A 40 year old woman presented with 4 days of abdominal pain, distended abdomen and faeculent vomiting. She was in septic shock on presentation and laparotomy revealed a sigmoid perforation with four quadrant peritonitis. Postoperatively she was extubated, but dependent on noradrenaline. Overnight, her vasopressor requirements escalated despite additional fluid resuscitation. Transthoracic echo suggesed hypovolaemia, and as she was hypoalbuminaemic she was given regular boluses of 20% albumin which resulted in transient improvments in blood pressure. Despite a return to theatre for further washout, she developed multiorgan failure and died.
What is the evidence behind the use of Albumin as a resuscitation fluid in patients with septic shock?
Sam Clark
The concept of IV fluid administration was first introduced in 1832 by Robert Lewins, who pioneered the use of alkalinized salt solution for the treatment of patients with Cholera (1). Its use proceeded a pace with developments by both Sidney Ringer and Alexis Hartmann, who introduced variations on balanced salt solutions (2) in the late nineteenth and early twentieth centuries. The advent of blood fractionation, in 1941, allowed for the mass production of Human Albumin Solution (HAS) and it was employed effectively at Pearl Harbour for the burns patients. Albumin became the gold standard resuscitation fluid due to theoretical advantages based on Starling’s principle of the movement of fluid across a semipermeable membrane. It states that the principle forces are hydrostatic and oncotic pressures, and Albumin solution as a colloid contains a natural protein that is relatively incapable of crossing a healthy semipermeable membrane, will increase the intravascular oncotic forces encouraging other fluid to remain in the intravascular space. Theoretically, at least, this should give an advantage of a ratio 1:3 when compared with crystalloids. Albumin remains in the circulation for up to 30 days. However, it is can be both expensive to manufacture and distribute (3).
In 1998, Cochrane published a meta-analysis reviewing the evidence for the use of albumin in critically ill patients looking at 24 small RCTs of variable quality, including 1419 patients4. These studies compared albumin with normal saline in hypovolaemia, burns or hypoalbuminaemia. Their review demonstrated that for each of those categories there was an increase risk of death compared to the comparison group, as well as the pooled mortality (1.68, CI 1.26-2.23). The authors wrote that their data suggested an pooled absolute risk increase of 17. They concluded that there was no evidence that Albumin improved outcome and that there was a strong suggestion albumin may worsen mortality. Perhaps, unsurprisingly at the time and despite significant limitations including the small nature of studies incorporated, the absence of separation between albumin concentrations and mortality not being the primary end point all studies included, the conclusions cause considerable alarm across the intensive care community. It was even suggested that patients might have a case to legal recourse if albumin was inappropriately used.
A further meta-analysis published in 2001, assessing 55 trials (3504 patients) and also examined specific subgroups including liver patients (5). They included studies that were blinded, implemented cross over designs and had mortality as an end point. There was a non-significant trend towards improved survival in the Albumin group in the subgroup looking at the better methodology trials (RR 0.73; CI 0.48-to 1.12), but no overall significant difference (RR 0.94; CI 0.77-1.14). Again, there was no distinction made between difference concentrations of Albumin solutions.
The SAFE study was designed as a non-inferiority study to compare 4% Albumin with 0.9% Saline (6). A double-blinded RCT conducted in Australia and New Zealand, it examined the safety of Albumin in 6779 adults in ICU. They found no significant differences either in 28-day mortality (RR 0.99; CI 0.91-1.09), development of new organ failure, duration of mechanical ventilation, length of ICU stay or renal replacement therapy between the two groups. Subgroup analysis demonstrated trends towards survival for Albumin vs. Saline in severe sepsis (30.7% vs 35.3% (RR 0.87, 95% C.I. 0.74 – 1.02), P=0.09), but towards increased mortality for both trauma (3.6% vs. 10% (RR 1.36, 95% C.I 0.99 – 1.86), P=0.06) and brain injury (24.5% vs. 15.1% (RR 1.62, 95% C.I 1.12-2.34), P=0.009), the latter being a post-hoc analysis. It was a very large well-conducted trial with few weaknesses, except suffering with insufficient power for its subgroup analyses. The results could be and were interpreted in opposite directions, as support for Albumin’s safety profile or questioning the theoretical advantage of an expensive potentially allogenic fluid compare to simple crystalloid. However, it did lead to FDA stating that “the SAFE trial solved the doubts raised by the Cochrane Injuries Group in 1998, and there is no harm from intravenous albumin in critically ill patients.” (7). Finders et al conducted a further pre-planned subgroup analysis of 1218 patients with severe sepsis and demonstrated, using multivariate logistical regression that adjusted for baseline factors for 919 patients with complete baseline data, there was a significant reduction in the adjusted odds ratio for death (0.71; CI 0.52-0.97, p=0.03) (8).
The SOAP study was large European prospective multicenter observational study following all patients admitted to participating ICUs across 14 countries (9). Results from 3147 patients showed that 354 received albumin and 2793 did not. Those patients that received albumin had higher SOFA and SAPSII scores and were more likely to die. 30-day mortality was significantly worse in the albumin group compared to those that did not receive albumin (RR1.57; CI 1.19-2.07). Albumin tended to be administered to sicker patients, possibly creating a false association, however, the authors attempted to mitigate for this using Cox hazard modeling and propensity scoring in their statistical analysis. It is not appropriate to infer causality from an observational study, however, it does raise further questions about the timing and severity of the patients that albumin may be appropriate for, with other studies showing reduced albumin associated morbidity in severely hypoalbuminaemic patients as compared to those with an albumin above 30mg/dl (10).
As mentioned above, many of the studies and meta-analyses did not specify concentrations of albumin employed, however, one meta-analysis specifically examined small volume resuscitation with hyperoncotic albumin solutions (20-25%). It found that there was no significant increase in mortality using albumin, but was based on a very limited number of studies (11). These results led to the recently published multi-centered open label trial trial, ALBIOS, which studied the effects of 20% Albumin with crystalloid versus crystalloid alone in 1818 patients with severe sepsis across 100 ICUs in Italy (12). The design was stratified according to the participating ICU, and time between onset of sepsis and randomization (greater or less than 6 hours). The definition of severe sepsis was SIRS plus proven or suspected sepsis plus at least one organ failure as defined as SOFA scores. In the intervention arm patients received appropriate crystalloids and 300mls of 20% albumin to maintain a serum concentration of 30g/l or more. Median fluid volume given hardly differed between the two groups at (3.7L and 3.8L for each group respectively). The primary and secondary end points were 28-day and 90-day mortalities. There was no significant difference between the two groups. At 28 days, Albumin group mortality was 31.8% versus 32.0% in the control group (RR1.00; CI 0.87-1.14, p-0.04). Overall, there was no significant difference in organ failure (measured via SOFA scores, 6 in the albumin group vs. 5.62 in the crystalloid group, p=0.23), but there was evidence of both cardiovascular improvements in line with that seen in the SAFE study (SOFA score 1.2 vs. 1.42, P=0.03) and minor liver deterioration (0.28 vs. 0.2, p=0.02). The authors found that giving albumin as a resuscitation fluid and to correct hypoalbuminaemia, though safe, did not confer a survival advantage. ALBIOS was a pragmatic study with an excellent follow rate, and few significant flaws, but it could not be considered evidence that albumin should be a first line resuscitation fluid.
Conclusions:
This case report has allowed me to review the current evidence related to the use of albumin in sepsis. The evidence for the use of albumin in sepsis has produced a mixed picture. Since the 1998 Cochrane review, there have been a significant number of studies that endorse the safety of albumin use at both iso-oncotic and hyper-oncotic levels. Albumin can improve both blood pressure and lessen the requirement for cardiovascular support, however, the no consistent evidence that these advantages convey any tangible survival benefits on the septic population. However, the heterogeneity of the data might suggest that certain patients with a combination of factors may benefit for albumin administration: septic patients, in whom the albumin level is below 20g/l and the timing of the oncotic, haemodynamic and drug distribution support acts a bridge to some other improvement in the patients condition, as opposed to a direct biological improvement from the albumin alone. Either way albumin’s relationship with critical care is likely to continue with current data being inconclusive and further trials (such as CEASE) examining its effects.
References:
(1) Lewins R. Saline injections into the veins. London Medical Gazette. April 7, 1832:257-68.
(2) Lee JA. Sydney Ringer (1834-1910) and Alexis Hartmann (1898-1964). Anaesthesia 1981;36:1115-21.
(3) Myburgh J. & Mythen M Resuscitation fluids. NEJM 2013 369:13; 1243-1251.
(4) Cochrane Injuries Group Albumin Reviewers. Human albumin administra- tion in critically ill patients: systematic review of randomised controlled trials. BMJ 1998;317:235-40.
(5) Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. 2001;135(3):149-64.
(6) Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-56.
(7) Food and Drug Administration. Safety of Albumin Administration in Critically Ill Patients. May 16, 2005. FDA Report. [cited 2010 Sep 19]. Available on: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/BloodSafety/ucm095539.htm
(8) SAFE Study Investigators, Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, Norton R. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011;37(1):86-96.
(9) Vincent JL, Sakr Y, Reinhart K, Sprung CL, Gerlach H, Ranieri VM; ‘Sepsis Occurrence in Acutely Ill Patients’ Investigators. Is albumin administration in the acutely ill associated with increased mortality? Results of the SOAP study. Critical Care. 2005;9(6):R745-54
(10) Rubin H, Carlson S, DeMeo M, Ganger D, Craig RM. Randomized, double-blind study of intravenous human albumin in hypoalbuminemic patients receiving total parenteral nutrition. Crit Care Med. 1997;25(2):249-52
(11) Jacob M, Chappell D, Conzen P, Wilkes MM, Becker BF, Rehm M. Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized clinical trials. Crit Care. 2008;12(2):R34.
(12) Caironi P., Tognoni G., Masson S., et al. Albumin replacement in patients with severe sepsis or septic shock. NEJM (2014) 370;15: 1412-1421.
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