Multiple organ dysfunction syndrome: exploring the paradigm of complex nonlinear systems
Abstract
OBJECTIVES: The objectives of this article are to introduce and explore a novel paradigm based on complex nonlinear systems, and to evaluate its application to critical care research regarding the systemic host response and multiple organ dysfunction syndrome (MODS). DATA SOURCES: Published original work, review articles, scientific abstracts and books, as well as our personal files. STUDY SELECTION: Studies were selected for their relevance to the applications of nonlinear complex systems, to critical care medicine, and to the concepts presented. DATA EXTRACTION: We extracted all applicable data. DATA SYNTHESIS: Following a brief review of MODS, an introduction to complex nonlinear systems is presented, including clear concepts, definitions, and properties. By examining the multiple, nonlinear, interrelated, and variable interactions between the metabolic, neural, endocrine, immune, and inflammatory systems; data regarding interconnected antibody networks; and the redundant, nonlinear, interdependent nature of the inflammatory response, we present the hypothesis that the systemic host response to trauma, shock, or sepsis must be evaluated as a complex nonlinear system. This model provides a new explanation for the failure of trials using various antimediator therapies in the treatment of patients with sepsis and MODS. Understanding the host response as a complex nonlinear system offers innovative means of studying critical care patients, specifically by suggesting a greater focus on systemic properties. We hypothesize that analysis of variability and connectivity of individual variables offer a novel means of evaluating and differentiating the systemic properties of a complex nonlinear system. Current applications of evaluating variability and connectivity are discussed, and insights regarding future research are offered. CONCLUSION: The paradigm offered by the study of complex nonlinear systems suggests new insights to pursue research to evaluate, monitor, and treat patients with MODS.
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The pathogenesis of gut-derived sepsis is multifactorial, replete with biological redundancy.
“the pathogenesis of gut-derived sepsis, like most processes in critical illness, is multifactorial, replete with biological redundancy.”
From The microbiome and critical illness (2016) · cites this paper as [107]
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Translational Systems Approaches to the Biology of Inflammation and Healing
Yoram Vodovotz, B., Constantine, G. M., Faeder, J. R., Mi, Q., Rubin, J. E., Bartels, J. D., Sarkar, J., Squires, R. H., Okonkwo, D. O., Gerlach, J. C., et al. (2010) · Immunopharmacology and Immunotoxicology · doi:10.3109/08923970903369867 · Cited by 77 · see citing works
The systemic implications of aneurysmal subarachnoid hemorrhage
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Norris, P. R., Stein, P. K., & Morris, J. A. (2007) · Journal of Critical Care · doi:10.1016/j.jcrc.2007.08.001 · Cited by 75 · see citing works
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Sanchez-Pinto, L. N., Stroup, E. K., Pendergrast, T. R., Pinto, N. P., & Luo, Y. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2020.9271 · Cited by 74 · see citing works
Glossary of terms and definitions
Sarginson, R. E., Taylor, N. F., & van Saene, H. K. F. (2001) · Current Anaesthesia and Critical Care · doi:10.1054/cacc.2001.0316 · Cited by 72 · see citing works
Fractal variability: An emergent property of complex dissipative systems
SEELY, A. J. E., & Macklem, P. T. (2012) · Chaos An Interdisciplinary Journal of Nonlinear Science · doi:10.1063/1.3675622 · Cited by 71 · see citing works
Self-citationDescribing organ dysfunction in the intensive care unit: a cohort study of 20,000 patients
Soo, A., Zuege, D. J., Fick, G. H., Niven, D. J., Berthiaume, L. R., Stelfox, H. T., & Doig, C. J. (2019) · Critical Care · doi:10.1186/s13054-019-2459-9 · Cited by 75 · see citing works
Does severe non-infectious SIRS differ from severe sepsis?
Dulhunty, J. M., Lipman, J., & Finfer, S. R. (2008) · Intensive Care Medicine · doi:10.1007/s00134-008-1160-2 · Cited by 70 · see citing works
An, G. C., Faeder, J. R., & Yoram Vodovotz, B. (2008) · Journal of Burn Care & Research · doi:10.1097/bcr.0b013e31816677c8 · Cited by 70 · see citing works
Papaioannou, V. E., Giannakou, M., Maglaveras, N., Sofianos, E., & Giala, M. (2007) · Journal of Critical Care · doi:10.1016/j.jcrc.2007.04.006 · Cited by 69 · see citing works
Papaioannou, V. E., Dragoumanis, C., Theodorou, V., Gargaretas, C., & Pneumatikos, I. A. (2009) · Journal of Critical Care · doi:10.1016/j.jcrc.2008.11.010 · Cited by 68 · see citing works
Schmidt, H., Hoyer, D., Hennen, R., Heinroth, K. M., Rauchhaus, M., Prondzinsky, R., Hottenrott, K., Buerke, M., Müller‐Werdan, U., & Werdan, K. (2008) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181653263 · Cited by 65 · see citing works
Venkatram, S. K., Rachmale, S., & Kanna, B. (2009) · Journal of Critical Care · doi:10.1016/j.jcrc.2009.06.016 · Cited by 67 · see citing works
Temperature Curve Complexity Predicts Survival in Critically Ill Patients
Varela, M. G., Churruca, J., González, A. L., Martin, A. D., Ode, J., & Galdós, P. (2006) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200601-058oc · Cited by 65 · see citing works
Papaioannou, V. E., Verkerk, A. O., Amin, A. S., & de Bakker, J. M. (2013) · Current Cardiology Reviews · doi:10.2174/157340313805076359 · Cited by 63 · see citing works
Papaioannou, V. E., Maglaveras, N., Houvarda, I., Antoniadou, E., & Vretzakis, G. I. (2006) · Journal of Critical Care · doi:10.1016/j.jcrc.2005.12.007 · Cited by 63 · see citing works
Prognostic impact of autonomic information flow in multiple organ dysfunction syndrome patients
Hoyer, D., Friedrich, H., Zwiener, U., Pompe, B., Baranowski, R., Werdan, K., Müller‐Werdan, U., & Schmidt, H. (2005) · International Journal of Cardiology · doi:10.1016/j.ijcard.2005.05.031 · Cited by 61 · see citing works
Variability Analysis and the Diagnosis, Management, and Treatment of Sepsis
Buchan, C. A., Bravi, A., & SEELY, A. J. E. (2012) · Current Infectious Disease Reports · doi:10.1007/s11908-012-0282-4 · Cited by 60 · see citing works
Self-citationMarkewitz, A., Lante, W., Franke, A., Marohl, K., Kuhlmann, W. D., & WEINHOLD, C. (2001) · Shock · doi:10.1097/00024382-200116001-00003 · Cited by 60 · see citing works
Endothelial cell dynamics and complexity theory
Aird, W. C. (2002) · Critical Care Medicine · doi:10.1097/00003246-200205001-00002 · Cited by 60 · see citing works
Embracing complexity in sepsis
Schuurman, A. R., Sloot, P. M. A., Wiersinga, W. J., & van der Poll, T. (2023) · Critical Care · doi:10.1186/s13054-023-04374-0 · Cited by 59 · see citing works
COMPLEX SYSTEMS ANALYSIS: A TOOL FOR SHOCK RESEARCH
Buchman, T. G., Cobb, P. J., Lapedes, A. S., & Kepler, T. B. (2001) · Shock · doi:10.1097/00024382-200116040-00002 · Cited by 59 · see citing works
Namas, R. A., Ghuma, A., Hermus, L., Zamora, R., Okonkwo, D., Billiar, T., & Yoram Vodovotz, B. (2008) · Libyan Journal of Medicine · doi:10.3402/ljm.v4i3.4824 · Cited by 59 · see citing works
An, G. C. (2006) · Journal of Critical Care · doi:10.1016/j.jcrc.2005.11.012 · Cited by 57 · see citing works
Sepsis, Severe Sepsis, and Septic Shock
Munford, R. S., & Suffredini, A. F. (2010) · Elsevier eBooks · doi:10.1016/b978-0-443-06839-3.00070-9 · Cited by 55 · see citing works
Sturmberg, J. P., Bennett, J. M., Picard, M. A., & SEELY, A. J. E. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00169 · Cited by 53 · see citing works
Self-citationModeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia
Scheff, J. D., Mavroudis, P. D., Calvano, S. E., Lowry, S. F., & Androulakis, I. P. (2011) · Physiological Genomics · doi:10.1152/physiolgenomics.00040.2011 · Cited by 53 · see citing works
Lundelin, K. J., Vigil, L., Bua, S., Gomez-Mestre, I., Honrubia, T., & Varela, M. G. (2010) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181ce49cf · Cited by 52 · see citing works
Practical Applications in Biomedical Engineering
Andrade, A. O., Alves Pereira, A., Naves, E. L. M., & Soares, A. B. (2013) · InTech eBooks · doi:10.5772/3331 · Cited by 52 · see citing works
Multiscale, multiorgan and multivariate complexity analyses of cardiovascular regulation
Cerutti, S., Hoyer, D., & Voss, A. (2009) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2008.0267 · Cited by 50 · see citing works
Alam, M., Deng, X., Philipson, C. W., Bassaganya-Riera, J., Bisset, K. R., Carbo, A., Eubank, S., Hontecillas, R., Hoops, S., Mei, Y., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136139 · Cited by 50 · see citing works
Yoram Vodovotz, B., Clermont, G., Hunt, C. A., Lefering, R. L., Bartels, J. D., Seydel, R., Hotchkiss, J. R., Ta’asan, S., Neugebauer, E. A. M., & An, G. C. (2007) · Journal of Critical Care · doi:10.1016/j.jcrc.2006.12.001 · Cited by 49 · see citing works
Fan, X., Zhu, J., Sun, Y., Luo, L., Yan, J., Yang, X., Yu, J. H., Tang, W., Ma, W., & Liang, H. (2017) · Inflammation · doi:10.1007/s10753-017-0546-0 · Cited by 49 · see citing works
Multiscale model for the assessment of autonomic dysfunction in human endotoxemia
Foteinou, P. T., Calvano, S. E., Lowry, S. F., & Androulakis, I. P. (2010) · Physiological Genomics · doi:10.1152/physiolgenomics.00184.2009 · Cited by 45 · see citing works
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Translational Potential of Systems‐Based Models of Inflammation
Foteinou, P. T., Calvano, S. E., Lowry, S. F., & Androulakis, I. P. (2008) · Clinical and Translational Science · doi:10.1111/j.1752-8062.2008.00051.x · Cited by 42 · see citing works
Complexity, chaos, and incomprehensibility: Parsing the biology of critical illness
Marshall, J. C. (2000) · Critical Care Medicine · doi:10.1097/00003246-200007000-00080 · Cited by 42 · see citing works
Bradley, B. D., Green, G. C., Ramsay, T., & SEELY, A. J. E. (2012) · Critical Care Medicine · doi:10.1097/ccm.0b013e31826a47de · Cited by 41 · see citing works
Self-citationAnalysis of heart rate variability as an index of noncardiac surgical stress
Ushiyama, T., Mizushige, K., Wakabayashi, H., Nakatsu, T., Ishimura, K., Tsuboi, Y., Maeta, H., & Suzuki, Y. (2008) · Heart and Vessels · doi:10.1007/s00380-007-0997-6 · Cited by 41 · see citing works
Early Asymmetric Cardio-Cerebral Causality and Outcome after Severe Traumatic Brain Injury
Gao, L., Smielewski, P., Czosnyka, M., & Ercole, A. (2017) · Journal of Neurotrauma · doi:10.1089/neu.2016.4787 · Cited by 40 · see citing works
The Alteration of Autonomic Function in Multiple Organ Dysfunction Syndrome
Schmidt, H., Hoyer, D., Wilhelm, J., Söffker, G., Heinroth, K. M., Hottenrott, K., Said, S. M., Buerke, M., Müller‐Werdan, U., & Werdan, K. (2008) · Critical Care Clinics · doi:10.1016/j.ccc.2007.10.003 · Cited by 40 · see citing works
The plasma metabolome of women in early pregnancy differs from that of non-pregnant women
Handelman, S. K., Romero, R. J., Tarca, A. L., Pacora, P., Ingram, B. O., Maymon, E., Chaiworapongsa, T., Hassan, S. S., & Erez, O. (2019) · PLoS ONE · doi:10.1371/journal.pone.0224682 · Cited by 38 · see citing works
Is Severe Sepsis a Neuroendocrine Disease?
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Jit, M. (2004) · British journal of rheumatology · doi:10.1093/rheumatology/keh491 · Cited by 37 · see citing works
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Embracing the Certainty of Uncertainty: Implications for Health Care and Research
Seely, A. J. E. (2013) · Perspectives in Biology and Medicine · doi:10.1353/pbm.2013.0009 · Cited by 36 · see citing works
Self-citationImplications of complexity theory for clinical practice and healthcare organization
Tuffin, R. (2016) · BJA Education · doi:10.1093/bjaed/mkw013 · Cited by 36 · see citing works
Estimation of Complexity of Sampled Biomedical Continuous Time Signals Using Approximate Entropy
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Chaos, Fractals, and Our Concept of Disease
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The role of astrocytes and microglia in persistent pain
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Organ dysfunction and mortality risk factors in severe canine bite wound trauma
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Green, G. C., Bradley, B. D., Bravi, A., & SEELY, A. J. E. (2013) · Journal of Critical Care · doi:10.1016/j.jcrc.2013.04.001 · Cited by 33 · see citing works
Self-citationThe sick euthyroid syndrome in paediatric cardiac surgery patients
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The Protective Role of Curcumin in Zymosan-Induced Multiple Organ Dysfunction Syndrome in Mice
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Jacono, F. J., Georgia, M. A. D., Wilson, C. G., Dick, T. E., & Loparo, K. A. (2010) · Journal of Healthcare Engineering · doi:10.1260/2040-2295.1.3.337 · Cited by 32 · see citing works
- Authors
- Seely, A. J. E., & Christou, N. V.
- Affiliations
- McGill University Health Centre (CA)
- ORCID
- Seely, Andrew J. E.
- Venue
- Critical Care Medicine
- Published
- 2000-07
- Volume
- 28
- Issue
- 7
- Pages
- 2193-2200
- ISSN
- 0090-3493 (ISSN-L)
- OpenAlex
- W2028553295
- Cited by
- 287
- References
- 59
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 9 · 2019: 8 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 14 · 2014: 9 · 2013: 18 · 2012: 16
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Physical Sciences › Physics and Astronomy › Statistical and Nonlinear Physics › Complex Systems and Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- multiple organ failure, complex nonlinear systems, sepsis, shock, trauma (physical injury), inflammation, intensive care monitoring
- MeSH terms
- Critical Care, Heart Rate, Humans, Multiple Organ Failure, Nonlinear Dynamics
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