Key findings
We attempted to quantify renal cortical microvascular perfusion in a non-invasive manner in critically ill patients on vasopressors using CEUS. We found that renal CEUS was feasible and administration of UCA well-tolerated even in haemodynamically unstable patients. We found that a noradrenaline-induced increase in MAP was not associated with an overall change in renal perfusion indices as measured by CEUS. In contrast, the intervention was associated with highly heterogeneous responses at a patient-level, with observed increase or decrease by >25% of baseline values in a quarter of the patients.
Relationship to previous studies
Several animal studies [
22],[
23] have demonstrated that noradrenaline may increase RBF in vasodilated/hypotensive states. This effect seems to be mediated by an increase in systemic blood pressure and an associated decrease in renal sympathetic tone through a baroreceptor response [
23]. The effect of noradrenaline
per se on renal vasculature tone was examined in an animal model of septic shock [
24]. In this study, although noradrenaline administration was associated with an increase in MAP under all conditions, it was only associated with an increase in RBF (as measured by implanted ultrasonic flowmeters) when renal vascular vasodilatation was present. These findings suggest that noradrenaline infusion, in acute endotoxemia reverses systemic hypotension and may improve RBF independent of perfusion pressure.
However, the human data confirming these experimental findings is extremely limited. There are only a few studies that report RBF measurement in critical illness and its changes in response to noradrenaline administration. In particular, Redfors
et al. [
25] have measured global RBF in critically ill patients, with invasive renal vein blood sampling. In this very detailed physiological study, an increase from 60 to 75 mmHg of the MAP was associated with an increase in GFR and urine flow but not in RBF.
Other authors have used surrogate measures of RBF and measured renal vascular resistive indices in critically ill patients. These indices, however, have been shown to be poorly correlated with RBF [
26]. However, such parameters can be predictive of reversibility of AKI [
27] and perform better than urinary indices for diagnosing persistent AKI.
Current recommendations for MAP target [
11] in septic shock (grade 1C) are based on small physiological studies that demonstrated the absence of changes in several physiological parameters [
28],[
29]. A recent large clinical trial [
12] randomly allocated 776 patients with septic shock to undergo resuscitation with a MAP target of either 65 to 70 mmHg or 80 to 85 mmHg. In this trial, there was no difference in 28- or 90-day mortality between the two groups. In the subgroup of patients with chronic hypertension, however, there was a decrease in the need for RRT. Our data, suggesting high heterogeneity in renal perfusion in response to a similar change in MAP, could provide an explanation for these findings. Indeed, a pre-determined one-size-fits-all MAP target might not be suitable for a highly heterogeneous group such as critically ill patients. On the contrary, a tailored MAP target aiming at restoring tissue perfusion, based on assessment of mental status, skin appearance, urinary output and perhaps CEUS parameters could represent an alternative approach [
30].
Strengths and limitations
This study is the first to use CEUS to evaluate renal microvascular perfusion induced by a change in the noradrenaline infusion rate. CEUS is a new technology, which is applicable at the bedside and could improve our understanding of organ perfusion in critical illness. This study provides pathophysiological insight into an important and unresolved question that persists despite large randomized controlled trials. However, this study has several limitations. First, the small sample size precludes advanced statistical analyses and determination of factors predicting response and the classification of patients into responders and non-responders remains arbitrary. Second, no measure of renal vascular resistive indices was performed. If consistent with CEUS data, this measure would have made our conclusions stronger. However, for technical reasons, such data were not collected.
Changes between measurements could be random variations associated with an overly sensitive technique. Indeed, CEUS measurements can be limited by numerous factors such as organ depth, echogenicity of surrounding tissues, breathing artefacts, US equipment settings, and fluid retention. This is illustrated by the large variability of baseline measurements among patients. However, such parameters are unlikely to have influenced the results because, for each patient, both CEUS scans were performed within a very short time window (<45 minutes) in which ventilation parameters, fluid and medications infusions, patient-position and US machine settings were all kept constant. Only comparison of measurements obtained in a single patient, as all other factors are kept constant can be interpreted. CEUS data were obtained by a single experienced operator aware of all these limitations.
In ventilated patients with low tidal volumes, respiration-related renal displacement can be dealt with by selecting a probe angle limiting this motion and by the use of an advanced image stabilisation algorithm in the VueBox® software. Therefore, a breath-holding manoeuvre was not necessary.
Consistency between parameters used to determine perfusion indices was fairly good, however, 25% of measurements suggested changes in perfusion in opposite directions. Further studies would be required to clarify the causes of such disagreements, how to prevent them and how to handle them.
Finally, the clinical relevance of our findings and the applicability of CEUS derived parameters remains to be determined. Indeed, as illustrated by a recent animal study [
31] the relationship between renal microcirculation and renal function are complex and still poorly understood. Our findings suggest the need for further studies aiming at understanding factors that predict changes in CEUS-derived parameters and to evaluate whether the presence or absence of change in CEUS-derived parameters in response to an increase in MAP are associated with specific clinical outcomes.