Neuroprotection Provided by
Local Administration of LowDose Cold Albumin in Acute
Ischemic Stroke
Vance Fredrickson
Wayne State University
School of Medicine
Albumin – functions in plasma
Major protein (t1/2 ~ 20 days)
 Creates 80% of the colloid oncotic
pressure
 Transporter of endogenous substances

◦ fatty acids
◦ Unconjugated bilirubin
◦ Hormones
Main drug binding protein
 Buffers pH

Clinical Uses

(widespread consensus for use)
Paracentesis
◦ infused after volumes of >5 L removed

Therapeutic Plasmapheresis
◦ Infused after exchanges of > 20 mL/kg

Spontaneous bacterial peritonitis
◦ In association with antibiotics
Albumin in Acute Ischemic Stroke
(animal studies – with systemic administration )

Neuroprotective properties
(25% Alb, 1.25 – 2.5
g/kg)
◦
◦
◦
◦
◦

Improved neurological scores
Decreased infarction size
Reduced brain swelling
Improved cerebral perfusion
Normalizes changes seen on MRI
Therapeutic window: 4-5 hours
Possible Mechanisms of
Neuroprotection
Increase in plasma oncotic pressure
 Increase pyruvate dehydrogenase in
astrocytes

◦ increase flux of glucose and lactate
Maintenance of normal vascular
permeability
 Inhibition of endothelial cell apoptosis

Clinical Trials
(systemic Albumin administration)

ALIAS Pilot Trial (0.34-2.05 g/kg)
◦ Pulmonary Edema (dose-dependent)
 16.7 % in patients receiving 1.03 g/kg Alb
 27.8 % in patients receiving 1.37 g/kg Alb

ALIAS Part 1 Trial (2 g/kg)
◦ Pulmonary edema
 3-higher in Alb treated group compared to control
◦ Suspended due to safety concerns
Clinical Trial
(systemic Albumin administration)

ALIAS Part 2 Trial (2 g/kg systemic Alb)
◦ Additional measures taken
 Require normal baseline serum troponin
 Restriction of IV fluids
 Mandatory diuretics
◦ Trial in progress
◦ Will likely restrict the number of patients
receiving therapy
Questions Addressed in our
Animal Model of Acute Ischemic
Stroke
Can a local low-dose albumin infusion
provide similar neuroprotection as
systemic high-dose?
 Does a local low-dose cold albumin
infusion provide additional benefit?

Experiment Design
64 Male Sprague-Dawley rats
MCA occlusion induced by a modified
microcatheter (2 hr occlusion)
 Local infusion treatment groups


◦ Catheter withdrawn 1-2 mm for reperfusion
and treatment infusion was begun

Systemic infusion treatment groups
◦ Catheter withdrawn completely and albumin
administered via femoral artery

Infused volumes 2.5 mL
Experimental Groups

Non-treatment group (n=8)

Local Infusion Groups

Systemic Infusion Groups
◦ 2 hr MCA occlusion followed by 48 hours of
reperfusion
◦ cold (0°C) saline (0.9% NS, n=12)
◦ low-dose cold (0°C) human Alb (0.5 g/kg, n=12)
◦ low-dose normothermic (37°C) human Alb (0.5
g/kg, n=12)
◦ low-dose normothermic (37°C) human Alb (0.5
g/kg, n=8)
◦ high-dose normothermic (37°C) human Alb (1.5
g/kg, n=12)
Results - Hypothermia
(local cold saline and cold Alb infusion groups)
Hypothermia induced in less than 3 mins
 Cerebral cortex (region supplied by the
MCA)

◦ 37.2 ± 0.20C to 30.5 ± 0.40C

Striatum
◦ 37.8 ± 0.10C to 30.8 ± 0.40C

Temperatures remained reduced for up to
45 mins.
Results – Lesion Volume
Brain Infarct Volume
Infarct Volume (Mean% ±SEM)
80
60
*
**
#
40
*
*
20
0
Nontreatment

Local 0°C
Systemic 37°C
saline (2.5ml)
Alb (0.5g/kg)
Local 0°C Alb Local 37°C Alb Systemic 37°C
(0.5g/kg)
(0.5g/kg)
Alb (1.5g/kg)
Local low-dose cold albumin results in
smallest lesion volume.
Results – Lesion Volume
Brain Infarct Volume
Infarct Volume (Mean% ±SEM)
80
60
*
**
#
40
*
*
20
0
Nontreatment

Local 0°C
Systemic 37°C
saline (2.5ml)
Alb (0.5g/kg)
Local 0°C Alb Local 37°C Alb Systemic 37°C
(0.5g/kg)
(0.5g/kg)
Alb (1.5g/kg)
Local low-dose Alb provides a similar
reduction in lesion volume as systemic
high-dose Alb
Results – Neurological Exam
Neurological Deficits
5
Nontreatment
Mean Score (±SEM)
4.5
4
3.5
3
2.5
*
# *
2
*
1.5
# *
* *
Local 0°C AIb
(0.5g/kg)
Local 0°C Saline
(2.5ml)
Local 37°C AIb
(0.5g/kg)
Systemic 37°C AIb
(1.5g/kg)
Systemic 37°C AIb
(0.5g/kg)
1
0.5
0
30 Min

24 Hrs
48Hrs
Local low-dose cold Alb treatment results in strongest reduction
in deficits according to neurological exam
Results – Neurological Exam
Neurological Deficits
5
Nontreatment
Mean Score (±SEM)
4.5
4
3.5
3
2.5
*
# *
2
*
1.5
# *
* *
Local 0°C AIb
(0.5g/kg)
Local 0°C Saline
(2.5ml)
Local 37°C AIb
(0.5g/kg)
Systemic 37°C AIb
(1.5g/kg)
Systemic 37°C AIb
(0.5g/kg)
1
0.5
0
30 Min

24 Hrs
48Hrs
Local low-dose and systemic high-dose Alb treatments resulted in
similar improvement in neurological exam
Results – Motor Evaluation
Forelimb Fault
6
Local 0°C saline (2.5ml)
Local 0°C Alb (0.5g/kg)
Error (Mean±SEM)
5
4
3
2
Nontreatment
Local 37°C Alb (0.5g/kg)
Systemic 37°C Alb (1.5g/kg)
*
Systemic 37°C Alb (0.5g/kg)
**
#
*
*
1
0
2 Days after Reperfusion
Results – Motor Evaluation
Parallel Bars
Error (Mean±SEM)
10
8
6
4
*
**
*
*
#
2
0
2 Days after Reperfusion
Results – Motor Evaluation
Ladder Climbing
Duration (Mean Second±SEM)
70
60
50
40
30
*
*
**
#
*
20
10
0
2 Days after Reperfusion
Results – Motor Evaluation
Duration (Mean Second±SEM)
Rope Climbing
120
100
*
80
60
*
**
#
*
40
20
0
2 Days after Reperfusion
Summary
Local low-dose and systemic high-dose
Alb provide similar neuroprotection
 Synergistic effect of regional brain
hypothermia and local low-dose Alb
administration
 This protocol combined with tPA or
mechanical embolectomy, may be of
benefit in the clinical setting.

Questions?
References





Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke:
Marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke;
a journal of cerebral circulation. 2001;32:553-560
Ginsberg MD, Hill MD, Palesch YY, Ryckborst KJ, Tamariz D. The alias pilot trial: A dose-escalation
and safety study of albumin therapy for acute ischemic stroke--i: Physiological responses and
safety results. Stroke; a journal of cerebral circulation. 2006;37:2100-2106
Palesch YY, Hill MD, Ryckborst KJ, Tamariz D, Ginsberg MD. The alias pilot trial: A dose-escalation
and safety study of albumin therapy for acute ischemic stroke--ii: Neurologic outcome and efficacy
analysis. Stroke; a journal of cerebral circulation. 2006;37:2107-2114
Ginsberg MD, Palesch YY, Martin RH, Hill MD, Moy CS, Waldman BD, et al. The albumin in acute
stroke (alias) multicenter clinical trial: Safety analysis of part 1 and rationale and design of part 2.
Stroke; a journal of cerebral circulation. 2011;42:119-127
Liumbruno G, Bennardello F, Lattanzio A, et al. Recommendations for the use of albumin and
immunoglobulins. Blood Transfus. 2009;7:216–34.