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Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients.

ABSTRACT: BACKGROUND:The administration of endovenous immunoglobulins in patients with septic shock could be beneficial and preparations enriched with IgA and IgM (ivIgGAM) seem to be more effective than those containing only IgG. In a previous study Berlot et al. demonstrated that early administration of ivIgGAM was associated with lower mortality rate. We studied a larger population of similar patients aiming either to confirm or not this finding considering also the subgroup of patients with septic shock by multidrug-resistant (MDR) pathogens. METHODS:Adult patients with septic shock in intensive care unit (ICU) treated with ivIgGAM from August 1999 to December 2016 were retrospectively examined. Collected data included the demographic characteristics of the patients, the diagnosis at admission, SOFA, SAPS II and Murray Lung Injury Score (LIS), characteristics of the primary infection, the adequacy of antimicrobial therapy, the delay of administration of ivIgGAM from the ICU admission and the outcome at the ICU discharge. Parametric and nonparametric tests and logistic regression were used for statistic analysis. RESULTS:During the study period 107 (30%) of the 355 patients died in ICU. Survivors received the ivIgGAM earlier than nonsurvivors (median delay 12 vs 14 h), had significantly lower SAPS II, SOFA and LIS at admission and a lower rate of MDR- and fungal-related septic shock. The appropriateness of the administration of antibiotics was similar in survivors and nonsurvivors (84 vs 79%, respectively, p: n.s). The delay in the administration of ivIgGAM from the admission was associated with in-ICU mortality (odds ratio per 1-h increase?=?1.0055, 95% CI 1.003-1.009, p?

SUBMITTER: Berlot G

PROVIDER: S-EPMC6288102 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients.

Berlot Giorgio G Vassallo Michele Claudio MC Busetto Nicola N Nieto Yabar Margarita M Istrati Tatiana T Baronio Silvia S Quarantotto Giada G Bixio Mattia M Barbati Giulia G Dattola Roberto R Longo Irene I Chillemi Antonino A Scamperle Alice A Iscra Fulvio F Tomasini Ariella A

Annals of intensive care 20181210 1

<h4>Background</h4>The administration of endovenous immunoglobulins in patients with septic shock could be beneficial and preparations enriched with IgA and IgM (ivIgGAM) seem to be more effective than those containing only IgG. In a previous study Berlot et al. demonstrated that early administration of ivIgGAM was associated with lower mortality rate. We studied a larger population of similar patients aiming either to confirm or not this finding considering also the subgroup of patients with se ...[more]

PMID: 30535962

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Project description:BackgroundA profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear.MethodsIn this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed.ResultsOf the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068).ConclusionsAlthough we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registration DRKS00025794 , German Clinical Trials Register, https://www.drks.de . Registered 6 July 2021.

Project description:BackgroundIntravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C's enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock.MethodsThis was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations.ResultsMedian plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35-62) hours and in the placebo group was 54 (95% CI 41-62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05).ConclusionsOur pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence.Trial registrationACTRN12617001184369 (11/8/2017).

Project description:IntroductionIn patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250?mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose.Methods and analysisThe study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60?mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100?mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250?mg/kg. The primary endpoint will be all-cause mortality at 28 days.Ethics and disseminationThe study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell'Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences.Trial registration detailsThe trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov (NCT04182737) on 2 December 2019.

Project description:BackgroundPolyclonal 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.MethodsSingle-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.ResultsThe 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.ConclusionsA 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.

Project description:BACKGROUND:Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite treatment being in line with current guidelines, mortality remains high in those with septic shock. Intravenous immunoglobulins represent a promising therapy to modulate both the pro- and anti-inflammatory processes and can contribute to the elimination of pathogens. In this context, there is evidence of the benefits of immunoglobulin M (IgM)- and immunoglobulin A (IgA)-enriched immunoglobulin therapy for sepsis. This manuscript aims to summarize current relevant data to provide expert opinions on best practice for the use of an IgM- and IgA-enriched immunoglobulin (Pentaglobin) in adult patients with sepsis. MAIN TEXT:Sepsis patients with hyperinflammation and patients with immunosuppression may benefit most from treatment with IgM- and IgA-enriched immunoglobulin (Pentaglobin). Patients with hyperinflammation present with phenotypes that manifest throughout the body, whilst the clinical characteristics of immunosuppression are less clear. Potential biomarkers for hyperinflammation include elevated procalcitonin, interleukin-6, endotoxin activity and C-reactive protein, although thresholds for these are not well-defined. Convenient biomarkers for identifying patients in a stage of immune-paralysis are still matter of debate, though human leukocyte antigen-antigen D related expression on monocytes, lymphocyte count and viral reactivation have been proposed. The timing of treatment is potentially more critical for treatment efficacy in patients with hyperinflammation compared with patients who are in an immunosuppressed stage. Due to the lack of evidence, definitive dosage recommendations for either population cannot be made, though we suggest that patients with hyperinflammation should receive an initial bolus at a rate of up to 0.6 mL (30 mg)/kg/h for 6 h followed by a continuous maintenance rate of 0.2 mL (10 mg)/kg/hour for???72 h (total dose???0.9 g/kg). For immunosuppressed patients, dosage is more conservative (0.2 mL [10 mg]/kg/h) for???72 h, without an initial bolus (total dose???0.72 g/kg). CONCLUSIONS:Two distinct populations that may benefit most from Pentaglobin therapy are described in this review. However, further clinical evidence is required to strengthen support for the recommendations given here regarding timing, duration and dosage of treatment.

Dataset Information

Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients.

Publications

Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients.

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