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• W4226397777 abstract "Critically ill patients requiring catecholamine infusion may require extracorporeal membrane oxygenation (ECMO) support. Initiating ECMO support may affect the circulating catecholamine levels, which directly influences the circulatory support. We measured the timed plasma levels of epinephrine, norepinephrine, and dopamine infused at a constant rate in pigs supported on the ECMO. Plasma levels of catecholamines decreased at 10 minutes after the initiation of ECMO, followed by a return to steady-state concentrations for the next 2 hours. Catecholamines levels in patients initiated on ECMO may follow similar changes. While ECMO provides essential life-sustaining circulatory support, it also introduces critical variables that directly alter the pharmacokinetics through drug distribution,1 drug adsorption,2 and drug elimination.3 Literature supporting the altered drug metabolism in patients supported with ECMO is available for different antibiotics,1 analgesics,4 and sedatives,5 commonly used in critical care units. However, the literature on the effects of ECMO on commonly used inotropes (epinephrine [EPI], dopamine [DOP]) and vasopressors (norepinephrine [NE]) is lacking. We examined the plasma levels of commonly used inotropes and vasopressor medications in pigs supported on the ECMO circuit. After institutional Institution Animal Care and Utilization Committee approval, six 30 kg (body surface area 0.77 m2) juvenile Yorkshire pigs were anesthetized and maintained on a ventilator with inhaled isoflurane. Under sterile technique, intravenous catheters were placed in the external jugular (EJ) and femoral veins, and an arterial line in the carotid artery. All drugs and fluids were given through the EJ vein, while all plasma samples were taken from the femoral vein, to avoid contamination from the infusion site. Pigs underwent median sternotomy, heparinized to achieve an activated clotting time between 175 and 200 seconds, ascending aorta and right atrial appendage were cannulated, with a 16 French wire reinforced arterial cannula and 32 French venous cannula (both Edwards Lifescience, Irvine, CA) for central ECMO. The ECMO circuit was made up of 3/8 inch tubing (Maquet Softline Coating, Hirrlingen, Germany), a Biomedicus BPX-80 pumphead (Medtronic, Minneapolis, MN), and a Maquet Quadrox ID adult oxygenator. In addition, a Maquet reservoir was in line for priming and volume supplementation. The circuit was primed with 400 ml of Plasma-lyte (Baxter International Inc., Deerfield, IL). After collecting pre-ECMO timed blood samples (below), ECMO support was initiated to maintain a flow of 2.2 L/m2 for a 30 kg pig for 2 hours.6 After vascular access was achieved, two baseline plasma samples were collected 15 minutes apart before administering any inotropes. The inotrope/vasopressor medications were prepared and mounted on a syringe pump programmed to set delivery rates as follows: epinephrine 0.05 μg/k/min, norepinephrine 0.05 μg/k/min, and dopamine at 5 μg/k/min. Next, all vasopressors were infused at the specified rates for 15 minutes; then, two more samples were collected at 15 minutes apart representing pre-ECMO drug levels. Timed plasma samples were collected again after initiation of ECMO at 5, 10, 15, 30 minutes, and then every 30 minutes for 2 hours. Catecholamine levels were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) with a lower limit of detection of 0.2 ng/mL for each analyte. The resulting concentrations at each time point were pooled for analysis. Prism 8.4 (Graph Pad) was used for statistical analyses. The median baseline catecholamine levels were 0.69 [0.44–1.23] ng/ml, 0.68 [0.52–0.71] ng/ml for NE, DOP, respectively, and below the limit of detection for EPI. Immediately before initiation of ECMO, the levels were 0.52 [0.34–0.79] ng/ml, 0.54 [0.46–0.71] ng/ml, and 0.09 [0.06–0.22] ng/ml for NE, DOP, and EPI, respectively, (Figure 1). After the initiation of ECMO support, plasma catecholamines numerically increased at 5 minutes but were not statistically different from baseline levels. A reduction in the catecholamine concentrations were observed at the 10 minute time point compared to the levels at 5 minute time point (p = 0.138, p = 0.045, p = 0.029 for NE, DOP, and EPI, respectively). These levels then returned to the baseline concentrations by 15 minutes and were sustained throughout the remaining 2 hours.Figure 1.: Catecholamine concentrations at sampling timepoints.In pigs supported with catecholamine infusions held at a constant rate when initiated on ECMO support showed a transient decrease in circulating catecholamines at 10 minutes followed by a return to steady-state concentrations by 15 minutes. In critically ill patients, maintaining therapeutic levels of inotropes/vasopressors is crucial in providing adequate circulatory support and monitoring the signs of improvement. Extracorporeal membrane oxygenation support is well known to alter drug availability of antibiotics and analgesics1,4; however, literature examining the effect of ECMO on catecholamine levels is sparse. In an ex vivo single-dose close-loop crystalloid-based ECMO circuit, Mehta et al.7 demonstrated a drop of dopamine and epinephrine levels from the baseline by 10% and 16% at 30 minutes after initiation of ECMO and a further decrease of 53% and 23% by 3 hours. When they tested the epinephrine levels in a similar setup, but with blood-based circuit, they only noticed a drop of 7% at 3 hours. These observations are in line with our study findings, where the blood-based circuit did decrease the catecholamine levels transiently but returned to steady-state level in less than an hour. The key factors associated with decreased drug levels on initiation of ECMO are higher lipid solubility, higher protein binding, and use of roller pump with silicone fiber oxygenator.1 Lipid solubility of a drug is standardized with octanol/water partition constant (logP).8 Drugs with higher logP such as fentanyl (4.05) compared to morphine (0.89) loose up 96% of steady-state level in 24 hours when placed on ECMO.9 The logP of epinephrine, norepinephrine, dopamine (−1.37, −1.24, and −0.98) are low. As we might expect based on this chemical property, we did not find a significant drop in drug concentration over the 2 hours of ECMO flow. The majority of current ECMO pumps are centrifugal pumps with hollow-fiber membrane oxygenators, like the one used for this study. These pumps have features known to decrease drug adsorption.1,9 Monitoring catecholamines levels in our swine ECMO model provide a real-life picture of changes in catecholamine levels to be observed in patients placed on ECMO. Because the catecholamine levels remain steady after a brief decrease in levels after initiating the ECMO, sustained hemodynamic support from catecholamine is expected in patients initiated on ECMO. A lack of sustained support as expected from catecholamine infusion is unlikely the result of drug adsorption to the ECMO circuit." @default.
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• W4226397777 date "2021-02-09" @default.
• W4226397777 modified "2023-09-29" @default.
• W4226397777 title "Effect of Extracorporeal Membrane Oxygenation Support on the Plasma Levels of Commonly Utilized Catecholamines" @default.
• W4226397777 doi "https://doi.org/10.1097/mat.0000000000001372" @default.
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