Medline ® Abstracts for References 3-10
of 'Investigational and ineffective therapies for sepsis'
3
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Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study.
AU
Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, Viell B, Marget W, Seewald M, Walger P, Stuttmann R, Speichermann N, Peckelsen C, Kurowski V, Osterhues HH, Verner L, Neumann R, Müller-Werdan U, Score-Based Immunoglobulin Therapy of Sepsis (SBITS) Study Group
SO
Crit Care Med. 2007;35(12):2693.
OBJECTIVE:
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.
DESIGN:
Randomized, double-blind, placebo-controlled, multicenter trial.
SETTING:
Twenty-three medical and surgical intensive care units in university centers and large teaching hospitals.
PATIENTS:
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).
INTERVENTIONS:
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).
MEASUREMENTS AND MAIN RESULTS:
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.
CONCLUSIONS:
In patients with score-defined severe sepsis, ivIgG with a total dose of 0.9 g/kg body weight does not reduce mortality.
AD
Department of Medicine III, University Hospital, Martin-Luther-University Halle-Wittenberg, Germany. karl.werdan@medizin.uni-halle.de
PMID
4
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Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock.
AU
Alejandria MM, Lansang MA, Dans LF, Mantaring JB 3rd
SO
Cochrane Database Syst Rev. 2013;
BACKGROUND:
Mortality from sepsis and septic shock remains high. Results of trials on intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have been conflicting. This is an update of a Cochrane review that was originally published in 1999 and updated in 2002 and 2010.
OBJECTIVES:
To estimate the effects of IVIG as adjunctive therapy in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital.
SEARCH METHODS:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1966 to December 2012), and EMBASE (1988 to December 2012). We contacted investigators in the field for unpublished data. The original search was performed in 1999 and updated in 2002 and 2008.
SELECTION CRITERIA:
We included randomized controlled trials comparing IVIG (monoclonal or polyclonal) with placebo or no intervention in patients of any age with bacterial sepsis or septic shock.
DATA COLLECTION AND ANALYSIS:
Two authors independently assessed the studies for inclusion and undertook methodologic quality assessment and data abstraction. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation.
MAIN RESULTS:
We included 43 studies that met our inclusion criteria in this updated review out of 88 potentially eligible studies. The studies included a large polyclonal IVIG trial in neonates that was concluded in 2011 and classified as ongoing in the 2010 version of this review. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality in adults with sepsis compared to placebo or no intervention (relative risk (RR) 0.81; 95% confidence interval (CI) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates, which now includes the recently concluded large polyclonal IVIG trial, showed no significant reduction in mortality for standard IVIG (RR 1.00; 95% CI 0.92 to 1.08; five trials, n = 3667) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; three trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; five trials, n = 945) and neonates (RR 1.01; 95% CI 0.93 to 1.09; three trials, n = 3561). Mortality was not reduced among patients (eight trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (nine trials,n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97).
AUTHORS' CONCLUSIONS:
Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.
AD
Department of Clinical Epidemiology and Section of Infectious Diseases, Department of Medicine, Philippine General Hospital, University of the Philippines, Manila, Philippines, 1000.
PMID
5
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Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review.
AU
Pildal J, Gøtzsche PC
SO
Clin Infect Dis. 2004;39(1):38.
Randomized trials of adjunctive treatment of bacterial sepsis with polyclonal immunoglobulin show conflicting results. We performed a systematic review and a meta-analysis of the results of randomized trials that compared reductions in mortality rates in patient groups treated with polyclonal immunoglobulin versus either placebo or no treatment in addition to conventional treatment. High-quality trials had adequate concealment of allocation, were double-blinded and placebo-controlled, and made data available for intention-to-treat analyses. Twenty trials were included. Meta-analysis of all trials showed a relative risk of death with immunoglobulin treatment of 0.77 (95% confidence interval [CI], 0.68-0.88). High-quality trials (involving a total of 763 patients, 255 of whom died) showed a relative risk of 1.02 (95% CI, 0.84-1.24), whereas other trials (involving a total of 948 patients, 292 of whom died) showed a relative risk of 0.61 (95% CI, 0.50-0.73). Because high-quality trials failed to demonstrate a reduction in mortality, polyclonal immunoglobulin should not be used for treatment of sepsis except in randomized clinical trials.
AD
The Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark.
PMID
6
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Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock.
AU
Kreymann KG, de Heer G, Nierhaus A, Kluge S
SO
Crit Care Med. 2007;35(12):2677.
OBJECTIVE:
There is ongoing debate about the efficacy of polyvalent immunoglobulins as adjunctive therapy for sepsis or septic shock. Two meta-analyses by the Cochrane collaboration calculated a significant reduction in mortality. However, data of the largest study were missing in one, and a subset of four high-quality studies failed to show an effect in the other. To broaden the database, we performed a meta-analysis of all randomized controlled studies published so far.
DATA SOURCE:
MEDLINE, EMBASE, Cochrane Library of randomized trials, and personal files.
STUDY SELECTION:
Meta-analysis of all published randomized controlled studies published on polyvalent immunoglobulins (Ig) for treatment of sepsis or septic shock in adults, children, or neonates.
DATA EXTRACTION:
Twenty-seven trials with a total of 2,202 patients fulfilled the inclusion criteria.
DATA SYNTHESIS:
As the immunologic state of neonates is different than that of adults or older children, data were evaluated separately for each group. Fifteen trials on 1,492 adults could be included. The pooled effect on mortality was a relative risk of death (RR) of 0.79 (95% confidence interval [CI]0.69-0.90, p<or= .0003). There was a strong trend in favor of an immunoglobulin preparation enriched with IgA and IgM (IgGAM) (RR = 0.66, 95% CI 0.51-0.84, p<or= .0009) compared with preparations containing only IgG (RR = 0.85, 95% CI 0.73-0.99, p<or= .04). In 12 trials on 710 neonates, the pooled effect on mortality was 0.56 (95% CI 0.42-0.74, p<or= .0001). There was also a positive although less pronounced trend favoring the effect of IgGAM (RR = 0.50, 95% CI 0.34-0.73, p<or= .0003) compared with IgG (RR = 0.63, 95% CI 0.42-0.96, p<or= .03). A sensitivity analysis selecting eight trials in adults and ten in neonates of highest methodological quality confirmed these results.
CONCLUSIONS:
Polyvalent immunoglobulins exert a significant effect on mortality in sepsis and septic shock, with a trend in favor of IgGAM.
AD
Department of Intensive Care, University Medical Centre, Hamburg-Eppendorf, Germany. kreymann@uke.uni-hamburg.de
PMID
7
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Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis.
AU
Laupland KB, Kirkpatrick AW, Delaney A
SO
Crit Care Med. 2007;35(12):2686.
OBJECTIVES:
To systematically review the literature to assess whether adjunctive therapy with polyclonal intravenous immunoglobulin (ivIg) reduces mortality among critically ill adults with severe sepsis and septic shock.
DATA SOURCE:
MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases; the meta-register of controlled trials; and the Medical Editors Trial Amnesty register.
STUDY SELECTION:
Prospective randomized clinical trials (RCTs) evaluating ivIg treatment in critically ill adults with severe sepsis or septic shock were included. Two reviewers conducted assessment of suitability for inclusion.
DATA EXTRACTION:
Two authors independently determined the validity of included studies and extracted data.
DATA SYNTHESIS:
The effect of ivIg on all-cause mortality was quantified using a fixed-effect meta-analysis.
RESULTS:
Fourteen RCTs published between 1988 and 2006 were included. Most were small, used relatively low doses of ivIg, and included predominantly surgical patients with Gram-negative infections. There was a significant reduction in mortality associated with use of ivIg treatment with a pooled odds ratio of 0.66 (95% confidence interval 0.53-0.83; p<.0005). In general, a greater treatment effect was seen among studies of lower methodological quality, studies using higher doses of ivIg, and studies that did not use albumin as a control. There was evidence of between-study heterogeneity (chi-square p = .009), and this was at least moderate as measured by the I2 value (I2 = 53.8%). When only high-quality studies were pooled, the odds ratio for mortality was 0.96 (95% confidence interval 0.71-1.3; p = .78).
CONCLUSIONS:
This meta-analysis demonstrates an overall reduction in mortality with the use of ivIg for the adjunctive treatment of severe sepsis and septic shock in adults, although significant heterogeneity exists among the included trials and this result was not confirmed when only high-quality studies were analyzed. These data warrant a well-designed, adequately powered, and transparently reported clinical trial.
AD
Department of Critical Care Medicine, University of Calgary, Calgary, AB, Canada.
PMID
8
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Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
AU
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP
SO
Crit Care Med. 2017;45(3):486.
OBJECTIVE:
To provide an update to "Surviving Sepsis CampaignGuidelines for Management of Sepsis and Septic Shock: 2012."
DESIGN:
A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
METHODS:
The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable.
RESULTS:
The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions.
CONCLUSIONS:
Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
AD
1St. George's Hospital London, England, United Kingdom. 2New York University School of Medicine New York, NY. 3McMaster University Hamilton, Ontario, Canada. 4Brown University School of Medicine Providence, RI. 5Instituto di Anestesiologia e Rianimazione, UniversitàCattolica del Sacro Cuore, Rome, Italy. 6Vall d'Hebron University Hospital Barcelona, Spain. 7University of Manitoba Winnipeg, Manitoba, Canada. 8Emory University Hospital Atlanta, GA. 9Hadassah Hebrew University Medical Center Jerusalem, Israel. 10Sunnybrook Health Sciences Centre Toronto, Ontario, Canada. 11University of Pittsburgh Critical Care Medicine CRISMA Laboratory Pittsburgh, PA. 12Hospital Raymond Poincare Garches, France. 13Saint Thomas Hospital London, England, United Kingdom. 14University College London Hospitals London, England, United Kingdom. 15Vanderbilt University Medical Center Nashville, TN. 16Service de Reanimation Medicale Paris, France. 17CHIREC Hospitals Braine L'Alleud, Belgium. 18Western Hospital Victoria, Australia. 19Keio University School of Medicine, Tokyo, Japan. 20Vivantes-Klinikum Neukölln, Berlin, Germany. 21Karl Heusner Memorial Hospital Belize Healthcare Partners Belize City, Belize. 22Cooper Health System Camden, NJ. 23University of Mississippi Medical Center Jackson, MS. 24Jupiter Hospital Thane, India. 25Rush University Medical Center Chicago, IL. 26ASAN Medical Center University of Ulsan College of Medicine Seoul, South Korea. 27Hospital de Clinicas de Porto Alegre Porto Alegre, Brazil. 28Federal University of Sao Paulo Sao Paulo, Brazil. 29Regions Hospital St. Paul, MN. 30Saint Michael's Hospital Toronto, Ontario, Canada. 31Washington University School of Medicine St. Louis, MO. 32Ottawa Hospital Ottawa, Ontario, Canada. 33Nepean Hospital, University of Sydney Penrith, New South Wales, Australia. 34Mount Sinai Hospital Toronto, Ontario, Canada. 35UCINC, Centro Hospitalar de Lisboa Central, Lisbon, Portugal. 36University of New South Wales, Sydney, New South Wales, Australia. 37Universitàdellla Magna Graecia Catanzaro, Italy. 38Fujita Health University School of Medicine, Toyoake, Aich, Japan. 39Rigshospitalet Copenhagen, Denmark. 40UniversitàSapienza, Rome, Italy. 41Christiana Care Health Services Newark, DE. 42University of Pittsburgh School of Medicine Pittsburgh, PA. 43Stanford University School of Medicine Stanford, CA. 44Kaust Medical Services Thuwal, Saudi Arabia. 45University of Kansas Medical Center Kansas City, KS. 46Wolfson Institute of Biomedical Research London, England, United Kingdom. 47Massachusetts General Hospital Boston, MA. 48California Pacific Medical Center San Francisco, CA. 49University of Amsterdam Amsterdam, Netherlands. 50ErasméUniversity Hospital Brussels, Belgium. 51University of Amsterdam, Amsterdam, Netherlands. 52Houston Methodist Hospital, Houston, TX.
PMID
9
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To use or not to use? Polyclonal intravenous immunoglobulins for the treatment of sepsis and septic shock.
AU
Neugebauer EA
SO
Crit Care Med. 2007;35(12):2855.
AD
PMID
10
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Intravenous immunoglobulin and mortality in pneumonia patients with septic shock: an observational nationwide study.
AU
Tagami T, Matsui H, Fushimi K, Yasunaga H
SO
Clin Infect Dis. 2015;61(3):385.
BACKGROUND:
The role of intravenous immunoglobulin (IVIG) as an adjunctive treatment for severe sepsis remains controversial. We hypothesized that IVIG could be effective for treating pneumonia patients who have septic shock.
METHODS:
Mechanically ventilated pneumonia patients with septic shock were identified in the nationwide Japanese Diagnosis Procedure Combination inpatient database from 1 July 2010 to 31 March 2013. The effect of IVIG use on 28-day mortality was evaluated using propensity score and instrumental variable analyses.
RESULTS:
Eligible patients (n = 8264) from 1014 hospitals were divided into an IVIG group (n = 1324) and a control group (n = 6940). Propensity score matching created a matched cohort of 1045 pairs with and without IVIG treatment. There was no significant difference in 28-day mortality between the IVIG and control groups in the unmatched analysis (37.8%, 501/1324 vs 35.3%, 2453/6940; difference, 2.5%; 95% confidence interval [CI], -.3 to 5.3) or the propensity score-matchedanalysis (36.7%, 383/1045 vs 36.0%, 376/1045; difference, 0.7%; 95% CI, -3.5 to 4.8). Logistic regression analysis did not show a significant association between IVIG use and 28-day mortality in propensity score-matched patients (1.03; 95% CI, .86 to 1.23). Analysis using the pattern of hospital IVIG use as an instrumental variable found that IVIG use was not associated with a reduction in 28-day mortality (difference, -3.1%; 95% CI, -13.2 to 7.0).
CONCLUSIONS:
In this large retrospective nationwide study, we found that there may be no significant association between IVIG use and mortality in mechanically ventilated pneumonia patients with septic shock.
AD
Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, University of Tokyo Department of Emergency and Critical Care Medicine, Nippon Medical School.
PMID