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Clinical efficacy of IgM-enriched immunoglobulin as adjunctive therapy in neonatal and pediatric sepsis: a systematic review and meta-analysis
Dinleyici, E. C., Frey, G., Kola, E., Wippermann, U., Bauhofer, A., Staus, A., Griffiths, P., Azharry, M., Rohsiswatmo, R.
Frontiers in pediatrics. 2023;11:1239014
Abstract
BACKGROUND Sepsis is a major cause of mortality and morbidity globally, with around one-quarter of all sepsis-related deaths occurring in children under the age of 5. We conducted a meta-analysis and systematic review of the literature to evaluate the clinical effectiveness of an IgM-enriched immunoglobulin preparation in pediatrics patients and neonates with sepsis. METHODS Systematic searches of PubMed, the Cochrane Library and Embase databases were performed in November 2022, with no date limitations, to identify studies in which IgM-enriched immunoglobulin was used as adjunctive therapy in neonatal and pediatric patients with sepsis. RESULTS In total, 15 studies fulfilled the eligibility criteria, 13 neonatal studies and 2 pediatric studies. Pooled estimates from all studies indicated that mortality rates were significantly lower in patients who received treatment with the IgM-enriched immunoglobulin compared with controls (OR 0.41; 95% CI 0.32-0.55). Further analyses in neonatal studies, alone, showed a significant benefit with longer treatment durations (>3 days) vs. the recommended treatment duration (3 days) (OR 0.32; 95% CI 0.22-0.47) vs. (OR 0.61; 95% CI 0.41-0.92). Treatment with IgM-enriched immunoglobulin was associated with a lower mortality risk compared with controls in prospective studies vs. retrospective analyses (OR 0.37; 95% CI 0.27-0.51) vs. (OR 0.73; 95% CI 0.41-1.30). CONCLUSIONS This systematic review suggests that adjunctive treatment with IgM-enriched immunoglobulin may reduce the risk of mortality in neonatal and pediatric populations. However, large randomized controlled trials are required to further substantiate and evaluate these findings.
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Prothrombin complex concentrate (PCC) for treatment of trauma-induced coagulopathy: systematic review and meta-analyses
Hannadjas, I., James, A., Davenport, R., Lindsay, C., Brohi, K., Cole, E.
Critical care (London, England). 2023;27(1):422
Abstract
BACKGROUND Trauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrombin complex concentrate (PCC) is used as a potential treatment for the correction of TIC, but the efficacy, timing, and evidence to support its use in injured patients with hemorrhage are unclear. METHODS A systematic search of published studies was performed on MEDLINE and EMBASE databases using standardized search equations. Ongoing studies were identified using clinicaltrials.gov. Studies investigating the use of PCC to treat TIC (on its own or in combination with other treatments) in adult major trauma patients were included. Studies involving pediatric patients, studies of only traumatic brain injury (TBI), and studies involving only anticoagulated patients were excluded. Primary outcomes were in-hospital mortality and venous thromboembolism (VTE). Pooled effects of PCC use were reported using random-effects model meta-analyses. Risk of bias was assessed for each study, and we used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence. RESULTS After removing duplicates, 1745 reports were screened and nine observational studies and one randomized controlled trial (RCT) were included, with a total of 1150 patients receiving PCC. Most studies used 4-factor-PCC with a dose of 20-30U/Kg. Among observational studies, co-interventions included whole blood (n = 1), fibrinogen concentrate (n = 2), or fresh frozen plasma (n = 4). Outcomes were inconsistently reported across studies with wide variation in both measurements and time points. The eight observational studies included reported mortality with a pooled odds ratio of 0.97 [95% CI 0.56-1.69], and five reported deep venous thrombosis (DVT) with a pooled OR of 0.83 [95% CI 0.44-1.57]. When pooling the observational studies and the RCT, the OR for mortality and DVT was 0.94 [95% CI 0.60-1.45] and 1.00 [95% CI 0.64-1.55] respectively. CONCLUSIONS Among published studies of TIC, PCCs did not significantly reduce mortality, nor did they increase the risk of VTE. However, the potential thrombotic risk remains a concern that should be addressed in future studies. Several RCTs are currently ongoing to further explore the efficacy and safety of PCC.
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Emergency administration of fibrinogen concentrate for haemorrhage: systematic review and meta-analysis
Itagaki Y, Hayakawa M, Takahashi Y, Hirano S, Yamakawa K
World journal of emergency surgery : WJES. 2023;18(1):27
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Editor's Choice
Abstract
INTRODUCTION The occurrence of massive haemorrhages in various emergency situations increases the need for blood transfusions and increases the risk of mortality. Fibrinogen concentrate (FC) use may increase plasma fibrinogen levels more rapidly than fresh-frozen product or cryoprecipitate use. Previous several systematic reviews and meta-analyses have not effectively demonstrated FC efficacy in significantly improving the risk of mortality and reducing transfusion requirements. In this study, we investigated the use of FC for haemorrhages in emergency situations. METHODS AND ANALYSIS In this systematic review and meta-analysis, we included controlled trials, but excluded randomized controlled trials (RCTs) in elective surgeries. The study population consisted of patients with haemorrhages in emergency situations, and the intervention was emergency supplementation of FC. The control group was administered with ordinal transfusion or placebo. The primary and secondary outcomes were in-hospital mortality and the amount of transfusion and thrombotic events, respectively. The electronic databases searched included MEDLINE (PubMed), Web of Science, and the Cochrane Central Register of Controlled Trials. RESULTS Nine RCTs in the qualitative synthesis with a total of 701 patients were included. Results showed a slight increase in in-hospital mortality with FC treatment (RR 1.24, 95% CI 0.64-2.39, p = 0.52) with very low certainty of the evidence. There was no reduction in the use of red blood cells (RBC) transfusion in the first 24 h after admission with FC treatment (mean difference [MD] 0.0 Unit in the FC group, 95% CI - 0.99-0.98, p = 0.99) with very low certainty of the evidence. However, the use of fresh-frozen plasma (FFP) transfusion significantly increased in the first 24 h after admission with FC treatment (MD 2.61 Unit higher in the FC group, 95% CI 0.07-5.16, p = 0.04). The occurrence of thrombotic events did not significantly differ with FC treatment. CONCLUSIONS The present study indicates that the use of FC may result in a slight increase in in-hospital mortality. While FC did not appear to reduce the use of RBC transfusion, it likely increased the use of FFP transfusion and may result in a large increase in platelet concentrate transfusion. However, the results should be interpreted cautiously due to the unbalanced severity in the patient population, high heterogeneity, and risk of bias.
PICO Summary
Population
Patients admitted to hospital with emergency haemorrhage (9 randomised controlled trials, n= 701).
Intervention
Emergency supplementation of fibrinogen concentrate (FC).
Comparison
Standard transfusion treatments or placebo.
Outcome
Results showed a slight increase in in-hospital mortality with FC treatment (RR 1.24; 95% CI [0.64, 2.39]) with very low certainty of the evidence. There was no reduction in the use of red blood cells transfusion in the first 24 h after admission with FC treatment (mean difference [MD] 0.0 Unit in the FC group, 95% CI [- 0.99, 0.98]) with very low certainty of the evidence. The use of fresh-frozen plasma transfusion significantly increased in the first 24 h after admission with FC treatment (MD 2.61 Unit higher in the FC group, 95% CI [0.07, 5.16]). The occurrence of thrombotic events did not significantly differ with FC treatment.
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Different Concentrations of Albumin Versus Crystalloid in Patients with Sepsis and Septic Shock: A Meta-Analysis of Randomized Clinical Trials
Geng L, Tian X, Gao Z, Mao A, Feng L, He C
Journal of intensive care medicine. 2023;:8850666231170778
Abstract
OBJECTIVE The best type of resuscitation fluids for sepsis and septic shock patients remains unclear. The aim of this study was to evaluate the efficacy of different concentrations of albumin on reducing the mortality rate of theses patients by meta-analysis. MATERIALS AND METHODS PubMed, EMBASE, and Web of Science databases were used for screening the relevant studies. Randomized controlled trials (RCTs) were eligible if they compared the effects of albumin with crystalloid on mortality in patients with sepsis and septic shock. Data were examined and extracted by two reviewers independently. Any disagreements were resolved by consensus with or without the help from a third reviewer. Data including mortality, sample size of the patients, and resuscitation endpoints were extracted. Meta-analysis was carried based on the corresponding odds ratios with 95% confidence intervals. RESULTS Eight studies with a total of 5124 septic patients and 3482 septic shock patients were included in this study. Compared with crystalloid, the use of albumin may represent a trend toward reduced the 90-day mortality of septic patients (OR 0.91 [0.80, 1.02]; P = .11) and significantly improved the outcome of septic shock patients (OR 0.85 [0.74, 0.99]; P = .04). Further analysis showed a potentially beneficial role of both 4% to 5% and 20% albumin on reducing the mortality of septic patients. The use of 20% albumin significantly decreased the 90-day mortality of septic shock patients (OR 0.81 [0.67, 0.98]; P = .03), which was better than 4% to 5% albumin and crystalloid. CONCLUSIONS Albumin treatment, particularly 20% albumin, significantly reduced the 90-day mortality in septic shock patients. Both 4% to 5% and 20% of albumin may work better than crystalloid in improving the survival rate of patients with sepsis, but more relative RCTs are required for validation.
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Efficacy of IVIG therapy for patients with sepsis: a systematic review and meta-analysis
Pan, B., Sun, P., Pei, R., Lin, F., Cao, H.
Journal of translational medicine. 2023;21(1):765
Abstract
BACKGROUND Sepsis is an overwhelming reaction to infection that comes with high morbidity and mortality. It requires urgent interventions in order to improve outcomes. Intravenous immunoglobulins (IVIG) are considered as potential therapy in sepsis patients. Results of trials on IVIG as adjunctive therapy for sepsis have been conflicting due to the variability in population characteristics, country geography and drug dosage form in different studies. METHODS A systematic article search was performed for eligible studies published up to January, 31, 2023, through the PubMed, Embase, Cochrane Library and Chinese National Knowledge Infrastructure database. The included articles were screened by using rigorous inclusion and exclusion criteria. Subgroup analyses were conducted according to different IVIG types, ages and economic regions. All analyses were conducted using Review Manager 5.4. Quality of studies and risk of bias were evaluated. RESULTS In total, 31 randomized controlled trials were included with a sample size of 6,276 participants. IVIG could reduce the mortality (RR 0.86, 95% CI: 0.77-0.95, p = 0.005), the hospital stay (MD - 4.46, 95% CI: - 6.35 to - 2.57, p = 0.00001), and the APACHE II scores (MD - 1.65, 95% CI: - 2.89 to - 0.63, p = 0.001). Additionally, the results showed that IgM-enriched IVIG was effective in treating sepsis (RR 0.55, 95% CI: 0.40 - 0.76; p = 0.0003), while standard IVIG failed to be effective (RR 0.91, 95% CI: 0.81-1.02, p = 0.10). And the effect of IVIG in reducing neonatal mortality was inconclusive (RR 0.93, 95% CI: 0.81-1.05, p = 0.24), but it played a large role in reducing sepsis mortality in adults (RR 0.70, 95% CI: 0.57-0.86, p = 0.0006). Besides, from the subgroup of different economic regions, it indicated that IVIG was effective for sepsis in high-income (RR 0.89, 95% CI: 0.79-0.99, p = 0.03) and middle-income countries (RR 0.49, 95% CI: 0.28-0.84, p = 0.01), while no benefit was demonstrated in low-income countries (RR 0.56, 95% CI: 0.27-1.14, p = 0.11). CONCLUSIONS There is sufficient evidence to support that IVIG reduces sepsis mortality. IgM-enriched IVIG is effective in both adult and neonatal sepsis, while standard IVIG is only effective in adult sepsis. IVIG for sepsis has shown efficacy in high- and middle-income countries, but is still debatable in low-income countries. More RCTs are needed in the future to confirm the true clinical potential of IVIG for sepsis in low-income countries.
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Interventions for reducing late-onset sepsis in neonates: an umbrella review
Razak A, Alhaidari OI, Ahmed J
Journal of perinatal medicine. 2022
Abstract
OBJECTIVES Neonatal sepsis is one of the leading causes of neonatal deaths in neonatal intensive care units. Hence, it is essential to review the evidence from systematic reviews on interventions for reducing late-onset sepsis (LOS) in neonates. METHODS PubMed and the Cochrane Central were searched from inception through August 2020 without any language restriction. Cochrane reviews of randomized clinical trials (RCTs) assessing any intervention in the neonatal period and including one or more RCTs reporting LOS. Two authors independently performed screening, data extraction, assessed the quality of evidence using Cochrane Grading of Recommendations Assessment, Development and Evaluation, and assessed the quality of reviews using a measurement tool to assess of multiple systematic reviews 2 tool. RESULTS A total of 101 high-quality Cochrane reviews involving 612 RCTs and 193,713 neonates, evaluating 141 interventions were included. High-quality evidence showed a reduction in any or culture-proven LOS using antibiotic lock therapy for neonates with central venous catheters (CVC). Moderate-quality evidence showed a decrease in any LOS with antibiotic prophylaxis or vancomycin prophylaxis for neonates with CVC, chlorhexidine for skin or cord care, and kangaroo care for low birth weight babies. Similarly, moderate-quality evidence showed reduced culture-proven LOS with intravenous immunoglobulin prophylaxis for preterm infants and probiotic supplementation for very low birth weight (VLBW) infants. Lastly, moderate-quality evidence showed a reduction in fungal LOS with the use of systemic antifungal prophylaxis in VLBW infants. CONCLUSIONS The overview summarizes the evidence from the Cochrane reviews assessing interventions for reducing LOS in neonates, and can be utilized by clinicians, researchers, policymakers, and consumers for decision-making and translating evidence into clinical practice.
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Comparison of 3-factor versus 4-factor prothrombin complex concentrate for emergent warfarin reversal: a systematic review and meta-analysis
Margraf DJ, Brown SJ, Blue HL, Bezdicek TL, Wolfson J, Chapman SA
BMC emergency medicine. 2022;22(1):14
Abstract
BACKGROUND Patients requiring emergent warfarin reversal (EWR) have been prescribed three-factor prothrombin complex concentrate (PCC3) and four-factor prothrombin complex concentrate (PCC4) to reverse the anticoagulant effects of warfarin. There is no existing systematic review and meta-analysis of studies directly comparing PCC3 and PCC4. METHODS The primary objective of this systematic review and meta-analysis was to determine the effectiveness of achieving study defined target INR goal after PCC3 or PCC4 administration. Secondary objectives were to determine the difference in safety endpoints, thromboembolic events (TE), and survival during the patients' hospital stay. Random-effects meta-analysis models were used to estimate the odds ratios (OR), and heterogeneity associated with the outcomes. The Newcastle-Ottawa Scale was used to assess study quality, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS Ten full-text manuscripts and five abstracts provided data for the primary and secondary outcomes. Patients requiring EWR had more than three times the odds of reversal to goal INR when they were given PCC4 compared to PCC3 (OR = 3.61, 95% CI: 1.97-6.60, p < 0.001). There was no meaningful clinical association or statistically significant result between PCC4 and PCC3 groups in TE (OR = 1.56, 95% CI: 0.83-2.91, p = 0.17), or survival during hospital stay (OR = 1.34, 95% CI: 0.81-2.23, p = 0.25). CONCLUSION PCC4 is more effective than PCC3 in meeting specific predefined INR goals and has similar safety profiles in patients requiring emergent reversal of the anticoagulant effects of warfarin.
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Efficacy of albumin with diuretics in mechanically ventilated patients with hypoalbuminemia: A systematic review and meta-analysis
Itagaki, Y., Yoshida, N., Banno, M., Momosaki, R., Yamada, K., Hayakawa, M.
Medicine. 2022;101(37):e30276
Abstract
BACKGROUND Hypoalbuminemia is associated with fluid overload, the development of acute respiratory distress syndrome, and mortality. The co-administration of albumin and diuretics for the treatment of patients with hypoalbuminemia is expected to increase urine output, without hemodynamic instability, and improve pulmonary function; however, these effects have not been systematically investigated. Here, we aimed to clarify the benefits of the co-administration of albumin and diuretics in mechanically ventilated patients. METHODS We searched for randomized, placebo-controlled trials that investigated the effects of the co-administration of albumin and diuretics compared with placebo and diuretics, in mechanically ventilated patients with hypoalbuminemia. We searched these trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, and EMBASE databases. Primary outcomes were hypotensive events after the intervention, all-cause mortality, and the length of mechanical ventilation. Secondary outcomes were improvement in the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (P/F ratio) at 24 hours, total urine output (mL/d), and the clinical requirement of renal replacement therapy (RRT). RESULTS From the 1574 records identified, we selected 3 studies for quantitative analysis. The results of albumin administration were as follows: hypotensive events (risk ratio [RR] -1.05 [95% confidence interval {CI}: 0.15-0.81]), all-cause mortality (RR 1.0 [95% CI: 0.45-2.23]), the length of mechanical ventilation in days (mean difference -1.05 [95% CI: -3.35 to 1.26]), and improvement in P/F ratio (RR 2.83 [95% CI: 1.42-5.67]). None of the randomized controlled trials reported the total urine output, and one reported that no participants required RRT. Adverse events were not reported during the trials. The certainty of evidence was low (in the hypotensive events after the intervention and all-cause mortality) to moderate (in the length of mechanical ventilation in days, improvement of P/F ratio, clinical requirement of RRT, and adverse events). CONCLUSIONS Although this treatment combination reduced the number of days for which mechanical ventilation was required, it did not reduce the all-cause mortality at 30 days. In conclusion, the co-administration of albumin and diuretics may reduce hypotensive events and improve the P/F ratio at 24 hours.
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International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn
Lieberman L, Lopriore E, Baker JM, Bercovitz RS, Christensen RD, Crighton G, Delaney M, Goel R, Hendrickson JE, Keir A, et al
British journal of haematology. 2022
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Abstract
Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.
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Adsorption of insulin onto neonatal infusion sets: should intravenous administration of insulin to treat hyperglycemia in preterm babies on the NICU be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get to a stable insulin dose?
Mian P, Bolhuis MS, Maurer JM, van Stuijvenberg M
Molecular and cellular pediatrics. 2022;9(1):20
Abstract
Insulin is used to treat neonatal hyperglycaemia when blood glucose concentrations are consistently high, and to treat neonatal diabetes. Within this brief report, a review of the existing literature is conducted to determine if intravenous administration of insulin should be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get a stable insulin dose. Within this literature search, we focused on experimental insulin adsorption data (in vitro studies).