Acute kidney injury in ECMO patients

It is possible to provide RRT by incorporating a hemofilter into the ECMO circuit [9, 15, 31] (Fig. 1a). The hemofilter is placed after the pump pre-oxygenator so that the oxygenator can trap air and clots. The positive pressure from the ECMO circuit will forward the blood flow through the hemofilter. Then, blood is returned from the filter to the ECMO circuit before the pump. The blood flow rate in the hemofilter is the difference between the total ECMO blood flow rate and the actual flow delivered to the patient, which is measured by placing an ultrasonic probe on the arterial return line from the ECMO circuit. This technique is mainly used for ultrafiltration via the SCUF mode. CVVH or CVVHD can be delivered by adding replacement fluid (CVVH) or dialysis fluid (CVVHD) through standard infusion pumps. Ultrafiltration rate is regulated by connecting a standard infusion device to the effluent port of the hemofilter. However, the amount of removed fluid is less accurate and prone to error up to 800 ml/day [34]. A more precise method is to weigh the actual volume of ultrafiltration using a scale or a volumetric measuring device but this method is labor-intensive. Since hemofilters are not designed for use with high pressure systems and the maximal volume of the infusion pump is limited at 1 l/h, convective and diffusive clearance are less effective than with CRRT using conventional membranes. The hemofilter blood flow rate can be adjusted via a stopcock or a flow-restrictor. Nevertheless, the generated turbulent flow might cause hemolysis and trigger thrombus formation. Most importantly, there is no pressure monitoring with this technique, which may lead to delayed detection of hemolysis, filter rupture or clot formation.

Setting up an independent RRT device is simple as it does not require ECMO circuit manipulation (Fig. 1b). Dose and modality can be adjusted, and fluid balance can be controlled in a precise manner as per usual protocol. Regional anticoagulation can also be added and optimised to prolong filter longevity. However, the need to insert a separate vascular access whilst systemically anticoagulated poses a risk for line-related mechanical and infectious complications. This technique also requires an additional extracorporeal blood volume, which might interfere with ECMO performance [9, 15, 31].

There are several ways to incorporate a RRT device into the ECMO circuit using two high-flow Luer lock three-way taps as connectors to the RRT access (inlet) line and return (outlet) line [9, 31, 33, 35] (Fig. 1c–f). The pressure before the ECMO pump is negative (range: − 20 to − 100 mmHg) and post-pump is positive (range: + 150 to + 350 mmHg), which might interfere with the RRT circuit. If a centrifugal pump is used, the RRT access line should be placed post-pump (either before or after the oxygenator) to avoid air entrapment (Fig. 1d, e). The RRT return line should be connected before the oxygenator (either pre- or post-pump) to avoid air embolism, clot formation and venous admixture. Careful attention should be paid to the inherently set pressure limits of the ECMO circuit and RRT devices from different manufacturers. The default access pressure of the RRT machine is typically negative. High post-pump pressure may trigger pressure alarms at the entry point of the RRT machine although current RRT machines can tolerate higher pressures or allow adjustment of alarm settings up to + 350 to + 500 mmHg. To overcome the alarm limits of the RRT machine, a long monitoring extension line attached to the RRT access tubing or reducing the blood flow rates can help to lower the pressure from the ECMO circuit [8]. Another option is to use clamps on the connectors or flow restrictors placed outside the tubing to adjust the RRT circuit pressure on the access or, alternatively, on the return line to avoid extreme pressures [36]. However, this may cause turbulence in blood flow and trigger hemolysis or thrombosis. When withdrawing blood post-oxygenator and returning blood before pump, re-circulation in the RRT circuit (shunt within a shunt) and RRT underdosing may occur. Alternatively, the access and return lines may be safely connected through Luer locks immediately before and after the oxygenator to avoid pressure alarms (Fig. 1f).

Combining RRT into the ECMO circuit has several benefits. No additional vascular access is needed and complications related to line insertion are avoided. This method is more effective than using an in-line hemofilter and provides more precise ultrafiltration control and solute clearance by any modality of choice. Use of the heater on the CRRT device is optional. There is also no need for routine additional anticoagulation. However, every connection and disconnection requires support from an ECMO specialist/perfusionist and might pose a risk of air embolism/clot to both devices.

There are few studies comparing the efficacy between the different techniques. Compared with an in-line hemofilter technique, integrating a RRT machine into the ECMO circuit was shown to provide more accurate fluid management [37]. A recent study concluded that independent RRT access was associated with fewer effective sessions and shorter filter lives in comparison with the integrated system [38]. However, the average prescribed RRT dose was 40 ml/kg/h, which is higher than currently recommended. In addition, the CVVH modality was used with 33% of replacement fluid given pre-filter, which might result in a relatively high filtration fraction. Regional citrate anticoagulation was not used [39]. Another study also reported longer filter life for the integrated system compared with the parallel technique [35]. With regards to clearance, a recent study demonstrated similar efficacy for solute clearance and ultrafiltration between the parallel and the integrated methods [40].

Although raised cytokine concentrations have been demonstrated in patients with AKI receiving ECMO and might be implicated in multiorgan dysfunction [41], there is insufficient evidence to recommend blood purification therapy outside the setting of AKI for patients receiving ECMO. Therefore, the use of RRT and/or hemoadsorption with the sole intention of clearing pro- or anti-inflammatory mediators during ECMO is not recommended [9].

Systemic infusion of unfractionated heparin is the standard anticoagulation in patients receiving RRT and ECMO unless contraindicated. However, significant clotting or excessive bleeding precluding the use of systemic heparin may require the addition of regional citrate anticoagulation to ensure effective RRT delivery [42]. Nevertheless, significant citrate dilution might occur. If the RRT access line is connected from the post-oxygenator limb and the return line is connected to the pre-oxygenator limb, infused citrate will be partially delivered and mixed with pre-oxygenator blood. This may reduce clotting in the oxygenator. Calcium should be infused via a separate central venous access to reduce clotting in the system.

ECMO and RRT can significantly alter the pharmacokinetics of medications such as antibiotics and sedatives, yet little is known about the optimal regimen for patients treated with both RRT and ECMO. Generally, ECMO increases the volume of distribution and reduces drug clearance. The ECMO circuit might act as a reservoir and redistribute the sequestered drug back into the patient leading to prolonged effects, especially of lipophilic medications with a large volume of distribution (e.g., voriconazole, propofol, fentanyl, midazolam) [8]. In contrast, the ECMO membrane and tubing may adsorb some drugs and reduce plasma concentrations. The presence of RRT increases the risk of both under- and over-dosing further. A preliminary analysis showed that standard dosing of meropenem (1 g 8-hourly) is likely to maintain sufficient trough concentrations (> 2 mg/l) to treat highly susceptible gram-negative pathogens but might be inadequate for higher trough targets [43]. Individualizing drug regimens in patients receiving concomitant ECMO and RRT using therapeutic drug monitoring is suggested where possible until more pharmacokinetic data become available.