Combination of Cytokine Hemosorption and High-volume Hemofiltration in Acute Pancreatitis

Overview

Mortality from severe acute pancreatitis reaches 42%. The prognosis of acute pancreatitis is associated with the development of acute inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Due to the lack of etiological therapy, the treatment of acute pancreatitis is predominantly symptomatic. Severity and mortality are associated with early systemic inflammatory response syndrome (SIRS) and septic complications at a later stage of the disease. With regard to the pronounced inflammatory response ("cytokine storm") during the early phase of endogenous OP intoxication, extracorporeal removal of cytokines is a promising therapeutic approach. This prospective study examines the effect of the combined hemosorption method (Efferon CT) in combination with high volume hemofiltration (HVHF) on the severity of clinical symptoms of endogenous intoxication and indicators of organ dysfunction in acute pancreatitis.

Full Title of Study: “An Open Controlled Randomized Study of the Efficacy and Safety of the Method of Combined Use of Non-selective Hemosorption (Efferon CT) and High Volume Hemofiltration (HVHF) in Patients With Acute Pancreatitis.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 30, 2024

Detailed Description

Acute pancreatitis in emergency surgery takes the 3rd place in terms of the frequency of its manifestation, second only to acute appendicitis and cholecystitis. The incidence of acute pancreatitis is growing from year to year and is more than 38 patients per 10,000 population per year. In 25% of patients, the development of pancreatitis is destructive. Mortality in this pathology is mainly associated with the development of severe necrotic forms that cause a systemic inflammatory response of the body. The formation of pancreatic necrosis occurs within 1-2 days of illness, and it is at this time that the therapeutic effect is most effective. Mortality in patients with acute pancreatitis reaches 20-60% depending on the nature of the disease, the phase of the pathological process, the severity of comorbidities, the severity of multiple organ failure syndrome (MODS), purulent-septic complications, and the development of septic shock. The main factors determining an unfavorable prognosis are the frequency of MOF and the development of sepsis, and their intensity, as well as the developed septic shock. In the case of the onset and progression of PON in the first 48 hours, they speak of early severe pancreatitis, which is characterized by a more unfavorable prognosis. Unsatisfactory results of treatment of this contingent of patients, especially those of working age, and high economic costs determine the socio-economic significance of the disease and the relevance of improving diagnostic and treatment methods. Acute pancreatitis is a systemic rather than a local critical condition. Associated complications include sepsis, MOF, ARDS, acute renal failure, DIC, acute liver failure, etc. According to some reports, at least 50% of deaths in the early stage of acute pancreatitis are associated with MODS, and with the failure of three or more organs, mortality increases to 95%. In the study, the modified CTSI AUC was significantly higher than the Ranson score (p = 0.02) as well as the BISAP score (p = 0.002) in predicting the severity of acute pancreatitis. APACHE II was also found to have high sensitivity and negative predictive value for predicting pancreatic necrosis (93.33% vs. 96.15%), organ failure (92.86% vs. 96.15%), and admission to the intensive care unit. (92.31% and 95.8%), making it an ideal scoring system for referral decisions to higher centres. Therefore, it seems interesting to use a combination of several scales, namely APACHE II + BISAP + CTSI, when assessing a patient's prognosis. Thus, often, the time when adequate treatment can affect the outcome of the disease is missed. After that, against the background of the picture of pancreatic necrosis, complications arise at lightning speed and like an avalanche, despite the measures taken to prevent them. In this regard, the earliest identification of patients with an aggressive, destructive nature of the disease for the entire complex of intensive care seems to be very important. The severity of the patient's condition with acute pancreatitis is largely determined by the severity of endotoxemia. The latter, in turn, depends on the cytokine response of the body. To date, the early pathogenetic mechanisms of acute pancreatitis and its complications are poorly understood. The question of what happens at the subcellular level, what processes are responsible for the development of severe forms of the disease, extraorganic complications remains insufficiently studied. Treatment of acute pancreatitis is traditionally divided into conservative and surgical. The start time of conservative measures, their components, an adequate assessment of effectiveness affect the timing and extent of surgical intervention. In Russia and other countries, protocols for managing patients with this pathology have been developed. There are opposing views on many aspects of treatment: the duration of antisecretory therapy with somatostatin drugs and its effect on the outcome of the disease, the feasibility of antibiotic prophylaxis in destructive forms, the nature of nutritional support, the need for immediate surgery in diagnosed infected pancreatic necrosis, indications for one or another volume of surgical treatment, and many others. . At the moment, there is no specific surgical tactics for sterile and infected pancreatic necrosis, as well as for its purulent-septic complications. It is known that lethality from infected pancreatic necrosis is 2-3 times higher than from a sterile process. Prospects for choosing the optimal treatment strategy should be associated with advances in diagnosis, the real possibilities of antibiotic therapy, and relevant knowledge about the pathogenesis of destructive pancreatitis. "Cytokine storm", which occurs in the acute phase of pancreatitis, leads to aggravation of intoxication, inadequate and untimely correction of which underlies the development of pancreatogenic shock, multiple organ failure and septic complications. Organ hypoperfusion, tissue hypoxia, endotoxicosis, systemic inflammatory and anti-inflammatory reactions induced by "mediator aggression", water-sectoral and electrolyte disturbances are the most important links in the etiopathogenesis of OP and associated PON. Therefore, the use of detoxification methods aimed at the elimination of toxic substances, the normalization of water sector and electrolyte disorders, the normalization of organ perfusion, the reduction of systemic inflammation in the treatment of patients with acute pancreatitis is pathogenetically justified in order to prevent MOF and the development of pancreatic shock and sepsis. In the past 10 years, various methods of extracorporeal detoxification have become widespread in the practice of intensive care for severe forms of acute pancreatitis. Despite this, there is no consensus among specialists regarding the timing of the application of certain techniques in the context of the phase course of acute pancreatitis, the required frequency of procedures, and their effectiveness. In acute pancreatitis, severe endotoxemia occurs early, which leads to the development of multiple organ failure. Allocate biochemical, immunological and microbial components of endogenous intoxication, which include intermediate and final metabolites of the processes of autolysis and secondary infection. Detoxification underlies the prevention and pathogenetic treatment of complications of acute pancreatitis. Numerous studies have shown that the use of extracorporeal sorption methods that eliminate pro-inflammatory cytokines improves the results of treatment of patients with manifestations of endogenous intoxication. Many techniques have been described – infusion therapy, enterosorption, hemofiltration (HF), high-volume hemofiltration (HVHF), ultrahemofiltration (UHF), hemosorption (HS), plasmapheresis (PF). Evidence accumulated in recent years indicates that continuous veno-venous haemofiltration (CVVH) is beneficial in acute pancreatitis due to the removal of inflammatory molecules and medium and low molecular weight toxic substances by convection. Particular attention is paid to high-volume hemofiltration (HVHF), which can give a better effect in the treatment of acute pancreatitis. CVVH was developed as a continuous renal replacement therapy for patients with severe conditions and has been widely used, mainly in intensive care, replacing intermittent hemodialysis. It can remove non-selective inflammatory mediators, balance hypercatabolism and fluid overload, and maintain acid-base disturbances, which is why it has been used to treat SIRS and MODS secondary to AP. The use of CVVH has been evaluated in an animal model of OP. It can significantly improve survival time in therapeutic and prophylactic applications, especially in the latter case. The 2012 study by La-Ping Chu (China) "Clinical Effects of Pulse High-Volume Hemofiltration on Severe Acute Pancreatitis Complicated With Multiple Organ Dysfunction Syndrome" also confirmed that CVVH has a pronounced beneficial effect on clinical symptoms and laboratory parameters in acute pancreatitis flowing with PON. In acute pancreatitis, a large number of soluble inflammatory mediators circulate in the patient's blood. Thus, the elimination of cytotoxins with standard continuous hemofiltration (CVVH) with a water exchange rate of 35 ml/kg/h may not be adequately adequate to the severity of the disease symptoms. The advantage of "high volume" is the removal of higher molecular weight substances, which include many inflammatory mediators. Numerous animal studies have shown a positive effect of high volume hemofiltration (HVHF) on survival in endotoxic models. Human studies have demonstrated that HVHF improves hemodynamics in septic shock. But a great concern of researchers has always been associated with the difficulties of conducting and the high cost of HVHF as a continuous method. That is why it is interesting to study the effectiveness of the use of short pulsed HVHF techniques in acute pancreatitis. Recently, there has been a search for new approaches to the treatment of patients in the early stages of acute pancreatitis, even before the development of severe complications that significantly worsen the prognosis of the disease. One of them may be the extracorporeal removal of excessively produced mediators of the inflammatory response (cytotoxins) from the systemic circulation by the method of sorption. Nevertheless, very few studies have been devoted to the use of the hemosorption method in the early stage of acute pancreatitis, before the appearance of septic complications. Hemosorption is the most modern method of removing substances toxic to body cells from the patient's blood. The procedure is carried out outside the body by pumping the blood flow through a device filled with a sorbent (hemoperfusion procedure). Critical parameters for therapeutic efficacy are the type of sorbent, its volume, the number of repeated procedures; they are individualized depending on the identified pathological disorders and the patient's condition. The technology of extracorporeal purification of blood from cytokines has been used for more than 25 years. The scope of its medical application is constantly expanding, while being accompanied by implementation in an increasing number of countries. Many studies have shown that the use of hemosorption stabilizes the condition of patients with sepsis. Currently, there are no multicenter randomized studies confirming the need for the use of EGC methods as one of the main areas of pathogenetic therapy for acute pancreatitis. At the same time, the increasing emergence of data on the significant influence of the "cytokine storm" on the pathogenesis of the disease and its progressive deterioration suggests a possible positive role of the method of cytokine hemosorption performed in the early phase of acute pancreatitis. In connection with the above data in this CT, it seems interesting to determine the degree of influence of the combined method of cytokine hemosorption (Efferon CT) and high volume hemofiltration (HVHF) on the clinical manifestations of endogenous intoxication and organ dysfunction of acute pancreatitis occurring without septic complications.

Interventions

  • Device: Efferon CT
    • Efferon CT (JSC Efferon, Moscow, RF) is a device for extracorporeal blood purification by direct hemoperfusion. Detoxification is carried out by sorption of cytokines and other products of endogenous intoxication with a molecular size of up to 55 kDa.

Arms, Groups and Cohorts

  • No Intervention: Baseline therapy
    • Basic therapy – the routine practice of an institution for the treatment of patients with uninfected acute pancreatitis
  • Experimental: Basic therapy + Efferon CT + HVHF
    • Basic therapy, which is the routine practice of an institution for the treatment of patients with acute nonseptic pancreatitis in combination with extracorporeal hemoperfusion therapy (Efferon CT) and high-volume hemofiltration (HVHF).

Clinical Trial Outcome Measures

Primary Measures

  • Effect of the combined use of the Efferon CT device and HVHF on indicators of organ dysfunction
    • Time Frame: 1-72 hours
    • The value of indicators on the SOFA scale every 24 hours ± 1 hour from the start of hemoperfusion (0 hour) to 72 hours.

Secondary Measures

  • Effect of using the combined use of the Efferon CT device and HVHF on systemic hemodynamic parameters
    • Time Frame: 1-72 hours
    • Time (number of hours) from randomization to end of vasopressor support.
  • Effect of the combined use of the Efferon CT device and HVHF on pulmonary oxygen metabolism function
    • Time Frame: 1-72 hours
    • Value of oxygenation index (Pa02 / Fi02 (Pa) every 24 hours ± 1 hour from the start of hemoperfusion (hour 0) to 72 hours.
  • Effect of the combined use of the Efferon CT device and HVHF on the indicators of the cardiac index
    • Time Frame: 1-72 hours
    • Ultrasound assessment of LVOT VTI or RVOT VTI gain

Participating in This Clinical Trial

Inclusion Criteria

  • Age from 18 to 75 years old, – Acute pancreatitis according to the Atlanta classification of OP (2012), without signs of infection, – Acute pancreatitis confirmed by tomography. Score according to the Modified CTSI Pancreatitis Severity Index: from 4 points and above, – No more than 3 days from the onset of an attack of acute pancreatitis, – APACHE II score – at least 10, – The patient must receive adequate fluid therapy (at least 30 ml/kg) from the time of randomization until the first therapy, – The patient's condition allows therapy for at least 4 hours. Exclusion Criteria:

  • Age over 75, – More than 3 days from the onset of an attack of acute pancreatitis, – An attack of acute pancreatitis, as an exacerbation of chronic pancreatitis. – Acute pancreatitis as a complication of a surgical operation, – DS – Septic shock (Sepsis-3, 2016) – The presence of a focus of non-sanitized surgical infection, – Charlson comorbidity index> 5 points, – Critical hypoxemia (PaO2/FiO2 < 150 mm Hg), – GCS level of consciousness < 12 points, – Obesity 3 degrees and above (weight over 150 kg), – Blood triglyceride level >1000 mg/dl, (11.2 mmol/l), – Dementia, – Inability to achieve or maintain min SBP ≥ 65 mm Hg. Art., despite vasopressor therapy and infusion therapy in tech. 24 hours – Presence of end-stage renal disease requiring RRT, – The presence of cirrhosis of the liver (> 5 points according to the Child-Pugh classification), – Unresolved biliary hypertension syndrome, – Acute thromboembolism of the pulmonary artery, confirmed by tomography, – Acute myocardial infarction within the last 4 weeks, – Acute cerebrovascular accident, – Transfusion reaction, – Severe congestive heart failure, – Uncontrolled bleeding (acute blood loss in the last 24 hours).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Efferon JSC
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Makariy Mendibaev, MD, Principal Investigator, Demikhov City Clinical Hospital of the Moscow Health Department
  • Overall Contact(s)
    • Alexandr Shelehov-Kravchenko, PhD, MD, +79636564765, alexandr.shelehov@gmail.com

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