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Human albumin: ICU


Table 1: Randomised clinical trials on human albumin administration in critically ill patients Study


Patients Sample size


SAFE


(Saline versus Albumin Fluid Evaluation study)


EARSS


(Early Albumin Resuscitation during Septic Shock)


ALBIOS


(Albumin Italian Outcome Sepsis Study)


Critically ill


Septic shock


Severe sepsis


6997


Time of enrolment


Not specified 794 Treatment


4% albumin versus


0.9% NaCl (double-blind)


< 6 hours 20% albumin versus


0.9% NaCl (open-label)


1800*


< 24 hours


20% albumin and crystalloids versus crystalloids (open-label)


PRECISE


(Fluid Resuscitation with 5% albumin versus Normal Saline in Early Septic Shock)


RASP


(Lactated Ringer versus Albumin in Early Sepsis Therapy)


Septic shock


1808*


< 8 hours 5% albumin versus


0.9% NaCl (double-blind)


Severe sepsis


360*


< 6 hours 4% albumin versus


Ringer Lactate (double-blind)


* Estimated sample size, being the relative studies still unpublished Fluid resuscitation


Target: hemod. stability


Fluid


resuscitation (fix doses)


Albumin replacement 28 days 3 days Primary:


28-day mortality Secondary: 90-day mortality


Primary:


28-day mortality Secondary: 90-day mortality


Fluid resuscitation 90 days Primary:


90-day mortality Secondary:


6-month mortality Primary:


7-day mortality Secondary: 28-day mortality


Recruiting –


Completed/ unpublished


Completed/ unpublished


Treatment target


Fluid resuscitation


Treatment duration


28 days


Survival endpoints


Primary: 28-day mortality Status Published


Results


20.9% versus 21.1% (p = 0.87)








Planned/not yet recruiting





human albumin, two different studies, one in patients with severe sepsis and the other in patients with acute lung injury, have reported increased plasma thiol levels after albumin supplementation.1


Moreover, such


supplementation appeared to improve thiol-dependent antioxidant properties of plasma obtained from these categories of patients, suggesting a direct effect of albumin replacement on the overall plasma antioxidant capability. Finally, in a single-centre study including critically ill patients with hypoalbuminaemia, albumin supplementation for a maximal period of 28 days appeared to be associated with a reduction of the severity and the number of organ failures, indirectly suggesting a clinical benefit related to albumin secondary properties.3,14


16


The trial enrolled approximately 7000 critically ill patients, in need of volume replacement, randomised to receive either 4% albumin or normal saline for intravascular fluid resuscitation (see Table 1). Mortality rate after 28 days appeared to be identical


First RCT in the critically ill After the publication of several meta- analyses of the possible role of albumin administration, the first large RCT evaluating the safety of human albumin in critically ill patients was concluded in 2004.15


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between the two groups (relative risk of death 0.99; 95% CI 0.91–1.09; p = 0.87). Moreover, no differences were observed among the secondary outcomes of the study. On the whole, therefore, the study concluded that, in critically ill patients, the use of either 4% albumin or normal saline for fluid resuscitation results in similar outcomes, as originally hypothesised by the investigators, and in contrast to previous findings, suggesting potential harm related to human albumin administration. In addition to the main findings of the


In both subgroups, the findings did not achieve a statistical significance, but strongly suggested two important differences in the treatment effect to be further investigated.


trial, a post hoc analysis on pre-defined subgroups identified two specific categories of patient in which a potentially different effect of the treatment applied was observed. In patients with severe sepsis, the administration of albumin was associated with a tendency towards a reduction in mortality rate (relative risk of death 0.87; 95% CI 0.74–1.02, p=0.09), whereas in patients with trauma the administration of albumin was observed to be associated with an increased risk of death (relative risk of death 1.36; 95% CI 0.99–1.86, p=0.06), especially in those with associated brain injury.15


Traumatic brain injury Following the conclusion of the SAFE study, and the observation of possible harm of albumin administration in patients with traumatic brain injury, the same investigators performed a post hoc follow-up study on patients with traumatic brain injury at the time of randomisation.16


After a detailed


characterisation of the brain injury at baseline, 460 patients, randomised in the SAFE study to receive either 4% albumin or crystalloids for intravascular fluid resuscitation, were followed for 24 months. Survival analysis confirmed a significant increased risk of death associated with the use of human albumin as compared to crystalloids (relative risk of death 1.63; 95% CI 1.17–2.26; p=0.003), which appeared greater in patients with severe brain injury at the time of randomisation. After a subsequent analysis, an increased intracranial pressure during the first week of treatment with albumin appeared to be the most likely mechanism associated with the increased mortality observed.17


findings have been criticised,18


Although these at the


moment, patients with a traumatic brain injury are the first category of critically ill patients in which a specific and strong indication regarding human albumin administration has been achieved, including at the end a ban on its use.


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