Adjunctive Hemoadsorption Therapy with CytoSorb in Septic/Vasoplegic Shock: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Axel Nierhaus.

There are no approved therapies to modulate the excessive immune response and limit hyperinflammation with the goal of preventing related organ failure and death. In this context, extracorporeal blood purification therapies aiming at the alteration of the host inflammatory response through broad-spectrum, non-selective removal of inflammatory mediators have come into focus. A novel hemoadsorption device (CytoSorb®, CytoSorbents Inc., Princeton, NJ, USA) has shown promising results in patients with hyperinflammation from various origins. Although a significant body of literature exists, there is ongoing research to address many important remaining questions, including the optimal selection of patient groups who might benefit the most, optimal timing for therapy initiation, optimal schedule for adsorber exchanges and therapy duration, as well as an investigation into the potential removal of concomitant antibiotics and other medications. 

  • shock
  • vasoplegic shock
  • septic shock
  • hemoadsorption
  • CytoSorb therapy

1. Background

A dysregulated host response is a common feature in critically ill patients due to both infectious and non-infectious origins that can lead to life-threatening organ dysfunction [1]. Despite advances in critical care, this overwhelming response of the host immune system still represents a major challenge in everyday practice, and especially within the domain of sepsis, it remains a global health and economic problem [2].
The pathophysiology of hyperinflammation-related critical illness is multifaceted and involves a complex interplay between cellular and biochemical interactions, ultimately resulting in the disruption of the well-balanced immunological state between the pro-inflammatory and anti-inflammatory forces. It is mediated by the activation of the innate immune system and typically results in a hyperinflammatory state, which is characterized by an overwhelming production and release of inflammatory mediators that are often referred to as a “cytokine storm” [3]. The binding of pathogen or damage-associated molecular patterns (PAMPs and DAMPs, respectively) to specific receptors induces a complex intracellular signaling system with the activation of pro- and anti-inflammatory pathways [4], leading to endothelial barrier dysfunction, disturbances of microcirculation, vasodilatation, progressive tissue damage, and multiple organ dysfunction [5]. The most extensively studied dysregulated inflammatory condition leading to critical illness is, without doubt, sepsis and septic shock.
The current standard therapeutic approach during the early stage of septic shock is well defined and is also supported by substantial evidence [6]. However, when standard medical therapy and advanced organ support fail to improve the patient’s condition after several hours of guideline-directed treatment, adjunctive therapies, which are aimed at modulating the host response, may be considered (Figure 1). However, despite considerable advances in its management, most sepsis trials investigating promising technologies and drugs that modulate the inflammatory response have failed in the past to produce convincing results [4]. One of the potential adjunctive therapies is extracorporeal hemoadsorption, of which the most studied platform is CytoSorb® [7]. Notwithstanding considerable data that has been generated over the years, definitive evidence is still lacking, despite the increasing number of treatments worldwide. Furthermore, especially in early studies, management of CytoSorb® therapy was not always performed in an optimal manner, which might have confounded the observed results.
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Figure 1. Therapeutic Concepts in Sepsis and Septic Shock—Dilemma and Challenge. MABs, monoclonal antibodies. RRT, renal replacement therapy. MODS, multiple organ dysfunction syndrome. SMT, standard medical therapy. SSC, surviving sepsis campaign. PAMPs, pathogen-associated molecular patterns. DAMPs, damage-associated molecular patterns.

2. Potential Role of Extracorporeal Cytokine Adsorption

Although extracorporeal cytokine adsorption as an adjunctive therapy has been introduced predominantly for sepsis [8[8][9][10],9,10], the therapeutic potential of hemoadsorption likely transcends sepsis, since hyperinflammation is common to many other pathologies. In addition to bacterial infections, viral [11[11][12],12], fungal [13[13][14],14], and protozoan [15], infections can also result in a dysregulated host response and systemic hyperinflammation.
As demonstrated in a large cohort of 1886 hospitalized patients with community-acquired pneumonia (CAP), those with concurrently high levels of both pro- and anti-inflammatory cytokines have the highest risk of death [16]. These findings suggest that excessive production of cytokines plays a crucial, and potentially harmful role in the process. Therefore, removing inflammatory mediators from the circulation in a balanced, concentration-dependent manner has a pathophysiological basis; restoring the physiological immune response may foster improved organ function(s) and expedite recovery. Additionally, non-infectious conditions with systemic inflammatory repercussions, such as major burns [17[17][18],18], major trauma [19], severe pancreatitis [20], and major surgery [21,22][21][22] can exhibit many of the clinical features of hyperinflammation. Hemoadsorption has proven notably effective in treating patients with crush syndrome who have rhabdomyolysis, with CytoSorb® successfully eliminating both myoglobin and creatine kinase [23]. In an interesting case study by Dilken and coworkers, the importance of timing was demonstrated where the late application of CytoSorb®, while being highly effective in removing myoglobin, was too late to reverse the clinical deterioration of the patient [24].

3. The CytoSorb Adsorber

3.1. Properties of the Device

Properties of the CytoSorb® technology are based on highly biocompatible, porous polymer beads designed to capture and adsorb primarily hydrophobic substances in the middle molecular range with a size selectivity up to approximately 60 kDa, a range where most cytokines reside. CytoSorb® hemoadsorption beads are polystyrene-divinylbenzene porous particles (average particle diameter 450 μm, 0.8–5 nm pore diameter, 850 m2/g surface area) with a biocompatible polyvinyl-pyrrolidone coating [25]. These beads create a tightly structured network within the cartridge, and the surface relevant for adsorption is located inside the beads. The substances must be small enough to enter the beads and hydrophobic to form the necessary physico-chemical interactions with the polymer. Removal is concentration-dependent (“autoregulation”), indicating that high removal efficiency takes place only at elevated concentrations [26]. The use of the device is not associated with significant removal of albumin, coagulation factors, and immunoglobulins [27], there is also no activation of the coagulation and complement system and only minor and transient reduction in platelets. Overall, the device has a favorable safety profile with more than 200,000 treatments delivered worldwide to date across a wide range of critical care conditions [28].

3.2. Effects of CytoSorb Therapy on Circulating Cytokines

Over the past several years, extensive in vitro modeling and in vivo testing have been performed on the CytoSorb® polymer, miniaturized CytoSorb® cartridges and the commercially available CytoSorb® 300 mL device, to determine its ability to remove both endogenous (e.g., cytokines) as well as exogenous compounds (e.g., drugs). As shown in a multitude of studies, CytoSorb® is able to effectively reduce serum levels of pro- and anti-inflammatory mediators as well as other molecules involved in the inflammatory process (tumor necrosis factor -TNF-α, interleukin -IL-1β, IL-6, IL-10, NF-κB, chemokines CXCL-1, Mb and CCL2) in both animal [29,30,31,32][29][30][31][32] and human studies [33].

3.3. Effects of CytoSorb Therapy on Clinical Parameters

One of the most consistent effects of CytoSorb® hemoadsorption therapy in septic/vasoplegic shock is an improvement in hemodynamic stability, accompanied by a reduction in vasopressor requirements, as summarized in a recent review article [34]. In total, 33 eligible articles, including 353 patients, were analyzed, showing evidence of a significant reduction in norepinephrine (NE) requirements after treatment; median NE dose decreased from 0.55 to 0.09 μg/kg/min (p < 0.001). An analysis of four studies with control groups that included 140 patients in total revealed a large and significant pooled effect size, indicating a decrease in vasopressor requirements at 24 h (with a standardized mean difference of 1.64[95% CI: 0.53–2.76]), though data were characterized by high heterogeneity (I2 = 85.09%) [35,36,37,38][35][36][37][38]. Despite these promising results, several questions—including appropriate patient selection, timing of initiation, and dosing of CytoSorb® therapy—remain unanswered.

3.4. Patient Selection

The decision process to use CytoSorb® should always begin with the identification of the right patient candidates who are most likely to benefit from the therapy. In one of the earliest studies, Friesecke et al. prospectively studied cytokine adsorption in 20 patients with refractory shock. This was defined as an already elevated (>0.3 µg/kg/min) and further increasing vasopressor dose (over the preceding 2 h) required to maintain a mean arterial blood pressure above 65 mmHg or already high lactate (>2.9 mmol/L), and further increasing levels, despite standard early goal-directed shock therapy, for at least six hours [39]. Following the initiation of CytoSorb®, the norepinephrine dose was significantly reduced after 6 (p = 0.03) and 12 h (p = 0.001), while lactate clearance also showed a significant improvement. Shock reversal was achieved in 13 (65%) patients; 28-day survival was 45% compared to a predicted mortality from the sequential organ failure assessment (SOFA) score of >80%. In a retrospective propensity score matching analysis, Scharf et al. included 19 matched patient pairs with an IL-6 > 10,000 pg/mL [41][40]. Whilst they found no difference in IL-6 reduction, hemodynamic stabilization, or mortality between patients receiving CytoSorb® treatment and the matched patient cohort, it is noteworthy to mention that patients in the CytoSorb® group were evidently more ill, as indicated by significantly higher IL-6 levels, simplified acute physiology score (SAPS) II, requirement for continuous renal replacement therapy (CRRT), norepinephrine doses, and lactate levels. However, this study primarily analyzed the effects of the first adsorber used on each patient, where the required minimum duration for CytoSorb® use was merely 90 min, which is a duration that is arguably insufficient to significantly lower IL-6 levels exceeding 10,000 pg/mL.

3.5. Timing

The timing of therapy initiation is the second critical component for clinicians to consider when deciding on CytoSorb® therapy. Several studies have reported on the timepoint of initiation of CytoSorb® therapy, however, with quite some heterogeneity regarding the reference events (e.g., after intensive care unit—ICU admission, after diagnosis of septic shock, after the start of standard therapy, etc.). In their proof-of-concept randomized controlled pilot study, Hawchar et al. [37] investigated the effects of early extracorporeal cytokine removal with CytoSorb applied as a standalone treatment in 10 vs. 10 patients with early (<24 h) septic shock. Patients with the following criteria were included: mechanical ventilation; norepinephrine > 10 μg/min; PCT > 3 ng/mL; and without the need for renal replacement therapy (RRT). In the CytoSorb® group, norepinephrine requirements, as well as PCT concentrations, decreased significantly compared to the controls. In the retrospective, the propensity-matched, single-center study by Rugg et al., septic shock patients receiving CytoSorb®, in addition to RRT (n = 42), were analyzed and compared to the closely matched control patients (n = 42) [35]. In this cohort, CytoSorb® was started, on average, 21.4 h after ICU admission. The catecholamine requirements remained unchanged in the control patients, but in those treated with CytoSorb®, the levels were reduced by half to 0.26 µg/kg/min within 24 h of therapy initiation. 

3.6. Dosing

Duration (overall length of treatment), as well as intensity (time interval between adsorber changes), represent very important “dosing” variables for the optimization of CytoSorb® therapy. According to the “Instructions for Use” (IFU) of the device, the maximum treatment time per adsorber is 24 h, while in everyday clinical practice, many institutions have discovered that more frequent exchanges, especially at the start (i.e., every 12 h), are critical for achieving the desired effect. Since shock reversal should be accomplished as soon as possible, it is important to achieve the maximal therapeutic effect quickly by starting with a higher dose (similar to the “bolus”, or “loading dose” concept with drug therapy). After shorter exchange intervals of 8–12 h on the first and possibly also the second treatment days, or once stabilization has been achieved then less frequent (i.e., every 24 h) adsorber changes may be sufficient (i.e., “maintenance dose”). This approach, which intends to ensure the rapid onset and continuous maintenance of high removal rates during device use, is being prospectively evaluated in the ongoing PROCYSS randomized control trial (ClinicalTrials.gov Identifier: NCT04963920). Generally, sepsis/septic shock patients are likely to require both a more intense and longer treatment to show sufficient and sustained therapeutic success. Nevertheless, even when applied for only 24 h (mostly only one adsorber used in total) in a cohort of patients with septic shock with [35] or without [37], the need for renal replacement therapy, CytoSorb, use was still associated with improved hemodynamic status [35,37][35][37] and improved survival [35]. The largest dataset available to date is the CytoSorb® international registry, which includes 1437 patients treated with CytoSorb® [50][41]. In the sepsis cohort (n = 939), the median number of adsorbers used was two, and treatment lasted for a median of 43 h. At the end of the course of hemoadsorption, 85% of the patients were alive, and physicians reported an improvement based on their overall subjective impression in 54% of cases. Although there was no significant improvement in the overall SOFA score, the cardiovascular and respiratory SOFA sub-scores improved significantly after therapy (median change of −0.4 and −0.2 score points, respectively) as compared to baseline.

3.7. Therapeutic Goals

The therapeutic strategy of CytoSorb® hemoperfusion centers around modulating the host response to infection and mitigating organ dysfunction at an early point in time. To verify this objectively and reproducibly, proximal clinical endpoints, like change in (∆) SOFA [51][42], cumulative vasopressor dose [52][43], lactate clearance [53][44], time spent on mechanical ventilation, days on renal replacement therapy, and, perhaps, length of ICU stay, should be taken into account.

3.8. Safety

As the device removes not only cytokines but various other substances as well, there is the theoretical concern that the potential unwanted removal of otherwise important molecules (e.g., certain drugs) may be disadvantageous and potentially impact the safety profile. The risk of the unintended removal of concomitantly administered drugs in critically ill patients is an important issue that needs consideration with the use of all extracorporeal therapies. The clinical relevance of potential drug removal by CytoSorb® depends not only on the impact of the device, but also on drug-specific variables such as volume of distribution, protein binding, and elimination half-life. The duration of device exposure, and initiation of drug administration versus steady-state conditions, are further aspects requiring consideration when assessing the clinical relevance of potential drug removal. CytoSorb® drug adsorption kinetics show that most of the adsorption occurs in the first few hours of device exposure. Therefore, for drugs prone to adsorption, an increased loading dose and/or an additional dose after the first 1–2 h of treatment should be considered.

3.9. Procedural Details

CytoSorb® is intended for use in conjunction with standard commercially available bloodlines compatible with the utilized pump system. The cartridge can be integrated into all standard extracorporeal blood pumps, including intermittent hemodialysis, continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO), and cardiopulmonary bypass (CPB). Pressure monitoring of the bloodline between the blood pump and CytoSorb® is recommended. When used with ECMO, CytoSorb® should be placed in a shunt off the primary flow, flow monitoring should be used with the flow rate adjusted to ensure delivery of the desired flow to the patient (≤700 mL/min). Of note, a flow rate of 600 mL/min through the adsorber circuit will shunt approximately 20% of the blood flow from the patient. In combination with renal replacement therapy, the device can be incorporated either upstream (proximal) or downstream (distal) of the hemofiltration/dialysis device. Moreover, the priming process is crucial, with the blood lines requiring thorough priming with saline to prevent air entry, which could lead to clotting and reduced device efficacy. Multiple priming options, including gravity and pump priming, are available.

3.10. Anti-Infectives

Schneider et al. also provided data on the removal of various anti-infective drugs by CytoSorb®, compared to sham hemoperfusion, in a highly standardized and controlled pig model. The tested drugs were beta-lactams (for example: classical antibiotics such as, e.g., meropenem or piperacillin), antifungals (such as fluconazole), aminoglycosides (tobramycin), and other types of anti-infectives (such as linezolid or clindamycin). Based on the findings, hemoadsorption with CytoSorb® appears to have a limited effect on the pharmacokinetics of the majority of drugs tested. However, clearance of fluconazole, linezolid, and liposomal amphotericin B appeared to be increased by the procedure. Nevertheless, the authors state that any required dose modification would likely be minor [55][45].

3.11. Anticoagulation

The need and type of anticoagulation with CytoSorb® therapy are similar to standard strategies used with many other extracorporeal circuits during clinical practice. Options for anticoagulation include unfractionated heparin, citrate, or other anticoagulant strategies, depending on individual patient factors, coagulation profiles, and institutional protocols. Systemic heparinization is typically employed, with an aPTT of 60–80 s or an ACT of 160–210 s serving as adequate parameters for CytoSorb® therapy. Regular monitoring of aPTT or ACT is essential to maintain appropriate anticoagulation levels. Alternatively, regional anticoagulation with citrate can be considered, involving the initial dose, blood flow rate, and meticulous control and adjustment of calcium and citrate according to the designated protocol. Monitoring ionized calcium levels, both within the CRRT circuit and the patient, is advised at the initiation of treatment and at regular intervals. The determination of the appropriate dosage and target values is ultimately at the discretion of the attending physician. It is important to note that usage of CytoSorb® in hemoperfusion (stand-alone) mode without a hemofilter, heparin anticoagulation, is the preferred approach.

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