Blood levels of macrophage migration inhibitory factor after successful resuscitation from cardiac arrest

Christian Stoppe, Michael Fries, Rolf Rossaint, Gerrit Grieb, Mark Coburn, David Simons, David Brücken, Jürgen Bernhagen, Norbert Pallua, Steffen Rex, Christian Stoppe, Michael Fries, Rolf Rossaint, Gerrit Grieb, Mark Coburn, David Simons, David Brücken, Jürgen Bernhagen, Norbert Pallua, Steffen Rex

Abstract

Introduction: Ischemia-reperfusion injury following cardiopulmonary resuscitation (CPR) is associated with a systemic inflammatory response, resulting in post-resuscitation disease. In the present study we investigated the response of the pleiotropic inflammatory cytokine macrophage migration inhibitory factor (MIF) to CPR in patients admitted to the hospital after out-of-hospital cardiac arrest (OHCA). To describe the magnitude of MIF release, we compared the blood levels from CPR patients with those obtained in healthy volunteers and with an aged- and gender-matched group of patients undergoing cardiac surgery with the use of extracorporeal circulation.

Methods: Blood samples of 17 patients with return of spontaneous circulation (ROSC) after OHCA were obtained upon admission to the intensive care unit, and 6, 12, 24, 72 and 96 h later. Arrest and treatment related data were documented according to the Utstein style.

Results: In patients after ROSC, MIF levels at admission (475.2±157.8 ng/ml) were significantly higher than in healthy volunteers (12.5±16.9 ng/ml, p<0.007) and in patients after cardiac surgery (78.2±41.6 ng/ml, p<0.007). Six hours after admission, MIF levels were decreased by more than 50% (150.5±127.2 ng/ml, p<0.007), but were not further reduced in the subsequent time course and remained significantly higher than the values observed during the ICU stay of cardiac surgical patients. In this small group of patients, MIF levels could not discriminate between survivors and non-survivors and were not affected by treatment with mild therapeutic hypothermia.

Conclusion: MIF shows a rapid and pronounced increase following CPR, hence allowing a very early assessment of the inflammatory response. Further studies are warranted in larger patient groups to determine the prognostic significance of MIF.

Trial registration: ClinicalTrials.gov NCT01412619.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Comparison of MIF levels in…
Figure 1. Comparison of MIF levels in patients after ROSC with those obtained in patients after cardiac surgery.
Values are represented as mean ±SD at predefined timepoints after succesful CPR. MIF levels of healthy volunteers are additionally depicted at the time point “admission". * p<0.007 vs. baseline. § p<0.007 vs patients after ROSC. # p<0.007 vs. group of healthy volunteers.
Figure 2. Serum levels of MIF, TNF-α,…
Figure 2. Serum levels of MIF, TNF-α, IL-6 and CRP after admission to the ICU and 6, 24, 72 and 120 hours later.
* p

Figure 3. MIF serum levels in patients…

Figure 3. MIF serum levels in patients who recieved MTH in comparison with normothermically treated…

Figure 3. MIF serum levels in patients who recieved MTH in comparison with normothermically treated patients.
Values are represented as mean ±SD at predefined timepoints after succesful CPR.

Figure 4. MIF serum levels in survivors…

Figure 4. MIF serum levels in survivors and non-survivors.

Values are represented as mean ±…

Figure 4. MIF serum levels in survivors and non-survivors.
Values are represented as mean ±SD at predefined timepoints after succesful CPR.
Figure 3. MIF serum levels in patients…
Figure 3. MIF serum levels in patients who recieved MTH in comparison with normothermically treated patients.
Values are represented as mean ±SD at predefined timepoints after succesful CPR.
Figure 4. MIF serum levels in survivors…
Figure 4. MIF serum levels in survivors and non-survivors.
Values are represented as mean ±SD at predefined timepoints after succesful CPR.

References

    1. Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 2004;30:2126–8.
    1. Fries M, Kunz D, Gressner AM, Rossaint R, Kuhlen R. Procalcitonin serum levels after out-of-hospital cardiac arrest. Resuscitation. 2003;59:105–109.
    1. Fries M, Stoppe C, Brücken D, Rossaint R, Kuhlen R. Influence of mild therapeutic hypothermia on the inflammatory response after successful resuscitation from cardiac arrest. J Crit Care. 2009;24:453–7.
    1. Laurent I, Monchi M, Chiche JD, Joly LM, Spaulding C, et al. Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol. 2002;40:2110–2116.
    1. Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 2008;118:2452–83.
    1. Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like" syndrome. Circulation. 2002;106:562–8.
    1. Fink K, Schwarz M, Feldbrügge L, Bourgeois N, Helbing T, et al. Severe endothelial injury and subsequent repair in patients after successful cardiopulmonary resuscitation. Crit Care. 2010;14:R104.
    1. Gando S, Nanzaki S, Morimoto Y, Kobayashi S, Kemmotsu O. Out-of-hospital cardiac arrest increases soluble vascular endothelial adhesion molecules and neutrophil elastase associated with endothelial injury. Intensive Care Med. 2000;26:38–44.
    1. Kim JJ, Hyun SY, Hwang SY, Jung YB, Shin JH, et al. Hormonal responses upon return of spontaneous circulation after cardiac arrest: a retrospective cohort study. Crit Care. 2011;15:R53.
    1. Beiser DG, Carr GE, Edelson DP, Peberdy MA, Hoek TL. Derangements in blood glucose following initial resuscitation from in-hospital cardiac arrest: a report from the national registry of cardiopulmonary resuscitation. Resuscitation. 2009;80:624–30.
    1. Trzeciak S, Jones AE, Kilgannon JH, Milcarek B, Hunter K, et al. Significance of arterial hypotension after resuscitation from cardiac arrest. Crit Care Med. 2009;37:2895–903.
    1. Negovsky VA, Gurvitch AM. Post-resuscitation disease-a new nosological entity. Its reality and significance. Resuscitation. 1995;30:23–7.
    1. Nolan JP, Soar J, Zideman DA, Biarent D, Bossaert LL, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation. 2010;81:1219–76.
    1. Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, et al. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care. 2004;10:208–12.
    1. Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003;3:791–800.
    1. Simons D, Grieb G, Hristov M, Pallua N, Weber C, et al. Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment. J Cell Mol Med. 2011;15:668–78.
    1. Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med. 1994;179:1895–902.
    1. Zernecke A, Bernhagen J, Weber C. Macrophage migration inhibitory factor in cardiovascular disease. Circulation. 2008;117:1594–602.
    1. Noels H, Bernhagen J, Weber C. Macrophage migration inhibitory factor: a noncanonical chemokine important in atherosclerosis. Trends Cardiovasc Med. 2009;19:76–86.
    1. Morand EF, Leech M, Bernhagen J. MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. Nat Rev Drug Discov. 2006;5:399–410.
    1. Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med. 2000;6:164–170.
    1. Chagnon F, Metz CN, Bucala R, Lesur O. Endotoxin- induced myocardial dysfunction: effects of macrophage migration inhibitory factor neutralization. Circ Res. 2005;96:1095–1102.
    1. Sakuragi T, Lin X, Metz CN, Ojamaa K, Kohn N, et al. Lung-derived macrophage migration inhibitory factor in sepsis induces cardio-circulatory depression. Surg Infect (Larchmt) 2007;8:29–40.
    1. Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature. 1995;377:68–71.
    1. de Mendonça-Filho HT, Pereira KC, Fontes M, Vieira DA, de Mendonça ML, et al. Circulating inflammatory mediators and organ dysfunction after cardiovascular surgery with cardiopulmonary bypass: a prospective observational study. Crit Care. 2006;10:46.
    1. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007;2007; 13:587–96.
    1. Miller EJ, Li J, Leng L, McDonald C, Atsumi T, et al. Macrophage migration inhibitory factor stimu- lates AMP-activated protein kinase in the ischaemic heart. Nature. 2008;451:578–582.
    1. Qi D, Hu X, Wu X, Merk M, Leng L, et al. Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/ reperfusion. J Clin Invest. 2009;119:3807–3816.
    1. Derwall M, Stoppe C, Brücken D, Rossaint R, Fries M. Changes in S-100 protein serum levels in survivors of out-of-hospital cardiac arrest treated with mild therapeutic hypothermia: a prospective, observational study. Crit Care. 2009;13:R58.
    1. Nolan JP, Deakin CD, Soar J, Bottiger BW, Smith G. European Resuscitation Council guidelines for resuscitation 2005. Section 4. Adult advanced life support. Resuscitation. 2005;67(Suppl 1):S39–86.
    1. Cummins RO, Chamberlain D, Hazinski MF, Nadkarni V, Kloeck W, et al. Recommended guidelines for reviewing, reporting, and conducting research on in- hospital resuscitation; The in-hospital ‘Utstein style’; a statement for healthcare professionals from the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Australian Resuscitation Council, and the Resuscitation Councils of South Africa. Circulation. 1997;95:2213–39.
    1. Safar P. Resuscitation after Brain Ischemia. In: Grenvik A, Safar P, editors. Brain Failure and Resuscitation. New York: Churchill Livingstone; 1981. pp. 155–184.
    1. Grieb G, Simons D, Piatkowski A, Bernhagen J, Steffens G, et al. Macrophage migration inhibitory factor-A potential diagnostic tool in severe burn injuries? Burns. 2010;36:335–42.
    1. Stoppe C, Schälte G, Rossaint R, Coburn M, Graf B, et al. The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients. Crit Care Med. 2011;39:1879–85.
    1. Leng L, Metz CN, Fang Y, Xu J, Donnelly S, et al. MIF signal transduction initiated by binding to CD74. J Exp Med. 2003;197:1467–76.
    1. Bernhagen J, Mitchell RA, Calandra T, Voelter W, Cerami A, et al. Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry. 1994;33:14144–55.
    1. Roger T, David J, Glauser M, Calandra T. MIF regulates innate immune responses through modulation of Toll-like receptor-4. Nature. 2001;414:920–4.
    1. Yende S, Angus DC, Kong L, Kellum JA, Weissfeld L, et al. The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia. FASEB J. 2009;23:2403–11.
    1. Gando S, Nishihira J, Kobayashi S, Morimoto Y, Nanzaki S, et al. Macrophage migration inhibitory factor is a critical mediator of systemic inflammatory response syndrome. Intensive Care Med. 2001;27:1187–1193.
    1. Merk M, Zierow S, Leng L, Das R, Du X, et al. The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). Proc Natl Acad Sci USA. 2011;108:E577–85.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever