The use of lipopolysaccharide adsorption employing advanced domestically manufactured cartridges in the comprehensive treatment of maternal sepsis and septic shock

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Introduction

Sepsis and septic shock (SS) are life-threatening conditions with mortality rates of up to 50 % [1; 2]. Traditionally, SS remains one of the main causes of maternal mortality in developing countries of Africa, Asia and Latin America at 9.7, 13.7 and 7.7 %, respectively [3]. In recent years, an increase in mortality from obstetric sepsis has been noted in developed countries: in the UK and France - up to 10 %, in Southeast Asia – up to 13.7 % [3-5]. In the Russian Federation, this indicator is 10 % [6].

It has been established that in more than 80 % of cases of SS, an increased level of endotoxin is detected in the blood, and in 30 % there is a high level with an endotoxin activity of 0.6 conventional units or more [7]. There is evidence that the blood endotoxin content in patients with SS serves as an early predictor of mortality. The higher the endotoxin activity, the more often unfavorable outcomes of sepsis and SS treatment occur [8–10].

Comprehensive treatment of maternal sepsis and SS currently includes early initiation of broad-spectrum antibiotic therapy, effective infusion and respiratory therapy, and correction of arterial hypotension with vasopressors [6]. A particularly important factor is the need for “source control,” i.e. surgical elimination of infection. Under certain circumstances, sanitization of the source of infection is the only effective treatment method, and emergency surgery can save the patient's life. Examples include surgical treatment of necrotizing soft tissue infections, removal of an infected foreign body, curettage of residual products of conception from the uterine cavity, drainage of a pelvic abscess that is unresponsive to drug therapy, and surgical intervention for endometritis. Preference is given to minimally invasive manipulations and surgery operations [6; 11; 12].

Extracorporeal detoxification methods are used to remove endotoxins from the circulatory system, as well as excess of inflammatory mediators as additional methods of treating maternal sepsis and SS [9; 10; 12]. Selective lipopolysaccharide adsorption (LPS adsorption) reduces the level of endotoxin in the blood, which has a positive effect on the state of the cardiovascular and respiratory systems [7; 13]. Toraymyxin PMX-20R (PM X) cartridges manufactured by Toray (Japan) and Alteco ® LPS Adsorber (Lund, Sweden) [13–16] are most often used for the procedure abroad. In 2017, the domestic Efferon LPS cartridge (PJSC Efferon, Russia) appeared, which has been used in 65% of cases in Russia in recent years when performing LPS adsorption. A number of studies have been published showing its effectiveness in the treatment of sepsis and SS in patients with surgical and therapeutic profiles [13; 17; 18]. Studies on the use of LPS adsorption using the domestic cartridge Efferon LPS in the treatment of maternal sepsis were launched in 2022.

The aim of the study is to evaluate the results of LPS adsorption using the domestic cartridge Efferon LPS in the comprehensive treatment of maternal sepsis and septic shock.

Materials and Methods

22 patients with maternal sepsis or SS were treated from 2022 to 2023 in the Perm Regional Clinical Hospital. They underwent one to three sessions of selective adsorption of endotoxin in addition to complex treatment in accordance with the clinical guidelines "Initial intensive care for septic shock in obstetrics" from 2019 and "Septic shock in obstetrics" from 2022. The age of the patients ranged from 22 to 49 years, with a median of 32 years. In the majority (20), the cause of sepsis or SS was pyometra, in two – chorioamnionitis. In seven cases, the diseases developed in the late postpartum period after a cesarean section in the lower segment, and in 13 cases, as a result of premature birth with the development of severe preeclampsia, HELP syndrome and thrombotic microangiopathy. Half of the patients were diagnosed with intrauterine fetal death. In two cases, women were admitted after termination of pregnancy at 12 to 17 weeks after an out-of-hospital infected abortion (1) and an incomplete abortion with the development of endometritis (1). The majority of patients (63.64 %) had a severe comorbid context: acquired immunodeficiency syndrome (5), chronic viral hepatitis C with an outcome in liver cirrhosis class A or B (4), bronchial asthma (2), diabetes mellitus (4), kidney cancer (1), cystic fibrosis (1). Some patients had two or more severe concomitant diseases. At the time of HIV diagnosis, only one in five patients was receiving antiretroviral therapy and was being monitored by infectious disease specialists. The Charlson index ranged from 0 to 6 with a median of 1 point (0; 2). Most were admitted in a state of septic shock (12; 54.55 %) and on artificial lung ventilation (ALV) (13; 59 %). In order to sanitize the source of infection, all patients underwent surgery, they underwent hysterectomy with tubes.

Additionally, the patients underwent selective absorption of lipopolysaccharides on the first day after surgery. The procedure was performed using a perfusion apparatus - B. Braun Dialog and absorption of Efferon LPS columns ("PJSC Efferon", Russia) with a perfusion rate of 150 ml/min, a duration of 6 hours and an interval of 24 hours for the second and third absorption.

The results of clinical and laboratory examinations were compared before and 24, 48 and 72 hours after sessions of extracorporeal selective sorption of endotoxin. The APACHE, SOFA scales, and routine blood tests were used to assess the condition of patients. The level of inflammation biomarkers – C-reactive protein (CRP), procalcitonin (PCT), presepsin – was determined using quantitative immunochemiluminescence. Endotoxin activity (EAA) was studied using a chemiluminescent assay kit (Endotoxin Activity Assay Kit, Canada). The content of tumor necrosis factor (TNF), interleukins (IL) 1b, 6, 8, 10 were also determined using an enzyme immunoassay, as well as the level of natriuretic peptide (NT-proBNP) using an electrochemiluminescent immunoassay (Cobase 601, Roche).

Statistical processing of the material was performed using the Statistica 10 software. Given the small number of patients, nonparametric statistical methods were used. The median, 25th and 75th quartiles were used as descriptive statistics; the Wilcoxon test for paired comparisons was used to compare significant differences in the groups before and after absorption. The relationship between fatal outcomes and other parameters was established using multivariate correlation analysis. The Spearman rank correlation coefficient (r) was calculated, as well as the level of its significance. Differences were considered reliable at p ≤ 0.05.

Results and Discussion

On admission, the median severity of multiple organ failure according to the SOFA scale was 7.5 scores (6; 11). After the surgical intervention, a tendency towards worsening of the clinical condition of the patients was noted. The median severity of multiple organ failure according to the SOFA scale increased to 10.5 scores (7; 14). The number of patients with septic shock increased to 16 (72.72 %), the same number were on mechanical ventilation (APV). In 14 cases (63.63 %), renal failure with a severity of one to four scores on the SOFA scale was detected. 8 patients (36.36 %) out of them required renal replacement therapy.

All patients showed an increase in inflammation biomarkers (lactate, PCT, presepsin, LDH), EAA, TNF and levels of most IL. The parameters of the patients at the time of inclusion in the study and 72 hours after LPS absorption using Efferon LPS columns are presented in the table.

 

Clinical and laboratory parameters before and 72 h after LPS absorption using Efferon LPS columns in patients with maternal sepsis

Parameter	Before LPS absorption. Median (25th and 75th quartiles), n = 22	72 hours after absorption. Median (25th and 75th quartiles), n = 22	р
Age, years	32 (26. 38)	–	–
Gestational age, weeks	30.5 (24.2; 34.5)	–	–
BMI	26.5 (25; 32)	–	–
Septic shock, n/N (%)	16/22 (72.72)	7/22 (31.82)	0.02*
Charlson index, scores	1 (0; 6)	–	–
APACHE 2, scores	18 (14; 19)	–	–
SOFA before surgery, scores	7.5 (6; 11)	–	–
SOFA before/after LPS absorption, scores	10.5 (7; 14)	5 (1; 9)	0.00*
Norepinephrine dose, mcg/kg/min	0.39 (0; 0.71)	0 (0; 1.6)	0.01*
SBP, mmHg	80 (90; 125)	83.6 (76; 93)	0.07
ALV, n/N (%)	16/22 (72.72)	4/22 (18. 18)	0.00*
Oxygenation index	188 (156; 304)	345 (280; 480)	0.01*
Patient requires RRT, n/N (%)	8/22 (36.36)	3/22 (13.64)	0.08
Erythrocytes, 1012/l	3.24 (3; 3.62)	3.4 (3.2; 3.89)	0.4
Leukocytes, 109/l	19 (15.3; 24)	15 (11; 23)	0.43
Thrombocytes, 109/l	96.5 (57; 189)	113 (76; 139)	0.74
Total bilirubin, mmol/l	15.5 (10; 33)	17 (11; 38)	0.82
Urea, mmol/l	10.34 (4.1; 14)	7.4 (6; 10)	0.78
Creatinine, mmol/l	136 (85; 235)	100 (58; 124)	0.01*
Total protein, g/l	47.5 (43; 52)	51.5 (46; 57)	0.03*
Albumin, g/l	25.5 (24; 30)	29.5 (25; 33)	0.04*
LDH, U/L	350 (254; 557)	290 (240; 351)	0.00*
Lactate, mmol/l	2.6 (2; 3.7)	2.37 (0.5; 2.8)	0.15
Leukocytes, 109/l	19 (16; 24)	15 (12.6; 23)	0.46
CRP, mg/l	123 (76; 184)	100 (68; 143)	0.47
PCT, ng/ml	9.98 (2.1; 26)	1.85 (0.75; 7.25)	0.00*
Presepsin, pg/ml	1145 (700; 2737)	1067 (639; 2162)	0.87
EAA, conventional units	0.66 (0.51; 0.82)	0.52 (0.38; 0.91)	0.28
Response	0.93 (0.88; 0.96)	0.91 (0.88; 0.95)	0.32
IL-1b, pg/ml (normal 0–11)	4.8 (2.3–7.9)	2.7 (1.5–4.7)	0.04*
IL-6, pg/ml (normal 0–7)	161.9 (56.6; 422)	121. 25 (48; 171.2)	0.24
IL-8, pg/ml (normal less than 62)	76.3 (37.6–135.3)	41.1 (20.9; 55.1)	0.02*
IL-10, pg/ml (normal 0–31)	41 (13; 123.8)	13.9 (7.2–29)	0.00*
TNF, pg/ml (normal 0–8.21)	12. 3 (4.6; 24)	6.1 (1.5; 12.4)	0.01*
NT-proBNP (normal 0–125)	1204 (852; 4156)	4352 (1263; 10516)	0.88
28-day mortality	5 (22.72 %)	–	–
Overall mortality	8 (36.36 %)	–	–

Note: Wilcoxon test, Fisher's exact test, * – the difference is statistically significant.

 

Most patients (18) underwent two sessions of LPS absorption, one – underwent one, and three more – three. One procedure was performed on a patient who died 24 hours after the start of complex treatment due to refractory septic shock. Three sessions were performed in cases of insufficient effect from two LPS absorptions. All three patients also died within 28 days from the start of septic shock treatment. There were no complications during the procedure. After the sessions of extracorporeal selective absorption of endotoxin, the clinical condition of the patients improved significantly: the need for mechanical ventilation significantly decreased and the oxygenation index increased, in nine cases the arterial pressure normalized without vasopressor support, and in two more cases the dose of norepinephrine decreased by half.In one case, no improvement in the clinical condition was observed after LPS sorption, and the patient died of refractory septic shock. The median SOFA score significantly decreased to five. A significant decrease in the levels of creatinine, lactate dehydrogenase (LDH), PCT, IL-1b, 8, 10, a tendency to decrease in the number of leukocytes in the blood, urea content, CRP, presepsin, IL-6, TNF, EAA activity was noted (see table). The NT-proBNP value after LPS absorption sessions tended to increase and exceeded the initial level by 3.5 times. It was found that the maximum effect of LPS absorption using Efferon LPS columns occurs after the first session. After the second procedure, the severity according to the SOFA scale, endotoxin activity, PCT and lactate levels decreased slightly. After 72 hours, some inflammation biomarkers (PCT and lactate) tended to increase. The severity according to the SOFA scale, EAA remained at the same level or decreased slightly (Fig. 1–3).

 

Fig. 1. Content of PCT, lactate and IL-1b before and after LPS absorption

 

Fig. 2. Content of IL-6, -8, -10 and SOFA scores before and after LPS absorption

 

Fig. 3. Reduction of EAA activity as a result of LPS absorption with the Efferon LPS cartridge

 

The content of all ILs significantly decreased after the first selective absorption of endotoxin, then a tendency for their increase was found. After the second procedure, the IL level again tended to decrease, and 72 hours after the start of LPS absorption, the content of IL-1b, IL-8 and IL-10 returned to normal, and IL-6 significantly decreased compared to the initial values (see Fig. 1, 2).

The endotoxin activity after LPS absorption decreased maximally after the first procedure and maintained this trend after 72 hours (see Fig. 3).

It was found that fatal outcomes had a positive average correlation with the initial condition of patients in the course of statistical analysis. The higher were the scores on the APACHE, SOFA scales, the Charlson index, the initial dose of norepinephrine (r = 0.38, p = 0.00; r = 0.37, p = 0.00; r = 0.34, p = 0.00; r = 0.43, p = 0.02, respectively), the worse was the result of complex treatment of maternal sepsis. The initial level of LDH and PCT also significantly positively correlated with adverse outcomes (r = 0.39, p = 0.05; r = 0.30, p = 0.03, respectively).

The 28-day hospital mortality rate was 22.73 % (5 of 22). All patients who died were diagnosed with septic shock before LPS absorption. Four patients underwent two LPS absorptions. One patient died a day after selective endotoxin absorption from refractory septic shock.

The overall mortality rate was 36.36 % (8 of 22). Three more patients died on the 33rd–62nd day from the start of complex treatment. In one case, sepsis was diagnosed in the patient with and severe concomitant diseases (HIV, chronic hepatitis C with an outcome in class A liver cirrhosis). Two more patients were in septic shock. They underwent three sessions of LPS absorption with Efferon LPS columns. They died from the second wave of sepsis against the background of bilateral nosocomial pneumonia.

Despite all the advances in diagnosis and treatment, mortality from maternal sepsis and septic shock remains high and amounts to 11 % [2; 19; 20]. The basic principles of treatment of obstetric sepsis have been developed and implemented in practice [6; 21]. It has been established that with its gram-negative etiology, a high level of endotoxin is detected in the blood, and its selective elimination from the body can reduce mortality [8; 10].

The 2023 clinical guidelines for the treatment of septic shock in adults and obstetric sepsis recommend the use of sorption techniques to remove cytokines and toxins, the indication for which is the presence of gram-negative sepsis, multiple organ failure with a SOFA score of more than 7 and endotoxin activity of more than 0.6 [1; 21]. In our study, the severity of the patients' condition before LPS absorption corresponded to 10.5 scores on the SOFA scale, the median endotoxin activity exceeded 0.6 conventional units, and the median PCT level was more than 9.98 ng/ml.

A number of studies have shown the positive effect of LPS absorption in patients with maternal sepsis. In this case, cartridges with different mechanisms of capturing endotoxin from the bloodstream were used – "Torey", "Alteko". A positive effect on the cardiovascular, respiratory, renal systems, the level of inflammation biomarkers, and endotoxin activity was noted [7; 9; 11; 15]. In 2017, a new type of cartridge was developed in the Russian Federation – “Efferon LPS”, which combines the properties of selective and non-selective absorption methods [22]. The presence of a porous matrix with mesopores in combination with ligands makes it possible to simultaneously eliminate endotoxins and cytokines from the bloodstream. There are publications indicating the effectiveness of using Efferon LPS in the treatment of sepsis and septic shock in surgical patients [18; 23; 24]. The procedure was performed on the first day after surgery. An improvement in both the clinical condition and laboratory parameters was noted – a decrease in the levels of PCT, CRP, IL-6, and EAA activity [23; 24; 25].

In our patients, the median EAA activity before LPS absorption was 0.66, indicating the severity of endotoxemia. A significant increase in IL-6 (23 times) and NT-proBNP (9.5 times) levels was also found, as well as a slight increase in IL-8, IL-10. The content of IL-1b and TNF was within the reference values, indicating the absence of significant disorders of the patients' immune system before the start of LPS absorption. At the same time, their level had significant fluctuations, reflecting both a decrease and an increase in immunity in a number of patients before the procedure. The results of our work showed a reliable decrease in SOFA scores in patients with maternal sepsis and septic shock as a result of improved cardiovascular and respiratory function, a significant decrease in creatinine, LDH, PCT, interleukins 1b, 8, 10, a tendency to decrease the number of leukocytes in the blood, the content of CRP, presepsin, IL-6, TNF, and EAA activity. It was noted that the maximum effect of LPS absorption with Efferon LPS columns occurs after the first procedure. EAA activity decreased from 0.66 to 0.56 conventional units a day after the procedure and maintained this trend after 72 hours.

The unfavorable result with the inclusion of LPS absorption with domestic Efferon LPS columns in the complex treatment of maternal sepsis and septic shock depended on the severity of the initial condition of the patients, the presence of severe concomitant pathology, the content of LDH, PCT, as well as the reaction to the first procedure. Conducting LPS absorption sessions contributed to the improvement of the patients' condition.

Conclusions

1. The introduction of LPS absorption with domestic Efferon LPS columns in the complex treatment of maternal sepsis and septic shock allows achieving a reliable reduction in the number of scores on the SOFA scale, levels of creatinine, LDH, PCT, interleukins 1b, 8, 10, and a tendency to decrease the activity of EAA.
2. Fatal outcomes were positively correlated with the initial indicators of SOFA score, LDH and PCT levels.

About the authors

L. P. Kotelnikova

Ye.A. Vagner Perm State Medical University

Email: veralex80@mail.ru
ORCID iD: 0000-0002-8602-1405

DSc (Medicine), Professor, Head of the Department of Surgery with a Course in Cardiovascular Surgery and Invasive Cardiology

Russian Federation, Perm

A. V. Vereshchagin

Perm Regional Clinical Hospital

Author for correspondence.
Email: veralex80@mail.ru
ORCID iD: 0000-0002-1163-2316

Intensive Care Specialist

Russian Federation, Perm

S. B. Lyapustin

Ye.A. Vagner Perm State Medical University

Email: veralex80@mail.ru
ORCID iD: 0009-0001-8566-1494

PhD (Medicine), Head of the Department of Anesthesiology, Intensive Care and Emergency Medicine

Russian Federation, Perm

References

Supplementary files