Neuroprotection Provided by Local Administration of Low-Dose Cold Albumin in Acute Ischemic Stroke

Vance Fredrickson Wayne State University

School of Medicine

Albumin – functions in plasmaMajor protein (t1/2 ~ 20 days) Creates 80% of the colloid oncotic

pressureTransporter of endogenous substances

◦fatty acids ◦Unconjugated bilirubin ◦Hormones

Main drug binding proteinBuffers 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 NeuroprotectionIncrease in plasma oncotic pressureIncrease 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 ratsMCA 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◦Catheter withdrawn 1-2 mm for reperfusion and treatment infusion was begun

Systemic infusion treatment groups ◦Catheter withdrawn completely and albumin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)

◦2 hr MCA occlusion followed by 48 hours of reperfusionLocal Infusion Groups

◦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) Systemic Infusion Groups

◦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.

Brain Infarct Volume

0

20

40

60

80

Nontreatment Local 0°Csaline (2.5ml)

Systemic 37°CAlb (0.5g/kg)

Local 0°C Alb(0.5g/kg)

Local 37°C Alb(0.5g/kg)

Systemic 37°CAlb (1.5g/kg)

Infa

rct V

olum

e (M

ean%

±SE

M)

* ***#

*

Results – Lesion Volume

Local low-dose cold albumin results in smallest lesion volume.

Brain Infarct Volume

0

20

40

60

80

Nontreatment Local 0°Csaline (2.5ml)

Systemic 37°CAlb (0.5g/kg)

Local 0°C Alb(0.5g/kg)

Local 37°C Alb(0.5g/kg)

Systemic 37°CAlb (1.5g/kg)

Infa

rct V

olum

e (M

ean%

±SE

M)

* ***#

*

Results – Lesion Volume

Local low-dose Alb provides a similar reduction in lesion volume as systemic high-dose Alb

Results – Neurological Exam

Local low-dose cold Alb treatment results in strongest reduction in deficits according to neurological exam

Neurological Deficits

00.5

11.5

22.5

33.5

44.5

5

30 Min 24 Hrs 48Hrs

Mea

n Sc

ore

(±SE

M)

Nontreatment

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)

#* *

#* **

*

Results – Neurological Exam

Local low-dose and systemic high-dose Alb treatments resulted in similar improvement in neurological exam

Neurological Deficits

00.5

11.5

22.5

33.5

44.5

5

30 Min 24 Hrs 48Hrs

Mea

n Sc

ore

(±SE

M)

Nontreatment

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)

#* *

#* **

*

Results – Motor Evaluation Forelimb Fault

0

1

2

3

4

5

6

2 Days after Reperfusion

Erro

r (M

ean±

SEM

)Nontreatment

Local 0°C saline (2.5ml)

Local 0°C Alb (0.5g/kg)

Local 37°C Alb (0.5g/kg)

Systemic 37°C Alb (1.5g/kg)

Systemic 37°C Alb (0.5g/kg)

**#

* *

*

Results – Motor Evaluation Parallel Bars

#

* *

0

2

4

6

8

10

2 Days after Reperfusion

Erro

r (M

ean±

SEM

)

**

*

Results – Motor Evaluation Ladder Climbing

#

* *

0

10

20

30

40

50

60

70

2 Days after Reperfusion

Dura

tion

(Mea

n Se

cond

±SEM

)

***

Results – Motor Evaluation Rope Climbing

#

* *

0

20

40

60

80

100

120

2 Days after Reperfusion

Dura

tion

(Mea

n Se

cond

±SEM

)

**

*

Summary Local low-dose and systemic high-dose

Alb provide similar neuroprotectionSynergistic 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.