Antiepileptic Drugs in Critically Ill Patients

Salia Farrokh; Pouya Tahsili-Fahadan; Eva K. Ritzl; John J. Lewin III; Marek A. Mirski

Disclosures

Crit Care. 2018;22(153) 

In This Article

Special Therapeutic Considerations

Extracorporeal Removal of Antiepileptic Drugs

Antiepileptic drug removal by renal replacement therapies. The renal route of elimination, low protein binding, low volume of distribution, and molecular weight are physiochemical factors that impact the propensity for drug removal via dialysis (Table 8). Unfortunately, kinetic data on optimal dosing of AEDs in RRT are not readily available. Clearly such patients benefit from careful TDM and a multidisciplinary approach. There are extensive expert reviews available in the medical literature.[103,104]

Intermittent Hemodialysis

The removal of most AEDs by intermittent hemodialysis (IHD) is usually well characterized in the drug's labeled prescribing information or other references. Two common drugs that are removed by IHD and for which data recommendations exist are levetiracetam and lacosamide. In addition, while phenobarbital is predominantly hepatically metabolized, some reports suggest partial elimination by IHD prompting several experts to suggest supplemental dosing after IHD and monitoring of serum drug levels.[103,105,106]

Continuous Renal Replacement Therapy

There is insufficient evidence to recommend clear dosing guidelines for AEDs in continuous renal replacement therapy (CRRT), and more research is needed to appropriately guide therapy. AEDs that are eliminated via IHD will also be eliminated by CRRT, often times even more so (depending on the duration of CRRT as well as the mode and flow rates) thereby requiring higher doses. For drugs where serum levels are available, TDM is indicated. Estimations of drug removal can be performed to estimate the removal of medications by CRRT based on flow rates, as well as drug and filter properties. The reader is referred to other resources for a more comprehensive discussion on these methods.[107,108] A recent review of the literature proposed dosing recommendations based on AED protein binding and the extent of renal versus hepatic elimination.[104] This is a reasonable approach, although clinicians should also factor in CRRT flow rates, the clinical condition of the patient, and other factors into their clinical decision making accordingly.

Antiepileptic drug removal by plasmapheresis. In the neurocritical care unit, plasmapheresis (PLEX) is often employed to manage neuroautoimmune diseases. Unlike RRT, which removes the free fraction of a drug, PLEX removes whole plasma which includes both the free fraction of a drug as well as the protein-bound portion. Thus, a key factor in determining the whole body removal of a drug with PLEX is its volume of distribution. Other factors can include the duration/frequency of PLEX and exchange volume, as well as the rate of intercompartmental equilibration. In general, drugs with low volumes of distribution (< 0.2 L/kg) predominantly reside in the vascular compartment and PLEX would be expected to remove a significant portion of the total body stores of these drugs. As for AEDs with high volumes of distribution such as phenytoin, PLEX appears to remove only about 2.5–10% of total body phenytoin.[109,110]

Antiepileptic drug removal by extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation (ECMO) can impact the pharmacokinetics of drugs in a number of ways. ECMO circuits are well known to sequester drugs given the large surface area of the tubing and membranes which can result in an increase in the volume of distribution initially,[111] while later releasing the drug into the circulation resulting in an unpredictable effect.[112] Lipophilic and highly protein-bound drugs are considered to be particularly vulnerable, but other physiochemical factors such as molecular weight, protein binding, and ionization may all play a role.[113] In addition, ECMO is typically associated with reduced drug clearance as a result of alterations of end-organ perfusion. ECMO is also often combined with some form of RRT, further complicating predictability. One case report suggests ECMO has little impact on the disposition of levetiracetam (which has a low volume of distribution and low protein binding).[114] Where available, clinicians should monitor serum levels to guide dosing in patients on AEDs.

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