Pharmacokinetic Modeling of Optimized Midazolam and Pentobarbital Dosing Used in Treatment Protocols of Refractory Status Epilepticus.

OBJECTIVES: To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status epilepticus (RSE). DESIGN: One- and two-compartment in silico pharmacokinetic models of midazolam and pentobarbital. SETTING: Not applicable. SUBJECTS: Not applicable. INTERVENTIONS: We compared the model variables used in midazolam and pentobarbital protocols for standard RSE. MEASUREMENTS AND MAIN RESULTS: Standard RSE treatment protocols result in steady-state serum concentrations that are 6.2-9.0-fold higher for the one-compartment model and 2.3-4.7-fold higher for the two-compartment model. In the model, not including bolus doses delays the achievement of serum steady-state concentration by 0.5 and 2.7 hours for midazolam and pentobarbital, respectively. Abrupt discontinuation of these medications reduces modeled medication exposure by 1.1 and 6.4 hours, respectively. CONCLUSIONS: Our in silico pharmacokinetic modeling of standard midazolam and pentobarbital dosing protocols for RSE suggests potential variables to optimize in future clinical studies.

Childhood Infectious Encephalitis: An Overview of Clinical Features, Investigations, Treatment, and Recent Patents.

BACKGROUND: Infectious encephalitis is a serious and challenging condition to manage. This overview summarizes the current literature regarding the etiology, clinical manifestations, diagnosis, management, and recent patents of acute childhood infectious encephalitis. METHODS: We used PubMed Clinical Queries as a search engine and used keywords of "encephalitis" AND "childhood" Patents were searched using the key term "encephalitis" in google.patents.- com and patentsonline.com. RESULTS: Viral encephalitis is the most common cause of acute infectious encephalitis in children. In young children, the clinical manifestations can be non-specific. Provision of empiric antimicrobial therapy until a specific infectious organism has been identified, which in most cases includes acyclovir, is the cornerstone of therapy. Advanced investigation tools, including nucleic acid-based test panel and metagenomic next-generation sequencing, improve the diagnostic yield of identifying an infectious organism. Supportive therapy includes adequate airway and oxygenation, fluid and electrolyte balance, cerebral perfusion pressure support, and seizure control. Recent patents are related to the diagnosis, treatment, and prevention of acute infectious encephalitis. CONCLUSION: Viral encephalitis is the most common cause of acute infectious encephalitis in children and is associated with significant morbidity. Recent advances in understanding the genetic basis and immunological correlation of infectious encephalitis may improve treatment. Third-tier diagnostic tests may be incorporated into clinical practice. Treatment is targeted at the infectious process but remains mostly supportive. However, specific antimicrobial agents and vaccines development is ongoing.

Meaning of Intracranial Pressure-to-Blood Pressure Fisher-Transformed Pearson Correlation-Derived Optimal Cerebral Perfusion Pressure: Testing Empiric Utility in a Mechanistic Model.

OBJECTIVES: Time-averaged intracranial pressure-to-blood pressure Fisher-transformed Pearson correlation (PRx) is used to assess cerebral autoregulation and derive optimal cerebral perfusion pressure. Empirically, impaired cerebral autoregulation is considered present when PRx is positive; greater difference between time series median cerebral perfusion pressure and optimal cerebral perfusion pressure (ΔCPP) is associated with worse outcomes. Our aims are to better understand: 1) the potential strategies for targeting optimal cerebral perfusion pressure; 2) the relationship between cerebral autoregulation and PRx; and 3) the determinants of greater ΔCPP. DESIGN: Mechanistic simulation using a lumped compartmental model of blood pressure, intracranial pressure, cerebral autoregulation, cerebral blood volume, PaCO2, and cerebral blood flow. SETTING: University critical care integrative modeling and precision physiology research group. SUBJECTS: None, in silico studies. INTERVENTIONS: Simulations in blood pressure, intracranial pressure, PaCO2, and impairment of cerebral autoregulation, with examination of "output" cerebral perfusion pressure versus PRx-plots, optimal cerebral perfusion pressure, and ΔCPP. MEASUREMENTS AND MAIN RESULTS: In regard to targeting optimal cerebral perfusion pressure, a shift in mean blood pressure or mean intracranial pressure with no change in mean blood pressure, with intact cerebral autoregulation, impacts optimal cerebral perfusion pressure. Second, a positive PRx occurs even with intact cerebral autoregulation. In relation to ΔCPP, for a given input blood pressure profile, with constant intracranial pressure, altering the degree of impairment in cerebral autoregulation or the level of PaCO2 maintains differences to within ±5 mm Hg. Change in intracranial pressure due to either an intermittently prolonged pattern of raised intracranial pressure or terminal escalation shows ΔCPP greater than 10 mm Hg and less than -10 mm Hg, respectively. CONCLUSIONS: These mechanistic simulations provide insight into the empiric basis of optimal cerebral perfusion pressure and the significance of PRx and ΔCPP. PRx and optimal cerebral perfusion pressure deviations do not directly reflect changes in cerebral autoregulation but are, in general, related to the presence of complex states involving well-described clinical progressions with raised intracranial pressure.

Management protocols for status epilepticus in the pediatric emergency room: systematic review article.

OBJECTIVE: This systematic review of national or regional guidelines published in English aimed to better understand variance in pre-hospital and emergency department treatment of status epilepticus. SOURCES: Systematic search of national or regional guidelines (January 2000 to February 2017) contained within PubMed and Google Scholar databases, and article reference lists. The search keywords were status epilepticus, prolonged seizure, treatment, and guideline. SUMMARY OF FINDINGS: 356 articles were retrieved and 13 were selected according to the inclusion criteria. In all six pre-hospital guidelines, the preferred route of medication administration was to use alternatives to the intravenous route: all recommended buccal and intranasal midazolam; three also recommended intramuscular midazolam, and five recommended using rectal diazepam. All 11 emergency department guidelines described three phases in therapy. Intravenous medication, by phase, was indicated as such: initial phase - ten/11 guidelines recommended lorazepam, and eight/11 recommended diazepam; second phase - most (ten/11) guidelines recommended phenytoin, but other options were phenobarbital (nine/11), valproic acid (six/11), and either fosphenytoin or levetiracetam (each four/11); third phase - four/11 guidelines included the choice of repeating second phase therapy, whereas the other guidelines recommended using a variety of intravenous anesthetic agents (thiopental, midazolam, propofol, and pentobarbital). CONCLUSIONS: All of the guidelines share a similar framework for management of status epilepticus. The choice in route of administration and drug type varied across guidelines. Hence, the adoption of a particular guideline should take account of local practice options in health service delivery.

Management protocols for status epilepticus in the pediatric emergency room: systematic review article / Protocolos de manejo de estado de mal epiléptico no pronto socorro pediátrico: análise sistemática

Abstract Objective: This systematic review of national or regional guidelines published in English aimed to better understand variance in pre-hospital and emergency department treatment of status epilepticus. Sources: Systematic search of national or regional guidelines (January 2000 to February 2017) contained within PubMed and Google Scholar databases, and article reference lists. The search keywords were status epilepticus, prolonged seizure, treatment, and guideline. Summary of findings: 356 articles were retrieved and 13 were selected according to the inclusion criteria. In all six pre-hospital guidelines, the preferred route of medication administration was to use alternatives to the intravenous route: all recommended buccal and intranasal midazolam; three also recommended intramuscular midazolam, and five recommended using rectal diazepam. All 11 emergency department guidelines described three phases in therapy. Intravenous medication, by phase, was indicated as such: initial phase - ten/11 guidelines recommended lorazepam, and eight/11 recommended diazepam; second phase - most (ten/11) guidelines recommended phenytoin, but other options were phenobarbital (nine/11), valproic acid (six/11), and either fosphenytoin or levetiracetam (each four/11); third phase - four/11 guidelines included the choice of repeating second phase therapy, whereas the other guidelines recommended using a variety of intravenous anesthetic agents (thiopental, midazolam, propofol, and pentobarbital). Conclusions: All of the guidelines share a similar framework for management of status epilepticus. The choice in route of administration and drug type varied across guidelines. Hence, the adoption of a particular guideline should take account of local practice options in health service delivery.

Resumo Objetivo: Esta análise sistemática de diretrizes nacionais ou regionais publicadas em inglês tem como objetivo entender melhor a diferença no tratamento do estado de mal epiléptico pré-hospitalar e no departamento de emergência. Fontes: Pesquisa sistemática de diretrizes nacionais ou regionais (janeiro de 2000 a fevereiro de 2017) contidas nas bases de dados do Pubmed e do Google Acadêmico e listas de referência de artigos. As palavras-chave da busca foram estado de mal epiléptico, convulsão prolongada, tratamento e diretriz. Resumo dos achados: Foram identificados 356 artigos e 13 foram selecionados de acordo com os critérios de inclusão. Em todas as seis diretrizes pré-hospitalares, o caminho preferencial de administração da medicação foi usar opções à via intravenosa: todas recomendaram midazolam bucal e intranasal; três também recomendaram midazolam intramuscular; e cinco recomendaram usar o diazepam via retal. Todas as 11 diretrizes de departamento de emergência descreveram três fases na terapia. No que diz respeito à medicação intravenosa, por fase, temos: fase inicial - 10/11 diretrizes recomendaram lorazepam e 8/11 recomendaram diazepam; segunda fase - a maioria (10/11) das diretrizes recomendou fenitoína, porém outras opções foram fenobarbital (9/11), ácido valproico (6/11) e fosfenitoína ou levetiracetam (individualmente, 4/11); terceira fase - 4/11 diretrizes incluíram a opção de repetir a terapia da segunda fase, ao passo que as outras diretrizes recomendaram usar diversos agentes anestésicos intravenosos (tiopental, midazolam, propofol e pentobarbital). Conclusões: Todas as diretrizes compartilham uma estrutura semelhante para manejo do estado de mal epiléptico. A escolha da via de administração e do tipo de medicamento variou em todas as diretrizes. Assim, a adoção de uma diretriz específica deve levar em consideração as opções da prática local na prestação de serviços de saúde.