Perspectives in Medicine (2012) 1, 194197

Bartels E, Bartels S, Poppert H (Editors):

New Trends in Neurosonology and Cerebral Hemodynamics an Update.
Perspectives in Medicine (2012) 1, 194197

journal homepage: www.elsevier.com/locate/permed

Cerebral autoregulation in acute ischemic stroke

Matthias Reinhard a,, Sebastian Rutsch a, Andreas Hetzel a,b

a
Department of Neurology, University of Freiburg, Germany
b
Department of Neurology, Park Klinikum, Bad Krozingen, Germany

KEYWORDS Summary Cerebral autoregulation is particularly challenged in acute ischemic stroke. In this
Cerebral review we summarize the data of our previous studies on autoregulation regarding the effect of
autoregulation; rtPA on autoregulation after stroke. A pooled analysis of two studies (45 patients) has shown a
Acute cerebral worsening of the autoregulatory index Mx between an early (rst 48 h) and late (days 57) mea-
ischemia; surement. This increase was more pronounced on affected sides than on unaffected sides. Poor
Transcranial Doppler ipsilateral Mx was associated with a greater volume of MCA infarction at a late measurement
sonography and related to poor clinical outcome. Overall, autoregulatory impairment tends to increase
mainly in large infarction and generalize to the contralateral side during the rst days after
ischemic stroke. As a limitation, transcranial Doppler sonography does not allow to detect focal
areas of dysautoregulation in smaller strokes. To better understand the temporal and spatial
dynamics of dysautoregulation in acute stroke in relation to the type and size of infarction, new
bedside hemodynamic monitoring techniques (like multi-channel near-infrared spectroscopy)
are needed.
2012 Elsevier GmbH. Open access under CC BY-NC-ND license.

Introduction appropriately autoregulatory action occurs [2]. A recent

Cerebral autoregulation is particularly challenged during
acute ischemic stroke. Working autoregulation is impor-
tant both during the acute vessel occlusion and during
the reperfusion phase. Potential changes in autoregulatory
capacity are considered in the treatment of blood pressure
in ischemic stroke [1].
Dynamic autoregulation allows to noninvasively assess
the autoregulatory capacity in acute stroke. Thereby, spon-
taneous uctuations in blood pressure and cerebral blood
ow velocity (assessed by transcranial Doppler sonography)
are analyzed to extract information about how quickly and
systematic review of TCD autoregulation studies in acute
ischemic stroke revealed a considerable heterogeneity in
autoregulation methodology and time points of measure-
ment [3]. Most of the included studies comprised a small
number of patients with various types and locations of
ischemic stroke.
In this review we summarize data of our previous stud-
ies on autoregulation assessed by TCD in acute ischemic
stroke. We focus on the time course of autoregulation in
acute stroke and clinical factors associated with autoregu-
lation in acute stroke and will discuss future challenges in
the eld of autoregulation in acute stroke.

Methods
Corresponding author at: Department of Neurology, Univer-
sity of Freiburg, Neurocenter, Breisacherstr. 64, D-79106 Freiburg,
Germany. This review comprises a total of 45 patients from two
E-mail address: matthias.reinhard@uniklinik-freiburg.de previous studies [4,5]. Patients were admitted with acute
(M. Reinhard). ischemic stroke in the middle cerebral artery (MCA) territory

2211-968X 2012 Elsevier GmbH. Open access under CC BY-NC-ND license.

doi:10.1016/j.permed.2012.02.028
Cerebral autoregulation in acute ischemic stroke 195

to our stroke unit and had no relevant obstructive carotid

artery disease. The protocol for the studies included an early
measurement of autoregulation (within 48 h after stroke
onset) and a late measurement around days 57.
Flow velocity in both MCA was measured by TCD
and blood pressure was recorded noninvasively via n-
ger plethysmography. Cerebral autoregulation was assessed
from spontaneously occuring uctuations in blood pressure
during a period of 10 min in each study. In this review we
focus on results of the correlation coefcient analysis. With
this approach (index Mx), mean values of ABP and CBFV are
correlated by Pearsons correlation coefcient. In case of a
high correlation, CBFV uctuations depend on those of ABP.
Higher Mx values thus reect poorer autoregulation [6].

Results

The course of autoregulation during the rst week

after stroke onset
In a group of 45 patients with acute MCA stroke, the index
Mx increased signicantly between an early measurement
within 48 h after stroke onset and a second (late) measure-
ment around day 6 (late). This increase indicates worsening
autoregulation and was larger on the MCA side affected by
the stroke, but was also signicant on the contralateral side
(Fig. 1a). Group mean values did not differ from those of
controls. A separate analysis of patients with large MCA
stroke, however, showed that Mx is clearly impaired in the
MCA ipsilateral to the stroke side around day 6 after stroke
onset but not during the rst day after stroke (Fig. 1).
The relation between autoregulation and clinical
factors
Deteriorating autoregulation (increasing Mx) on ipsi- more
than contralateral sides between days 12 and days 57 was
Figure 2 Relation between autoregulation (index Mx) and
outcome after stroke. Data sets of 44 eligible patients from
previous studies [7]. Pearson correlation between autoregula-
tory index Mx (higher values mean poorer autoregulation in the
middle cerebral artery ipsilateral to the stroke) and outcome.
The index Mx was measured around day 6 after stroke onset,
outcome assessed after 4 2 months by modied Rankin scale
(mRS).
associated with larger infarcts [7]. Furthermore, there was a
positive relation between poorer ipsilateral autoregulation
and poorer clinical status (NIH stroke scale) at the early
and late measurement. On contralateral sides, a similar
but non signicant trend was observed. Poorer autoregu-
lation (higher Mx) around day 6 was associated with poorer
outcome (Fig. 2). In a multivariate model, however, only
infarction size remained a signicant predictor for clinical

Figure 1 Cerebral autoregulation after ischemic stroke. Signicant oncrease of Mx on ipsi- and contralateral sides between the
early (rst 48 h) and late (days 57) measurement after stroke onset [7]. Separate analysis of patients with poor outcome and large
infarction (62 21% of MCA territory) [5]. Controls refer to 71 age-matched healthy persons (64 9 years).
196
outcome. A separate detrimental effect of rtPA treatment
on autoregulation after stroke was not found [5].
Discussion
The main ndings of our studies so far is that dynamic
autoregulation in acute stroke detected by TCD worsens
over the rst days after stroke onset (more on affected
than unaffected sides) and that this worsening of autoreg-
ulation associates with a larger MCA infarct size and poorer
outcome.
Various other studies have generally shown mild to mod-
erate impairment of dynamic autoregulation affecting the
MCA ipsi- and contralateral to the ischemic stroke [8,9].
Previous TCD studies on autoregulation in stroke did not
consider the actual size of infarction [9,10].
When using TCD for measuring dynamic autoregula-
tion in acute ischemic stroke, two mechanisms need to
be considered: 1. Local dysautoregulation related to the
affected stroke territory. Within the infarction core, cere-
bral autoregulation is probably severely disturbed in the
early stages. Tissue lactate acidosis leads to local vasoparal-
ysis, compromising the autoregulatory mechanism in both
the ischemic core and the direct periinfarct region [11]. Such
a presumed early impairment is, however, not univocally
detected by the index Mx in larger strokes in our studies. The
Mx value rather indicated a secondary decline in autoregu-
lation after reperfusion mainly in large infarcts. This means
that either autoregulation in the area of large infarction
becomes worse, or that additional areas within the territory
become involved. Such a pattern of secondary deterioration
was also reported in a study using invasive autoregulation
monitoring of malignant MCA stroke [11]. A vicious cycle of
reperfusion, producing inammatory vasotoxic substances,
dysautoregulation, edema and further ischemia has been
discussed [5,11]. Whether such a mechanism also exists for
smaller MCA infarctions cannot be determined by transcra-
nial Doppler sonography. However, an impairment within
large areas of the MCA territory seems unlikely in this situ-
ation, because TCD recordings in the MCA should then have
produced clearly pathological results.
There seems to occur a milder and more global autoreg-
ulatory dysfunction which probably evolves during the rst
Figure 3 Spatially resolved autoregulation mapping with multi-channel near infrared spectroscopy. Example of a 68-year-old
patient with near occlusion of left internal carotid artery [14]. Dynamic autoregulation is graded from the phase shift between
respiratory-induced 0.1 Hz oscillations in ABP and oxy-hemoglobin. Autoregulation is impaired on the side ipsilateral to the stenosis
and this is most prominent in the borderzone between middle cerebal and anterior cerebral artery.
M. Reinhard et al.
days after ischemic stroke. Studies in which autoregula-
tion in the MCA was measured once within four days of
MCA- or non-MCA-territory stroke onset found a bilateral
reduction in dynamic autoregulatory capacity independent
of infarct type and vascular risk factors [9,10]. Such changes
were not detectable for static autoregulation, leading to the
assumption that dynamic autoregulatory measures are more
sensitive to general vascular dysfunction in acute stroke
[10]. The reason for this general impairment, which seems
to be limited to dynamic autoregulation, is not clear. Pre-
existing endothelial dysfunction may exacerbate within an
acute phase response shortly after cortical ischemic stroke
[12], when inammatory or autonomic changes addition-
ally affect the cerebral vasculature. In a further study,
we found that secondary impairment of autoregulation in
the subacute stage after stroke was associated with alter-
ations in the neurovascular coupling mechanism outside the
infarcted area using functional magnetic resonance imaging
[13]. This underlines the assumption of a secondary endothe-
lial dysfunction leading to both impaired autoregulation and
impaired neurovascular coupling. A general autoregulatory
dysfunction could thus potentially interfere with functional
restitution and thus affect the clinical outcome [13].
We have indeed found an association between impaired
autoregulation after ischemic stroke and clinical outcome.
The association between autoregulation and outcome might,
however, be linked via the size of MCA infarction. How-
ever, the infarction size in the current cohort of patients
was mainly derived from demarcated lesions visualized by
follow-up imaging. Dysautoregulation could still have con-
tributed to the nal size of infarction.
A main methodological problem of the studies reported
here is the low spatial resolution of TCD. A small infarct
within the MCA territory could also lead to severe focal
dysautoregulation without a clear autoregulatory impair-
ment in the main stem of the MCA. To better understand
the spatial characteristics of impaired autoregulation in
ischemic stroke (focal versus global dysautoregulation) we
need new bedside hemodynamic monitoring techniques
with a high spatial resolution. One promising but tech-
nically demanding method is multi-channel near-infrared
spectroscopy. A rst example of noninvasive autoregula-
tion mapping with this technology in a patient with severe
carotid stenosis is illustrated in Fig. 3 [14].
Cerebral autoregulation in acute ischemic stroke
Conclusions
Impairment of dynamic autoregulation detected by TCD in
acute ischemic stroke is associated with larger MCA stroke
and a poor clinical status. It tends to worsen and gen-
eralize during the initial post-stroke days and associates
with poor clinical outcome. To better understand the tem-
poral and spatial dynamics of dysautoregulation in acute
stroke in relation to the type and size of infarction, new
bedside hemodynamic monitoring techniques (like multi-
channel near-infrared spectroscopy) are needed.
References
[1] Guidelines for management of ischaemic stroke and transient
ischaemic attack 2008. Cerebrovasc Dis 2008;25(5):457507.
[2] Panerai RB. Transcranial Doppler for evaluation of cerebral
autoregulation. Clin Auton Res 2009;19:197211.
[3] Aries MJ, Elting JW, De Keyser J, Kremer BP, Vroomen PC. Cere-
bral autoregulation in stroke. A review of transcranial Doppler
studies. Stroke 2010;41(11):2697704.
[4] Reinhard M, Roth M, Guschlbauer B, Harloff A, Timmer J,
Czosnyka M, et al. Dynamic cerebral autoregulation in acute
ischemic stroke assessed from spontaneous blood pressure uc-
tuations. Stroke 2005;36:16849.
[5] Reinhard M, Wihler C, Roth M, Harloff A, Niesen WD,
Timmer J, et al. Cerebral autoregulation dynamics in acute
ischemic stroke after rtPA thrombolysis. Cerebrovasc Dis
2008;26:14755.
[6] Reinhard M, Roth M, Muller T, Czosnyka M, Timmer J, Hetzel A.
Cerebral autoregulation in carotid artery occlusive disease
197
assessed from spontaneous blood pressure uctuations by the
correlation coefcient index. Stroke 2003;34:213844.
[7] Reinhard M, Rutsch S, Lambeck J, Wihler C, Czosnyka M,
Weiller C, et al. Dynamic cerebral autoregulation associates
with infarct size and outcome after ischemic stroke. Acta Neu-
rol Scand 2011:100404.
[8] Dawson SL, Panerai RB, Potter JF. Serial changes in static and
dynamic cerebral autoregulation after acute ischaemic stroke.
Cerebrovasc Dis 2003;16:6975.
[9] Eames PJ, Blake MJ, Dawson SL, Panerai RB, Potter JF. Dynamic
cerebral autoregulation and beat to beat blood pressure con-
trol are impaired in acute ischaemic stroke. J Neurol Neurosurg
Psychiatry 2002;72:46772.
[10] Dawson SL, Blake MJ, Panerai RB, Potter JF. Dynamic but not
static cerebral autoregulation is impaired in acute ischaemic
stroke. Cerebrovasc Dis 2000;10:12632.
[11] Dohmen C, Bosche B, Graf R, Reithmeier T, Ernestus RI,
Brinker G, et al. Identication and clinical impact of
impaired cerebrovascular autoregulation in patients with
malignant middle cerebral artery infarction. Stroke 2007;38:
5661.
[12] Stevenson SF, Doubal FN, Shuler K, Wardlaw JM. A system-
atic review of dynamic cerebral and peripheral endothelial
function in lacunar stroke versus controls. Stroke 2010;41:
e43442.
[13] Altamura C, Reinhard M, Vry MS, Kaller CP, Hamzei F, Vernieri F,
et al. The longitudinal changes of BOLD response and cerebral
hemodynamics from acute to subacute stroke. A fMRI and TCD
study. BMC Neurosci 2009;10:151.
[14] Rutsch S, Schelter B, Kaller CP, Timmer J, Hetzel A, Reinhard M.
Spatial mapping of dynamic cerebral autoregulation with
multichannel near infrared spectroscopy. Cerebrovasc Dis
2010;29(Suppl. 1):51.