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

At A Glance

• Sepsis is a life-threatening syndrome caused by a dysregulated inflammatory response to infection.
• Standard treatments such as antibiotics and vasopressors address infection and organ support but do not directly treat the underlying septic response.
• Therapeutic plasma exchange (TPE) may help restore balance by removing harmful inflammatory and coagulation mediators while replacing depleted protective plasma proteins.
• Small clinical trials and meta-analyses suggest TPE may reduce mortality in adults with severe sepsis or septic shock.
• Larger randomized clinical trials are needed to determine whether TPE can provide definitive survival benefits.

Sepsis is a complex syndrome rather than a single disease.

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 one-third 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

Sepsis Mortality and Clinical Complexity

• Sepsis is a syndrome caused by a dysregulated inflammatory response to infection.
• Clinical presentations may include organ dysfunction, hypotensive shock, systemic coagulopathy and immune suppression.
• Disease progression varies depending on pathogen type, infection site, genetic factors, age and underlying health conditions.
• Septic shock is associated with mortality rates exceeding 30 percent.
• Sepsis accounts for more than one-third of hospital deaths in the United States.

Dysregulated inflammation and coagulation drive sepsis-related organ failure.

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 anti-inflammatory 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 pro-inflammatory 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.

Inflammatory and Coagulation Pathways in Sepsis

• Sepsis involves disruption of the normal balance between proinflammatory and anti-inflammatory mediators.
• Excess production of inflammatory cytokines such as IL-1β and TNF contributes to systemic inflammation.
• Protective anti-inflammatory mediators may become depleted during severe infection.
• Microvascular injury and coagulation abnormalities can lead to multiple organ dysfunction syndrome.
• Severe cases may progress to disseminated intravascular coagulation with high mortality.

Plasma failure may explain the persistent imbalance in severe sepsis.

“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

Concept of Plasma Failure in Critical Illness

• Plasma failure describes the collective dysfunction of multiple circulating plasma components during severe illness.
• Excess proinflammatory and procoagulant mediators may coexist with depletion of protective regulatory proteins.
• This imbalance contributes to uncontrolled inflammation and coagulation abnormalities.
• Plasma failure has also been described in trauma-induced coagulopathy, acute liver failure and severe COVID-19.

Therapeutic plasma exchange may restore physiologic balance in sepsis.

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).

Mechanism of Therapeutic Plasma Exchange in Sepsis

• Therapeutic plasma exchange removes circulating plasma and replaces it with donor plasma.
• The procedure may reduce excessive inflammatory and procoagulant mediators.
• Replacement plasma may restore protective proteins involved in regulating inflammation and coagulation.
• Repeated exchanges may help reestablish physiologic balance in critically ill patients.

Clinical studies suggest potential survival benefits of TPE in sepsis.

A number of small RCTs and case-control 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

Evidence From Clinical Studies of TPE in Sepsis

• Small randomized trials and observational studies have evaluated therapeutic plasma exchange in severe sepsis.
• Reported outcomes include reductions in short-term mortality compared with standard care.
• Clinical studies have also examined organ failure scores, inflammatory cytokines and coagulation markers.
• Recent meta-analyses published in 2023 and 2024 reported lower mortality among adults receiving adjunctive TPE.
• Some studies also reported improved hemodynamic stability and reduced vasopressor requirements.

Large randomized trials are needed to confirm the role of TPE in sepsis treatment.

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.

Research Priorities for Therapeutic Plasma Exchange in Sepsis

• Larger randomized clinical trials are needed to confirm survival benefits of TPE in sepsis.
• Future studies must address different sepsis subtypes including MODS and septic shock with DIC.
• Trial design considerations include treatment timing, plasma exchange volume and number of procedures.
• Funding challenges remain a major barrier to conducting large clinical trials.

Frequently Asked Questions

What is therapeutic plasma exchange?

Therapeutic plasma exchange is a medical procedure in which a patient’s plasma is removed and replaced with donor plasma or other replacement fluids. The process can remove harmful circulating substances while restoring important plasma proteins.

Why is sepsis difficult to treat?

Sepsis involves a complex dysregulated immune response to infection affecting many inflammatory and coagulation pathways simultaneously. This complexity makes it difficult for single-target drugs to restore physiologic balance.

How might plasma exchange help patients with sepsis?

Plasma exchange may remove excessive inflammatory mediators and procoagulant proteins while replacing depleted protective plasma components. This process may help restore balance in the immune and coagulation systems.

What evidence exists for plasma exchange in sepsis?

Several small randomized trials and observational studies have evaluated plasma exchange in severe sepsis and septic shock. Meta-analyses published in recent years suggest the therapy may reduce short-term mortality in adults.

Is therapeutic plasma exchange currently a standard treatment for sepsis?

Therapeutic plasma exchange is not currently a standard treatment for sepsis. Larger randomized clinical trials are needed to determine its effectiveness and define appropriate treatment protocols.

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