Identification of cardiovascular and molecular prognostic factors for the medium-term and long-term outcomes of sepsis (ICROS): protocol for a prospective monocentric cohort study

Sina M Coldewey, Charles Neu, Philipp Baumbach, Andre Scherag, Björn Goebel, Katrin Ludewig, Frank Bloos, Michael Bauer, Sina M Coldewey, Charles Neu, Philipp Baumbach, Andre Scherag, Björn Goebel, Katrin Ludewig, Frank Bloos, Michael Bauer

Abstract

Introduction: Sepsis is one of the most prevalent life-threatening conditions in the intensive care unit. Patients suffer from impaired organ function, reduced physical functional capacity and decreased quality of life even after surviving sepsis. The identification of prognostic factors for the medium-term and long-term outcomes of this condition is necessary to develop personalised theragnostic approaches. Sepsis can cause cardiac impairment. The impact of this septic cardiomyopathy on patient's long-term outcome remains unclear. This study aims to evaluate cardiovascular risk factors, particularly the occurrence of septic cardiomyopathy, regarding their suitability as prognostic factors for the short-term and long-term outcomes of septic patients. Additionally, the study seeks to validate preclinical pathophysiological findings of septic cardiomyopathy in the clinical setting.

Methods and analysis: In this prospective monocentric cohort study, patients will be clinically assessed during the acute and postacute phase of sepsis and two follow-ups after 6 and 12 months. To determine the effect of septic cardiomyopathy and concomitant cellular and molecular changes on patient mortality and morbidity, a comprehensive cardiovascular and molecular deep phenotyping of patients will be performed. This includes an echocardiographic and electrocardiographic assessment, and the evaluation of heart rate variability, body composition, mitochondrial oxygen metabolism, macrocirculation and microcirculation, and endothelial barrier function. These analyses are complemented by routine immunological, haematological and biochemical laboratory tests and analyses of the serum metabolome and lipidome, microbiome and epigenetic modifications of immune cells. The reversibility of patients' organ dysfunction, their quality of life and physical functional capacity will be investigated in the follow-ups. Patients with cardiomyopathy without infection and healthy subjects will serve as control groups.

Ethics and dissemination: Approval was obtained from the Ethics Committee of the Friedrich Schiller University Jena (5276-09/17). The results will be published in peer-reviewed journals and presented at appropriate conferences.

Trial registration numbers: DRKS00013347; NCT03620409.

Keywords: cardiomyopathy; infectious diseases; intensive & critical care; molecular diagnostics.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Statistical power of a χ2 test (two-sided α=0.05). Based on a 6-month mortality of 60% in the complete sample of septic patients, different scenarios for the mortality of patients without (p1) or with (p2) septic cardiomyopathy and varying sample sizes are displayed. The percentage of patients with septic cardiomyopathy was set to 0.33 (2:1 allocation). The two panels display different scenarios for an increased (A, p2/p1>1) or reduced (B, p2/p1<1) mortality rate of patients with septic cardiomyopathy compared with patients without, respectively. For example, the topmost graph of panel A displays the statistical power for varying total numbers of septic patients, while the mortality risk of patients with septic cardiomyopathy (p2=0.9) is twice as high as that of patients without septic cardiomyopathy (p1=0.45).

References

    1. Singer M, Deutschman CS, Seymour CW, et al. . The third International consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801–10. 10.1001/jama.2016.0287
    1. Lozano R, Naghavi M, Foreman K, et al. . Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet 2012;380:2095–128. 10.1016/S0140-6736(12)61728-0
    1. Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity 2014;40:463–75. 10.1016/j.immuni.2014.04.001
    1. Winters BD, Eberlein M, Leung J, et al. . Long-Term mortality and quality of life in sepsis: a systematic review. Crit Care Med 2010;38:1276–83. 10.1097/CCM.0b013e3181d8cc1d
    1. Needham DM, Davidson J, Cohen H, et al. . Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference. Crit Care Med 2012;40:502–9. 10.1097/CCM.0b013e318232da75
    1. Landesberg G, Gilon D, Meroz Y, et al. . Diastolic dysfunction and mortality in severe sepsis and septic shock. Eur Heart J 2012;33:895–903. 10.1093/eurheartj/ehr351
    1. Schmidt H, Hoyer D, Hennen R, et al. . Autonomic dysfunction predicts both 1- and 2-month mortality in middle-aged patients with multiple organ dysfunction syndrome. Crit Care Med 2008;36:967–70. 10.1097/CCM.0B013E3181653263
    1. Schmidt H, Müller-Werdan U, Hoffmann T, et al. . Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med 2005;33:1994–2002. 10.1097/01.CCM.0000178181.91250.99
    1. Parker MM, Shelhamer JH, Bacharach SL, et al. . Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984;100:483–90. 10.7326/0003-4819-100-4-483
    1. Vieillard Baron A, Schmitt JM, Beauchet A, et al. . Early preload adaptation in septic shock? A transesophageal echocardiographic study. Anesthesiology 2001;94:400–6. 10.1097/00000542-200103000-00007
    1. Martin L, Derwall M, Al Zoubi S, et al. . The septic heart: current understanding of molecular mechanisms and clinical implications. Chest 2019;155:427–37. 10.1016/j.chest.2018.08.1037
    1. Huang SJ, Nalos M, McLean AS. Is early ventricular dysfunction or dilatation associated with lower mortality rate in adult severe sepsis and septic shock? A meta-analysis. Crit Care 2013;17:R96. 10.1186/cc12741
    1. Stanzani G, Duchen MR, Singer M. The role of mitochondria in sepsis-induced cardiomyopathy. Biochim Biophys Acta Mol Basis Dis 2019;1865:759–73. 10.1016/j.bbadis.2018.10.011
    1. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 2014;5:66–72. 10.4161/viru.26907
    1. Mik EG, Stap J, Sinaasappel M, et al. . Mitochondrial PO2 measured by delayed fluorescence of endogenous protoporphyrin IX. Nat Methods 2006;3:939–45. 10.1038/nmeth940
    1. Mik EG. Special article: measuring mitochondrial oxygen tension: from basic principles to application in humans. Anesth Analg 2013;117:834–46. 10.1213/ANE.0b013e31828f29da
    1. Harms FA, Bodmer SIA, Raat NJH, et al. . Non-Invasive monitoring of mitochondrial oxygenation and respiration in critical illness using a novel technique. Crit Care 2015;19:343. 10.1186/s13054-015-1056-9
    1. Baumbach P, Neu C, Derlien S, et al. . A pilot study of exercise-induced changes in mitochondrial oxygen metabolism measured by a cellular oxygen metabolism monitor (PICOMET). Biochim Biophys Acta Mol Basis Dis 1865;2019:749–58.
    1. Drobnik W, Liebisch G, Audebert F-X, et al. . Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res 2003;44:754–61. 10.1194/jlr.M200401-JLR200
    1. Revelly J-P, Tappy L, Martinez A, et al. . Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med 2005;33:2235–40. 10.1097/01.CCM.0000181525.99295.8F
    1. Mirnezami R, Kinross JM, Vorkas PA, et al. . Implementation of molecular phenotyping approaches in the personalized surgical patient journey. Ann Surg 2012;255:881–9. 10.1097/SLA.0b013e31823e3c43
    1. Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol 2017;2:135–43. 10.1016/S2468-1253(16)30119-4
    1. Rubio I, Osuchowski MF, Shankar-Hari M, et al. . Current gaps in sepsis immunology: new opportunities for translational research. Lancet Infect Dis 2019;19:e422–36. 10.1016/S1473-3099(19)30567-5
    1. Rivers E, Nguyen B, Havstad S, et al. . Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368–77. 10.1056/NEJMoa010307
    1. Bosy-Westphal A, Schautz B, Later W, et al. . What makes a BIA equation unique? validity of eight-electrode multifrequency BIA to estimate body composition in a healthy adult population. Eur J Clin Nutr 2013;67 Suppl 1:S14–21. 10.1038/ejcn.2012.160
    1. Stapel SN, Looijaard WGPM, Dekker IM, et al. . Bioelectrical impedance analysis-derived phase angle at admission as a predictor of 90-day mortality in intensive care patients. Eur J Clin Nutr 2018;72:1019–25. 10.1038/s41430-018-0167-1
    1. Piccoli A, Rossi B, Pillon L, et al. . A new method for monitoring body fluid variation by bioimpedance analysis: the RXc graph. Kidney Int 1994;46:534–9. 10.1038/ki.1994.305
    1. Lee YH, Lee J-D, Kang DR, et al. . Bioelectrical impedance analysis values as markers to predict severity in critically ill patients. J Crit Care 2017;40:103–7. 10.1016/j.jcrc.2017.03.013
    1. Rochwerg B, Cheung JH, Ribic CM, et al. . Assessment of Postresuscitation volume status by bioimpedance analysis in patients with sepsis in the intensive care unit: a pilot observational study. Can Respir J 2016;2016:1–8. 10.1155/2016/8671742
    1. Ubbink R, Bettink MAW, Janse R, et al. . A monitor for cellular oxygen metabolism (comet): monitoring tissue oxygenation at the mitochondrial level. J Clin Monit Comput 2017;31:1143-1150. 10.1007/s10877-016-9966-x
    1. Harms FA, Stolker RJ, Mik EG. Cutaneous respirometry as novel technique to monitor mitochondrial function: a feasibility study in healthy volunteers. PLoS One 2016;11.
    1. Malbrain MLNG, Huygh J, Dabrowski W, et al. . The use of bio-electrical impedance analysis (BIA) to guide fluid management, resuscitation and deresuscitation in critically ill patients: a bench-to-bedside review. Anaesthesiol Intensive Ther 2014;46:381–91. 10.5603/AIT.2014.0061
    1. Rabin R, Gudex C, Selai C, et al. . From translation to version management: a history and review of methods for the cultural adaptation of the EuroQol five-dimensional questionnaire. Value Health 2014;17:70–6. 10.1016/j.jval.2013.10.006
    1. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories Ats statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–7. 10.1164/ajrccm.166.1.at1102
    1. Lang RM, Badano LP, Mor-Avi V, et al. . Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of echocardiography and the European association of cardiovascular imaging. J Am Soc Echocardiogr 2015;28:e14:1–39. 10.1016/j.echo.2014.10.003
    1. Vieillard-Baron A. Septic cardiomyopathy. Ann Intensive Care 2011;1:6. 10.1186/2110-5820-1-6
    1. Sevilla Berrios RA, O'Horo JC, Velagapudi V, et al. . Correlation of left ventricular systolic dysfunction determined by low ejection fraction and 30-day mortality in patients with severe sepsis and septic shock: a systematic review and meta-analysis. J Crit Care 2014;29:495–9. 10.1016/j.jcrc.2014.03.007
    1. Landesberg G, Gilon D, Meroz Y, et al. . Diastolic dysfunction and mortality in severe sepsis and septic shock. Eur Heart J 2012;33:895–903. 10.1093/eurheartj/ehr351
    1. Müller-Werdan U, Ebelt H, Wilhelm J, et al. . Mikrozirkulationsstörung, zytopathische Hypoxie und septische Kardiomyopathie In: Werdan K, Müller-Werdan U, Schuster HP, et al., eds Sepsis und MODS: Springer science and business media, 2016: 137–9.
    1. Schmidt K, Gensichen J, Thiel P, et al. . A prospective, observational registry of patients with severe sepsis: the Canadian sepsis treatment and response registry. Infection 2013;41:S84–5.
    1. Pulido JN, Afessa B, Masaki M, et al. . Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock. Mayo Clin Proc 2012;87:620–8. 10.1016/j.mayocp.2012.01.018
    1. Weng L, Liu Y-tai, Du B, et al. . The prognostic value of left ventricular systolic function measured by tissue Doppler imaging in septic shock. Crit Care 2012;16:R71. 10.1186/cc11328
    1. Turner KL, Moore LJ, Todd SR, et al. . Identification of cardiac dysfunction in sepsis with B-type natriuretic peptide. J Am Coll Surg 2011;213:139–46. 10.1016/j.jamcollsurg.2011.03.027
    1. McLean AS, Huang SJ, Hyams S, et al. . Prognostic values of B-type natriuretic peptide in severe sepsis and septic shock. Crit Care Med 2007;35:1019–26. 10.1097/01.CCM.0000259469.24364.31
    1. Mokart D, Sannini A, Brun J-P, et al. . N-Terminal pro-brain natriuretic peptide as an early prognostic factor in cancer patients developing septic shock. Crit Care 2007;11:R37. 10.1186/cc5721
    1. Brueckmann M, Huhle G, Lang S, et al. . Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis. Circulation 2005;112:527–34. 10.1161/CIRCULATIONAHA.104.472050
    1. Vieillard-Baron A, Caille V, Charron C, et al. . Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 2008;36:1701–6. 10.1097/CCM.0b013e318174db05
    1. von Elm E, Altman DG, Egger M, et al. . The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;370:1453–7. 10.1016/S0140-6736(07)61602-X
    1. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372:793–5. 10.1056/NEJMp1500523

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit