These trials clearly indicate that persistent use with presumably weak indication has Perifosine no beneficial effect or may even be harmful for critically ill patients.2. We suggest that HES should be limited to acute volume resuscitation for initial haemodynamic stabilisation when hypovolaemia is present. We also suggest re-assessment of volume status with clearly defined stopping rules for HES. Total time period of acute volume resuscitation with HES should not last longer than 24 h (if volume responsiveness is still present beyond 24 h, further application of HES is not recommended). (We acknowledge that this suggestion is in marked contrast to current practice and in conflict with its licensing or marketing authorisation.
)In the two large pragmatic 6S and CHEST trials [2,3], patients were resuscitated according to the fluid algorithm of the participating ICU and the clinicians were allowed to vary the algorithm from patient to patient (for example sometimes the physiological variable could be a central venous pressure below 10 mmHg, which clearly has been shown to be unrelated to hypovolaemia [36]; in another patient this could be a heart rate above 90 beats per minute (bpm)). Although the use of varying algorithms between participating centres in pragmatic trials may increase the generalisability of the results, patients are at an increased risk of receiving overdosed HES in the absence of a standardised and reliable algorithm for volume resuscitation. Indeed, the lack of goal-directed fluid management may have caused overinfusion of HES, aggravated haemodilution and potentially increased risk of blood transfusions in the 6S [3], VISEP [1] and CHEST [2] trials, at least in part.
3. We suggest using standardised and reliable algorithms of fluid responsiveness and predefined haemodynamic endpoints for acute volume resuscitation in order to restrict HES to hypovolaemic patients and to avoid hypervolaemia and any overdosing.As HES should be limited to hypovolaemic patients, physicians have to pay more attention at haemodynamic parameters and specific triggers for volume therapy before HES infusion starts. However, in the majority of studies [1-4,7,18,20,21], we could not fully reproduce adequate indicators for haemodynamic instability, hypovolaemia, nor increased lactate from published baseline data, respectively.
Only three trials [5,6,19] reported data on clinical signs that reasonably indicate hypovolaemia, thereby demonstrating that criteria for ‘presumably correct indication’ were met.4. We suggest that initiation of HES infusion should be limited to patients with haemodynamic instability primarily due to absolute or relative hypovolaemia. (We acknowledge that this suggestion AV-951 is in contrast to current practice and in conflict with its licensing or marketing authorisation.