IgM-enriched immunoglobulins (Pentaglobin) may improve the microcirculation in sepsis: a pilot randomized trial

Roberta Domizi, Erica Adrario, Elisa Damiani, Claudia Scorcella, Andrea Carsetti, Paolo Giaccaglia, Erika Casarotta, Vincenzo Gabbanelli, Simona Pantanetti, Elena Lamura, Silvia Ciucani, Abele Donati, Roberta Domizi, Erica Adrario, Elisa Damiani, Claudia Scorcella, Andrea Carsetti, Paolo Giaccaglia, Erika Casarotta, Vincenzo Gabbanelli, Simona Pantanetti, Elena Lamura, Silvia Ciucani, Abele Donati

Abstract

Background: Polyclonal or IgM-enriched immunoglobulins may be beneficial during sepsis as an adjuvant immunomodulatory therapy. We aimed to test whether the infusion of IgM-enriched immunoglobulins improves microvascular perfusion during sepsis.

Methods: Single-centre, randomized, double-blind, placebo-controlled phase II trial including adult patients with a diagnosis of sepsis or septic shock for less than 24 h. Patients received an intravenous infusion of 250 mg/kg (5 mL/kg) per day of IgM-enriched immunoglobulins (Pentaglobin, n = 10) for 72 h or placebo (NaCl 0.9%, n = 9). At baseline and after 24 and 72 h of infusion, the sublingual microcirculation was assessed with Incident Dark Field videomicroscopy. Thenar near-infrared spectroscopy (NIRS) was applied with a vascular occlusion test to assess tissue oxygenation and microvascular reactivity. Levels of interleukin (IL) 1-beta, IL-6, IL-8, IL-10 and tumour necrosis factor alpha were measured in the serum.

Results: The perfused vessel density (PVD) for small vessels (diameter < 20 micron) increased in the Pentaglobin group (from 21.7 ± 4.7 to 25.5 ± 5.1 mm/mm2) and decreased in the placebo group (from 25 ± 5.8 to 20.7 ± 4.1 mm/mm2, p for interaction < 0.001, two-way analysis of variance). The absolute between-group difference at 72 h was 4.77 (standard error 2.34), p = 0.140. The microvascular flow index for small vessels increased at 24 h in the Pentaglobin group (from 2.68 [2.38-2.78] to 2.93 [2.82-3], p < 0.01) and decreased at 72 h in the placebo group (from 2.83 [2.60-2.97] to 2.67 [2.48-2.73], p < 0.05). Changes in general parameters, cytokines and NIRS-derived parameters were similar between the two groups, except for IL-6 and IL-10 that significantly decreased at 72 h only in the Pentaglobin group.

Conclusions: A 72-h infusion of IgM-enriched immunoglobulins (Pentaglobin) in patients with sepsis or septic shock may be associated with an increase in sublingual microvascular perfusion. Further studies are needed to confirm our findings. Trial registration NCT02655133, www.ClinicalTrials.gov, date of registration 7th January 2016, https://www.clinicaltrials.gov/ct2/show/NCT02655133.

Keywords: Immunoglobulins; Immunomodulation; Microcirculation; Pentaglobin; Sepsis.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study flow chart
Fig. 2
Fig. 2
Comparison of microcirculatory and NIRS-derived parameters. Data are expressed as mean and standard deviation of median [interquartile range]; lines indicate individual changes. *p < 0.05, **p < 0.01 versus baseline, Two-way ANOVA for repeated measures with Sidack’s post hoc test or Friedman test with Bonferroni post hoc test, as appropriate. #p < 0.05 versus placebo, Two-way ANOVA for repeated measures with Sidack’s post hoc test or Mann–Whitney U test, as appropriate
Fig. 3
Fig. 3
Comparison of the delta values (variations from baseline) for the perfused vessel density
Fig. 4
Fig. 4
Images of the sublingual microcirculation of a patients at baseline and after 72 h of Pentaglobin infusion. Non-perfused vessels are indicated with stars

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