“…Lidocaine has proven to be effective in several observational studies in both term and preterm neonates and is favoured as a second‐ or third‐line anticonvulsant therapy in several European countries. The most important safety risk of the use of lidocaine is cardiac toxicity (bradycardia, arrhythmias or asystole), most likely to occur at plasma concentrations exceeding 9 mg/L …”

Section: Introductionmentioning

confidence: 99%

Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen

Favié

Huitema

Broek

et al. 2020

Brit J Clinical Pharma

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Aims:Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. Methods: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred.Results: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54-0.84%). During therapeutic hypothermia (33.5 C), lidocaine clearance was reduced by 21.8% (7.26%/ C, 95% confidence interval 1.63-11.2%) compared to normothermia (36.5 C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed.A complete list of non-author contributors appears in the Acknowledgements section.The authors confirm that the Principal Investigators for this paper are Timo R. de Haan and Floris Groenendaal and that they had direct clinical responsibility for patients. Conclusion: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures. K E Y W O R D Sclinical pharmacology, drug utilization, mass spectrometry, modelling and simulation, neonatology, pharmacometrics

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“…We noted a clinically important, although not statistically significant, difference in seizure incidence between dopamineexposed and control infants. Seizures are a common sequela of an initial ischemic injury, portend a worse outcome (30)(31)(32), and represent ongoing cerebral injury, potentially partially due to inadequate cerebral perfusion. While cerebral perfusion was not directly measured in this study, it is concerning that seizures tended to accompany other signs of impaired systemic perfusion.…”

Section: Discussionmentioning

confidence: 99%

Blood Pressure Profiles in Infants With Hypoxic Ischemic Encephalopathy (HIE), Response to Dopamine, and Association With Brain Injury

et al. 2020

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Objective: To describe mean arterial blood pressure (MABP), responsiveness to dopamine, and relationship to brain injury in infants with moderate/severe hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). We hypothesized that, when utilized, dopamine would rapidly and effectively increase MABP in treated patients. Methods: Continuous arterial blood pressure measurements were prospectively recorded from infants with moderate/severe HIE undergoing TH in a multi-institutional cohort from 2010 to 2018. Treatment with dopamine was at the discretion of the medical team for hypotension/hypoperfusion. MABP values of treated infants were compared to those obtained at an equivalent time period in control infants receiving TH but not dopamine (24 h after birth). MRI was obtained per unit protocols and included T1/T2/DWI sequences. Injury was classified as no injury/mild injury or moderate/severe injury using a standardized scoring system. Seizures were confirmed with conventional EEG. Results: Eighteen infants were treated with dopamine and were similar to untreated controls (n = 36) with the exception of lower cord gas pH (6.92 ± 0.2 vs. 7.07 ± 0.2, p < 0.05). Dopamine was initiated at a mean of 24 h after birth. MABP was significantly lower in the dopamine group at the start of therapy (39.9 ± 2.0 vs. 49.1 ± 1.3, p < 0.01) and 1 h later (44.3 ± 2.0 vs. 49.8 ± 1.1, p < 0.05). However, after 9 h of treatment, dopamine increased the MABP by an average of 9 mmHg and MABP values were similar to untreated controls for the remainder of the observation period. There were no significant differences in rates of seizures, brain injury, or death. Conclusion: Neonates with moderate/severe HIE treated with dopamine during TH had MABP significantly lower than controls. The majority of infants responded to dopamine monotherapy following adequate volume resuscitation. An association between requirement for dopamine and severity of brain injury was not detected.

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Pharmacotherapy for Seizures in Neonates with Hypoxic Ischemic Encephalopathy

Cited by 24 publications

References 147 publications

Transient ischemia facilitates neuronal chloride accumulation and severity of seizures

Transient ischemia facilitates neuronal chloride accumulation and severity of seizures

Lidocaine as treatment for neonatal seizures: Evaluation of previously developed population pharmacokinetic models and dosing regimen

Blood Pressure Profiles in Infants With Hypoxic Ischemic Encephalopathy (HIE), Response to Dopamine, and Association With Brain Injury

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