In this retrospective, investigator initiated study we analyzed the course of treatment in 70 surgical intensive care patients who received hemoadsorption with the CytoSorb® adsorber in septic shock or non-infectious SIRS in addition to standard therapy [1, 38]. No possible side effects occurred during the course of the hemoadsorption treatment which suggests that the therapy is well tolerated and does not pose added risks to the patient. The mortality rate of 50% was clearly lower than predicted by APACHE-II (73.3%) and SOFA score (62.1%).
A main goal of our study was to identify parameters of response and predictors of survival associated with the treatment. As a major predictor we found an association of the applied dose with survival (Fig. 2 and Fig. 4). So far, no dose-response relationship had been described. We calculated the dose as the amount of blood purified (ABP) by the adsorber as a function of blood flow and duration in relation to body weight. Differences in ABP were caused by 3 mechanisms:
First, the blood flow through the CVVHD was set according to standard protocols for CRRT with citrate anticoagulation, resulting in blood flows from 100–150 ml/min. The blood flow was adjusted for CVVHD needs but was not targeted in respect to ABP. As a result, smaller patients received higher doses of hemoadsorption. Second, for the lack of data on when to end treatment, hemoadsorption was stopped at the discretion of the treating intensivist, e.g. after hemodynamic stabilisation, resulting in different treatment periods. Third, some patients with a foudroyant course of the disease had died early before the planned end of hemoadsorption treatment.
The duration of hemoadsorption treatment in our cohort (85.6 h) was longer than previously described, which ranged from 50 h , 56 h  up to 63 h . Since no exact data on blood flow were reported, we can only speculate that ABP was higher in our cohort. Compared to data from the international CytoSorb® registry  the disease severity (APACHE II 29.8 vs. 28.97) and the predicted mortality (70.4% vs. 69.4%) were similar, but we observed a much lower mortality (50% vs. 66.2%). The number of adsorbers used was 3.2 on average in our cohort, but was much lower in the registry in a range of 1–5 adsorbers per patient . These patients received a mean hemoadsorption treatment of 50 h, which is comparable to the low ABP cluster of < 6 ml/kg BW (48.9 h) in our cohort with a quite similar mortality of 65%. If a dose of ≥ 13 l/kg BW were targeted, the only way this could be achieved within 50 h with a blood flow of at least 303 ml/min, assuming a body weight of 70 kg. In reality, very few dialysis machines are able to deliver such blood flows, especially with the use of citrate anticoagulation. Other authors recommend lower blood flow rates . We conclude that an ABP of ≥ 13 l/kg BW was not achieved in any of the previous investigations.
As a clinical consequence we have started targeting an ABP of ≥ 13 l/kg BW for standard application. To calculate the desired dose we have provided an Excel (Microsoft Corp. Redmont, WA. U.S.A.) based tool in the online supplements. Additionally, we have to consider the saturation kinetics of the adsorber over time [23, 25]. It is possible that the effect on the observed reduction in mortality may also be depending on the change intervals and useful life of the cartridge. Whether reducing the recommended change interval from 24 h to 12 h or even 8 h in the acute phase of massive hyperinflammation has an additional effect on outcome, should be investigated in further studies.
IL-6 levels at baseline were substantially higher in our cohort than in other previously published studies targeting the same disease population [29–31, 39, 40] and were considerably higher than recommended entry levels  (Fig. 5). A possible explanation may be the early and frequent monitoring of IL-6 levels leading to detection of high IL-6 levels that occur early in septic shock and rapidly decrease in the further course of the disease . The course of decreasing levels of IL-6 is concordant with the concentration dependent adsorption kinetics of the adsorber cartridge [23, 25] and explains the visible approximation of the IL-6 levels after only four hours (Fig. 5). However, contrary to previous data [39, 43], the IL-6 levels were not directly related to mortality. Instead, the time course of IL-6 and the ABP were predictive of outcome suggesting that the ability to efficiently remove IL-6 faster than new cytokines are released by the organism is crucial for survival. In consequence, persistent high or increasing levels of IL-6 during the treatment phase were associated with worse outcome and may represent important prognosis factors.
We have not observed any differences in MAP between survivors and non-survivors or between the three ABP clusters. We assume that this is mainly the result of an effective vasopressor regime that targets the standard MAP values. Among survivors, vasopressor use decreased to 31.6% after 72 hours and to 26.3% after 96 hours compared to baseline. In accordance with previous studies [28, 29, 32, 40, 44] a rapid shock reversal was achieved (Fig. 5).
There was a trend, though not statistically significant, to lower MAP in the highest ABP cluster (C) at the start of hemoadsorption which corresponds to the high IL-6 levels at baseline. Presumably, these patients had sepsis-induced volume deficit [1, 45], insufficient norepinephrine doses or a decrease in cardiac output . It is possible that an individual adjustment of the MAP target has been made . Non-survivors exhibited higher norepinephrine (Fig. 5) and lactate levels, probably due to impaired microcirculation  and more vasoplegia, which means a higher risk of death. Elevated lactate levels are considered an independent risk factor for death in septic shock . These differences were not observed between ABP clusters.
IL-6 has been reported to be associated with sepsis severity, end organ damage [49, 50] and increased mortality in septic patients [42, 49]. Frencken and colleagues observed that high levels of IL-6 and IL-10 are both associated with increased mortality. Of note, the ratio of the pro-inflammatory (IL-6) to the anti-inflammatory (IL-10) cytokine had no influence on mortality . However, a better understanding of the „double-edged sword“ of pro- and anti-inflammatory cytokines and their interaction in a temporal context is crucial for the creation of new therapeutic approaches . In respect to cytokine load, patients with high ABP had exhibited a specifically severe pro-inflammatory situation (cytokine storm) with the highest IL-6 values of all clusters (Table 3, Fig. 3). The fact that those patients actually did well implies differences in pathophysiology at baseline. We conclude that patients with extreme hyperinflammation may be the greatest beneficiaries from a therapeutic approach that specifically targets removal of pro-inflammatory substances, although the initial IL-6 levels were not directly related to mortality.
Previous studies in patients in septic shock with hemoadsorption had identified a pneumogenic focus as an independent risk factor for death . In contrast, we could not establish such a correlation for any infectious focus, however all patients were surgical patients and pneumonia was postoperative. Likewise, a non-infectious SIRS was not relevant for mortality.
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), which first appeared in December 2019 in China, has spread rapidly around the world. Some patients develop a severe cytokine release syndrome (CRS), a cytokine storm, in response to the virus. Subsequent organ failure can potentially lead to death [52–56]. Such hyperinflammatory state can lead to impairment or destruction of the lungs and other organs. As an extreme increase in various pro- and anti-inflammatory cytokines such as IL-1, IL-2, IL-7, IL-10, G-CSF, MCP-1, MIP-1α, INF-γ and TNF-α  has been postulated some authors have advocated for the use of hemoadsorption in treating COVID-19-associated cytokine storm syndrome [56–59]. As a consequence, in April 2020, the CytoSorb® was temporarily approved by the U.S. Food and Drug Administration (FDA) for emergency use in patients with CRS under certain conditions .
The present study has several limitations. As in every retrospective design treatment effects may be overestimated, side effects may be underestimated and confounders may not be adequately represented. We have also included some patients who presented similarly from a biological perspective with initial high accumulation of different cytokines from the IL-6 family  but did not have an-infectious cause of SIRS. Even so, the phenotype was quite similar to septic patients with proven infection. Our cohort of patients received a new intervention with standardized indication and was comparable by physiologic means to other published data. We used a stepwise backward design to identify factors associated with improved outcome and found an association between the amount of blood purified and survival. These results are for hypothesis generating and should be used for adequately powered prospective trials.