Florida Neonatal Neurologic Network

V. Neurologic and Seizure ManagementSection ContentsWhat medications should be used for analgesia during hypothermia?When and how should infants be monitored for seizures?How should seizures be managed in neonates with HIE?What is the optimal time for neuroimaging in neonates with HIE?ReferencesI. What medications should be used for analgesia during hypothermia?Though optimal therapy for sedation in neonates is a highly debated topic, neonates being cooled do demonstrate agitation and irritability in response to cooling. Studies of animal models of global hypoxic insults demonstrate that unsedated piglets subjected to hypothermia post hypoxic injury do not benefit from total body cooling and have grossly elevated cortisol levels, shivering, and generally increased motor activity that is postulated to diminish and even counteract the neuroprotective benefits of total body hypothermia. Due to known suppression of the cytochrome P450 pathway due to cooling as well as the risk for polypharmacy and drug interactions in acutely ill neonates, care must be taken in choosing a medication for analgesia.Recommendations:Begin an opiate or dexmedetomidine infusion upon initiation of cooling. The recommended starting doses are: Fentanyl 0.5 mcg/k/hour and dexmedetomidine 0.3 mcg/k/hour ADDIN EN.CITE <EndNote><Cite><Author>O'Mara</Author><Year>2018</Year><RecNum>1871</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1871</rec-number><foreign-keys><key app="EN" db-id="vrrvp2a0wvapdbefva5pvzz30v0xfpxade0t" timestamp="1562009397">1871</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>O'Mara, K.</author><author>Weiss, M. D.</author></authors></contributors><auth-address>Department of Pharmacy, University of Florida Health Shands Hospital, University of Florida, Gainesville, Florida.Department of Pediatrics, University of Florida, Gainesville, Florida.</auth-address><titles><title>Dexmedetomidine for Sedation of Neonates with HIE Undergoing Therapeutic Hypothermia: A Single-Center Experience</title><secondary-title>AJP Rep</secondary-title></titles><periodical><full-title>AJP Rep</full-title></periodical><pages>e168-e173</pages><volume>8</volume><number>3</number><keywords><keyword>dexmedetomidine</keyword><keyword>hypoxic-ischemic encephalopathy</keyword><keyword>neonate</keyword><keyword>sedation</keyword></keywords><dates><year>2018</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>2157-6998 (Print)2157-7005 (Linking)</isbn><accession-num>30186671</accession-num><urls><related-urls><url>;[1].May consider titrating continuous infusions based on the neurologic exam and NPASS score (range: -10 to 10). NPASS scores should be assessed every 3 hours. Goal is score less than 3.If any NPASS score is below 0, wean the sedation. If the NPASS score is 0 for 3 consecutive assessments, wean the sedation.If The NPASS score is consistently between 0-3, consider weaning. If the score is 3 or higher, increase the dose to achieve target scores. Stop unnecessary analgesia and sedation after warming has occurred. If opiate or dexmedetomidine at low dosages does not provide adequate analgesia, the dose can be gradually increased or alternate infusion may be added (see above). The goal should be continuous and adequate analgesia and anxiolysis to prevent excessive irritability/agitation and not an attempt to maintain the infant on mechanical ventilation, unless clinically indicated. For intermittent agitation, may consider a small bolus of either agent as needed for NPASS scores exceeding 3.The clinician may consider obtaining a serum cortisol to assess the degree of stress. The cortisol along with the heart rate may aid the clinician with the management of sedation. Level of Evidence: V Expert opinion based on current review of the literature and animal models.II. When and how should infants be monitored for seizures?Multiple studies have shown the benefit of continuous EEG monitoring of neonates with HIE. Besides being a very useful early predictor of neurologic outcomes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmVzc2xlcjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

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ADDIN EN.CITE.DATA [2, 3], studies have shown that aggressive treatment of seizures decreases neurologic sequlae ADDIN EN.CITE <EndNote><Cite><Author>van Rooij</Author><Year>2010</Year><RecNum>1872</RecNum><DisplayText>[4]</DisplayText><record><rec-number>1872</rec-number><foreign-keys><key app="EN" db-id="vrrvp2a0wvapdbefva5pvzz30v0xfpxade0t" timestamp="1562097412">1872</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Rooij, L. G.</author><author>Toet, M. C.</author><author>van Huffelen, A. C.</author><author>Groenendaal, F.</author><author>Laan, W.</author><author>Zecic, A.</author><author>de Haan, T.</author><author>van Straaten, I. L.</author><author>Vrancken, S.</author><author>van Wezel, G.</author><author>van der Sluijs, J.</author><author>Ter Horst, H.</author><author>Gavilanes, D.</author><author>Laroche, S.</author><author>Naulaers, G.</author><author>de Vries, L. S.</author></authors></contributors><auth-address>Wilhelmina Children's Hospital, Department of Neonatology, KE 04.123.1, PO Box 85090, 3508 AB Utrecht, Netherlands.</auth-address><titles><title>Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>e358-66</pages><volume>125</volume><number>2</number><keywords><keyword>Electroencephalography/*methods</keyword><keyword>Humans</keyword><keyword>Hypoxia-Ischemia, Brain/*complications/physiopathology</keyword><keyword>Infant, Newborn</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Monitoring, Physiologic</keyword><keyword>Seizures/*diagnosis/*drug therapy/etiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1098-4275 (Electronic)0031-4005 (Linking)</isbn><accession-num>20100767</accession-num><urls><related-urls><url>;[4]. Due to the large amount of resources consumed by continuous EEG monitoring, amplitude integrated EEG has been used extensively for neonates with HIE for monitoring. The ease of application and interpretation of aEEG makes it especially useful in continuous monitoring.Recommendations:Upon admission to the NICU, neonates suspected of having HIE should have an aEEG placed (see #3).Monitoring duration via aEEG should optimally occur during the entire systemic hypothermia process, including warming.If video EEG is used for continuous monitoring instead of aEEG, someone at the bedside of the patient should be trained in interpretation of the EEG or the aEEG feature on the video EEG should be monitored by the bedside personnel.If aEEG demonstrates seizure activity and/or an abnormal background pattern, it is recommended to obtain formal EEG evaluation and continuously monitor for electrographic seizures until warming has occurred and seizures are under control (2).Level of Evidence: IIC based on outcome data and case control studiesIII. How should seizures be managed in neonates with HIE?HIE is the number one cause of neonatal seizures. Despite the high incidence of seizures in this population of neonates, a Cochrane review did not find benefit in morbidity and mortality with routine use of prophylactic anti-epileptic medications ADDIN EN.CITE <EndNote><Cite><Author>Evans</Author><Year>2007</Year><RecNum>1860</RecNum><DisplayText>[5]</DisplayText><record><rec-number>1860</rec-number><foreign-keys><key app="EN" db-id="vrrvp2a0wvapdbefva5pvzz30v0xfpxade0t" timestamp="1551718538">1860</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Evans, D. J.</author><author>Levene, M. I.</author><author>Tsakmakis, M.</author></authors></contributors><auth-address>Southmead Hospital, Neonatal Intensive Care Unit, Southmead Hospital, Bristol, UK, BS10 5NB. david.evans@nbt.nhs.uk</auth-address><titles><title>Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD001240</pages><number>3</number><keywords><keyword>Anticonvulsants/*therapeutic use</keyword><keyword>Asphyxia Neonatorum/*drug therapy/mortality</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Seizures/mortality/*prevention & control</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul 18</date></pub-dates></dates><isbn>1469-493X (Electronic)1361-6137 (Linking)</isbn><accession-num>17636659</accession-num><urls><related-urls><url>;[5].Though there is no evidence to support routine prophylaxis, studies have shown a definite benefit to aggressive therapy of seizures: clinical or electrographic. FDA approved management for seizures in neonates is limited to Phenobarbital and Fosphenytoin. Studies have not demonstrated a benefit of Phenobarbital over Fosphenytoin ADDIN EN.CITE <EndNote><Cite><Author>Glass</Author><Year>2007</Year><RecNum>1861</RecNum><DisplayText>[6]</DisplayText><record><rec-number>1861</rec-number><foreign-keys><key app="EN" db-id="vrrvp2a0wvapdbefva5pvzz30v0xfpxade0t" timestamp="1551718667">1861</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Glass, H. C.</author><author>Ferriero, D. M.</author></authors></contributors><auth-address>Donna M. Ferriero, MD University of California San Francisco, Neonatal Brain Disorders Center, Box 0663, 521 Parnassus Avenue, C-215, San Francisco, CA 94143, USA. ferrierod@neuropeds.ucsf.edu.</auth-address><titles><title>Treatment of hypoxic-ischemic encephalopathy in newborns</title><secondary-title>Curr Treat Options Neurol</secondary-title></titles><periodical><full-title>Curr Treat Options Neurol</full-title></periodical><pages>414-23</pages><volume>9</volume><number>6</number><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1092-8480 (Print)1092-8480 (Linking)</isbn><accession-num>18173941</accession-num><urls><related-urls><url>;[6]. Recent randomized control studies have demonstrated that Keppra is a safe and effective therapy in neonatal seizures with vastly better pharmacokinetics and side effect profile than Phenobarbital and Fosphenytoin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmVuZDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [7-9]. Some studies have also demonstrated a potential neuroprotective benefit of Keppra and neurotoxic side effects associated with Phenobarbital and Fosphenytoin ADDIN EN.CITE <EndNote><Cite><Author>Cilio</Author><RecNum>1527</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1527</rec-number><foreign-keys><key app="EN" db-id="vrrvp2a0wvapdbefva5pvzz30v0xfpxade0t" timestamp="0">1527</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cilio, M. R.</author><author>Ferriero, D. M.</author></authors></contributors><auth-address>Newborn Brain Research Institute, University of California, San Francisco, California, USA.</auth-address><titles><title>Synergistic neuroprotective therapies with hypothermia</title><secondary-title>Semin Fetal Neonatal Med</secondary-title></titles><periodical><full-title>Semin Fetal Neonatal Med</full-title></periodical><pages>293-8</pages><volume>15</volume><number>5</number><edition>2010/03/09</edition><keywords><keyword>Acetylcysteine/therapeutic use</keyword><keyword>Anticonvulsants/*therapeutic use</keyword><keyword>Body Temperature</keyword><keyword>Cannabinoids/therapeutic use</keyword><keyword>Combined Modality Therapy</keyword><keyword>Erythropoietin/therapeutic use</keyword><keyword>Fructose/analogs & derivatives/therapeutic use</keyword><keyword>Humans</keyword><keyword>Hypothermia, Induced/*methods</keyword><keyword>Hypoxia-Ischemia, Brain/drug therapy/*therapy</keyword><keyword>Infant, Newborn</keyword><keyword>Melatonin/therapeutic use</keyword><keyword>Neuroprotective Agents/*therapeutic use</keyword><keyword>Piracetam/analogs & derivatives/therapeutic use</keyword><keyword>Xenon/therapeutic use</keyword></keywords><dates><pub-dates><date>Oct</date></pub-dates></dates><isbn>1878-0946 (Electronic)1744-165X (Linking)</isbn><accession-num>20207600</accession-num><urls><related-urls><url>(10)00013-2 [pii]10.1016/j.siny.2010.02.002</electronic-resource-num><language>eng</language></record></Cite></EndNote>[10].Recommendations:Any electrographic or clinical evidence of seizures should be aggressively treated with appropriate anti-epileptic therapy and close monitoring for recurrence as over 50% of seizures from HIE will require more than one medication for treatment.Initial treatment may be with either an intravenous benzodiazepine or IV Phenobarbital at 20 mg/kg.Maintenance treatment may be started if neonates continue to have seizure activity. If maintenance is started, recheck in one week to reassess if AED can be discontinued.VI. What is the optimal time for neuroimaging in neonates with HIE?Appropriate neuroimaging is an important part of evaluating the etiology of HIE and predicting long term neurodevelopemental outcomes. Magnetic Resonance Imaging with diffusion weighted images and spectroscopy of the basal ganglia is the imaging study of choice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2ljaG90PC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48

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ADDIN EN.CITE.DATA [11, 12]. Deep gray matter injuries including basal ganglia injuries and thalamic injury can indicate acute injury while injuries in the watershed areas can indicate prolonged partial hypoxia ADDIN EN.CITE <EndNote><Cite><Author>Glass</Author><Year>2007</Year><RecNum>1861</RecNum><DisplayText>[6]</DisplayText><record><rec-number>1861</rec-number><foreign-keys><key app="EN" db-id="vrrvp2a0wvapdbefva5pvzz30v0xfpxade0t" timestamp="1551718667">1861</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Glass, H. C.</author><author>Ferriero, D. M.</author></authors></contributors><auth-address>Donna M. Ferriero, MD University of California San Francisco, Neonatal Brain Disorders Center, Box 0663, 521 Parnassus Avenue, C-215, San Francisco, CA 94143, USA. ferrierod@neuropeds.ucsf.edu.</auth-address><titles><title>Treatment of hypoxic-ischemic encephalopathy in newborns</title><secondary-title>Curr Treat Options Neurol</secondary-title></titles><periodical><full-title>Curr Treat Options Neurol</full-title></periodical><pages>414-23</pages><volume>9</volume><number>6</number><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1092-8480 (Print)1092-8480 (Linking)</isbn><accession-num>18173941</accession-num><urls><related-urls><url>;[6].Recommendations:Head ultrasound should be acquired on admission.MRI with diffusion weighted images and spectroscopy of the basal ganglia is the preferred study.Suggested MRI imaging can be performed at 4-5 days of life and again at 7-12 days. If only one MRI can be performed, it should occur during the 7-12 day period. These recommendations may need to be adjusted in critically ill neonates who will be compromised in obtaining the MRI.Level of Evidence: IA randomized control trials.V. References ADDIN EN.REFLIST 1.O'Mara, K. and M.D. Weiss, Dexmedetomidine for Sedation of Neonates with HIE Undergoing Therapeutic Hypothermia: A Single-Center Experience. AJP Rep, 2018. 8(3): p. e168-e173.2.Pressler, R.M., et al., Early serial EEG in hypoxic ischaemic encephalopathy. Clin Neurophysiol, 2001. 112(1): p. 31-7.3.de Vries, L.S. and M.C. Toet, Amplitude integrated electroencephalography in the full-term newborn. Clin Perinatol, 2006. 33(3): p. 619-32, vi.4.van Rooij, L.G., et al., Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics, 2010. 125(2): p. e358-66.5.Evans, D.J., M.I. Levene, and M. Tsakmakis, Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst Rev, 2007(3): p. CD001240.6.Glass, H.C. and D.M. Ferriero, Treatment of hypoxic-ischemic encephalopathy in newborns. Curr Treat Options Neurol, 2007. 9(6): p. 414-23.7.Abend, N.S., et al., Levetiracetam for treatment of neonatal seizures. J Child Neurol, 2011. 26(4): p. 465-70.8.Khan, O., et al., Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol, 2011. 44(4): p. 265-9.9.Ramantani, G., et al., Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol, 2011. 15(1): p. 1-7.10.Cilio, M.R. and D.M. Ferriero, Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med. 15(5): p. 293-8.11.Boichot, C., et al., Term neonate prognoses after perinatal asphyxia: contributions of MR imaging, MR spectroscopy, relaxation times, and apparent diffusion coefficients. Radiology, 2006. 239(3): p. 839-48.12.Barkovich, A.J., et al., MR imaging, MR spectroscopy, and diffusion tensor imaging of sequential studies in neonates with encephalopathy. AJNR Am J Neuroradiol, 2006. 27(3): p. 533-47. ................
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