Role of Albumin in Critical Care and Intensive Care setting.

1. Role of Albumin in PICU
DR FARHANSHAIKH
Consultant Pediatric Intensivist
In-charge Quality and Accreditation
Rainbow Children’s Hospital
Hyderabad

2. 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

3. 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

4. • 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”.

5. • In regions where endothelium has large gaps,
the filtration of albumin is passive
• In regions where endothelium is nonfenestrated Albumin filtration is active, under
the particular action of a specific receptor, i.e.,
“albondin”.

6. Molecular structure of albumin
Three main characteristics
(i) cysteine residues
(ii) domains I and II and
(iii) imidazole residues.

7. 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.

8. • 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

9. 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

10. 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.

11. • 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.

12. WHAT DOES THE LITERATURE
SAY ?

13. YEAR 1998

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

16. 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.

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

18. 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

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

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

21. Meta-analysis regression
analysis
A statistically significant correlation was observed
between the rate of complications and the plasma level
of albumin

22. The authors concluded :
"Currently there is no reason for not administering
albumin when clinically appropriate."

24. • 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.

25. 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.

26. 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 antioxidant administered after damage has
started can create more reactive species
which catalyse ROS formation.

27. 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

28. 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.

29. 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.

30. • 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

31. The SAFE study

32. 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

33. About 7,000 patients were enrolled.
Three predefined subgroups of patients with
specific diseases i.e.
• sepsis,
• trauma and
• acute respiratory distress syndrome.

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

35. 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

36. 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.

37. 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).

38. 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.

39. 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)

40. 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"

41. 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.

42. Year 2006 Dubois study
Crit Care Med 2006;34:2536-40.

43. 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.

44. 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.

45. The authors, concluded that
"Albumin administration may improve organ
function in hypoalbuminaemic critically ill
patients"
Crit Care Med 2006;34:2536-40.

46. 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.

47. Albumin Vs Artificial Colloids

48. 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

49. 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.

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

51. 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.

52. 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.

53. 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.

54. 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.

55. 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.

56. • 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.

57. Lack of evidence may not
necessarily exclude the
possible beneficial effect

58. 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)

59. The ALBIOS Study
(ALBumin Italian Outcome Sepsis)
• 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.
Gattinoni L, Caironi P. The AlbIOS Study. Newsletter 36. http://
www.negrisud.it/albios/news/newsletter_albios_36.pdf Accessed 28
March 2012.

60. • 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.

63. • 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.

64. CONCLUSION
Apart 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

65. 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.

66. 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.