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Blood purification in sepsis and COVID-19: what´s new in cytokine and endotoxin hemoadsorption

Journal of Anesthesia, Analgesia and Critical Care volume 2, Article number: 15 (2022) Cite this article

Abstract

Sepsis and COVID-19 are two clinical conditions that can lead to a dysregulated inflammatory state causing multiorgan dysfunction, hypercytokinemia, and a high risk of death. Specific subgroups of critically ill patients with particular characteristics could benefit from rescue treatment with hemoadsorption. There is a lack of adequately designed randomized controlled trials evaluating the potential benefits of cytokine or endotoxin hemoadsorption. Critically ill COVID-19 patients with severe acute respiratory failure poorly responsive to conventional treatment could be candidates to receive cytokine hemoadsorption in the presence of high levels of interleukin 6. This treatment can also be suitable for patients with refractory septic shock and hypercytokinemia. In the context of high endotoxin activity, hemoadsorption with polymyxin B could improve clinical parameters and the prognosis of patients with refractory septic shock. Predictive enrichment, using biomarkers or other individual features, identifies potential responders to cytokine, endotoxin, or sequential hemoadsorption. Besides, recognizing the particular subsets of patients likely to respond to one or both types of hemoadsorption will aid the design of future studies that accurately validate the effectiveness of these therapies.

Background

Sepsis results from an inappropriate and dysregulated host response to infection, leading to an imbalance of pro-inflammatory and anti-inflammatory responses [1]. An excess of pro-inflammatory cytokines causes endothelial damage and systemic inflammatory response syndrome (SIRS). Severe cases progress to multiple organ failure and death [2]. Therefore, a rigorously regulated balance in the cytokine network is essential for controlling the infection and restricting excessive tissue-damaging inflammation. This network involves pro-inflammatory cytokines [tumor necrosis factor-alpha [TNF-α], interleukin 6 (IL-6), interleukin 1 (IL-1), interleukin 12 (IL-12), macrophage migration inhibitory factor (MIF), and interferon-gamma (IFN-γ)], anti-inflammatory cytokines [interleukin 10 (IL-10), interleukin 4 (IL-4), transforming growth factor-beta (TGF-β)], and soluble inhibitors of pro-inflammatory cytokines [3] [TNF receptor (TNFR), IL-1 receptor antagonist (IL-1Ra), and IL-2 receptor antagonist (IL-1R2)] [4, 5]. IL-10 and TGF-β decrease the production of pro-inflammatory mediators in immune cells and increase the production of IL-1Ra and sTNFRs [6, 7]. TNF-α and IL-1 are the primary mediators of inflammation-induced coagulation [8]. These two molecules amplify inflammatory cascades in an autocrine and paracrine manner by activating macrophages to secrete lipid mediators, other pro-inflammatory cytokines, and reactive oxygen and nitrogen species. These processes cause sepsis-induced organ dysfunction [1, 9]. TNF-α enhances the expression of adhesion molecules in the endothelium and increases the adhesiveness and extravasation of neutrophils into tissues [10, 11]. IL-6 induces fever [12] and is the central mediator of the acute phase of the inflammatory response [13, 14]. IL-6 binds to the soluble form of the IL-6 receptor. This complex combines with the signal-transducing component glycoprotein 130, which is present in various cells, including the endothelial cells, to elicit IL-6 signaling activation. However, IL-6 also has been shown to promote anti-inflammatory responses by inhibiting the release of TNF-α and IL-1 [15] and enhancing plasma levels of anti-inflammatory mediators [16,17,18].

Cytokine hemoadsorption in sepsis

Several studies have found a relationship between IL-6 hypercytokinemia and organ dysfunction in sepsis, the response to conventional treatment, and prognosis [19]. In contrast, non-decreasing values or slowly progressive decreases of IL-6 levels have been observed in non-survivors [20, 21]. In a previous study [22], 82% of patients with community-acquired pneumonia and systemic elevation of cytokine levels, the patients with high levels of IL-6 and IL-10 were at increased risk for severe organ dysfunction [23, 24] and death [22, 24]. Other studies have reproduced these findings [20, 21, 23, 24]. IL-10 overproduction is also a strong predictor of severity and mortality [25, 26].

Given the central role of abnormal systemic inflammation in the pathophysiology of sepsis-induced organ dysfunction, the development of therapies modulating the cytokine storm could help improve immune homeostasis. Extracorporeal blood purification therapies have emerged as strategies to improve the outcome of sepsis patients, diminishing the systemic expression of pro- and anti-inflammatory mediators and immune homeostasis recovering [22]. These include various cytokine hemoadsorption techniques: (a) Cytosorb® (CytoSorbents Corporation, Monmouth Junction, NJ, USA); (b) oXiris® (Baxter, Meyzieu, France); (c) Alteco® LPS Adsorber (Alteco Medical AB, Lund, Sweden); (d) HA-330® and HA-380® (Jafron Biomedical Co., Zhuhai, Guangdong, China).

Cytosorb® is a highly bio- and hemocompatible cytokine adsorber approved for its use in clinical infectious and non-infectious conditions associated with increased levels of cytokines. The cartridge is the most used worldwide [27, 28]. The device comprises porous polymer beads within a vast and efficient surface area. It allows for adsorption and permanent binding of molecules in the 5–60 kDa range. This range includes most cytokines and other inflammatory molecules [29]. The primary mechanism involved in CytoSorb® cytokine adsorption is the passage of blood through polymer beads within a perfused cartridge by extracorporeal circulation [23]. This process can attenuate both the inflammatory response and aid recovery of balance much earlier. Its benefits have been addressed in different contexts and clinical conditions, such as sepsis, COVID-19, SIRS secondary to cardiopulmonary bypass, liver failure, and rhabdomyolysis-induced myoglobinemia [20, 21, 24].

There is a high burden of evidence from observational studies on the potential clinical benefits of using Cytosorb® in septic shock to reduce vasopressor support and mortality, though a high quality of evidence derived from randomized controlled trials evaluating the clinical benefits of cytokine depuration is scarce. Friesecke et al. [30] studied 20 consecutive patients with refractory septic shock and hypercytokinemia after 6 h of conventional treatment. Refractory septic shock was defined as a progressive shock despite full-conventional therapy, lactate levels ≥ 2.9 mmol/L (or increasing values compared to baseline), and high vasopressor requirements (noradrenaline dose > 0.3 mcg/kg/min). The mean IL-6 levels were 25.523 ng/mL (1052–491260). In this observational study, Cytosorb® therapy was associated with a significant decrease in vasopressor requirements and increased lactate clearance. This finding was associated with shock resolution in 13 patients. In another study of 45 patients with septic shock [31], a significant vasopressor dose reduction was observed in patients treated with cytokine hemoadsorption. Norepinephrine was reduced by 51.4%, epinephrine by 69.4%, and vasopressin by 13.9%. Also, a reduction in IL-6 levels by 52.3% and lactate levels by 39.4% was observed in the survivors. A survival rate of 75% was documented in patients who received treatment within 24 h of intensive care unit (ICU) admission. Sixty-eight percent of patients who received treatment within 24–48 h after ICU admission survived. In a retrospective study [32], Cytosorb® was associated with lower all-cause mortality at 28 days in patients with septic shock. Hawchar et al. [33] performed a proof of concept, prospective, randomized pilot study to assess the usefulness of Cytosorb® in 20 patients with early-onset septic shock. Cytosorb® reduced the need for vasopressor support. In a case-control study of septic shock patients [34] who received cytokine hemoadsorption with CytoSorb®, the median catecholamine requirements approximately halved within 24 h after the initiation of therapy. In-hospital mortality was significantly lower in the CytoSorb® group (35.7% vs 61.9%; p = 0.015). The benefits of cytokine hemoadsorption have been documented in the subgroup of patients who have refractory septic shock and very high levels of plasma cytokines (IL-6). Further studies are needed to determine the influence of hemadsorption in eliminating other substances. It can increase antimicrobial clearance, which could be clinically significant in the case of linezolid, teicoplanin, fluconazole, liposomal amphotericin B, and posaconazole [35].

Cytokine hemoadsorption may be beneficial as rescue therapy in the subgroup of patients with refractory septic shock, hyperlactatemia, multiorgan failure, and very high hypercytokinemia (Fig. 1). This strategy does not necessarily imply acting when multi-organ dysfunction is already established, as there is a risk of losing a valuable therapeutic window to change outcomes. The optimal timing to start cytokine hemoadsorption is not well defined. Earlier actions, particularly before the development of overt renal failure, have been shown to be safe and have significant effects in reducing norepinephrine requirements. Predictive enrichment in well-designed randomized controlled trials should be performed to validate the usefulness of cytokine hemoadsorption.

Fig. 1
figure 1

Potential applications of cytokine and endotoxin hemoadsorption in sepsis and COVID-19. ECMO: extracorporeal membrane oxygenation

Full size image

Cytokine hemoadsorption in COVID-19

The extracorporeal cytokine hemoadsorption cartridge, Cytosorb®, was approved for its use in critically ill COVID-19 patients [36, 37]. The device has been previously used for cytokine storm-related hyperinflammatory conditions [38] and has been subject to many recent studies [39]. In the medical literature, cytokine storm refers to a heterogeneous group of disorders characterized by life-threatening hyperinflammation [40].

Since COVID-19 presents three distinct stages of disease progression, there are several challenges when managing patients [41]. The different clinical profiles correspond to different clinical stages, individual responses to therapy, and prognoses [42]. The following three stages determine the severity of COVID-19: early, pulmonary, and hyperinflammatory. The hyperinflammatory phase of COVID-19 is characterized by a multisystemic inflammatory syndrome, high levels of inflammatory biomarkers (the so-called “cytokine storm”), and an increased risk of organ dysfunction and death [43, 44]. Since early reports from China, the cytokine storm was recognized as the primary clinical feature associated with the severity of the disease [45].

There is accumulating evidence that the resulting inflammatory response in COVID-19 is not homogeneous throughout the disease [46, 47]. During the initial asymptomatic phase, hypercytokinemia is not clinically evident. In later stages, during the hyperinflammatory state, the massive cytokine release, which begins within the first 24–48 h of disease onset, causes a worsening of disease progression and severity that becomes evident after 7 to 10 days of infection [48]. During this stage, clinical deterioration is ubiquitous, and overt acute respiratory failure appears, as dysregulated immune response leads to diffuse alveolar damage, hyaline membrane formation, thrombus formation, fibrin exudates, and fibrotic healing [49]. These mechanisms lead to acute respiratory distress syndrome (ARDS) [50], whose frequency is up to 26% in SARS-CoV-2 infection [51, 52].

Potentially useful rescue therapies do not fit all COVID-19 patients. The indication for delivering cytokine hemoadsorption as adjuvant treatment in critically ill COVID-19 patients should be individualized [53]. Avoiding immunosuppression is the primary goal during the initial stages, as high viral loads are present. Thus, patients presenting a mild-moderate disease do not benefit from adjuvant therapies, such as cytokine hemoadsorption. In subsequent advanced stages, immunomodulation is the cornerstone for treatment [54, 55]. There are two distinct clinical phenotypes of COVID-19 patients [55]. The first phenotype is characterized by a mild-moderate disease and low viral loads, in which preserved interferon responses, regulated production of cytokines, and rapid recovery from initial lymphopenia are observed. Instead, a particular subset of patients presents the second phenotype, characterized by a severe disease with a high risk of death, high viral loads and cytokine plasma levels, impaired interferon response, and sustained lymphopenia. We indicate cytokine hemoadsorption in patients with severe acute respiratory failure refractory or poorly responsive to prone positioning in the context of a hyperinflammatory state (determined by very high levels of biomarkers, such as IL-6, ferritin, and D-dimer) (Fig. 1).

Several organizations support the use of cytokine hemoadsorption in patients with severe SARS-CoV-2 infection, even though the clinical experience is scarce and comes mainly from case reports and some case series [56,57,58]. The National Health Commission and National Administration of Traditional Chinese Medicine have recommended cytokine hemoadsorption with Cytosorb® as adjuvant treatment for severe and critical COVID-19 [59]. The Brescia Renal Covid Task Force supports the use of Cytosorb® hemoadsorption in COVID-19 patients with ARDS or acute kidney injury requiring continuous renal replacement therapy (CRRT) [60]. The Panamanian Association of Critical Medicine and Intensive Therapy recommends using Cytosorb® in patients with hyperlactatemia and high-dose vasopressors, not responding to conventional therapy. Also, patients with severe ARDS and high respiratory support requirements are considered [61]. The Colombian consensus recommends cytokine hemoadsorption in patients with cytokine storm and lack of response to treatment [62]. In April 2020, the Food and Drug Administration issued an Emergency Use Authorization for Cytosorb® to treat patients 18 years of age or older with confirmed COVID-19 admitted to the ICU, who have established or imminent respiratory failure, severe disease, or life-threatening disease (e.g., respiratory failure, septic shock or multiorgan dysfunction) [36].

Large-scale studies evaluating cytokine hemadsorption in critically ill COVID-19 patients are lacking, and some have introduced important selection bias when sampling from heterogeneous populations of critically ill patients. Rampino et al. [63] published a case series of 9 consecutive critically ill COVID-19 patients requiring continuous positive airway pressure. In their study, all patients who received the treatment survived, and only two needed endotracheal intubation. The inclusion criteria were confirmed SARS-CoV-2 pneumonia, in addition to a PaO2/FiO2 ratio < 200 mmHg, C-reactive protein levels > 10 mg/dL, and a lymphocyte count < 1500/mm3. In another study [64], the authors delivered hemoadsorption with Cytosorb® for 24 to 48-h-sessions to 11 critically ill COVID-19 patients who required invasive mechanical ventilation due to rapidly progressive ARDS. Nassiri et al. [65] used Cytosorb® in 26 critically ill COVID-19 patients with moderate ARDS (PaO2/FiO2 ratio < 200), C-reactive protein > 50 mg/l and ferritin > 1500 mcg/l). Overall, 46.2% of patients received mechanical ventilation. Paisey et al. [66] studied 15 patients with severe COVID-19 who received cytokine hemoadsorption (HA-330 cartridges were used in 5 patients, and Cytosorb® adsorbents in 10). All patients were on invasive mechanical ventilation and CRRT, and 11 received extracorporeal membrane oxygenation (ECMO) support. In a multicenter study [67], the authors evaluated the response of 37 mechanically ventilated patients who had received cytokine hemoadsorption using the oXiris® membrane. The indication for hemoadsorption was systemic inflammation associated with AKI, hemodynamic instability, or multiorgan dysfunction.

Another potential application of cytokine hemoadsorption is the adjunctive therapy in pediatric patients with multiorgan dysfunction due to multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. In a previous report [68], rapid improvements in shock and multiorgan dysfunction parameters were achieved, and cytokine levels (IL-6 and IL-10) decreased considerably. C-reactive protein, soluble CD25 [sCD25], and ferritin levels decreased following the attenuation of hyperinflammation. Although causality could not be confirmed because other treatment interventions could have contributed to a good outcome, a temporal relationship between the initiation of hemoadsorption and clinical improvement was evident. Rapid improvements in organ function were documented 24 h after initiation of therapy.

Clinicians should consider the undesirable effects of hemoadsorption. Alterations in the pharmacokinetics of some antibiotics, such as teicoplanin, have been described [69]. Therefore, it is necessary to monitor antibiotic concentrations, particularly when prolonged sessions of hemoadsorption are indicated. Regarding infectious complications, hemoadsorption sessions are of short duration, and the risk of infection of intravascular devices used for extracorporeal support is low, particularly in critical care units where preventive measures are widely implemented. Previous experience in sepsis showed that cytokine hemoadsorption is a safe procedure with no associated adverse effects [70]. Hemoadsorption-associated infections have not been described.

Critically ill COVID-19 patients with severe ARDS refractory to prone positioning and hypercytokinemia can receive adjuvant treatment with cytokine hemoadsorption [71]. Also, children with MIS-C and multiorgan dysfunction could be candidates for receiving this adjuvant treatment. Cytokine hemoadsorption therapy is a promising intervention for immunomodulation in patients with severe ARDS. Further studies and well-designed randomized controlled trials should be conducted to accurately set the indications and clinical benefits of cytokine hemoadsorption in COVID-19.

Baseline biomarker levels and the clinical response to cytokine hemadsorption

Critically ill COVID-19 patients do not present increased plasma levels of biomarkers as other subsets of critically ill patients (e.g., septic shock or sepsis with ARDS patients). Previous studies have found mild to moderate elevations of C-reactive protein, IL-6, and ferritin [72]. However, there are no established thresholds of inflammatory biomarker levels to recommend cytokine hemoadsorption. Individual responses are heterogeneous, and numerous underlying factors affect biomarker levels. Thus, the real possibility to establish valid thresholds is uncertain. Damiani et al. [64] showed the median values of IL-6 to indicate hemoadsorption were 355 pg/mL (interquartile range, IQR, 263–466), 118 pg/mL (IQR 19–221, p = 0.003) at the end of therapy and 169 pg/mL (IQR 61–253, p = 0.03) after 24 h of therapy. The authors found a significant decrease in C-reactive protein and PaO2/FiO2 ratio improvements. Similar findings were reported in another study [65], in which PaO2/FiO2 ratio, sequential organ function assessment (SOFA) score, and inflammatory biomarkers (procalcitonin, CRP, and ferritin) improved significantly. The mortality rate was 19.2%. Cytokine hemoadsorption can reduce ferritin, C-reactive protein, procalcitonin, and lactate levels [66].

Nevertheless, no significant differences have been found in studies documenting mild to moderate increases in baseline IL-6 and IL-10 levels before treatment [66]. Villa et al. [67] initiated cytokine hemoadsorption after 3 to 4 days from ICU admission and 2 weeks of symptom onset. The reductions in IL-6 concentrations were significant during the first 24 of treatment. Baseline levels were high [1230 pg/ml (IQR 895) that diminished to 479 pg/ml (IQR 531) at 24 h of treatment initiation, 320 pg/ml (IQR 259) at 48 h, and 160 pg/ml (IQR 141) at 72 h (p = 0.001)]. Organ function and the risk of death improved following reductions in biomarker levels.

Some studies do not support the use of Cytosorb® in critically ill COVID-19 patients. The CYCOV trial [73] included 34 patients with severe COVID-19 pneumonia requiring ECMO. Seventeen patients received cytokine hemoadsorption for 72 h. There were no significant differences in IL-6 levels between the two groups after 72 h of treatment. This finding is explained by the low median baseline IL-6 concentrations that decreased from 357 pg/mL (IQR 177.4–118.0) to 98.6 pg/mL (71–192.8) in the cytokine adsorption group and from 289.0 pg/mL (87–787.0) to 110.0 pg/mL (48–198.5) in the control group. The results of the CYVOV trial are not comparable with the results of ongoing studies recruiting patients with highly increased IL-6 levels, as the rate of cytokine elimination by hemoadsorption depends on the presence of baseline high plasma levels of cytokines [22]. Moreover, the strategy for delivering cytokine hemadsorption also influences outcomes. Previous studies used fixed hemoadsorption regimens overlooking changes in IL-6 levels during therapy. Real-time IL-6 levels can be measured during the hemoadsorption sessions to withhold the treatment when IL-6 levels decrease, and the patient improves.

Endotoxin hemoadsorption with polymyxin B in sepsis

Endotoxin is a lipopolysaccharide (LPS) is a component present in the outer membrane of gram-negative bacteria. Its presence results in the elevation of pro-inflammatory and anti-inflammatory cytokines [74], activating the innate immune response and mediating the clinical manifestations of early sepsis. LPS elicits its actions through the transmembrane receptor toll-like receptor 4, expressed on innate immune system cells. The LPS-binding protein (LBP) carries circulating endotoxin and facilitates its recognition by the cell through receptor CD14. Recognition of the LPS-LBP complex transduces the intracellular endotoxin signal to the cell nucleus, resulting in the expression of a vast and complex network of inflammatory mediators, activation of macrophages, neutrophils, endothelial cells, and the coagulation cascade [75, 76].

Endotoxin activity is a valuable biomarker of disease severity. The lipid-A domain of endotoxin is the primary cause of the toxicity associated with LPS. The clinical syndrome is characterized by fever, diarrhea, hemodynamic instability, multiple organ failure, and death [77]. There is a tight correlation between endotoxin levels and severity of septic shock, organ dysfunction, and the risk of death [76]. Up to 82% of patients with septic shock have endotoxemia, showing intermediate or high endotoxin activity [78]. High endotoxin activity is associated with significantly high lactate concentration levels and the need for high-dose inotropes.

However, the measurement of human endotoxin is troublesome. The first diagnostic test available was the chromogenic Limulus amebocyte lysate assay that provided indirect endotoxin activity measures [79]. However, the assay is not specific for endotoxin, as other microbial products, especially fungi, can activate the Limulus reaction. Subsequently, in 2004, the endotoxin activity assay (EAA) was developed, a chemiluminescent rapid (30 min) assay described by Romaschin in 1998 [80]. It is based on the ability of an antibody to assemble an antibody-antigen complex in whole blood. This antibody targets the lipid A epitope of endotoxin. It has very high sensitivity due to its high binding affinity. Outstandingly, the antibody does not cross-react with fungal or gram-positive components (has high specificity). The assay results are expressed in EAA units (< 0.39 is considered low, 0.40–0.59 intermediate, 0.60–0.89 high, and > 0.9 very high or extreme). This assay uses neutrophils as a readout system; therefore, storing specimens for later assaying is impossible. Measurements must be performed within 3 h of collecting the sample. The EAA is the only assay approved by the Food and Drug Administration of the USA for measuring endotoxin activity in whole blood.

Consequently, endotoxin has been considered a therapeutic target in critically ill patients with sepsis and septic shock. Hemoadsorption with a fiber column immobilized with polymyxin B (PMX) (Toraymyxin®; Toray, Tokyo, Japan) is one of the best-known endotoxin depuration strategies. Another endotoxin and cytokine absorptive device is the oXiris® hemofilter (Baxter, Meyzieu, France).

Various clinical trials have evaluated the clinical efficacy of endotoxin hemoadsorption in septic shock. In a pilot study, 36 surgical patients with severe sepsis or septic shock due to intraabdominal infection were randomized to receive endotoxin hemoadsorption with PMX over 2 h (n = 17) or conventional therapy (n = 19) [81]. There were no statistically significant differences in EAA from baseline to 6, 8, or 24 h of treatment initiation between the two groups. Five of the eighteen (28%) patients in the control group and five of the seventeen (29%) patients in the PMX group died during the study period. There were no statistically significant differences in survival, the mean duration of ICU stay, or the number of ICU-free days between the two groups. However, PMX hemoperfusion improved cardiac and oxygen delivery indices and decreased the need for CRRT.

The studies evaluating the clinical effects of endotoxin hemadsorption have shown that the treatment is well-tolerated with virtually no significant side effects. In the previously mentioned study, the use of a PMX cartridge was safe and could improve cardiac and renal dysfunction. The EUPHAS trial [82] evaluated hemodynamic improvements with PMX hemoperfusion in 64 patients with intraabdominal infection-related severe sepsis and septic shock. The treatment was effective in reducing the dose of vasopressors and SOFA scores. PMX hemoadsorption decreased the 28-day mortality rate in the intervention group (32%) compared to the standard treatment group (53%). In the ABDOMIX trial [83], the authors included 243 patients who developed septic shock within the 12-h postoperative period after emergency laparotomy for secondary peritonitis. The PMX hemoperfusion group (n = 119) received two sessions of hemoadsorption in addition to conventional treatment. There were no significant differences in the SOFA score and 28-day mortality rate between the intervention and control groups (27.7% vs. 19.5%). A total of 220 sessions were performed, and early interruption of the first treatment session was registered in 25 cases (11%) due to circuit clotting. A total of two PMX hemoperfusion sessions were delivered in only 81 of 119 patients (69.8%). None of the previously discussed studies performed plasma EAA levels.

The EUPHRATES trial [84] was a well-performed randomized controlled trial with a large sample of patients and sufficient scientific rigor. This study used EAA for predictive enrichment in the selection of patients. The authors included 450 critically ill patients with septic shock and an EAA level of 0.6 or higher. The intervention group received PMX hemoperfusion (90–120 min sessions) in addition to standard therapy. The sessions were completed within 24 h of study enrollment (n = 224). The control group received simulated or “sham” hemoperfusion plus standard treatment (n = 226). PMX hemoperfusion did not significantly reduce the 28-day mortality at the end of the study. However, a post hoc analysis of the EUPHRATES trial [85], including 194 patients with EAA between 0.6 and 0.89, demonstrated a survival benefit from PMX hemoperfusion. Monti et al. [86] published the first study evaluating PMX hemoperfusion as rescue therapy in 52 patients with refractory septic shock poorly responsive to conventional therapy. The median SOFA score was 10 (8–14), and the serum lactate level was 5.89 ± 4.04 mmol/L. All patients were mechanically ventilated, and 90% had received corticosteroids. Rapid improvement in organ dysfunction was achieved after treatment. The overall 30-day mortality was lower (29%) than estimated by the acute severity scores (47%).

Accordingly, the subset of critically ill patients with refractory septic shock, severe multiorgan dysfunction, adequate source control, and EAA 0.6–0.9 are suitable candidates for endotoxin hemoadsorption. A prospective, multicenter, randomized, open-label trial of standard medical care plus the PMX cartridge versus standard medical care alone, the TIGRIS study [87], is currently recruiting critically ill patients with septic shock and EAA within the range of ≥ 0.60 to < 0.90. Eligible and consented participants are randomized to receive either two sessions of PMX hemoperfusion (for 1½ to 2 h per treatment session approximately 24 h apart) plus standard medical care or standard medical care alone. Their mortality status is assessed at 28 days of treatment. Follow-up is done for up to 12 months after enrollment.

Sequential hemoadsorption

Recent experience has shown that hemoadsorption aids the recovery of immune homeostasis. However, in some patients, endotoxin-only adsorption may be insufficient [88]. Endotoxemia and the overproduction of inflammatory mediators, in the form of cytokine storm, are paramount for the severity of sepsis and septic shock and determine prognosis [21, 89, 90]. Sequential hemoadsorption (endotoxin hemoadsorption with PMX, Toraymixin®, and subsequent cytokine hemoadsorption with Cytosorb®) has been applied in highly selected patients [91]. Precision medicine has allowed for a better selection of individuals according to their phenotypic and genetic profile to identify patients who could benefit from sequential hemadsorption (cytokine and endotoxin hemoadsorption). The candidates for sequential hemoadsorption are patients with refractory septic shock, multi-organ dysfunction, high endotoxemia, and hypercytokinemia (extremely high levels of IL-6). Real-time monitoring of plasma cytokines (IL-6, IL-10) can guide clinicians to withhold therapy [71]. The persistence of high levels of IL-10 is a valuable biomarker of a state of immunoparalysis [92]. Sequential hemoadsorption is intended to remove the primary stimulus that induces the dysregulated inflammatory response.

Hybrid therapies, such as the combined use of endotoxin hemoadsorption and coupled plasma filtration in a single circuit [93], have been studied in a particular group of cardiac surgery patients complicated with sepsis and EAA levels > 0.6. However, some researchers have excluded patients with high vasopressor requirements and acute severity scores in their studies. The presence of adequate drainage of infection source and the severity profile of patients should be considered before using hybrid hemoadsorption as adjunctive therapy.

We have clinical experience in sequential hemoadsorption with Toraymyxin® and Cytosorb, but other researchers have applied different approaches. Rossetti et al. [94] approach in pediatric patients proposes a double hemoadsorption using the CRRT circuit with the oXiris® membrane in association with two runs of Toraymyxin. Besides describing sequential techniques, novel advances have shown the scientific community that complementary hemoadsorption strategies are plausible to achieve homeostasis, are safe and have no adverse effects.

Conclusions

Blood purification remains an alternative for rescue treatment in the most severe cases with features that make them suitable to improve after treatment. Critically ill COVID-19 patients with severe ARDS refractory to prone positioning and hypercytokinemia can be considered to receive adjuvant treatment with cytokine hemoadsorption. Endotoxin and cytokine hemoadsorption remain a suitable rescue therapy for subsets of sepsis patients with high endotoxemia or hypercytokinemia and multiorgan dysfunction. Further studies and well-designed randomized controlled trials should be conducted to accurately set the indications and clinical benefits of cytokine hemoadsorption in COVID-19. Predictive enrichment should be used to improve the future design of trials evaluating the role of blood purification in sepsis.

Availability of data and materials

Not applicable.

Abbreviations

IL-6:

Interleukin 6

IL-10 :

Interleukin 10

ICU:

Intensive care unit

ARDS:

Acute respiratory distress syndrome

CRRT:

Continuous renal replacement therapy

MIS-C:

Multisystem inflammatory syndrome in children

ECMO:

Extracorporeal membrane oxygenation

SOFA:

Sequential organ function assessment

EAA :

Endotoxin activity assay

PMX:

Polymyxin B

References

  1. Cohen J (2002) The immunopathogenesis of sepsis. Nature 420(6917):885–891. https://doi.org/10.1038/nature01326

    Article  CAS  PubMed  Google Scholar 

  2. Levi M, van der Poll T (2017) Coagulation and sepsis. Thromb Res 149:38–44. https://doi.org/10.1016/j.thromres.2016.11.007

    Article  CAS  PubMed  Google Scholar 

  3. Matsumoto H, Ogura H, Shimizu K, Ikeda M, Hirose T, Matsuura H, Kang S, Takahashi K, Tanaka T, Shimazu T (2018) The clinical importance of a cytokine network in the acute phase of sepsis. Sci Rep 8(1):13995. https://doi.org/10.1038/s41598-018-32275-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hack CE, Aarden LA, Thijs LG (1997) Role of cytokines in sepsis. Adv Immunol 66:101–195. https://doi.org/10.1016/s0065-2776(08)60597-0

    Article  CAS  PubMed  Google Scholar 

  5. van der Poll T, van Deventer SJ (1999) Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 13(2):413–426, ix. https://doi.org/10.1016/s0891-5520(05)70083-0

    Article  PubMed  Google Scholar 

  6. de Waal MR, Abrams J, Bennett B, Figdor CG, de Vries JE (1991) Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 174(5):1209–1220. https://doi.org/10.1084/jem.174.5.1209

    Article  Google Scholar 

  7. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A (1991) IL-10 inhibits cytokine production by activated macrophages. J Immunol 147(11):3815–3822

    CAS  PubMed  Google Scholar 

  8. Schouten M, Wiersinga WJ, Levi M, van der Poll T (2008) Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 83(3):536–545. https://doi.org/10.1189/jlb.0607373

    Article  CAS  PubMed  Google Scholar 

  9. Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF et al (1989) Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J Exp Med 170(5):1627–1633. https://doi.org/10.1084/jem.170.5.1627

    Article  CAS  PubMed  Google Scholar 

  10. Nakae H, Endo S, Inada K, Takakuwa T, Kasai T (1996) Changes in adhesion molecule levels in sepsis. Res Commun Mol Pathol Pharmacol 91(3):329–338

    CAS  PubMed  Google Scholar 

  11. Shimaoka M, Park EJ (2008) Advances in understanding sepsis. Eur J Anaesthesiol Suppl 42:146–153. https://doi.org/10.1017/s0265021507003389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chai Z, Gatti S, Toniatti C, Poli V, Bartfai T (1996) Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice. J Exp Med 183(1):311–316. https://doi.org/10.1084/jem.183.1.311

    Article  CAS  PubMed  Google Scholar 

  13. Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Köhler G (1994) Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368(6469):339–342. https://doi.org/10.1038/368339a0

    Article  CAS  PubMed  Google Scholar 

  14. Tilg H, Dinarello CA, Mier JW (1997) IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol Today 18(9):428–432. https://doi.org/10.1016/s0167-5699(97)01103-1

    Article  CAS  PubMed  Google Scholar 

  15. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA (1990) Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75(1):40–47. https://doi.org/10.1182/blood.V75.1.40.40

    Article  CAS  PubMed  Google Scholar 

  16. Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK (2003) IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab 285(2):E433–E437. https://doi.org/10.1152/ajpendo.00074.2003

    Article  CAS  PubMed  Google Scholar 

  17. Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW (1994) Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83(1):113–118. https://doi.org/10.1182/blood.V83.1.113.113

    Article  CAS  PubMed  Google Scholar 

  18. Zhang XL, Topley N, Ito T, Phillips A (2005) Interleukin-6 regulation of transforming growth factor (TGF)-beta receptor compartmentalization and turnover enhances TGF-beta1 signaling. J Biol Chem 280(13):12239–12245. https://doi.org/10.1074/jbc.M413284200

    Article  CAS  PubMed  Google Scholar 

  19. Kumar AT, Sudhir U, Punith K, Kumar R, Ravi Kumar VN, Rao MY (2009) Cytokine profile in elderly patients with sepsis. Indian J Crit Care Med 13(2):74–78. https://doi.org/10.4103/0972-5229.56052

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tschaikowsky K, Hedwig-Geissing M, Braun GG, Radespiel-Troeger M (2011) Predictive value of procalcitonin, interleukin-6, and C-reactive protein for survival in postoperative patients with severe sepsis. J Crit Care 26(1):54–64. https://doi.org/10.1016/j.jcrc.2010.04.011

    Article  CAS  PubMed  Google Scholar 

  21. Jekarl DW, Lee SY, Lee J, Park YJ, Kim Y, Park JH, Wee JH, Choi SP (2013) Procalcitonin as a diagnostic marker and IL-6 as a prognostic marker for sepsis. Diagn Microbiol Infect Dis 75(4):342–347. https://doi.org/10.1016/j.diagmicrobio.2012.12.011

    Article  CAS  PubMed  Google Scholar 

  22. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC (2007) Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 167(15):1655–1663. https://doi.org/10.1001/archinte.167.15.1655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Oda S, Hirasawa H, Shiga H, Nakanishi K, Matsuda K, Nakamua M (2005) Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis. Cytokine 29(4):169–175. https://doi.org/10.1016/j.cyto.2004.10.010

    Article  CAS  PubMed  Google Scholar 

  24. Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, Bozza MT, Castro-Faria-Neto HC, Bozza PT (2007) Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care 11(2):R49. https://doi.org/10.1186/cc5783

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gogos CA, Drosou E, Bassaris HP, Skoutelis A (2000) Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 181(1):176–180. https://doi.org/10.1086/315214

    Article  CAS  PubMed  Google Scholar 

  26. Chaudhry H, Zhou J, Zhong Y, Ali MM, McGuire F, Nagarkatti PS, Nagarkatti M (2013) Role of cytokines as a double-edged sword in sepsis. In Vivo 27(6):669–684

    CAS  PubMed  Google Scholar 

  27. Krenn CG, Steltzer H (2021) Hämoadsorption zur Blutreinigung – Unvergleichbarkeit der klinisch angebotenen Verfahren [Hemoadsorption for blood purification-incomparability of clinically available procedures]. Med Klin Intensivmed Notfmed 116(5):449–453. German. https://doi.org/10.1007/s00063-020-00702-2

    Article  CAS  PubMed  Google Scholar 

  28. Köhler T, Schwier E, Praxenthaler J, Kirchner C, Henzler D, Eickmeyer C (2021) Therapeutic modulation of the host defense by hemoadsorption with CytoSorb®-Basics, indications and perspectives-a scoping review. Int J Mol Sci. 22(23):12786. https://doi.org/10.3390/ijms222312786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bonavia A, Groff A, Karamchandani K, Singbartl K (2018) Clinical utility of extracorporeal cytokine hemoadsorption therapy: a literature review. Blood Purif. 46(4):337–349. https://doi.org/10.1159/000492379 Epub 2018 Sep 3. PMID: 30176653

    Article  CAS  PubMed  Google Scholar 

  30. Friesecke S, Stecher SS, Gross S, Felix SB, Nierhaus A (2017) Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: a prospective single-center study. J Artif Organs 20(3):252–259. https://doi.org/10.1007/s10047-017-0967-4

    Article  CAS  PubMed  Google Scholar 

  31. Paul R, Sathe P, Kumar S, Prasad S, Aleem M, Sakhalvalkar P (2021) Multicentered prospective investigator initiated study to evaluate the clinical outcomes with extracorporeal cytokine adsorption device (CytoSorb(®)) in patients with sepsis and septic shock. World J Crit Care Med 10(1):22–34. https://doi.org/10.5492/wjccm.v10.i1.22

    Article  PubMed  PubMed Central  Google Scholar 

  32. Brouwer WP, Duran S, Kuijper M, Ince C (2019) Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study. Crit Care 23(1):317. https://doi.org/10.1186/s13054-019-2588-1

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hawchar F, László I, Öveges N, Trásy D, Ondrik Z, Molnar Z (2019) Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study. J Crit Care 49:172–178. https://doi.org/10.1016/j.jcrc.2018.11.003

    Article  CAS  PubMed  Google Scholar 

  34. Rugg C, Klose R, Hornung R, Innerhofer N, Bachler M, Schmid S, Fries D, Ströhle M (2020) Hemoadsorption with CytoSorb in Septic Shock Reduces Catecholamine Requirements and In-Hospital Mortality: A Single-Center Retrospective ‘Genetic’ Matched Analysis. Biomedicines 8(12). https://doi.org/10.3390/biomedicines8120539

  35. Schneider AG, André P, Scheier J, Schmidt M, Ziervogel H, Buclin T, Kindgen-Milles D (2021) Pharmacokinetics of anti-infective agents during CytoSorb hemoadsorption. Sci Rep. 11(1):10493. https://doi.org/10.1038/s41598-021-89965-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. U.S. Food and Drug Administration. CytoSorb ® 300 mL device approved by FDA for emergency treatment of COVID-19. 2020.

  37. Yang XH, Sun RH, Zhao MY, Chen EZ, Liu J, Wang HL, Yang RL, Chen DC (2020) Expert recommendations on blood purification treatment protocol for patients with severe COVID-19. Chronic Dis Transl Med 6(2):106–114. https://doi.org/10.1016/j.cdtm.2020.04.002

    Article  PubMed  PubMed Central  Google Scholar 

  38. Napp LC, Bauersachs J (2020) Extracorporeal hemoadsorption: an option for COVID-19-associated cytokine storm syndrome. Shock 54(5):700–701. https://doi.org/10.1097/shk.0000000000001568

    Article  CAS  PubMed  Google Scholar 

  39. Al Shareef K, Bakouri M (2021) Cytokine blood filtration responses in COVID-19. Blood Purif 50(2):141–149. https://doi.org/10.1159/000508278

    Article  CAS  PubMed  Google Scholar 

  40. Weaver LK, Behrens EM (2017) Weathering the storm: Improving therapeutic interventions for cytokine storm syndromes by targeting disease pathogenesis. Curr Treatm Opt Rheumatol 3(1):33–48. https://doi.org/10.1007/s40674-017-0059-x

    Article  PubMed  PubMed Central  Google Scholar 

  41. Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF (2020) Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med 46(4):579–582. https://doi.org/10.1007/s00134-020-05967-x

    Article  CAS  PubMed  Google Scholar 

  42. Siddiqi HK, Mehra MR (2020) COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant 39(5):405–407. https://doi.org/10.1016/j.healun.2020.03.012

    Article  PubMed  PubMed Central  Google Scholar 

  43. Robba C, Battaglini D, Pelosi P, Rocco PRM (2020) Multiple organ dysfunction in SARS-CoV-2: MODS-CoV-2. Expert Rev Respir Med 14(9):865–868. https://doi.org/10.1080/17476348.2020.1778470

    Article  CAS  PubMed  Google Scholar 

  44. Kox M, Waalders NJB, Kooistra EJ, Gerretsen J, Pickkers P (2020) Cytokine levels in critically ill patients with COVID-19 and other conditions. Jama. 324(15):1565. https://doi.org/10.1001/jama.2020.17052

    Article  CAS  PubMed Central  Google Scholar 

  45. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223):497–506. https://doi.org/10.1016/s0140-6736(20)30183-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Osuchowski MF, Winkler MS, Skirecki T, Cajander S, Shankar-Hari M, Lachmann G, Monneret G, Venet F, Bauer M, Brunkhorst FM, Weis S, Garcia-Salido A, Kox M, Cavaillon JM, Uhle F, Weigand MA, Flohé SB, Wiersinga WJ, Almansa R, de la Fuente A, Martin-Loeches I, Meisel C, Spinetti T, Schefold JC, Cilloniz C, Torres A, Giamarellos-Bourboulis EJ, Ferrer R, Girardis M, Cossarizza A, Netea MG, van der Poll T, Bermejo-Martín JF, Rubio I (2021) The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity. Lancet Respir Med 9(6):622–642. https://doi.org/10.1016/s2213-2600(21)00218-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lopes-Pacheco M, Silva PL, Cruz FF, Battaglini D, Robba C, Pelosi P, Morales MM, Caruso Neves C, Rocco PRM (2021) Pathogenesis of multiple organ injury in COVID-19 and potential therapeutic strategies. Front Physiol 12:593223. https://doi.org/10.3389/fphys.2021.593223

    Article  PubMed  PubMed Central  Google Scholar 

  48. Pedersen SF, Ho YC (2020) SARS-CoV-2: a storm is raging. J Clin Invest 130(5):2202–2205. https://doi.org/10.1172/jci137647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LFF, de Oliveira EP, Saldiva PHN, Mauad T, Negri EM (2020) Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost 18(6):1517–1519. https://doi.org/10.1111/jth.14844

    Article  CAS  PubMed  Google Scholar 

  50. Liu Q, Zhou YH, Yang ZQ (2016) The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol 13(1):3–10. https://doi.org/10.1038/cmi.2015.74

    Article  CAS  PubMed  Google Scholar 

  51. Murthy S, Gomersall CD, Fowler RA (2020) Care for Critically Ill Patients With COVID-19. Jama 323(15):1499–1500. https://doi.org/10.1001/jama.2020.3633

    Article  PubMed  Google Scholar 

  52. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z (2020) Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. Jama 323(11):1061–1069. https://doi.org/10.1001/jama.2020.1585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ruiz-Rodríguez JC, Molnar Z, Deliargyris EN, Ferrer R (2021) The use of CytoSorb therapy in critically ill COVID-19 patients: review of the rationale and current clinical experiences. Crit Care Res Pract 2021:7769516. https://doi.org/10.1155/2021/7769516

    Article  PubMed  PubMed Central  Google Scholar 

  54. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395(10229):1033–1034. https://doi.org/10.1016/s0140-6736(20)30628-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ingraham NE, Lotfi-Emran S, Thielen BK, Techar K, Morris RS, Holtan SG, Dudley RA, Tignanelli CJ (2020) Immunomodulation in COVID-19. Lancet Respir Med 8(6):544–546. https://doi.org/10.1016/s2213-2600(20)30226-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rizvi S, Danic M, Silver M, LaBond V (2021) Cytosorb filter: An adjunct for survival in the COVID-19 patient in cytokine storm? a case report. Heart Lung 50(1):44–50. https://doi.org/10.1016/j.hrtlng.2020.09.007

    Article  PubMed  Google Scholar 

  57. Berlot G, Tomasini A, Roman Pognuz E, Randino A, Chiella F, La Fata C, Piva M, Amato P, di Maso V, Bianco F, Gerini U, Tomietto P, Trenti T (2020) The combined use of tocilizumab and hemoadsorption in a patient with SARS-COV-2-19-associated pneumonia: a case report. Nephron 144(9):459–462. https://doi.org/10.1159/000509738

    Article  CAS  PubMed  Google Scholar 

  58. Mezger M, Eite L, Ensminger S, Pogorzalek D, Huang Z, Graf T (2020) Sequential use of hemoadsorption using cytosorb and biosky filter-technology in a COVID-19 patient suffering from severe ARDS. Arch Clin Med Case Rep 5:969–977

    Google Scholar 

  59. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) (2020) Chin. Med J (Engl) 133(9):1087–1095. https://doi.org/10.1097/cm9.0000000000000819

    Article  Google Scholar 

  60. Alberici F, Delbarba E, Manenti C, Econimo L, Valerio F, Pola A, Maffei C, Possenti S, Piva S, Latronico N, Focà E, Castelli F, Gaggia P, Movilli E, Bove S, Malberti F, Farina M, Bracchi M, Costantino EM, Bossini N, Gaggiotti M, Scolari F (2020) Management of patients on dialysis and with kidney transplantation during the SARS-CoV-2 (COVID-19) pandemic in Brescia, Italy. Kidney Int Rep 5(5):580–585. https://doi.org/10.1016/j.ekir.2020.04.001

    Article  PubMed  PubMed Central  Google Scholar 

  61. Asociación Panameña de Medicina Critica y Terapia Intensiva, Guías Nacionales de Atención de Pacientes Adultos COVID-19 Versión 2.0. Published on March 22nd on https://medcriticapanama.com. Accessed on 7 Dec 2021.

  62. González C, Yama E, Yomayusa N, Vargas J, Rico J, Ariza A et al (2020) Consenso colombiano de expertos sobre recomendaciones informadas en la evidencia para la prevención, el diagnóstico y el manejo de la lesión renal aguda por SARS-CoV-2/COVID-19. Rev Colomb Nefrol 7(1):89–117. https://doi.org/10.22265/acnef.7.Supl.2.473

    Article  Google Scholar 

  63. Rampino T, Gregorini M, Perotti L, Ferrari F, Pattonieri EF, Grignano MA, Valente M, Garrone A, Islam T, Libetta C, Sepe V, Albertini R, Bruno R, Belliato M (2021) Hemoperfusion with CytoSorb as adjuvant therapy in critically ill patients with SARS-CoV2 pneumonia. Blood Purif 50(4-5):566–571. https://doi.org/10.1159/000511725

    Article  CAS  PubMed  Google Scholar 

  64. Damiani M, Gandini L, Landi F, Borleri G, Fabretti F, Gritti G, Riva I (2021) Extracorporeal cytokine hemadsorption in severe COVID-19 respiratory failure. Respir Med 185:106477. https://doi.org/10.1016/j.rmed.2021.106477

    Article  PubMed  PubMed Central  Google Scholar 

  65. Nassiri AA, Hakemi MS, Miri MM, Shahrami R, Koomleh AA, Sabaghian T (2021) Blood purification with CytoSorb in critically ill COVID-19 patients: A case series of 26 patients. Artif Organs 45(11):1338–1347. https://doi.org/10.1111/aor.14024

    Article  CAS  PubMed  Google Scholar 

  66. Paisey C, Patvardhan C, Mackay M, Vuylsteke A, Bhagra SK (2021) Continuous hemadsorption with cytokine adsorber for severe COVID-19: a case series of 15 patients. Int J Artif Organs 44(10):664–674. https://doi.org/10.1177/03913988211023782

    Article  CAS  PubMed  Google Scholar 

  67. Villa G, Romagnoli S, De Rosa S, Greco M, Resta M, Pomarè Montin D, Prato F, Patera F, Ferrari F, Rotondo G, Ronco C (2020) Blood purification therapy with a hemodiafilter featuring enhanced adsorptive properties for cytokine removal in patients presenting COVID-19: a pilot study. Crit Care 24(1):605. https://doi.org/10.1186/s13054-020-03322-6

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ruiz-Rodríguez JC, Chiscano-Camón L, Palmada C, Ruiz-Sanmartin A, García-de-Acilu M, Plata-Menchaca E, Perurena-Prieto J, Hernandez-Gonzalez M, Pérez-Carrasco M, Soler-Palacin P, Ferrer R (2021) Hemadsorption as a treatment option for multisystem inflammatory syndrome in children associated with COVID-19. a case report. Front Immunol 12:665824. https://doi.org/10.3389/fimmu.2021.665824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Reiter K, Bordoni V, Dall'Olio G, Ricatti MG, Soli M, Ruperti S, Soffiati G, Galloni E, D'Intini V, Bellomo R, Ronco C (2002) In vitro removal of therapeutic drugs with a novel adsorbent system. Blood Purif 20(4):380–388. https://doi.org/10.1159/000063108

    Article  CAS  PubMed  Google Scholar 

  70. Honore PM, Hoste E, Molnar Z, Jacobs R, Joannes-Boyau O, Malbrain M, Forni LG (2019) Cytokine removal in human septic shock: Where are we and where are we going? Ann Intensive Care 9(1):56. https://doi.org/10.1186/s13613-019-0530-y

    Article  PubMed  PubMed Central  Google Scholar 

  71. Ruiz-Rodríguez JC, Chiscano-Camón L, Ruiz-Sanmartin A, Palmada C, Plata-Menchaca EP, Franco-Jarava C, Pérez-Carrasco M, Hernández-González M, Ferrer R (2021) Cytokine hemoadsorption as rescue therapy for critically ill patients with SARS-CoV-2 pneumonia with severe respiratory failure and hypercytokinemia. Front Med (Lausanne) 8:779038. https://doi.org/10.3389/fmed.2021.779038

  72. Leisman DE, Ronner L, Pinotti R, Taylor MD, Sinha P, Calfee CS, Hirayama AV, Mastroiani F, Turtle CJ, Harhay MO, Legrand M, Deutschman CS (2020) Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med 8(12):1233–1244. https://doi.org/10.1016/s2213-2600(20)30404-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Supady A, Weber E, Rieder M, Lother A, Niklaus T, Zahn T, Frech F, Müller S, Kuhl M, Benk C, Maier S, Trummer G, Flügler A, Krüger K, Sekandarzad A, Stachon P, Zotzmann V, Bode C, Biever PM, Staudacher D, Wengenmayer T, Graf E, Duerschmied D (2021) Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial. Lancet Respir Med 9(7):755–762. https://doi.org/10.1016/s2213-2600(21)00177-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ankawi G, Neri M, Zhang J, Breglia A, Ricci Z, Ronco C (2018) Extracorporeal techniques for the treatment of critically ill patients with sepsis beyond conventional blood purification therapy: the promises and the pitfalls. Crit Care 22(1):262. https://doi.org/10.1186/s13054-018-2181-z

    Article  PubMed  PubMed Central  Google Scholar 

  75. Lakshmikanth CL, Jacob SP, Chaithra VH, de Castro-Faria-Neto HC, Marathe GK (2016) Sepsis: in search of cure. Inflamm Res 65(8):587–602. https://doi.org/10.1007/s00011-016-0937-y

    Article  CAS  PubMed  Google Scholar 

  76. Marshall JC, Foster D, Vincent JL, Cook DJ, Cohen J, Dellinger RP, Opal S, Abraham E, Brett SJ, Smith T, Mehta S, Derzko A, Romaschin A (2004) Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis 190(3):527–534. https://doi.org/10.1086/422254

    Article  CAS  PubMed  Google Scholar 

  77. Ronco C (2014) Endotoxin removal: history of a mission. Blood Purif 37(Suppl 1):5–8. https://doi.org/10.1159/000356831

    Article  CAS  PubMed  Google Scholar 

  78. Bottiroli M, Monti G, Pinciroli R, Vecchi I, Terzi V, Ortisi G, Casella G, Fumagalli R (2017) Prevalence and clinical significance of early high Endotoxin Activity in septic shock: An observational study. J Crit Care 41:124–129. https://doi.org/10.1016/j.jcrc.2017.04.030

    Article  CAS  PubMed  Google Scholar 

  79. Levin J, Bang FB (1968) Clottable protein in Limulus; its localization and kinetics of its coagulation by endotoxin. Thromb Diath Haemorrh 19(1):186–197. https://doi.org/10.1055/s-0038-1651195

    Article  CAS  PubMed  Google Scholar 

  80. Romaschin AD, Harris DM, Ribeiro MB, Paice J, Foster DM, Walker PM, Marshall JC (1998) A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence. J Immunol Methods 212(2):169–185. https://doi.org/10.1016/s0022-1759(98)00003-9

    Article  CAS  PubMed  Google Scholar 

  81. Vincent JL, Laterre PF, Cohen J, Burchardi H, Bruining H, Lerma FA, Wittebole X, De Backer D, Brett S, Marzo D, Nakamura H, John S (2005) A pilot-controlled study of a polymyxin B-immobilized hemoperfusion cartridge in patients with severe sepsis secondary to intra-abdominal infection. Shock 23(5):400–405. https://doi.org/10.1097/01.shk.0000159930.87737.8a

    Article  CAS  PubMed  Google Scholar 

  82. Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, Malcangi V, Petrini F, Volta G, Bobbio Pallavicini FM, Rottoli F, Giunta F, Ronco C (2009) Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. Jama 301(23):2445–2452. https://doi.org/10.1001/jama.2009.856

    Article  CAS  PubMed  Google Scholar 

  83. Payen DM, Guilhot J, Launey Y, Lukaszewicz AC, Kaaki M, Veber B, Pottecher J, Joannes-Boyau O, Martin-Lefevre L, Jabaudon M, Mimoz O, Coudroy R, Ferrandière M, Kipnis E, Vela C, Chevallier S, Mallat J, Robert R (2015) Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med 41(6):975–984. https://doi.org/10.1007/s00134-015-3751-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dellinger RP, Bagshaw SM, Antonelli M, Foster DM, Klein DJ, Marshall JC, Palevsky PM, Weisberg LS, Schorr CA, Trzeciak S, Walker PM (2018) Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial. Jama 320(14):1455–1463. https://doi.org/10.1001/jama.2018.14618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Klein DJ, Foster D, Walker PM, Bagshaw SM, Mekonnen H, Antonelli M (2018) Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial. Intensive Care Med 44(12):2205–2212. https://doi.org/10.1007/s00134-018-5463-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Monti G, Terzi V, Calini A, Di Marco F, Cruz D, Pulici M, Brioschi P, Vesconi S, Fumagalli R, Casella G (2015) Rescue therapy with polymyxin B hemoperfusion in high-dose vasopressor therapy refractory septic shock. Minerva Anestesiol 81(5):516–525

    CAS  PubMed  Google Scholar 

  87. Iba T, Klein DJ (2019) The wind changed direction and the big river still flows: from EUPHRATES to TIGRIS. J Intensive Care 7(1):31. https://doi.org/10.1186/s40560-019-0386-0

    Article  PubMed  PubMed Central  Google Scholar 

  88. Malard B, Lambert C, Kellum JA (2018) In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp 6(1):12. https://doi.org/10.1186/s40635-018-0177-2

    Article  PubMed  PubMed Central  Google Scholar 

  89. Opal SM, Scannon PJ, Vincent JL, White M, Carroll SF, Palardy JE, Parejo NA, Pribble JP, Lemke JH (1999) Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J Infect Dis 180(5):1584–1589. https://doi.org/10.1086/315093

    Article  CAS  PubMed  Google Scholar 

  90. Chousterman BG, Swirski FK, Weber GF (2017) Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 39(5):517–528. https://doi.org/10.1007/s00281-017-0639-8

    Article  CAS  PubMed  Google Scholar 

  91. Ruiz-Rodríguez JC, Chiscano-Camón L, Palmada C, Ruiz-Sanmartin A, Pérez-Carrasco M, Larrosa N, González JJ, Hernández-González M, Ferrer R (2021) Endotoxin and cytokine sequential hemoadsorption in septic shock and multi-organ failure. Blood Purif:1–4. https://doi.org/10.1159/000518229

  92. Hamers L, Kox M, Pickkers P (2015) Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options. Minerva Anestesiol 81(4):426–439

    CAS  PubMed  Google Scholar 

  93. Yaroustovsky M, Abramyan M, Krotenko N, Popov D, Plyushch M, Rogalskaya E (2015) A pilot study of selective lipopolysaccharide adsorption and coupled plasma filtration and adsorption in adult patients with severe sepsis. Blood Purif 39(1-3):210–217. https://doi.org/10.1159/000371754

    Article  CAS  PubMed  Google Scholar 

  94. Rossetti E, Guzzo I, Ricci Z, Bianchi R, Picardo S (2019) Double extracorporeal blood purification in refractory pediatric septic shock. Paediatr Anaesth 29(9):966–967. https://doi.org/10.1111/pan.13700

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Intensive Care Department, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Passeig de la Vall d’Hebron, 119-129, Barcelona, Spain

    Juan Carlos Ruiz-Rodríguez, Erika P. Plata-Menchaca, Luis Chiscano-Camón, Adolf Ruiz-Sanmartin & Ricard Ferrer

  2. Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Juan Carlos Ruiz-Rodríguez, Erika P. Plata-Menchaca, Luis Chiscano-Camón, Adolf Ruiz-Sanmartin & Ricard Ferrer

  3. Departament de Medicina, Universitat Autonoma de Barcelona, Bellatera, Spain

    Juan Carlos Ruiz-Rodríguez, Luis Chiscano-Camón, Adolf Ruiz-Sanmartin & Ricard Ferrer

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  1. Juan Carlos Ruiz-Rodríguez
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  2. Erika P. Plata-Menchaca
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  3. Luis Chiscano-Camón
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  4. Adolf Ruiz-Sanmartin
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  5. Ricard Ferrer
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Contributions

All authors have made substantial contributions to the conception and design of the work. JCR, AR, and LC contributed to the design of the work, interpretation of data, and drafting of the work. EPM contributed to the interpretation of data and contributed substantially to writing the final version of the work. RF substantively revised the content and design of the work. All authors have approved the submitted version for its publication. All authors read and approved the final manuscript.

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Correspondence to Ricard Ferrer.

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JCR have received fees from Palex. RF have received fees from Cytosorbents and Estor. The rest of the authors declare that they have no competing interests.

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Ruiz-Rodríguez, J.C., Plata-Menchaca, E.P., Chiscano-Camón, L. et al. Blood purification in sepsis and COVID-19: what´s new in cytokine and endotoxin hemoadsorption. J Anesth Analg Crit Care 2, 15 (2022). https://doi.org/10.1186/s44158-022-00043-w

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Keywords

Journal of Anesthesia, Analgesia and Critical Care

ISSN: 2731-3786

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