Introduction
Sepsis and septic shock are a major health burden worldwide leading to approximately 5 million deaths annually [
1‐
3]. Although the reported incidence of sepsis varies widely and is notoriously unreliable, it is the leading cause of mortality globally, and its incidence currently is thought to rise due to aging populations, increasing comorbidity and greater recognition due to increasing awareness of this disease over the past decades [
4,
5]. Septic shock is thought to arise from a disrupted balance between pro-inflammatory and anti-inflammatory cytokines in response to infection, ultimately leading to cell and organ dysfunction [
5]. Recent advances in the field of sepsis treatment had variable success, presumably because sepsis is a very heterogeneous disease entity and therefore resists a one-size-fits-all approach. To date, only advancement in supportive care, such as timely delivery of antibiotics and early fluid resuscitation, has led to a significant improvement in the outcome of sepsis [
4]. Other treatment modalities, such as continuous renal replacement therapy (CRRT) have not shown clinical benefit, although it was shown that cytokines such as tumour necrosis factor (TNF) α and interleukin (IL) 1β could be cleared from serum [
6‐
8].
Recently, CytoSorb has been developed and approved in Europe since 2011 for use in patients with severe cytokinaemia [
9‐
11]. CytoSorb is a filter which can be used in addition to continuous renal replacement therapy (CRRT), and other devices such as hemodialysis, heart-lung machines and extracorporeal membrane oxygenation. It is a non-pyrogetic, sterile single-use filter for the removal of endotoxins and cytokines [
10]. Since it is able to reduce circulating cytokines such as IL-1β, TNF-α, IL-6 and IL-10 by more than 90%, CytoSorb is thought to have considerable impact on a derailed host response causing shock [
10,
12]. This treatment modality has shown promising results in animal studies [
13,
14] and case reports [
15‐
18]. Nevertheless, a recent randomized trial in patients with septic shock and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) assessed, but was not powered for mortality, and found no difference in clinical outcome [
11,
19]. It is therefore unknown whether CytoSorb leads to a survival benefit.
Hence, the aim of the current study is to investigate whether the application of CytoSorb in addition to CRRT leads to a reduction in 28-day mortality compared to CRRT alone in patients with septic shock in the ICU, by using the inversed probability of treatment weights method.
Discussion
In this investigator-initiated retrospective study, we have shown for the first time that CytoSorb therapy may improve the 28-day mortality for patients with septic shock, compared to CRRT. To our knowledge, this represents the largest cohort of septic shock patients treated with CytoSorb therapy in which mortality was assessed as a primary outcome. The observed mortality rate for CytoSorb therapy was significantly below the predicted risk of death according to the SOFA score [
21,
22]. For CytoSorb, factors associated with a higher chance of 28-day mortality were older age, higher lactate levels at the start of therapy and pneumosepsis.
In the current study, it was investigated whether CytoSorb improves survival when compared to CRRT alone in an IPTW analysis. Per protocol, patients were only treated with CytoSorb in case of septic shock, at the discretion of the treating intensive care physician. As a result, it was found that at the start of therapy, patients treated with CytoSorb had a worse septic shock than those treated with CRRT alone as shown by higher lactate and noradrenaline levels, and lower mean arterial blood pressure. Despite that CytoSorb-treated patients had a worse shock, in an unbalanced analysis, the mortality rate was comparable to patients treated with CRRT alone. However, it could be argued that patients treated with CRRT alone were older with more comorbidities and more often having non-surgical sepsis. Therefore, observed versus predicted mortality rates were analysed within treatment groups. This analysis showed that the mortality rates in this study were lower than that predicted by the SOFA score at the start of therapy [
21]. The results of our study are in line with a previous prospective study in 20 patients with septic shock treated with CytoSorb, where a 28-day mortality rate of 45% was reported as well [
20].
It is important to investigate factors which are associated with survival for CytoSorb treatment. For the current cohort, next to older age, we found that higher lactate levels at baseline of CytoSorb therapy were associated with a worse outcome. Indeed, these factors are components of the SOFA score itself. Apparently, particularly the measures of the hemodynamic components of the SOFA score showed the strongest association with outcome. Hence, it seems reasonable to assume that CytoSorb therapy should be initiated as early as possible in the disease course. Nonetheless, 8 (12%) patients received CytoSorb at least 1 day after CRRT was already started. We performed a sensitivity analysis in which we excluded these patients and found no deviations from the main results.
In our cohort, it was found that CytoSorb therapy did not seem to provide with a survival benefit for patients with pneumosepsis. This may in part be due to combined difficulties in adequate ventilation and/or presence of ALI or ARDS in these severely ill patients. These findings are underlined by a recent randomized trial which assessed IL-6 levels as a primary outcome in patients with ALI and ARDS and found no survival benefit in these patients as a secondary (but not powered for) outcome measure [
11].
Since the current study is a retrospective data analysis, there is inherent bias to take into account. Importantly, by applying IPTW, confounding by indication was as much as possible eradicated [
24]. Still, chance of residual confounding remains, and some variables were imbalanced at the start of therapy. Only MAP was associated with the primary endpoint, which was accounted for by multivariable analysis. Moreover, the precise amount of fluid balances and ultrafiltration rates were not available for both treatment groups, which was complicated because this would need a dynamic statistical analysis. Indeed, fluid balances may be important measures as several studies show an association with more positive fluid balances and mortality [
26,
27], but there are also controversial findings with studies showing an association between higher fluid balance and improved survival [
28,
29], and even no differences in early goal-directed therapy [
30‐
32]. It should be underlined that it is uncertain whether the association between a positive fluid balance and mortality is a true dose-response causal relationship. Even though the omission of data on the fluid balance may be a limitation of the study, both groups received exactly the same standard of care fluid resuscitation protocols since this is a mono-centre study. On this basis, both groups are not expected to differ accordingly.
Albeit patients had a severe refractory septic shock and were treated with CytoSorb as a last -resort, one may argue that this treatment modality could have potential detrimental effects. One of these effects may be that CytoSorb could filter out antibiotics leaving patients exposed to levels below the therapeutic range [
33]. In the current study, we did not have antibiotic levels available. Nonetheless, there were no observations or indications of excessive need for antibiotics or persistence of infections in the CytoSorb group. Moreover, septic shock originates from a severe host-response derailment and endotoxinaemia and as such these patients may benefit more from CytoSorb therapy than antibiotics alone, which is underlined by the current data. Our data also shows that CytoSorb leads to a better outcome in patients with less severe lactataemia. Given possible antibiotic filtration, caution is warranted since the positive effect may be tipped towards a more negative effect if CytoSorb therapy is initiated too early. Lastly, a recent pilot study showed positive effects on lactate and procalcitonin when CytoSorb was used as a stand-alone therapy [
34]. We did not have procalcitonin or interleukin levels available in our study. Future randomized trials comparing CytoSorb to CRRT should further elucidate the effect on interleukin, procalcitonin and antibiotic levels, and what the timing and duration of CytoSorb therapy should be.
Conclusion
We have shown, to our knowledge, in the largest cohort of septic shock patients to date, that CytoSorb treatment may lead to an improved 28-day survival compared to CRRT alone, both on basis of observed versus predicted mortality rates as well as by IPTW. The current data should be further corroborated by randomized clinical trials.
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