[Randomized controlled multicenter study of albumin replacement therapy in septic shock (ARISS)]
Der Anaesthesist. 2021
Albumin replacement therapy in immunocompromised patients with sepsis - Secondary analysis of the ALBIOS trial
Journal of critical care. 2021;63:83-91
BACKGROUND The best fluid replacement strategy and the role of albumin in immunocompromised patients with sepsis is unclear. METHODS We performed a secondary analysis of immunocompromised patients enrolled in the ALBIOS trial which randomized patients with severe sepsis or septic shock to receive either 20% albumin (target 30 g per liter or more) and crystalloid or crystalloid alone during ICU stay. RESULTS Of 1818 patients originally enrolled, 304 (16.4%) were immunocompromised. One-hundred-thirty-nine (45.7%) patients were randomized in the albumin while 165 (54.2%) in the crystalloid group. At 90 days, 69 (49.6%) in the albumin group and 89 (53.9%) in the crystalloids group died (hazard ratio - HR - 0.94; 95% CI 0.69-1.29). No differences were observed with regards to 28-day mortality, SOFA score (and sub-scores), length of stay in the ICU and in the hospital, proportion of patients who had developed acute kidney injury or received renal replacement therapy, duration of mechanical ventilation. Albumin was not independently associated with a higher or lower 90-day mortality (HR 0.979, 95% CI 0.709-1.352) as compared to crystalloid. CONCLUSION Albumin replacement during the ICU stay, as compared with crystalloids alone, did not affect clinical outcomes in a cohort of immunocompromised patients with sepsis.
Evaluation of the Effect of Intravenous Immunoglobulin Dosing on Mortality in Patients with Sepsis: A Network Meta-analysis
Clinical therapeutics. 2019
PURPOSE Intravenous immunoglobulin (IVIG) has been proposed as an adjunctive therapy for sepsis. Related systematic reviews and meta-analyses of IVIG in sepsis indicate that IVIG can reduce the mortality of sepsis in adults. However, the effective dose of IVIG has not been clearly determined to date. We aimed to conduct an updated meta-analysis and use a network meta-analysis to elucidate the efficacy of IVIG dosing regimens in sepsis treatment. METHODS We searched PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE for articles published on or before February 14, 2019. We performed a direct meta-analysis to update a previous meta-analysis of the effects of IVIG therapy on mortality in adult patients with septic shock and a network meta-analysis to evaluate the efficacy of IVIG dosing regimens in sepsis treatment. FINDINGS Compared with the control treatment, the IVIG treatment reduced the all-cause mortality of patients with sepsis (odds ratio = 0.61; 95% CI, 0.41-0.92; P = 0.018), but significant heterogeneity was found across the studies (I(2) = 45.0%; P = 0.04). Regarding the IVIG dosage regimens, the highest total dose range (1.5-2 g/kg) was the optimal dose of administration (surface under the cumulative ranking curve = 84.7%). IMPLICATIONS On the basis of the available data, IVIG treatment is likely to reduce the all-cause mortality of patients with sepsis, and the highest total dose range (1.5-2 g/kg) is likely the optimal dose of administration.
IgM-enriched immunoglobulins (Pentaglobin) may improve the microcirculation in sepsis: a pilot randomized trial
Annals of intensive care. 2019;9(1):135
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/mm(2)) and decreased in the placebo group (from 25 +/- 5.8 to 20.7 +/- 4.1 mm/mm(2), 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.
Prolonged intravenous immunoglobulin treatment in very low birth weight infants with late onset sepsis
Journal of neonatal-perinatal medicine. 2019
BACKGROUND Neonatal infections are a leading cause of morbi-mortality despite advances in antimicrobials and neonatal care. Preterm infants have greater susceptibility to sepsis due to an immature immune system and lower immunoglobulin levels. Intravenous immunoglobulins (IVIG) have been used in several studies as an adjuvant treatment to improve this physiological immune deficiency, with different outcomes. METHODS Very low birth weight (VLBW) infants who developed sepsis in the neonatal ICU were studied. They were randomly divided in 2 groups: one group was treated with antibiotics (Group I), and the other received antibiotics plus a 500 mg/kg/dav of IVIG during 7 days (Group II). Serum IgG concentration was determined at initiation, during and after treatment Group I, and daily during the 7 days of therapy in Group II. RESULTS The baseline IgG concentration in group II was 486 g/dL, and increased to 852 mg/dL after the first dose of IVIG (p < 0.01). After the seventh day of infusion a mean IgG level of 1898 mg/dL was achieved. A direct correlation (r = 0.94) between IgG concentration and days of treatment was observed. Blood cultures were positive in 70% of the infants in group I and 75.5% in group II. Staphylococcus epidermidis was the most frequent isolated bacteria in blood cultures. The lethality rate was 25.0% in group I and 5.0% in Group II (p < 0.03). We did not observe collateral effects with the administration of IVIG. CONCLUSIONS Therapy with IVIG seems to be safe and effective as an adjuvant treatment in VLBW infants with sepsis.
Lactated Ringer's Versus 4% Albumin on Lactated Ringer's in Early Sepsis Therapy in Cancer Patients: A Pilot Single-Center Randomized Trial
Critical care medicine. 2019
OBJECTIVE To investigate the effects of the administration of 4% albumin on lactated Ringer's, when compared with lactated Ringer's alone, in the early phase of sepsis in cancer patients. DESIGN Single-center, randomized, double-blind, controlled-parallel trial. SETTING A tertiary care university cancer hospital. PATIENTS Cancer patients with severe sepsis or septic shock. INTERVENTIONS Between October 2014 and December 2016, patients were randomly assigned to receive either bolus of albumin in a lactated Ringer's solution or lactated Ringer's solution alone during the first 6 hours of fluid resuscitation after intensive care medicine (ICU) admission. Primary outcome was defined as death from any cause at 7 days. Secondary outcomes were defined as death from any cause within 28 days, change in Sequence Organ Failure Assessment scores from baseline to day 7, days alive and free of mechanical ventilation, days alive and free of vasopressor, renal replacement therapy during ICU stay, and length of ICU and hospital stay. MEASUREMENTS AND MAIN RESULTS A total of 360 patients were enrolled in the trial. At 7 days, 46 of 180 patients (26%) died in the albumin group and 40 of 180 (22%) died in the lactated Ringer's group (p = 0.5). At 28 days, 96 of 180 patients (53%) died in the albumin group and 83 of 180 (46%) died in the lactated Ringer's group (p = 0.2). No significant differences in secondary outcomes were observed. CONCLUSIONS Adding albumin to early standard resuscitation with lactated Ringer's in cancer patients with sepsis did not improve 7-day survival.
Prognostic value of secretoneurin in patients with severe sepsis and septic shock: data from the albumin italian outcome sepsis study
Critical Care Medicine. 2018;46((5):):e404-e410
OBJECTIVES Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable. DESIGN Multicenter, interventional randomized clinical trial. SETTING Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis). PATIENTS OR SUBJECTS In total, 540 patients with septic shock and 418 patients with severe sepsis. INTERVENTIONS Either 20% human albumin and crystalloids or crystalloid solutions alone. MEASUREMENTS AND MAIN RESULTS We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05-4.93]; p = 0.04) and 90-day mortality (2.04 [1.02-4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34-7.20]; p = 0.008) and 90-day mortality (2.69 [1.26-5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes. CONCLUSIONS Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability.
Comparison of the effects of albumin and crystalloid on mortality among patients with septic shock: systematic review with meta-analysis and trial sequential analysis
Sao Paulo medical journal = Revista paulista de medicina. 2018;136((5):):421-432.
BACKGROUND This study aimed to compare the effects on mortality of albumin and crystalloid, used for fluid resuscitation among adult patients with septic shock, through conducting a meta-analysis and trial sequential analysis (TSA). DESIGN AND SETTING Meta-analysis and TSA conducted at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. METHODS Data were collected from several major databases including MEDLINE, EMBASE, Clinical Trials.gov and Cochrane Central Register of Controlled Trials. Studies that compared the effects of albumin therapy versus crystalloid therapy on mortality among adult septic shock patients were eligible for inclusion in the analyses. The study name, year of publication, country of the trial, albumin concentration, type of crystalloid and all reported mortalities at different follow-up endpoints were extracted. RESULTS Compared with crystalloid, albumin did not decrease all-cause mortality at the final follow-up. However, in TSA, the required information size was not achieved in all groups, which means that the effect size was not definitive and further RCTs are needed to confirm or deny these findings. CONCLUSIONS Compared with crystalloid solutions, albumin was unable to decrease all-cause mortality. However, TSA indicated that these results could be false-negative. Additional randomized controlled trials are needed to clarify this discrepancy.
Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial
Annals of Intensive Care. 2016;6((1)):43.
BACKGROUND We aimed at assessing the benefit-to-risk ratio of activated protein C (drotrecogin-alfa activated, DAA) and corticosteroids, given alone or in combination, in patients with septic shock. METHODS We implemented an investigator-led, publicly funded, multicenter, randomized according to a 2 x 2 factorial design, placebo-controlled, double-blind trial in four parallel groups in which adults with persistent septic shock and no contraindication to DAA were assigned to either DAA alone (24 mg/kg/h for 96 h), or hydrocortisone (50 mg intravenous bolus q6 for 7 days) and fludrocortisone (50 microg once daily through the nasogastric tube for 7 days) alone, or their respective combinations, or their respective placebos. Primary endpoint was 90-day mortality rate. Follow-up duration was 6 months. Statistical analysis was planned to be performed in intent-to-treat once after all participants completed 180-day follow-up and according to the 2 x 2 factorial design. RESULTS The first patient was recruited in September 2008. The trial was suspended on October 25, 2011, owing to the withdrawal from the market of DAA. At this time, 411 patients had been enrolled. On May 17, 2012, the continuation of the trial on two parallel groups was approved by all legal authorities with the aim of investigating the benefit-to-risk ratio of corticosteroids. On June 30, 2014, the trial was suspended again by the study sponsor upon request of the independent data and safety monitoring board. Recruitment restarted on October 7, 2014, after any safety concern was ruled out. Finally, the trial was completed on June 23, 2015, with the recruitment of 1241 patients. CONCLUSIONS This report details the design, statistical plan and conduct of a randomized controlled trial of hydrocortisone and fludrocortisone in septic shock. Trial registration The trial was registered at ClinicalTrials.gov under NCT00625209.
Intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clinical effectiveness
Minerva Anestesiologica. 2016;82((5)):559-72.
INTRODUCTION Sepsis is characterized by a complex immune response. In this study we aimed to provide a review of the mechanisms of action of immunoglobulin (Ig) related to sepsis and an updated meta-analysis of the clinical effectiveness of the Ig use in septic patients. EVIDENCE ACQUISITION We performed two separate searches of Medline and other databases with the keywords Ig, sepsis, septic shock, septicemia, septicemia with no language restrictions in order to review the mechanisms of action of Igs in sepsis and to update the previous meta-analysis on the effects of the Ig therapy on the mortality of adult patients with septic shock. EVIDENCE SYNTHESIS Pathogens and toxin clearance, anti-inflammatory effects and anti-apoptotic effects on immune cells seems to be the main mechanisms of action of Ig therapy in sepsis. The meta-analysis of 18 RCTs indicated that the use of intravenous Ig reduces the mortality risk of septic patients (odds ratio=0.50 [95% CI 0.34-0.71], I2=44.68%). Low study quality, heterogeneous dosing regimens and type of Ig preparations, and different control interventions (placebo or albumin) may have influenced our results. CONCLUSIONS Our study showed that the use of intravenous Ig therapy in adult septic patients may have a rationale and seems to be associated with a reduced mortality. Anyway, the treatment effect generally tended to be smaller or less consistent if considering only those studies that were deemed adequate on each indicator. So, the available evidence is not clearly sufficient to support the widespread use of Ig in the treatment of sepsis.