The effects of direct hemoperfusion using a polymyxin B-immobilized column in a pig model of severe Pseudomonas aeruginosa pneumonia

Li Bassi et al. Ann. Intensive Care (2016) 6:58 DOI 10.1186/s13613-016-0155-3 Open Access RESEARCH The effects of direct hemoperfusion using a polymyxin B‑immobilized column in a pig model of severe Pseudomonas aeruginosa pneumonia Gianluigi Li Bassi1,2,3,4, Joan Daniel Marti1,2,3, Eli Aguilera Xiol1,3, Talitha Comaru1, Francesca De Rosa1,5, Montserrat Rigol1,2,3, Silvia Terraneo1,5, Mariano Rinaudo1, Laia Fernandez1,2,3,4,6, Miguel Ferrer1,2,3,4 and Antoni Torres1,2,3,4* Abstract Background: Hemoperfusion through a column containing polymyxin B-immobilized fiber (PMX-HP) is beneficial in abdominal sepsis. We assessed the effects of PMX-HP in a model of severe Pseudomonas aeruginosa pneumonia. Methods: Eighteen pigs with severe P. aeruginosa pneumonia were mechanically ventilated for 76 h. Pigs were randomized to receive standard treatment with fluids and vasoactive drugs, or standard treatment with two 3-h PMX-HP sessions. Antibiotics against P. aeruginosa were never administered. We assessed endotoxemia through the endotoxin activity assay (EA). We measured the static lung elastance, ratio of arterial partial pressure per inspiratory fraction of oxygen (PaO2/FIO2), mean arterial pressure, cardiac output, systemic vascular resistance and inotropic score. Finally, every 24 h, we assessed complete blood count. Results: In comparison with the control group, PMX-HP decreased percentage of circulating neutrophils from 47.4 ± 13.8 to 40.8 ± 11.5 % (p = 0.009). In a subgroup of animals with the worst hemodynamic impairment, EA in the control and PMX-HP groups was 0.50 ± 0.29 and 0.29 ± 0.14, respectively (p = 0.018). Additionally, in the control and PMX-HP groups, static lung elastance was 26.9 ± 8.7 and 25.3 ± 7.5 cm H2O/L (p = 0.558), PaO2/FIO2 was 347.3 ± 61.9 and 356.4 ± 84.0 mmHg (p = 0.118), mean arterial pressure was 81.2 ± 10.3 and 81.6 ± 13.1 mmHg (p = 0.960), cardiac output was 3.30 ± 1.11 and 3.28 ± 1.19 L/min (p = 0.535), systemic vascular resistance was 1982.6 ± 608.4 and 2011.8 ± 750.0 dyne/s/cm¯5 (p = 0.939), and inotropic score was 0.25 ± 0.10 and 0.26 ± 0.18 (p = 0.864). Conclusions: In mechanically ventilated pigs with severe P. aeruginosa pneumonia, PMX-HP does not have any valuable clinical benefit, and studies are warranted to fully evaluate a potential role of PMX-HP in septic shock associated with severe pulmonary infections. Keywords: Lung—endotoxemia, Intensive care—pulmonary, Complications—septicemia, Infection—bacterial Background Bacterial endotoxin is a crucial component of the outer membrane of Gram-negative bacteria. During the course *Correspondence: 1 Division of Animal Experimentation, Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, Barcelona, Spain Full list of author information is available at the end of the article of an infection, the lipid A component of the molecule is released by bacteria that duplicate or die [1]. This activates a vivid inflammatory response by the host immunitary system and plays a crucial role in the development of sepsis and associated organ failure. Indeed, administration of endotoxin in healthy humans increases circulating cytokines and activates coagulation and complement pathways, mimicking the classical clinical signs of sepsis [2, 3]. © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Li Bassi et al. Ann. Intensive Care (2016) 6:58 In the latest decade, there has been an increasing interest in selective removal of endotoxin from blood to reduce the burden of sepsis [1, 4]. In particular, polymyxin B is an antibiotic with the attractive ability to bind and inactivate endotoxin. Yet, the systemic use of this drug is limited by the associated neurotoxicity and nephrotoxicity. In the 1990s, a novel affinity column, characterized by polymyxin B, covalently immobilized to a polystyrenederived fiber, was developed in Japan [5]. When blood passes through this column, via an extracorporeal circuit, endotoxin is efficiently cleared, with no detectable polymyxin B in the elute [6]. In a pilot trial [7] in septic patients, hemoperfusion through the column containing polymyxin B-immobilized fiber (PMX-HP) produced a significant improvement in hemodynamic parameters. In the EUPHAS trial [8], 64 patients were treated, following abdominal surgery, with two 2-h sessions of PMX-HP. The 28-day absolute risk of death improved from 53 to 32 % (p = 0.03). Conversely, in a recently completed trial [9], patients who underwent surgical procedures for abdominal infections were randomized to standard or PMX-HP treatment. PMX-HP was not associated with any survival benefit, and it did not reduce risks for developing organ failures. Importantly, in both studies only patients with abdominal sepsis, who promptly underwent surgery to control the primary source of infection, were enrolled. Thus, PMX-HP was primarily aimed at clearing the residual circulating endotoxin. Besides the effects of PMX-HP on sepsis-associated cardiovascular dysfunction, a few investigators have suggested that PMX-HP could also improve pulmonary function in exacerbated idiopathic pulmonary fibrosis [10], interstitial pneumonia [11] and acute lung injury (ALI) [12–15]. In particular, patients with pulmonary comorbidities, hospitalized for prolonged periods or undergoing invasive mechanical ventilation (MV) present the greatest risks for developing pneumonia by Gram-negative pathogens [16–18]. Yet, to date there is a lack of evidence on the potential benefits of PMX-HP in the early stages of severe Gram-negative pneumonia. Thus, we designed a prospective randomized trial in pigs with severe Pseudomonas aeruginosa and on MV for 76 h to examine whether PMX-HP would reduce endotoxin activity (EA) and consequently improve hemodynamic, pulmonary and clinical variables. Methods The study protocol was approved by the Animal Experimentation Ethics Committee of the University of Barcelona. Animals were managed according to the Declaration of Helsinki conventions for the use and care of animals. Page 2 of 10 Study animals, handlings, end of the study Eighteen Large White–Landrace female pigs (weight 32.8 ± 2.9 kg) were induced [19], intubated and connected to a mechanical ventilator (SERVO-I, Maquet, NJ, USA). Anesthesia was maintained with a continuous infusion of midazolam, 0.2–0.8 mg/kg/h, and fentanyl, 5–10 µg/kg/h, in order to maintain cessation of spontaneous movements following painful stimulation. Pigs were ventilated in volume control, tidal volume 10 mL/kg, positive end-expiratory pressure (PEEP) and respiratory rate adjusted to maintain gas exchange withi (...truncated)