Intravenous immunoglobulin for prophylaxis of nosocomial sepsis. Use of intravenously administered immune globulin to prevent nosocomial sepsis in low birth weight infants: report of a pilot study. Intravenous immune globulin prophylaxis of late-onset sepsis in premature neonates. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. The use of prophylactic intravenous immunoglobulin therapy in very low birthweight infants. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. Multicenter randomized placebo controlled trial of therapy with intravenous immunoglobulin in decreasing mortality due to neonatal sepsis. Intravenous gammaglobulin in the prophylaxis of late sepsis in very-low-birth-weight infants: preliminary results of a randomized, double-blind, placebo-controlled trial. Intravenous immune globulin therapy for early-onset sepsis in premature neonates. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Intravenous immunoglobulin for sepsis prevention in preterm infants. [Infection prevention in elective large intestine surgery. Results of a prospective randomized comparative study]. The use of intravenously administered immunoglobulins in the prevention of severe infection in very low birth weight neonates. High-dose weekly intravenous immunoglobulin to prevent infections in patients undergoing autologous bone marrow transplantation or severe myelosuppressive therapy. A study of the American Bone Marrow Transplant Group. Effect on neutrophil kinetics and serum opsonic capacity of intravenous administration of immune globulin to neonates with clinical signs of early-onset sepsis. A randomized trial comparing peripherally inserted central venous catheters and peripheral intravenous catheters in infants with very low birth weight. Randomized comparison of ganciclovir plus intravenous immune globulin (IVIG) with IVIG alone for prevention of primary cytomegalovirus disease in children receiving liver transplants.
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 evaluate the use of intravenously administered immune globulin (IVIG) for prevention of sepsis in preterm infants, we administered IVIG in a protocol designed to maintain a therapeutic serum "target level" of 700 mg/dl. The 200 patients who were eligible for the study (600 to 2000 gm birth weight) were monitored throughout their initial hospitalization. Of these, 115 patients were randomly assigned in a double-blind, controlled trial to treatment and placebo groups. The remaining 85 infants were not randomly assigned to a group, by parental request, but were followed and analyzed separately. In one patient who received IVIG, transient tachycardia and a decrease in blood pressure developed during an infusion; resolution occurred promptly after the infusion was discontinued. No persistent hepatic or renal abnormalities were noted in either the IVIG- or the placebo-treated group. There were seven episodes of sepsis in the placebo group and nine in the group whose parents refused consent to the study. No infant who received IVIG acquired nosocomial sepsis (p less than 0.01). All patients in the placebo group in whom sepsis developed had serum IgG levels less than 400 mg/dl at the time sepsis developed. Serum IgG levels were maintained near 700 mg/dl in patients who received IVIG. These data indicate that administration of sufficient IVIG to maintain target serum IgG levels throughout hospitalization may decrease the incidence of nosocomial sepsis in preterm infants. 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 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. 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. The objective of this study was to assess the impact on outcome of adjuvant therapy (high-dose of immunoglobulin [Ig] M-enriched intravenous Ig, IVIG) in intensive care unit (ICU) patients who underwent surgery by abdominal sepsis. This was a prospective, randomized, double-blind, controlled study set in the medical/surgical ICUs of seven teaching hospitals. Patients with severe sepsis and septic shock of intra-abdominal origin admitted to the ICU within 24 h after the onset of symptoms were included in the study. Polyvalent IgM-enriched Ig (Pentaglobin; IVIG group) at a dosage of 7 mL/kg/day for 5 days or an equal amount of 5% human albumin (control group) was randomized. Fifty-six patients were enrolled. The overall mortality rate was 37.5.%. Twenty patients had shock and 36 had severe sepsis (the mortality rate was 55.0% and 25.0%, respectively). In the intent-to-treat analysis, the mortality rate was reduced from 48.1% in patients treated with antibiotic (ATB) plus albumin to 27.5% (P = 0.06) for patients with ATB plus IVIG. The organ failure score (1.0 +/- 0.6 vs. 1.2 +/- 0.9), organ dysfunction score (1.7 +/- 1.1 vs. 1.8 +/- 1.0), and reoperation rate (17.2% vs. 29.6%) were not different between IVIG and control groups, respectively. Eight patients (14.3%) received inappropriate ATB initial therapy (IAT), and seven died (87.5%). IAT was the only variable independently associated with death (odds ratio, 19.4) in a logistic regression model. We conclude that IVIG administration, when used in combination with adequate antibiotics, improved the survival of surgical ICU patients with intra-abdominal sepsis. The initial choice of antibiotic has a dramatic impact on outcome. 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 The efficacy of intravenous immunoglobulin (IVIG) as prophylaxis for late sepsis was evaluated in a placebo-controlled, randomized, double-blind trial involving 240 infants of very low birth weight (less than 1,300 g). Each infant received a total of five doses of either IVIG (1 g/d) or an albumin placebo. The first four doses were administered between days 1 and 5 of life, and the last dose was administered on day 15 or shortly thereafter. Preliminary analysis of data available for 126 patients showed that in the first 30 days, sepsis developed in nine of 61 patients given IVIG and in 16 of 65 given placebo (one-tailed P = .065). At 70 days, the number who developed sepsis was similar in the two groups: 20 for those who received IVIG vs. 23 for those who received placebo. When patients with coagulase-negative staphylococcal infections were deleted from the totals, the results were essentially the same, i.e., three of 61 who received IVIG vs. nine of 65 who received placebo (one-tailed P = .041), developed sepsis during the first 30 days and 12 of 61 vs. 13 of 65, respectively, had developed sepsis at 70 days. In the IVIG group, the median peak level of serum IgG at day 7 was 1,700 mg/dL and the IgG levels were significantly greater than those in the placebo group for days 7-42. These data suggest that infusions of IVIG at the doses and dosing intervals used in this study may be effective in decreasing the incidence of late-onset sepsis during the first month of life in infants of very low birth weight. 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. Intravenous immunoglobulin as an adjunctive treatment in sepsis was regarded as promising by a Cochrane meta-analysis of smaller trials. In this phase III multicenter trial, we assessed whether intravenous immunoglobulin G (ivIgG) reduced 28-day mortality and improved morbidity in patients with score-defined severe sepsis.
                Randomized, double-blind, placebo-controlled, multicenter trial.
                Twenty-three medical and surgical intensive care units in university centers and large teaching hospitals.
                Patients (n = 653) with score-defined sepsis (sepsis score 12-27) and score-defined sepsis-induced severity of disease (Acute Physiology and Chronic Health Evaluation II score 20-35).
                Patients were assigned to receive either placebo or ivIgG (day 0, 0.6 g/kg body weight; day 1, 0.3 g/kg body weight).
                The prospectively defined primary end point was death from any cause after 28 days. Prospectively defined secondary end points were 7-day all-cause mortality, short-term change in morbidity, and pulmonary function at day 4. Six hundred fifty-three patients from 23 active centers formed the intention-to-treat group, 624 patients the per-protocol group (placebo group, n = 303; ivIgG group, n = 321). The 28-day mortality rate was 37.3% in the placebo group and 39.3% in the ivIgG group and thus not significantly different (p = .6695). Seven-day mortality was not reduced, and 4-day pulmonary function was not improved. Drug-related adverse events were rare in both groups. Exploratory findings revealed a 3-day shortening of mechanical ventilation in the surviving patients and no effect of ivIgG on plasma levels of interleukin-6 and tumor necrosis factor receptors I and II.
                In patients with score-defined severe sepsis, ivIgG with a total dose of 0.9 g/kg body weight does not reduce mortality. The aim of this study was to investigate whether intravenous immunoglobulin (IVIG) can prevent sepsis in premature newborn infants. The study group consisted of 80 preterm newborn infants, who were divided into two groups: 40 preterm newborns received IVIG prophylactically (group A) and the control group (group B, n = 40) did not receive IVIG. IVIG was given at a dose of 500 mg/kg to infants. weighing greater than 1500 g, and 700 mg/kg to those weighing less than 1500 g at birth on days one, two and eight of life. By two, eight and 12 days of age, the treatment group had significantly greater IgG concentrations than the control group. Mortality was 7.5 percent (3/40) in group A and 27.5 percent (11/40) in group B (p < 0.01). Bacteremia was determined in three blood cultures in group A and eight in group B, particularly S.aureus and S.enteritis. In a prospective randomized trial clinical results of orthograde bowel lavage alone (group I) versus combined bowel lavage and parenteral antibiotic prophylaxis with 4 gm Cefoxitin (group II) in two separate dosages (perioperative short-term-prophylaxis) are compared with regard to the reduction of septic complications after colorectal surgery. Septic wound complications were 11/27 = 41% in group I and 2/30 = 7% in group II. The rate of anastomotic leakages was significantly different in the two groups (5/27 in group I, 0 in group II). The monetary costs for given antibiotics and the duration of hospitalization were less in group II. Orthograde bowel lavage alone proved to be of no effect in reducing the rate of septic complications when used without antibiotic perioperative short-term-prophylaxis and therefore cannot be recommended to be used solely. 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. To determine whether intravenous immunoglobulin (IVIG) prevents severe infections during autologous bone marrow transplantation or equivalent high-dose myelosuppressive therapy.
                Randomized, stratified, nonblinded study.
                Three tertiary care university hospitals.
                One hundred seventy patients entered the study; 82 received IVIG and 88 were untreated controls. The study groups were similar for parameters capable of influencing the likelihood of infection.
                Intravenous immunoglobulin was given weekly at a dose of 500 mg/kg body weight from the initiation of cytotoxic therapy to the resolution of neutropenia.
                The development of bloodstream or other clinically proven infection, platelet use, and the development of alloimmunity to platelet transfusion.
                Clinical infection, bacteremia, and fungemia occurred in 43%, 35%, and 6% of the IVIG-treated patients and in 44%, 34%, and 9% of the control patients. Gram-positive bacteremia and gram-negative bacteremia occurred in 28% and 11% of the IVIG group and in 23% and 13% of the control group. Death due to infection occurred in 4.9% of IVIG recipients and in 2.3% of controls. None of these observations was statistically significant (P > 0.2). Survival to hospital discharge was achieved in 86.6% of the IVIG group and in 96.6% of the control group. The survival difference (10%; 95% CI, 1.7% to 18.3%; P = 0.02) was due to a higher incidence of regimen-related toxic death in the IVIG-treated group.
                The use of IVIG did not prevent infection. Fewer deaths occurred among controls due to a higher incidence of fatal hepatic veno-occlusive disease in patients receiving IVIG. This study was designed to test the hypothesis that administration of immune globulin to human neonates with early-onset bacterial sepsis would (1) facilitate neutrophil egress from the marrow, (2) improve serum opsonic capacity, and (3) facilitate recovery from the infectious illness. Twenty-two newborn infants with clinical signs of early-onset sepsis were given an intravenous infusion of either 750 mg of immune globulin (IVIG) per kilogram of body weight or the same volume of a vehicle control (albumin). All 22 infants survived, but significant hematologic, immunologic, and respiratory differences were observed after the IVIG and not after the control infusion. Eleven of the patients had neutropenia; 24 hours after the infusions, the neutropenia had resolved in all six IVIG recipients but persisted in all five control recipients (p less than 0.001). Ten patients had I/T neutrophil ratios (a measure of immature neutrophils to total neutrophils on the leukocyte differential count) of less than 0.2. One hour after completion of the infusions, all five IVIG recipients had elevated I/T ratios (mean +/- SEM:0.10 +/- 0.05 before vs 0.43 +/- 0.03 after infusion; p less than 0.001), suggesting a prompt release of neutrophils from the marrow neutrophil storage pool into the circulation; no increase in the I/T ratio was observed in the control recipients. Six hours after the IVIG infusions, the ratio of arterial oxygen tension to fraction of inspired oxygen increased; no increase was observed after control infusions. Serum concentrations of IgG, IgG1, IgG2, IgG3, IgG4, and total hemolytic complement and the capacity of serum to support opsonophagocytosis of type II and type III group B streptococci increased markedly in the IVIG recipients but not in the control subjects. We conclude that administration of 750 mg IVIG per kilogram to neonates with clinical signs of early-onset sepsis was associated with immunologic, hematologic, and physiologic improvement. To determine whether percutaneously inserted central venous catheters (PICC) and peripheral intravenous catheters (PIV) in infants with very low birth weight (VLBW) differ with respect to (1) incidence of sepsis, (2) number of insertion attempts and catheters required for total intravenous therapy, (3) courses of antibiotics, and (4) total duration of intravenous (IV) use.
                A randomized comparative trial was conducted involving 63 VLBW infants (<1,251 g) who required IV therapy. Infants were assigned randomly at 1 week of age to either a PIV or a PICC catheter and followed up prospectively until an IV was no longer required or the infant was transferred out of the neonatal intensive care unit.
                Data were analyzed on an intention-to-treat basis. There was no difference in the incidence of sepsis (P = .64), number of courses of antibiotics (P = .16), or total duration of IV use (P= .34) between the 2 groups. The number of insertion attempts required for total IV therapy was significantly lower in the PICC group than in the PIV group (P = .008). There also was a significantly lower number of total catheters utilized in the PICC group (P = .002). When data were controlled for birth weight strata the results were similar.
                PICC lines reduced the number of painful IV procedures in VLBW infants without additional morbidity. A randomized placebo-controlled trial was conducted to determine the benefit of ganciclovir (5 mg/[kg x d]) for 30 days in addition to intravenous immune globulin (IVIG) for 16 weeks for prevention of primary cytomegalovirus (CMV) disease in children receiving liver transplants. Patients were monitored for 6 months after transplantation. The two groups of patients (recipients of 29 ganciclovir plus IVIG and 27 recipients of IVIG alone) were similar in terms of age, sex, and underlying disease. The incidence of CMV disease among the ganciclovir plus IVIG recipients and the IVIG alone recipients was 17% and 26%, respectively, and the time to disease in these recipients was 46 days and 32 days, respectively. There was no difference between groups in terms of survival; episodes of rejection, bacteremia, or fungemia; use of immunosuppressive agents; and incidence of leukopenia or thrombocytopenia. These results suggest that a 4-week course of ganciclovir with IVIG is not more effective than IVIG alone for prevention of primary CMV disease. Since short-term prophylaxis with ganciclovir may delay the onset of CMV disease, further studies with a longer course of ganciclovir prophylaxis are warranted.
IVIG administration results in a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection but is not associated with reductions in other clinically important outcomes, including mortality. Prophylactic use of IVIG is not associated with any short-term serious side effects.
The decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes. There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infections in preterm and/or LBW infants.