Efficacy of Coupled Plasma Filtration Adsorption in Treating Patients with Severe Intra-Abdominal Infection: A Retrospective Study

Abstract

Background:

Coupled plasma filtration adsorption (CPFA) is an extracorporeal treatment based on plasma filtration associated with an adsorbent cartridge and hemofiltration. CPFA is able to remove inflammatory mediators and it has been used to treat severe sepsis and multiple organ dysfunction. Limited experience exists on the use of CPFA in treating intra-abdominal infection (IAI).

Methods:

In this study, the efficacy of CPFA in treating patients with severe IAI and liver failure was evaluated in a retrospective analysis of 76 cases.

Results:

The survival rate of patients treated with CPFA was 82.6%, with effective removal of endotoxin and inflammatory mediators.

Conclusion:

Our data suggest that CPFA can be safely and effectively used to lower morbidity and mortality rates of patients with severe IAI and liver failure.

Introduction

Intra-abdominal infection (IAI) is an increasing incidence of morbidity and mortality that is caused by abdominal trauma and complex surgical strategies.¹ Early diagnosis, adequate control, and appropriate therapy are critical for the management of IAI.² However, inappropriate first strategy and complex disease conditions can trigger reinfection in the abdominal cavity, which is more troublesome, and the treatment of severe IAI usually stops when liver failure and multiple organ failure happens.³ In the vicious cycle of liver failure, endotoxins are absorbed and inflammatory mediators are constantly released, which seriously distorts the liver function and hampers the regeneration and healing of liver cells.⁴ No effective warning and intervention indicators can be used for early identification of live dysfunction.⁵ The level of bilirubin can reflect the function of liver because the accumulation of bilirubin can damage the liver physiology.^6–8 Thus, most of evaluation systems choose bilirubin level as an indicator of liver failure. However, whether other parameters can also be used to describe the severity of the early-stage liver failure is still unknown. Currently, the therapies used to treat liver failure included drugs, monoclonal antibodies, and other extracorporeal treatments, which are mainly directed against a single substance or mediator.⁹ This high selective effect seems to represent their major limitations.¹⁰

Coupled plasma filtration adsorption (CPFA) is an extracorporeal treatment combining plasma filtration with an adsorbent cartridge and hemofiltration.¹¹ It can absorb a wide range of inflammatory mediators that are responsible for the development and maintenance of liver failure and multiple organ dysfunction syndrome.¹² The main clinical application of CPFA is the treatment of sepsis.¹³ With the application of CPFA, time can be saved for the regeneration and recovery of natural hepatocytes, as well as the implementation of many etiological treatments, which contribute to a higher survival rate in patients with sepsis.¹⁴ Moreover, the efficacy of CPFA for the treatment of liver failure has also been reported by many studies.^3,15,16 However, limited data exist on the use of CPFA in the setting of IAI patients. This study evaluated the clinical prognosis of 76 IAI-induced liver failure cases that were employed CPFA to reduce the levels of endotoxins and inflammatory mediators on the body system.

Methods

General data

According to the exclusion criteria, a total of 76 cases with severe intra-abdominal-induced liver failure and multiple organ dysfunction syndrome (Grade IV, total bilirubin >240 μmol/L) from January 2010 to May 2018 in the intestinal fistula center of Jinling Hospital of China were recruited in this study, including 64 men and 12 women, aged 51.4 ± 15.6 years (range 11–86 years). There were 17 cases of pancreatitis, 34 cases of severe abdominal trauma, and 25 cases of postoperative gastrointestinal surgery (Table 1). The exclusion criteria were as follows: (1) having a history of chronic hepatitis, cirrhosis, liver tumor (surgery-treated), or other primary hepatic disease; (2) having the complication of severe trauma in biliary system; (3) having a history of long-term hormone use, chemoradiotherapy for malignant tumor, and autoimmune disease. All patients had been treated with CPFA. The study was approved by the ethics committee of Jinling Hospital and patients' family members have signed written informed consent.

Table 1.

General Clinical Data Comparison Between the 2 Groups (Mean ± Standard Deviation)

	Survivors (n = 14)	Nonsurvivors (n = 62)	P
Age	51.5 ± 12.7	51.4 ± 16.3	.91
Gender			.44
Men	13	51
Women	1	11
Etiology
Pancreatitis	2	15
Trauma	8	26
Postoperative gastrointestinal surgery	4	21

Treatment

In addition to conventional, symptomatic, and supportive treatments, each patient received standard infection control measures: fluid resuscitation, infection biological clearance, drainage, nutritional support, and use of antibiotics. Temporary access was opened with cannula connecting femoral vein in 76 patients. Blood purification system used was Edwards^® Continuous Renal Replacement Therapy (Baxter International, Inc.). Extracorporeal circulation introduced low molecular heparins to prolong the whole blood activated clotting time by 1.5–2 times (200 seconds). With modified CPFA, the whole blood was separated with hollow fiber dialyzer, EC-40W (Asahi Kasei Medical, Tokyo, Japan; blood flow velocity of 200–250 mL/min and plasma separation rate of 90 mL/min). The plasma was filtered with continuous venovenous hemofiltration equipped with polysulfone membrane (Fresenius, Germany). Ultrafiltration rate (UFR) was 66 mL/min (4000 mL/h). Bicarbonate exchange liquid (4000 mL/h) was infused into plasma separator. The UFR was set accordingly, usually 250–500 mL/h for 8 hours. Blood samples before and after each round of treatment were prepared.

To make pretreatment samples, the blood to be infused into the instrument was drawn from the catheter connecting the artery. To make post-treatment samples, the blood 20 minutes after the treatment was taken. Vital signs before and after the treatment were recorded. Acute pathological function and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA) scoring, and lactic acid (LAC) detection were carried out before and after the treatment. All samples were analyzed for blood biochemical and coagulation function. The end points were patient safety, system efficiency, biochemical indicators, and coagulation parameters. Secondary end points were the effect of survival. In every patient, we monitored invasive arterial blood pressure, central venous pressure, heart rate, and SpO2. Arterial blood gas, blood routine, total and direct bilirubin (TBIL and DBIL), aspartoacylase (AST), alanine aminotransferase (ALT), platelets (PLA), prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio, and bacteremia were also measured before and after treatment.

Statistical analysis

Data were presented as mean ± standard deviation. Statistical analysis was performed using IBM^® software SPSS 23.0 (Chicago, IL). Differences in categorical variables between groups were analyzed using the χ²-test. Comparison between the 2 groups (survivors and nonsurvivors) used t-test. P < .05 was considered statistically significant.

Results

Clinical survival rate of IAI patients

After treatment of CPFA, most patients showed significantly improved health conditions, reduction of jaundice and bleeding. Of the 76 patients, 62 survived with a survival rate of 81.6%, and 14 succumbed with a mortality rate of 18.4%. Based on the classification of factors for IAI-induced liver failure, the survival rates were as follows: pancreatitis 88.2% (15/17), trauma 76.4% (26/34), and postoperative gastrointestinal surgery 84.0% (21/25).

Comparison before and after CPFA treatment

Before CPFA treatment, the levels of DBIL, TBIL, and the ratio of DBIL to TBIL were significantly higher in survivor group compared with that of nonsurvivor group. Moreover, the levels of LAC and bacteremia were also significantly lower in the survivor group than that of nonsurvivor group. However, no significant difference was found in the levels of AST, ALT, PLA, PT, APTT, INT, and APACHE II score between the 2 groups. These findings suggest that the levels of DBIL, TBIL, LAC, bacteremia, and SOFA may be the critical factors that affect the survival rate of IAI patients. No matter in the survivor group or the nonsurvivor group, the patients' clinical conditions rapidly improved as shown by the decreased levels of TBIL, DBIL, and the ratio of DBIL to TBIL after treatment with CPFA.

Discussion

CPFA has been extensively used to treat septic shock,^12,13,17 but it has been seldom used in patients with IAI-induced liver failure. Some IAI patients are prone to develop liver failure, multiple organ failure, or even death. The process of multiple organ failure in sepsis and liver failure is interrelated and gradual and this type of liver failure has a bad prognosis. In addition to routine infection control, CPFA shows increasing therapeutic value. However, clinical evaluation of the prognosis of CPFA in the treatment of IAI-induced liver failure is rare. In this study, 76 cases of abdominal infection with CPFA treatment were selected and the prognosis of the treatment was comprehensively evaluated. To the best of our knowledge, this is the first study describing CPFA administration in the treatment of IAI patients.

The liver is the largest solid organ in the human body and plays an irreplaceable role in metabolism, synthesis, secretion, detoxification, and immune defense. Owing to the key roles of host defense (control of bacteremia, mediating cytokine, and synthesizing protein in acute state), the liver is susceptible to sepsis caused by multiple organ failure.¹⁴ In this study, the ratio of DBIL to TBIL in the survival group was significantly higher than those in the nonsurvivor group, which were consistent with the other reports.^18,19 The higher ratio of DBIL to TBIL indicates that more functional hepatocytes survive, and endotoxin and inflammatory mediators can be eliminated, whereas a lower proportion shows less survival of hepatocytes.

Although inflammatory mediators are removed, liver function cannot be restored and irreversible multiple organ failure can occur. Thus, the predictive value of SOFA score for the prognosis of sepsis has been fully demonstrated.²⁰ Our study also confirms this by showing that SOFA score was significantly decreased in the survivor group than that of nonsurvivor group, indicating the importance of SOFA score in the detection and early treatment of IAI patients.

With the occurrence of liver dysfunction, the ability of the liver to eliminate bacteria has been weakened. Then, bacteria enter the bloodstream, releasing toxins, thereby aggravating liver damage. In this vicious cycle, the excessive inflammatory reaction caused by a large number of inflammatory cytokines is from liver failure, ignoring the usefulness of antibiotics.²¹ However, the effective indicators of early liver failure are not clear. In this study, we found that bacteremia may be the key indicator of the liver failure, because the level of bacteremia was significantly decreased in the survival group compared with that of nonsurvivor group.

There are many different methods to reduce endotoxin and circulating inflammatory mediators. However, there is still no consensus, and the best strategy to stop the so-called septic cascade. The main benefit of using CPFA is in its ability to remove a wide spectrum of molecules, thus improving the inflammatory systemic framework through balancing different types of sepsis mediators.²² Moreover, it also allows quick clinical recovery in the patients and prompts reversal of the inflammatory imbalance.²² Our previous studies have confirmed that the modified CPFA can improve the internal environment by effectively reducing bilirubin, toxin, and inflammatory mediators.^23,24 In this study, the patients' clinical conditions rapidly improved as shown by the decreased levels of TBIL, DBIL, and the ratio of DBIL to TBIL after treatment with CPFA. This is the first report that bilirubin level in patients with IAI-induced liver failure could be successfully improved with CPFA. Proinflammatory substances such as cytokines are commonly involved in several specific pathological processes observed in the liver failure and multiple organ dysfunction caused by IAI.³

The main advantages of using CPFA in treating IAI associated with liver failure are the following: (1) the ability to effectively remove endotoxin and inflammatory mediators and (2) the chance to describe and indicate severity of the early-stage liver failure simultaneously. Thus, further studies are required to clarify the possible application of CPFA in the treatment of clinical IAI patients when indicated.

Footnotes

Disclosure Statement

No competing financial interests exist.

References

Vincent

. Clinical sepsis and septic shock—Definition, diagnosis and management principles. Langenbecks Arch Surg, 2008; 393:817–824.

Sartelli

, Catena

, Abu-Zidan

, et al. Management of intra-abdominal infections: Recommendations by the WSES 2016 consensus conference. World J Emerg Surg, 2017; 12:22.

, Wang

, et al. Part of plasmapheresis with plasma filtration adsorption combined with continuous hemodiafiltration in the treatment of severe acute liver failure. Exp Ther Med, 2016; 12:2582–2584.

Yan

, Li

. The role of the liver in sepsis. Int Rev Immunol, 2014; 33:498–510.

Marshall

, Cook

, Christou

, Bernard

, Sprung

, Sibbald

. Multiple organ dysfunction score: A reliable descriptor of a complex clinical outcome. Crit Care Med, 1995; 23:1638–1652.

Kramer

, Jordan

, Druml

, Bauer

, Metnitz

. Incidence and prognosis of early hepatic dysfunction in critically ill patients—A prospective multicenter study. Crit Care Med, 2007; 35:1099–1104.

Jäger

, Drolz

, Michl

, et al. Jaundice increases the rate of complications and one-year mortality in patients with hypoxic hepatitis. Hepatology, 2012; 56:2297–2304.

Brienza

, Dalfino

, Cinnella

, Diele

, Bruno

, Fiore

. Jaundice in critical illness: Promoting factors of a concealed reality. Intensive Care Med, 2006; 32:267–274.

Vincent

, Moreno

, Takala

, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med, 1996; 22:707–710.

10.

Harm

, Falkenhagen

, Hartmann

. Endotoxin adsorbents in extracorporeal blood purification: Do they fulfill expectations?. Int J Artif Organs, 2014; 37:222–232.

11.

Bellomo

, Tetta

, Ronco

. Coupled plasma filtration adsorption. Intensive Care Med, 2003; 29:1222–1228.

12.

Livigni

, Bertolini

, Rossi

, et al. Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: A multicenter randomised controlled clinical trial. BMJ Open, 2014; 4:e003536.

13.

, Sun

, Zhu

, et al. Effects of coupled plasma filtration adsorption on septic patients with multiple organ dysfunction syndrome. Ren Fail, 2012; 34:834–839.

14.

Panagiotou

, Gaiao

, Cruz

. Extracorporeal therapies in sepsis. Intensive Care Med, 2013; 28:281–295.

15.

Evenepoel

, Laleman

, Wilmer

, et al. Detoxifying capacity and kinetics of Prometheus—A new extracorporeal system for the treatment of liver failure. Blood Purif, 2005; 23:349–358.

16.

Sentürk

, Esen

, Ozcan

, et al. The treatment of acute liver failure with fractionated plasma separation and adsorption system: experience in 85 applications. J Clin Apher, 2010; 25:195–201.

17.

Berlot

, Agbedjro

, Tomasini

, et al. Effects of the volume of processed plasma on the outcome, arterial pressure and blood procalcitonin levels in patients with severe sepsis and septic shock treated with coupled plasma filtration and adsorption. Blood Purif, 2014; 37:146–151.

18.

Bakker

, Gris

, Coffernils

, Kahn

, Vincent

. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg, 1996; 171:221–226.

19.

Dellinger

, Levy

, Rhodes

, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med, 2013; 41:580–637.

20.

Singer

, Deutschman

, Seymour

, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 2016; 315:801–810.

21.

Strnad

, Tacke

, Koch

, Trautwein

. Liver—Guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol, 2017; 14:55–66.

22.

Level

, Chauveau

, Guisset

, et al. Mass transfer, clearance and plasma concentration of procalcitonin during continuous venovenous hemofiltration in patients with septic shock and acute oliguric renal failure. Crit Care, 2003; 7:R160–R166.

23.

Zhu

, Gong

, Xu

, Liu

, Ji

. Combined CVVH-bilirubin adsorption therapy on patients with hyperbilirubinemia. Nephrol Dialy Transplant, 2011; 3:204–211.

24.

Yang

, Zhao

, Chen

, Zhang

, Li

. Effect of continuous veno-venous hemofiltration on the plasma levels of endotoxin and cytokine in patients with severe intra-abdominal infection. Chin J Prac Surg, 2014; 22:444–446.