The Role of IV Albumin in ICU

The use of IV albumin is not uncommon in the Intensive care unit. However, the evidence for its routine use is conflicting. In this podcast, we critically appraise the available evidence to inform the Intensive care community on the role of IV albumin in the intensive care unit.

Albumin was one of the first human proteins to be isolated and extracted from plasma for clinical use. First crystallized in 1934, preparation was made available for clinical use in the 1940s [9,10]. Early successful use in multi-trauma and severely burned patients led to the rapid expansion of the so-called human albumin program in the USA [11], and albumin use spread from the military setting to civilian hospitals and into regular use in operating and emergency rooms around the world. The first commercially available preparations of intravenous human albumin solutions were developed using the cold alcohol fractionation technique created by Edwin Joseph Cohn.

Albumin solutions have been used worldwide for the treatment of critically ill patients since they became commercially available in the 1940s. However, driven largely by the results of a widely publicized meta-analysis in 1998 that reported increased mortality rates in patients who received albumin solutions [2], the role of albumin administration in critically ill patients became highly controversial.

It is also well established that low serum albumin levels, a common occurrence in critically ill patients, are associated with worse outcomes [4,5].  A meta-analysis by Vincent et al of 90 cohort studies that evaluated hypoalbuminemia as a prognostic biomarker in acutely ill patients, showed:

• Each 10g/L decrease in serum albumin concentration was associated with: 
  • 137% increase in odds of death
  • 89% increase in morbidity
  • 71% increase in length of hospital stay

There is a clear association between albumin level and severity of the underlying insult. The real question is whether the relationship between hypoalbuminaemia and mortality is a simple association, or a cause-effect relationship? 

There would therefore seem to be a good rationale for use of albumin infusions in critically ill patients.

However, albumin solutions also limitations, including high costs relative to possible alternatives, notably crystalloids, and potential (rare) risks of transmission of microorganisms, anticoagulant, and allergic effects [6-8]. Because there are no definitive randomized controlled trials (RCTs) demonstrating an outcome benefit of albumin in heterogeneous groups of critically ill patients, routine administration of albumin for fluid resuscitation is not warranted in all patients, but there is evidence to support its use in some patient populations.

Albumin has loads of physiological effects:

• Regulating colloid osmotic pressure
• Binding and transporting drugs and hormones in the blood
• Antioxidant properties
• Nitric oxide modulation
• Maintenance of microvascular integrity
• Buffering 
  • Particularly relevant in critically ill patients.
  • We also know that low serum albumin levels, commonly found in the critically ill, may be associated with worse outcomes.
• Anticoagulant effects

Evidence – 

the first RCT of albumin administration was only published some 30 years later in 1975 (Table 1). This early RCT, conducted in just 16 patients undergoing abdominal aortic surgery, compared the effects of intraoperative use of albumin solution with those of a sodium-rich fluid during surgery and showed that albumin infusion led to less extracellular fluid expansion. The Cochrane meta-analysis [2] was published in 1998 the average sample size of the 32 included studies was just 46 patients. Although the results of many studies take years to be published and to change clinical practice – if indeed they ever do – this Cochrane report influenced practice rapidly around the world, especially in the UK where use of albumin decreased by 40 to 45% in the 6 months after publication [47].

In 2004, the results of the Saline versus Albumin Fluid Evaluation (SAFE) RCT in almost 7,000 critically ill patients were published, showing that a 4% albumin solution was as safe as normal saline when used as a resuscitation fluid [49].

Subgroup analysis of the SAFE study suggested there may be a benefit in patients with severe sepsis (35% of whom had septic shock), with an adjusted odds ratio for death of 0.71 (95% CI, 0.52 to 0.97; P = 0.03) for albumin compared with saline [54]. A subsequent meta-analysis that included 17 RCTs comparing albumin solutions with other fluids for fluid resuscitation in patients with sepsis reported that albumin use was associated with decreased mortality (odds ratio, 0.82; 95% CI, 0.67 to 1.0; P = 0.047) [58]. Guidelines currently suggest (grade 2C) that albumin use should be considered as a resuscitation fluid in patients with severe sepsis, particularly if those patients are not responding to crystalloid infusion [59,60], based on data from the meta-analysis [58].

In the ALBIOS study, conducted in 100 ICUs in Italy [62], 1,818 patients with severe sepsis or septic shock were randomized either to receive 300 ml of 20% albumin plus crystalloid or to receive crystalloid alone  initially to achieve the target resuscitation goals of the early goal-directed therapy protocol used by Rivers and colleagues [73]. Over the subsequent 28 days, albumin infusions were adjusted to maintain serum albumin ≥30 g/l; crystalloid solutions were given when considered clinically indicated by the attending physician. More patients in the albumin group than in the crystalloid group reached the target mean arterial pressure within 6 hours after randomization (86% versus 82.5%, P = 0.04), and during the first 7 days the mean arterial pressure was higher and the net fluid balance lower in the albumin group than in the crystalloid group [62], despite similar amounts of fluid being administered to the two groups. There were, however, no overall differences in 28-day mortality rates (32% albumin vs 32% crystalloid; relative risk in the albumin group, 1.00; 95% CI, 0.87 to 1.14; P = 0.94) or 90-day mortality rates (41% albumin vs 44% crystalloid; relative risk, 0.94; 95% CI, 0.85 to 1.05; P= 0.29) between the groups. Of the 1,818 patients, 579 (31.8%) were randomized within 6 hours and 1,239 (68.2%) more than 6 hours after meeting the clinical criteria for severe sepsis; there were no significant differences in outcomes according to the interval between meeting clinical criteria and randomization. In the subgroup of patients with septic shock at enrollment (n = 1,121), however, those who received albumin had significantly lower 90-day mortality rates than those who received saline (44% versus 50%; relative risk, 0.87; 95% CI, 0.77 to 0.99; P = 0.03).
In the multicenter EARSS study in France, so far published only in abstract form [61], 798 patients with septic shock of less than 6 hours duration were randomized to receive 100 ml of 20% albumin or 100 ml of 0.9% saline every 8 hours for 3 days. Almost all patients had severe hypoalbuminemia at study inclusion. There were no significant differences in mortality rates between the two groups (24.1 vs 26.3%).

Criticism – 

SAFE trial results represent the post hoc analysis of a trial not designed to assess the benefits of albumin in patients with sepsis.6 The Therapy in the Colloids vs Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial showed no benefit in 28- or 90-day mortality in septic patients treated with albumin (4% and 20% solutions) vs those treated with normal saline.7 The Albumin Italian Outcome Sepsis (ALBIOS) trial assessed whether albumin replacement with a 20% solution in septic patients for 28 days to a target of 3 g/dL was beneficial.8,9 Despite achieving higher serum albumin levels in the treatment group, there was no difference in 28-day or 90-day mortality. Post hoc analysis of the septic shock subgroup showed no difference in 28-day mortality but suggested a 90-day mortality benefit favoring albumin, an effect that lost significance when adjusted for clinically relevant variables. ALBIOS did not show that albumin provides a benefit in the occurrence of new organ failure or duration of mechanical ventilation. Although lower heart rates and higher mean arterial pressures were reported in the albumin-treated group, such differences do not represent patient-centered outcomes. Multiple meta-analyses have shown that albumin does not provide a benefit in mortality or the need for renal replacement therapy in critically ill patients, including those with hypoalbuminemia and sepsis.10-13 A metaanalysis, using data dominated by the ALBIOS trial, found no mortality benefit in patients with severe sepsis.12 In the septic shock group, a 90-day mortality benefit was reported, but 28-day mortality was not analyzed. In summary, albumin used either as a resuscitation agent or to normalize albumin levels in septic patients has not been shown to provide a benefit in mortality, new organ failure, or duration of mechanical ventilation. Furthermore, the hemodynamic benefits should be interpreted with caution because they are not associated with beneficial outcomes.
Analysis of the SAFE trial suggested that albumin was associated with a larger reduction in pH and increase in serum chloride compared with normal saline when a large amount of resuscitation fluids were administered in the first 24 h.16 Moreover, albumin was associated with a more prolonged activated partial thromboplastin time and higher hepatic sequential organ failure assessment scores (driven by bilirubin levels) compared with normal saline.6,17 The latter finding has been attributed to the presence of bilirubin in the albumin solution from the chromatographic fractionation manufacturing process in the product studied; the clinical significance is unclear.

Cost –Effective Analysis – 

The US acquisition cost of normal saline or lactated Ringer’s solution is $1 to $2, whereas the acquisition cost of 100 mL of 25% albumin is approximately $82. 

The median volume of albumin in AlbIOS was 1,100 mL. Using our cost of $82 for 100 mL of 25% albumin as a guide, this approach in the United States would add a median cost of $902 per case of septic shock (in the first 7 days). The median volume of crystalloid in the albumin group was reduced by 2 L, reducing the bill by approximately $3. The post hoc\ analysis suggested an absolute reduction in 90-day mortality of 6.6% in the albumin group, indicating a number-needed-to-treat of 16 patients per additional life saved. The additional critical care cost per life saved would then be $14,384, a reasonable cost. However—and this is a huge however—the calculation depends on the reliability of the data,

Albumin for hypoalbuminemia – 

The effects of increasing albumin concentrations by giving exogenous albumin have also been investigated in the critically ill. A meta-analysis of nine prospective controlled trials on correcting hypoalbuminemia in acutely ill patients suggested that complication rates were reduced in patients who achieved serum albumin concentrations >30 g/l after albumin administration [5]. However, in a subgroup analysis of the SAFE study in patients with hypoalbuminemia, using a cut-off value of 25 g/l [4], there were no significant differences in outcomes in hypoalbuminemic patients and normoalbuminemic patients who received albumin. In a pilot

RCT of 100 hypoalbuminemic critically ill patients who were randomized either to receive 300 ml of 20% albumin solution on the first day and then 200 ml/day if the serum albumin concentration remained <30 g/dl or to receive no albumin, Dubois and colleagues reported that organ function (as assessed by change in the Sequential Organ Failure Assessment score) improved more in the albumin-treated patients (P = 0.03) [30]; these patients also had a less positive fluid balance (P =0.04). There was also a beneficial effect on cumulative calorie intake during the first week, suggesting that albumin may have helped decrease intestinal edema.

The effects of albumin administration may also depend on the simultaneous use of diuretics to prevent an albumin infusion-induced increase in hydrostatic pressure, which may increase (rather than decrease) edema formation. Some studies have suggested that the concurrent use of albumin may increase furosemide-induced diuresis in hypooncotic patients with acute respiratory distress syndrome/acute lung injury [65,66] and cirrhosis-induced ascites [67], although not in all critically ill patients [68]; whether this strategy has any effect on patient-centered clinical outcomes is unclear.
In 1999 Sort and colleagues published the results of a RCT in 126 patients with cirrhosis and spontaneous bacterial peritonitis comparing treatment with intravenous cefotaxime or cefotaxime plus intravenous albumin for plasma volume expansion [52]. Renal impairment developed in fewer patients in the patients who received albumin (P = 0.002) and these patients also had reduced hospital and 3-month mortality rates (both P = 0.01). A more recent RCT reported beneficial effects of albumin plus antibiotic on renal and circulatory function in 110 patients with cirrhosis and infections other than spontaneous bacterial peritonitis; treatment with albumin was an independent predictive factor of survival [69]. A meta-analysis of 16 RCTs also suggested that albumin use was associated with a significant reduction in mortality (odds ratio, 0.46; 95% CI, 0.25 to 0.86) and renal impairment (odds ratio, 0.34; 95% CI, 0.15 to 0.75) in patients with cirrhosis and any infection [70]. Two small RCTs have also demonstrated improved renal function in patients with cirrhosis and hepatorenal syndrome treated with albumin and terlipressin [71,72].

Summary – 

Albumin administration, although unlikely to cause harm in most patients, is not necessary in all critically ill patients and should be reserved for use in specific groups of patients in whom there is evidence of benefit.

 A hypotonic albumin solution should be avoided as a resuscitation fluid in patients with traumatic brain injury, based on the results of the SAFE subgroup analysis [55].

There is now enough evidence – albeit largely from subgroup analyses – and plausible biological rationale to support use of albumin in patients with septic shock when a colloid is considered [54,62].

Albumin administration should be considered in patients with cirrhosis and spontaneous bacterial peritonitis [52], but possibly also other infections