Efficacy of Albumin Administration for Volume Replacement in Patients With Severe Sepsis or Septic Shock - the ALBumin Italian Outcome Sepsis (ALBIOS) Study

BACKGROUND AND RATIONALE The association between mortality and hypoalbuminemia has been documented in several diseases, including liver cirrhosis, nephrosic syndrome, and others. Being responsible for about 80% of the oncotic power of plasma protein in humans, albumin is a key factor in regulating the fluid exchange between interstitial and intravascular spaces, thereby extensively affecting hemodynamics. Besides its oncotic properties, albumin presents other characteristics potentially important in critically ill patients: 1 - a binding capacity for several physiological molecules and drugs, 2 - a scavenging action on oxygen free radicals, 3 - a modulating activity on nitric oxide (NO) metabolism, and 4 - a buffer power for the acid-base equilibrium.

Regardless its theoretical usefulness, the efficacy of albumin administration on survival in critically ill patients is controversial. The critical review published by the Cochrane Albumin Reviewers in 1998, including 30 clinical studies, has shown an increased mortality of critically ill patients treated with albumin. A further meta-analysis performed in 2001, including 55 clinical trials, has concluded that albumin administration is safe although with no effects on survival. In a more recent meta-analysis, including 90 cohort studies, and, separately, 9 prospective controlled trials on correcting albumin level, hypoalbuminemia has been shown to be a negative prognostic factor in terms of mortality, morbidity and length of stay, with a dose-dependent effect. In particular, each 10-g/l decline in plasmatic albumin level has been observed to significantly increase the odds of mortality by 137%. Moreover, the analysis performed within 9 controlled trials has suggested that complication rates may be reduced when plasmatic albumin concentration is maintained above 30 g/l. To clarify these controversial findings, a multicenter double-blinded randomized prospective study has been performed in about 7000 critically ill patients, comparing the effects of 4% albumin vs. saline infusion for volume replacement. Although no difference in the overall mortality has been observed, a predefined subgroup analysis has shown a trend of improvement in survival in patients treated with albumin affected by severe sepsis (p=0.09). In contrast, a trend towards a worse outcome in patients treated with albumin has been observed in the subgroup of patients with trauma (p=0.06), likely due to the higher number of patients with trauma associated to brain injury who did not survive in the albumin-treated group. These findings, therefore, highlight the importance of characterizing different types of critically ill patients who may benefit or not from albumin administration.

More recently, a further prospective, randomized controlled study has shown, in a series of 100 patients admitted to an intensive care unit (ICU), a significant reduction of organ dysfunction, as detected by the Sequential Organ Failure Assessment (SOFA) score, after correction of hypoalbuminemia with albumin administration.

In parallel to the investigations on the role of albumin in critically ill patients, an increasing interest has been focused on the timing and the hemodynamic target of volume replacement in septic patients. In particular, a recent randomized controlled study performed in patients with sepsis has shown a better survival in the group of patients in which fluid replacement has been obtained as early as possible according to predefined hemodynamic targets ("early goal-directed therapy"), as compared to the control group. Focusing our attention on septic patients, we can, therefore, conclude that: a - the early-goal directed volume replacement improves survival, and, b - the "type" of volume replacement may have a further effect on survival. In fact, volume replacement with the use of saline requires a greater amount of fluid and may lead to metabolic acidosis. On the other hand, volume replacement with the use of hydroxyethyl starch is potentially harmful. Volume replacement with the use of albumin does not involve any known risk and may also be beneficial in septic patients.

The current study aims to verify whether volume replacement with the use of albumin and its maintenance within plasmatic physiologic ranges may have beneficial effects in terms of mortality, morbidity and length of stay in patients with severe sepsis or septic shock, as compared to a standard volume replacement with the use of crystalloids. For this purpose, and to overcome the possible biases explained above, the study design will include two different and important aspects: 1 - for both arms of the study population, i.e., patients treated with albumin or with crystalloids, volume replacement will be performed according to the "early-goal directed therapy"; 2 - during volume replacement, and for the following days of treatment until the 28th day of admission in ICU (or until the day of ICU discharge, whichever comes first), serum albumin level will be monitored and kept equal or above a level of 30 g/l only in the albumin treated group. Such a study design will have several advantages. In particular, the introduction of the "early-goal directed therapy" both in patients treated with albumin or crystalloids, with the use of pre-defined hemodynamic targets, will standardize and optimize volume replacement for all the septic patients according to the standard care at the moment suggested worldwide. Moreover, it will allow us to specifically observe the direct effects of albumin administration per se and the maintenance of its serum level within normal range. In fact, besides its oncotic properties, it is conceivable that the physiological characteristics of albumin potentially important in septic patients (such as NO modulation, free oxygen radical scavenging, and acid-base homeostasis) may have a possible benefit on survival, especially after the early resuscitation phase.