This study aimed to identify predictors regarding the increase of arterial pressure after volume expansion. Fluid challenge was ineffective in about one third of patients and the cardiovascular and renal variables analyzed in this study did not allow any kind of prediction regarding the increase of arterial pressure.
Study results
We assessed fluid responsiveness from a clinical instead of physiological point of view. Fluid administration is traditionally considered as effective if it increases cardiac output. This has a pathophysiological rationale and dynamic indices appear quite reliable predictors with this approach [
11,
12]. Nevertheless a frequent clinical reason for fluid administration is hypotension whereas cardiac output increase is not required in most of intensive care patients [
13,
14]. In our study dynamic indices were available for prediction only in 19% of the population. This finding was explained by the two main limitations of dynamic indices assessment, namely, the absence of both spontaneous respiratory activity and arrhythmias [
9‐
11]. These requirements are frequently violated in critically ill patients. Arrhythmias have been reported in 15% of patients in Intensive Care Unit [
17] and early resumption of some spontaneous respiratory activity is recommended to facilitate weaning from mechanical ventilation and to prevent ventilation-induced diaphragmatic dysfunction [
18,
19]. We did not consider the use of low tidal volume ventilation as exclusion criteria for use of dynamic indices. Low tidal volume ventilation is recommended during acute lung injury [
3] but this ventilatory approach reduces the accuracy of fluid responsiveness prediction by dynamic indices [
15,
20,
21]. If we considered even low tidal volume ventilation as exclusion criteria for dynamic indices evaluation, then dynamic indices would have been available in only 2 out of 36 patients (6%). Therefore dynamic indices could be a useful resource in non-critically ill patients, for example in perioperative settings. Indeed, spontaneous respiratory activity and low tidal volume ventilation are not frequently used during general anesthesia. Moreover, dynamic indices are a good predictor of fluid responsiveness evaluated by cardiac index increase, and supranormal values of cardiac index and oxygen delivery are also associated with better outcomes in high risk patients undergoing major surgery [
22].
When we tried to predict the effect of fluid challenge, we obtained frustrating results. Before fluid challenge all variables were similar between responders and non-responders. Moreover, study variables displayed very low accuracy in identifying responders to fluid challenge, with their areas under ROC curves ranging from 0.502 to 0.604. Finally, even logistic regression did not identify any variables associated with responder status. These results further discourage the use of central venous pressure to drive fluid administration in hypotensive patients.
Most variables tested in this study depends mainly on pressure and flow. Therefore our results suggest that physiological variables depending on flow and pressure could not accurately predict arterial pressure changes after fluid administration. For this purpose it appears more appropriate an approach based on the arterial elastance evaluation as calculated by ratio between pulse pressure variation and stroke volume variation [
23].
In previous studies fluid challenge increased cardiac output or stroke volume in 40-64% of patients [
9,
10,
15,
20,
21] and similarly, in our study, fluid challenge worked in 61% of the patients. At least one in every three hypotensive patients does not show any improvement after fluid challenge. On the contrary, inappropriate fluid administration negatively impacts on several relevant outcomes [
5‐
8]. Considering the impossibility of predicting the effect of volume expansion on arterial pressure and the high rate of non-responders, cardiac output monitoring or estimation could help to guide therapy in hypotensive patients whose arterial pressure does not increase after fluid challenge or who are at risk of fluid overload.
The results of this study strongly depended on fluid challenge technique used, the timing of outcome evaluation, study outcome, patient and variable selection.
Fluid challenge
We chose to administer maximal fluid challenge to avoid any possibility of fluid underresuscitation. Each fluid challenge was scheduled to administer about 500 ml over 30 minutes for patients of 70 kg in weight [
3,
24]. Because some patients could require larger volumes [
3], we decided to repeat the fluid challenge provided that there were no criteria for stopping fluid administration. The total amount of hydroxyethyl starch remained largely below the safety threshold dose even when both fluid challenges were carried out [
25].
Timing
Previous studies on fluid responsiveness have evaluated the outcome either at the end of volume infusion [
9,
15,
20,
21] or at 30 minutes after it [
10]. We performed outcome measurements at 1 hour after the end of fluid challenge to avoid misclassification of transient effects as clinically relevant effects. At this time, the volume effect of hydroxyethyl starch was fully maintained [
25]. Moreover timing of measurement of effect of volume expansion on cardiac output and arterial pressure could strongly influence results. In fact changes of cardiac output and arterial pressure after fluid challenge have different time course. In preload-dependent patients cardiac output can initially increase by a large extent despite minimal arterial pressure increase because of decrease in systemic vascular resistance. Then cardiac output returns to baseline value and arterial pressure increases for the combined effect of an increase of venous capacitance associated to disappearance of initial decrease in systemic vascular resistance. This dynamic process begins immediately after the fluid challenge and it is complete in few hours. In particular the evaluation of fluid responsiveness should be delayed at least 40 minutes after the fluid challenge to allow the first acute stabilization of cardiac output and arterial pressure [
26].
Patients
Fluid administration should follow different approaches in the first hours of resuscitation and after the stabilization of the patients [
3,
4,
27]. If, in the first hours, more fluid is better than less [
4], liberal fluid administration should be avoided in the following phases [
5‐
8]. We aimed to study only stable patients after the start phase of fluid resuscitation. We avoided selecting patients with specific clinical diagnosis because they are often extremely heterogeneous from a pathophysiologic point of view. For example, patients with septic shock/severe sepsis are probably the most studied population of critically ill hypotensive patients. All these patients share an infection-related hypotension but they should be considered a heterogeneous population when they are enrolled in a physiological study. It is well recognized that they could have low or normal or high cardiac preload associated with low or normal or high cardiac output [
3]. Therefore we chose to increase the external validity of the study both avoiding apparent homogeneity and including patients independently of cardiac output measurement, cardiac rhythms and modality of ventilation. This study should be considered as a pilot trial and the sample size was considered convenient for this purpose. Nevertheless these preliminary data have shown that predictors were much too weak for a successful prediction even in much more patients.