SEARCH

SEARCH BY CITATION

Keywords:

  • Albumin dialysis;
  • Phenytoin;
  • Oxidative stress

Abstract

  1. Top of page
  2. Abstract
  3. PATIENT AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary:  Purpose: Toxicity is common in patients of epilepsy treated with phenytoin (PHT), requiring careful drug level monitoring and supportive care. Specific treatment options are limited, although charcoal haemofiltration has been used previously. We attempted to demonstrate that severe PHT toxicity can be treated successfully with the Molecular Adsorbents Recirculating System (MARS). The mechanism of drug removal by the system also was studied.

Methods: A 45-year-old patient of status epilepticus with acute renal failure and severe PHT toxicity, associated with cardiac arrhythmias, hepatotoxicity, and altered sensorium, was treated with the MARS, a blood-purification system based on albumin dialysis, and including a charcoal filter, for 11.5 h. Serum PHT levels and blood levels of oxygen-based free radicals (by electron paramagnetic resonance spectroscopy) were measured before and after treatment.

Results: Serum total and free PHT levels declined sharply (32 to 11 μM and 9.8 to 2.0 μM, respectively), with clinical improvement and a 65% reduction in measured oxidative stress. The mechanism of drug removal, deduced by measuring PHT in the dialysate collected from different segments of the MARS circuit, was by clearance from blood into the albumin dialysate, and ultimately removal by the charcoal filter.

Conclusions: The observed removal of PHT by MARS, along with the clinical improvement of the patient and reduction of the associated oxidative stress after treatment, indicates that MARS offers a promising option in PHT toxicity.

Phenytoin (PHT) is one of the most commonly used antiepileptic drugs (AEDs). However, it has a narrow therapeutic range, and a total serum level >80 μM is associated with clinically relevant toxicity in many patients. Usually it is metabolised by hepatic enzymes and excreted via the kidneys, but the hepatic enzymes are readily saturated, and, in the presence of renal failure, toxic accumulation of PHT can occur (1). However, as it is 90% albumin bound, it is not removed by haemodialysis (2), although studies have suggested that uraemic toxins may increase free drug levels by displacing PHT from albumin (3); haemodialysis using a high-flux cellulose membrane, by removing these toxins, can actually reduce free PHT levels (4). Treatment involving multiple oral dosing with activated charcoal is usually used, and in severe cases, charcoal haemoperfusion has been used with some success (5). However, haemoperfusion is not easily available in many parts of the world. Therefore a system that could remove PHT from the patient's blood and is safe and relatively easily available would be invaluable. We describe the use of the Molecular Adsorbents Recirculating System (MARS), a blood-purification system based on the principle of albumin dialysis, as such a system.

PATIENT AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENT AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A 45-year-old man with status epilepticus was admitted in the Intensive Therapy Unit of the University College London Hospitals, London, in January 2001. He received high doses of intravenous PHT, and concomitantly developed rhabdomyolysis, leading to acute renal failure. This contributed to drug accumulation (serum PHT: total, 79 μM; free, 17.6 μM; with a plasma albumin level of 27 g/L). Subsequently PHT was replaced by phenobarbitone (PB), and despite continuous veno-venous haemofiltration (CVVHF) for anuria (haemodialysis not being feasible because of haemodynamic instability), the PHT level reduced very slowly to 40 μM (total) over the following 8 days in spite of receiving enteral activated charcoal treatment. He remained unconscious even after discontinuation of sedation. Hepatic enzymes increased (alanine aminotransferase, 367 IU/L; alkaline phosphatase, 1,493 IU/L), indicating hepatic toxicity, and tachyarrhythmias developed (with episodic ventricular tachycardia) interspersed with bradyarrhythmias, requiring temporary cardiac pacing. No cause, other than PHT toxicity, could be recognized to explain the hepatic toxicity or the arrhythmias.

MARS treatment

After informed consent from next-of-kin, he was treated with MARS (Teraklin AG, Rostock, Germany), a blood-purification system that has been used as an extracorporeal liver-support device. It uses a hollow-fibre module to remove albumin-bound toxins based on the principle of albumin dialysis. Activated charcoal and anion-exchange resin are used to cleanse the albumin, enabling it to recirculate. It is used in conjunction with haemodialysis/haemofiltration to remove water-soluble toxins (6). In this case, it was used concomitant with haemofiltration (Hospal BSM 22c, France). Figure 1 gives a schematic diagram of the MARS circuit.

image

Figure 1. Scheme of the MARS system showing the direction of flow and the total (and free) phenytoin levels (μM) at varying time points in the samples collected from the ports during treatment, in addition to the total (free) phenytoin levels in the patients serum before and during MARS treatment.

Download figure to PowerPoint

Laboratory measurements

In addition to the routine clinical investigations, total and free PHT levels were measured in the patient's serum and in the albumin dialysate by fluorescence polarization immunoassay (FPIA) and ultrafiltration. Samples were collected from the four segments of the MARS circuit (see Fig. 1) just before, during (at 1.5 h and 3 h), and at the end of the MARS treatment session.

Blood levels of oxygen-based free radicals were measured by using a spin trap (α-phenyl-tert-butylnitrone; Sigma, Poole, Dorset) immediately added to venous blood collected before and after MARS treatment, extracted into toluene, and measured by using electron paramagnetic resonance (EPR) spectroscopy (Bruker EMX, Karlsruhe, Germany).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENT AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

MARS treatment was performed over a single session, which lasted for 11.5 h. During treatment, both the total and free serum PHT levels decreased linearly and rapidly (from 32 to 11μM and 9.8 to 2.0 μM, respectively; correlation coefficients r2 = 0.9932 and 0.9403; Fig. 1). The next day the patient regained consciousness. Electrocardiogram normalized over a further 24 h, and hepatic enzymes gradually decreased over the following 5 days, after which he was successfully discharged from the intensive care unit.

Analysis of the albumin dialysate showed an increase in levels of PHT, clearly indicating its removal from the blood. The measured total PHT apparently increased across the haemofiltration component, ports 1 and 2, probably reflecting the removal of water. There was a consistent, significant reduction in both the total and free PHT across the charcoal column (ports 2 and 3), indicating that this was the main site of removal of the drug from the albumin. As would be anticipated, no significant difference was observed across the anion-exchange column (ports 3 and 4), indicating that this does not contribute to PHT removal.

Along with effective removal of PHT, measured oxidative stress decreased as well. EPR spectroscopy showed a decrease in the amount of oxygen-based free radical production in the blood of 65% over the MARS treatment period (Fig. 2).

image

Figure 2. EPR spectra showing the α-phenyl-tert-butylnitrone spin-trap signal extracted into toluene from the blood samples collected immediately before and after MARS treatment. A 65% decrease in signal, representative of free radical production, is observed between samples. Measurement conditions: temperature, 22°C; microwave frequency, 9.470 GHz; microwave power, 12.66 mW; time constant, 40.96 ms; and modulation amplitude, 8G.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENT AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The patient described in this report had a very high free serum PHT level, which was definitely in the toxic range (>8 μM) (7), compared with only a moderately high total drug level. This can be attributed to this patient's low plasma albumin level (27 g/L), which is a known factor causing such discrepancies between the two (8). The high free PHT level can be considered particularly significant, as this is regarded to be more reliable as a marker for drug-toxicity monitoring (9). The presence of PHT in the albumin dialysate clearly indicated its removal from the blood. However, it must be emphasised that PHT levels in the MARS “closed” circuit cannot be directly compared with plasma levels, which relate to body volume. As the concentration of albumin in the circuit (200 g/L) is considerably higher than that in the patient's blood (27 g/L in this case), there is substantially increased binding capability, which facilitates the removal of albumin-bound substances from the blood. There was a consistent, significant reduction of PHT levels across the charcoal column, indicating that this was the main site of removal of the drug from the albumin. The concentration gradient was not large, and only a small amount of the drug would be removed during each circulation of the dialysate. However, after ∼170 circulations in 11.5 h (600 ml dialysate flowing at 150 ml/min), a substantial amount of PHT would be removed. This would account for the sharp reduction of serum drug levels. The role of charcoal can be explained by the fact that bound PHT has been found to dissociate from albumin in the presence of activated charcoal and subsequently becomes adsorbed to the activated charcoal (5).

Along with effective removal of PHT, blood levels of oxygen-based free radicals decreased as well. Free radical production in the vasculature by PHT has been shown previously (10), and its removal by MARS would explain the observed reduction in oxidative stress and may in part explain the patient's clinical improvement. Direct removal of free radicals by MARS itself may also be a contributing factor.

PHT-associated toxicity is a significant clinical problem, with 4,021 cases being reported in 2000 in the United States, of whom 138 had major adverse effects with two deaths (11). Most severe toxicities occur in association with hepatic and renal compromise (1), in which therapeutic options are particularly limited (5). The treatment with MARS not only removes PHT from the blood, but also reduces oxidative stress and most important, brings about a rapid clinical improvement. Moreover, our study suggests that MARS might have applications in the treatment of other albumin-bound drug toxicities.

Acknowledgment: We thank the medical and nursing staff of the Intensive Care Unit at the University College London Hospitals for the help and support with the MARS treatment.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENT AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Chua HC, Venketasubramanian N, Tjia H, et al. Elimination of phenytoin in toxic overdose. Clin Neurol Neurosurg 2000;102: 68.
  • 2
    Martin E, Gambertoglio JG, Adler DS, et al. Removal of phenytoin by hemodialysis in uremic patients. JAMA 1977;238: 17503.
  • 3
    Dasgupta A, Abu-Alfa A. Increased free phenytoin concentrations in predialysis serum compared to postdialysis serum in patients with uremia treated with hemodialysis: role of uremic compounds. Am J Clin Pathol 1992;98: 1925.
  • 4
    Frenchie D, Bastani B. Significant removal of phenytoin during high flux dialysis with cellulose triacetate dialyzer. Nephrol Dial Transplant 1998;13: 8178.
  • 5
    Kawasaki C, Nishi R, Uekihara S, et al. Charcoal hemoperfusion in the treatment of phenytoin overdose. Am J Kidney Dis 2000;35: 3236.
  • 6
    Stange J, Mitzner SR, Risler T, Erley A, et al. Molecular adsorbent recycling system (MARS): clinical results of a new membrane-based blood purification system for bioartificial liver support. Artif Organs 1999;23: 31930.
  • 7
    Winkler SR, Luer MS. Antiepileptic drug review: part 1. Surg Neurol 1998;49: 44952.
  • 8
    Lindow J, Wijdicks EF. Phenytoin toxicity associated with hypoalbuminemia in critically ill patients. Chest 1994;105: 6024.
  • 9
    Burt M, Anderson DC, Kloss J, et al. Evidence-based implementation of free phenytoin therapeutic drug monitoring. Clin Chem 2000;46: 11325.
  • 10
    Liu CS, Wu HM, Kao SH, et al. Phenytoin-mediated oxidative stress in serum of female epileptics: a possible pathogenesis in the fetal hydantoin syndrome. Hum Exp Toxicol 1997;16: 17781.
  • 11
    Litovitz TL, Klein-Schwartz W, White S, et al. 2000 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001;19: 33795.