Discussion
To our knowledge, this is the first research to investigate the effect
of TPE on CFP and SUL pharmacokinetics in critically ill TTP patients.
The TPE specific properties and pharmacokinetic characteristics of the
drug are two key factors determining drug elimination during TPE. The
time between the drug infusion and TPE initiation are two factors that
affect the amount of drug extracted from TPE. Researches have shown that
the closer the time between drug infusion and TPE initiation, the
greater the amount of drug removed by TPE [10]. In our presented
four cases, TPE was initiated 10 min after intravenous infusion, at
which point the majority of drugs would
be primarily present in the
intravascular space, and could therefore be removed by TPE [4,16].
Besides, volume of exchange is another significant TPE specific
parameter driving the amounts of drug be removed by TPE. The
treatment target for a plasma exchange procedure should be 1 to
1.5
PV, equivalent to a removal of
approximately 63% and 78% of plasma contents respectively [17].
An increase in volume of exchange
can increase a greater amount of drug extracted. In this study, the
average volume of exchange is approximately 1970±36.74 mL, corresponding
to nearly one PV.
The pharmacokinetic properties of Vd and Pb are considered to be the
most dominant factors determining whether a drug is susceptible to
removal by TPE. Low Pb and high Vd always correlate with drug’s
distribution in tissues and cells and therefore are unsusceptible to
removal by TPE. In contrast, drug with small Vd (<0.2 L
kg-1) and high Pb (>80%) are more easier to be
removed during TPE due to the greater distribution of the drug in the
vascular space [12,17]. In our study, we found that approximately
2000 mL exchange yielded a higher KelTotal than the
Kelpatient without TPE , suggesting that TPE lead to
increases in the rate of CFP and SUL elimination. QPEand fe % seems to be the most reliable parameters for the
determination of the amount of drug removed via TPE. The fraction
eliminated by TPE (fe %) was significant for CFP as 11.38±3.18%
(range 8.43~16.75%). SUL is eliminated by TPE with only
2.74±1.13% (range 1.35~4.28%) from effluent port of
depleted plasma. The fe % of CFP is over 4-fold higher than that
of SUL. The calculated smaller Vd (0.14±0.03 L kg-1for CFP vs. 0.48±0.15 L kg-1 for SUL) and higher Pb
(70-93% for CFP vs. 38% for SUL, obtained from non-critically ill
patients) may contribute to the remarkable increased fraction eliminated
by TPE. In addition, it was suggested that a 30% increase in
%CLPE could be considered a clinically significant
effect [13]. %CLPE of CFP and SUL were about 27%
and 6%, respectively. It is suggest that CFP is more likely to be
removed than SUL during TPE. However, CFP and SUL removal by TPE may not
be clinically significant.
There were only slight differences in parameters between session I and
session II in those four patients(Table 3) . Unexpectedly, AUC0-8 and Vd of CFP
on session I were slightly increased than those on session II, contrary
to our expectations. There are many aspects needed to be considered.
First, it seems that TPE did not alter the pharmacokinetic behavior of
CFP and SUL significantly. Then, the relatively elevated peak
concentration at session I might due to pharmacokinetic instability
might increase the AUC0-8. Finally, the number of
patients included in our trial is limited and two of four critically ill
patients with severe infection or septic shock received aggressive fluid
resuscitation. Overhydrating status may lead to pharmacokinetics
changes, such as AUC and Vd [18].
Additionally, TTP is considered as a life-threatening critical illness
and often associated with severe complications such as hypoalbuminemia
and multiple organ dysfunction (MOF). Hypoalbuminemia might cause
decreased drugs binding resulting in less distribution of drugs in the
vascular space, in favor of tissue distribution, especially for CFP with
a larger Pb [19]. Besides, positive correlation was observed between
QPE and plasma drug concentration before TPE, however it
failed to reach statistical significance. SUL is mainly excreted by
kidney (84%) while most of CFP is excreted via bile. Organ dysfunction
is an important factor leading to elevated plasma drug concentration. In
our cohort, the largest amount of CFP removed (645 mg) was noted in the
patient with impaired bile excretion (TBIL 71.9 µmol
L-1, DBIL 31.5 µmol L-1). Similarly,
the largest amount of SUL (51 mg) removed in the patient with impaired
renal function (Ccr 36 mL min-1, serum creatinine 156
μmol L-1). It is suggested that elevated plasma drug
concentration and extended half-life due to organ dysfunction allow more
drug removal by TPE. It is more remarkable when drug distribution
half-life (T1/2a) is longer than 2 hours of the TPE
procedure duration [20]. In our
cohort, T1/2a of CFP
and SUL showed a prolongation compared with previous parameters in
noncritically ill patients
(~1.7 h for CFP and
~1 h for SUL).
T1/2a of CFP is longer than 2 hours, which is one of the
reasons why its fe % is
higher than that of SUL.
The pharmacokinetics of CFP/SUL vary widely among critically ill
patients. Therefore, it would be worthwhile to carry out further studies
to confirm these results.