TO STUDY THE EFFICACY OF POLYMYXIN B HEMOPERFUSION IN SEPSIS

Introduction:

Sepsis is marked by a struggle between foreign microbial agents and body’s homeostatic mechanisms. The main pathophysiological feature of sepsis is the uncontrollable activation of both pro- and anti-inflammatory responses arising from the overwhelming production of mediators such as pro- and anti-inflammatory cytokines3,4”. Collection of such inflammatory mediators and bacterial toxins in the circulation triggers various physiological reactions that result in further deterioration of the affected patient. To overcome this,it is postulated that extracorporeal blood purification will help in getting rid of inflammatory mediators as well as bacterial toxins from the blood that would be helpful in modulating the host inflammatory response in a favourable manner5. Purification of blood from inflammatory mediators and cytokines can be done by high-volume hemofiltration (HVHF), CytoSorb hemoadsorption cartridge and coupled plasma filtration adsorption (CPFA) among others6. Polymyxin B Hemoperfusion is another popular technique for endotoxin removal in sepsis. During hemoperfusion blood comes in direct contact with adsorbents. These adsorbents employ a number of physicochemical principles like hydrophobic interaction, hydrogen bonding, van der Waals forces, and ionic bonding in order to pull the solute or endotoxins in the blood5. Contemporary evidence with respect to use of Polymyxin B in sepsis shows mixed results 7-10. The present study evaluated the safety and efficacy of Polymyxin B hemoperfusion in treatment of Sepsis.

Methods:

A total of 50 consecutive ICU admitted sepsis patients aged between 16 and 70 years, requiring vasopressor to maintain MAP > 65 mmHg despite adequate volume resuscitation, having at least one of the following criteria for new onset organ dysfunction, viz. (i) Requirement for positive pressure ventilation via an endotracheal tube or tracheostomy tube, (ii) thrombocytopenia defined as acute onset of platelet count < 150,000 μ/L or a reduction of 50% from prior known levels, (iii) acute oliguria defined as urine output < 0.5 ml/kg/hr. for at least 6 hours despite adequate fluid resuscitation were enrolled in the study after excluding patients failing to maintain a minimum mean arterial pressure (MAP) of ≥ 65 mmHg despite vasopressor therapy and fluid resuscitation, having end stage renal disease, patients having severe congestive heart failure with NYHA Class IV symptoms, post CPR patients without immediate return to communicative state, acute myocardial infarction within the past 4 weeks, pregnant women, patients having uncontrolled hemorrhage, major trauma within the last 36 hours, those having severe leucopenia (< 1000 cells/mm3) or severe thrombocytopenia (< 30,000 cells/mm3), HIV patients, extensive third-degree burn patients, body weight <35 kg, patients showing hypersensitivity to Polymyxin B, patients with known sensitivity or allergy to heparin or has a history of heparin associated thrombocytopenia and those having any other end stage chronic illness with no reasonable expectation of survival to hospital discharge. The patients were then randomized using sealed and opaque envelopes to one into two study groups as follows: Cases (n=25): In these patients Polymyxin B hemoperfusion cartridge filter was used in addition to the standard ICU protocol used for management of sepsis patients at our facility. A total of 2 sessions spanning 2 hours, 24 hours apart were carried out. Controls (n=25): In these patients underwent standard ICU protocol for management of sepsis patients was used. Heparin was used as the anticoagulant as and where necessary and feasible. The recommended heparin doses for PMX were as follows: Priming (circuit) 4 Units (U)/ml, Bolus 2500 U, Maintenance (per hemoperfusion line) 10 U/kg body weight/hr. to a maximum of 1000 U/hr. All the patients were followed up at 6, 12, 24, 48, 72 hours and day 7 after admission. At each follow-up following parameters were noted: Blood pressure, Urinary output, Serum lactate, Platelet count, Glasgow Coma Score (GCS), Sequential Organ Failure Assessment (SOFA), Duration of ICU Stay upto day 7 and Death. Improvement in SOFA scores at 72 hours was the primary outcome of concern. Secondary outcomes were change in blood pressure, urine output, irea, Serum Creatinine, electrolytes at 72 hours. Final outcome was assessed at day 7.

Results:

Mean age of cases and controls was 53.04±15.50 and 55.48±13.92 years respectively (p=0.561). Majority of cases (56%) as well as controls (80%) were males (p=0.069). Mean body weight of cases was 60.48±7.38 kg which was comparable to that of controls (60.80±10.50 years) (p=0.901). Statistically, there was no significant difference between the two groups for age, sex, systolic blood pressure, urinary output, serum lactate, platelet count, interleukin-6 and procalcitonin levels. Mean SOFA, Vasopressor dependency index and D-dimer were significantly higher in cases as compared to that in the controls (p<0.05). Culture positivity rate was 20% in cases as compared to 15% in controls but this difference was not significant statistically (p=0.440) (Table 1). At 72 hours, survival rate was 44% in cases as compared to 48% in controls, thus showing no statistically significant difference between the two groups (p=0.776). Among survivors, as compared to baseline cases showed a significant decline in VDI, S. lactate, SOFA, interleukin-6, CRP, procalcitonin and D-dimer levels and a significant increase in urinary output. Among controls too, a significant decline in s. lactate, SOFA, interleukin-6, CRP, procalcitonin and D-dimer levels. As compared to baseline controls did not show a significant decline in  VDI  but showed a significant decline in platelet count too (p<0.05) (Table 2). At day 7, survival rate was 44% in cases as compared to 40% in controls but this difference was not significant statistically (p=0.774). Among survivors, as compared to baseline cases showed a significant decline in VDI, S. lactate, SOFA, interleukin-6, CRP, procalcitonin and D-dimer levels and a significant increase in urinary output. However, among controls significant decline from baseline was seen in S. lactate, interleukin-6, CRP, procalcitonin and D-Dimer levels. As compared to baseline, controls did not show a significant change in urinary output, VDI and SOFA scores but showed a significant decline in platelet count (Table 3).

Conclusions:

The present study showed a faster and sustainable recovery path in sepsis cases treated with use of Polymyxin B in addition to standard treatment protocol as compared to those placed on standard treatment protocol only, though no significant impact of additional use of polymyxin B could be seen on mortality. One of the most important impacts of the Polymyxin B use was a swift reduction in vasopressor dependency and a significant improvement in urinary output. Polymyxin B use also seemed to have a protective effect against fall in platelet count in the patients. The extent of improvement in SOFA scores was also higher in Polymyxin added group as compared to controls. The findings in the present study are similar to that reported by Kim et al.11 who also found that total SOFA score, renal SOFA and coagulation SOFA were significantly improved in the PMX group but not in the control group. In an earlier study, Cutuli et al.12 too observed a significant improvement in cumulative SOFA score as well as in different organ specific components of SOFA within 72 hours from the first cycle of PMX. It may be highlighted that use of PMX has been shown to instrumental in modulation of human leukocyte antigen DR13, vasopressor need14 and other clinical benefits associated with endotoxin removal12. The findings of the present study also show that PMX helps to reduce the inflammatory activity and tends to reduce the severity of sepsis. The present study is one of the only few studies evaluating the impact of PMX use on the clinical course of sepsis, however, most of the earlier studies had focused on the mortality. In the present study we found that ICU mortality was lower in cases (56%) as compared to that in controls (60%) but this difference was not significant statistically. As far as impact of hemoperfusion by PMX on mortality is concerned, the current evidence is divided. There are a large number of studies that similar to the present study do not find it to be significant7,12,13,15,16,, however, there are some studies that find it to be useful in reducing the mortality17-19. There was one study that reported that PMX impact on mortality is dependent on the initial SOFA scores9. One of the reasons for absence of difference in mortality rate between the two groups could be owing to a small sample size and a high mortality rate. Despite showing some promising results, the present study suffered from certain limitations, like a small sample size owing to which even the baseline characteristics could not be matched completely between the two groups and could have some confounding impact on the outcome too. Moreover, our facility being a base services hospital gets referrals from various primary and secondary care services facilities and most of the sepsis patients are very serious and have a poor chance of survival resulting in a high in ICU mortality. We also feel that use of some other ICU severity scores like APACHE II could also have helped to study other dimensions of hemoperfusion by PMX intervention. Further studies on larger sample size with inclusion of other variables that indicate the clinical course and outcome are recommended. However, within limitations, the present study shows usefulness of hemoperfusion by PMX that is sufficient for recommendation of its routine use.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.