Гемадсорбция для инфекционного эндокардита, требующего операции на открытом сердце

• Куанышбек А.С.
• Лесбеков Т.Д.
• Бекишев Б.Е.
• Калиев Р.Б.
• Джабаева Н.А.
• Фаизов Л.Р.

Резюме

Инфекционный эндокардит (ИЭ) связан с высоким уровнем смертности, чрезмерной системной гиперинфекционной реакцией или сепсисом. Лечение тяжелого ИЭ включает в себя комбинацию хирургического вмешательства и антибиотиков. Однако традиционной терапии может оказаться недостаточно для борьбы с инфекцией. В последнее время гемадсорбция является многообещающей терапией для лечения пациентов с сепсисом. Этот метод все чаще используется для предотвращения септических осложнений после операций на сердце. Гемадсорбция (ГА) была предложена в качестве дополнительной терапии ИЭ, но ее эффективность остается неясной.

Мы провели собственное исследование, изучающее влияние длительной гемадсорбционной терапии на концентрацию маркеров воспаления у пациентов, оперированных по поводу ИЭ в раннем послеоперационном периоде, сравнивая CytoSorb-300 с адсорберами HA-330. Поскольку результаты являются предварительными, мы провели обзор литературы, чтобы сопоставить полученные данные и ответить на вопросы об эффективности и безопасности гемадсорбционной терапии у пациентов после кардиохирургических вмешательств по поводу инфекционного эндокардита.

Цель - оценить безопасность и эффективность длительной гемадсорбционной терапии у пациентов с ИЭ, перенесших операцию на открытом сердце.

Материал и методы. Мы провели всестороннее компьютеризированное исследование литературы, чтобы выявить исследования, анализирующие терапию ГA при ИЭ, используя MEDLINE и EMBASE с января 2020 г. по 15 мая 2020 г., используя как терминологию заголовков медицинских тем (MeSH), так и релевантные ключевые слова для строк поиска. Для поиска исследований использовались следующие термины: “гемадсорбция”, “инфекционный эндокардит” и “операция на открытом сердце”. Мы провели это исследование, чтобы ответить на вопросы об эффективности и безопасности гемадсорбционной терапии. Кроме того, данные нашего исследования изучают влияние периоперационной терапии ГК на показатели воспаления и гемодинамический статус у прооперированных пациентов, оперированных по поводу ИЭ. Где пациенты были случайным образом распределены на терапию CytoSorb-300, или Jafron НА-330, или в контрольную группу. Терапия ГА была начата интраоперационно и продолжалась в течение 72 ч после операции.

Результаты. С января 2021 г. по апрель 2022 г. 39 пациентов были включены в исследование и случайным образом распределены в группу гемадсорбции или контрольную группы. 3 из них были исключены из-за невозможности подписания информированного согласия.Таким образом, в исследование были включены 36 пациентов: ЦитоСорб-300 (n=12), НА-330 (n=13), контрольная группа (n=11).

Количество койко-дней в отделении интенсивной терапии (р=0,6), длительность искусственной вентиляции легких (р=0,57), а также количество осложнений, таких как значимое кровотечение (р=1), ишемический инсульт (р=0,53), делирий (р=0,78) не отличалась между группами гемадсорбции и контрольной группой. Статистически значимая разница была обнаружена по показателям IL-10 (р<0,01), IL-8 через 24 ч после операции (р=0,04) и СРБ (р<0,01).

При сравнении цитокиновых фильтров и контроля во всех исследованиях не было выявлено существенной разницы в операционной смертности, продолжительности искусственной вентиляции легких, сроках пребывания в больнице и отделении интенсивной терапии.

Заключение. Применение процедур ГА интраоперационно и в послеоперационном периоде оказывает влияние на снижение концентрации маркеров воспаления. Мы считаем, что терапия ГА может быть полезна пациентам с ИЭ и высоким риском сепсиса.

Ключевые слова:гемадсорбция; инфекционный эндокардит; кардиохирургия

Abbreviations

AKI - Acute kidney injury

APACHE - Acute physiology and chronic health evaluation

CPB - Cardiopulmonary bypass

CRP - C-reactive protein

HA - Hemadsorption

HIT - Heparin-induced thrombocytopenia

ICU - Intensive care unit

IL - Interleukin

IE - Infectious Endocarditis

NT-proBNP - N-terminal pro-B-type natriuretic peptide

PCT- Procalcitonin

TNF-α -Tumor necrosis factor-alpha

WBC - White blood cells

Infectious endocarditis (IE) is a multiorgan disease caused by microbial infection of the endocardium. Despite advances in medicine in the past decade, its incidence and mortality rates have not declined [1]. Treatment of IE is associated with a longer hospital stay. Early surgery is performed in approximately half of patients for the treatment of IE [2]. Patients who are operated on for IE are at high risk of developing complications such as excessive systemic hyperinflammation and sepsis [3].

The duration and severity of harmful triggers for IE have a negative impact on the future course of the disease. In fact, the systemic inflammatory background is exacerbated by massive therapeutic interventions and enhanced by surgical trauma, cardiopulmonary bypass (CPB) [4] and hematransfusion in patients requiring surgery [5]. Our concept was to control this overwhelming inflammatory response by hemadsorption throughout the perioperative period to improve organ function. This study aims to assess the safety and efficacy of cytokine prolonged hemadsorption therapy for patients with IE undergoing open heart surgery.

Material and methods

We conducted a retrospective study of prospectively collected data in a single tertiary care center. The presented data were collected prospectively at the intensive care unit at the National Research Cardiac Surgery Center (NRCSC) between January 2021 and April 2022. All patients included were treated per protocol as part of standard care. The study was approved by the Local Bioethics Committee of the National Research Cardiac Surgery Center (N 01-74/2021 from 10/06/20), and registered in Clinical Trials.gov PRS, Protocol registration and results system (NCT05042622). The preliminary results of the study are presented in the article.

Study participants

Patients with confirmed native heart valve IE (IE was confirmed by an investigation at ECHO), who underwent cardiac surgery, were recruited into the study between January 2021 and April 2022. Inclusion criteria for the study were having diagnosis IE and open valve surgery with CPB, being 18 years old or higher, and giving an informed consent to participate in the study. Patients with acute kidney injury (AKI) at baseline were excluded from the study.

Thirty-nine patients with IE were enrolled in this single-center intervention study. Written informed consent was obtained from participants and their legal guardians to participate in the study. Three patients were excluded because they were unable to sign an informed consent form thus, 36 patients were enrolled in the study: CytoSorb-300 (n=12), HA-330 (n=13), control group (n=11). Patients in the control group had not received the HA intervention during this study.

Study outcomes

The primary endpoint of the study was the postoperative course of inflammatory markers and infection parameters (IL 6, IL-8, Il-10, TNF-α, C-reactive protein (CRP), leukocytes, lactate, and procalcitonin). Secondary outcomes compared between groups were days of mechanical ventilation, days of ICU stay, NT - proBNP level, and health complications as acute kidney injury (AKI), liver injury, delirium, heparin-induced thrombocytopenia (HIT), ischemic stroke.

Study data

The concentrations of inflammatory markers were determined in blood samples. Blood sampling was carried out seven times: before surgery, 2 hours (h) after the start of CPB, 6 h after surgery, 24 h after surgery, 36 h after surgery, 48 h after surgery, and 72 h after surgery. APACHE II score was used to assess the status of the patients at 6 h after surgery in the ICU.

Study procedures

Two types of adsorbers were used for the procedures from HA: CytoSorb-300 (Cytosorbents Europe GmbH) and НА-330 (Jafron Biomedical Co., Ltd. China). HA-330 is made of proprietary and patented cross-linked divinylbenzene polymer with pores size of 60kDa, while CytoSorb-300 is a styrene-divinylbenzene copolymer adsorbing molecules with size ranging from 10 to 60 kDa. The maximum pressure and maximum duration of hemadsorption with HA-330 are 760 mm Hg and 24 h, and 750 mm Hg and 6 h for CytoSorb-300. The cartridge volume is slightly bigger in HA-330 (330 ml) than in CytoSorb-300 (300 ml).

Three consecutive HA procedures were applied to each patient in the study groups (one in the intraoperative period and two procedures in the postoperative period). Duration of HA with CytoSorb-300 adsorber was set at 24 h, and 6 h with HA-330 adsorber, as recommended by a manufacturer.

Priming and heparinization were performed according to the manufacturer’s instructions: 5 min with 2000 ml of 0.9% NaCl solution for CytoSorb in 5 min and 50 min with 2500 ml of 0.9% NaCl solution and 12 500 ME heparin. The blood flow rate in the hemoperfusion device was 160-200 ml/min. Anticoagulation targeting ACT 180-210 s was achieved by administration of heparin (individual dose depending on laboratory data and postoperative bleeding status).

The first HA procedure was initiated intraoperatively with the onset of cardiopulmonary bypass (CPB). Intraoperative application of HA was performed with a standard CPB roller system (Stockert S5, LivaNova Deutschland GmbH), with a mean aortic pressure between 68 and 84 mmHg. Cytokine adsorption was performed on the CPB circuit (shown in fig. 1) or separately with a hemoperfusion machine (shown in fig. 2) and/or via an ECMO circuit and/or in combination with renal replacement therapy (RRT).

The second procedure was continued in the early postoperative period in the intensive care unit, 6 h after surgery. The third HA procedure was initiated 24 h after the second procedure. In the postoperative intensive care unit (ICU) phase, days of mechanical ventilation, average days of ICU stay, average days of hospital stay, and in-hospital mortality were evaluated.

Statistical analysis

Data were analyzed using IBM SPSS Statistics version 26 software (SPSS Inc. Chicago, IL. USA) and R statistical software. Normally distributed continuous data were presented as means and standard deviations (SD), while non-normal data were summarised as medians and interquartile ranges (IQR). Categorical variables were presented as absolute and relative frequencies. The time adjusted AUC was used to compare the levels of inflammatory markers between treatment groups over time. The change in levels of inflammatory markers was estimated by using the trapezoidal rule. Data correction for missing values was not performed. Kruskal-Wallis test was performed to compare time-adjusted AUC values between treatment groups as the number of patients in each group was small. Repeated measures of inflammatory markers at each time point [before, 2 h after, 6 h after, 24 h after, 36 h after, 48 h after and 72 h after surgery] were also compared using the Kruskal-Wallis test. Post hoc pairwise comparisons between treatment groups were made with the Mann-Whitney U test using the Bonferroni correction. Statistical significance level was identified at p-value less than 0.05.

Results

Baseline parameters and details of the surgery

The mean age of the HA-330 group was 49.5±14.5 years, that of the CytoSorb-300 group was 54.3±18.9 years and that of the control group was 54.3±14.2 years. 72 percent of the patients were male. There were no statistically significant differences between the groups in terms of baseline demographic characteristics (table 1).

The most common comorbidity was arterial hypertension, with 85% frequency in all groups. The next most frequent comorbidities among patients were insulin-dependent diabetes, persistent atrial fibrillation, and ischemic heart disease. Fifteen patients were diagnosed with a single valvular heart defect and 21 with multiple valvular heart defects (table 1).

The mean score on the Apache II scale was around 23-25 points (table 1). Five patients required reoperation (four in the HA-330 group and one in the control group). A patient in the control group underwent emergency surgery.

Sixteen patients underwent single valve surgery. Fourteen patients underwent double valve surgery and six patients underwent triple valve surgery. The mean value of the CBP time was 242±77.2 min in the HA-330 group, 203±43.8 min in the CytoSorb-300 group and 202±60.7 min in the control group. The cross-clamp time was similar in all groups with an average value of 140 min.

Two patients had circulatory arrest with hypothermia, one in the HA-330 group and the other in the control group. In the postoperative period, five patients required ECMO support due to hemodynamic instability.

Primary outcomes

The initial levels of interleukins and inflammatory markers were elevated in all patients due to valve infection. Interleukin levels were elevated immediately after the start of surgery and decreased 2-6 h after surgery (fig. 3). Similarly, inflammatory markers such as CRP, leukocytes, and PCT were elevated after the start of surgery and decreased 24-36 h after surgery (fig. 4). The use of HA had positive effects on some laboratory indicators.

Median IL-10 concentrations over time for treatment groups with HA-330(184.1) and CytoSorb-300 (72.1) were lower than in control group (280.4). This difference was statistically significant (p>0.001) (table 2). Median CRP concentrations were also lower in treatment groups with HA-330 (22.9) and CytoSorb-300 (48.6) than in control group (56.5). The difference in these values was also statistically significant (p>0.01). There were not any other statistically significant differences between control and both treatment groups for changes in the levels of other interleukins and inflammatory markers over time (table 2).

A statistically significant difference was found across in IL-10 (p<0.01), IL-8 24 h after surgery (p=0.04) and CRP (p<0.01) (table 3). No statistically significant differences were found for other laboratory parameters (IL-6, TNF-α, leukocytes, PCT).

Postoperative characteristics

There were no statistically significant differences in the length of stay in the ICU, hospital stay, and days of mechanical ventilation (table 4). Patients experienced complications in the postoperative period. The most common complications were: AKI (HA-330 group - 23.1%, CytoSorb-300 group - 25.0%, control group - 18.2%), delirium (HA-330 group - 15.4%, CytoSorb-300 group - 25.0%, control group - 27.3%), bleeding (more than 400 ml per 3 h) was observed in all groups (HA-330 group - 15.4%, CytoSorb-300 group - 8.3%, control group - 9.1%). One patient in the Jafron HA-330 group and one in the CytoSorb-300 group had liver damage (table 4).

There was a statistically significant difference in the concentration of IL-10 between treatment and control groups before surgery (p<0.001), 2 h (p<0.01), 6 h (p=0.04) and 72 h (p=0.04) after the surgery (table 3). The level of IL-8 was also different across groups 2 h after the surgery (p=0.04). CPR level differed between treatment and control groups at all time points after one day passed from the surgery (p=0.04, p<0.01, p=0.04, p<0.01). No statistically significant differences were detected for other laboratory parameters (IL-6, TNF, leukocytes, PCT).

Secondary outcomes

There were no statistically significant differences in the duration of the ICU stay, hospital stay, and mechanical ventilation days. In the postoperative period, the patients had complications. The most common complications were: Acute kidney injury (AKI) (HA-330 group - 23.1%, CytoSorb-300 group - 25.0%, control group - 18.2%), Delirium (HA-330 group - 15.4%, CytoSorb-300 group - 25.0%, control group - 27.3%), Bleeding (more than 400 ml per 3 h) were detected in all groups (HA-330 group - 15.4%, CytoSorb-300 group - 8.3%, control group - 9.1%).

The liver injury had one patient in the Jafron HA-330 group, one in the CytoSorb-300 group (table 4). Laboratory-diagnosed heparin-induced thrombocytopenia (HIT) was found in one patient in the HA-330 group, and in one patient in the control group. Mortality was observed in all groups. In absolute numbers, one incident occurred in the HA-330 group, one in the CytoSorb-300 group, and two incidents occurred in the control group.

Discussion

Epidemiology of infectious endocarditis

In the largest comprehensive review estimating the burden of IE globally, Bin Abdulhak et al. reported that the incidence rate ranged between 1.5 cases and 9.6 cases per 100,000 people [6]. Moreover, the incidence varies considerably according to region and country, and even within national borders. In high-income countries, its incidence is approximately one case for every 1000 hospital admissions [7]. Epidemiological data on IE in Kazakhstan cannot be found in available publications, yet the incidence of cardiovascular disease is high according to the World Health Organization (WHO) [8].

Therapy of infectious endocarditis

Therapy options for IE include antibiotics, surgery and adjuvant methods. Optimal therapy for infective endocarditis requires bactericidal antibiotics for a prolonged period. The exact duration and use of single-drug vs combination drug therapy vary according to the pathogen, the presence of antibiotic resistance (as discussed below), and whether the infection involves a native or prosthetic valve [9]. Guidelines for surgical treatment of infective endocarditis are largely based on observational studies [10]. Indications for surgical valve repair or replacement include acute complications, such as valve dysfunction resulting in heart failure, which are associated with a higher risk of mortality or major morbidity than if treated with antibiotic therapy alone. Surgery is performed during the index hospitalization in about half of left-sided infections (infection of a native or prosthetic mitral or aortic valve) most commonly for heart failure due to acute, severe valvular regurgitation [11].

Hemadsorption therapy

Hemadsorption is the elimination of inflammatory cytokines by adsorption depending on their plasma concentration by using biocompatible highly porous polymer cartridges. One example is the Cytokine (RenalTech International, New York, NY, USA) adsorber, which demonstrated its initial efficacy of cytokines removal in vitro. [12]. Septic shock leads to an uncontrolled release of pro-inflammatory cytokines and mediators known as “cytokine storm” leading to increased mortality. Additional case reports and case series revealed beneficial outcomes with improved hemodynamics and inflammatory parameters when treating septic patients with Cytokine adsorbers [13-18].

This therapeutic removal of a wide range of inflammatory cytokines has recently been applied in treating the novel SARS-CoV-2 virus. Severe vasodilation and release of high levels of IL-6 have been identified as predictors of fatal outcomes in COVID-19 disease. Randomised clinical trials are currently being conducted to investigate outcomes when using Cytosorb adsorber in patients suffering from COVID-19 [19, 20].

The theoretical benefits for the application of cytokine filters during CPB in cardiac surgery include the effective reduction of cytokines produced, and thus cytokine-induced organ damage, improved haemodynamics, resulting in reduced postoperative complications, and therefore costs [8].

Patients operated for infective endocarditis are at high risk of excessive systemic hyperinflammatory state, resulting in systemic inflammatory response syndrome and septic shock. In this occasion, HA by cytokine adsorbers has been successfully applied to remove inflammatory mediators [21]. Different studies have shown contrasting results for perioperative HA procedures. According to Silke Asch et al. [20], HA therapy did not reduce inflammatory parameters or improve postoperative hemodynamics in 25 patients. The primary endpoint of the study was the postoperative course of cytokine levels (IL-6, TNF-α, IL-1b) and inflammatory parameters (CRP, PCT, leukocytes). Morbidity was the secondary endpoint estimated from SOFA. SAPS II and APACHE II scores, postoperative catecholamine and fluid requirements, and in-hospital mortality. The authors concluded that IE per se does not seem to be an indication for HA therapy in cardiac surgery, regardless of the severity of SIRS or sepsis.

However, some studies supported the hemadsorption method. Perioperative HA could reduce the incidence of postoperative sepsis and sepsis-related death. Additionally, patients with intraoperative hemadsorption showed greater hemodynamic stability. These data suggest that intraoperative hemadsorption may improve surgical outcomes in patients with mitral valve endocarditis [18].

In our center, we had a promising sporadic experience with the use of HA for cytokine storms (both CytoSorb-300 and Jafron HA-330 adsorbers). Therefore, we decided to compare the efficacy and safety of CytoSorb-300 and HA-330 adsorbers in the perioperative period in patients with IE who require open heart surgery. We found that in the perioperative period, the concentration of inflammatory markers was greatly increased. After completion of valve surgery and within 72 h (during HA procedures), IL-6, CRP, and leukocyte levels decreased, but after 6-24 h, a repeated increase was observed. The mean length of stay in the ICU and the mortality rate were almost the same in both groups.

According to our study, the use of HA procedures may have an impact on the level of inflammatory markers. However, more than three follow-up procedures are required in patients with IE. This issue requires further research.

According to our data, the application of the HA procedure is possible with both CytoSorb-300 and HA-330 adsorbers. The application of both cartridges does not cause any technical difficulties.

Conclusion

The results of our study and literature review suggest that the use of hemadsorption in patients undergoing open-heart surgery due to IE neither associated with clinical course improvement, nor higher morbidity and mortality. Nevertheless, laboratory findings from our research substantiated statistically significant decrease in the level of IL-10, IL-8, and CRP. This effect was permanent for the whole period of extracorporeal HA application for both CytoSorb-300 and Jafron HA-330 devices. Other bigger studies on the HA are needed to identify the correct management of IE patients with unfavorable clinical course to choise the methodology, proper duration of HA, and the proper device.

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