Multicenter randomized placebo controlled trial of therapy with intravenous immunoglobulin in decreasing mortality due to neonatal sepsis. The use of prophylactic intravenous immunoglobulin therapy in very low birthweight infants. Intravenous immunoglobulin for prophylaxis of nosocomial sepsis. Intravenous immune globulin prophylaxis of late-onset sepsis in premature neonates. The use of intravenously administered immunoglobulins in the prevention of severe infection in very low birth weight neonates. Intravenous immune globulin therapy for early-onset sepsis in premature neonates. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure.
To determine whether therapy with intravenous immunoglobulin G (IVIG) would decrease mortality in neonatal sepsis.
                Three tertiary care neonatal intensive care units in the city of Bangalore.
                All neonates admitted to the Neonatal Intensive Care Units with the clinical diagnosis of sepsis and having at least C-reactive protein and one other rapid diagnostic criteria positive were enrolled. Neonates with a birth weight of less than 1000 g and those with any major congenital malformation were excluded. The neonates were randomized to receive 1 g/kg of IVIG on three consecutive days or an equivalent amount of placebo. The rest of the treatment including antibiotics and supportive care was as per the treating physician's decision. The main outcome variable was survival.
                The trial was carried out over a period of 8 months and recruited 58 neonates. Seven neonates who qualified but did not receive either IVIG or placebo were taken into a separate control group, and one baby who received only one dose of IVIG was excluded from the analysis. Twenty-five neonates were enrolled into the IVIG arm and 25 in the placebo arm. The neonates in the therapy and placebo groups were comparable in terms of birth weight (2144+/-675 g vs. 2072+/-682 g), gestation (37.0+/-3.56 vs. 35.8+/-3.52 weeks), sex distribution, duration of stay, and number requiring ventilation. The placebo group had a significantly higher number of babies with positive blood culture. Seven babies in each group died (p>0.05). There was no significant benefit in using IVIG (OR 1.0; 95% CI 0.25-4.07) (p = 0.74).
                In the sample studied therapy with IVIG did not reduce mortality in neonatal sepsis Nosocomial infections are a major cause of death in premature infants, especially in very low birthweight (VLBW) infants. The VLBW infants have low serum immunoglobulin G levels, which may have an effect on infections in early infancy. Thus, prophylactic administration of intravenous immunoglobulin (IVIG) is proposed to maintain higher immunoglobulin G and reduce the rate of hospital-acquired infection.
                A study for the effects of prophylactic IVIG therapy in VLBW infants was performed. A total of 61 VLBW infants were enrolled, and divided into the IVIG group (n = 31) and the control group (n = 30). The dose for each infant was 750-1000 mg/kg for those whose birthweight was less than 1000 g, and 500-750 mg/kg for infants whose birthweight was between 1001 and 1500 g. The control group received saline infusion. The infusions were given every 2 weeks until the infant weighed 1800 g, or was discharged.
                The results showed: there were no major differences in the perinatal and neonatal characteristics between the two groups, consistently higher IgG levels were found in the IVIG group, and the age of first documented sepsis was earlier in the control group.
                In this study, the prophylactic IVIG therapy may give substantially higher IgG levels, which may last for 2 months. However, a prophylactic effect for hospital-acquired infections was not observed. A total of 76 premature newborn infants with gestational age of 34 weeks or less were enrolled in a randomized controlled study to determine whether intravenously administrated immunoglobulin (IVIG) is able to prevent nosocomial sepsis. Forty infants were given 0.5 g/kg IVIG on the first day of life and 36 infants with similar gestational age and birth weight were selected as controls and did not receive IVIG. The frequency of proven sepsis, with a positive blood and/or cerebrospinal fluid culture, was significantly lower in infants who received IVIG as compared to controls (42.5 vs 80.0%) (p < 0.01). The mortality rate attributable to infection was not different in IVIG recipients and in controls (41 vs 48%) (p > 0.05). The overall mortality rates in the two groups were not different either (35.0 vs 44.4%) (p > 0.05). The majority of micro-organisms isolated from the blood culture of the patients were gram negative microorganisms (Klebsiella, Enterobacter). IVIG therapy was believed to be effective for prophylaxis of nosocomial infection, but such therapy was not able to reduce overall mortality rate or mortality rate due to systemic infection in prematurely born infants in our intensive care unit where the causative pathogens are usually gram negative microorganisms. To determine whether a single dose of intravenously administered immune globulin (IVIG) decreases late-onset sepsis in premature infants, we prospectively entered 753 neonates with birth weight 500 to 2000 gm, gestation < or = 34 weeks, and age < or = 12 hours into a multicenter, double-blind, controlled trial. Infants were randomly selected to receive a single intravenous infusion, 10 ml/kg, of either IVIG (500 mg/kg) or albumin (5 mg/kg) and were observed for 8 weeks for infection. Maternal and neonatal risk factors for infection did not differ between groups. Although serum IgG values before infusion were related to gestation (R = 0.62), the change in serum IgG or half-life of IgG after IVIG infusion was not (R < or = 0.09). The serum IgG concentration was increased (p < 0.05) in IVIG-treated patients for 8 weeks. There were 88 episodes of late-onset sepsis in 79 neonates (10.5%). Causative organisms included the following: Staphylococcus epidermidis (37 episodes), Enterococcus (9), Staphylococcus aureus (7), Candida (6), Escherichia coli (6), and multiple organisms (11). Sepsis, death, and death as a result of infection were unaffected by treatment. We conclude that a single infusion of IVIG, 500 mg/kg, shortly after birth was not effective prophylaxis for late-onset infection in premature neonates. Future studies of late-onset sepsis prophylaxis should consider IVIG with known pathogen-specific antibody concentrations against organisms causing these infections, in particular S. epidermidis. In a randomized prospective study in 116 selected neonates with very low birth weight, the effect of standard doses of intravenously administered immunoglobulins (IVIG) on the occurrence of severe infections was studied. No difference in infection rate or severity of infection could be observed between the treated neonates and the control group. The lack of effect could not be explained by an insufficient increase in the IgG serum levels, or inversely, by high immunosuppressive IgG levels. It is concluded that in very low birth weight neonates the administration of IVIG, under the conditions used in this investigation, does not protect against severe infection. Newborn infants may have IgG deficiencies that increase their susceptibility to bacterial infection. To determine whether intravenous immune globulin (IVIG) therapy improves survival rates in early-onset sepsis, we prospectively entered 753 neonates (birth weight 500 to 2000 gm, gestation less than or equal to 34 weeks, age less than or equal to 12 hours) into a multicenter, double-blind, controlled trial. Blood culture specimens were obtained and infants randomly assigned to receive 10 ml (per kilogram) intravenously of a selected IVIG (500 mg/kg) or albumin (5 mg/kg) preparation. Maternal and neonatal risk factors were not different between groups. Thirty-one babies (4.2%) had early-onset sepsis; the causative organisms were group B streptococcus (12 babies), Escherichia coli (6), and others (13). Of these 31 neonates, 7 (23%) died. Total serum IgG was higher for 7 days after IVIG therapy than after albumin treatment (p less than 0.05). During these 7 days, 5 (30%) of 17 albumin-treated and none of 14 IVIG-treated patients died (p less than 0.05). The survival rate at 56 days of age, however, was not significantly improved. Group B streptococcus type-specific IgG antibody was significantly increased after IVIG treatment and appeared to be related to the amount of IVIG specific antibody. Infusion-related adverse reactions were less frequent in patients receiving IVIG therapy (0.5%) than in those receiving albumin. The IVIG therapy in neonates with early-onset sepsis, while reducing the early mortality rate, did not significantly affect the overall survival rate. Further studies are necessary to confirm these findings and to determine more effective therapeutic regimens. In a recently reported study, low doses of intravenous immunoglobulins (IVIG) were shown to be as effective as high doses in protecting chronic lymphocytic leukemia (CLL) patients against infections, although a control group was not included. With this background we started a crossover study of low-dose IVIG prophylaxis aimed at investigating its superiority over empirical treatment of infections.
                Forty-two CLL patients with hypogammaglobulinemia (IgG < 600 mg/dL) and/or a history of at least one episode of severe infection in the 6 months preceding inclusion in the study were randomly allocated to receive either an infusion of 300 mg/kg IVIG every 4 weeks for 6 months or no treatment. Then they were switched to observation or IVIG for another 12 months; finally, they received IVIG or no therapy for 6 more months.
                A significantly lower incidence of infectious episodes was observed during IVIG prophylaxis in 30 patients who completed the 6-month period of either observation or IVIG therapy. The same applied to the 17 patients who completed 12 months of either observation or IVIG prophylaxis. Interestingly, the restoration of serum IgG levels obtained in 17 out of 25 patients (mean percent value of IgG increase, 41.8%) did not parallel a decrease in the number of infectious episodes.
                A protective effect against infections is demonstrated for low-dose IVIG in the present study. A benefit was shown in patients who completed either 12 or 6 months of IVIG prophylaxis; however, even this low-dose treatment is not a cost effective way to prevent infection in CLL patients. Although inhaled nitric oxide (iNO) may be a promising treatment for newborn infants with severe respiratory failure, the results from 3 previous small trials were inconclusive.
                Infants of <34 weeks' gestation, <28 days old, and with severe respiratory failure requiring ventilatory support were randomized to receive or not receive iNO. The study was not blinded.
                Recruited were 108 infants (55 allocated to receive iNO and 53 not allocated to receive iNO) from 15 neonatal units in the United Kingdom and Republic of Ireland. Fifty-nine percent (64 of 108) died, and 84% of the survivors (37 of 44) had signs of some impairment or disability, 9 (20%) of them classified as severely disabled. There was no evidence of an effect of iNO on the primary outcomes: death or severe disability at 1 year corrected age (relative risk [RR]: 0.99; 95% confidence interval [CI]: 0.76 to 1.29); death or supplemental oxygen on expected date of delivery (RR: 0.84; 95% CI: 0.68 to 1.02); or death or supplemental oxygen at 36 weeks' postmenstrual age (RR: 0.98; 95% CI: 0.87 to 1.12). There was a trend for infants allocated to the iNO group to spend more time on the ventilator (log rank: 3.6), on supplemental oxygen (log rank: 1.4), and in hospital (log rank: 3.5) than those allocated to receive no iNO. This pattern predominantly reflected the infants who died. Mean total costs at 1 year corrected age were significantly higher in the iNO group, partly because of the costs of the gas but mainly because of the difference in initial hospitalization costs.
                Evidence of prolongation of intensive care and increased costs of such care, without clear beneficial effects, implies that iNO cannot be recommended for preterm infants with severe hypoxic respiratory failure. Inhaled nitric oxide (iNO) reduces the use of extracorporeal membrane oxygenation (ECMO)/incidence of death in term and near-term neonates with severe hypoxic respiratory failure. We conducted a randomized, double masked, multicenter trial to determine whether administration of iNO earlier in respiratory failure results in additional reduction in the incidence of these outcomes.
                Neonates who were born at > or =34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI) > or =15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy.
                The trial enrollment was halted after 75% of target sample size was reached because of decreasing availability of eligible patients. The 150 infants who were given early iNO and 149 control infants had similar baseline characteristics. Arterial oxygen tension increased by >20 mm Hg in 73% of early iNO and 37% of control infants after study gas initiation. Control infants received standard iNO and deteriorated to OI >40 more often than infants who were given early iNO. The incidence of death (early iNO, 6.7% vs control, 9.4%), ECMO (10.7% vs 12.1%), and their combined incidence (16.7% vs 19.5%) were similar in both groups.
                iNO improves oxygenation but does not reduce the incidence of ECMO/mortality when initiated at an OI of 15 to 25 compared with initiation at >25 in term and near-term neonates with respiratory failure.
In previous reviews, we encouraged researchers to undertake well-designed trials to confirm or refute the effectiveness of IVIG in reducing adverse outcomes in neonates with suspected infection. Such a trial has been undertaken. Results of the INIS trial, which enrolled 3493 infants, carry a heavy weight in the current update of this review, and the undisputed results show no reduction in death or major disability at 2 years of age. Routine administration of IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended.