key: cord-1001505-dugdvahf authors: Selewski, David T.; Wille, Keith M. title: Continuous renal replacement therapy in patients treated with extracorporeal membrane oxygenation date: 2021-03-25 journal: Semin Dial DOI: 10.1111/sdi.12965 sha: 7535cdb755dcc94bc083526e01265f23074f96a3 doc_id: 1001505 cord_uid: dugdvahf Extracorporeal membrane oxygenation (ECMO) is a life‐saving therapy utilized for patients with severe life‐threatening cardiorespiratory failure. Patients treated with ECMO are among the most severely ill encountered in critical care and are at high‐risk of developing multiple organ dysfunction, including acute kidney injury (AKI) and fluid overload. Continuous renal replacement therapy (CRRT) is increasingly utilized inpatients on ECMO to manage AKI and treat fluid overload. The indications for renal replacement therapy for patients on ECMO are similar to those of other critically ill populations; however, there is wide practice variation in how renal supportive therapies are utilized during ECMO. For patients requiring both CRRT and ECMO, CRRT may be connected directly to the ECMO circuit, or CRRT and ECMO may be performed independently. This review will summarize current knowledge of the epidemiology of AKI, indications and timing of CRRT, delivery of CRRT, and the outcomes of patients requiring CRRT with ECMO. Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy utilized for patients of all ages with severe life-threatening cardiopulmonary failure. 1 The indications for ECMO include reversible conditions with a high predicted mortality of ≥80%. Although ECMO was originally developed as a rescue therapy for neonates with respiratory failure, in recent years the number of adults placed on ECMO has surpassed the number of pediatric and neonatal patients combined. [1] [2] [3] Patients treated with ECMO represent the sickest patients encountered in critical care and are at highrisk of developing multiple organ dysfunction and associated sequelae, including acute kidney injury (AKI) and fluid overload (FO). utilized in patients on ECMO to manage AKI, prevent and treat FO. This review will summarize our current understanding of the epidemiology and impact of AKI, indications and timing for CRRT, delivery of CRRT, and the outcomes associated with CRRT for patients on ECMO. The pathophysiology and high incidence of AKI in those on ECMO is multifactorial in nature with significant contributions from the underlying disease and additional factors inherent to ECMO. Individuals being placed on ECMO are among the highest risk patients to develop AKI prior to cannulation related to their severity of illness as well as the etiology and treatment of their primary disease (respiratory failure, cardiac failure, hypotension requiring vasopressor support, cardiac arrest, ischemia, nephrotoxic exposures). 4, 5 There are a multitude of pathophysiologic mechanisms inherent to ECMO that potentially contribute to the exacerbation of existing and/ or development of new AKI. The hemodynamic changes around the time of ECMO cannulation can impact renal blood flow resulting in ischemic/ reperfusion injury. 6, 7 Additional variables associated with ECMO that can predispose to AKI include systemic inflammation, 8, 9 hemolysis, 10,11 microcirculatory dysfunction, and platelet/ coagulation abnormalities. 12, 13 DOI: 10.1111/sdi.12965 Acute kidney injury has been shown to occur commonly in patients of all ages treated with ECMO (Table 1) . AKI occurs commonly across all populations treated with ECMO with incidence ranging from 42% to 85%. [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] The existing data show clearly that a significant amount of AKI is present at the time of ECMO cannulation and the majority develops within 48 h of ECMO initiation. 15, 16, 18, 19, 22 The data evaluating outcomes associated with AKI consistently shows that the highest stage of AKI is associated with increased morbidity and mortality across populations. The small size, low power and single center nature of these studies likely explains the inconsistent association with low stages of AKI with outcomes. The only multicenter study to date has been performed by the KIDMO study group and clearly shows that AKI of any stage is associated with increased morbidity (increase length of ECMO in those with AKI, 149 vs 121 h) and mortality (adjusted odds ratio, 1.52; 1.04-2.21) in a cohort 832 pediatric and neonatal patients from six centers. 16 Further multicenter collaborative work is needed to understand the problem across medicine. The indications for renal replacement therapy for patients on ECMO are similar to those of other critically ill populations and include: acidosis, electrolyte abnormalities, intoxications, FO, and uremia. 4, 5 In 2010, the Kidney Interventions During Membrane Oxygenation (KIDMO) study group surveyed 65 participating Extracorporeal Life Support Organization (ELSO) centers and showed that the most common indications for initiating CRRT on ECMO were: FO (43%), FO prevention (16%), and AKI (35%). 24 In 2020, the KIDMO study group performed a similar survey focused on pediatric and neonatal centers and showed the treatment and/ or prevention of FO was the primary indication for CRRT on ECMO in 85% of centers (in press ASAIO). These data highlight the importance of FO in decision making surrounding the initiation of CRRT on ECMO. An in-line hemofilter or CRRT circuit may be integrated into the ECMO circuit. The inlet limb (access port) of a hemofilter can be connected after the blood pump, and the outlet limb (return port) is typically connected prior to the membrane oxygenator ( Figure 1 ). This approach is less costly compared to CRRT, but disadvantages include a lack of pressure alarms and poor control of net ultrafiltration. A stopcock or similar instrument to restrict blood flow can be added but may increase the risk of thrombosis or hemolysis. SCUF is typically the most common modality used for RRT with a hemofilter, the blood flow through which is driven by the ECMO pump. and to improve acidosis in hypercapnic respiratory failure. There are several ways that a CRRT circuit can be combined Nineteen studies were identified that described the methods for performing CRRT with ECMO: independent CRRT access, placement of a hemofiltration filter into the ECMO circuit, and placement of a CRRT device into the ECMO circuit. For ECMO survivors receiving CRRT, overall fluid balance was less than that in non-CRRT survivors. They identified a higher mortality (OR 5.89; 95% CI 4.38-7.92; p < 0.0001) and longer ECMO duration when CRRT was added to ECMO but concluded that the two modalities could be combined and performed together in a safe manner. Their aim was to assess outcomes and complications according to the duration of CRRT received: ≤3 days, 4-6 days, and ≥7 days. French ICUs and identified factors independently associated with death by 6 months post-ICU discharge: age, body mass index, immunocompromised status, prone positioning, days of mechanical ventilation, sepsis-related organ failure assessment, plateau pressure, and positive end-expiratory pressure. 97 Survival differed by PRESERVE score classification-97% (score 0-2), 79% (score 3-4), 54% (score 5-6), and 16% (score ≥7). While renal insufficiency was recorded, it was not associated with mortality in this cohort. The RESP score utilized ELSO registry data from 2000 to 2012 to develop a model for predicting hospital survival at the initiation of ECMO for respiratory failure. 98 With continued growth in the use of ECMO for critically ill patients, several opportunities arise that may help improve the safety and efficacy of this technology, particularly when CRRT is also required. CRRT is yet to be defined. Similarly, the intensity of anticoagulationstandard vs low-dose-and best strategies for monitoring efficacy and complications have not been widely studied. There is also limited data on pharmacokinetics and medication dosing, particularly with combined circuits. Given the effects of respiratory failure, hemodynamic compromise, mechanical ventilation, and ECMO initiation on the incidence of AKI, studies that aim to determine best management methods are warranted. Developing and validating better AKI predictive models for ECMO patients, and identifying factors predictive of survival and renal recovery, are needed for this population. How ECMO affects the reliability and utility of AKI biomarkers is unclear and not yet widely studied in this population. 107 While the deleterious impact of AKI and FO on outcomes for ECMO patients is clear, critical questions warranting further study remain regarding the role of CRRT in patient management, including device, modality, and optimal timing of initiation. Finally, management strategies that ultimately prevent the occurrence of AKI in the setting of ECMO and lower AKI-associated morbidity and mortality are desired. The authors wish to acknowledge Mr. Leo Black and Ms. Kela Beans for their assistance with the critical review of this manuscript. 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