Articles

Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

Abstract

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

1. Trinka E, Kälviäinen R. 25 years of advances in the definition, classification and treatment of status epilepticus. Seizure 2017;44:65-73.
2. Yasiry Z, Shorvon SD. How phenobarbital revolutionized epilepsy therapy: the story of phenobarbital therapy in epilepsy in the last 100 years. Epilepsia 2012;53:26-39.
3. Hocker S, Clark S, Britton J. Parenteral phenobarbital in status epilepticus revisited: Mayo Clinic experience. Epilepsia 2018;59:193-7.
4. Temkin NR. Preventing and treating posttraumatic seizures: the human experience. Epilepsia 2009;50:10-3.
5. Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta‐analysis of controlled trials. Epilepsia 2001;42:515-24.
6. Schierhout G, Roberts I. Antiepileptic drugs for preventing seizures following acute traumatic brain injury. Cochrane Database Syst Rev 2001;4:CD000173.
7. Gupta Y, Gupta M. Post traumatic epilepsy: a review of scientific evidence. Indian J Physiol Pharmacol 2006;50:7-16.
8. Uchida T, Takayanagi M, Kitamura T, Nishio T, Numata Y, Endo W, et al. High‐dose phenobarbital with intermittent short‐acting barbiturates for acute encephalitis with refractory, repetitive partial seizures. Pediatr Int 2016;58:750-3.
9. Hayner CE, Wuestefeld NL, Bolton PJ. Phenobarbital treatment in a patient with resistant alcohol withdrawal syndrome. Pharmacotherapy 2009; 29:875-8.
10. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs 2014;28: 401-10.
11. Murphy JE. Clinical pharmacokinetics. 6th ed. Bethesda: ASHP; 2017.
12. Boucher BA, Wood GC, Swanson JM. Pharmacokinetic changes in critical illness. Crit Care Clin 2006;22:255-71
13. Yamamoto Y, Takahashi Y, Horino A, Usui N, Nishida T, Imai K, et al. Influence of Inflammation on the Pharmacokinetics of Perampanel. Ther Drug Monit 2018;40:725-9.
14. Szaflarski JP, Nazzal Y, Dreer LE. Post-traumatic epilepsy: current and emerging treatment options. Neuropsychiatr Dis Treat 2014;10:1469-77.
15. McIntosh TK. Novel pharmacologic therapies in the treatment of experimental traumatic brain injury: a review. J Neurotrauma 1993;10:215-61.
16. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient—concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 2014;77:3-11.
17. Slaviero KA, Clarke SJ, Rivory LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol 2003;4:224-32.
18. Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong J. Introduction to drug pharmacokinetics in the critically III patient. Chest 2012;141:1327-36.
19. Brzaković B, Pokrajac M, Dzoljić E, Lević Z, Varagić V. Cerebrospinal fluid and plasma pharmacokinetics of phenobarbital after intravenous administration to patients with status epilepticus. Clin Drug Investig 1997;14:307-13.
20. NELSON E, POWELL JR, CONRAD K, LIKES K, BYERS J, BAKER S, et al. Phenobarbital pharmacokinetics and bioavailability in adults. J Clin Pharmacol 1982;22:141-8.
21. Pokorná P, Posch L, Šíma M, Klement P, Slanar O, van den Anker J, et al. Severity of asphyxia is a covariate of phenobarbital clearance in newborns undergoing hypothermia. J Matern Fetal Neonatal Med 2019;32:2302-9.
22. Schalen W, Sonesson B, Messeter K, Nordström G, Nordström CH. Clinical outcome and cognitive impairment in patients with severe head injuries treated with barbiturate coma. Acta Neurochir (Wien) 1992;117:153-9.
23. Boucher BA, Hanes SD. Pharmacokinetic alterations after severe head injury. Clinical pharmacokinet 1998;35:209-21.
24. Heinemeyer G, Roots I, Dennhardt R. Monitoring of pentobarbital plasma levels in critical care patients suffering from increased intracranial pressure. Ther Drug Monit 1986;8:145-50.
25. Shah RR, Smith RL. Addressing phenoconversion: the Achilles' heel of personalized medicine. Br J Clin Pharmacol 2015;79:222-40.
26. Shah RR, Smith RL. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos 2015;43:400-10.
27. Renton KW. Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug Metab Toxicol 2005;1:629-40.
28. Monostory K, Nagy A, Tóth K, Bűdi T, Kiss Á, Déri M, et al. Relevance of CYP2C9 Function in Valproate Therapy. Curr Neuropharmacol 2019;17: 99-106.
29. Macnab M, Macrae D, Guy E, Grant I, Feely J. Profound reduction in morphine clearance and liver blood flow in shock. Intensive Care Med 1986;12:366-9.
30. Krishnan V, Murray P. Pharmacologic issues in the critically ill. Clin Chest Med 2003;24:671-88.
31. Lambie D, Johnson R. The effects of phenytoin on phenobarbitone and primidone metabolism. J Neurol Neurosurg Psychiatry 1981;44:148-51.
32. Vora TK, Karunakaran S, Kumar A, Chiluka A, Srinivasan H, Parmar K, et al. Intracranial pressure monitoring in diffuse brain injury-why the developing world needs it more? Acta Neurochir (Wien) 2018;160:1291-9.
Files
IssueVol 60 , No 1 (2022) QRcode
SectionArticles
DOI https://doi.org/10.18502/acta.v60i1.8323
Keywords
: Phenobarbital Pharmacokinetics Brain injury Critical illness Therapeutic drug monitoring

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Khezrnia SS, Shahrami B, Rouini MR, Najafi A, Sharifnia HR, Sadrai S, Ahmadi A, Jafarzadeh kohneloo A, Najmeddin F, Mojtahedzadeh M. Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury. Acta Med Iran. 2022;60(1):18-25.