Role of Albumin in PICU

DR FARHANSHAIKHConsultant Pediatric Intensivist

In-charge Quality and AccreditationRainbow Children’s Hospital

Hyderabad

WHY ALBUMIN IS “HOT” TOPIC?

• A search of word ALBUMIN on pubmed yields 199,905 results !

• Search word “Hemoglobin” yields 155311 results!

• Almost 40% of all the publications on albumin have been concentrated in the last 10 years

Physiology and pathophysiology of albumin in humans

• Molecular weight of 66,500 Daltons,

• Albumin is responsible for about 80% of the intravascular oncotic pressure.

Weil MH, Henning RJ, Puri VK. Colloid oncotic pressure: clinical significance. Crit Care Med 1979;7:113-6

• The liver produces albumin, which is immediately secreted into the intravascular space by the cells without being stored.

• From the intravascular space, albumin passes into the interstitial space to different degrees and at different rates depending on the anatomical location, in a process called "transcapillary filtration”.

• In regions where endothelium has large gaps, the filtration of albumin is passive

• In regions where endothelium is non-fenestrated Albumin filtration is active, under the particular action of a specific receptor, i.e., “albondin”.

Molecular structure of albumin

Three main characteristics

(i) cysteine residues (ii) domains I and II and (iii) imidazole residues.

How Albumin Helps?

The oncotic properties of this protein play a critical role in regulating volaemic status particularly during adverse clinical conditions where volaemia is very often altered.

• Cysteine residues in position 34 expose a –SH radical group (thiol), which is one of the main extracellular antioxidants.

• Moreover, –SH residues bind nitric oxide to form S-nitrous thiols, thereby neutralizing one of the most important mediators of pathological conditions mainly sepsis

Albumin may also neutralize the vasodilating effect of nitric oxide, which is the most important mediator altering vascular tone during sepsis or other pathological conditions such as hepat-orenal syndrome

Albumin domains I and II are responsible for the transport of the numerous molecules, both endogenous and exogenous, that are extensively carried by human albumin.

• Finally, albumin has 16 histidine imidazole residues, which are responsible for the “buffer function” of albumin.

• Having a pH of about 6.75, the residues may both give up or accept H+ from the environment depending on the surrounding pH, thereby acting as a buffer molecule.

WHAT DOES THE LITERATURE SAY ?

YEAR 1998

This Cochrane report based on a meta-analysis suggested the potentially harmful effect of albumin administration as compared to other fluids for volume replacement

The meta-analysis, included 32 clinical trials involving a total of 1,419 patients, and showed, among patients with surgery- or trauma-induced hypovolaemia, no differences in mortality between those treated with albumin and those treated with crystalloids.

In fact, patients with burns who were treated with albumin appeared to have a higher mortality rate as compared to those treated with crystalloids.

The authors concluded.."There is no evidence that the administration of albumin reduces mortality in critically ill patients with hypovolemia, burns, hypoalbuminemia, but rather a strong indication that it increases mortality”

This led to an extensive reduction of the use of albumin in some countries

Use of Albumin in Intensive Care Units in the United Kingdom J. M. BROWN et al. Critical Care and Resuscitation 2001; 3: 19-21

Meta-analysis published in 2001, concluding that ALBUMIN ADMINISTRATION WAS SAFE, although it had no effects on global mortality.

A third meta-analysis, which included nine prospective, randomized clinical trials on critically ill patients with hypoalbuminaemia, was concluded and published in 2003.

A statistically significant correlation was observed between the rate of complications and the plasma level of albumin

Meta-analysis regression analysis

The authors concluded :

"Currently there is no reason for not administering albumin when clinically appropriate."

Three Meta-analyses produced completely

opposite and controversial results!

• The first metanalysis appeared to be AGAINST

• The second one was NEUTRAL and

• The third one was IN FAVOUR of the clinical use of albumin.

WHY THIS CONTROVERSY..??

• Many Heterogenous studies with heterogeneous patient selection

• The point in time at which fluid was administered to patients enrolled in these trials could have been crucial.

anti- oxidant paradox effect• A good anti-oxidant is a reducing agent.

• Oxidative damage releases transition metals from damaged metallo-proteins.

• By reducing these transition metals, an anti- oxidant administered after damage has started can create more reactive species which catalyse ROS formation.

Higher doses of albumin, and Its Delayed administration,

May not BE comparable with LOWER DOSES AND ITS early Administration

Hypoalbuminemia in Acute Illness: Is There a Rationale for Intervention? A Meta-Analysis of Cohort Studies and Controlled Trials. Jean-Louis Vincent et al ANNALS OF SURGERY Vol. 237, No. 3, 319–334

Study protocols also varied with regard to fluid volume administration: • some used fixed doses, • others targeted cardiovascular parameters or

metabolic markers of perfusion and • others allowed clinical discretion.

EVERY ALBUMIN IS NOT SAME!!Albumin from different batches of the same product contain molecules with a wide range of variable post-translational modifications including ..• glycosylation, • missing terminal amino acids and

cysteinylation and nitrosilation of the free cysteine residue

Bar-Or D, Bar-Or R, Rael LT et al. Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Crit Care Med 2005;33:1638-41.

• Some of these variations lead to a loss of oxidant-buffering capacity, and abolish the molecules’ ability to chelate free copper.

• Thus clinical effects may vary and this can seriously affect the final outcome.

• Genetically engineered recombinant Albumin may eliminate such variations and allow more predictable clinical outcomes.

Hypoalbuminemia in Acute Illness: Is There a Rationale for Intervention? A Meta-Analysis of Cohort Studies and Controlled Trials. Jean-Louis Vincent et al ANNALS OF SURGERY Vol. 237, No. 3, 319–334

The SAFE study

The SAFE study

16 ICU in Australia and New Zealand conducted a prospective, randomized, double- blind study, the Saline vs. Albumin Evaluation (SAFE) study

The study compared the effects of the infusion of 4% albumin and saline solution (0.9% NaCl) for volume replacement in critically ill patients with hypovolemia Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56

About 7,000 patients were enrolled.

Three predefined subgroups of patients with specific diseases i.e.• sepsis, • trauma and• acute respiratory distress syndrome.

No difference in 28-day mortality, length of stay, or organ dysfunction was observed between the groups of patients receiving the two different treatment.

Thus, clearly demonstrating that 4% albumin infusion for volume replacement in critically ill patients does not offer any advantage as compared to normal saline, or, in other words, that albumin administration is "safe".

Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56

Albumin may be as safe as Saline, but that does not mean Albumin is better !

Agreed..However..• The SAFE study was not designed to

investigate possible beneficial effects of albumin

• The amount of study fluid was relatively limited.

The great contribution of the SAFE study came from the subgroup analysis performed

• The patients with trauma, especially after head injury, treated with albumin tended to have a higher mortality rate (P = 0.06)

• those with severe sepsis tended to show a better survival, although the difference did not reach statistical significance (P = 0.09).

SAFE study, for the first time, turned the attention of researchers towards the possible crucial role of different categories of patients, when dealing with the type of fluid to be employed for volume replacement.

Patients with traumatic brain injury

A post- hoc follow-up of the patients with traumatic brain injury previously enrolled in the SAFE study,

Higher mortality was observed in patients with severe traumatic brain injury, with mortality rates of 41.8% and 22.2% in patients treated with albumin or saline, respectively (p < 0.001)

The authors, therefore, concluded that “critically ill patients with traumatic brain injury, fluid resuscitation with albumin was associated with higher mortality rates than was resuscitation with saline"

Hypoalbuminemia Vs Mortality

Many studies in children as well as adults have demonstrated strong association between hypoalbuminemia and mortality

Powers KA, Kapus A, Khadaroo RG, et al. Twenty-five percent albumin prevents lung injury following shock/ resuscitation. Crit Care Med 2003;31:2355-63. Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol 1997;50:693-703. 38) Roberts I, Bunn F. Egg on their faces. The story of human albumin solution. Eval Health Prof 2002; 25:130-8.

Year 2006 Dubois study

Crit Care Med 2006;34:2536-40.

This study investigated the hypothesis that correcting hypoalbuminaemia in critically ill patients in an attempt to maintain plasma albumin concentration within the normal range (greater than 3 g/dL) may have beneficial effects on organ function.

In Dubois study, patients were randomized to receive 300 mL of 20% albumin solution on the first day after randomization and 200 mL/day if their plasma albumin concentration was lower than 3 g/dL in the treated group, or to receive no albumin infusion in the control group.

Crit Care Med 2006;34:2536-40.

The authors, concluded that "Albumin administration may improve organ function in hypoalbuminaemic critically ill patients"

Crit Care Med 2006;34:2536-40.

This study provided, for the first time, some evidence about the critical role of maintaining plasma albumin concentrations within a normal range, throughout the ICU admission, with a possible impact on organ function.

Albumin Vs Artificial Colloids

This systematic review includes the results of four recent randomized clinical trials of HES 130/0.38-0.45 comprising more than 3000 patients with sepsis

The study showed Hydroxy Ethyl Starch increased…

• the use of renal replacement therapy • transfusion with red blood cells,• Resulted in more serious adverse events

inpatients with sepsis.

The authors concluded that..

“It seems unlikely that hydroxyethyl starch provides overall clinical benefit for patients with sepsis”.

Clinical indications of using Albumin

Three important categories can be made:

• Patients with traumatic brain injury, • Patients with peripheral oedema during their

recovery phase, and • Patients with severe sepsis.

Patients with traumatic brain injury

Patients with an active brain injury due to cerebral trauma, albumin administration should be avoided, preferring other types of fluids, such as normal saline, for acute volume resuscitation.

Patients with peripheral oedema during their recovery phase

In using crystalloids for volume replacement, the most important disadvantage is ..

• the greater amount of fluids to be infused in order to reach the same volume effect of albumin or other synthetic colloids

• a consequent increased risk of peripheral oedema and weight gain.

Artificial colloids • Not found to be beneficial in sepsis

• May cause coagulopathy, because of absorption of the factor VII/von Willebrand factor complex,

• May lead to an increased risk of developing acute renal failure.

de Jonge E, Levi M. Effects of different plasma substitutes on blood coagulation: a comparative review. Crit Care Med 2001;29:1261-7.

THEORATICALLY…

• During Acute phase , due to leaky capillaries even Albumin can leak out of the blood vessels but Albumin leaks slower than crystalloids thus reducing overall fluid required for resuscitation.

(e.g. In Dengue Shock )

• During “recovery phase” as the capillaries stabilize, and Albumin will hold on intravascularly and improve the hemodynamics.

• Unfortunately, no clear evidence from randomized clinical trials or other forms of large studies are currently available in this regard.

• However, the soundness of the biological and pathophysiological rationale may at least partially justify such an indication for albumin administration.

Lack of evidence may not necessarily exclude the possible beneficial effect

In spite of no clear evidence from randomized clinical trials Albumin can be considered useful in patients with..• marked hypoalbuminaemia, • peripheral edema, and • in serious need of water elimination, especially

in their recovery phase after acute volume replacement.

(Severe edema in Nephrotic syndrome, Post Cardio Pulmonary Bypass targetting Sr Albumin > 2.5gm% by Albumin transfusion and Diuretics)

• Recently completed recruiting 1,818 patients fulfilling criteria for severe sepsis or septic shock.

• All patients were resuscitated with crystalloids according to early goal-directed therapy protocols.

The ALBIOS Study (ALBumin Italian Outcome Sepsis)

Gattinoni L, Caironi P. The AlbIOS Study. Newsletter 36. http:// www.negrisud.it/albios/news/newsletter_albios_36.pdf Accessed 28 March 2012.

• In addition, the intervention group received 300 mL 20% HAS on day 1 and further daily infusions to maintain serum albumin at or above 3 g/dL for the next 27 days.

• The primary outcome was originally 28-day mortality, although this has been extended to 90 days.

• In patients with sepsis albumin infusion compared to crystalloids alone provided hemodynamic advantages, and more favorable fluid balance without survival benefits.

• In patients with septic shock, hemodynamic fluid balance advantages were greater than in general population and, in addition, these patients survived significantly more at 90 days.

CONCLUSIONApart from its oncotic properties, albumin may be useful in critical care through its secondary functions, such as..

• The modulating action on nitric oxide metabolism • free radical production• its buffer effect in the acid-base equilibrium,• its action as a transporter of many different

substances and drugs

Patients with severe sepsis

Although Albumin can leak through capillaries in early shock but it will leak slower than crystalloids, hence it can still be used during acute shock state to reduce overall fluid requirement.

During later stages, it will be beneficial in maintaining oncotic pressure, fluid shifts.

Albumin may have a beneficial impact..

• In patients with severe hypoalbuminaemia and peripheral oedema

• During the recovery phase after acute volume replacement

• On the elimination of the excessive accumulated volume.