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Annals of Intensive Care
Published in: Annals of Intensive Care 1/2019

Open Access 01-12-2019 | Septicemia | Research

The clinical efficacy of intravenous IgM-enriched immunoglobulin (pentaglobin) in sepsis or septic shock: a meta-analysis with trial sequential analysis

Authors: Jie Cui, Xuxia Wei, Haijin Lv, Yuntao Li, Ping Li, Zhen Chen, Genglong Liu

Published in: Annals of Intensive Care | Issue 1/2019

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Abstract

Background

Sepsis is characterized by a complex immune response. This meta-analysis evaluated the clinical effectiveness of intravenous IgM-enriched immunoglobulin (IVIgGM) in patients with sepsis and septic shock.

Methods

Four databases, PubMed, the Cochrane Library, the ISI Web of Knowledge, and Embase, were systematically searched from inception to June 2018 to update the 2013 edition of the Cochrane review by two investigators, who independently selected studies, extracted relevant data, and evaluated study quality. Data were subjected to a meta-analysis and trial sequential analysis (TSA) for the primary and secondary outcomes. Level of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scale.

Results

Nineteen studies comprising 1530 patients were included in this meta-analysis. Pooled analyses showed that the use of IVIgGM reduced the mortality risk of septic patients (relative risk 0.60; 95% confidence interval [CI] 0.52–0.69, I2 = 0%). TSA showed that IVIgGM had a significant effect on mortality. Additionally, the meta-analysis suggested that use of IVIgGM shortened length of mechanical ventilation (mean difference − 3.16 days; 95% CI − 5.71 to − 0.61 days) and did not shorten length of stay in the intensive care unit (mean difference − 0.38 days; 95% CI − 3.55 to 2.80 days). The GRADE scale showed that the certainty of the body of evidence was low for both benefits and IVIgGM.

Conclusion

Administration of IVIgGM to adult septic patients may be associated with reduced mortality. Treatment effects tended to be smaller or less consistent when including only those studies deemed adequate for each indicator. The available evidence is not clearly sufficient to support the widespread use of IVIgGM in the treatment of sepsis.
Trial registration PROSPERO registration number: CRD42018084120. Registered on 11 February 2018.
Appendix
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Literature
1.
Kadri SS, Rhee C, Strich JR, Morales MK, Hohmann S, Menchaca J, Suffredini AF, Danner RL, Klompas M. Estimating ten-year trends in septic shock incidence and mortality in United States academic medical centers using clinical data. Chest. 2017;151(2):278–85.PubMedCrossRef
2.
Artenstein AW, Higgins TL, Opal SM. Sepsis and scientific revolutions. Crit Care Med. 2013;41(12):2770–2.PubMedCrossRef
3.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.PubMedPubMedCentralCrossRef
4.
5.
Tamayo E, Fernandez A, Almansa R, Carrasco E, Heredia M, Lajo C, Goncalves L, Gomez-Herreras JI, de Lejarazu RO, Bermejo-Martin JF. Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. Eur Cytokine Netw. 2011;22(2):82–7.PubMed
6.
Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, Viell B, Marget W, Seewald M, Walger P, et al. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med. 2007;35(12):2693–701.PubMedCrossRef
7.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–77.PubMedCrossRef
8.
Cavazzuti I, Serafini G, Busani S, Rinaldi L, Biagioni E, Buoncristiano M, Girardis M. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Med. 2014;40(12):1888–96.PubMedCrossRef
9.
Giamarellos-Bourboulis EJ, Tziolos N, Routsi C, Katsenos C, Tsangaris I, Pneumatikos I, Vlachogiannis G, Theodorou V, Prekates A, Antypa E, et al. Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins. Clin Microbiol Infect. 2016;22(6):499–506.PubMedCrossRef
10.
Alejandria MM, Lansang MA, Dans LF, Mantaring JB III. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;16(9):Cd001090.
11.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65–94.PubMedCrossRef
12.
Brunner R, Rinner W, Haberler C, Kitzberger R, Sycha T, Herkner H, Warszawska J, Madl C, Holzinger U. Early treatment with IgM-enriched intravenous immunoglobulin does not mitigate critical illness polyneuropathy and/or myopathy in patients with multiple organ failure and SIRS/sepsis: a prospective, randomized, placebo-controlled, double-blinded trial. Crit Care. 2013;17(5):R213.PubMedPubMedCentralCrossRef
13.
Toth I, Mikor A, Leiner T, Molnar Z, Bogar L, Szakmany T. Effects of IgM-enriched immunoglobulin therapy in septic-shock-induced multiple organ failure: pilot study. J Anesth. 2013;27(4):618–22.PubMedCrossRef
14.
Welte T, Dellinger RP, Ebelt H, Ferrer M, Opal SM, Singer M, Vincent JL, Werdan K, Martin-Loeches I, Almirall J, et al. Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). Intensive Care Med. 2018;44(4):438–48.PubMedPubMedCentralCrossRef
15.
Lefebvre C, Glanville J, Wieland LS, Coles B, Weightman AL. Methodological developments in searching for studies for systematic reviews: past, present and future? Syst Rev. 2013;2:78.PubMedPubMedCentralCrossRef
16.
17.
Thorlund K EJ, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for trial sequential analysis (TSA). In Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark; 2011: p. 1 –115. www.​ctu.​dk/​tsa.
18.
Behre G, Ostermann H, Schedel I, Helmerking M, Schiel X, Rothenburger M, et al. Endotoxin concentrations and therapy with polyclonal IgM -enriched immunoglobulins in neutropenic cancer patients with sepsis syndrome: pilot study and interim analysis of a randomized trial. Anti Infect Drugs chemother. 1995;13:129–34.
19.
Buda S, Riefolo A, Biscione R, Goretti E, Cattabriga I, Grillone G, Bacchi-Reggiani L, Pacini D. Clinical experience with polyclonal IgM-enriched immunoglobulins in a group of patients affected by sepsis after cardiac surgery. J Cardiothorac Vasc Anesth. 2005;19(4):440–5.PubMedCrossRef
20.
Hentrich M, Fehnle K, Ostermann H, Kienast J, Cornely O, Salat C, Ubelacker R, Buchheidt D, Behre G, Hiddemann W, et al. IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial. Crit Care Med. 2006;34(5):1319–25.PubMedCrossRef
21.
Just HM, Metzger M, Vogel W, Pelka RB. Effect of adjuvant immunoglobulin therapy on infections in patients in an surgical intensive care unit. Results of a randomized controlled study. Klinische Wochenschrift. 1986;64(6):245–56.PubMedCrossRef
22.
Karatzas S, Boutzouka E, Venetsanou K, Myrianthefs P, Fildisis G, Baltopoulos G. The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis: another point of view. Crit Care. 2002;6(6):543–4.PubMedPubMedCentralCrossRef
23.
Reith HB, Mittelkftter U. Markers of inflammation for prognosis and therapy control in patients with abdominal sepsis—options for using adjuvant intravenous immunoglobulins. In: Faist E, editor. Immunological screening and immunotherapy in critically ill patients with abdominal infections. New York: Springer; 2001. p. 15–38.CrossRef
24.
Rodríguez A, Palizas F, Neira J, et al. Immunoglobulina polivalente enel tratamiento de la sepsis abdominal. Med Intensiva. 2001;18:11–5.
25.
Rodriguez A, Rello J, Neira J, Maskin B, Ceraso D, Vasta L, Palizas F. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. Shock (Augusta, Ga). 2005;23(4):298–304.CrossRef
26.
Schedel I, Dreikhausen U, Nentwig B, Hockenschnieder M, Rauthmann D, Balikcioglu S, Coldewey R, Deicher H. Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. Crit Care Med. 1991;19(9):1104–13.PubMedCrossRef
27.
Spannbrucker N, Hg Munch, Kunze R, Vogel F. auswirkungen von immunglobulinsubstitution bei sepsis. Intensivmedizin. 1987;6:314.
28.
Tugrul S, Ozcan PE, Akinci O, Seyhun Y, Cagatay A, Cakar N, Esen F. The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis [ISRCTN28863830]. Crit Care. 2002;6(4):357–62.PubMedPubMedCentralCrossRef
29.
Vogel F. Bewertung der intravenösen IgM-Therapie bei schweren nosokomialen Infektionen (Ergebnis einer kontrollierten randomisierten Studie). Klinisch angewandte Immunologie. Berlin, Heidelberg; 1988. p. 30–41.
30.
Wesoly C, Kipping N, Grundmann R. Immunoglobulin therapy of postoperative sepsis. Z Exp Chir Transplant Kunstliche Organe. 1990;23:213–6.PubMed
31.
Yavuz L, Aynali G, Aynali A, Alaca A, Kutuk S, Ceylan BG. The effects of adjuvant immunoglobulin M-enriched immunoglobulin therapy on mortality rate and renal function in sepsis-induced multiple organ dysfunction syndrome: retrospective analysis of intensive care unit patients. J Int Med Res. 2012;40(3):1166–74.PubMedCrossRef
32.
Neilson AR, Burchardi H, Schneider H. Cost-effectiveness of immunoglobulin M-enriched immunoglobulin (Pentaglobin) in the treatment of severe sepsis and septic shock. J Crit Care. 2005;20(3):239–49.PubMedCrossRef
33.
Norrby-Teglund A, Haque KN, Hammarstrom L. Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis. J Intern Med. 2006;260(6):509–16.PubMedCrossRef
34.
Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med. 2007;35(12):2686–92.PubMed
35.
Soares MO, Welton NJ, Harrison DA, Peura P, Shankar- Hari M, Harvey SE, Madan JJ, Ades AE, Palmer SJ, Rowan KM. An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis. Health Technol Assess. 2012;16(7):1–186.PubMedPubMedCentralCrossRef
36.
Busani S, Damiani E, Cavazzuti I, Donati A, Girardis M. Intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clinical effectiveness. Minerva Anestesiol. 2016;82(5):559–72.PubMed
37.
Kakoullis L, Pantzaris ND, Platanaki C, Lagadinou M, Papachristodoulou E, Velissaris D. The use of IgM-enriched immunoglobulin in adult patients with sepsis. J Crit Care. 2018;47:30–5.PubMedCrossRef
38.
Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, et al. Albumin replacement in patients with severe sepsis or septic shock. New Engl J Med. 2014;370(15):1412–21.PubMedCrossRef
39.
Martin-Loeches I, Muriel-Bombin A, Ferrer R, Artigas A, Sole-Violan J, Lorente L, Andaluz-Ojeda D, Prina-Mello A, Herran-Monge R, Suberviola B, et al. The protective association of endogenous immunoglobulins against sepsis mortality is restricted to patients with moderate organ failure. Ann Intensive Care. 2017;7(1):44.PubMedPubMedCentralCrossRef
40.
Gruenberg DA, Shelton W, Rose SL, Rutter AE, Socaris S, McGee G. Factors influencing length of stay in the intensive care unit. Am J Crit Care. 2006;15(5):502–509.39.PubMed
41.
Bermejo-Martin JF, Rodriguez-Fernandez A, Herran-Monge R, Andaluz-Ojeda D, Muriel-Bombin A, Merino P, Garcia-Garcia MM, Citores R, Gandia F, Almansa R, et al. Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014;276(4):404–12.PubMedCrossRef
42.
Almansa R, Tamayo E, Andaluz-Ojeda D, Nogales L, Blanco J, Eiros JM, Gomez-Herreras JI, Bermejo-Martin JF. The original sins of clinical trials with intravenous immunoglobulins in sepsis. Crit Care. 2015;19:90.PubMedPubMedCentralCrossRef
43.
Taccone FS, Stordeur P, De Backer D, Creteur J, Vincent JL. Gamma-globulin levels in patients with community-acquired septic shock. Shock (Augusta, Ga). 2009;32(4):379–85.CrossRef
44.
Ahsan N. Intravenous immunoglobulin induced-nephropathy: a complication of IVIG therapy. J Nephrol. 1998;11(3):157–61.PubMed
45.
Chapman SA, Gilkerson KL, Davin TD, Pritzker MR. Acute renal failure and intravenous immune globulin: occurs with sucrose-stabilized, but not with D-sorbitol-stabilized, formulation. Ann Pharmacother. 2004;38(12):2059–67.PubMedCrossRef
Metadata
Title
The clinical efficacy of intravenous IgM-enriched immunoglobulin (pentaglobin) in sepsis or septic shock: a meta-analysis with trial sequential analysis
Authors
Jie Cui
Xuxia Wei
Haijin Lv
Yuntao Li
Ping Li
Zhen Chen
Genglong Liu
Publication date
01-12-2019
Publisher
Springer International Publishing
Published in
Annals of Intensive Care / Issue 1/2019
Electronic ISSN: 2110-5820
DOI
https://doi.org/10.1186/s13613-019-0501-3

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