Letters to the Editor

luminal Angioplasty Study (CAVATAS): a randomised trial. Lancet.

2001;357:1729 1737.
4. Featherstone RL, Brown MM Coward LJ, for the ICSS Investigators.
International Carotid Stenting Study (ICSS): protocol for a randomised
clinical trial comparing carotid stenting with endarterectomy in symptomatic carotid artery stenosis. Cerebrovascular Diseases
2004;18:69 74.

Serum Albumin Level as a Predictor of

Ischemic Stroke Outcome
To the Editor:
We read with great interest the recent article by Dr Dziedzic et
al1 on the relationship between serum albumin level and ischemic
stroke outcome. Even though low serum albumin has been
associated with an increased incidence of stroke in epidemiologic
studies,2 a high serum albumin level in acute stroke patients was
described, for the first time, to decrease the risk of poor outcome
among hospitalized patients. The neuroprotective effects of
endogenous albumin on the capillary microcirculation in the
early reperfusion phase were proposed to explain the cellular
mechanism of this association, and the role of exogenous
albumin therapy in stroke recovery was briefly reviewed.
It is important to recognize the role of serum albumin as a
marker of clinical outcomes in vascular disease. Apart from
stroke, serum albumin has been associated with adverse vascular
events in patients with cardiac3 and renal4 diseases. Among
hospitalized patients, hypoalbuminemia was found to be associated with frequent hospitalizations, higher mortality, and readmission,5 and an independent prognostic factor for all deaths
among healthy middle-aged individuals in population studies.6
Serum albumin is regulated by factors influencing protein synthesis, breakdown, leakage to the extravascular space, and food
intake. In clinical practice, serum albumin is often considered a
marker of nutritional status and a negative phase protein that
decreases in concentration during injury and sepsis.7
There has been conflicting evidence in the literature on
albumin therapy in treating patients with hypoalbuminemia from
an underlying vascular disease. Albumin has a molecular weight
of about 66 kDa, thus preventing it from passing through the
blood brain barrier by diffusion or by carrier systems through
these membranes. Local redistribution, crystalloid dilution, and
changes in the metabolism of albumin, which result in ineffective
delivery and concentration within the central nervous system,
frustrate therapeutic interventions. In septic patients, albumin
therapy was not associated with a rise in serum albumin. Instead,
a fall in serum albumin was observed and this was hypothesized
to be secondary to capillary leakage.8
Until these important questions on albumin therapy are answered in randomized controlled studies, therapeutic options in
patients with hypoalbuminemia should be directed toward treating the underlying cause, avoiding or treating salt and water
overload, instituting prompt medical and surgical treatment of
inflammation and sepsis, and providing appropriate nutritional
support to enhance recovery in patients with ischemic strokes.
Raymond CS Seet, MRCP
Erle CH Lim, MMed (Int Med)
Bernard PL Chan, MRCP
Benjamin KC Ong, FRCP
Divison of Neurology
Department of Medicine
National University Hospital
Singapore
1. Dziedzic T, Slowik A, Szczudlik A. Serum albumin level as a predictor
of ischemic stroke outcome. Stroke. 2004;35:156 158.
2. Gillum RF, Ingram DD, Makuc DM. Relation between serum albumin
concentration and stroke incidence and death: the NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1994;140:876 888.

2435

3. Schillinger M, Exner M, Mlekusch W, Amighi J, Sabeti S, Schlager O,

Wagner O, Minar E. Serum albumin predicts cardiac adverse events in
patients with advanced atherosclerosisinterrelation with traditional cardiovascular risk factors. Thromb Haemost. 2004;91:610 618.
4. Cooper BA, Penne EL, Bartlett LH, Pollock CA. Protein malnutrition and
hypoalbuminemia as predictors of vascular events and mortality in ESRD.
Am J Kidney Dis. 2004;43:61 66.
5. Herrmann FR, Saqfran C, Levkoff SE, Minaker KL. Serum albumin level
on admission as a predictor of death, length of stay, and readmission.
Arch Intern Med. 1992;152:125130.
6. Phillips A, Shaper AG, Whincup PH. Assocation between serum albumin
and mortality from cardiovascular disease, cancer and other causes.
Lancet. 1989;2:1434 1436.
7. Liao WS, Jefferson LS, Taylor JM. Changes in plasma albumin concentration, synthesis rate, and mRNA level during acute inflammation. Am J
Physiol. 1986; C928 C934.
8. Margarson MP, Soni NC. Changes in serum albumin concentration and
volume expanding effects following a bolus of albumin 20% in septic
patients. Br J Anaesth. 2004;92:821 826.

Response:
We thank Dr Seet and colleagues for their thoughtful comments to our article. We agree that hypoalbuminemia appears to
be a predictor of poor prognosis in different clinical settings and
even in apparently healthy individuals.1 It is still unknown in
which way hypoalbuminemia can impair the prognosis. The
mechanisms responsible for this phenomenon are not limited to
energy depletion only, but can be also related to impaired
immune and endocrine response, as well as extracellular water
expansion.2 On the other hand, experimental studies revealed a
beneficial effect of albumin infusion in animal models of
cerebral ischemia and it was suggested that this neuroprotective
effect is mediated by multiple specific actions of albumin
including antioxidative properties, influence on endothelial functions, and venular perfusion.3,4 Which of the above-mentioned
mechanisms of albumin action are relevant to human stroke
remains to be established.
Albumin belongs to negative acute phase proteins. In our study
we measured albumin level within 36 hours after stroke onset.
We cant exclude that acute phase response accompanying
ischemic stroke can to some degree decrease albumin level in
this time period. Inflammatory reaction defined as C-reactive
protein level was found to be the most pronounced 3 to 7days
after stroke onset.5 Davalos et al found fall in albumin concentration between day 1 and day 7 of stroke (40.74.6 versus
39.55.3 g/L) with borderline statistical significance (P0.05).6
Other authors observed significant decrease in albumin level 2
and 4 weeks after stroke onset and this phenomenon couldnt be
explained by acute phase reaction.7 Unfortunately there is a lack
of studies investigating changes in serum albumin level during
acute phase of stroke.
Could albumin infusion be beneficial in human stroke? We
share some concerns of Dr Seet and colleagues that this form of
the therapy could be ineffective. However, we think that promising results of animal studies warrant the attempt to conduct
clinical trials. In our opinion, 2 issues can be addressed in clinical
studies: first, if correction of hypoalbuminemia (if possible) can
influence the stroke outcome; second, if albumin infusion in
early stroke in patients with normoalbuminemia can be beneficial
as shown in animal models.
Tomasz Dziedzic, MD, PhD
Department of Neurology
Collegium Medicum
Jagiellonian University
Krakow, Poland
1. Phillips A, Shaper AG, Whincup PH. Association between serum albumin
and mortality from cardiovascular disease, cancer, and other causes.
Lancet. 1989;2:1434 1436.

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2436

Letters to the Editor

2. Franch-Arcas G. The meaning of hypoalbuminaemia in clinical practice.

Clin Nutr. 2001;20:265269.
3. Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol P, Zhao W,
Busto R, Ginsberg MD. Albumin therapy of transient focal cerebral
ischemia: in vivo analysis of dynamic microvascular responses. Stroke.
2002;33:10771084.
4. 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. 2001;32:
553560.
5. Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffarth
GU, Grau AJ, Green FR, Grond-Ginsbach C, Schwaninger M. Multiple
levels of regulation of the interleukin-6 system in stroke. Stroke. 2003;
34:1864 1869.
6. Davalos A, Ricart W, Gonzalez-Huix F, Soler S, Marrugat J, Molins A,
Suner R, Genis D. Effect of malnutrition after acute stroke on clinical
outcome. Stroke. 1996;27:1028 1032.
7. Gariballa SE, Parker SG, Taub N, Castleden CM. Influence of nutritional
status on clinical outcome after acute stroke. Am J Clin Nutr.
1998;8:275281.

Association Between Pulse Pressure Values During

the Acute Stroke Stage and Stroke Outcome
To the Editor:
We read with great interest the recent Research Report by
Aslanyan et al.1 The authors reported that elevated weighted
average pulse pressure (PP) during the first 60 hours of ischemic
stroke was independently associated with poor outcome assessed
by mortality, Barthel index, National Institutes of Health Stroke
Score and modified Rankin Scale score. Elevated baseline PP
was associated with Barthel Index and Rankin score but not with
mortality. Weighted average PP was the only blood pressure
(BP) component to be consistently associated with all outcome
measures.
We have also evaluated the prognostic value of the different
BP components in 198 patients with acute stroke (146 cases
with cerebral infarction and 42 cases with intracerebral
hemorrhage) by means of 24-hour BP-monitoring.2 Our results indicated an independent association between increasing
24-hour PP levels and 1-year mortality after correcting for
stroke risk factors, stroke subtypes, clinical (stroke severity
and level of consciousness) and radiological characteristics
(brain edema, mass effect and hemorrhagic transformation).
Higher PP levels on hospital admission were related to an
increased risk of 1-year mortality on univariate analysis, but
in the multivariate Cox-regression model this association did
not retain its statistical significance. This finding underlines
the superiority of 24-hour BP variables over admission BP
measurements in predicting stroke outcome. It is in keeping
with the results of Aslanyan et al and other investigators,
which indicate that variables describing BP course during the
acute stroke period, such as 24-hour,2,3,4 beat-to-beat5 and
weighted average1 BP recordings correlate more strongly and
independently with stroke outcome.
On the other hand, other studies failed to document any
association between PP levels in acute stroke and early5 or
late outcome.4 Since, antihypertensive medication have been
shown to have a differential effect on conduit vessel stiffness
and to selectively alter the different BP components,6 8 we
believe that the prognostic impact of PP levels at baseline and
especially during the first hours of ictus on stroke outcome
needs further clarification. An increasing body of evidence
suggests that raised BP levels following acute stroke may not
be a benign phenomenon and are associated with adverse
prognosis.9 However, before embarking in a large random-

ized, placebo-controlled trial the question of whether the

lowering of the pulsatile, the steady or both BP components in
acute stroke might improve outcome remains to be answered.
Konstantinos N. Vemmos, MD
Acute Stroke Unit
Department of Clinical Therapeutics
University of Athens
Athens, Greece
Georgios Tsivgoulis, MD
Konstantinos Spengos, MD
Department of Neurology
University of Athens
Athens, Greece
1. Aslanyan S, Weir CJ, Lees KR; GAIN International Steering Committee
and Investigators. Elevated pulse pressure during the acute period of
ischaemic stroke is associated with poor stroke outcome. Stroke. 2004;
35:e153 e155.
2. Vemmos KN, Tsivgoulis G, Spengos K, Manios E, Daffertshofer M,
Kotsis V, Lekakis JP, Zakopoulos N. Pulse pressure in acute stroke is an
independent predictor of long-term mortality. Cerebrovasc Dis. 2004;18:
30 36.
3. Robinson T, Waddington A, Ward-Close S, Taub N, Potter J. The predictive role of 24-hour compared to casual blood pressure levels on
outcome following acute stroke. Cerebrovasc Dis. 1997;7:264 272.
4. Robinson TG, Dawson SL, Ahmed U, Manktelow B, Fortherby MD,
Potter JF. Twenty-four hour systolic blood pressure predicts long-term
mortality following acute stroke. J Hypertens. 2001;19:21272134.
5. Dawson SL, Manktelow BN, Robinson TG, Panerai RB, Potter JF.
Which parameters of beat-to-beat blood pressure and variability best
predict early outcome after acute ischemic stroke? Stroke. 2000;31:
463 468.
6. Safar ME, van Bortel LM, Struijker-Boudier HA. Resistance and conduit
arteries following converting enzyme inhibition in hypertension. J Vasc
Res. 1997;34:67 81.
7. Heesen WF, Beltman FW, Smit AJ, May JF, de Graeff PA, Havinga TK,
Schuurman FH, van der Veur E, Meyboom-de Jong B, Lie KI. Effect of
quinapril and triamterene/hydrochlorothiazide on cardiac and vascular
end-organ damage in isolated systolic hypertension. J Cardiovasc
Pharmacol. 1998;31:187194.
8. Ting CT, Chen CH, Chang MS, Yin FC. Short- and long-term effects of
antihypertensive drugs on arterial reflections, compliance, and
impedance. Hypertension. 1995;26:524 530.
9. Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute
stroke and subsequent outcome: a systematic review. Hypertension.
2004;43:18 24.

Does Preventing Stroke Prevent All Kinds

of Dementia?
To the Editor:
The recent publication in Stroke regarding dementia after
stroke1 makes interesting observations. However, there are some
points in the article to which I would like to draw attention.
First, the subgroup analysis in the text mentions that the 4
allele for apolipoprotein E (ApoE) genotype was present in
17.3% of the cases and in 22% of the controls. Table 1 in the
article seems to have a printing error in that the above percentages have been reversed in the table (ie, 22% of cases and 17%
of controls have 4 allele for ApoE genotype).
Second, the changing denominators in Table 1 show that a lot
of baseline data were actually missing. A mention of this would
have been appropriate in the limitations of the study.
Last, it seems logical to conclude that the prevention of stroke
would reduce the burden of vascular dementia. The authors
conclude that primary and secondary prevention of stroke should
significantly decrease the risk of all dementia. I wonder how
valid that observation could be. It is true that a proportion of
stroke cases had Alzheimer disease (AD), but the proportion of
AD still remained higher among controls. There is no statistical

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Serum Albumin Level as a Predictor of Ischemic Stroke Outcome

Raymond CS Seet, Erle CH Lim, Bernard PL Chan and Benjamin KC Ong
Stroke. 2004;35:2435-2436; originally published online October 7, 2004;
doi: 10.1161/01.STR.0000145487.89910.12
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2004 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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