PILOT STUDY in the Use of Therapeutic Plasma Exchange in Adult Patients With Severe Sepsis

Background

The incidence of sepsis has increased over the last four decades (1). Sepsis is a life-threatening condition that arises when the body's response to an infection injures its own tissues and organs. Severe sepsis and septic shock are among the leading causes of death for patients admitted to critical care units with mortality ranging from 20-70% depending on totality of organ dysfunction (2, 3). The literature is replete with initial promising phase 2 therapies failing in definitive randomized trails (4-8). In fact, a recent systematic review concluded that no evidence exists for any pharmacologic intervention that has consistently reduced mortality in critically ill patients (9). This is both surprising and frustrating for the author. The most recent guidelines have tried to redefine sepsis as a 'syndrome' since neither validated criterion nor do standard diagnostic tests exist (10). The authors argue that sepsis should be viewed as organ dysfunction caused by a dysregulated or non-homeostatic host response. Most of the clinical manifestations of severe infections are caused by an intense, generalized inflammatory response in the host mediated by a multitude of interrelated cellular and humoral factors (3).

Plasmapheresis or therapeutic plasma exchange (TPE) involves the separation of plasma from whole blood. The removed plasma is 'exchanged or replaced' with crystalloids, albumin, fresh frozen plasma or a combination thereof. TPE use is well established in many neurological disorders including Guillain-Barre syndrome (11), Myasthenia Gravis (12, 13) and antibody mediated syndromes(14, 15). It is considered the standard of care for thrombotic thrombocytopenic purpura (TTP) (16, 17). The rationale for the use of TPE in sepsis, a non-selective intervention, is to remove multiple toxic mediators including endotoxins, activated complement, pro-inflammatory cytokines and pro-coagulant factors (18, 19). If fresh-frozen plasma is used as replacement fluid, consumed plasma factors are substituted, thereby possibly restoring the opsonic capacity and improving the coagulation abnormalities and microcirculation.

Plasma exchange has been reported since the late 1970s as a potential adjunctive or salvage therapy in severe sepsis in both pediatric and adult patients (20-24). These case reports, retrospective reviews and observational studies suggest a survival advantage when compared to historical controls. However, the obvious bias limits any meaningful interpretation. A literature review found only 4 studies with any attempt at randomization. One study enrolled only adults (25), two were exclusively pediatric patients (26, 27) and one study involved both adults and children (28). Excluding the pediatric studies, the adult protocols had few similarities:

1. Reeves and colleagues attempted a multi-center Australian study but terminated enrollment after 22 adult and 8 children (28). The mean APACHEII scores for adults were 25.2. They aggressively exchanged 5 plasma volumes continuously over 36 hours using a combination of fresh frozen plasma (FFP) and albumin (1/4 ratio). Mortality was reported at 14 days. No data on ICU or hospital length of stay was provided. This trial reported significant decrease in certain inflammatory markers.
2. Busund's larger trail involved 106 adults and reported mortality at 28 days (25). They performed a single 30-40mls/kg exchange that could be repeated once if no clinical improvement was observed. The replacement used was FFP and albumin in a 1:1 ratio. Six episodes of transient hypotension and 1 allergic reaction to FFP was reported (the only trial to report adverse events). There was an encouraging trend towards improved survival (33% vs 53%) versus historical controls. No data on ICU or hospital length of stay was provided.