Initial central venous pressure could be a prognostic marker for hemodynamic improvement of polymyxin B direct hemoperfusion: a retrospective cohort study
© The Author(s). 2016
Received: 12 April 2016
Accepted: 15 September 2016
Published: 10 October 2016
Direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP) could improve the hemodynamic status of septic shock patients. As PMX-DHP is an invasive and costly procedure, it is desirable to estimate the therapeutic effect before performing the therapy. However, it is still unclear when this therapy should be started and what type of sepsis it should be employed for. In this study, we retrospectively examined the clinical effect of patients treated with PMX-DHP by using central venous pressure (CVP).
Seventy patients who received PMX-DHP for septic shock during the study period were recruited and divided into a low CVP group (n = 33, CVP < 12 mmHg) and a high CVP group (n = 37, CVP≧12 mmHg). The primary endpoint was vasopressor dependency index at 24 hours after starting PMX-DHP, and the secondary endpoint was the 28-day survival rate. Additionally, we performed a multivariate linear regression analysis on the difference in the vasopressor dependency index.
The vasopressor dependency index significantly improved at 24 h in the low CVP group (0.33 to 0.16 mmHg−1; p < 0.01) but not in the high CVP group (0.43 to 0.34 mmHg−1; p = 0.41), and there was a significant difference between the two groups in the index at 24 h (p = 0.02). The 28-day survival rate was higher in the low CVP group (79 vs. 43 %; p < 0.01). Multivariate linear regression analysis showed that CVP (p = 0.04) was independently associated with the difference in the vasopressor dependency index.
Our study indicates that the clinical effect of PMX-DHP for septic shock patients with higher CVP (≧12 mmHg) might be limited and that the initial CVP when performing PMX-DHP could function as an independent prognostic marker for the hemodynamic improvement.
KeywordsPolymyxin B Hemoperfusion Septic shock Central venous pressure PMX-DHP
Both the 2008 and 2012 Surviving Sepsis Campaign Guidelines (SSCG) recommend the rapid infusion of intravenous fluids until a central venous pressure (CVP) of 8–12 mmHg is achieved during initial resuscitation [1, 2]. However, many studies show that excess fluid accumulation is associated with adverse outcomes in critically ill patients [3–5]. In particular, positive fluid balance seems to be harmful for patients whose comorbid burden includes chronic heart failure and/or chronic kidney disease [6, 7]. In order to avoid excess volume expansion in those patients, it is important to carefully monitor intravascular volume by the following parameters: CVP, stroke volume variance, or extravascular lung water.
Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP), which can effectively adsorb bacterial endotoxin and lead to an earlier recovery from shock state, was first reported in 1994, and it has been used for the treatment of septic shock in many countries [8–11]. Although many clinical reports, including two randomized control trials, have shown the clinical effect of adapting PMX-DHP for septic shock patients, there is no clear consensus about the effect of the hemoperfusion [9–12]. As PMX-DHP is an invasive and costly procedure, it is desirable to accurately estimate the therapeutic effect before performing the therapy . However, it is still unclear when this therapy should be started and what type of sepsis it should be employed for.
The utility of CVP as a marker of intravascular volume has been questioned for many years [13, 14]. However, we consider that CVP is one of the most widely used hemodynamic parameters because of the promptness of the measurement and the ability to perform it in any hospital facility. Actually, many clinical studies also demonstrated that high CVP was associated with positive fluid balance [1, 5, 15].
In this study, in order to clarify the application of PMX-DHP for septic shock patients, we retrospectively examined the hemodynamic improvement and the mortality of patients treated with PMX-DHP by using CVP values. Moreover, we investigated whether the CVP values at the start of PMX-DHP could function as an independent prognostic factor for the hemodynamic improvement of the hemoperfusion.
We conducted a retrospective cohort study among all consecutive patients who received PMX-DHP for septic shock between May 2008 and April 2013 in the intensive care unit (ICU), high care unit (HCU), and cardiovascular care unit (CCU) at the Japanese Red Cross Kyoto Daini Hospital and the Kyoto University Hospital in Japan. After initial resuscitation to achieve the early goal directed therapy (EGDT), PMX-DHP was applied along the Japanese health insurance system, as follows : septic shock patients who require vasopressor support because of endotoxin or gram-negative bacteria. The following patients were excluded: (1) those who were under 18 years old, (2) those who were admitted to the ICU, HCU, or CCU for reasons other than sepsis, (3) those who were not given vasopressors when starting PMX-DHP, and (4) those in whose medical records CVP was not sufficiently recorded.
Vascular access was placed at the femoral or the internal jugular vein. PMX-DHP with PMX-20R (Toray Industries, Tokyo, Japan) was performed for at least 120 min per session once or twice per patient per day for 2 days. The blood flow volume was 80–120 mL/min. The duration of hemoperfusion was decided by the attending physician. The therapy was terminated when the attending physician deemed it appropriate to conclude PMX-DHP for any reason. The anticoagulant used in PMX-DHP was nafamostat mesilate, low molecular weight heparin, or unfractionated heparin. All other cardiovascular management, including cardiac output management, setting of blood pressure goals, and fluid and inotropic therapy, were performed on the basis of SSCG recommendations by the attending physician.
Definitions and classification
In this study, we classified the patients into two groups: patients with CVP values greater than or equal to (≧) 12 mmHg when starting PMX-DHP were placed in the high CVP group, while the remaining patients whose CVP values were less than (<) 12 mmHg were placed in the low CVP group. CVP was measured using the standard method when starting PMX-DHP and expressed as mmHg, as described previously [16, 17]. This classification is also based on the SSCG recommendations, which suggest that in mechanical ventilation patients, a higher target CVP of 12 mmHg should be achieved .
And, vasopressor dependency index was calculated as the inotropic score/MAP. The parameters were calculated before the first PMX-DHP, immediately thereafter and 24 h after the first PMX-DHP.
Relevant clinical background, medical history, and clinical data of all patients were collected at appropriate times during the treatment for sepsis. Basic cardiopulmonary data and laboratory data obtained at the time of starting PMX-DHP were considered baseline values. These included age, sex, body mass index, systolic blood pressure, diastolic blood pressure, dopamine infusion rate, noradrenaline infusion rate, inotropic score, vasopressor dependency index, heart rate, central venous pressure, cardiac output, cardiac index, body temperature, arterial pH, lactate, arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) ratio (P/F ratio), positive end-expiratory pressure (PEEP), renal replacement therapy, surgery, hemoglobin, platelet count, C-reactive protein (CRP), total bilirubin, total protein, Acute Physiologic and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, time from admission to care units until starting PMX-DHP, duration of PMX-DHP, total fluid dosage from ICU admission until starting PMX-DHP, site of infection, and microorganism types. Cardiac output and cardiac index were measured by an arterial catheter attached to the FlotracTM pulse counter device (VigileoTM, Edwards Lifesciences, Irvine, CA, USA) or a pulmonary artery catheter attached to VigilanceTM monitor (VigileoTM, Edwards Lifesciences, Irvine, CA, USA).
The primary outcome was vasopressor dependency index at 24 h after starting PMX-DHP. The secondary outcome was the 28-day survival rate.
Statistical analysis was performed using JMP for Macintosh version 10.0.2 software (SAS Institute, Tokyo, Japan). Categorical variables are expressed as the number of patients (%) and were analyzed by using the χ 2 test or Fisher’s exact test. Continuous variables are expressed as means and 95 % confidence intervals (CIs). Comparison of continuous variables between the two groups was conducted with the t test or the Mann-Whitney U test, according to the distribution of the variables. Evaluation of significance between groups over time points was done by repeated measure ANOVA. As post hoc analysis, the three pair-wise comparisons of the hemodynamic status within a single group among different time points were made using Bonferroni adjustment. Therefore, p values less than 0.016 were considered significant only in this comparison. In the other comparisons, statistical significance was defined as p values <0.05. Kaplan-Meier curves were constructed for the comparison of the survival rate in the two groups and were tested for difference using the log-rank test.
To ensure the assumption that the CVP at the beginning of PMX-DHP could be an independently prognostic factor for the hemodynamic improvement of the hemoperfusion, we performed a multivariate linear regression analysis that focused on the difference in the vasopressor dependency index before PMX-DHP and 24 h after hemoperfusion. The relationships between the parameter and continuous variables were examined using Pearson’s correlation coefficient, and categorical variables were examined using Spearman’s R test. All variables with p values <0.20 in the univariate analysis were included in the multivariate analysis. To ensure that the assumptions for regression analysis were not violated, an analysis of residuals was carried out. Moreover, we performed multivariate Cox regression analysis to assess the covariates that were associated with time to mortality.
Baseline characteristics of the patients
Low CVP group n = 33
High CVP group n = 37
Median (95 % CI)
Median (95 % CI)
Body mass index, kg/m2
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Mean blood pressure, mmHg
Dopamine infusion rate, μg/kg/min
Noradrenaline infusion rate, μg/kg/min
Vasopressor dependency index, mmHg−1
Heart rate, bpm
Cardiac output, L/min
Cardiac index, L/min/m2
Body temperture, °C
Renal replacement therapy, n(%)
Platelet count, ×109/L
Total Bilirubin, mg/dL
Total Protein, mg/dL
APACHE II score
SOFA central nerve system
Time from ICU admission until starting PMX-DHP, min
PMX-DHP duration, min
Total fluid dosage from ICU admission until starting PMX-DHP, ml
Isolated microorganisms by treatment group
Low CVP group n = 33
High CVP group n = 37
Site of infection
The survival rates of both groups after 28 days were analyzed by the Kaplan-Meier method (Fig. 3). The survival rate was significantly higher in the low CVP group than in the high CVP group (p < 0.01), as determined by log-rank test.
Results of multivariate regression analysis for the difference in the vasopressor dependency index between before and 24 h after PMX-DHP
Regression coefficient (β)
95 % CI
−0.0168 − −0.0009
−0.0348 − −0.0007
−0.0166 − 0.0497
−1.2656 − −0.0171
In this study, we observed the association between CVP and the hemodynamic improvement with PMX-DHP. Our results yielded two interesting findings. First, the hemodynamic status of patients with higher CVP did not improve significantly by PMX-DHP. In other words, our retrospective results did not support the guideline’s recommendations, which suggested that septic shock patients with mechanical ventilation should achieve a higher target of CVP 12 to 15 mmHg2. Second, the initial CVP when performing PMX-DHP could function as an independent prognostic factor for the hemodynamic improvement of the therapy. To the best of our knowledge, this is the first study that investigated this particular association and prognosis.
Actually, in this study, we observed that the patients in the high CVP group suffered from hemodynamic impairment due to high CVP. The proportion of patients who received renal replacement therapy was non-significantly larger in the high CVP group, which suggests that many of the attending physicians might think the intravascular volume in the high CVP group patients is too large. Additionally, the P/F ratio and PEEP were also non-significantly lower in the high CVP group, which indicated that some of the patients had a high intrathoracic pressure. Hence, we consider that high CVP group patients did not have adequate venous return because excess fluid therapy or high intrathoracic pressure reduces the gradient between MCFP and CVP. On the other hand, the significant improvement in the low CVP group could be because they genuinely received the clinical effect of PMX-DHP. Generally, PMX-DHP can reduce plasma cytokine levels by absorbing endotoxin, immune cells, and anandamide [23–25]. These physiological and pathological responses could be equivalent in both groups in our study. However, the harmful effect of high CVP at the start of PMX-DHP differentiated the clinical effect of both groups. In other words, fluid toxicity or increase in intrathoracic pressure might be deleterious beyond the beneficial effect of PMX-DHP in patients with high CVP in our study.
Previous studies have reported that early initiation of PMX-DHP reduced the catecholamine requirement and that early improvement in inotropic score and vasopressor dependency index after PMX-DHP might be a prognostic factor [18, 23, 26]. In our study, the patients in the low CVP group who received PMX-DHP earlier also tended to show a decrease in their vasopressor dependency index. Meanwhile, in terms of the time between ICU admission and starting PMX-DHP, there was neither a statistical difference between the two groups nor a significant association with hemodynamic improvement in our study. However, because the sample size of our study was not large enough to demonstrate the association, our results should be viewed with this limitation in mind. In addition, although we performed PMX-DHP for around 6 h in both groups, a recent study has indicated that a longer duration of PMX-DHP therapy can be expected to improve the hemodynamics and pulmonary oxygenation capacity of patients with severe sepsis/septic shock . Thus, longer operation of PMX-DHP might contribute to improve the outcome of patients with low CVP.
Other limitations of our study need to be acknowledged. First, we could not show the data on intrinsic PEEP, so-called auto-PEEP, which might have a direct influence on the CVP values in the high CVP group. However, we consider that it may not fundamentally change our conclusion. Auto-PEEP-induced hypotension is not a result of hyper-inflammatory response to sepsis, but it is rather a patient-ventilator interaction. Thus, it is obvious that PMX-DHP is less effective for the high CVP patients with auto-PEEP-induced hypotension. Additionally, this clinical study is not for acute exacerbation of chronic obstructive pulmonary disease, bronchial asthma, or acute respiratory distress syndrome, and it only evaluated patients with septic shock. Thus, we consider that there were not a large proportion of the study patients with auto-PEEP in our study. Second, the previous studies reported that high CVP was associated with a poor prognosis [28, 29]. Indeed, high CVP might have a negative influence on the cardiac function during the treatment in patients with high CVP group, although cardiac output and index were not significantly different in both groups at the beginning of the hemoperfusion . Therefore, regardless of the effect of PMX-DHP, there may be a possibility of observing the clinical course of patients with a poor prognosis. Third, this study was not a randomized controlled trial, and we cannot rule out the possibility of selection bias, especially referral bias and Neyman bias. Fourth, perhaps we could not extract the patients whose conditions changed rapidly or whose case was extremely severe because our study patients had enough time to receive the hemoperfusion. Fifth, vasopressors were regulated by local physicians, depending on the patient’s condition. Therefore, the protocol for titrating the vasopressors was different among the attending physicians. Further study is required to clarify these unsolved issues.
Our study indicated that the effect of PMX-DHP for septic shock patients with higher CVP (≧12 mmHg) may be limited and that the initial CVP in performing PMX-DHP could be an independent prognostic marker for hemodynamic improvement. Further study is required to clarify the mechanisms of PMX-DHP that affect sepsis treatment.
Acute Physiologic and Chronic Health Evaluation
Cardiovascular care unit
Central venous pressure
Early goal directed therapy
High care unit
Intensive care unit
Mean arterial pressure
Mean circulatory filling pressure
- P/F ratio:
Arterial oxygen tension/fractional inspired oxygen ratio
Positive end-expiratory pressure
Direct hemoperfusion with polymyxin B-immobilized fiber column
Sequential Organ Failure Assessment
Surviving Sepsis Campaign Guidelines
We thank Juan Alejandro Oliva Trejo (Medical Innovation Center, TMK project, Graduate School of Medicine, Kyoto University) for serving as an advisor and the medical staff of the intensive care unit, high care unit, and cardiac care unit of both the Japanese Red Cross Kyoto Daini Hospital and Kyoto University Hospital.
None of the authors received any funding for this study.
Availability of supporting data
The datasets supporting the conclusions of this article are included within the article and in Additional file 1.
HY designed the study protocols, acquired the data, performed the statistical analysis, and completed the manuscript for publication. TT revised the manuscript and approved it for publication. HN and KO helped with the data analysis. SH, RI, MY, and MD supervised the interpretation of the results and writing of the reports. All authors have read and approved the final version of the manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was presented in part at the 10th International Society for Apheresis Congress May 15, 2015, Cancun, Mexico, and at the 26th Annual Meeting of the Japan Society for Blood Purification in Critical Care October 9, 2015, Tokyo, Japan.
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- Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77.PubMedGoogle Scholar
- Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign. Crit Care Med. 2013;41(2):580–637.PubMedGoogle Scholar
- Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564–75.PubMedGoogle Scholar
- Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int. 2009;76(4):422–7.PubMedGoogle Scholar
- Boyd JH, Forbes J, Nakada T-a, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality*. Crit Care Med. 2011;39(2):259–65.PubMedGoogle Scholar
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147–239.PubMedGoogle Scholar
- Tsai YC, Tsai JC, Chen SC, et al. Association of fluid overload with kidney disease progression in advanced CKD: a prospective cohort study. Am J Kidney Dis. 2014;63(1):68–75.PubMedGoogle Scholar
- Shoji H. Extracorporeal endotoxin removal for the treatment of sepsis: endotoxin adsorption cartridge (toraymyxin). Ther Apher Dial. 2003;7(1):108–14.PubMedGoogle Scholar
- Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301(23):2445–52.PubMedGoogle Scholar
- Berto P, Ronco C, Cruz D, Melotti RM, Antonelli M. Cost-effectiveness analysis of polymyxin-B immobilized fiber column and conventional medical therapy in the management of abdominal septic shock in Italy. Blood Purif. 2011;32(4):331–40.PubMedGoogle Scholar
- Cruz DN, Perazella MA, Bellomo R, et al. Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit Care. 2007;11(2):R47.PubMedPubMed CentralGoogle Scholar
- Payen DM, Guilhot J, Launey Y, et al. Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med. 2015;41(6):975–84.PubMedPubMed CentralGoogle Scholar
- Hoffman MJ, Greenfield LJ, Sugerman HJ, Tatum JL. Unsuspected right ventricular dysfunction in shock and sepsis. Ann Surg. 1983;198(3):307–19.PubMedPubMed CentralGoogle Scholar
- Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense*. Crit Care Med. 2013;41(7):1774–81.PubMedGoogle Scholar
- Van Biesen W, Yegenaga I, Vanholder R, et al. Relationship between fluid status and its management on acute renal failure (ARF) in intensive care unit (ICU) patients with sepsis: a prospective analysis. J Nephrol. 2005;18(1):54–60.PubMedGoogle Scholar
- Magder S. Central venous pressure: a useful but not so simple measurement. Crit Care Med. 2006;34(8):2224–7.PubMedGoogle Scholar
- Magder S, Bafaqeeh F. The clinical role of central venous pressure measurements. J Intensive Care Med. 2007;22(1):44–51.PubMedGoogle Scholar
- Kobayashi A, Iwasaki Y, Kimura Y, Kawagoe Y, Ujike Y. Early recovery in hemodynamics after direct hemoperfusion with polymyxin B-immobilized fibers may predict mortality rate in patients with septic shock. J Anesth. 2010;24(5):709–15.PubMedGoogle Scholar
- Gelman S. Venous function and central venous pressure: a physiologic story. Anesthesiology. 2008;108(4):735–48.PubMedGoogle Scholar
- Magder S. Bench-to-bedside review: an approach to hemodynamic monitoring—Guyton at the bedside. Crit Care. 2012;16(5):236.PubMedPubMed CentralGoogle Scholar
- Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014;4:21.PubMedPubMed CentralGoogle Scholar
- Henderson WR, Griesdale DE, Walley KR, Sheel AW. Clinical review: Guyton—the role of mean circulatory filling pressure and right atrial pressure in controlling cardiac output. Crit Care. 2010;14(6):1.Google Scholar
- Ikeda T, Ikeda K, Nagura M, et al. Clinical evaluation of PMX-DHP for hypercytokinemia caused by septic multiple organ failure. Ther Apher Dial. 2004;8(4):293–8.PubMedGoogle Scholar
- Nishibori M, Takahashi HK, Katayama H, et al. Specific removal of monocytes from peripheral blood of septic patients by polymyxin B-immobilized filter column. Acta Med Okayama. 2009;63(1):65–9.PubMedGoogle Scholar
- Kohro S, Imaizumi H, Yamakage M, et al. Anandamide absorption by direct hemoperfusion with polymixin B-immobilized fiber improves the prognosis and organ failure assessment score in patients with sepsis. J Anesth. 2006;20(1):11–6.PubMedGoogle Scholar
- Takeyama N, Noguchi H, Hirakawa A, et al. Time to initiation of treatment with polymyxin B cartridge hemoperfusion in septic shock patients. Blood Purif. 2012;33(4):252–6.PubMedGoogle Scholar
- Yamashita C, Hara Y, Kuriyama N, Nakamura T, Nishida O. Clinical effects of a longer duration of polymyxin B-immobilized fiber column direct hemoperfusion therapy for severe sepsis and septic shock. Ther Apher Dial. 2015;19(4):316–23.PubMedGoogle Scholar
- Wang XT, Yao B, Liu DW, Zhang HM. Central venous pressure dropped early is associated with organ function and prognosis in septic shock patients: a retrospective observational study. Shock. 2015;44(5):426–30.PubMedGoogle Scholar
- Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol. 2009;53(7):582–8.PubMedGoogle Scholar