160 C . C . Honeycutt et al .: J Extra Corpor Technol 2023 , 55 , 159 – 166
ECLS can influence pharmacokinetics via three general mechanisms : 1 ) Drug adsorption by circuit components ; 2 ) Drug clearance by the circuit ( e . g ., hemofiltration and dialysis ); and 3 ) Physiological alterations triggered by the circuit and / or underlying critical illness [ 9 – 16 ]. It is therefore important to understand how drugs , such as meropenem , interact with ECLS circuits .
During ECMO , nonspecific drug interactions with multiple circuit components , including the tubing , oxygenator , and hemofilter have been implicated in drug extraction from circulation [ 17 ]. High lipophilicity and high protein binding are associated with greater drug extraction in ex vivo ECMO studies [ 18 , 19 ]. During CRRT , drug clearance by the hemofilter may be impacted by protein binding , volume of distribution , interaction with CRRT circuit components , and molecular weight [ 20 ]. CRRT preferentially removes drugs with low lipophilicity , low protein binding , and low molecular weight [ 21 , 22 ].
Meropenem is a hydrophilic ( logP �0.6 ) small molecule ( 383 Da ) with low protein binding (~ 2 %) and a low volume of distribution [ 17 ]. Based on these physicochemical properties , we hypothesized that meropenem would undergo rapid clearance by CRRT and minimal clearance by ECMO . However , previous studies done with older equipment present inconclusive data concerning meropenem extraction by ECMO and CRRT [ 23 – 32 ]. To address the incomplete understanding of how ECMO and CRRT impact the pharmacokinetics of meropenem , we designed a study to investigate meropenem extraction from ex vivo ECMO and CRRT circuits .
Materials and methods Circuit configurations
To determine the contribution of each ECMO circuit component to drug extraction , three different ECMO circuit configurations were used ( Figures 1A – 1C ). The ECMO Complete circuit included a 10-fr Bio-Medicus arterial cannula ( Medtronic , Dublin , Ireland ), 3 / 8-inch phosphorylcholine-coated polyvinyl chloride ( PVC ) Smart Tubing ( Sorin , Saluggia , Italy ), a Revolution centrifugal pump ( Sorin ), a DHF0.2 hemofilter ( Sorin ), and a Quadrox iD polymethylpentene adult oxygenator ( Getinge , Gothenburg , Sweden ) ( Figure 1A ). The ECMO Oxygenator circuit was identical , except that it lacked a hemofilter ( Figure 1B ). The ECMO Pump circuit lacked both a hemofilter and an oxygenator ( Figure 1C ).
CRRT circuits ran on a PRISMAX System ( Baxter Healthcare ) with a TherMax heater ( Baxter Healthcare , Deerfield , IL ) and HF1000 filter set ( Baxter Healthcare , Deerfield , IL ) connected via a 500 ml EXACTAMIX EVA bag ( Baxter Healthcare , Deerfield , IL ).
ECMO circuit configurations were run in triplicate and the CRRT circuit configuration was run in quadruplicate . One of four CRRT circuits failed following sampling at the 2-hour time point . Thus , CRRT circuit data includes three replicates with sampling out to four hours and one replicate with sampling outto2h .
Extracorporeal membrane oxygenation circuit setup
ECMO circuits ( Figures 1A – 1C ) were assembled according to standard clinical practice . The circuits were primed with a blood , plasma , and electrolyte mixture . The blood prime for the Complete and Oxygenator circuits consisted of 1 unit of packed human red blood cells ( adenine saline added leukocytes reduced [~ 350 mL ]), 0.5 units of human fresh human frozen plasma (~ 175 mL ), and Plasma-Lyte A crystalloid ( Baxter Healthcare , Deerfield , IL ) ( 500 mL ). In order to minimize the impact on clinical blood supply , we used recently expired blood products donated by the American Red Cross . Heparin sodium ( 500 units , 0.5 mL ), sodium bicarbonate ( 7 mEq , 7 mL ), tromethamine ( 2 g , 25 mL ), calcium gluconate ( 650 mg , 6.5 mL ), and albumin ( 12.5 g , 50 mL ) were added to prevent coagulation and to mimic physiological conditions . In Pump circuits , all prime solution components added were scaled down to 2 / 3 of what was used in other circuit configurations because the oxygenator itself holds ~ 1 / 3 of the prime solution volume .
ECMO circuits were completed with a double-spiked intravenous bag , which had adequate volume to prevent air from entering . The flow was set to 1 L / min and measured postoxygenator with an ultrasonic flowmeter ( Sorin ). In the Complete and Oxygenator circuits , a constant temperature of 37 ° C was maintained with a Cincinnati Sub-Zero Hemotherm ( Terumo Cardiovascular , Ann Arbor , MI ). In the Pump circuit , a constant temperature of 37 ° C was maintained via heating pads wrapped around the reservoir and tubing . Temperature and pH were monitored in real-time using a CDI Blood Parameter Monitoring System ( Terumo Cardiovascular ). Physiological pH ( 7.2 – 7.5 ) was maintained by the administration of sodium bicarbonate via the drug administration port and / or carbon dioxide via the sweep gas .
Continuous renal replacement therapy circuit setup
CRRT circuits ( Figure 1D ) were assembled according to the manufacturer ’ s instructions for the HF1000 filter set . Circuits were primed with a solution of 1 unit of human red blood cells ( adenine saline added leukocytes reduced [~ 300 mL ]), ~ 0.4 units of human fresh human frozen plasma ( 125 mL ), heparin sodium ( 350 units ), sodium bicarbonate ( 7 mEq ), tromethamine ( 1.5 g ), calcium gluconate ( 180 mg ), and human serum albumin ( 6.25 g ). Blood was maintained at 37 ° C by the TherMax blood warmer . Physiological pH ( 7.2 – 7.5 ) of circuit blood was tested each hour with an i-STAT 1 Analyzer ( Flextronics Manufacturing , Singapore ) and EG6 + cartridge ( Abbott , Abbott Park , IL ) and was maintained with tromethamine .
For pre-blood pump , dialysis , and replacement fluids , PrismaSATE 4 / 2.5 Dialysis Solution ( Baxter Healthcare , Deerfield , IL ) was used . CRRT circuits were run in continuous venovenous hemodiafiltration ( CVVHDF ) mode with the following specifications : blood flow rate ( Q B ) of 150 mL / min , dialysis fluid flow rate ( Q D ) of 1000 mL / h , pre-blood pump fluid flow rate of 700 mL / h , replacement fluid flow rate ( Q R ) of 300 mL / h delivered after filtration , and patient fluid removal