104 A . Chevalier et al .: J Extra Corpor Technol 2024 , 56 , 101 – 107
Dialysis |
clearance |
was |
determined |
by |
the |
following |
equation : |
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|
|
|
|
|
Cl ¼ Q eff S a
where Cl is the clearance via dialysis , Q eff is the total effluent flow , and S a is the saturation coefficient .
Statistics Statistical analysis was performed using the statistical software R , with the addition of the Tidyverse , Ggpubr , and Rstatix packages [ 24 – 26 ]. A two-sample t-test with an alpha level of 0.05 was used to compare the plasma percent recovery between the circuits and the control samples after the experiment .
Results Ketamine ECMO circuits
Ketamine concentrations decreased rapidly in the ECMO circuits ( Figure 2 ). The mean recovery of ketamine from ECMO circuits was 43.8 % ( n = 3 , SD = 0.6 %) after 8 h . In contrast , ketamine levels remained relatively constant over time in the control sample with 100 % ( n = 3 , SD = 4 %) recovery after 8 h , a difference that reached statistical significance ( p < 0.001 ).
Ketamine and dexmedetomidine CRRT circuits
Similar to the ECMO circuits , ketamine was rapidly cleared from CRRT circuits ( Figure 3A ) with a mean recovery of 3.3 % ( n = 3 , SD = 0.5 %) after 6 h . Percent recovery of ketamine was significantly different from the control samples ( p < 0.001 ). Ketamine concentrations in hemofiltrate were similar to those in plasma ( Figure 3B ) with a mean saturation coefficient of 0.72 ( SD = 0.06 ), corresponding to a transmembrane clearance of 9.6 ml / min at an effluent rate of 800 ml / h in our experiment .
Compared to ketamine , dexmedetomidine was more slowly cleared from CRRT circuits ( Figure 4A ) with a mean recovery of 20.3 % ( n = 3 , SD = 1.8 %) after 6 h . In contrast , the previously reported data for dexmedetomidine control experiments revealed a mean recovery of 99 % ( n = 9 , SD = 26 %) at 4 h [ 15 ]. The average saturation coefficient was 0.18 ( SD = 0.01 ), corresponding to a transmembrane clearance of 2.4 ml / min at the effluent flow rate used in our experiments ( Figure 4B ).
Discussion
These experiments demonstrated significant interactions between ECLS circuits and two common sedatives , ketamine and dexmedetomidine .
Ketamine recovery from ECMO circuits was significantly lower than control samples . ECMO circuit extraction was likely related to the adsorption of ketamine to circuit components , including the oxygenator , pump , and tubing . This degree of circuit interaction confirms our hypothesis that ketamine ’ srelative lipid solubility ( logP = 3.12 ) [ 27 ] leads to significant circuit
Figure 2 . The percent recovery of ketamine from control ( red ) and ex-vivo ECMO circuits ( blue ) over time . Error bars represent one standard deviation n = 3 control and n = 3 experimental circuits .
adsorption and suggests the need for dosing adjustments of ketamine for patients on ECMO . These findings differ somewhat from prior literature [ 11 , 12 , 28 – 30 ]. One case report found a higher volume of distribution and clearance for ketamine in an adult patient supported by ECMO compared to healthy patients [ 29 ]. However , these pharmacokinetic parameters were similar to those reported in critically ill patients not on ECMO [ 29 ]. A second case report of an adult patient on ECMO observed target sedation levels after standard doses of a ketamine infusion , although goal sedation occurred at lower ketamine concentrations than standard [ 30 ]. Importantly , these reports cannot distinguish the degree to which differences in ketamine exposure and / or response result from the ECMO circuit itself or the underlying critical illness of the patient . While these reports could suggest that ketamine dosing adjustments are not required , additional research is required to reveal the extent to which ketamine dosing should be adjusted in patients on ECMO .
Ketamine recovery from CRRT circuits declined rapidly . Some of the ketamine extraction was presumably related to clearance across the dialysis membrane , with a relatively high saturation coefficient of 0.72 . This degree of ketamine filtration is the result of ketamine ’ s moderate degree of protein binding ( 54 %) [ 27 ], with almost half of the medication unbound and available for filtration . Prior studies of ketamine pharmacokinetics in CRRT are limited to a single identified case series [ 31 ]. This study revealed similar in-vivo transmembrane clearance and saturation coefficients across dialysis filters as noted in our study but did not report on the degree of circuit absorption . The rapid alterations in ketamine levels observed in our experiments would suggest that alterations in dosing are needed .
Dexmedetomidine concentrations were significantly altered by the CRRT circuit , albeit at a slower rate than ketamine . Clearance across the dialysis membrane was minimal , with