Therapeutic Plasma Exchange as a Strategy to Reverse Multiple Organ Dysfunction Syndrome in Patients Receiving Extracorporeal Life Support*

Therapeutic plasma exchange (TPE) as a strategy to reverse multiple organ dysfunction syndrome (MODS) in severe sepsis has been gaining interest for the past decade. In an abstract earlier this year at the 43rd Critical Care Annual Congress, Ruth et al (1) reported the use of extracorporeal therapies in pediatric severe sepsis by using the Pediatric Health Information System (PHIS) database of 561,947 critically ill children from 37 hospitals during 2004–2012. A total of 39,372 patients met criteria for severe sepsis. These investigators found that TPE was used in 4.2% pediatric severe sepsis patients with a mortality of 20.9%. Other extracorporeal therapies such as continuous renal replacement therapy (CRRT) and extracorporeal life support (ECLS) were used in 5.3% and 4.2% in the same patient population with mortalities of 45% and 49.5%, respectively. Recently, Fink and Warren (2) wrote an informative review highlighting numerous failed phase II and III randomized controlled trials during the past three decades of specific monopharmacological adjuvant or “silver bullet” agents for sepsis. This experience has likely contributed to the rise of interest in the use of nonspecific therapies for sepsis, such as TPE. Based on the existing evidenced-based literature on the use for TPE for severe sepsis induced MODS, the American Society for Apheresis gives the following category III recommendation, which is that “optimum role of apheresis therapy is not established” and “decision making should be individualized” (3). In a recent meta-analysis of randomized trials of blood purification for sepsis, Zhou et al (4) reported that blood purification for sepsis decreased mortality compared with no blood purification (35.7% vs 50.1%; risk ratio, 0.69 [95% CI, 0.56–0.84]; p < 0.001; 16 trials, n = 827). They found that blood purification using hemoperfusion (risk ratio, 0.63 [95% CI, 0.50–0.80]; p < 0.001; 10 trials, n = 557) or TPE (risk ratio, 0.63 [95% CI, 0.42–0.96]; p < 0.03; two trials, n = 128) was associated with a decrease in mortality. In adults with severe sepsis, two of three randomized studies have reported that TPE had a significant beneficial treatment effect. Busund et al (5) reported that TPE significantly decreased the 28-day mortality. Darmon et al (6) reported that TPE significantly decreased hospital mortality and reversed MODS. Reeves et al (7) reported that there was a trend toward reversing MODS but not improvement in survival. In pediatrics, there are “three proof of concept” published studies reporting the beneficial treatment effect of TPE in inflammation phenotype-specific sepsis-induced MODS. We previously reported a small study of pediatric patients with the thrombocytopenia-associated multiple organ failure (TAMOF) phenotype who had low α disintegrin and metalloproteinase with thrombospondin motifs-13 (ADAMTS-13) (a.k.a. von Willebrand factor [VWF]-cleaving protease) activities and elevated VWF activities (8). We demonstrated on autopsies that these patients with TAMOF died with disseminated VWF-rich microvascular thromboses, which was the proposed mechanism of MODS in this phenotype. Using TPE as it is used to treat thrombotic thrombocytopenic purpura (3), we demonstrated that TPE replenishes ADAMTS-13, removes pathologic ultra-large VWF multimers, and reverses organ dysfunction in patients with sepsis-induced TAMOF. Sevketoglu et al (9) recently reported from the Turkish TAMOF Network that TPE was associated with improved survival in pediatric TAMOF. Demirkol et al reported from the Turkish Secondary Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) Critical Care Study Group that TPE along with intravenous immunoglobulin and methylprednisone improved survival in HLH/MAS associated with TAMOF (10). In support of this observation, we found that 50% of patients with HLH at Texas Children’s Hospital had clinical TAMOF with autopsy evidence of disseminated microvascular thromboses (11). Because TPE removes other soluble plasma molecules and replenishes the septic plasma milieu with normal fresh-frozen plasma (FFP), others have hypothesized that TPE would have effects in other pathophysiologic processes of sepsis-induced MODS. In this issue of Pediatric Critical Care Medicine, Kawai et al (12) report their institutional experience of using TPE as strategy to reverse MODS in pediatric patients requiring ECLS for refractory septic shock. This study is significant for several reasons. First, it provides information on the technical aspect of combining two different extracorporeal therapies together into an existing circuit such as TPE and CRRT onto an existing ECLS circuit. Second, it reports a very high survival rate of 71.4% for patients with sepsis-induced MODS receiving TPE with ECLS, whereas the PHIS database reports a survival rate of 50.5% for ECLS with severe sepsis and the Extracorporeal Life Support Organization registry 50% for severe sepsis. Third, it reports a decrease in Organ Failure Index and Vasoactive-Inotropic Score after two to six treatments with TPE. This reduction in severe sepsis-induced MODS could be related in part to reversal of TAMOF as described above or to other ECLS-specific mechanisms such as removal of free plasma hemoglobin caused by circuit-induced hemolysis. Free hemoglobin is associated with mortality and MODS in ECLS (13). Despite this encouraging report, the use of TPE on or off ECLS is not without challenges. Use of citrated blood products in TPE chelates calcium and can lead to hypotension; therefore, careful attention to hypocalcemia and appropriate calcium replacement therapy is required. This need for calcium replacement increases with younger age because bone mass relative to body size is decreased reducing the ability of the patient to maintain and mobilize calcium stores. Loss of catecholamines and sedatives from the blood compartment also occurs and leads to the need for replacement of both during the procedure. There are also risks specific to patients on ECLS. Plasma exchange will normalize international normalized ratio, and remove heparin; therefore, careful monitoring of anticoagulation, as well as treatment with anticoagulants, is needed during the procedure. In summary, there is accumulating and encouraging evidence of better outcomes being associated with blood purification for sepsis-induced MODS. However, there are still very limited data on blood purification for the very critically patients requiring ECLS for refractory shock. Current available blood purification meta-analysis data suggest that the hemoperfusion and TPE techniques are the first choice to study and use for severe sepsis. There are still limited data for clinicians to make a decision on important details including type of replacement fluids, such as albumin versus FFP, duration of TPE, and time to initiation of TPE. There are sufficient preliminary data to support design of randomized controlled trials to evaluate the role of TPE in sepsis-induced MODS. It would be prudent to stratify randomization in those who are and are not receiving ECLS at the time of enrollment.