Effect of albumin administration on outcomes in hypoalbuminemic patients hospitalized with community-acquired pneumonia (ALBUCAP): a prospective, randomized, phase III clinical controlled trial-a trial protocol

Alexander Rombauts, Gabriela Abelenda-Alonso, Antonella Francesca Simonetti, Guillermo Verdejo, Yolanda Meije, Lucia Ortega, Mercedes Clemente, Jordi Niubó, Yolanda Ruiz, Carlota Gudiol, Cristian Tebé, Sebastian Videla, Jordi Carratalà, Alexander Rombauts, Gabriela Abelenda-Alonso, Antonella Francesca Simonetti, Guillermo Verdejo, Yolanda Meije, Lucia Ortega, Mercedes Clemente, Jordi Niubó, Yolanda Ruiz, Carlota Gudiol, Cristian Tebé, Sebastian Videla, Jordi Carratalà

Abstract

Background: Community-acquired pneumonia (CAP) remains a leading cause of death worldwide, and hypoalbuminemia is associated with worse outcomes. However, it remains uncertain whether albumin administration could have any beneficial effects. We aim to assess whether the administration of albumin in hypoalbuminemic patients with CAP increases the proportion of clinically stable patients at day 5 compared with the standard of care alone.

Methods: This is a trial protocol for a superiority, non-blinded, multicenter, randomized, phase 3, interventional controlled clinical trial. The primary endpoint will be the proportion of clinical stable patients at day 5 (intention to treat), defined as those with stable vital signs for at least 24 h. The secondary endpoints will be time to clinical stability, duration of intravenous and total antibiotic treatment, length of hospital stay, intensive care unit admission, duration of mechanical ventilation and vasopressor treatment, adverse events, readmission within 30 days, and all-cause mortality. The trial has been approved by the Spanish Medicines and Healthcare Products Regulatory Agency. The investigators commit to publish the data in peer-reviewed journals within a year of the study completion date. Subjects will be recruited from three Spanish hospitals over a planned enrolment period of 2 years. A follow-up visit will be performed 1 month after discharge. We have estimated the need for a sample size of 360 patients at a two-sided 5% alpha-level with a power of 80% based on intention to treat. Eligible participants must be hospitalized, hypoalbuminemic (≤ 30 g/L), non-immunosuppressed, adults, and diagnosed with CAP. They will be randomly assigned (1:1) to receive standard care plus albumin (20 g in 100 mL) every 12 h for 4 days or standard care alone.

Discussion: If this randomized trial confirms the hypothesis, it should lead to a change in current clinical practice for the management of hypoalbuminemic patients with CAP.

Trial registration: European Clinical Trials Database (EudraCT) 2018-003117-18 . Registered on 12 April 2019. ClinicalTrials.gov NCT04071041 . Registered on 27 August 2019.

Keywords: Albumin; Community-acquired pneumonia; Inflammation; Randomized controlled trial.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

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Fig. 1
Participant timeline

References

    1. Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al. Diagnosis and treatment of adults with Community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200:E45–67.
    1. Ramirez JA, Wiemken TL, Peyrani P, Arnold FW, Kelley R, Mattingly WA, et al. Adults hospitalized with pneumonia in the United States: incidence, epidemiology, and mortality. Clin Infect Dis. 2017;65:1806–12.
    1. World Health Organization (WHO): Summary tables of mortality estimates by cause, age and sex, globally and by region, 2000–2016. . Accessed 28 Oct 2019.
    1. Naghavi M, Abajobir AA, Abbafati C, Abbas KM, Abd-Allah F, Abera SF, et al. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1151–10.
    1. Wuerth BA, Bonnewell JP, Wiemken TL, Arnold FW. Trends in pneumonia mortality rates and hospitalizations by organism, United States, 2002–2011. Emerg Infect Dis. 2016;22:1624–7.
    1. Marshall DC, Goodson RJ, Xu Y, Komorowski M, Shalhoub J, Maruthappu M, et al. Trends in mortality from pneumonia in the Europe union: a temporal analysis of the European detailed mortality database between 2001 and 2014. Respir Res. 2018;19:81.
    1. Walden AP, Clarke GM, McKechnie S, Hutton P, Gordon AC, Rello J, et al. Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Crit Care. 2014;18:R58.
    1. Eurich DT, Marrie TJ, Minhas-Sandhu JK, Majumdar SR. Ten-year mortality after community-acquired pneumonia. A prospective cohort. Am J Respir Crit Care Med. 2015;192:597–604. doi: 10.1164/rccm.201501-0140OC.
    1. Viasus D, Garcia-Vidal C, Manresa F, Dorca J, Gudiol F, Carratalà J. Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia. J Infect. 2013;66:27–33.
    1. Corrales-Medina VF, Musher DM, Wells GA, Chirinos JA, Chen L, Fine MJ. Cardiac complications in patients with community-acquired pneumonia. Circulation. 2012;125:773–81.
    1. Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax. 2012;67:71–79. doi: 10.1136/thx.2009.129502.
    1. Tong S, Amand C, Kieffer A, Kyaw MH. Trends in healthcare utilization and costs associated with pneumonia in the United States during 2008–2014. BMC Health Serv Res. 2018;18:715. doi: 10.1186/s12913-018-3529-4.
    1. Hauck K, Zhao X. How dangerous is a day in hospital? A model of adverse events and length of stay for medical inpatients. Med Care. 2011;49:1068–75.
    1. Halm EA, Fine MJ, Marrie TJ, Coley CM, Kapoor WN, Obrosky DS, et al. Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines. JAMA. 1998;279:1452–7.
    1. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007;167:1655-63.
    1. Méndez R, Menéndez R, Amara-Elori I, Feced L, Piró A, Ramírez P, et al. Lymphopenic community-acquired pneumonia is associated with a dysregulated immune response and increased severity and mortality. J Infect. 2019;78:423–31.
    1. Siljan WW, Holter JC, Nymo SH, Husebye E, Ueland T, Aukrust P, et al. Cytokine responses, microbial aetiology and short-term outcome in community-acquired pneumonia. Eur J Clin Investig. 2018;48:e12865. doi: 10.1111/eci.12865.
    1. Vincent J-L, Dubois M-J, Navickis RJ, Wilkes MM. Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg. 2003;237:319–34.
    1. Yin M, Si L, Qin W, Li C, Zhang J, Yang H, et al. Predictive value of serum albumin level for the prognosis of severe sepsis without exogenous human albumin administration: a prospective cohort study. J Intensive Care Med. 2018;33:687–94.
    1. Miyazaki H, Nagata N, Akagi T, Takeda S, Harada T, Ushijima S, et al. Comprehensive analysis of prognostic factors in hospitalized patients with pneumonia occurring outside hospital: serum albumin is not less important than pneumonia severity assessment scale. J Infect Chemother. 2018;24:602–9.
    1. Hatipoğlu U, Wells BJ, Chagin K, Joshi D, Milinovich A, Rothberg MB. Predicting 30-day all-cause readmission risk for subjects admitted with pneumonia at the point of care. Respir Care. 2018;63:43–49.
    1. Viasus D, Garcia-Vidal C, Simonetti A, Manresa F, Dorca J, Gudiol F, et al. Prognostic value of serum albumin levels in hospitalized adults with community-acquired pneumonia. J Infect. 2013;66:415–23.
    1. Lee JH, Kim J, Kim K, Jo YH, Rhee J, Kim TY, et al. Albumin and C-reactive protein have prognostic significance in patients with community-acquired pneumonia. J Crit Care. 2011;26:287–94.
    1. Fanali G, Di Masi A, Trezza V, Marino M, Fasano M, Ascenzi P. Human serum albumin: from bench to bedside. Mol Aspects Med. 2012;33:209–90.
    1. Levitt DG, Levitt MD. Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements. Int J Gen Med. 2016;9:229–55.
    1. Ballmer PE, Ochsenbein AF, Schütz-Hofmann S. Transcapillary escape rate of albumin positively correlates with plasma albumin concentration in acute but not in chronic inflammatory disease. Metabolism. 1994;43:697–705. doi: 10.1016/0026-0495(94)90117-1.
    1. Barle H, Gamrin L, Essén P, McNurlan MA, Garlick PJ, Wernerman J. Growth hormone does not affect albumin synthesis in the critically ill. Intensive Care Med. 2001;27:836–43.
    1. Komáromi A, Estenberg U, Hammarqvist F, Rooyackers O, Wernerman J, Norberg Å. Simultaneous assessment of the synthesis rate and transcapillary escape rate of albumin in inflammation and surgery. Crit Care. 2016;20:370. doi: 10.1186/s13054-016-1536-6.
    1. Barle H, Januszkiewicz A, Hållström L, Essén P, McNurlan MA, Garlick PJ, et al. Albumin synthesis in humans increases immediately following the administration of endotoxin. Clin Sci (Lond). 2002;103:525–31.
    1. Ferrer R, Mateu X, Maseda E, Yébenes JC, Aldecoa C, De Haro C, et al. Non-oncotic properties of albumin. A multidisciplinary vision about the implications for critically ill patients. Expert Rev Clin Pharmacol. 2018;11:125–37.
    1. Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet. 2011;50:99–110. doi: 10.2165/11539220-000000000-00000.
    1. Taverna M, Marie AL, Mira JP, Guidet B. Specific antioxidant properties of human serum albumin. Ann Intensive Care. 2013;3:4.
    1. Jürgens G, Müller M, Garidel P, Koch MHJ, Nakakubo H, Blume A, et al. Investigation into the interaction of recombinant human serum albumin with Re-lipopolysaccharide and lipid A. J Endotoxin Res. 2002;8:115–26.
    1. Kremer H, Baron-Menguy C, Tesse A, Gallois Y, Mercat A, Henrion D, et al. Human serum albumin improves endothelial dysfunction and survival during experimental endotoxemia: concentration-dependent properties. Crit Care Med. 2011;39:1414–22.
    1. Plantier J-L, Duretz V, Devos V, Urbain R, Jorieux S. Comparison of antioxidant properties of different therapeutic albumin preparations. Biologicals. 2016;44:226–33.
    1. Aubin É, Roberge C, Lemieux R, Bazin R. Immunomodulatory effects of therapeutic preparations of human albumin. Vox Sang. 2011;101:131–7.
    1. O’Brien AJ, Fullerton JN, Massey KA, Auld G, Sewell G, James S, et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med. 2014;20:518–23.
    1. Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet. 2018;391:2417–29.
    1. Di Pascoli M, Fasolato S, Piano S, Bolognesi M, Angeli P. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int. 2019;39:98–105. doi: 10.1111/liv.13968.
    1. Tokunaga C, Bateman RM, Boyd J, Wang Y, Russell JA, Walley KR. Albumin resuscitation improves ventricular contractility and myocardial tissue oxygenation in rat endotoxemia. Crit Care Med. 2007;35:1341–7.
    1. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–56.
    1. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412–21.
    1. Xu JY, Chen QH, Xie JF, Pan C, Liu SQ, Huang LW, et al. Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care. 2014;18:702.
    1. Patel A, Laffan MA, Waheed U, Brett SJ. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014;349:g4561. doi: 10.1136/bmj.g4561.
    1. Jiang L, Jiang S, Zhang M, Zheng Z, Ma Y. Albumin versus other fluids for fluid resuscitation in patients with sepsis: a meta-analysis. PLoS One. 2014;9:e114666. doi: 10.1371/journal.pone.0114666.
    1. Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, et al. Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41:1561–71.
    1. Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011;39:386–91.
    1. Uhlig C, Silva PL, Deckert S, Schmitt J, de Abreu MG. Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care. 2014;18:R10. doi: 10.1186/cc13187.
    1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43:304–77.

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