The main findings of this prospective observational study are the following: RRI value on first day of ICU admission (i) significantly correlates with P(cv−a)CO2)/ (C(a−cv)O2) ratio and arterial lactate levels; ii) is independently associated with the presence of circulatory shock; (iii) its combination with P(cv−a)CO2)/ (C(a−cv)O2 ratio and arterial lactate better predicts the ICU mortality than each one index separately.
The finding of the significant association between RRI and global tissue hypoperfusion indices, to the best of our knowledge, is first described in the present study. This finding supports the hypothesis that under conditions of tissue hypoperfusion, the renal vasculature can early respond to an oxygen supply and demand mismatch by modulating the vascular tone. Furthermore, it is indirectly consistent with the findings of a recent study demonstrating that RRI of patients admitted with shock was higher than RRI in patients without shock [13]. Likewise, a similar relationship between RRI and shock was also observed in the present study. The odds of shock for a patient with abnormal RRI were 13.2 times the odds of shock for a patient with normal RRI. Therefore, by extrapolating this finding, the association we found between RRI and tissue oxygenation indices seems to be expected and reasonable.
The ability of RRI to detect, beyond a renal blood flow impairment, global tissue hypoperfusion provides evidence to the recently reported concept of the ultrasound-based assessment of visceral end-organ perfusion in the critically ill [1], expanding thus, the bedside clinical monitoring window for hypoperfusion in shock states and offering new insights in shock pathophysiology. Corradi et al, have provided analogous evidence in normotensive polytrauma patients without biochemical signs of hypoperfusion [15]. Specifically, they reported that a RRI greater than 0.7 on admission to the emergency department was predictive of progression to hemorrhagic shock suggesting thus, that renal blood flow redistribution occurs very early in response to an occult bleeding. Similarly, early detection of peripheral hypoperfusion through the evaluation of RRI has recently been demonstrated in a patient with occult blood loss, enhancing thus, the role of RRI as a new index in critical care [29]. Furthermore, in another study in patients with acute lung injury, short-term mild hypoxemia has been reported to increase RRI (30).
Interestingly, in accordance with our findings, a positive association of RRI and lactate has also been described in a recent study dealing with factors associated with RRI in critically ill patients [28]. However, in that study the interpretation of this association, by the authors, was that RRI values might be associated with greater clinical severity, because lactate had been considered as an isolated severity marker.
Taken together, the present data, in conjunction with findings from the aforementioned studies, underline the importance of RRI as a potential surrogate marker for assessment of systemic hypoperfusion, besides the other hemodynamic parameters routinely used in daily practice. Of note, since hemodynamic disturbance could influence RRI, we performed the RRI assessment within the first 24 hours, after a seeming normalization of the systemic blood pressure. Therefore, despite a restored arterial pressure, an increased RRI value could unmask a persistence of tissue hypoperfusion, warning thus, for closer and probably further titration of the hemodynamic treatment.
Among all the O2- and CO2-derived parameters, the venous-arterial content CO2 (Cv−aCO2) to C(a−v)O2 is considered a reliable marker of global anaerobic metabolism (17–21). Because the calculation of P(v−a)CO2 is simpler, P(v−a)CO2 has been used to replace C(v−a)CO2 in the clinical practice. Although it could be argued that there may be a difference between the PCO2 and the CCO2, the relation between them is almost linear over the physiological range [19]. Furthermore, P(v−a)CO2 / C(a−v)O2 ratio highly correlates with the arterial lactate levels [17, 31]. In the analyses, we used the threshold value of 1.4 of this ratio, since Mekontso-Dessap et al, have shown that it better predicts the presence of hyperlactatemia, compared to other parameters [17]. Since pulmonary artery catheters are less commonly used today than in the past [32], we sampled the central venous blood, as a surrogate of mixed venous blood for the P(v−a)CO2 /C(a−v)O2 ratio calculation as previously reported [20].
Clinical outcome in ICU patients is known to be complex and multifactorial. In the present study, we found an association of RRI with ICU mortality; this finding is in agreement with that of a previous study in critically ill patients [11]. Interestingly, we further found that P(v−a)CO2)/ (C(a−v)O2 and lactate were also related to mortality and that the combination of RRI, lactate and P(v−a)CO2)/ (C(a−v)O2) ratio further improves the prognostic accuracy. To interpret this novel finding we must take into account that the P(v−a)CO2)/ (C(a−v)O2) ratio expresses the global hypoperfusion, whereas an increased RRI expresses end-organ hypoperfusion of a vital organ (kidney), whose dysfunction significantly increases the mortality risk [33–35]. Therefore, this could be a probable explanation for the better performance of their combination in outcome prediction, and underlines the need for evaluation of blood flow in vital end-organs, in addition to global tissue hypoperfusion indices, in order to guide therapies to reduce mortality.
Certain limitations of the present study should be pointed out. Firstly, the non- homogeneous sample of critically ill patients suffering from various types of shock did not allow for separate information on different tissue hypoxia types. Secondly, the specific role of large-vessel dysfunction, such as arterial stiffness parameters [36] on RRI value was not assessed. Nevertheless, the data hereby presented, showing the significant correlation between RRI and tissue hypoperfusion indices in a mixed ICU population, might indicate a further role of RRI in this context.