## 4 Conclusions and Discussion  
A model that combined whole body circulation with detailed kidneys representation, along with baroreflex control and dialysis unit was developed. While the present model derives from previous developments by others [21; 30; 31; 42], this work used it in assessing a novel therapy (therapeutic hypothermia) pertinent to our clinical research. As seen in Figure 3, our implementation is capable of qualitatively reproducing flow-pressure waveforms [43], in addition to providing difficult to measure information such as shear as well as population wide expectation. Figure 11: Sensitivity of clinically relevant model outputs to parameters. In all panels, \(\mathrm{E_{dis,rv}}\) represents diastolic right ventricle elastance; \(\mathrm{E_{sys,rv}}\) represents systolic right ventricle elastance; IHR represents intrinsic heart rate; \(\mathrm{R_{up1}}\) represents upper body resistance; G represents baroreflex regulatory parameter; \(\mathrm{R_{spl}}\) represents splanchnic resistance; \(\mathrm{R_{lll}}\) represents legs resistance; \(\mathrm{C_{a}}\) represents aorta compliance; \(\mathrm{R_{inlet}}\) represents kidney inlet resistance. In line with our clinical observations, the model suggests that HD augments cardiac output, heart rate, as well as shear stress (Figure 4). While HD induced augmentation of heart rates and shears may be undesirable side effects [44], TH appears to impart benefit by reducing heart rates and normalizing vascular shear stress, in agreement with clinical finding [45]. It can be appreciated that the normalized wall shear stress is a direct result of vascular diameter reduction (Equation (1)) leading to an augmented microvascular increase in resistance while cardiac output reduces to a certain extent. Atrial fibrillation (AF) is a prevalent condition among critically ill patients such as those with renal failure. The presented model suggests that AF potentially exacerbates the HD induced augmentation of heart rate (Figure 5B) and lowers blood pressure (Figure 5C,D). Therapeutic hypothermia neither reduced the HD induced heart rate increase, nor did it reverse the HD induced lowered blood pressure. However, the model does suggest that shear stress in blood vessels, due to its lower intra-population heterogeneity, is strongly linked to underlying AF. The simulated AF had a marginal effect on model behaviour, an observation that is aligned with the findings of [PERSON] et al. [37]. The benefit of TH under AF conditions appears to be reduction of both shear stress and intra-population heterogeneity. The modelled exercise conditions (Figure 6) increased cardiac outputs but beneficially lowered systolic blood pressure. TH imparts further benefit under exercise by primarily in reducing large vessel (aortic) as well as small vessel (renal) shear, which may provide hemodynamic stability. Within the confines of the model, renal resistance appears to affect renal flow more than renal compliance (Figures 7 and 8). The present findings are aligned with our previous findings [14] where large vessel compliance and small vessel resistance was found to affect overall whole body hemodynamics. Our recent clinical observations in renal failure patients show that dialysis increased blood flow heterogeneity in visceral organs, while therapeutic hypothermia may reduce it. Figures 7 and 8 show that the cause may be found within the population wide heterogeneity measure of standard deviation, or in the absolute measurement of microvascular flow heterogeneity in the organ (Figure 9). The effectiveness of dialysis was assessed using relative changes of plasma volume (Figure 10). As a simple definition, a larger fraction of plasma volume removed from the body by the dialyzer was defined as more effective HD. TH reduced the amount of plasma volume removed. In addition, pathological alterations of the hemodynamics such as atrial fibrillation and renal failure were also seen to reduce the amount of plasma volume to be removed by dialysis.