A 50-year-old man was brought to the emergency department. He had sustained a burn affecting 55% of his total body surface area and a significant inhalational injury.  In the emergency department he was intubated and ventilated, central venous, arterial and urinary catheters were placed and resuscitation begun using the Parkland formula.

He was transferred to burns intensive care.  Fluid resuscitation was continued using Hartmann’s solution.  A bronchoscopy was performed; 1.26% sodium bicarbonate was used for lavage.  He became increasingly tachycardic and hypotensive.  He was oliguric.  His haematocrit was 0.45.  Fluid status was difficult to assess clinically; he felt warm to touch.  An oesophageal Doppler probe was sited which demonstrated low stroke volume and corrected flow time.  His Doppler parameters improved with each 250ml bolus of Hartmann’s solution but the effect was short lived.  Noradrenaline and then adrenaline infusions were used in an attempt to maintain blood pressure.  After a significant volume of crystalloid had been given, approximately 12 hours after the time of injury, 4.5% human albumin solution was requested.  This seemed to have a more prolonged effect than Hartmann’s solution.  Over the next 12 hours the patient’s haemodynamic status stabilised and he was able to undergo initial surgical management of his burn 36 hours after presentation.

What is the evidence for the use of human albumin solution for fluid resuscitation in critically ill patients.

Fiona Wallace

Fluid resuscitation of patients with major burns can be very challenging.  The modified Parkland formula is commonly used to estimate fluid requirements but the most appropriate goals of resuscitation are uncertain.  Under resuscitation increases haemodynamic instability, while excessive fluid administration is associated with significant harm including poor wound healing, increased extravascular lung water and abdominal compartment syndrome.  There is significant interest in the use of albumin for fluid resuscitation in patients with burns, as an effective means of expanding intravascular volume and maintaining plasma oncotic pressure.  There is significant commonality with fluid resuscitation in severe sepsis, for which albumin continues to be recommended by the Surviving Sepsis Guidelines ‘when patients require substantial amounts of crystalloids’ (grade 2C)(1).

Compared with crystalloid solutions, albumin has a number of potential advantages.  A smaller volume of albumin is required for equivalent intravascular volume expansion, although the ratio in on large study was 1:1.4 rather than 1:3 as anticipated based on physiological modelling.  It has been suggested that albumin may have a role in maintaining the glycocalyx, thereby reducing capillary leak(2), and may act as a free radical scavenger.

There are also a number of significant disadvantages to the use of albumin.  It is a fractionated blood product, heated to minimise the risk of viral transmission.  It is expensive and antigenic, carrying a small risk of anaphylaxis.

The 1998 Cochrane Injuries Group Albumin Reviewers conducted a meta-analysis of 1419 patients in 30 small randomised controlled trials comparing crystalloids to albumin in critically ill patients with hypovolaemia, burns and hypoalbuminaemia(3).  They reported an increased risk of death with albumin in every subgroup.  Overall the relative risk of death for patients receiving albumin was 1.68 (95% confidence interval 1.26-2.23); for patients with burns the relative risk was 2.40 (1.11 to 5.19).  They concluded that, given there was no evidence that albumin was of benefit to these patients and that there was a strong suggestion of harm, albumin should not be used for fluid resuscitation outside of clinical trials.  A subsequent meta-analysis was published in 2001, including 55 trials and 3504 patients(4).  In contrast, they found no significant effect on mortality, which they concluded supported the safety of albumin.  They highlighted the need for a well-designed clinical trial.

The Saline versus Albumin Fluid Evaluation (SAFE) trial was carried out in Australia and New Zealand aiming to address the uncertainty regarding the effect of albumin for resuscitation of critically ill patients.  Unlike most other countries, albumin is provided free to hospitals in Australia(5).  The SAFE Study Investigators compared 0.9% saline with 4% albumin for resuscitation in critically ill patients in a blinded, randomised controlled trial of 6997 patients(6).  It was powered to detect a 3% difference in mortality with an estimated baseline mortality of 15%.  There was no difference in the primary outcome, which was 28-day mortality.  This is usually interpreted as meaning that albumin is safe compared with 0.9% saline, although given that 0.9% saline is generally avoided in intensive care due to the high chloride load this statement should be viewed with caution.  Pre-defined subgroup analysis of patients with severe sepsis suggested albumin may be associated with a reduced risk of death(7).  A post hoc follow-up study found resuscitation with albumin was associated increased two year mortality in patients with traumatic brain injury, relative risk 1.63 (1.17 to 2.26)(8).

In 2006 Dubois and colleagues published a pilot study examining 100 critically ill patients with hypoalbuminaemia(9).  Patients were randomised to receive 20% albumin while serum albumin was less than 31g/l or to receive no albumin.  They found that organ function improved more in the albumin than control group and that fluid gain was three times higher in the control group.

Following this, the Albumin Italian Outcome Study (ALBIOS) was conducted in 1818 severely septic patients(10).  Patients were randomised to receive either 20% albumin administered to maintain serum albumin of 30g/l plus crystalloid as clinically indicated or crystalloid alone.  It was powered to detect a 7.5% difference in mortality at 28 days with an estimated baseline mortality of 45%.  There was no difference in the primary outcome of 28-day mortality (31.8% vs. 32.0%).  However the lower than expected mortality increases the possibility of a type two error, i.e. failing to detect a true difference.  A post hoc subgroup analysis of 1121 patients with septic shock at enrolment found reduced mortality (43.6% vs. 49.9%) and is hypothesis generating.  There was no significant difference in the volume of fluid administered in the first seven days although the treatment group did achieve a significantly more negative fluid balance than controls.

The ALBUR study, published in 2006, compared Ringer’s Lactate and albumin in patients with at least 20% TBSA burns(11).  The study was suspended early due to slow enrolment; 42 of an intended 90 patients were enrolled.  There was no difference in the primary outcome, which was a difference in multiple organ dysfunction score.  Predicted mortality was 18.6% in the treatment group and 9.4% in the control group and only one patient received an adrenergic agent.  Actual mortality was 3/19 in the treatment group and 1/23 in the control group, p=0.313.  The authors calculated that a sample of 1162 patients would be required to power a study to detect 6% difference in mortality in patients with three validated risk factors for mortality, meaning such a trial is not feasible.

---

Lessons learnt

Human albumin solution is used in critical care for resuscitation and to assist in achieving a negative fluid balance.  However there is significant variation in practice both across different intensive care units and between different consultants.

There is limited evidence that albumin as a resuscitation fluid is of benefit to critically ill patients, although there is no convincing evidence of harm.  Studies in patients who may benefit, such as those with septic shock and severe burns with high predicted mortality have not been conducted.  In the case of severe burns it is unlikely that an adequately powered study will ever be carried out.  Experience suggests that patients receiving albumin after large volumes of crystalloid often appear to benefit, this practice is in keeping with the Surviving Sepsis Guidelines.  However I am also mindful of the FEAST study(12), which found that fluid boluses were associated with shock reversal at one hour but actually increased mortality and wonder whether we should be moving towards a more restrictive approach to fluid resuscitation in general.

---

 

References

1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med. Springer-Verlag; 2013;39(2):165–228.
2. Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF. Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular permeability. Anesthesiology. 2006 Jun;104(6):1223–31.
3. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. BMJ Group; 1998 Jul 25;317(7153):235–40.
4. Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. 2001 Aug 7;135(3):149–64.
5. van Haren F, Zacharowski K. What’s new in volume therapy in the intensive care unit? Best Pract Res Clin Anaesthesiol. Elsevier; 2014 Sep;28(3):275–83.
6. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. NEJM. 2004 May 27;350(22):2247–56.
7. SAFE Study Investigators, Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, et al. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. Springer-Verlag; 2011 Jan;37(1):86–96.
8. SAFE Study Investigators, Australian and New Zealand Intensive Care Society Clinical Trials Group, Australian Red Cross Blood Service, George Institute for International Health, Myburgh J, Cooper DJ, et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. NEJM. 2007 Aug 30;357(9):874–84.
9. Dubois M-J, Orellana-Jimenez C, Melot C, De Backer D, Berre J, Leeman M, et al. Albumin administration improves organ function in critically ill hypoalbuminemic patients: A prospective, randomized, controlled, pilot study. Crit Care Med. 2006 Oct;34(10):2536–40.
10. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin replacement in patients with severe sepsis or septic shock. NEJM. 2014 Apr 10;370(15):1412–21.
11. Cooper AB, Cohn SM, Zhang HS, Hanna K, Stewart TE, Slutsky AS, et al. Five percent albumin for adult burn shock resuscitation: lack of effect on daily multiple organ dysfunction score. Transfusion. Blackwell Science Inc; 2006 Jan;46(1):80–9.
12. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011 Jun 30;364(26):2483–95.