Retrospective evaluation of efficacy of CytoSorb® therapy in septic shock patients in a tertiary care intensive care unit

Abstract

BACKGROUND

Cytokines and inflammatory mediators are the key factors that are involved in the pathology of sepsis. Extracorporeal cytokine hemoadsorption devices offer an innovative clinical support system to alleviate the effects of the cytokine storm associated with sepsis.

AIM

To retrospectively evaluate the efficacy of CytoSorb^® therapy as an adjunct to standard care in intensive care unit (ICU) patients with septic shock.

METHODS

A retrospective study was designed. Data were obtained for the patients who were treated with the CytoSorb^® adsorber for the past 5 years. The effects of therapy were assessed by changes in vasopressor requirements, specifically, norepinephrine and epinephrine. In addition, cytokine levels, such as interleukin (IL)-6 and inflammatory biomarkers including C-reactive protein (CRP), procalcitonin, as well as substances such as serum lactate and lactate dehydrogenase were also evaluated. In addition, mean arterial pressure (MAP) and ventilator requirements were also recorded. The survival outcomes were analyzed based on the length of patients' stay in the ICU, and the severity of illness was assessed using Acute Physiology and Chronic Health Evaluation (APACHE II) and Sepsis-associated Organ Failure Assessment (SOFA) scores recorded at baseline and post-therapy.

RESULTS

Following CytoSorb^® therapy, the requirement for vasopressor drugs, particularly norepinephrine, was reduced by 40% and a statistically significant improvement in MAP by 7.8%. Additionally, significant reductions were observed in IL-6 and serum lactate levels by 83% and 52% respectively. Around 56% had a delta lactate score of > 1.5, while 23% patients had a score ranging from 1 to < 1.5, and 16% patients had a score between 0.5 and < 1 and merely 5% patients had a score of ≤ 0.5. Besides, serum levels of creatinine, procalcitonin and CRP were significantly reduced by 17.2%, 41.5% and 53.8% respectively. There was a significant reduction in scores, including APACHE II [to 23 (18-29) from 27 (23-33)], and SOFA [to 12 (10-14) from 13 (11-15)]. Mechanical ventilation was required by 96% patients, with a median duration of 12 days, and the median length of hospital stay in overall patients was 26 days, while the median ICU stay was 18 days.

CONCLUSION

CytoSorb^® therapy seems to be a promising adjunctive approach in the management of septic shock.

Key Words: CytoSorb^® therapy; Cytokine hemoadsorption; Septic shock; Acute Physiology and Chronic Health Evaluation scores; Sepsis associated organ failure scores; Mean arterial pressure; Mechanical ventilation

Core Tip: CytoSorb^® is an innovative extracorporeal cytokine hemoadsorption device designed to stabilize hemodynamic parameters and regulate the cytokine storm in sepsis. This retrospective study evaluated the efficacy of CytoSorb^® hemoadsorption therapy as an adjunct to standard care in intensive care unit patients with septic shock. The findings indicate significant reductions in inflammatory biomarkers, vasopressor requirements, along with improvements in organ recovery and survival outcomes. Additionally, no major adverse events were reported in patients receiving the therapy. The study underscores CytoSorb^® ability to modulate hyperinflammation from cytokine storms and stabilize hemodynamics, thus facilitating early shock reversal, and improving clinical outcomes in critically ill patients.

INTRODUCTION

Sepsis poses a significant global health burden and stands as the primary cause of mortality among adult patients in intensive care units (ICUs)[1]. It is a life-threatening medical emergency triggered by the body's exaggerated response to infection, resulting in the widespread release of inflammatory mediators and leading ultimately to organ failure[1-3]. Infectious stimuli trigger both pro- and anti-inflammatory responses, affecting multiple systems, and may lead to hyperinflammatory response or sepsis-associated immunosuppression[4,5]. The heightened inflammatory response referred to as "cytokine storm", is marked by increased levels of key cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-8, IL-10, etc. Consequently, this excessive release of inflammatory mediators plays a crucial role in the development and progression of shock and organ failure, also termed as Sepsis Associated Organ Failure as measured by SOFA score[6]. Sepsis is diagnosed clinically by a ≥ 2-point increase in the SOFA score, correlating with a high mortality. Septic shock, an even more critical form of sepsis, is characterized by significant cellular, metabolic, coagulopathic and circulatory dysfunction, including a lactate level greater than 2 mmol/L and the need for vasopressors to maintain mean arterial pressure (MAP) ≥ 65 mmHg despite adequate fluid resuscitation[2]. It has a complex pathophysiology as shown in Figure 1.

Figure 1 Pathophysiology of septic shock. PAMPs: Pathogen-associated molecular Patterns; DAMPs: Damage-associated molecular patterns; PMN: Polymorphonuclear neutrophils; TNF: Tumor necrosis factor; IL: Interleukin; TGF: Transforming growth factor; HAI: Healthcare-associated infections; MODS: Multiple organ dysfunction syndrome.

With millions of cases reported globally each year, sepsis results in a substantial burden on public health[1]. As per the global burden of disease study 2020, sepsis accounts for about 11 million deaths every year[7], with mortality rates for sepsis ranging from 20% to 50%[1,5]. The INDICAP study conducted in India found that sepsis affects 28.3% of patients, with 20.5% of these cases being acquired in the ICU, and it reported an ICU mortality rate of 34%[8,9].

The cornerstone of sepsis management includes source control, appropriate and timely antibiotic administration, hemodynamic optimization and organ support measures. However, for optimum management of sepsis, early identification and prompt treatment initiation are critical for improving patient outcomes[3,10,11]. More recent treatment strategies for managing sepsis are also directed towards achieving immunological homeostasis through the removal of the highly elevated inflammatory mediators from the blood and reduce potential damage to the organs[5,12]. Treatments, which have been proposed in this regard, include extracorporeal therapies or blood purification techniques (BPT)[13] such as haemofiltration, haemoperfusion, intermittent or continuous high-volume haemofiltration, plasmapheresis or hemoadsorption[5,12]. These therapies try to attenuate the immune response by removing circulating cytokines and triggers that potentiate the response, such as, pathogen associated molecular patterns (PAMPs), damage associated molecular patterns (DAMPs), leukocytes, and endotoxins, thereby targeting to achieve homeostasis[14-17]. While the 2021 Surviving Sepsis Campaign guidelines highlight the lack of sufficient evidence to make a definitive recommendation on BPT, nonetheless, considering the theoretical rationale and emerging pieces of evidence, they emphasize the need for further research in this field[11].

CytoSorb^®, an extracorporeal therapy developed by CytoSorbents (New Jersey, United States), employs an advanced porous polymer bead technology to eliminate small to medium-sized hydrophobic molecules (up to 60 kDa) from the bloodstream, including substances like cytokines, myoglobin and bilirubin. Figure 2 illustrates the CytoSorb technology, its features and its adsorption spectrum. By effectively removing cytokines associated with the cytokine storm, this therapy plays a crucial role in reducing systemic inflammation, supporting early shock reversal and potentially enhancing patient outcomes[18,19]. It may also be useful in patients with liver failure or rhabdomyolysis, as well as for the elimination of direct oral anticoagulants or in acute intoxications[20]. Its properties of reducing elevated levels of hydrophobic molecules in a concentration-dependent manner make it a very suitable choice of treatment in various indications in the ICU[18]. In addition, the therapy is well-tolerated and was shown to be safe for several indications and critically-ill patient populations[18,20]. There are numerous published reports regarding the use of CytoSorb^®, including pilot RCTs, multicenter prospective and retrospective studies, international registries, case series and several case reports[5,21-27]. Comparison of various parameters before and after CytoSorb^® therapy demonstrates efficacy of this treatment. Having this as the backdrop, the current study aims to evaluate the efficacy of CytoSorb^® therapy retrospectively as an adjunct to standard care in ICU patients with septic shock. The study aims to address the lack of real-world evidence of CytoSorb and its impact on patient outcomes, especially in the Indian context.

Figure 2 Key features of the cytoSorb therapy. A: CytoSorb adsorber-bead based technology; B: CytoSorb size selective removal.

MATERIALS AND METHODS

Study population and study design

A retrospective study was designed based on the principles outlined in the STROBE guidelines[28]. The analysis focused on patients who were admitted to the ICU at Nanavati Max Super-Speciality Hospital, Mumbai, India and treated with CytoSorb^® adsorber between 2017 and 2022. The study protocol received approval from the Institutional Ethics Committee and was conducted in accordance with the principles of the current International Council for Harmonisation, Good Clinical Practice and applicable local regulatory guidelines[29].

Study characteristics

Inclusion/exclusion criteria: The data was collected from the medical records of patients hospitalized in the ICU between 2017 and 2022, diagnosed with septic shock, as per the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) and who received CytoSorb^® therapy as part of their treatment regimen. Patients who were ≥ 18 years of age and hospitalized due to sepsis with multiorgan failure/septic shock were included in the study. This selection process aimed to provide a thorough evaluation of CytoSorb^®'s effectiveness as timely adjuvant to standard of care in managing septic shock during the study period. Pediatric patients (6 to 8 years of age) and patients whose documentation was not available were excluded from the study.

Study procedure

Data collection: Baseline data regarding relevant patient demographics, clinical characteristics, vitals, laboratory parameters, and outcomes were collected from electronic medical records and case record forms. In addition, details regarding various treatment modalities administered were documented. Sepsis is defined as the dysregulated host response to an infection with life-threatening organ dysfunction as indicated by sequential rise in SOFA score by 2 points or more. Septic shock is defined as a subset of sepsis patients having a profound circulatory, cellular and metabolic abnormalities clinically recognized by the need for vasopressors to maintain the MAP ≥ 65 mmHg and serum lactate levels > 2 mmol/L (> 18 mg/dL)[2]. Alongside information on CytoSorb^® therapy, the study includes the number of devices utilized, the number of sessions given, the length of ICU stay, and the overall hospital stay for each patient. Decision parameters predominantly rely on the clinical factors like worsening organ failures, changes in MAP and increasing vasopressor requirement. Along with the clinical parameters, biomarkers such as Lactate, CRP, IL-6, etc. are considered to substantiate clinical approach (Supplementary Table 1).

Evaluation of primary and secondary outcomes

The primary outcomes included evaluation of the effectiveness of CytoSorb^® therapy by assessing changes in vasopressor requirements, specifically, the reduction in the dosage of vasopressor medications, such as norepinephrine and epinephrine, following therapy was closely monitored. In addition, cytokine levels, such as IL-6, were measured before and after CytoSorb^® use to evaluate the therapy's impact on inflammatory mediators.

The secondary outcomes involved assessing the impact of CytoSorb^® therapy on key laboratory parameters and vital signs. Lab parameters were evaluated pre- and post-therapy, with particular attention to further inflammatory biomarkers such as CRP and Procalcitonin as well as substances such as S. Lactate and LDH. The delta lactate score which represents a ratio of serum lactate levels before CytoSorb^® therapy and after CytoSorb^® therapy was calculated[30].

Additional data collected included the median values for parameters like activated partial thromboplastin time/activated clotting time, heparin dosage, and the time from ICU admission to the initiation of therapy, along with the overall duration of therapy. Important clinical parameters such as MAP, ventilator requirements, and oxygenation parameters (including FiO₂, PaO₂, and PCO₂) were documented. Percentage changes in pre- and post-therapy values were calculated at the end of treatment.

Survival outcomes analysis

Survival outcomes were analyzed based on the length of patients' stay in the ICU. The severity of illness was assessed using scoring systems such as APACHE II and SOFA scores that were recorded at baseline and post therapy. All relevant data for calculating the SOFA score at the time of ICU admission (pre-CytoSorb^®) and following CytoSorb^® therapy (post-CytoSorb^®) were systematically gathered using standardized forms and then entered into a database for subsequent mortality analysis. The delta SOFA, which represents the change in the SOFA score following CytoSorb^® therapy, was calculated and recorded. The predicted mortality (PM) calculated using initial SOFA scores was utilized to determine expected mortality rates as demonstrated by Ferreira et al[31] (Table 1).

Table 1 Predicted mortality based on initial sepsis associated organ failure score.

Initial sepsis associated organ failure score	Predicted mortality
0-1	0
2-3	6.0%
4-5	20.0%
6-7	21.5%
8-9	33.3%
10-11	50.0%
> 11	95.2%

Statistical analysis

Descriptive statistics were used to summarize patient characteristics, CytoSorb^® administration details, and clinical outcomes. Continuous variables were expressed as mean ± SD or median with interquartile range (IQR), while categorical variables were presented as frequencies and percentages. The effectiveness of CytoSorb^® therapy was evaluated by comparing pre- and post-treatment parameters. The test used was- a variant of student's t test > 'paired two sample for means' comparing differences in means of pre and post therapy groups. P values < 0.05 were statistically significant. Statistical analyses were conducted in the R software package (R Core Team, 2014).

RESULTS

Study population

We obtained data for 89 patients. Of these, 2 pediatric patients were excluded and the rest 87 were considered to be included in the study. Among these, 59 (67.8%) were males, with a median age of 63 years (IQR: 51-70). Among the comorbid conditions, hypertension and diabetes were observed in 46.0% and 32.2% of patients, respectively.

Evaluation of primary and secondary outcomes

The baseline characteristics and comparison of all primary and secondary outcomes with other laboratory parameters before and after treatment in overall patients are presented in Table 2.

Table 2 Demographic characteristics and comparison of laboratory and vital parameters pre- and post-therapy, n (%)/median (25^th-75^th percentiles).

Parameters	Overall patients (n = 87)
Gender (male)	59 (67.8)
Age (years)	63 (51-70)
Comorbidities
Diabetes	28 (32.2)
Hypertension	40 (46.0)
Chronic kidney disease	10 (11.5)
	Pre	Post	P value
Haemoglobin (gm/dL)	9.7 (8.8-11.9)	9.2 (8.1-10.3)	0.0007
Haematocrit (%)	30 (27-33)	30 (26.9-32)	0.866
Leucocytes (cells/mm3)	15680 (6880-28000)	11200 (5810-17100)	0.0001
Platelets (× 103/μL)	106 (44-208)	62 (34-121)	< 0.0001
LDH (U/L)	440.5 (260.5-933.5)	380 (156-1018)	0.2031
Creatinine (μmol/L)	1.57 (1.17-2.8)	1.3 (0.81-2)	< 0.0001
Lactate (mmol/L)	5 (3-11)	2.4 (1.3-7)	< 0.0001
Procalcitonin (ng/mL)	2.05 (0.57-23.6)	1.2 (0.2-9)	< 0.0001
C-reactive protein (mg/L)	210 (91-305)	97 (40-215)	< 0.0001
IL-6 (pg/mL)	4683.5 (1276-5000)	783.7 (181-3731.5)	0.0007
Albumin (gm/dL)	2.9 (2.5-3.4)	3.2 (2.9-3.7)	< 0.0001
PaO2/FiO2	175 (112-330)	225 (122-357)	0.1121
MAP (mmHg)	77 (73-86)	83 (76-90)	0.0130
Epinephrine dose (mcg/kg/min)	0.0 (0-0.09)	0 (0-0.05)	0.0004
NE dose (mcg/kg/min)	0.5 (0.2-0.75)	0.3 (0.08-0.6)	< 0.0001

LDH: Lactate dehydrogenase; PaO2/FiO2: Ratio of partial pressure of oxygen in blood, in millimetres of mercury, and the fraction of oxygen in the inhaled air; MAP: Mean arterial pressure; NE: Norepinephrine.

Primary outcomes

Following CytoSorb^® therapy, the requirement for vasopressor drugs was reduced by 40%, particularly norepinephrine from 0.5 (0.2-0.75) to 0.3 (0.08-0.6) and a synchronous statistically significant improvement in MAP by 7.8%. In addition, a statistically significant reduction (P = 0.0007) in IL-6 Levels by 83% was observed, with levels decreasing from 4683.5 (1276-5000) to 783.7 (181-3731.5).

Secondary outcomes

There was a consistent decrease in Serum lactate levels by 52%, with statistical significance (P = 0.0001). Interestingly, 49 patients (56%) had a Delta Lactate score greater than 1.5, 20 (23%) patients had a score in the range of 1 to < 1.5, 14 (16%) patients had a score between 0.5 and < 1 and merely 4 (5%) patients had a score of ≤ 0.5 (Figure 3A).

Figure 3 Sepsis severity and prognosis. A: Delta lactate score classification; B: Comparison of sepsis scores; C: Delta sepsis associated organ failure score classification. SOFA: Sepsis Associated Organ Failure; APACHE II: Acute Physiology and Chronic Health Evaluation; PRE: Values recorded pre/before CytoSorb; POST: Values recorded post/after CytoSorb.

We observed a 28.6% decrease in total leukocyte count (TLC) [from 156% (6880-28000) to 11200 (5810-17100); P = 0.0001] post CytoSorb therapy. Besides, S. creatinine, S. Procalcitonin and CRP reduced significantly by 17.2% (P < 0.0001), 41.5% (P = 0.0001) and 53.8% (P = 0.0001) respectively. Haemoglobin and hematocrit decreased slightly by 5.2% and 0.9% respectively post therapy, while S. Albumin levels increased by 10.3% [from 2.9 gm/dL (2.5-3.4) to 3.2 gm/dL (2.9-3.7); P = 0.0001]. There was statistically non-significant improvement of 29% in the PaO2/FiO2 ratio was observed, from 175 (112-330) to 225 (122-357); P = 0.1121.

Survival outcomes

Sepsis scores: Significant improvements were observed in various sepsis parameters following CytoSorb^® therapy. There was a significant reduction in scores, including APACHE II [to 23 (18-29) from 27 (23-33), P < 0.0001] and SOFA [to 12 (10-14) from 13 (11-15), P = 0.0039] (Figure 3B). High median APACHE II scores and SOFA scores at baseline suggest the sample was characterized by severely sick patients. The mean PM percentage, based on the SOFA scores, was 95% ± 24.2%, while the mean observed mortality percentage was 79.3% ± 27.2%. Following CytoSorb therapy, a decrease in Delta SOFA scores was observed in 47 patients (54%), indicating clinical improvement. There was no change in Delta SOFA scores in 18 patients (21%), while 22 patients (25%) showed an increase in Delta SOFA scores, suggesting a worsening of their condition (Figure 3C).

Number of CytoSorb^® devices used, days spent in ICU and overall stay in hospital: Using the clinicians’ designed scoring system[30] for initiation of CytoSorb^® therapy the ICU score at admission was < 8 in 3 (3.45%) patients, between 8 and 13 in 57 patients (65.5%) and > 13 in 27 patients (31.03%). It is important to note that over 96% of the CytoSorb usage was clinically indicated in patients with scores > 8. Most patients received one CytoSorb^® treatment only (n = 43, 49.4%), 25 patients underwent two therapy sessions (28.7%), 11 patients received three CytoSorb^® (12.6%) and only 8 patients (9.2%) underwent 4 or more therapy sessions. The different types of dialysis treatment given were CRRT (n = 77, 88.5%), slow low efficiency dialysis (SLED) (n = 4, 4.6%), CRRT + SLED (n = 4, 4.6%) and two patients (n = 2, 2.3%) required ECMO in addition to CRRT (Table 3). Out of a total of 87 patients, 14 (16.47%) began CytoSorb^® therapy on the same day of ICU admission. However, patients to whom therapy was initiated between 12-24 hours and 24-48 hours were 19 (22.35%) and 8 (9.41%) respectively. A few patients, 11 (12.94%), were given therapy after 72 hours and 10 (11.76%) patients were given it4 to 7 days post ICU admission while 23 (27.03%) were initiated with CytoSorb therapy one week after ICU admission (Figure 4). A high proportion (96%) of patients required mechanical ventilation, with a median duration of mechanical ventilation for 12 days (IQR: 6-16). The median length of hospital stay in overall patients was 26 days (IQR: 14.5-49), while the median ICU stay was 18 days (IQR: 13-32) underlying the severe subset of patients.

Figure 4 Time to initiate CytoSorb after intensive care unit admission. ICU: Intensive care unit.

Table 3 Number and type of CytoSorb devices used and other conditions, n (%)/median (25^th-75^th percentiles).

Parameters (number of devices used)	Overall patients
1	43 (49.43)
2	25 (28.74)
3	11 (12.64)
≥ 4 type of dialysis support	8 (9.2)
CRRT	77 (88.5)
SLED	4 (4.6)
CRRT + SLED	4 (4.6)
CRRT + ECMO	2 (2.3)
Flow rate (mL/minute)	150 (120-150)
APTT/ACT	40 (35-45)
Patients requiring anticoagulation therapy	52 (61.2)
Heparin dosage (unit/hour)	200 (150-200)

ACT: Activated clotting time; APTT: Activated partial thromboplastin time; CRRT: Continuous renal replacement therapy; ECMO: Extracorporeal membrane oxygenation; SLED: Sustained low efficiency dialysis.

DISCUSSION

In this study, we conducted a retrospective analysis of 87 patients with septic shock admitted to the ICU, to determine the efficacy of CytoSorb^® therapy used as an adjunctive therapy along with standard of care. A significant reduction in vasopressor requirements (40%), particularly norepinephrine (from 0.5 μg/kg/min to 0.3 μg/kg/min; P < 0.001), was observed following CytoSorb^® therapy. This is an important finding as vasopressors are used to maintain adequate blood pressure and perfusion in septic shock but can have adverse effects if used in high doses for prolonged periods[32]. In a study by Rugg et al[33], the catecholamines levels were nearly halved to 0.26 ug/kg/min, while being relatively steady in the controls within 24 hours of starting CytoSorb^® therapy. The ability of CytoSorb^® to stabilize hemodynamic parameters by mitigating the inflammatory response and improving vascular tone offers an advantage in sepsis management. The consensus by Carlos Sanchez et al[34] highlighted the potential benefits of CytoSorb in stabilizing hemodynamics, reducing the need for vasopressors, and improving overall patient outcomes, particularly when combined with standard care. Notably, significant reductions were observed in IL-6, CRP, procalcitonin, and TLC. These findings align with previous studies indicating that extracorporeal BPT can effectively remove circulating cytokines and inflammatory mediators, thereby reducing the systemic inflammatory response and potentially improving organ function[5,26].

The present study demonstrates that CytoSorb^® therapy significantly reduced key inflammatory responses in patients with septic shock. Use of CytoSorb^® resulted in IL-6 reductions by 83% and significant improvement in MAP by 7.8%. These findings support its potent anti-hyperinflammatory effects and its role in hemodynamic stabilization, both of which are essential in managing cytokine storms. IL-6 is a key pro-inflammatory cytokine implicated in the pathogenesis of sepsis, and its reduction correlates with improved clinical outcomes[35,36]. An Indian expert consensus has stated that despite IL-6 being a promising target in septic shock pathogenesis, its kinetics can be heterogeneous and influenced by various factors, excluding it as a sole predictor of patient outcomes which is of special importance in resource-limited settings like that of India and other lower and middle-income countries (LMIC). The consensus highlighted that CytoSorb^® therapy is effective when the decision is based on the clinical presentation of refractory septic shock rather than IL-6 Levels alone, suggesting that measuring IL-6 before initiating treatment is not mandatory[14].

“Lactime” referring to the duration in which lactate levels remain elevated above normal, proved to be a stronger predictor of mortality than the initial lactate measurement. A blood lactate concentration exceeding 4 mmol/L indicates organ hypoperfusion and is associated with increased mortality. Lactate serves as a biomarker, with a reduction of over 25% within 4 hours and 50% within 24 hours indicating improved chances of survival[30,37-39]. The present study found that 56% of patients showed significant lactate clearance based on Delta Lactate scores, while a small subset (5%) exhibited minimal to no improvement. Overall, these findings align with existing literature that associates higher lactate clearance with improved clinical outcomes in critically ill patients treated with CytoSorb^® therapy, highlighting the importance of monitoring lactate levels as a marker for metabolic recovery[30,37-39].

The PaO2/FiO2 ratio, a vital metric in the management of critically ill patients that offers insights into lung function, guides therapeutic strategies, and provides prognostic information, showed a statistically significant improvement in our study (P = 0.0102).

Additionally, the Indian expert consensus stated that CytoSorb^® therapy can lead to favorable outcomes, significantly reducing the need for vasopressors (noradrenaline) and increasing lactate clearance, which are indicators of improved prognosis in critically ill patients[14]. The number of adsorbers required may vary from patient to patient, with some patients needing more than one CytoSorb^® adsorber to achieve sufficient hemodynamic stabilization[14,35,38,40]. A retrospective cohort study by Schultz P observed lower than expected mortality rates in severely ill patients and a linear decrease in mortality with blood purification volumes exceeding 6 L/kg of body weight, suggesting that high doses of hemoadsorption may enhance survival outcomes[41]. As with every therapy, aspects of therapy management like patient selection, timing and dosing are crucial prerequisites for therapeutic success. However, in the present study, application of CytoSorb^® did not completely align with the recommendations outlined in a recent Best Practice consensus statement[19]. Thus, the therapy was not frequently initiated within the first 12-24 hours following the diagnosis of septic shock or the initiation of standard therapy, and the adsorbers were not replaced after 8-12 hours during the initial treatment phase. This should not be interpreted as a lack in knowledge or recognition by the authors, instead, it highlights the gaps from the assumed best practices and limitations associated with implementing such therapy in an Indian real-world setting, where financial constraints and the need to involve family members in funding the therapy present significant challenges. Still and despite the discussed limitations in regard to therapy management, use of CytoSorb was associated with a notably high reduction in clinical scores. The APACHE II and SOFA scores, which are established predictors of sepsis severity and mortality, showed significant reductions post-therapy, APACHE II (P < 0.0001) and SOFA (P = 0.0039). The study revealed a mean observed mortality of 79.3% vis-à-vis the PM percentage of 95% based on initial SOFA scores indicating that the actual outcomes were somewhat more favorable following CytoSorb^® therapy than initially anticipated mortality[31]. In 2019, Brouwer et al[39] demonstrated a significant decrease in observed mortality compared to the mortality predicted by the SOFA score[39]. Similar observations were reported by Rugg et al[33] (35.7% vs 61.9% in control group; P = 0.015) and Kogelmann et al[38] (89.9% PM vs 73% ICU mortality suggesting a potential benefit associated with CytoSorb^® therapy. A meta-analysis involving 744 critically ill patients demonstrated that the use of CytoSorb therapy in critically ill patients with septic shock significantly reduced in-hospital and day 28-30 mortality as well as need of the vasopressors. Thus, CytoSorb therapy can be added to standard of care for short-term improvement in survival[42].

The decrease in Delta SOFA scores in 54% of patients following CytoSorb therapy also suggests a significant clinical improvement, supporting previous studies that highlighted the effectiveness of SOFA score in predicting the outcome in critically ill patients diagnosed with septic shock. The highest Delta SOFA score can serve as an indicator of patient response to therapeutic strategies, as it identify the critical juncture at which patients demonstrate the most significant level of organ dysfunction during their ICU stay[31,39,43]. 25% of patients experienced worsening conditions as indicated by increased Delta SOFA scores, which might be explained by limitations in therapy management but might also highlight the heterogeneity complexity of sepsis responses and the necessity for ongoing assessment and tailored treatment strategies in critically ill populations. Notably, the Indian expert consensus stated that the effectiveness of CytoSorb^® therapy should be assessed using endpoints such as hemodynamic stabilization, inflammatory biomarkers, and improvement in organ function, rather than focusing solely on mortality[14], CytoSorb^® is designed to reduce cytokine levels and stabilize hemodynamics, and its efficacy should be evaluated based on its ability to achieve these outcomes, as demonstrated in our patients. However, the complex and heterogeneous nature of sepsis, particularly in severely ill patients as indicated by their sepsis scores, likely contributed to higher mortality rates.

The Indian expert consensus on the use of extracorporeal hemoadsorption in septic shock endorses and provides guidance on using CytoSorb^® haemoadsorption as an adjuvant treatment for septic shock to achieve optimal outcomes. Although, standard care for septic shock emphasizes source control, appropriate anti-infectives, fluid therapy, and catecholamines, a score principles, it does not adequately address the organ dysfunction associated with dysregulated immune response. For patients who do not respond adequately to the standard treatments, CytoSorb^® haemoadsorption therapy can facilitate restoration of immune balance by removing excessive inflammatory mediators like PAMPs, DAMPs, and cytokines, thereby addressing the underlying putative mechanism[14]. Figure 5 illustrates the treatment flow recommended by the Indian expert consensus[11,14,21,29], and our study tried to align with these recommendations as good as this was possible in our setting.

Figure 5 Treatment flowchart[11,21,29]. SOC: Standard of Care; NE: Norepinephrine; IL: Interleukin.

Furthermore, the safety assessments indicated that no major adverse events were reported with the treatment and a significant increase in serum albumin levels indicates that CytoSorb^® does not adversely affect albumin levels, suggesting its safety for clinical use. There was a significant reduction in platelet count, consistent with findings reported by Becker et al[44], who suggested that the drop in platelet levels was not directly attributable to the CytoSorb^® device itself but rather due to contact with an extracorporeal membrane in general or caused by the underlying clinical condition. Additionally, Mehta et al[45] reported a decrease in platelet count associated with CytoSorb^® use, though this reduction was not found to be clinically significant. These findings highlight the need to monitor platelet levels in patients undergoing extracorporeal treatments.

Main strengths of the study include 5 years aggregated data involving 87 patients with sepsis or septic shock from the resource-limited setting (LMIC) providing real-world insights with usage of CytoSorb therapy in sickest population. In addition, the study brings out the comprehensive analysis of micro- and macro-circulation, biomarkers, and insights on predicted and observed mortality outcomes. While the study provides valuable insights, it is important to acknowledge its limitations. The current study is a single arm observational evaluation without the control group. Furthermore, as a retrospective analysis from a single center, it may be subject to biases related to data collection, patient selection and survivorship bias. There was no clear selection of the right patient population, and the source of infection was not adequately segregated. In addition, the timing of initiation and the dosing of the CytoSorb therapy were non-standardised further limiting the interpretation of the outcomes. We did not assess the risk estimates such as odds ratio as study is single arm non-comparative study.

While using SOFA score as a predictor of mortality, it is still not clear whether initial, highest, mean or delta SOFA correlates best with the outcome measured. In our study, we did try to measure the initial SOFA and the delta SOFA to assess the severity of the disease and the corresponding recovery after the CytoSorb treatment respectively.

It was of significant note, as indicated by the checklist scoring system, over 31% of the CytoSorb usage happened in highly sick individuals where the futility of the therapy has been already demonstrated. Therefore, conducting future studies with a more focused and targeted population including the segregation based on the source of infection, based on well-established scoring systems and disease severity, along with timely intervention, would provide a more reliable assessment of CytoSorb’s efficacy in this difficult to treat population. Prospective, randomized controlled studies can help reduce the bias in patient selection. However, conducting such studies is difficult, resource-intensive and has its own limitations due to the heterogeneity of the study groups.

CONCLUSION

CytoSorb^® therapy appears to be a promising adjunctive treatment in the management of septic shock, showing significant reductions in vasopressors and inflammatory biomarkers, thereby leading to improved micro and macro circulation, better metabolic function and faster organ recovery, resulting in improved survival outcomes when compared to PM. However, right patient selection, appropriate timing and optimal dosing of CytoSorb therapy are crucial for maximizing its benefits.