Organ system network analysis and biological stability in critically ill patients

Abstract

BackgroundContinuous coordination among organ systems is necessary to maintain biological stability in humans. Organ system network analysis in addition to organ-oriented medicine is expected to improve patient outcomes. However, organ system networks remain beyond clinical application with little evidence for their importance on homeostatic mechanisms. This proof-of-concept study examined the impact of organ system networks on systemic stability in severely ill patients.MethodsPatients admitted to the intensive care unit of the University of Tokyo Hospital with one representative variable reflecting the condition of each of the respiratory, cardiovascular, renal, hepatic, coagulation, and inflammatory systems were enrolled. Relationships among the condition of individual organ systems, inter-organ connections, and systemic stability were evaluated between non-survivors and survivors whose organ system conditions were matched to those of the non-survivors (matched survivors) as well as between non-survivors and all survivors. We clustered these six organ systems using principal component analysis and compared the dispersion of the principal component scores of each cluster using the Ansari-Bradley test to evaluate systemic stability involving multiple organ systems. Inter-organ connections were evaluated using Spearman’s rank test.ResultsAmong a total of 570 enrolled patients, 91 patients died. The principal component analysis yielded the respiratory-renal-inflammatory and cardiovascular-hepatic-coagulation system clusters. In the respiratory-renal-inflammatory cluster, organ systems were connected in both the survivors and the non-survivors. The principal component scores of the respiratory-renal-inflammatory cluster were dispersed similarly (stable cluster) in the non-survivors, the matched survivors, and the total survivors irrespective of the severity of individual organ system dysfunction. Conversely, in the cardiovascular-hepatic-coagulation cluster, organ systems were connected only in the survivors, and the principal component scores of the cluster were significantly dispersed (unstable cluster) in the non-survivors compared to the total survivors (P = 0.002) and the matched survivors (P = 0.004).ConclusionsThis study demonstrated that systemic instability was closely associated with network disruption among organ systems irrespective of their dysfunction severity. Organ system network analysis is necessary to improve outcomes in severely ill patients.Electronic supplementary materialThe online version of this article (10.1186/s13054-019-2376-y) contains supplementary material, which is available to authorized users.

Organ System Network Disruption Is Associated With Poor Prognosis in Patients With Chronic Liver Failure

“…These findings support the hypothesis that decreased organ system interaction is associated with poor prognosis in chronic liver failure. Our findings also continue to support previous studies suggesting that systemic dysfunction in acute life-threatening pathophysiology with multisystem involvement is attributed to a loss of homeostatic interorgan connectivity ( Buchman, 2002 ; Chovatiya and Medzhitov, 2014 ), most notably in the recent studies published by Asada et al (2016 , 2019) . Although our study explores multisystem disease of a chronic nature, the characteristics associated with poor prognosis in non-survivors remain similar, namely the breakdown of organ system connectivity, loss of homeostatic stability and isolation of individual organ system clusters.…”

“…The presence of highly interlinked central clusters observed in the network maps of survivors reflects successful homeostatic organ system connectivity, yet this is unlikely to be seen in normal, healthy people as increased organ system connectivity has been established as a compensatory mechanism to maintain homeostatic stability in preventing mortality during life-threatening illness (Gabay and Kushner, 1999;Asada et al, 2019). In fact, the network structures observed may indeed be a reflection of overcompensation, the same way the fight or flight reaction is all or nothing.…”

“…SIRS is hence characteristically observed in decompensated cirrhosis patients regardless of the presence of bacterial infection and is further associated with complications including hepatic encephalopathy and variceal bleeding (Shawcross et al, 2004;Thabut et al, 2007;Cazzaniga et al, 2009). SIRS acts in the capacity of a compensatory mechanism in maintaining systemic stability in the presence of other dysfunctional systems against life threatening illness (Gabay and Kushner, 1999;Asada et al, 2019).…”

“…These include C-reactive protein (CRP), serum albumin, total bilirubin, prothrombin time, international normalised ratio (INR), ammonia, hemoglobin, serum creatinine, serum sodium, ascites and hepatic encephalopathy. Hepatic encephalopathy was classified as (0) unimpaired: no clinical evidence of hepatic encephalopathy and no defining EEG or psychometric abnormalities; (1) minimal hepatic encephalopathy: no clinical evidence of hepatic encephalopathy but abnormal EEG and/or impaired psychometric performance; and (2) overt hepatic encephalopathy: clinically evident neuropsychiatric disturbances (Asada et al, 2019). An addition of the MELD-Na (Elwir and Lake, 2016) and Child-Pugh (Child and Turcotte, 1964;Pugh et al, 1973) scores were calculated.…”

“…Such a network physiology approach for the early detection of critical illnesses facilitated by big data and novel analytic and computational approaches has merit and is encouraging, even in light of limitations ( Moorman et al, 2016 ). More recently, Asada et al (2019) followed up exploring the differences in connectivity between specific organ system clusters in critically ill patients. These include the respiratory-renal-inflammatory system cluster and the cardiovascular-hepatic-coagulation system cluster.…”