Background: Even with the use of extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS), mortality remains
high. Also, prognostication of patients with ARDS and ECMO is difficult.
Cytokines are thought to be markers of inflammation in both ARDS and in ECMO, however, understanding is limited. We aimed to study the association of three
serum cytokine levels with mortality in these patients with ARDS on ECMO. Methods: We performed a retrospective chart review of ARDS patients on ECMO between 2011 and 2017. Patients with serum TNF-α,
IL-6 and IL-2 measured while on ECMO were included, with measurements recorded
weekly up to a maximum of 4 measurements. A multivariable regression analysis
was performed and generalizing estimating equations were used to analyze longitudinal
trend of cytokines with mortality. Results: There were 47 patients with
ARDS on ECMO, of which 31 (68.9%) survived at 30 days and 2 were lost to follow
up. Initial IL-2 levels were found to be significantly higher among those who
were alive compared to those who died at 30 days (2720 ± 2432 pg/ml vs.
References
[1]
Petty, T.L. (2001) In the Cards Was ARDS: How We Discovered the Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine, 163, 602-603. https://doi.org/10.1164/ajrccm.163.3.16331
[2]
Bellani, G., Laffey, J.G., Pham, T., Fan, E., Brochard, L., Esteban, A., et al. (2016) Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA, 315, 788-800.
https://doi.org/10.1001/jama.2016.0291
[3]
Dolinay, T., Kim, Y.S., Howrylak, J., Hunninghake, G.M., An, C.H., Fredenburgh, L., et al. (2012) Inflammasome-Regulated Cytokines Are Critical Mediators of Acute Lung Injury. American Journal of Respiratory and Critical Care Medicine, 185, 1225-1234. https://doi.org/10.1164/rccm.201201-0003OC
[4]
Papazian, L., Aubron, C., Brochard, L., Chiche, J.D., Combes, A., Dreyfuss, D., et al. (2019) Formal Guidelines: Management of Acute Respiratory Distress Syndrome. Annals of Intensive Care, 9, Article No. 69.
https://doi.org/10.1186/s13613-019-0540-9
[5]
Awsare, B., Herman, J. and Baram, M. (2017) Management Strategies for Severe Respiratory Failure: As Extracorporeal Membrane Oxygenation Is Being Considered. Critical Care Clinics, 33, 795-811. https://doi.org/10.1016/j.ccc.2017.06.003
[6]
Protti, A., Andreis, D.T., Monti, M., Santini, A., Sparacino, C.C., Langer, T., et al. (2013) Lung Stress and Strain during Mechanical Ventilation: Any Difference between Statics and Dynamics? Critical Care Medicine, 41, 1046-1055.
https://doi.org/10.1097/CCM.0b013e31827417a6
[7]
Brodie, D. and Bacchetta, M. (2011) Extracorporeal Membrane Oxygenation for ARDS in Adults. New England Journal of Medicine, 365, 1905-1914.
https://doi.org/10.1056/NEJMct1103720
[8]
Clark, J.B., Wang, S., Palanzo, D.A., Wise, R., Baer, L.D., Brehm, C., et al. (2015) Current Techniques and Outcomes in Extracorporeal Life Support. Artificial Organs, 39, 926-930. https://doi.org/10.1111/aor.12527
[9]
Davies, M.G. and Hagen, P.O. (1997) Systemic Inflammatory Response Syndrome. The British Journal of Surgery, 84, 920-935. https://doi.org/10.1002/bjs.1800840707
[10]
Tomic, V., Russwurm, S., Moller, E., Claus, R.A., Blaess, M., Brunkhorst, F., et al. (2005) Transcriptomic and Proteomic Patterns of Systemic Inflammation in On-Pump and Off-Pump Coronary Artery Bypass Grafting. Circulation, 112, 2912-2920.
https://doi.org/10.1161/CIRCULATIONAHA.104.531152
[11]
Chew, M.S., Brandslund, I., Brix-Christensen, V., Ravn, H.B., Hjortdal, V.E., Pedersen, J., et al. (2001) Tissue Injury and the Inflammatory Response to Pediatric Cardiac Surgery with Cardiopulmonary Bypass: A Descriptive Study. Anesthesiology, 94, 745-753. https://doi.org/10.1097/00000542-200105000-00010
[12]
Thangappan, K., Cavarocchi, N.C., Baram, M., Thoma, B. and Hirose, H. (2016) Systemic Inflammatory Response Syndrome (SIRS) after Extracorporeal Membrane Oxygenation (ECMO): Incidence, Risks and Survivals. Heart & Lung, 45, 449-453.
https://doi.org/10.1016/j.hrtlng.2016.06.004
[13]
Plotz, F.B., van Oeveren, W., Bartlett, R.H. and Wildevuur, C.R. (1993) Blood Activation during Neonatal Extracorporeal Life Support. The Journal of Thoracic and Cardiovascular Surgery, 105, 823-832.
https://doi.org/10.1016/S0022-5223(19)34156-X
[14]
Risnes, I., Wagner, K., Ueland, T., Mollnes, T., Aukrust, P. and Svennevig, J. (2008) Interleukin-6 May Predict Survival in Extracorporeal Membrane Oxygenation Treatment. Perfusion, 23, 173-178. https://doi.org/10.1177/0267659108097882
[15]
Nelson, B.H. (2004) IL-2, Regulatory T Cells, and Tolerance. Journal of Immunology, 172, 3983-3988. https://doi.org/10.4049/jimmunol.172.7.3983
[16]
Ye, C., Brand, D. and Zheng, S.G. (2018) Targeting IL-2: An Unexpected Effect in Treating Immunological Diseases. Signal Transduction and Targeted Therapy, 3, Article No. 2. https://doi.org/10.1038/s41392-017-0002-5
[17]
D’Alessio, F.R., Tsushima, K., Aggarwal, N.R., West, E.E., Willett, M.H., Britos, M.F., et al. (2009) CD4+ CD25+ Foxp3+ Tregs Resolve Experimental Lung Injury in Mice and Are Present in Humans with Acute Lung Injury. Journal of Clinical Investigation, 119, 2898-2913. https://doi.org/10.1172/JCI36498
[18]
Matthay, M.A., Ware, L.B. and Zimmerman, G.A. (2012) The Acute Respiratory Distress Syndrome. Journal of Clinical Investigation, 122, 2731-2740.
https://doi.org/10.1172/JCI60331
[19]
He, J., Zhang, X., Wei, Y., Sun, X., Chen, Y., Deng, J., et al. (2016) Low-Dose Interleukin-2 Treatment Selectively Modulates CD4+ T Cell Subsets in Patients with Systemic Lupus Erythematosus. Nature Medicine, 22, 991-993.
https://doi.org/10.1038/nm.4148
[20]
Koreth, J., Matsuoka, K., Kim, H.T., McDonough, S.M., Bindra, B., Alyea, E.P., et al. (2011) Interleukin-2 and Regulatory T Cells in Graft-versus-Host Disease. The New England Journal of Medicine, 365, 2055-2066.
https://doi.org/10.1056/NEJMoa1108188
[21]
Saadoun, D., Rosenzwajg, M., Joly, F., Six, A., Carrat, F., Thibault, V., et al. (2011) Regulatory T-Cell Responses to Low-Dose Interleukin-2 in HCV-Induced Vasculitis. The New England Journal of Medicine, 365, 2067-2077.
https://doi.org/10.1056/NEJMoa1105143
[22]
Calfee, C.S., Delucchi, K., Parsons, P.E., Thompson, B.T., Ware, L.B. and Matthay, M.A. (2014) Subphenotypes in Acute Respiratory Distress Syndrome: Latent Class Analysis of Data from Two Randomised Controlled Trials. The Lancet Respiratory Medicine, 2, 611-620. https://doi.org/10.1016/S2213-2600(14)70097-9
[23]
Millar, J.E., Fanning, J.P., McDonald, C.I., McAuley, D.F. and Fraser, J.F. (2016) The Inflammatory Response to Extracorporeal Membrane Oxygenation (ECMO): A Review of the Pathophysiology. Critical Care (London, England), 20, 387.
https://doi.org/10.1186/s13054-016-1570-4
[24]
Mukhopadhyay, S., Hoidal, J.R. and Mukherjee, T.K. (2006) Role of TNFα in Pulmonary Pathophysiology. Respiratory Research, 7, Article No. 125.
https://doi.org/10.1186/1465-9921-7-125
[25]
Xing, Z., Gauldie, J., Cox, G., Baumann, H., Jordana, M., Lei, X.F., et al. (1998) IL-6 Is an Antiinflammatory Cytokine Required for Controlling Local or Systemic Acute Inflammatory Responses. Journal of Clinical Investigation, 101, 311-320.
https://doi.org/10.1172/JCI1368
[26]
Fattori, E., Cappelletti, M., Costa, P., Sellitto, C., Cantoni, L., Carelli, M., et al. (1994) Defective Inflammatory Response in Interleukin 6-Deficient Mice. Journal of Experimental Medicine, 180, 1243-1250. https://doi.org/10.1084/jem.180.4.1243
[27]
Goodman, R.B., Strieter, R.M., Martin, D.P., Steinberg, K.P., Milberg, J.A., Maunder, R.J., et al. (1996) Inflammatory Cytokines in Patients with Persistence of the Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine, 154, 602-611. https://doi.org/10.1164/ajrccm.154.3.8810593
[28]
Opal, S.M. and Cross, A.S. (1999) Clinical Trials for Severe Sepsis. Past Failures, and Future Hopes. Infectious Disease Clinics of North America, 13, 285-297.
https://doi.org/10.1016/S0891-5520(05)70075-1
