Therapeutic Plasma Exchange: A Promising New Treatment for Sepsis and Septic Shock

EACH YEAR, the pharmaceutical industry introduces new therapeutics to add to the vast armamentarium that clinicians already rely upon to treat human disease. Nearly all are single molecular entities that either target underlying disease pathology or counter its secondary effects. Many are lifesaving: Think of thrombolytics for myocardial infarction and acute ischemic stroke; insulins for type 1 diabetes; immunotherapies, hormone therapies and antimetabolites to treat various cancers.

Then there is sepsis, which isn’t a disease but a syndrome caused by a dysregulated inflammatory response to infection. Sepsis is the catch-all term for a spectrum of conditions that may include multiple organ dysfunction, hypotensive shock, systemic coagulopathy and immune suppression (Figure 1).¹ For any given individual, its course is shaped by the type of pathogen, site of infection, genetic determinants, age, pre-existing comorbidities and overall health status.² In the unfortunate subpopulation of patients who progress to septic shock, 30-day mortality well exceeds 30 percent.³ Today, sepsis accounts for more than onethird of all hospital deaths. Some 350,000 of the 1.7 million adults who develop sepsis each year will die during or shortly after their hospitalization.^4,5

Yet notwithstanding antibiotics, vasopressors and other drugs used in standard ICU treatment, there are no available therapies to treat sepsis itself. Well over 100 randomized clinical trials (RCTs) evaluating numerous drug candidates in hopes they could modulate the septic response and improve survival have all failed.⁶ The explanation for this dismal record lies in the complex pathophysiology of sepsis itself, much of which remains incompletely understood.

In a state of health, a balance between pro- and anti-inflammatory mediators and their interactions with local cellular stimuli govern the normal adaptive inflammatory process that helps promote leukocyte migration, complement-mediated lysis and other immune responses to the invasive pathogen. To cite just one example, the antiinflammatory cytokine TGF-ß suppresses production of inflammatory cytokines, downregulates endothelial adhesion and inhibits synthesis of nitric oxide to limit its potent vasodilatory activity.

But in a state of sepsis, this balanced interplay of numerous cellular and circulating elements becomes deranged. There is overproduction of specific proinflammatory mediators such as IL-1ß, TNF, C3a and C5a, while plasma levels of anti-inflammatory factors (e.g. TGFß, IL-10 and complement factor H) that normally regulate the inflammatory response can become exhausted. This hyperinflammatory, dysregulated state can result in widespread tissue damage and multiple organ dysfunction syndrome (MODS). In turn, injury to organ microvasculature in MODS can result in widespread formation of microthrombi, depleting circulating anticoagulant proteins such as antithrombin III (AT-III), protein C and tissue factor pathway inhibitor. In patients with severe sepsis and septic shock, profound dysregulation of coagulation function can progress to disseminated intravascular coagulation (DIC), with a mortality rate as high as 50 percent.

“Plasma Failure” and Therapeutic Plasma Exchange

It is widely agreed that the hyperinflammation and microvascular thrombosis observed in sepsis result from simultaneous excessive levels of circulating proinflammatory and procoagulant plasma elements, coupled with depleted levels of other circulating plasma elements that normally act to limit these responses to an invasive pathogen.

Diseases arising from deficiency of a single plasma protein, such as hemophilia A from a deficiency of factor VIII, can be effectively treated with replacement of the missing factor. But the pathophysiology of sepsis-induced organ dysfunction involves numerous dysregulated plasma components and pathways. So it’s not at all surprising that no one has found a “magic bullet” that can help restore homeostasis in these patients.

A recent review by critical care and apheresis medicine specialists has applied the term “plasma failure” in relation to sepsis in its various manifestations — the collective failure of numerous circulating plasma elements to control the hyperinflammatory and coagulopathic response to an invasive pathogen. Plasma failure is not unique to sepsis patients with MODS; it occurs as well in patients with trauma-induced coagulopathy, acute liver failure and severe COVID-19 (Figure 2).⁷

When understood in this context, a potential adjunctive treatment for worsening sepsis stands out: therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) to remove and replace the patient’s “failed” plasma with fresh donor plasma that contains balanced, physiologic levels of critical plasma elements needed to restore homeostasis. Repeated TPE can both reduce harmful supraphysiologic circulating levels of proinflammatory and procoagulant proteins and restore depleted levels of proteins whose function is to keep systemic inflammation and coagulation activity in check (Figure 3).

A number of small RCTs and casecontrol studies dating back more than two decades have been conducted in attempts to assess the potential effects of TPE on various clinical and laboratory outcome parameters.8,9,10 Most document 30 percent to 60 percent reductions in short-term (e.g., 28-day or in-hospital) mortality with the use of TPE compared to standard care. While mortality is the primary endpoint of interest in nearly all of these trials, other measured outcomes have included Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE II) score, plasma levels of both inflammatory cytokines and other injury-mediating factors, and protective factors such as AT-III, protein C and ADAMTS-13.

Unfortunately, the validity of these individual studies is limited both by their very small enrollment sizes and a host of known confounders. Nevertheless, results from a number of very recent meta-analyses, including three published in 2023 and 2024, consistently find that TPE therapy meaningfully improved survival in patients with severe sepsis and septic shock:

• Lee et al (J Intensive Care Med 2023): This meta-analysis of small RCTs and observational studies totaling 280 adult patients with severe sepsis found patients supported with TPE using FFP replacement had lower mortality (relative risk ratio [RR], 0.64; 95% confidence interval [CI], 0.49, 0.84) compared to those who did not.11 Interestingly, an analysis of studies in children with severe sepsis found TPE was associated with increased mortality.
• Kuklin et al (Crit Care 2024): Five small RCTs were selected for this metaanalysis, which included 331 septic patients of whom 166 received TPE. Patients treated with adjunctive TPE had a lower mortality rate (RR: 0.62; 95% CI: 0.46, 0.83) compared to those who received standard therapy alone.12 Separate analyses of six retrospective and nine prospective matched cohort studies respectively found patients who received TPE had significantly (RR: 0.33; 95% CI: 0.14, 0.76) and non-significantly (RR: 0.83; 95% CI: 0.44, 1.58) reduced risk of short-term mortality.
• Hernandez et al (Cureus 2024): A weighted analysis of three small RCTs and one cohort study comparing TPE to standard care in patients with septic shock again showed TPE is associated with a significantly reduced risk of mortality (RR: 0.43; 95% CI: 0.26, 0.72).¹³

Other studies have shown TPE improved hemodynamics in patients who had progressed to septic shock. A German group, for example, reported that the norepinephrine requirement to maintain systolic pressure in septic shock patients who received a single exchange of 12 units of FFP was significantly reduced relative to those who received standard care. In parallel, the mean lactate concentration showed a significant decline in the TPE group, while no decline was observed in the standard care group.¹⁴

Needed: Definitive Clinical Trials

While none of the sepsis/TPE trials reported to date have enrolled enough patients to overcome potential bias and random effects, collectively their results strongly suggest adjunctive TPE can meaningfully improve survival in adults across a range of sepsis presentations.

Needed now are carefully designed and adequately powered clinical trials that address different sepsis subsets, including in particular sepsis with MODS and severe sepsis or septic shock with laboratory-confirmed DIC. In addition to defining enrollment inclusion and exclusion criteria, study investigators will need to reach consensus on a number of key parameters that include:

• Timing of initiation of TPE therapy (ideally within 24 hours of diagnosis/ qualification)
• Volume of plasma exchanged with FFP
• Number of plasma exchanges
• Time interval between plasma exchanges

Then, of course, there is the elephant in the room: how to pay for these large, complex trials. The primary disposable supply item used to perform a single centrifuge- or membrane-based TPE procedure generates just a few hundred dollars for its manufacturers, at least an order of magnitude less than the pertreatment revenue a successful new drug can potentially generate for a drugmaker to justify a multi-million-dollar R&D investment. The money to support costly clinical trials to evaluate use of TPE in sepsis will have to come from elsewhere.

Without an industry sponsor, it will be especially challenging for proponents of TPE/sepsis research to secure the funding required for clinical trials able to definitively answer whether TPE can provide important survival benefit for patients diagnosed with sepsis or septic shock with multi-organ failure.

Hopefully that funding will materialize sooner than later for critical care specialists who see the lifesaving potential of TPE and are prepared to organize and conduct these trials. There may be no better opportunity to reduce the numbers of hospital deaths in all of medicine.