The INIS Study. International Neonatal Immunotherapy Study: Non-specific intravenous immunoglobulin therapy for suspected or proven neonatal sepsis: An international, placebo controlled, multicentre randomised trial

Background: Sepsis is an important cause of neonatal death and perinatal brain damage, particularly in preterm infants. While effective antibiotic treatment is essential treatment for sepsis, resistance to antibiotics is increasing. Adjuvant therapies, such as intravenous immunoglobulin, therefore offer an important additional strategy. Three Cochrane systematic reviews of randomised controlled trials in nearly 6,000 patients suggest that non-specific, polyclonal intravenous immunoglobulin is safe and reduces sepsis by about 15% when used as prophylaxis but does not reduce mortality in this situation. When intravenous immunoglobulin is used in the acute treatment of neonatal sepsis, however, there is a suggestion that it may reduce mortality by 45%. However, the existing trials of treatment were small and lacked long-term follow-up data. This study will assess reliably whether treatment of neonatal sepsis with intravenous immunoglobulin reduces mortality and adverse neuro-developmental outcome. Methods and design: A randomised, placebo controlled, double blind trial. Babies with suspected or proven neonatal sepsis will be randomised to receive intravenous immunoglobulin therapy or placebo. Eligibility criteria - Babies must be receiving antibiotics and have proven or suspected serious infection AND have at least one of the following: birthweight less than 1500 g OR evidence of infection in blood culture, cerebrospinal fluid or usually sterile body fluid OR be receiving respiratory support via an endotracheal tube AND there is substantial uncertainty that intravenous immunoglobulin is indicated. Exclusion criteria - Babies are excluded if intravenous immunoglobulin has already been given OR intravenous immunoglobulin is thought to be needed OR contra-indicated. Trial treatment - Babies will be given either 10 ml/kg of intravenous immunoglobulin or identical placebo solution over 4–6 hours, repeated 48 hours later. Primary outcome - Mortality or major disability at two years, corrected for gestational age. Data collection - Data will be collected at discharge from hospital and at 2 years of age (corrected for gestation) using a parental questionnaire and a health status questionnaire completed during a face-to-face follow-up appointment with the child's paediatrician. Trial registration: Current Controlled Trials ISCRTN94984750

Treatment of neonatal sepsis with intravenous immune globulin

BACKGROUN

Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes.

International audienceSepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single pro-inflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could well be explained by the widespread gene expression dysregulation known as "genomic storm" in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this "storm". Licensed pooled intravenous immunoglobulin preparations seemed to be a promising candidate but they have also failed in their present form to prevent sepsis-related death. We report here the protective effect of a single dose of intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of sepsis and aseptic systemic inflammation. The modification of the pooled immunoglobulin G molecules by exposure to ferrous ions resulted in their newly acquired ability to bind some pro-inflammatory molecules, complement components and endogenous "danger" signals. The improved survival in endotoxemia was associated with serum levels of pro-inflammatory cytokines, diminished complement consumption and normalization of the coagulation time. We suggest that intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in sepsis and related systemic inflammatory syndromes