EFFECTS OF EXTRACORPOREAL DETOXIFICATION METHODS ON MORTALITY IN SEPSIS



The WorldWide
Intensivist 		Date of Publication: 1998/10/01
  Constantin P.Zhidkov MD, Doctor of Medical Science
Vladimir Z.Klechikoff MD

Introduction Methods Results Discussion References

Summary

OBJECTIVE

DESIGN

SETTING

PATIENTS

INTERVENTIONS

MEASUREMENTS AND MAIN RESULTS

CONCLUSION

 
 
List of Abbreviations
DIC disseminated intravascular coagulopathy
EDM extracorporeal detoxification methods
ChH EDM-charcoal hemoperfusion
HBO hyperbaric oxygenation
MMWC middle molecular weight compounds
MODS multiple organ dysfunction syndrome
PSC porcine spleen crossperfusion
UBI ultraviolet blood-irradiation

Introduction

The problem of sepsis is characterised by: The results of two extensive reviews of American patients were that the mortality in septic patients is as high as 36.3% and 37.1% (1,2). According to data reported by Russian practitioners, the incidence of sepsis in surgical patients has fluctuated from 1:1,000 to 1:1,500 with a mortality rate of 53% in those patients over 50 years old (3).

The most recent opinion about the pathogenesis of multiple organ dysfunction syndrome (MODS) in sepsis, presumes that infectious agents induce the liberation of cytokines, arachidonic acid derivatives, complement and various other products of macrophage activity. When triggered by tumour necrosis factor, the biologically active products lead to circulatory instability, metabolic derangement and MODS (4-7).

Sepsis complicated by MODS, is associated with a toxic syndrome, induced by disorders in the body's detoxification systems and manifest by circulatory instability, respiratory failure, central nervous system dysfunction and an increase in the concentration of middle molecular weight compounds(MMWC) in serum.

Currently available extracorporeal methods of detoxification that make temporary use of natural detoxification systems are actively used in the treatment of endotoxicosis (8-10 ). The objective of this retrospective study is to evaluate the efficiency of application of extracorporeal methods and sessions of hyperbaric oxygenation in patients with sepsis, complicated by MODS.
 
 

Methods

In the current study we analysed 10 years of experience in the management of septic patients which were treated with traditional methods or a combination of traditional therapy with extracorporeal detoxification methods (EDM) and hyperbaric oxygen.

During the period from 1984 to 1997, 127 patients with sepsis of various origin were treated in ICU Hospital 26 (St. Petersburg). From the group of 127 septic patients we reviewed records of 81 patients with sepsis complicated by MODS and analysed the results of treatment.

To define the septic process, we used the criteria proposed by Bone (11) in concert with recommendation of the American Colleague of Chest Physicians and Society of Critical Care (12). The following definitions for MODS were used, modified from references (13-16).

All study patients were required to have dysfunction of at least three organ systems.

In 17 patients, episodes of septic shock were recognised. Patients underwent multiple operations for peritonitis, pancreatitis or multiple trauma of the extremities. Patients were followed until the time of discharge from the hospital or until the time of death.

The 81 patients were allocated in one of two groups. Group 1 was those patients who survived their hospitalisation ( 23 patients) and group 2 was those who died (58 patients).

The basic therapy in all 81 patients included:

  1. immediate and definitive surgical management of the cause of infection (draining , removal of foreign material, etc.).
  2. antimicrobial therapy- combination of cephalosporins, aminoglycosides and metronidazole. When bacteraemia was present, the selection of antibiotics depended on the type of pathogen isolated from blood and its sensitivity to the antibiotics.
  3. infusion therapy (plasma substitutes, packed blood cells, albumin, fresh frozen plasma).
  4. drugs with antiprotease activity.
  5. drugs containing SH-groups.
  6. drugs restoring host defence mechanisms (thymus extracts, interferon, antistaphylococcal plasma and immunoglobulin).
In 41 patients the above therapy was supplemented with EDM HBO. EDM included: ChH, UBI and HBO.

Definitions:

Charcoal hemoperfusion. Veno-venous method of ChH was used. A filter with SKN-type charcoal adsorbent (Ukrania; specific surface 1,200 m2/g,total volume of pores 0.6-1.0 cm3/g) was flushed with 1 L normal saline containing 10,000 U heparin. The priming volume of circuit and filter was 350 ml. Blood was pumped with a roller pump on the blood intake limb of a circuit at a speed of 100-120 ml per minute. Perfusion time varied from 60 to 90 minutes for one session. The ChH course consisted of 2 to 4 sessions with 2-3 day intervals between procedures.

Ultraviolet blood irradiation. A modified Knot's method was used (17) . The patient's venous blood was pumped at a speed of 50 ml/ minute through the quartz glass tube that was placed in a roller pump ("Izolda", Russia). In this apparatus, blood underwent ultraviolet irradiation (wave length of 254 nm) followed by transfusion into peripheral vein. The total amount of ultraviolet irradiated blood was 2 ml/kg of body weight. Each patient received from 2 to 4 UBI procedures.

Porcine spleen crossperfusion (PSC) . This technique is performed by the porcine spleen being removed immediately after an animal's slaughter and is then delivered in sterile condition to the operation theatre. This must be done in a period of 30 minutes or less. The spleen is cut in a lamina 2-3 mm thick. The spleen cuts are placed into a filter of 500 cm3 capacity and then flushed with 3 L of normal saline containing 5,000 U of heparin for 20 minutes. PSC is accomplished by the veno-venous method. Blood is pumped with a roller pump at a speed of 40-50 ml/min. Patients underwent two to three PSCs with 3-5 day intervals between procedures.

Hyperbaric oxygenation. The patients received sessions of HBO with a working pressure of 2-3 absolute atmospheres following the schedule: from first to third day - 2 sessions per day ; from fourth to tenth days - 1 session per day with a duration of 40-90 minutes. The HBO course thus comprised 8-10 sessions.

Frequency data were analyzed using Student's t-test.
 
 

Results

Fifty-eight patients who died after sepsis underwent autopsies. Autopsy revealed that the spleen was enlarged several times in size and its weight occasionally reached 900 g (mean weight 305+/-115 g). Microscopically, the splenic sinuses were engorged with blood and contained many polymorphonuclear leukocytes and occasionally bacteria. There was marked fatty and parenchymatous degeneration of heart, liver, and kidney. Myeloid hyperplasia was the most common finding in bone marrow. Lymph nodes were increased in size. Microscopically, the enlarged lymph nodes contained immunoblasts and plasma cells. In most of the DIC syndrome cases, besides signs of numerous petechial hemorrhages and alterations in small veins that varied from endotheliosis to septic trombophlebitis. Variants of septic process development are listed in Table 2.

Table 1. Variants of Sepsis
Variant Number of Patients(%) 
Otogenic 2(2.5)
Odontogenic 3(3.7)
Gynaecological 6(7.4)
Urological 11(13.6)
Following IV cannulation 11(13.6)
Post-surgical sepsis  28(34.5)
Cryptogenic 20(24.7)

As seen in Table 1, amongst the diseases, the leading cause of death was sepsis related to surgery. Septic patients died mainly from overwhelming sepsis, multiple organ failure (63.8%) and encephalopathy(19%). The etiologic agents of sepsis were identified in only 14 of 81 patients as seen in Table 2.

Table 2. Pathogens isolated from the blood of septic patients
Pathogens 

Gram-positive aerobes

 Number of Patients (%)
Staphylococcus aureus 7(8.6)
Streptococcus pyogenes 1(1.2)
Streptococcus viridans 1(1.2)
Gram-negative aerobes
Enterobacter 1(1.2)
Pseudomonas aeruginosa 1(1.2)
Acinetobacter 1(1.2)
Klebsiella 1(1.2)
Citrobacter 1(1.2)

 Demographic analysis did not reveal any statistically significant differences in age, gender, duration of sepsis, prehospitalisation period, frequency of septic shock episodes and occurrence of MOF in both groups. ( Table 3) This suggests that the two groups are comparable. 

Table 3. Demographic characteristics of patients with sepsis.
Group 1 

n=23

 Group 2 

 n=58
M/ F 13/10 22/36
Median age 

 (range)

 35.2 

(16-66)

 50.2 

(17-84)
Sepsis duration before hospitalisation 

(days)

 13.1 

(1-60)

 22.3 

(1-150)

 At the same time there was a significant difference in frequency of application of EDM between survivor and nonsurvivors groups. The analysis revealed that EDM was used significantly more often in patients that survived sepsis (Group 1). Thus in Group 1, ChH was used 3 times more frequently, UBI 8 times more frequently, PSC 10 times more frequently and HBO 4 times more frequently than in patients that died (Group 2)(Figure 1). We hypothesized that combination of EDM and HBO influenced on mortality rate in septic patients. In order to evaluate this hypothesis all 81 patients were reallocated in one of two new groups according to the principle of application of EDM and HBO. Group 3 - 40 patients which have been treated with traditional therapy and group 4 - 41 patients in which traditional therapy was supplemented with EDM and HBO. Demographic characteristics of patients 3 and 4 groups are summarized in the Table 4.

Table 4. Demographic characteristics of patients with sepsis.
Group 3 

n=40

 Group 4 

n=41
M/ F 14/26 23/18
Median age 

 (range)

 51,2 

(21-84)

 41,0 

(16-77)
Sepsis duration prior to hospitalisation 

(days)

 25.6 

(1-80)

 15,6 

(1-150)

 The demographic analysis did not reveal any significant statistical differences in age, gender and duration of the period before hospitalization in both groups. Nevertheless in group 3 mortality rate was 95%, in contrast to a mortality rate of 55% in group 4 (p<0.05 ) ( Figure 1).

After starting the extracorporeal detoxification program, the biochemical variables reflecting MODS (bilirubin, hepatic enzymes, creatinine and MMWC) came close to normal values within 14 days.
 
 

Discussion

The occurrence of liver failure and renal failure in patients with sepsis is thought to be due to entry into the circulation of toxic metabolites (creatinine, urea, neurotoxins, bilirubin, bile acids, middle molecular weight compounds, etc.) that are able, by themselves, to stimulate the syndrome of endogenous intoxication. Aside from this disorders in microcirculation distinctly reduce the rate of elimination of toxic metabolites (18)

Since Yatzidis and colleagues (19) published their individual reports, ChH has become increasingly popular with surgeons and specialists in hemodialysis. During the past two decades the great numbers of reports of the effective usage of ChH, in patients with exogenous and endogenous 'endotoxicoses' have been reported in the CIS (USSR). Mainly they are summarized in several monographs(8-10,20).

Apart from classic hepatic toxins - ammonia, free fatty acids, mercaptan and phenol - carbonaceous sorbents remove other toxic metabolites from the circulation, including creatinine, guanidinoacetic acid, and bilirubin (10,21-24).

Non-coated charcoal sorbents are able to absorb on their surface such substrates of endogenous intoxication as middle molecular weight compounds (MMWC)(25-27). We assert the importance of measuring the concentration of MMWC in serum as a leading sign of endogenous intoxication. The four -fold increase of MMWC in serum is by itself grounds for starting EDM. Normalization of MMWC in serum practically always is associated with the regression of MODS. In the 1980s the generally accepted idea about ChH was that a pure absorption process has occurred. It was demonstrated that autotransfusing blood after its contacting with sorbent was able to alter the sorption activity of the glycocalyx of all circulating erythrocytes. This phenomenon was combined with amelioration of peripheral tissue perfusion (28). The other nonabsorbtion phenomenon of ChH was that it prolonged the remission and enhanced the sensitivity to basic medicines in patients with autoimmune diseases (29-30).

Currently ChH is a  method of treating the toxic syndrome seen in patients with peritonitis, necrotizing pancreatitis, gangrene, and other purulent surgical diseases (10,31,32)

The earliest reports on PSC as a method of immunomodulation in septic patients are from 1985 to 1986 (33-35). It is presumed that the grounds for applying PSC in animal models and clinical trials were the observations that asplenic patients or those who underwent splenectomy were prone to overwhelming infection or fatal sepsis which was sometimes associated with DIC (36-39). Septic complications in asplenic patients were explained by the decrease in antibody production(40) and disorders in tuftsin synthesis (41), but still remain poorly delineated. In 1885 Shumakov et al., for the first time demonstrated that the donor's (pig) spleen allo- and xenograft when connected extracorporeally makes the leukocyte phagocytes active in septic animals and patients (PSC has been used in 20 patients with sepsis (34)). Grinev et al, in 1986 applied PSC in 14 patients with mechanical trauma and subsequent septic complications. The authors observed twice as many blood leukocytes   in the 24 hours immediately following the procedures (37). It was demonstrated that PSC normalized the activity of natural killer cells that had been depressed considerably before xenoperfusion (42). Moskalenko et al. report showing positive effects by using PSC in 14 patients with purulent septic diseases (43). Ryzhalo et al. applied PSC in the combined treatment of surgical burn sepsis in 5 patients(44). Sitnikov et al. simplified the PSC method. In 1992 they reported the results of using hemoperfusion through the porcine spleen followed by the infusion of xenosplenic perfusate in the treatment of purulent peritonitis and various suppurative complications in 109 patients. A positive effects resulted in 20% reduction mortality rate with 1.5-3.5 times shorter period of treatment (45).

UBI proved to be effective in the treatment of purulent diseases of the maxillofacial region (46) and severe sepsis when combined with ChH (47). Many studies done on the effects of UBI concerning immune and nonspecific responses have shown them stimulated after a few UBI procedures. It has been demonstrated that UBI increased the number of monocytes and lysozyme concentration in blood, raised the index of T-lymphocytes blast transformation (48) and improved some rheological characteristics of blood. This allowed it to be recommended as a supplemental method in patients with ischemic heart disease (49).

The use of HBO in intensive care is a well-established procedure used for many years. The reported advantages of HBO in critically ill patients include reductions in mortality of 95% in patients with acute myocardial infarction (50), the normalizing of PaO2, and a decrease in serum creatinine, billirubin and ammonia level in patients with acute renal failure (51). It has been reported that HBO is conducive to the repair of reversible (glutamine synthesis) and irreversible (urea synthesis) routes of ammonium binding in hepatocytes. These are disordered in chronic hepatitis (52). HBO when combined with ChH improved the functional capacity of cardiac muscle, facilitated reversal of anaerobic metabolism and normalized oxygen consumption (53).

Thus the extensive literature on EDM provides evidence that EDM decreases the level of toxic metabolites in blood and is able to temporarily support body detoxification systems. The present study demonstrates that EDM was used significantly more often in survivors than in the patients who died after sepsis. In patients treated with the combination of traditional methods plus EDM, the mortality rate was half that of patients treated with traditional methods.

The beneficial effects of applying EDM in septic patients may be related to two interacting mechanisms. First, there is the effect of detoxification due to the removal of toxic metabolites from circulation. Second, there is a systemic effect linked with the augmentation of the host defense system that is compromised in sepsis, as our previous studies and other author's studies have shown (34,35,42). The combined use of EDM in this study to a certain extent reflects the evolution of our understanding of sepsis. Sepsis is not only a state in which the defences of the host are compromised but when combined with MOF, it is also a consequence of accumulation of endogenous toxins.
 
 

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