In our study, at the end of the CVVHDF for 24 hours we detected that PRC and NIR were reduced in patients using Oxiris filter; urea, platelet count and PRC levels were decreased significantly in patients using AN69 filter. There was no statistically significant difference between the groups in terms of mortality.
LTA, a cell wall component specific to gram-positive bacteria, is the functional equivalent of LPS, the main cell wall component of gram-negative bacteria (18). LTA and LPS are also called pathogen-associated molecular patterns (PAMPs) and stimulate the natural immune response by binding to pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) expressed by monocytes, macrophages, neutrophils and other immune cell types. Gram-negative LPS mainly signals through TLR4, while Gram-positive LTA can bind to and signal through TLR2. (2). Both of these interactions stimulate the activation of Nuclear Factor kappa B (NF-κB), resulting in transcription and secretion of multiple pro-inflammatory cytokines such as tumor necrosis factor (TNF) -α, interleukin (IL) –1, IL–6, IL–8 and IL–10 that play important roles in inflammatory diseases such as sepsis (2,14). Damaged host cells express surface damage-associated molecular patterns (DAMPs) such as high-mobility-group-box–1 protein (HMGB1) on their surface. DAMPs can be released into circulation and are recognized by pattern recognition receptors (PRRs). Thus, leukocyte activation and cytokine synthesis are increased, fueling the vicious cycle of uncontrolled immuno-inflammatory process. Excessive release of cytokines in the blood is defined as a “cytokine storm” (14). As a result, sepsis or septic shock develops through vasodilatation, endothelial leakage and organ dysfunction (4). One of the organ dysfunctions in sepsis is AKI. Although the pathophysiological mechanism in septic AKI is not fully understood, it is clear that the inflammatory cascade of sepsis contributes to AKI (19). The basic pathophysiological paradigm correlates septic AKI with decreased global renal blood flow, secondary tubular epithelial cell death, or acute tubular necrosis. The reason for this belief is that AKI is associated with hypoperfusion and shock, and that ischemic damage can lead to intense cell death (eg acute tubular necrosis). However, the importance of ischemia-reperfusion is increasing (20).
Septic shock is associated with higher mortality compared to sepsis (1). Septic shock continues to account for 62% of general deaths and hospital mortality rates are above 40% (21). Mortality associated with AKI is high (40–60%) and the short- and long-term outcomes in the form of chronic or end-stage renal disease are devastating (5). AKI develops in more than 45% of patients with septic shock (21). The mortality rate of our study patients was 59.5%. Considering the fact that our patient group had septic shock-related AKI, our mortality rate was within normal limits. There was no significant difference between the groups in terms of mortality.
When we look at the results of four studies in the literature, which examined a large number of patients with sepsis, the most common source of sepsis was reported to be lungs with varying rates (39–68%). Although the ranking varies, other common sources of infection are the abdomen (8–22%), unclear (17–20%), urinary tract (9–14%) and soft tissue (10%) (22–25). In our study, the most common source of sepsis in the literature was the lungs (33%), followed by soft tissue (16%), unclear (16%), abdomen (12%), catheter-related infection (12%) and urinary tract (9%), respectively.
The Sepsis Occurrence in Acutely Ill Patients (SOAP) study reported an almost equal prevalence of gram-positive and gram-negative bacterial infections in patients with sepsis (24). Although subsequent studies (26) have suggested an increase in the incidence of gram-positive organisms, The 2012 Intensive Care Over Nations (ICON) study has shown that gram-negative bacterial infections are more common in the United States than gram-positive bacterial infections (27). In our study, gram-negative bacteria grew more in the blood cultures of the patients than gram-positive bacteria.
In a study of 13796 infected ICU patients published in 2009 S. aureus, Pseudomonas species, Enterobacteriaceae (especially E. coli) and fungi were the most common blood cultures. In this study, Acinetobacter accounted for 9% of patients with positive blood culture (25). In a review published in 2012, the most common isolated gram-negative bacteria were E. coli, P. aeruginosa and K. pneumonia; and and the most common gram-positive bacteria were S. aureus, S. pneumonia and Enterococcus spp. in patients with sepsis and septic shock (28). In our study, the most common gram-negative bacteria were P. aeruginosa, A. Baumannii, K. Pneumoniae and Enterobacter spp; and the most common gram-positive bacteria were S. epidermidis, S. aureus and S. hominis ssp hominis in the blood culture. Our study was consistent with previous studies in terms of blood culture reproduction. However, 20% of patients with positive blood culture had acinetobacter reproduction and this rate was higher than previous studies.
Continuous renal replacement therapy (CRRT) with improvement in extracorporeal blood purification techniques and membrane materials are widely used in critical illness (10). The theoretical cut-off for an RRT membrane is about 35 kDa. Throughout this membrane, diffusion and convection can take place. Diffusion follows a concentration gradient (as in intermittent hemodialysis) and is an ideal method to remove small (<500 Da) molecules such as creatinine. Convection follows a hydrostatic pressure gradient and is the best method for elimination of medium to large (500 Da to 60 kDa, 13,750 Da beta–2 microglobulin) and large molecules (60 to 100 kDa, eg 70 kDa albumin). In clinical practice, high (60 kDa) or median (50 kDa) cut-off membranes are almost never used because high cut-off membranes may increase the risk of albumin loss (11). Endotoxin molecules have a size of approximately 10 kDa, but can form aggregates of up to 1,000 kDa consisting of a covalently bonded lipid and polysaccharide (9). The smaller molecular weight of the cytokines, the more cytokines will be removed in the CRRT. The cutoff value of CRRT was 30–40 kDa, while IL–1β was 17 kDa, IL–1RA 15–20 kDa, IL–2 15 kDa, IL–6 26 kDa, IL–8 8 kDa, macrophage migration inhibitory factor (MIF) has a molecular weight of 12.5 kDa, IL–10 35–40 kDa and TNF-α51 kDa. Thus, only IL–10 and TNF-α are outside the threshold of CRRT; all other cytokines can be slowly removed with CRRT. High volume hemofiltration or treatments like the ones with the use of a high cut-off membrane can increase the clearance of inflammatory cytokines but it is still unknown if it could provide benefit to patients (10).
AN69 is a copolymer of hydrophobic acrylonitrile and hydrophilic sodium metahalylsulfonate. As AN69 is negatively charged due to sulfonate groups, the AN69 membrane adsorbs cytokines via ionic bonding between its sulfonate group and the amino group on the surface of a cytokine molecule (12). Oxiris is a high permeability polyacrylonitrile (AN69) based membrane on which a surface treatment of a positively charged polyethylene is added onto the hemofilter. Thanks to this positive charge on the surface of the Oxiris filter - in addition to the bulk cytokine elimination in the mass of the membrane - endotoxin (negatively charged) adsorption takes place (13). In in-vitro studies, Oxiris filter emerges as a hemoperfusion device capable of eliminating both endotoxin and cytokine (29). Endotoxin hemoadsorption can reduce the pathogenic activity and organ dysfunction of endotoxin. Cytokine removal by hemofiltration or hemoadsorption can restore the status of immune homeostasis. It is thought that the use of semi-permeable membranes that can provide endotoxin and cytokine elimination is a valuable treatment option in septic shock due to gram-negative bacterial infection (30). Endotoxin may also be present in the circulation due to translocation from the ischemic gut in gram-positive infections (4). Therefore, the use of oxiris in gram-positive sepsis or septic shock may be beneficial (14).
The main finding of our study is that CVVHDF performed with Oxiris filter improves hemodynamics, reduces NIR, is clinically applicable and has no side effects in patients with septic shock-related AKI. Our results confirm the results of some studies in which Oxiris filter was applied in the same patient group. Comparing Oxiris and AN69 filters in patients with septic shock-related AKI Broman et al. found a strong decrease in circulating endotoxin and cytokine levels as a result of CVVHDF treatment with Oxiris filter. This reduction was associated with a favorable hemodynamic effect, such as a faster decrease in blood lactate levels and a decrease in NIR required to maintain mean arterial pressure. There was a blunted cytokine response in both filter groups, but the decrease in TNF-α, IL–6, IL–8, and IFN- γ was more outstanding in patients treated with Oxiris than the AN69 filter (4). In the study of Schwindenhammer et al., 31 patients were diagnosed with septic shock between 2014 and 2019 and one of the continuous venovenous hemofiltration (CVVH) or CVVHDF therapies with Oxiris filter was applied. A relative decrease of 88% was observed in NIR. Lactatemia and pH improved significantly over time (13). In their study on 60 septic patients published in 2019, Turani et al. found that CVVHDF with Oxiris filter improved basic cardiorenal and respiratory parameters and decreased NIR (31).
Shum et al., in a study performed CVVH for 48 hours, found a 37% reduction in the SOFA score of sepsis-related AKI patients who underwent Oxiris filter compared to polysulfone-based standard filter (30). In their study published in 2019, Turani et al. found that the SOFA score of 60 septic patients applied CVVHDF with Oxiris filter decreased from 12.4 ± 2 to 9 ± 2 (31). In our study, no significant decrease was observed in the SOFA score by CVVHDF with Oxiris filter. This is due to the fact that our patients had very severe diseases with high mortality (septic shock-related AKI) and we evaluated the SOFA score after 24 hours of Oxiris administration. Longer CRRT could cause a significant decrease in SOFA score.
In their study on 13 patients with sepsis and multiorgan failure Dahaba AA et al. found that, PRC levels decreased significantly after 12 hours CVVH with AN69 filter (32). Turani et al. in their studies published in 2019, observed a decrease in the PRC level of 60 septic patients who received CVVHDF with Oxiris filter (31). In our study, we found that PRC levels decreased significantly in both groups using Oxiris and AN69 filters after 24 hours of CVVHDF. The cut-off value of AN69 filter is 35–40 kDa (32) and PCT molecular weight is 14.5 kDa (33). We attributed the significant decrease in PCT value after CVVHDF with both filters to the fact that the molecular weight of PCT was considerably lower than the cut-off value.
The limitation of our study is that we evaluate the blood cell counts, blood biochemistry, inflammation indicators, clinical conditions and the mortality results without considering other intermittent conditions after the 24 hours of CVVHDF. We compared the changes that occurred with only one CVVHDF application. In the future, randomized, controlled, double-blind, clinical trials can be planned to compare the changes in renal function and mortality rates of CVVHDF with longer or repeated administration.