1. What is albumin?
2. Why is it important?
3. What causes serum albumin to decrease?
4. Consequences of decreased plasma albumin
5. Disease processes associated with Hypoalbuminaemia
6. Albumin as a prognostic index
7. Correcting Hypoalbuminaemia
8. The recent fuss about albumin
9. Key Points

1. Capillary and interstitial free albumin concentration.
2. Capillary permeability to albumin.
3. Movements of solvent / solute.
4. Electrical charges across the capillary wall.
5. Lymph protein content is 80% that of plasma.

Measurement of serum albumin is by using a dye binding technique using bromocresol green or purple: this tends to overestimate albumin concentration when the serum albumin is low - especially when there is increased levels of a or b globulin. Because of this overestimation, is rare to see a serum albumin < 10 - 15g/l.

BCP is more sensitive than BCG.

1. Binding and transport.

2. Maintenance of colloid osmotic pressure.

3. Free radical scavenging.

4. Platelet function inhibition and antithrombotic effects.

5. Effects on vascular permeability.

There are actually four binding sites on albumin and these have varying specificity for different substances.

Competitive binding of drugs may occur at the same sit or at different sites (conformational changes) [eg. warfarin and diazepam].

The drugs that are important for albumin binding are: warfarin, digoxin, NSAIDS, midazolam, thiopentone.

The relevence of a low albumin and drug binding is unknown.

Albumin is responsible for 75 - 80 % of osmotic pressure.

Starling's equation: Transcapillary Flow = k [(Pcap + p i) - (Pi + p cap )]

Remember that albumin is the main protein both in the plasma and in the interstitium and it is the COP gradient rather than the absolute plasma value that is important: this is what distinguishes hypoalbuminaemia derived from redistribution (capillary leak) from that of pure full body deficiency.

Albumin is a major source of sulphydryl groups, these "thiols" scavenge free radicals (nitrogen and oxygen species).

Albumin may be an important free radical scavenger in sepsis.

The anticoagulant and antithrombotic effects of albumin are poorly understood this may be due to binding nitric oxide radicals inhibiting inactivation and permitting a more prolonged antiaggregatory effect.

In diabetes, glycosylated albumin may increase the incidence of thrombotic events and atherosclerosis.

In sepsis there is an increased rate of albumin loss into the tissues - this is probably related to increased capillary membrane permeability.

Plasma albumin concentation = intravascular albumin mass / plasma volume

Decreased plasma albumin:

1. Decreased synthesis.

2. Increased catabolism [ very slow ]

3. Increased loss:

• Nephrotic syndrome
• Exudative loss in burns
• Haemorrhage
• Gut loss

4. Redistribution:

• Haemodilution
• Increased capillary permeability (Increased interstitial albumin)
• Decreased lymph clearance.

1. Decreased ligand binding.

2. Decreased plasma colloid pressure: decreased colloid oncotic pressure, and oedema formation.

The formation of oedema is determined by:

The rate of fluid flux

The clearance of fluid by lymphatics.

• In critical illness, there is a stronger correlation between colloid oncotic pressure and Total protein than with albumin.
• In these patients the decreased albumin is compensated for by an increase in acute phase proteins.
• Unquestionably there is increased leakage of albumin and this drags fluid with it .
• Lymphoid function is important - if it is overwhelmed by increased capillary permeability or fluid flux then oedema will occur.
• It is likely that lymphoid dysfunction plays a significant role in oedema formation in critical illness. ?? do free radicals cause this lymphoid dysfunction?

Bottom line: low serum albumin does not necessarily mean low plasma oncotic pressure.

Malnutrition

Serum albumin does not appear to decrease in starvation.

The body maintains the serum albumin at the expense of muscular protein:

Decreased synthesis increased redistribution decreased catabolism.

Bottom line: decreased albumin in adults is a marker of associated disease not a feature of isolated protein-energy malnutrition.

Liver Dysfunction

Albumin is a poor marker of liver dysfunction; Prothrombin time is more reliable.

Renal disease

Albumin loss occurs in nephropathies (nephrotic syndrome).

There is a small loss of albumin in dialysis circuits.

Pre-Eclampsia

In normal pregnancy there is an increase in plasma volume. In PET there is a paradoxical decrease in plasma volume and capillary leak syndrome.

Interleukins cause a marked decease in synthesis of plasma proteins other than albumin.

In fact Albumin and Transferrins decrease in the stress response, a process often termed "negative acute phase proteins".

IL6 directly decreases the expression of albumin messenger RNA.

Overall, the picture in the stress response is:

1. Initial decrease in albumin associated with increase in acute phase proteins.

2. Subsequent global increase in hepatic protein synthesis; including albumin.

There is massive protein loss from the burn site & increased vascular permeability & decreased albumin synthesis & protein losing nephropathy.

Increased redistribution and transcapillary escape of albumin.

Decreased serum albumin preoperatively is an independent indicator of poor outcome.

SIRS - associated with increased capillary permeability, due to the effects, amongst others, of bacterial endotoxin and cytotoxic T cells.

In sepsis there is a profound reduction in plasma albumin associated with marked fluid shifts.

Albumin as a prognostic index

Low albumin is associated with dozens of diseases.

Controversy regarding whether or not albumin is a good indicator of prognosis in critical illness. One recent study suggests:

"In patients with acute and chronic illness serum albumin concentration is inversely related to risk of death. A systematic review of cohort studies meeting specified criteria estimated that for each 2.5 g/l decrement in serum albumin concentration the risk of death increases by between 24% and 56%."

Journal of Clinical Epidemiology 1997; 50; 693-703.

Following serum albumin levels may be of value - intial decrease associated with deterioration, later gradual increase signifies recovery in process.

Low serum albumin concentrations are the consequence of a disease process and successful treatmen of the underlying disease should result in a gradual return to normal serum albumin concentrations.

Studies have not shown that the theraputic "normalisation" of albumin levels in critically ill patients is beneficial. Indeed the Cochrane group's recent "meta" analysis suggests a higher mortality rate in critically ill patients treated with albumin.

Previous strategies have involved administering albumin to decrease the loss of intravascular volume by enhancement of collloid oncotic effect. However, in sepsis, 2/3 of administered albumin has been shown to extravascate within 4 hours of administration.

Debunked Myths (by randomised controlled trials):

• The use of 20% albumin and frusemide to reduce oedema in SIRS.
• The administration of albumin following paracentesis for ascites.
• The use of replacement albumin in nephrotic syndrome.

It is very questionable whether or not albumin should remain the colloid of first choice in paediatric practice.

Commercially available albumin is fractionated in ethanol and purified and heat treated for 10 hours at 60 degrees celcius.

This process:

Probably alters the charge on albumin - making it more permeable.

Contains significant quantities of residual ions - aluminium and vanadium.

BMJ 1998;317:235-240 ( 25 July )

Objective: To quantify effect on mortality of administering human albumin or plasma protein fraction during management of critically ill patients.

Design: Systematic review of randomised controlled trials comparing administration of albumin or plasma protein fraction with no administration or with administration of crystalloid solution in critically ill patients with hypovolaemia, burns, or hypoalbuminaemia.

Subjects: 30 randomised controlled trials including 1419 randomised patients.

Main outcome measure: Mortality from all causes at end of follow up for each trial.

• Human albumin solution has been used in the treatment of critically ill patients for over 50 years
• Currently, the licensed indications for use of albumin are emergency treatment of shock, acute management of burns, and clinical situations associated with hypoproteinaemia
• Our systematic review of randomised controlled trials showed that, for each of these patient categories, the risk of death in the albumin treated group was higher than in the comparison group
• The pooled relative risk of death with albumin was 1.68 (95% confidence interval 1.26 to 2.23) and the pooled difference in the risk of death was 6% (3% to 9%) or six additional deaths for every 100 patients treated
• We consider that use of human albumin solution in critically ill patients should be urgently reviewed

• Neil Soni, Consultant in intensive care.
  "I was asked to review the Cochrane Injuries Group's paper for the BMJ. I quote from my covering letter: "It should not be published."
• Altogether 30 randomised studies with population sizes ranging from 12 to 219 (over half had fewer than 30 patients) were assessed, with a total of 1419 patients. No account taken of the purpose, design, or specific end points of the studies.
• The end point of the review mortality was not an end point in most studies, many of which were over less than five days.
• Most deaths occurred outside the study times.
• Variables ignored included age, medical conditions, severity of disease, dose of albumin, mode of administration, and attributable mortality of the states of disease that were treated.
• The evolution of fluid management between the 1970s and now was also dismissed. Common factors were randomised controlled trials that compared administration of albumin with no administration or administration of crystalloid, and, of course, the term "critically ill."
• The message, presented with the combined weight of Cochrane and the BMJ, is that albumin, whether used in neonates or adults, whether for volume replacement or the support of biochemical variables, whether given intraoperatively as a single dose or long term over days or weeks, is potentially hazardous.
• Practice is already changing. Change, with its potential hazards, is entirely justifiable if the evidence is powerful enough to decree change but it is not.
• The review is a tribute to an association of key words and modern computer technology, and the results are serendipitous and amount to evidence that is at best circumstantial.
• The authors talk of totality of available evidence, but is that totality synonymous with adequacy?
• Evidence should lead to change, but surely there is a responsibility to ensure that the weight of evidence published by august bodies is adequate to justify that change.
• Does the responsibility lie with the researcher, the reviewer, or the journal? When does a strongly negative peer review become negative? Surely negative reviews should be acknowledged by the journal, otherwise publication fraudulently implies positive peer review.
• Finally, are these review methods valid? It is time to define their value because I believe that otherwise such studies will damage the credibility of not only the methods used, which are potentially powerful and useful, but also of the journals that carry them."

"On the basis of our systematic review of randomised trials we concluded that "there is no evidence that albumin administration reduces mortality in critically ill patients, and a strong suggestion that it may increase mortality." We read with anticipation the letters in response to our review, but note with concern that none of the correspondents provide any evidence that albumin is beneficial in critically ill patients, in which case our conclusions stand."

Ian Roberts, Director, Child Health Monitoring Unit.
Department of Epidemiology and Public Health, Institute of Child Health, London WC1N 1EH

Albumin is an important intravascular and extravascular protein; it contributes strongly to the maintenance of colloid osmotic pressure.

Binding and transport, osmotic pressure, free radical scavenging, platelet function inhibition and antithrombotic effects.

Decreased synthesis, increased catabolism, increased loss & redistribution.

• Consequences of decreased plasma albumin

1. Decreased ligand binding.

2. Decreased plasma colliod pressure

• Disease processes associated with Hypoalbuminaemia

In critical illness, there is a stronger correlation between colloid oncotic pressure and Total protein than with albumin.

Albumin decreases in burns, liver disease, renal disease, pre-eclampsia, stress and sepsis.

• Albumin as a prognostic index

Serum albumin concentration in critical illness is inversely related to the risk of death.

• Correcting Hypoalbuminaemia

The "normalisation" of plasma albumin concentrations has nor been shown to improve outcome in critical illness and in many of the traditional theraputic roles of albumin

• The recent fuss about albumin

The Cochrane report in the BMJ in July 1998 suggested that treatment with albumin was related to a 6% excess of deaths above control. Although this study was flawed in many ways, it has illustrated what many have believed for some time: that theraputic albumin therapy has little role in the management of most patients. Nevertheless, where albumin's use is well defined - in paediatrics / burns, it's abandonment does not appear justified at this time.