Effect of Cytosorb Coupled With Hemodialysis on Interleukin-6 and Hemodynamic Parameters in Patients With Systemic Inflammatory Response Sindrome: a Retrospective Cohort Study

doi:10.21203/rs.3.rs-1600509/v1

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Effect of Cytosorb Coupled With Hemodialysis on Interleukin-6 and Hemodynamic Parameters in Patients With Systemic Inflammatory Response Sindrome: a Retrospective Cohort Study

https://doi.org/10.21203/rs.3.rs-1600509/v1

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Background. Systemic inflammatory response syndrome (SIRS) is a complex pathophysiologic response to several hostile stimuli. The excessive release of cytokines during SIRS often leads to a cytokine storm causing refractory hypotension and ultimately multiple organ failure with high mortality. Cytokine removal with hemoadsorption has emerged as a possible adjuvant therapy, but data on IL-6 reduction and clinical outcomes are scarce. We aimed to evaluate the effect of CytoSorb hemoadsorption on laboratory parameters and clinical outcomes in shocked patients with SIRS.

Methods. We designed a retrospective analysis of all patients with SIRS treated with CytoSorb in intensive care units. Interleukin 6 (IL-6), hemodynamic parameters (mean arterial pressure – MAP and vasoactive inotropic score - VIS), pH and lactate levels at the beginning, after 6h, 12h, 24h and 48h of CytoSorb treatment were analyzed in the whole cohort and in a subgroup of patients with septic shock. Predicted and observed mortality rates were compared using Chi-squared test. Statistical significance was defined as p <0.05 and <0.012 in multiple comparisons where a Bonferroni correction was applied.

Results. After screening 147 patients, we included 118 patients with various etiologies of SIRS (septic shock 69%, SIRS after cardiac arrest 16%, SIRS after acute pancreatitis 6%, other 9%). In all but one patient CytoSorb was coupled with renal replacement therapy. During the observed period of 48 hours, a statistically significant decrease in IL-6 levels, increase in pH, increase in MAP and decrease in VIS was observed already from 6h onward. Reduction of lactate levels became statistically significant at 48 hours. In a subgroup of patients with septic shock, the results were similar, and PCT levels did decreased after 24 hours. Observed ICU and in-hospital mortalities in the whole group were lower than predicted by SOFA (61% vs 79%, p=0.005) and APACHE II (64% vs 78%, p=0.031). There were no serious complications attributed to CytoSorb treatment.

Conclusions. Hemoadsorption with CytoSorb used in patients with SIRS of different etiologies was associated with a rapid decrease in IL-6 and hemodynamic improvement, with improved observed vs. predicted survival. These results need to be confirmed in a randomized study.

Hemoadsorption

cytokines

dialysis

interleukin-6

Systemic inflammatory response syndrome (SIRS) is a complex pathophysiologic response to a number of infectious and non-infectious hostile stimuli, such as bacteremia, pancreatitis, ischemia, burns, trauma, hemorrhagic shock, immune-mediated organ injury, etc [1]. Inflammation results from stimuli signaling damage or infection. One of the major categories of inflammatory stimulation is the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [2]. PAMPs are derived from microorganisms and thus drive inflammation in response to infections (e.g. lipopolysaccharide on the outer cell wall of gram-negative bacteria). DAMPs are derived from host cells (e.g. tumor cells, dead or dying cells), or products released from cells in response to signals such as hypoxia. DAMPs induce a sterile inflammatory response as a consequence of trauma, ischemia, or tissue damage and do not require pathogenic infection. While the inflammatory and immune responses to such stimuli in the acute state of disease are usually protective, in SIRS there is an exaggerated and dysregulated immune response and hyperinflammation, which often result in organ dysfunction, failure and even death [3]. Septic shock remains the most common cause of cytokine storm - a life-threatening condition of hyperinflammation [4], where an enormous amount of relatively small cytokines, such as interleukin-6 (IL-6), IL-10, tumor necrosis factor etc (< 40 kDa) is released in the blood [5]. After the initial cytokine storm, immunoparalysis can occur. It is characterized by increased susceptibility to secondary opportunistic infections and viral reactivations thus contributing to majority of the late sepsis-associated deaths [6]. Cytokines also play a crucial role in the pathogenesis of severe acute pancreatitis [7] and post-cardiac arrest syndrome [8], conditions with high mortality rates [9, 10]. Therefore, it is not surprising that besides standard treatment of these deleterious conditions, cytokine elimination with extracorporeal blood purification techniques represents an attractive adjuvant treatment option.

In 90s, a non-selective removal of a broad spectrum of inflammatory mediators (including pro- and anti-inflammatory cytokines) with continuous veno-venous hemofiltration (CVVH) in patients with septic shock and acute kidney failure was demonstrated, but without important effects on their serum concentrations and with no clear clinical benefit [11, 12, 13, 14]. Performing CVVH with an AN69 membrane showed, that adsorption of cytokines to the membrane appeared to be the main mechanism of removal, but the membrane was significantly saturated after 6 hours and release of bound cytokines from the membrane was observed [15].

In the past decades, new adsorption materials were developed and tested for use in patients with severe cytokinemia. The only hemoadsorption cartridge approved in Europe to date is CytoSorb, made of biocompatible polystyrene-divinylbenzene copolymer beads with a large effective surface area of approximately 40.000 m². Hydrophobic molecules between 5–60 kDa in size (size range of many inflammatory mediators, endogenous molecules such as e.g., myoglobin or bilirubin, and some drugs) can easily get captured and irreversibly bound to inner surface of beads, while smaller or larger solutes, including electrolytes and larger immune cells recirculate unchanged. The removal is size and concentration dependent: the higher cytokine plasma levels are, the faster and more effective is reduction [16]. Since the removal of cytokines in SIRS represents so-called “desirable” effect of CytoSorb treatment, little is known of “undesirable” effects, such as a removal of antibiotics, the basics of sepsis therapy.

To our best knowledge, only one prospective and a few large observation studies have reported the use of CytoSorb and its effect on interleukin-6 (IL-6) removal and hemodynamics (as a surrogate outcome) in patients with refractory septic shock and/or hypercytokinaemic state [17, 18].

The aim of our study was to evaluate the effect of CytoSorb on clinical and laboratory parameters and mortality in critically ill patients with different etiology of refractory shock with SIRS.

Patients and study design

We performed a retrospective analysis of all patients treated with CytoSorb adsorber in intensive care units of University Medical Center Ljubljana, Slovenia, from January 2017 to October 2019. The study complied with the Declaration of Helsinki (as revised in Tokyo 2013) and was approved by the National Medical Ethics Committee (No. 0120–533/2019/5); patient consent was waived due to retrospective nature of the study.

CytoSorb treatment

According to the clinical practice in our institution CytoSorb treatment was initiated (a) within 2 hours in patients with suspected fulminant meningococcemia, necrotizing fasciitis, toxic shock syndrome or in post-splenectomy patients with suspected fulminant sepsis; (b) within 12 hours if the patient met one of the following criteria: refractory septic shock (see definition below) after 6 hours of standard treatment (fluid resuscitation, vasoactive therapy), cardiogenic shock (if SIRS was considered the most important contributing factors to hemodynamic instability), severe acute pancreatitis with shock and/or acute respiratory distress syndrome (ARDS), severe burns, SIRS after cardiac arrest (refractory shock after 6 hours of standard therapy, shockable initial rhythm, lay BLS). Exclusion criteria for CytoSorb treatment were advanced medical conditions with a limited life expectancy (e.g., advanced metastatic cancer, severe neurological impairment, end-stage chronic disease) or shock duration > 48 hours. Refractory shock was defined as (a) an increasing noradrenaline (NA) requirement (> 0.5 µg/kg/min) despite adding corticosteroids to maintain mean arterial pressure (MAP) ≥ 65 mmHg, (b) serum lactate level ≥ 2 mmol/L despite adequate volume resuscitation and (c) multi-organ failure (at least 2 organs).

We combined CytoSorb and renal replacement therapy in all, but one patient. CytoSorb cartridges were placed in a pre-filter position. CytoSorb was coupled with continuous veno-venous hemodialysis (CVVHD) in patients with severe hemodynamic instability or requirement for sustained fluid removal. CVVHD was performed with Prismaflex (Gambro, Lund, Sweden) dialysis monitors using automated regional citrate anticoagulation (RCA). Blood flow was set to 150–200 ml/min and dialysate flow between 1500–2000 ml/h. CytoSorb was coupled with intermittent hemodialysis (IHD) in patients with severe hyperkalemia, severe metabolic acidosis or hyperammonemia. IHD was performed with AK 200 (Gambro, Lund, Sweden) dialysis monitors using either RCA or unfractionated heparin (in cases of additional indication for heparin). Blood flow was set to 200–250 ml/min and dialysate flow between 300–500 ml/min. If electrolyte and acid-base balance was achieved, dialysate flow was stopped and only hemoperfusion was continued. For the purpose of removing calcium-citrate complexes and to avoid citrate accumulation, we switched to dialysis for 2 hours after every 2–3 hours of hemoperfusion. CytoSorb was discontinued when vasopressor requirement decreased below 20% of the initial dose or if patients’ clinical condition was not improving. If deterioration of clinical status after cessation was observed, treatment with CytoSorb was recommenced.

Data collection

Baseline patient demographics, laboratory values and indication for CytoSorb were collected from medical records. Indications for CytoSorb were categorized as (a) septic shock, (b) SIRS in patients with acute pancreatitis, (c) SIRS in patients after out-of- or in-hospital cardiac arrest (OHCA or IHCA), (d) other. Serum levels of IL-6, lactate, pH and procalcitonin (PCT), mean arterial blood pressure (MAP) and vasoactive-inotropic score (VIS) were recorded from medical records at the beginning of CytoSorb treatment, after approximately 6, 12, 24 and 48 hours of the beginning of the first procedure, when available, and compared to baseline. IL-6 was measured by an electrochemiluminescence assay (Cobas e 411, Roche Diagnostics GmbH, Mannheim, Germany). Values reported as > 5000 ng/L from the laboratory were analyzed as 5000 ng/L. VIS was calculated as follows: dopamine dose (µg/kg/min) + dobutamine dose (µg/kg/min) + 100 × epinephrine dose (µg/kg/min) + 100 × norepinephrine dose (µg/kg/min) + 10 × milrinone dose (µg/kg/min) + 10.000 × vasopressin dose (U/kg/min). Three-day, 10-day and 28-day-mortalities were recorded and intensive care unit (ICU) and in-hospital mortality rates were compared to predicted mortalities as calculated by modified SOFA (sequential organ failure assessment) and APACHE II (acute physiology and chronic health evaluation II) scores, which were calculated at the initiation of treatment to estimate disease severity.

Statistical analysis

Basic patients' characteristics and outcome parameters are presented as number (percent) for categorical parameters, mean +/- standard deviation (SD) or median and interquartile range (IQR) for normally and non-normally distributed continuous parameters, respectively. For greater clarity all main outcome parameters (IL-6, MAP, VIS, lactate, pH and PCT) were analyzed with nonparametric methods, although MAP was found to be normally distributed. Their change over time was analyzed by paired Wilcoxon signed-ranks test comparisons to baseline (time 0) values; due to multiple comparisons (five time points, four comparisons), a Bonferroni correction was applied and p value of < 0.012 (0.05/4) was considered statistically significant. Predicted ICU and in-hospital mortalities were calculated based on median SOFA [19, 20] and APACHE II scores [21, 22], respectively; from predicted mortality ratio we calculated predicted absolute number of fatalities for our cohort size. Predicted and observed mortalities were compared using Chi-squared test. Statistical significance was defined as p < 0.05, except in multiple comparisons, as described above. Statistical analyses were conducted in R (R Core Team, 2014) [23].

Patients’ and procedures’ characteristics

We screened 147 patients and finally included 118 patients (see Fig. 1), whose baseline characteristics and indication for hemoadsorption therapy are described in Table 1. In 90% of patients CytoSorb was coupled with IHD and only a minority (8%) received the combination of CytoSorb and CVVHD. Nineteen patients (16%) were treated with CytoSorb and IHD/CVVHD filter incorporated in parallel with extracorporeal membrane oxygenation (ECMO) circuit. Median procedure duration was 12.0 (IQR 8.0–14.1) hours and median number of procedures per patient was 1 (IQR 1–2, range 1–7). RCA was used in all but one IHD procedure and in all CVVHD procedures. No device-related adverse events were observed during treatment time. Two procedures were terminated prematurely due to dialysis machine dysfunction and risk of extracorporeal system coagulation. SOFA score, APACHE II score and VIS score at initiation of CytoSorb therapy are presented in Table 1.

Table 1

Patients’ characteristics at initiation of treatment and outcome. Data are presented as mean ± standard deviation, median [interquartile range] and number (percent) as appropriate.
Characteristics	Value
Demographics
N	118
Age (years)	63 [51–73]
Female gender	34 (29%)
Weight (kg)	84 [75–95]
Comorbidities
No comorbidities	30 (25%)
Hypertension	62 (53%)
Diabetes mellitus	26 (22%)
Peripheral artery disease	7 (6%)
Heart failure	8 (7%)
COPD	13 (11%)
Indication for CytoSorb treatment
Septic shock	81 (69%)
SIRS – after OHCA or IHCA	19 (16%)
SIRS – acute pancreatitis	7 (6%)
other	11 (9%)
Vital signs
MAP (mmHg)	69.6 ± 12.8
Heart rate (1/min)	105 ± 22
Organ support
Mechanical ventilation	114 (97%)
ECMO support	19 (16%)
Medications
Vasoactive support	118 (100%)
Hydrocortisone	90 (76%)
Antibiotic treatment	113 (96%)
Immunosuppression*	15 (13%)
Laboratory parameters
lactate (mmol/L)	6.3 [3.8–11.9]
IL-6 (ng/L)	5000 [800–5000]
pH	7.3 [7.2–7.4]
creatinine (µmol/L)	200 [139–308]
Disease severity scores
VIS score	70 [43–101]
SOFA score	14 [12–16]
APACHE II	33 [28–37]
Mortality
3-day mortality	30 (25%)
10-day mortality	47 (40%)
28-day mortality	66 (56%)
MAP – mean arterial pressure, ECMO – extracorporeal membrane oxygenation, COPD – chronic obstructive pulmonary disease, OHCA – out-of-hospital cardiac arrest, IHCA – in-hospital cardiac arrest, * chronic therapy for immune-mediated diseases

IL-6 and clinical outcomes

IL-6 values during the first 48 hours after initiation of the first CytoSorb treatment are shown in Fig. 2 and Table 2. Adsorption therapy was effective in reducing IL-6 levels, which decreased significantly already 6 h after initiation of treatment, with a slight increase between 12 and 24 hours, likely due to the effect of CytoSorb discontinuation.

Table 2

Serum interleukin-6 (IL-6) levels from the beginning of CytoSorb treatment to 48 hours after the start of the first CytoSorb treatment. Values presented as median, interquartile range.
Time (h)	0	6	12	24	48
IL-6 (ng/ml)	5000 [800–5000]	1524 [446–5000]	982 [242–3329]	1323 [273–4900]	499 [94–1837]
Compared to time 0 (p)	/	< 0.001	< 0.001	< 0.001	< 0.001
Compared to previous time category (p)	/	< 0.001	0.027	0.002	< 0.001

The observed reduction in IL-6 was accompanied by a favorable clinical response, indicated by a significant increase in MAP and a reduction of vasopressor therapy (VIS score) requirements from 6 h onward and a decrease in lactate levels, which became significant at 48 h. pH also increased significantly at 6 hours of combined treatment with RRT and CytoSorb (Fig. 3, Table 3).

Table 3

Hemodynamic and laboratory parameters from the beginning of CytoSorb treatment to 48 hours after the start of the first CytoSorb treatment. Values presented as median, interquartile range.
Time (h)	0	6	12	24	48
MAP (mmHg)	70 [63–77]	76 [66–85]	76 [68–87]	77 [68–84]	79 [72–87]
p-value	/	< 0.001	< 0.001	0.002	< 0.001
VIS	71 [43–101]	65 [39–98]	55 [27–85]	37 [18–67]	20 [4–55]
p-value	/	0.009	< 0.001	< 0.001	< 0.001
pH	7.30 [7.23–7.37]	7.36 [7.29–7.42]	7.38 [7.32–7.43]	7.37 [7.31–7.43]	7.40 [7.35–7.45]
p-value	/	< 0.001	< 0.001	< 0.001	< 0.001
s-lactate (mmol/L)	6.31 [3.38–11.94]	6.90 [3.50–10.80]	5.30 [2.33–10.81]	3.76 [2.00–9.23]	2.06 [1.40–3.58]
p-value	/	0.484	0.124	0.156	< 0.001

MAP – mean arterial pressure, VIS – vasoactive-inotropic score

Septic shock patients

In a subgroup of 68 patients with septic shock (as defined in consensus statement [1]) we observed similar results (Fig. 4, Table 4). There was a significant decrease of IL-6 levels, a significant increase of MAP and pH and decrease of VIS already 6 hours after the start of CytoSorb therapy. Forty-eight hours after CytoSorb therapy, IL-6 levels remained lower, compared to the values at the beginning of treatment. A continuous increase of pH was observed during treatment with RRT - CytoSorb. Lactate levels slowly decreased and were lower with borderline significance at 12 h and significantly lower after 48 h, compared to the initial values. PCT levels increased in first 6 hours, later the decrease of PCT concentration was observed and it became significant after 24 hours of CytoSorb treatment.

Table 4

Hemodynamic and laboratory parameters from the beginning of CytoSorb treatment to 48 hours after the start of the first CytoSorb treatment in a subgroup of patients with septic shock. Values presented as median and interquartile range.
Time (h)	0	6	12	24	48
IL-6 (ng/ml)	5000 [1639–5000]	2804 [885–5000]	1474 [297–4943]	2236 [672–4917]	958 [422–2147]
p-value	/	0.002	0.003	< 0.001	< 0.001
MAP (mmHg)	68 [63–75]	73 [66–82]	76 [6–84]	76 [67–82]	79 [73–86]
p-value	/	< 0.001	< 0.001	0.003	< 0.001
VIS	72 [44–100]	65 [40–95]	60 [36–88]	50 [29–75]	28 [6–59]
p-value	/	0.006	0.001	< 0.001	< 0.001
pH	7.29 [7.22–7.34]	7.37 [7.30–7.42]	7.38 [7.32–7.43]	7.37 [7.32–7.42]	7.39 [7.34–7.44]
p-value	/	< 0.001	< 0.001	< 0.001	< 0.001
lactate (mmol/L)	7.1 [4.0–12.0]	7.5 [4.3–10.3]	5.3 [2.5–10.3]	4.2 [2.3–10.6]	2.3 [1.7–3.6]
p-value	/	0.271	0.025	0.162	< 0.001
PCT (µg/L)	31 [9–89]	35 [8–71]	18 [7–68]	30 [8–66]	21 [7–55]
p-value	/	< 0.001	0.036	0.009	< 0.001

MAP – mean arterial pressure, VIS – vasoactive-inotropic score, PCT – procalcitonin

Predicted vs. observed mortality

In our cohort, three-day mortality was 25%, ICU mortality was 61% and in-hospital mortality was 64%. Predicted ICU-mortality, based on SOFA score, was 79% for our cohort, which was significantly higher than the observed 61% (p = 0.005, Table 5), and predicted in-hospital mortality, based on APACHE II score, was 78%, which was also significantly higher than the observed 64% (p = 0.031, Table 6). Analyses of patients’ mortality stratified by SOFA and APACHE II score are shown in Fig. 5 and Tables 5 and 6.

Table 5

Highest SOFA score and observed vs. predicted ICU mortality rate. Comparison for grouped ICU-mortality by Chi-squared test.
SOFA group	mortality - reference	mortality - predicted	mortality - observed	p-value
10–11	46%	8.3/18	5/18 (28%)	/
12–14	80%	29.6/37	22/37 (59%)	/
> 14	90%	46.8/52	38/52 (73%)	/
all		85/107 (79%)	65/107 (61%)	0.005

SOFA: sequential organ failure assessment

Table 6

APACHE II score, observed in-hospital mortality vs. predicted mortality rate. Comparison by Chi-squared test.
APACHE II group	mortality - reference	mortality - predicted	mortality - observed	p-value
15–19	27%	1/2	0/2 (0%)	/
20–24	50%	4/8	3/8 (38%)	/
25–29	65%	20/31	15/31 (48%)	/
30–34	80%	20/25	15/25 (60%)	/
> 34	89%	47/52	43/52 (83%)	/
all		92/118 (78%)	76/118 (64%)	0.031

APACHE II: acute physiology and chronic health evaluation II

To the best of our knowledge, this is one of the largest cohort studies of CytoSorb hemoadsorption in patients with SIRS where laboratory and clinical parameters related to shock as well as mortality were assessed. We have shown effective reduction in IL-6 levels with corresponding clinical response including reduction in vasopressor therapy and increase in MAP, suggesting efficacy of Cytosorb treatment. The observed ICU and in-hospital mortality rate in our cohort were significantly lower than the predicted ones according to the SOFA and APACHE II scoring system and these data support previous studies [16, 24], but not all [25]. For example, Schittek et al. in a retrospective controlled study did not find any reduction of ICU or hospital mortality after the implementation of hemoadsorption for patients in septic shock with acute renal failure [25]. While the majority of studies evaluated only patients with septic shock [16], patients with different causes of SIRS such as pancreatitis or post-cardiac arrest syndrome were included in our cohort, as cytokine storm is a common pathophysiology in these states.

Besides measuring MAP, we performed an assessment of hemodynamic status with calculations of vasoactive-inotropic score (VIS) during CytoSorb treatment and not only norepinephrine dosage [16], since in the majority of patients in shock multiple vasoactive drugs are usually used. We observed hemodynamic stabilization during and after CytoSorb treatment with statistically significant increase in MAP and decrease in VIS score, occurring early (within 6 h) in the course of treatment. Similar findings were described in some other smaller observational studies [16, 26, 27], while, on the other hand, in another study no significant reduction in norepinephrine dosage was observed over 24 hours of CytoSorb treatment [28]. Higher VIS values have been associated with worse outcomes in pediatric and adult patients [29, 30, 31] and are therefore an important surrogate outcome. Even though our set of patients had extremely high initial values of VIS (median 70 [43–101]) with a more profound hemodynamic instability in comparison to patients in Calabro et al. (VIS score of 20 [10–35][27]) at the beginning of adsorption treatment, mortality was similar (28-day mortality in our study 56%, 30-day-mortality 55% in Calabro study [27]).

Since severe acidosis is associated with catecholamine-refractory hypotension and decreased myocardial contractility, the correction of acidosis per se by renal replacement therapy is beneficial for an enhanced effect of catecholamines and achievement of hemodynamic stability. One of the advantages of IHD over CRRT is the ability for a fast correction of electrolyte disbalance, acid-base status and a greater clearance of small and middle-size molecules (e.g., urea, lactate, ammonia…). In 2019 study by Nogi et al. there was a statistically significant decrease in norepinephrine dose in patients with metabolic acidosis and septic shock, treated with IHD alone, and they assumed that the improvement of circulation was probably reflected by a slight decrease in lactate levels during IHD treatment [32]. In our clinical practice, we coupled CytoSorb with standard hemodialysis high-flux filters in the majority of our patients in order to accelerate clearance of lactate, correction of metabolic acidosis and to treat the commonly present hyperkaliemia. In line with Nogi’s findings [32] we observed a statistically significant increase of pH with a reduction of lactate levels that decreased slowly and reached statistical significance 48 h after CytoSorb was started.

To make comparison with other studies easier, we analyzed a subgroup of patients with septic shock within our cohort. Our results confirm data from previous prospective studies reporting significant reduction of IL-6 during CytoSorb procedures [17, 18]. On the contrary, in a randomized trial Schadler et al. were not able to detect a difference in plasma IL-6 levels between patients treated with CytoSorb for 6 hours as compared to controls [18], since there was a slow and sustained reduction in plasma IL-6 in both groups. In our cohort of septic patients, IL-6 levels substantially decreased during CytoSorb treatment coupled with IHD/CVVHD. Importantly, in our group the baseline IL-6 levels were very high compared to Schadler (5000 [800–5000] (ng/L) vs. 552 [162–874] (ng/L), which indicates a significantly sicker population. This might have affected the CytoSorb adsorbing effectiveness, which is known to be concentration-dependent. Nevertheless, controlled studies are necessary to firmly show the significance of IL-6 adsorption on the course of IL-6 levels and clinical outcomes.

Procalcitonin (PCT) is one of the markers of bacterial infection and its serum concentration is positively correlated with the severity of infection [33]. PCT may also have a toxic effect in sepsis [34], since it was reported to decrease cardiovascular stability in experimental models, so active removal of PCT could be beneficial. Because of a relatively small molecular weight (approx. 13–14 kDa) PCT can be removed using high-flux dialysis filters [35] predominantly with filtration [36, 37, 38], but can also be eliminated by adsorption on AN69ST membranes and CytoSorb [39]. After the expected initial increase at 6 hours, there was a tendency toward a decline in PCT levels, so it is possible that PCT was partially removed during the procedure. A statistically significant decrease of PCT levels observed 24 h after CytoSorb procedure could be explained by combined effects of removal with CytoSorb, improving clinical condition and timely antibiotic therapy.

Our study has several limitations. The most important are the observational design, multiple simultaneous interventions (CytoSorb, dialysis, …) and the lack of a control group. Therefore, it is not possible to determine any cause-effect relationship between the CytoSorb treatment, clinical improvement and mortality. Nevertheless, the study format is in line with similar studies in the same context [17]. Furthermore, because of the retrospective nature of the study, there was a significant number of missing data at some time points, reducing the power of the study.

In conclusion, we have shown that CytoSorb treatment, used in patients with SIRS of different etiologies, is associated with a decrease in IL-6 and a corresponding beneficial effect on hemodynamics and possibly also survival. Further randomized clinical trials are needed to fully elucidate the effect of CytoSorb on the removal of cytokines and survival.

SIRS

systemic inflammatory response syndrome

PAMPs

pathogen-associated molecular patterns

DAMPs

damage-associated molecular patterns

IL-6

interleukin-6

kDa

kilodalton

AN69

acrylonitrile

CVVH

continuous veno-venous hemofiltration

ARDS

acute respiratory distress syndrome

noradrenaline

MAP

mean arterial pressure

CVVHD

continuous veno-venous hemodialysis

RCA

regional citrate anticoagulation

IHD

intermittent hemodialysis

OHCA

out-of-hospital cardiac arrest

IHCA

in-hospital cardiac arrest

PCT

procalcitonin

VIS

vasoactive-inotropic score

ICU

intensive care unit

SOFA

sequential organ failure assessment

APACHE II

acute physiology and chronic health evaluation II

standard deviation

IQR

interquartile range

ECMO

extracorporeal membrane oxygenation

COPD

chronic obstructive pulmonary disease

confidence interval

AN69ST

acrylonitrile 69-surface treated.

Ethics approval and consent to participate

The study was approved by the National Medical Ethics Committee (No. 0120-533/2019/5); patient consent was waived due to retrospective nature of the study.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

The authors acknowledge the financial support from the Slovenian Research Agency (research core funding No. P3-0323) and the University Medical Center Ljubljana (Research & Development Grant No. 20200207).

Authors' contributions

VP, VG, AS, MJ and JG designed the study. VP, AJ, MM, JB, AS, ML and GT collected the data. AJ, JB and JG performed statistical analysis. VP and JG obtained the funding. VP wrote the manuscript draft. All authors revised the manuscript and approved the final version.

Acknowledgements

Not applicable.

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No competing interests reported.

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Effect of Cytosorb Coupled With Hemodialysis on Interleukin-6 and Hemodynamic Parameters in Patients With Systemic Inflammatory Response Sindrome: a Retrospective Cohort Study

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Abstract

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Background

Methods

Patients and study design

CytoSorb treatment

Data collection

Statistical analysis

Results

Patients’ and procedures’ characteristics

IL-6 and clinical outcomes

Septic shock patients

Predicted vs. observed mortality

Discussion

Conclusions

List Of Abbreviations

Declarations

References

Additional Declarations

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