## 4 Conclusions and Discussion
Surprisingly, exercise caused the minimal amount of plasma volume to be removed. Sensitivity analysis, using partial ranked correlation coefficients, permitted ranking of model parameters. Among the large number of model parameters, a handful emerged to be the most relevant (Figure 11). Identifying the parametric regulation of outputs will permit future development of the model mechanisms. As expected, the baroreflex control (represented by parameter G) regulates multiple model outputs of interest. Furthermore, the sensitivity of the model to baroreflex control appears to be reduced significantly by TH. The sensitivity of blood vessel shear also appears to be affected by the right ventricle elastance, as well as peripheral resistances (splanchnic and upper body). Limitations: The present model is primed for further development. Implementation of detailed organ level vasculature representations of cerebral [46], hepatic [47], pulmonary-respiratory [48], cardio-pulmonary [49], and other will better complement future clinical-modelling studies. Future inclusion of myogenic hemodynamic regulation [35; 50] will extend the spectrum of phenomena explored [51] and further refine the presented results. In addition to baroreflex control, vascular tone is known to be significantly regulated by renal function. The inclusion of biochemical mechanisms of gas exchange and metabolism [52; 53] will extend the model to permit drug testing, in addition to the presently tested physical therapy of TH. The inclusion of biochemical mechanisms is particularly relevant as we will extend our descriptions of organs as well as the dialyzer as an artificial kidney. The model will be extended to simulate ionic regulation of vascular tone [54; 55; 56]. Whereasthe presented dialyzer affects blood composition, the known effect that the dialyzer also affects the circulation [57] remains to be incorporated into the model. Complementary to phenomenological hemodynamics, a significant proportion of mechanisms at tissue and cellular levels are expected to be valuable in our future modelling-clinical-imaging approach. We are currently constructing multiscale cell to vasculature models driven by current understanding (e.g., see [54]) that will assist the dissection of pathophysiological disease mechanisms and pharmacological targets. The mechanisms and pathways of widespread sepsis infections during HD could be further illuminated using the multi-scale models [58]. Whereas the presented model incorporates parametric information representing specific patients (either dialyzed, hypothermia, atrial fibrillation, or exercised), the simulations may generate generic than specific populations as experimental data was unavailable to the study. In depth disease specific parameter identification using data along with improved population generating methods [59; 60] may provide better insights in our future studies. Doing so will inevitably permit uncovering of mechanisms and assist to make novel predictions. Often, the simulation of patient populations is driven by known parameter variability as well as inter-parameter independence [59; 61; 62]. While neither have been considered in this study, each of our populations encompasses a wide range of parameters representing inter-patient variability. Due to model limitations, the model may generate somewhat unrealistic and qualitative results. However, we believe that our results will largely remain valid in light of future model development. Summary of conclusions: To summarize, while HD, AF, and renal failure appear to be deleterious, TH and exercise may provide some benefit to the patient (Figure 1). We found that HD and AF give rise to undesirable augmentation of wall shear stress which may increase vascular inflammation. TH and exercise treatments may reduce the inflammation by reducing wall shear stress, and may also improve HD efficacy. However, microvascular disease such as renal failure may blunt the effectiveness of TH and exercise treatments.