The effect of exchange transfusion on mortality in neonatal sepsis: a meta-analysis
European journal of pediatrics. 2021
Although antimicrobials are the cornerstone of neonatal sepsis management, adjunctive therapies are required to improve outcomes. The aim of our study was to evaluate the effect of exchange transfusion (ET) on mortality (primary outcome) in neonatal sepsis, as well as on immunoglobulin, complement and neutrophil levels and assess its complications (secondary outcomes). Databases searched include PubMed, NCBI, Google Scholar, CINHAL, Ovid and Scopus. Randomized controlled trials (RCTs), controlled observational studies (COSs) and uncontrolled observational studies (UOSs) reporting mortality data from using ET in neonatal sepsis were included. Studies with additional interventions, non-septic ET indications and populations aged > 28 days were excluded. Data extracted include demographics, features of study, sepsis and ET, as well as mortality rates, immunological and laboratory changes and complications. Data was meta-analysed and displayed using forest plots. The meta-analysis of 14 studies (3 RCTs, 11 COSs) revealed a mortality benefit in septic neonates who underwent ET-RR 0.72 (CI 0.61-0.86, p = 0.01) and a significant increase in pooled immunological parameters (immunoglobulin, complement levels) (SMD 1.13, [0.25, 2.02], p = 0.02) and neutrophil levels (SMD 1.07 [0.04, 2.11], p = 0.03) compared to controls. The descriptive analysis of 9 UOSs revealed thrombocytopenia as the most frequently reported complication (n = 48). Moderate-high risk of bias was largely due to inadequate sample sizes and follow-up durations.Conclusion: Currently, the use of ET in neonatal sepsis is not directly recommended due to low certainty of evidence, inadequate power and moderate-high risk of bias and heterogeneity.Trial registration: PROSPERO (CRD42020176629) ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176629 ) What is Known: • Exchange transfusion is one of the adjunctive methods for treatment of neonatal sepsis. What is New: • The pooled analysis of all studies shows that exchange transfusion has a low certainty of evidence in the context of neonatal mortality. However, at this point, this intervention cannot be refuted or recommended due to heterogeneity of studies and inadequate power.
Outcome of Early Hemostatic Intervention in Children With Sepsis and Nonovert Disseminated Intravascular Coagulation Admitted to PICU: A Randomized Controlled Trial
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2020
Critically ill children with sepsis may develop catastrophic thrombotic and hemorrhagic syndrome of disseminated intravascular coagulopathy as a final common pathway. OBJECTIVES Evaluation of the outcome of early hemostatic management of disseminated intravascular coagulopathy in patients with severe sepsis/septic shock admitted to PICU, before the development of clinically overt disseminated intravascular coagulopathy. DESIGN Prospective interventional, open label randomized controlled clinical trial. SETTING PICU at Alexandria University Children's Hospital. PATIENTS The study included 80 patients with proven severe sepsis/septic shock in nonovert disseminated intravascular coagulopathy stage. They were randomly assigned into two groups (group 1 and group 2). INTERVENTIONS Specific intervention was applied for group 1 (plasma transfusion, low-dose unfractionated heparin, and tranexamic acid). MEASUREMENTS All patients had assessment of Pediatric Index of Mortality 2 score, Pediatric Logistic Organ Dysfunction score, inotropic score, routine laboratory, and hemostatic tests including fibrin degradation products and D-dimers. Disseminated intravascular coagulopathy risk assessment scores were calculated on daily basis. RESULTS Mortality rate was significantly higher in group 2. Progression to overt disseminated intravascular coagulopathy was significantly more common among group 2 patients than group 1 (45% and 10%, respectively) (p < 0.0001). Disseminated intravascular coagulopathyRisk Assessment Scores were significantly higher on the second and fifth days among group 2 patients. The initial specific hemostatic intervention was the only significant predictor of survival and prevention of progression to overt disseminated intravascular coagulopathy. CONCLUSIONS Our results suggest that early use of a combination of fresh frozen plasma transfusion, low-dose heparin, and tranexamic acid in children with severe sepsis/septic shock in the "window of opportunity" before the development of overt disseminated intravascular coagulopathy stage was associated with better outcome for survival and prevention of progression to overt disseminated intravascular coagulopathy, with no increase in bleeding risk. Larger multicenter studies are needed to further prove this practice.
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.
[Effects of 37 centigrade volume resuscitation on coagulation function and blood lactic acid in neonates with septic shock]
Zhonghua wei zhong bing ji jiu yi xue. 2018;30((12):):1146-1149.
OBJECTIVE To investigate the effect of volume resuscitation with normal saline (NS) at 37 centigrade on the coagulation function and microcirculation of neonates with septic shock. METHODS Children with septic shock admitted to neonatal intensive care unit (NICU) of the First Affiliated Hospital of Gannan Medical University were enrolled. Twenty-four newborns with septic shock were divided into two groups by random number table method (12 in each group), and were resuscitated with 10 mL/kg at 25 centigrade NS and 37 centigrade NS respectively on the basis of routine treatment. Factor II, V, VII, VIII, IX, X, and prothrombin time (PT), thrombin Time (TT), fibrinogen (FIB), activated partial thromboplastin time (APTT), D-Dimer (DD), lactic acid (Lac) were detected before treatment and 6 hours and 12 hours after treatment. RESULTS The levels of coagulation factors II, V, VII, VIII, IX, X were not significantly changed before and after treatment in the two groups, and there was no significant difference between the two groups. After treatment, PT and APTT in both groups were gradually shortened, DD and Lac were gradually decreased, FIB were gradually increased, while TT had no significant change. Among them, PT, APTT, DD and Lac at 6 hours after treatment in 37 centigradeNS group were significantly lower than those before treatment [PT (s): 14.07+/-1.02 vs. 17.08+/-1.54, APTT (s): 54.83+/-12.39 vs. 69.17+/-16.36, DD (mg/L): 2.40+/-0.63 vs. 4.18+/-0.88, Lac (mmol/L): 2.84+/-0.82 vs. 5.98+/-1.17, all P < 0.05]; DD and Lac at 6 hours after treatment in 25 centigrade NS group were significantly lower than those before treatment [DD (mg/L): 3.13+/-0.84 vs. 4.16+/-1.04, Lac (mmol/L): 4.83+/-0.64 vs. 5.69+/-0.74, both P < 0.05], and PT at 12 hours after treatment was significantly shorter than that before treatment (s: 14.63+/-1.14 vs. 16.48+/-1.61, P < 0.01); FIB in both 25 centigrade NS group and 37 centigrade NS group at 12 hours after treatment were significantly higher than those before treatment (g/L: 2.83+/-0.83 vs. 1.58+/-0.43, 2.87+/-0.87 vs. 1.47+/-0.41, both P < 0.01), but TT had no significant change. The comparison between groups showed that PT, DD and Lac in the 37 centigrade NS group were significantly lower than those in the 25 centigrade NS group at 6 hours after treatment [PT (s): 14.07+/-1.02 vs. 15.69+/-1.21, DD (mg/L): 2.40+/-0.63 vs. 3.13+/-0.84, Lac (mmol/L): 2.84+/-0.82 vs. 4.83+/-0.64, all P < 0.05]; at 12 hours after treatment, PT, APTT and DD in the 37 centigrade NS group were significantly lower than those in the 25 centigrade NS group [PT (s): 13.26+/-0.91 vs. 14.63+/-1.14, APTT (s): 37.08+/-10.43 vs. 54.75+/-14.96, DD (mg/L): 1.20+/-0.59 vs. 2.06+/-0.69, all P < 0.01], and FIB was significantly higher than that in the 25 centigrade NS group (g/L: 2.87+/-0.87 vs. 2.83+/-0.83, P < 0.05). CONCLUSIONS Volume resuscitation at 37 centigrade can improve the coagulation function and microcirculation of newborns with septic shock.
Fluid bolus over 15-20 versus 5-10 minutes each in the first hour of resuscitation in children with septic shock: a randomized controlled trial
Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2017;18((10):):e435-e445
OBJECTIVES To compare the effect of administration of 40-60 mL/kg of fluids as fluid boluses in aliquots of 20 mL/kg each over 15-20 minutes with that over 5-10 minutes each on the composite outcome of need for mechanical ventilation and/or impaired oxygenation-increase in oxygenation index by 5 from baseline in the initial 6 and 24 hours in children with septic shock. DESIGN Randomized controlled trial. SETTING Pediatric emergency and ICU of a tertiary care institute. PATIENTS Children (< 18 yr old) with septic shock. INTERVENTIONS We randomly assigned participants to 15-20 minutes bolus (study group) or 5-10 minutes bolus groups (control group). MEASUREMENTS AND MAIN RESULTS We assessed the composite outcomes in the initial 6 and 24 hours after fluid resuscitation in both groups. We performed logistic regression to evaluate factors associated with need for ventilation in the first hour. Data were analyzed using Stata 11.5. Of the 96 children, 45 were randomly assigned to "15-20 minutes group" and 51 to "5-10 minutes group." Key baseline characteristics were not different between the groups. When compared with 5-10 minutes group, fewer children in 15-20 minutes group needed mechanical ventilation or had an increase in oxygenation index in the first 6 hours (36% vs 57%; relative risk, 0.62; 95% CI, 0.39-0.99) and 24 hours (43% vs 68%; relative risk, 0.63; 95% CI, 0.42-0.93) after fluid resuscitation. We did not find any difference in secondary outcomes such as death (1.2; 0.70-2.03), length of stay (mean difference: 0.52; -1.72 to 2.7), or resolution of shock (0.98; 0.63-1.53). CONCLUSION Children receiving fluid boluses over 5-10 minutes each had a higher risk of intubation than those receiving boluses over 15-20 minutes each. Notwithstanding the lack of difference in risk of mortality and the possibility that a lower threshold of intubation and mechanical ventilation was used in the presence of fluid overload, our results raise concerns on the current recommendation of administering boluses over 5-10 minutes each in children with septic shock.
Double volume exchange transfusion in severe neonatal sepsis
Indian Journal of Pediatrics. 2016;83((2)):107-13.
OBJECTIVES To study the efficacy and safety of double volume exchange transfusion (DVET) in neonates>1000 g birth weight with severe sepsis. METHODS Eighty-three neonates weighing >1000 g with severe sepsis were randomly assigned to DVET or standard therapy (ST) group. Primary outcome was mortality by 14 d from enrollment. RESULTS A 21 % reduction in mortality, albeit non-significant, by 14 d from enrollment was observed in DVET group in comparison to ST group [RR: 0.79 (95 % C.I 0.45-1.3); p 0.4]. A similar trend in mortality reduction was observed with early mortality and mortality by discharge in DVET group. No difference was observed in normalization of dysfunctional organs by 14 d. Cardiovascular and hematological system benefitted the most, followed by renal dysfunction with DVET. A significant improvement in post DVET IgG, IgA, IgM, C3 and base deficit was observed. No serious adverse effects occurred following DVET. CONCLUSIONS In neonates >1000 g with severe sepsis, DVET was associated with a trend towards decrease in mortality by 14 d from enrollment. A significant improvement in immunoglobulin and complement C3 levels and acid base status were observed following DVET. DVET is a safe procedure in severely sick and septic neonates.
A randomised controlled trial of plasma filtration in severe paediatric sepsis
Critical Care & Resuscitation. 2013;15((3):):198-204.
OBJECTIVE To determine whether plasma filtration improves 28-day survival in infants and children with severe sepsis. DESIGN A multicentre randomised controlled trial. SETTING Paediatric intensive care units in teaching hospitals. PATIENTS Forty-eight infants and children with severe sepsis. INTERVENTIONS Patients were randomly assigned to receive plasma filtration (n = 25) or standard therapy (n = 23) for the treatment of septic shock. The primary outcome measure was 28-day survival. Secondary outcome measures included the number of failed organ systems on Day 7, a requirement for extracorporeal membrane oxygenation (ECMO), and the modified Glasgow outcome score (MGOS) at 6 months (where 1 is normal and 6 is dead). RESULTS The trial was stopped early due to poor recruitment. Patients in the plasma filtration group had higher initial disease severity as measured by serum lactate level, inotrope score and MGOS. Ten (40%) children died in the plasma filtration group and 4 (17%) died in the control group. With intention-to-treat analysis and adjustment for lactate level, ventilation index, inotrope score and MGOS at admission using logistic regression, the odds ratio for death with plasma filtration was 1.20 (95% CI, 0.23-6.20; P = 0.82). The median number of failing organ systems at 7 days was 2 (interquartile range [IQR], 1-4) in the plasma filtration group versus 2 (IQR, 1-3) in the control group. Two children in the plasma filtration group required ECMO for 2.5 and 123 hours, and one child in the control group required ECMO for 45 hours. The median MGOS at 6 months was 4 (IQR, 2-6) in the plasma filtration group and 2 (IQR, 1-4) in the control group. CONCLUSIONS Our study did not recruit enough patients to test the hypothesis that addition of plasma filtration to our standard care protocol reduces 28-day mortality in children with severe sepsis. However, mortality in the treatment and control groups was not significantly different after adjustment for severity of illness at the time of randomisation.
Biomarker response to drotrecogin alfa (activated) in children with severe sepsis: results from the RESOLVE clinical trial*
Pediatric Critical Care Medicine. 2012;13((6):):639-45.
OBJECTIVE REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE), a phase III trial of drotrecogin alfa (activated) in pediatric severe sepsis, examined biomarker changes in inflammation and coagulation. This report describes biomarker profiles in early severe sepsis and the pharmacodynamic assessment of drotrecogin alfa (activated) in RESOLVE. DESIGN Serial measurements of interleukin-1, interleukin-6, interleukin-8, interleukin-10, tissue necrosis factor-, procalcitonin, D-dimer, and thrombin-antithrombin complex were performed at baseline and daily over the first five study days. Protein C levels were performed at baseline and at the end of the 96-hr study drug infusion. Analysis of variance-based log-transformed data compared the treatment groups for each measured variable. SETTING : One hundred four pediatric intensive care units in 18 countries. PATIENTS Four hundred seventy-seven children between 38 wks corrected gestational age and 17 yrs with sepsis-induced cardiovascular and respiratory dysfunction. INTERVENTIONS Drotrecogin alfa (activated). MEASUREMENTS AND MAIN RESULTS Pharmacodynamic activity of drotrecogin alfa (activated) compared with placebo was observed with reduction of D-dimer on day 1 (p < .01) and thrombin-antithrombin complex on days 1-4 (p < .05). There were no significant changes by treatment in multiple cytokines or procalcitonin. In the overall population, a median protein C difference was not observed (p > .05) with drotrecogin alfa (activated) administration compared with placebo, although a difference (median percentage change from baseline) in favor of drotrecogin alfa (activated) was observed in patients >1 yr old (p = .0449). CONCLUSIONS While children in the RESOLVE trial were similar to adults in that they showed a relationship between severity of coagulation and inflammation abnormalities and mortality, their pharmacodynamic response to drotrecogin alfa (activated) differed with respect to changes in protein C activity and systemic inflammation.
Recombinant human activated protein C for severe sepsis in neonates
Cochrane Database of Systematic Reviews.. 2012;:CD005385.
BACKGROUND Sepsis is a common problem in preterm and term infants. The incidence of neonatal sepsis has declined, but mortality remains high. Recombinant human activated protein C (rhAPC) possess a broad spectrum of activity modulating coagulation and inflammation. In septic adults it may reduce mortality, but no significant benefit has been reported in children with severe sepsis. OBJECTIVES To determine whether treatment with rhAPC reduces mortality and/or morbidity in neonatal sepsis. SEARCH METHODS For this update searches were carried out in May 2011 of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and abstracts of annual meetings of the Pediatric Academic Societies. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched. No language restriction was applied. SELECTION CRITERIA Randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials should report at least one of the following outcomes: mortality during initial hospital stay, neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease, periventricular leukomalacia, intraventricular haemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events. DATA COLLECTION AND ANALYSIS Review authors were to independently evaluate the articles for inclusion criteria and quality, and abstract information for the outcomes of interest. Differences were to be resolved by consensus. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effect model was to be used for meta-analysis. Heterogeneity tests, including the I(2) statistic, were to be performed to assess the appropriateness of pooling the data. MAIN RESULTS No eligible trials were identified. In October 2011 rhAPC (Xigris[REGISTERED]) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Xigris[REGISTERED] (DrotAA)( rhAPC) should no longer be used in any age category and the product should be returned to the distributor. AUTHORS' CONCLUSIONS Despite the scientific rationale for its use, there is insufficient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of efficacy, an increase in bleeding and resulting withdrawal of rhAPC from the market, neonates should not be treated with rhAPC and further trials should not be conducted.
Treatment of neonatal sepsis with intravenous immune globulin
The New England Journal of Medicine. 2011;365((13):):1201-11.
BACKGROUND Neonatal sepsis is a major cause of death and complications despite antibiotic treatment. Effective adjunctive treatments are needed. Newborn infants are relatively deficient in endogenous immunoglobulin. Meta-analyses of trials of intravenous immune globulin for suspected or proven neonatal sepsis suggest a reduced rate of death from any cause, but the trials have been small and have varied in quality. METHODS At 113 hospitals in nine countries, we enrolled 3493 infants receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive two infusions of either polyvalent IgG immune globulin (at a dose of 500 mg per kilogram of body weight) or matching placebo 48 hours apart. The primary outcome was death or major disability at the age of 2 years. RESULTS There was no significant between-group difference in the rates of the primary outcome, which occurred in 686 of 1759 infants (39.0%) who received intravenous immune globulin and in 677 of 1734 infants (39.0%) who received placebo (relative risk, 1.00; 95% confidence interval, 0.92 to 1.08). Similarly, there were no significant differences in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes. In follow-up of 2-year-old infants, there were no significant differences in the rates of major or nonmajor disability or of adverse events. CONCLUSIONS Therapy with intravenous immune globulin had no effect on the outcomes of suspected or proven neonatal sepsis.