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Journal of Critical Care 29 (2014) 728–732

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Journal of Critical Care


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Polymyxin B-immobilized fiber column hemoperfusion removes


endotoxin throughout a 24-hour treatment period☆
Chieko Mitaka, MD, PhD a, b,⁎, Naoto Fujiwara, MD b, Mamoru Yamamoto, MD b,
Takahiro Toyofuku, MD, PhD a, Go Haraguchi, MD, PhD b, Makoto Tomita, PhD c
a
Department of Critical Care Medicine, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
b
Intensive Care Unit, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
c
Clinical Research Center, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Keywords: Purpose: The purpose of this study was to evaluate the extent of endotoxin adsorption by polymyxin
Endotoxin B-immobilized fiber column hemoperfusion (PMX) performed for a 24-hour treatment period in
Septic shock patients with septic shock.
Polymyxin B-immobilized fiber Materials and methods: Nineteen patients with septic shock were retrospectively studied. The plasma
column hemoperfusion
endotoxin concentrations of blood drawn from the radial artery and from the outlet circuit of the PMX
column were measured by kinetic turbidimetric limulus assay using an MT-358 Toxinometer
(Wako Pure Chemical Industries, Ltd, Osaka, Japan) after 24 hours of PMX treatment. The endotoxin
removal rate was defined by the following equation: ([radial artery endotoxin concentration − outlet
circuit of PMX column endotoxin concentration]/radial artery endotoxin concentration) × 100%.
Results: The patients had a median Acute Physiology and Chronic Health Evaluation II score of 29 at
intensive care unit admission and a 28-day mortality of 47%. Before the start of the PMX treatment, the
median radial arterial plasma endotoxin concentration was 16.48 pg/mL. After 24 hours of PMX
treatment, the median radial plasma endotoxin concentration had decreased to 1.857 pg/mL, and the
concentration at the outlet circuit of the PMX column was further decreased to 0.779 pg/mL. The median
endotoxin removal rate was 74.4%.
Conclusion: These findings suggest that 24-hour PMX treatment was effective in removing endotoxin
continuously throughout the entire treatment period.
© 2014 Elsevier Inc. All rights reserved.

1. Introduction lipid A of endotoxin. The covalent binding of polymyxin B onto the


surface of polystyrene-based carrier fiber in the PMX column
Endotoxin or lipopolysaccharide is an outer membrane component of inactivates the endotoxin in the blood without exerting toxicity [2,3].
Gram-negative bacteria that plays an important role in the pathogenesis Polymyxin B-immobilized fiber column treatment has been demon-
of septic shock. Endotoxin is opsonized by lipopolysaccharide-binding strated to confer beneficial effects on hemodynamics, on oxygenation,
protein, and the complex is recognized by the opsonic receptor CD14 on and on mortality in a systematic review and the early use of polymyxin B
the macrophage surface. The endotoxin–lipopolysaccharide-binding hemoperfusion in abdominal septic shock randomized controlled trial
protein–CD14 ternary complex activates Toll-like receptor 4/myeloid [4,5]. The manufacturer of the PMX column recommends 2 hours as the
differentiation 2 receptor complex, whereupon this pathway activates standard duration of PMX treatment for patients with septic shock.
nuclear factor-κB, inducing the production of proinflammatory Our group, however, has shown that a PMX treatment duration of
cytokines [1]. greater than 2 hours significantly improves hemodynamics and
Endotoxin adsorption therapy by polymyxin B-immobilized fiber significantly decreases the administration of norepinephrine, compared
column (PMX) hemoperfusion has been used as a standard treatment with the 2-hour duration [6]. In 2009, we observed that PMX treatment
for septic shock patients in Japan. Polymyxin B-immobilized fiber apparently retained its ability to remove endotoxin continuously over a
column treatment is based on the binding property of polymyxin B to 24-hour treatment period. Since then, we have routinely performed
PMX treatment for durations more than 24 hours at our institution. We
also measure endotoxin concentrations in blood drawn from the radial
☆ Conflicts of interest: The authors have no conflicts of interest to declare.
artery and from the outlet circuit of the PMX column after 24 hours as a
⁎ Corresponding author. Department of Critical Care Medicine, Tokyo Medical and
Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519,
routine procedure to quantify the endotoxin adsorption by PMX. Yet, as
Japan. Tel.: + 81 3 5803 5959; fax: + 81 3 5803 0168. of this writing, there have been no earlier reports on the optimal
E-mail address: c.mitaka.icu@tmd.ac.jp (C. Mitaka). duration of PMX treatment for endotoxin removal. We decided to

http://dx.doi.org/10.1016/j.jcrc.2014.03.031
0883-9441/© 2014 Elsevier Inc. All rights reserved.
C. Mitaka et al. / Journal of Critical Care 29 (2014) 728–732 729

retrospectively evaluate the extent to which the PMX column adsorbs 2.4. The endotoxin removal rate
endotoxin in septic shock patients more than 24 hours of treatment.
At 24 hours of PMX treatment for septic shock, the plasma
2. Materials and methods endotoxin concentrations were measured in blood drawn from the
radial artery and from the outlet circuit of the PMX column. The
2.1. Study design endotoxin removal rate was defined by the following equation:
([radial artery endotoxin concentration − outlet circuit of PMX
Nineteen patients with septic shock, as defined by the Consensus column endotoxin concentration]/radial artery endotoxin concentra-
Conference of the American College Physicians/Society of Critical Care tion] × 100%. This rate represents the ability of the PMX column to
Medicine criteria [7], were studied. This study was approved by the adsorb endotoxin and is routinely assessed to decide whether to use
Ethical Review Board of the Tokyo Medical and Dental University the second PMX column. In the present study, we concluded that a
Faculty of Medicine. Informed consent was obtained from the families second column was unnecessary when the plasma endotoxin
of the patients before the PMX treatment. Demographic data, routine concentration was less than 1.1 pg/mL after 24 hours of PMX.
biochemistry, microbiological data, the infection focus, the Acute
Physiology and Chronic Health Evaluation (APACHE) II score [8], and 2.5. Statistical analysis
28-day mortality were collected retrospectively from medical record.
Data were expressed as medians and range. Values were analyzed
by the Wilcoxon signed rank test. A P b .05 was considered
2.2. Measurement of plasma endotoxin concentration statistically significant.

Plasma endotoxin concentrations of blood drawn from the radial 3. Results


artery were measured. The endotoxin was assayed with separated
plasma from heparinized whole blood samples centrifuged at The clinical characteristics of our 19 patients with septic shock are
3000 rpm for 40 seconds. The 40-second duration for blood shown in Table 1. The APACHE II score at intensive care unit admission
centrifugation was adopted for 2 reasons. First, plasma endotoxin was greater than or equal to 24 in 15 of 19 patients. The 28-day
concentrations are significantly higher in platelet-rich plasma than mortality was 47%. The plasma endotoxin concentration of radial
those in platelet-poor plasma, as endotoxin is bound to platelets [9]. arterial blood was very high before the PMX treatment. After 24 hours
Second, the centrifugation of blood for more than 40 seconds of PMX treatment, the plasma endotoxin concentration from the
precipitates bacteria [10]. Hence, blood centrifugation for 40 seconds radial artery had decreased in 13 patients (2, 3, 5, 6, 7, 8, 9, 10, 12, 13,
yields platelet-rich plasma without bacteria precipitate. 14, 16, and 18). After 24 hours of PMX treatment, the plasma
The high-sensitivity assay was performed with a kinetic turbidi- endotoxin concentration at the outlet circuit was lower than the
metric limulus assay using the MT-358 Toxinometer (Wako Pure concentration in the radial artery in 11 patients (1, 2, 3, 4, 5, 6, 11, 13,
Chemical Industries, Ltd, Osaka, Japan). The heparinized plasma 15, 17, and 19), and the median endotoxin removal rate in those
samples were diluted (1/10), heated at 70°C for 10 minutes to patients was 74.4% (range, 29.0%-98.8%; interquartile range [IQR],
eliminate endotoxin inhibitors, and immediately placed in an ice bath 38.3%). The plasma endotoxin concentrations from the radial artery
until the assay. A toxinometer measures turbidity change at a 660 nm and the outlet circuit at 24 hours in the other 8 patients (7, 8, 9, 10, 12,
wavelength during the gelation of a “limulus amebocyte lysate”/ 14, 16, and 18) were within normal limits (less than 1.1 pg/mL).
endotoxin solution and automatically scores the gelation time of the The percentage of appropriate empirical antibiotic was 78.9%.
sample. The gelation time T(G), that is, the reaction time required to The techniques used and the time-to-source control for each
obtain a 5% decrease of R(t), is displayed on a display device and technique were laparotomy (3, 3 hours; 6, 6 hours), ureteral stent
printed out [11]. The detection limit for the turbidimetric assay is insertion (5, 4 hours), abdominal percutaneous drainage (11, 6 hours),
0.7 to 0.8 pg/mL, which corresponds to 0.007 to 0.008 endotoxin unit and debridement (13, 3 hours). All of the patients received early goal-
(EU)/mL, and it is dependent on manufacturing lot number of the directed therapy, including fluid resuscitation and vasopressors recom-
“limulus amebocyte lysate” reagent. This limulus assay test is specific mended by the surviving sepsis guidelines [14]. The mean concentration
to endotoxin and has no cross-reaction to β-glucan [12]. The cutoff of procalcitonin (n = 9) was decreased from 35.42 ng/mL (IQR, 47.86
plasma endotoxin concentration for the diagnosis of endotoxemia is ng/mL) to 4.265 ng/mL (IQR, 17.01 ng/mL) after 24 hours of PMX
1.1 pg/mL [13]. When the plasma endotoxin concentration exceeded treatment. The Supplemental Table 1 shows the changes in the other
1.1 pg/mL in our patients, the PMX treatment was commenced. clinical parameters at 24 hours, compared with the pretreatment values.

2.3. The PMX treatment 4. Discussion

The inclusion criterion for PMX treatment was severe sepsis or The arterial pressure was increased at 24 hours of PMX treatment,
septic shock with an increased plasma endotoxin concentration. whereas the heart rate, respiratory rate, body temperature, and white
Severe sepsis or septic shock was defined according to the consensus blood cell count were all decreased (see the Supplemental Table 1).
definition of the American College of Chest Physicians/Society of We had 3 reasons for adopting the 24-hour period. First, review of
Critical Care Medicine Consensus Conference Committee [7]. The anticoagulation strategies in continuous renal replacement therapy
exclusion criterion for PMX treatment was uncontrolled hemorrhage. has shown that, for circuit survival, a target between 24 and 72 hours
The PMX treatment was administered by the following method. A was recommended, and actual mean circuit survival time was
Toraymyxin 20-R PMX column (Toray Industries, Tokyo, Japan) was 26 hours [15]. Second, our experience has shown that a blood
washed by perfusion with 4 L of physiologic saline. After inserting a purification circuit can be safely perfused for 24 hours without
double-lumen catheter into a central vein, blood was drawn from the bleeding or clotting. Third, we usually started PMX treatment in the
proximal port, perfused through the Toraymyxin 20-R daytime, so a 24-hour circuit eliminated the need for endotoxin
column, and returned to the vein through the distal port of the measurements in the middle of the night. When a PMX column fills
catheter (V-V method). The blood was perfused at a rate of 80 to with endotoxin to maximum capacity, the plasma endotoxin
100 mL per minute using the protease inhibitor nafamostat mesilate concentration of the radial artery and outlet circuit become the
(Torii Pharmaceuticals, Co, Ltd, Tokyo, Japan) as an anticoagulant. same. The plasma endotoxin concentration of the radial artery
730 C. Mitaka et al. / Journal of Critical Care 29 (2014) 728–732

Table 1
Clinical characteristics of 19 patients with septic shock

No. Age Sex Diagnosis Microbes isolated APACHE Endotoxin (pg/mL) Endotoxin 28-Day
(y) in blood culture II score removal mortality
0-h 24-h
rate
PMX PMX

RA RA Outlet (%)

1 71 M Postesophagectomy, ARDS Klebsiella pneumoniae 29 126.700 132.000 14.550 88.9 Died


2 76 F Post-AVR, MVP, TAP, maze operation, Achromobacter xylosoxidans 34 4.300 1.857 0.740 60.2 Died
Catheter-related blood stream infection
3 78 M Perforation of intestine, panperitonitis Escherichia coli 25 189.700 39.000 10.000 74.4 Survived
4 36 F Chronic inflammatory demyelinating, Pseudomonas aeruginosa 25 32.540 100.200 71.170 29.0 Survived
polyneuropathy, immunodeficient Acinetobacter baumannii
5 67 F Pyelonephritis Escherichia coli 18 104.000 1.929 0.779 61.6 Survived
6 68 M Abdominal abscess, panperitonitis Enterobacter cloacae 40 17.800 4.638 0.779 83.2 Died
7 74 M Postesophagectomy Bacteroides fragilis 31 2.196 0.779 0.779 NA Died
Aspiration pneumonia, ARDS
8 75 F Postesophagectomy, catheter-related Serratia marcescens 24 16.480 0.779 0.779 NA Survived
blood stream infection
9 77 F Postgraft replacement for aortic Enterobactor cloacae 25 6.670 0.779 0.779 NA Survived
arch aneurysm
10 55 M Postresection of brain tumor Pseudomonas aeruginosa 13 20.530 0.779 0.779 NA Survived
Sinusitis sphenoidalis
11 72 M Abdominal abscess Acinetobacter baumannii 22 15.090 31.910 0.779 97.6 Survived
12 77 M Abdominal abscess Pseudomonas aeruginosa 25 23.410 0.779 0.779 NA Survived
13 81 M CREST syndrome, skin abscess Stenotrophomonas maltophilia 30 13.580 1.260 0.779 38.2 Died
MRSA
14 68 M Liver abscess, suppurative cholangitis Escherichia coli 29 7.582 0.779 0.779 NA Survived
Enterococcus faecalis
15 33 F Epstein syndrome, peritonitis – 14 3.115 3.463 2.186 36.8 Survived
16 75 F Postgraft replacement for ascending Enterococcus faecium 34 18.430 0.779 0.779 NA Died
aorta, AVR
17 30 M Leukemia Enterobacter cloacae 33 5.295 5.641 0.779 86.1 Died
Postbone marrow transplantation
18 83 F Necrosis of intestine, peritonitis Escherichia coli 29 9.352 0.779 0.779 NA Died
Enterococcus faecium
19 62 F Breast cancer, postmastectomy – 34 69.210 148.400 1.682 98.8 Died
Postchemotherapy
a
All patients 29 16.480 1.857 0.779 74.4

RA indicates radial artery; ARDS, acute respiratory distress syndrome; M, male; F, female; AVR, aortic valve replacement; CREST, calcinosis raynaud phenomenon esophageal
hypomotility sclerodactylia and telangiectasia; MVP, mitral valve plasty; MRSA, methicillin-resistant Staphylococcus aureus; TAP, tricuspid annuloplasty; NA, not applicable.
a
The expressed values are median.

exceeded that, at the PMX outlet circuit in 11 of our patients after to 2 L of bovine blood, the endotoxin concentration decreased from
24 hours of PMX treatment, and the median endotoxin removal rate at 40 000 pg/mL at baseline to 7500 pg/mL after 120 minutes of PMX
24 hours in those patients was 74.4%. The plasma endotoxin perfusion and remained unchanged up to 180 minutes. Under the
concentration reached the normal range in the other 8 patients after conditions mentioned, the PMX procedure removed 65 000 000 pg of
24 hours of PMX treatment, indicating the removal of endotoxin by endotoxin ([40 000 pg/mL − 7500 pg/mL] × 2000 mL [total bovine
that time point. blood volume, 2 L] = 65 000 000 pg). We take this as an indication that
Hence, the PMX seemed to retain its ability to adsorb significant a single PMX column is capable of removing the same amount,
amounts of endotoxin after 24 hours of PMX treatment. The findings 65 000 000 pg, by adsorption. Given that the very high endotoxin
also suggest that the endotoxin adsorption capability of a single PMX concentrations from the in vitro study of Sakai et al [18], concentra-
column may be greater than what was previously expected. The large tions far higher than those normally encountered with septic shock,
surface area of the fibrous material composing the PMX column might we speculate that abundant endotoxin adsorbed into a PMX column in
increase the adsorption capability. A computational multiscale the first 120 minutes may drastically reduce the endotoxin adsorption
analysis has demonstrated that fiber-grafted polymyxin B captures capability of the PMX column after 120 minutes. If this is the case, the
endotoxin molecules from distances far beyond the short-range extent of adsorption by 24-hour PMX treatment is presumably
interval [16]. This means that the hydrodynamics may affect the dependent on the plasma concentration before the PMX treatment.
adsorption potential. Six of the patients died in spite of the decreased radial plasma
Polymyxin B has both antibacterial and antiendotoxin actions. It endotoxin concentrations attained (2, 6, 7, 13, 16, and 18). The
destroys the bacterial outer membrane and selectively binds the lipid APACHE II scores (34, 40, 31, 30, 34, and 29, respectively) were high
A portion of endotoxin, thus neutralizing the adverse effects of for all 6. The PMX therapy might have been started too late to rescue
endotoxin on cells. There is still uncertainty, however, as to the these patients from multiple organ failure. We note, however, that 1
amount of endotoxin a single PMX column can remove from the of 3 patients with an APACHE II score of 29 survived. The cause of
blood. In an assessment of the amount of endotoxin removed from a death due to sepsis in the later phase has been shown to be related to
hemoglobin solution perfused through a column containing 2 g of immunosuppression rather than cytokine-induced inflammation [19].
PMX, the endotoxin concentration decreased from 686 EU/mL A study by Boomer et al [19] implicated immunosuppression as a
(68 600 pg/mL) to 12.1 EU/mL (1210 pg/mL) at 5-minute PMX main cause of death in sepsis patients by demonstrating decreased
perfusion [17]. The authors of that study, however, reported no details cytokine secretion and depleted CD4, CD8, and HLA-DR cells in the
on the duration of the PMX perfusion. When Sakai et al [18] evaluated postmortem spleen and lung tissues. Hence, immunosuppression may
endotoxin removal by PMX in a perfusion test with endotoxin added have been the main cause of death in the nonsurvivors from the
C. Mitaka et al. / Journal of Critical Care 29 (2014) 728–732 731

present study in spite of the endotoxin removal. We evaluated ments for measuring endotoxin, we believe that the endotoxin
immunosuppression in only some of the patients in our study, but we concentrations should be quantified before, during, and after the
determined that 3 of the nonsurvivors (7, 17, and 19) were leukopenic PMX treatment in normal clinical practice. If the plasma endotoxin
(1300/μL, 100/μL, and 600/μL, respectively) and immunosuppressed concentration increases in hemodynamically unstable patients, we
by either chemoradiotherapy, chemotherapy, or immunosuppressant recommend that PMX treatment be commenced at once. Conversely,
such as cyclosporine and cyclophosphamide. Host defense and we recommend a cessation of treatment if the plasma endotoxin
immunity may be related to mortality. concentration decreases to within normal limits. If the plasma
The plasma endotoxin concentrations of the radial artery de- endotoxin concentration is still high after 24 hours, we recommend
creased to within normal limits at 24 hours of PMX treatment, and the a switch to a second PMX column and continuation for a 24-hour
plasma endotoxin concentration of the PMX outlet circuit was also period. A third PMX column would pose a considerable expense, as
within normal limits in 8 of the patients in our study (7-10, 12, 14, 16, the national health insurance system in Japan covers up to 2 columns.
and 18). These findings prove that the PMX treatment removed the This study has several limitations. First, we performed no analysis
endotoxin. In the measurements before the PMX treatment, the to determine endotoxin serially. Without serial measurements, we
plasma endotoxin concentrations of these 8 patients ranged from were unable to determine if and when the endotoxin levels fell below
2.196 pg/mL to 23.41 pg/mL. Upon confirming that the concentration the threshold in 8 of the patients (7-10, 12, 14, 16, and 18) during
had decreased to normal at 24 hours, we discontinued the PMX treatment. Although these 8 patients might have faced a risk of
treatment in all 8 of them. If the plasma endotoxin concentration adverse effects associated with extracorporeal therapy with antico-
decreases to within normal limits through treatment with one PMX agulant for several hours of the PMX treatment, we were able to
column, a second PMX column may be unnecessary. Given the high continue the therapy safely without excessive bleeding. This may
price of the PMX column in Japan (¥347 000), the cost of septic shock have been a result of the nafamostat mesilate medication. Nafamostat
treatment can be significantly reduced by limiting PMX treatment to mesilate, a synthetic serine protease inhibitor, is commonly used in
just one column. Japan as an anticoagulant during PMX treatment and continuous renal
In another 6 patients (1, 4, 11, 15, 17, and 19), the plasma replacement therapy. The drug has been shown to provide sufficient
endotoxin concentrations increased at 24 hours of PMX treatment in filter survival without causing major bleeding during continuous renal
spite of moderate-to-high rates of endotoxin removal (29.0%-98.8%). replacement therapy [29]. Even when administering this medication,
These increases in plasma endotoxin concentrations may have been we should always strive for a favorable balance between the benefits
attributable to a steady release of endotoxin by systemically spreading and risks of PMX treatment and watch closely for adverse events
infection. Endotoxin removal from the blood by PMX treatment may related to extracorporeal therapy to prevent them.
enable a continuous withdrawal of endotoxin from the tissues during The present study would have gained much from an experimental
extracorporeal therapies by promoting a dynamic equilibrium control sample without PMX treatment. Polymyxin B-immobilized
between the tissue and blood compartments [20]. We know, however, fiber column hemoperfusion therapy is recognized as a standard
that antimicrobial agents induce bacteria cells to lyse and release treatment for septic shock in Japan and has been administered for
endotoxin [21]. As such, endotoxin may be continuously derived from condition clinically under the national health insurance system since
the lysis of bacteria present at the infection site. As a counteracting 1994. Ethical consideration thus prevented us from allocating patients
force, endotoxin is bound to circulating monocytes [22], erythrocytes to a control group without PMX therapy. As an alternative, we
[23], and platelets [9] during sepsis. Polymyxin B-immobilized compared clinical parameters before and after PMX treatment and
fiber column hemoperfusion therapy has been shown to remove quantified the hemodynamic improvement.
endotoxin-monocyte complex [24]. The lipid A portion of endotoxin In conclusion, 24-hour PMX treatment removed endotoxin at a
binds to the membrane of platelets [25] and erythrocytes [23], hence rate of 74.4% in patients with septic shock. These findings suggest that
theory would hold that the endotoxin bound to the platelets and 24-hour PMX treatment is effective in removing endotoxin. Further
erythrocytes is unremovable by PMX. In fact, plasma endotoxin studies to confirm this will be required.
concentrations are significantly higher in platelet-rich plasma than in Supplementary data to this article can be found online at http://dx.
platelet-poor plasma [9]. Accordingly, endotoxin bound to platelet doi.org/10.1016/j.jcrc.2014.03.031.
remains in blood after PMX therapy. Taken these findings together, we
can safely conclude that PMX therapy is incapable of removing
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