Acta Neurochir (Wien) (2007) 149: 549–555

DOI 10.1007/s00701-007-1160-y

Printed in The Netherlands

Clinical ArticleDynamic cerebral autoregulation: should intracranial pressurebe taken into account?

P. M. Lewis, P. Smielewski, J. D. Pickard, and M. Czosnyka

Academic Neurosurgical Unit, Addenbrooke’s Hospital, Cambridge, UK

Received March 21, 2006; accepted April 4, 2007; published online May 3, 2007

# Springer-Verlag 2007

Summary

Background. Although the inclusion of cerebral perfu-

sion pressure (CPP) is a standard feature in static testing

of autoregulation after head injury, controversy sur-

rounds the use of CPP versus arterial blood pressure

(ABP) in dynamic tests. The aim of our project was to

assess the discrepancies between methods of dynamic

autoregulation testing based on CPP or ABP, and study

possible differences in their prognostic value.

Method. Intermittent recordings of intracranial pres-

sure (ICP), ABP and middle cerebral artery blood flow

velocity (FV) waveforms were made in 151 anaesthe-

tised and ventilated adult head injured patients as part

of their required care. Indices of dynamic autoregula-

tion were calculated as a moving correlation coefficient

of 60 samples (total time 3 min) of 6 s mean values of

FV and ABP (Mxa) or FV and CPP (Mx). Values of Mx

and Mxa were averaged over multiple recordings in each

patient and correlated with outcome at 6 months post

injury.

Findings. Association between Mx and Mxa was

moderately strong (r2 ¼ 0.73). However, limit of 95%

accordance between both indices was �0.32. Mxa

was significantly greater than Mx (0.22 � 0.22 versus

0.062 � 0.28; p<0.000001). The difference between Mx

and Mxa decreased with impairment of autoregulation

(r¼�0.39; p<0.000001). Mean value of Mx showed

a significant difference between dichotomized outcome

groups (better autoregulation in patients with favourable

than unfavourable outcome), while Mxa did not.

Conclusions. Although relatively similar in a large

group of patients, the differences between these two

methods of assessment of dynamic autoregulation may

be considerable in individual cases. When ICP is moni-

tored, CPP rather than ABP should be included in the

calculation of the autoregulatory index.

Keywords: Autoregulation; intracranial pressure; tran-

scranial Doppler ultrasonography.

Introduction

Autoregulation of cerebral blood flow (CBF) may

be assessed using static or dynamic methods [12]. The

assessment of cerebral autoregulation (CA) using stat-

ic methods was based on the principle of analysing

the relationship between changes in cerebral blood

flow (CBF) [12, 24] provoked by induced (usually phar-

macologically) long-lasting changes in arterial blood

pressure (ABP). When the concept of cerebral perfusion

pressure was formulated [14] and the phenomenon of

‘false autoregulation’ described [8, 20], it became ap-

parent that CPP rather than ABP alone should be taken

into account when assessing autoregulation [2, 3, 25],

particularly in head injury. In contrast to ‘static auto-

regulation’ the term ‘dynamic autoregulation’ refers to

relatively fast, coherent changes of CPP or ABP, either

evoked or spontaneous, inducing the response of CBF

observed over time [1, 10, 18, 23, 27]. Some methods of

dynamic autoregulation testing, based on the observation

of spontaneous changes in CPP or ABP, are suited for

continuous monitoring as they do not require mechanical

alteration of arterial blood pressure.

Despite the current understanding of false autoregula-

tion and the implications of excluding ICP from tests

of autoregulation, significant differences remain in the

approach to autoregulation assessment taken by differ-

ent authors. Some studies on head injured patients clear-

ly describe the use of dynamic changes in ABP alone

[9, 13, 24]. Others include CPP in their autoregulation

calculations [5, 23]. Beyond head injury, there are also

studies where intracranial pressure was not measured

[1, 10, 27] due to reasons of practicality, such as when

studying carotid artery stenotic disease or volunteers.

Are their results regarding autoregulation valid and can

they be quantitatively compared to each other?

Recently a study by Hlatky et al. [10] compared the

results of dynamic autoregulation testing by the leg-cuff

deflation method [1] using ABP and CPP, concluding

that following the cuff release, changes in ICP are small

and delayed. Therefore ABP instead of CPP can be used

in the calculations with confidence.

However, there is no data regarding the influence of

using ABP vs CPP when continuous methods [11, 17, 19,

23, 27] of assessment of cerebral autoregulation are used.

We have studied a large group of patients after head

injury who required ICP monitoring and full intensive

care management as part of their clinical care. This group

has been presented before to investigate the relationship

between cerebral autoregulation, outcome, mean ICP and

CPP [4]. Taking advantage of digital recordings of MCA

blood flow velocity (FV), ICP and direct arterial pres-

sure, we have compared continuous indices of dynamic

autoregulation calculated using CPP and ABP, and con-

sidered which of them had greater clinical utility.

Material and methods

Patients

One hundred and seventy six patients admitted after

head injury to Addenbrooke’s Hospital (1992–98) with a

median admission Glasgow Coma Score (GCS) of 6

(range 3–13, 10% of patients with initial GCS >9) were

studied.

We excluded 25 patients. They were younger than 16

(9), of unknown initial or follow-up data (12) or mean

CPP was less than 40 mmHg (4). There were 30 women

and 121 men, their ages ranging from 16 to 75 years

(mean age 36 years). 30% had subdural hematomas on

their initial CT of which 60% were evacuated surgically.

Intracerebral hematoma was found in 25% (45% were

removed surgically) and extradural hematomas in 11%

of these patients. 13% had diffuse brain injury, 59%

brain swelling and 32% presented with a midline shift.

Subarachnoid blood was found in 23% of patients, with

only 4 demonstrating mean flow velocity above 120 cm=s.

No patients in whom bone flaps were removed were

included in this study but they have been reported else-

where [26].

Routine clinical and brain monitoring data (ICP, ABP

and FV) was collected prospectively with the approval

of the multidisciplinary local Neuro Critical Care Users

Group, and was retrospectively analysed as part of an

ongoing audit of clinical management and multimodal-

ity monitoring techniques. All data was anonymised

prior to analysis, such that identification of study parti-

cipants was not possible. Individual consent was not

required by Local Ethical Committee at the time of data

recording.

Monitoring and data processing

Intracranial pressure was monitored continuously us-

ing microtransducers (Camino Direct Pressure Monitor,

Camino Laboratories, San Diego, CA; or Codman

MicroSensor, Johnson&Johnson Professional, Rynham,

MA), inserted intraparenchymally into the frontal

region. Arterial pressure was monitored directly from

the radial or dorsalis pedis artery (System 8000, S&W

Vickers Ltd, Sidcup, UK or Solar 6000 System,

Marquette, USA). The MCA was insonated daily on the

side of the ICP monitoring probe for a period of 20 min

to 2 h starting from the day of admission until dis-

charge, or day 8 following head injury using the PCDop

842 Doppler Ultrasound Unit (Scimed, Bristol, UK) or

Neuroguard (Medasonics, Fremona, CA).

The insonation depth was between 4 and 6 cm and

was adjusted to isolate segments of the MCA that

were not affected by vasospasm (the PCDop 842 is

unable to detect flow velocity (FV) above 200 cm=s).

This was achieved by insonating more distal (reduced

depth) segments of the MCA or by taking measure-

1

Fig. 1. (a) Time series trend showing Mxa, Mx, ABP, CPP and FV. Slow waves in ABP, CPP and FV are positively correlated, producing positive

values of Mx and Mxa. (b) Time series trend showing Mxa, Mx, ABP, CPP and FV. Slow waves in ABP, CPP and FV are inversely correlated,

producing negative values of Mx and Mxa

550 P. M. Lewis et al.: Dynamic cerebral autoregulation

ments from the contralateral side. Signals were mon-

itored during periods of stable respiratory parameters,

free from physiotherapy, tracheal suction, and other

disturbances for periods from 10 min to 3 h (average

period 30 min).

Analog outputs from the pressure monitors and the

TCD unit (maximal frequency envelope) were connected

to the analogue-to-digital converter (DT 2814, Data

Translation, Marlboro, USA) fitted into an IBM AT lap-

top computer (Amstrad ALT 386 SX, UK). Data was

sampled, digitized and stored on the hard disk using

software specifically designed for waveform recording

(WREC, W. Zabolotny, Warsaw University of Technol-

ogy). 495 recordings daily recordings were stored for

retrospective analysis. Digital signals were then pro-

cessed using software developed in-house (ICMþ,

University of Cambridge, UK) [22].

Signals were low-pass filtered using a simple moving

median filter of 6 s length, moving-averaged for the

same period and then re-sampled at 0.33 Hz (every

3 s) prior to calculation of autoregulation indices.

Mean index (Mx) was calculated as a Pearson’s

correlation coefficient of 60 consecutive samples of

CPP (ABP–ICP) and FV, every 3 min. Mxa was calcu-

lated using the same method, substituting CPP with

ABP (19).

According to previously published evaluations [5,

11, 19], positive values of Mx (or Mxa) indicate that a

change in blood flow velocity is accompanied by a paral-

lel change in CPP or ABP; i.e. autoregulation is im-

paired (Fig. 1a). Zero or negative values indicate intact

autoregulation (Fig. 1b).

For statistical analysis data were averaged for each

patient and 151 independent points were used, to relate

autoregulation to outcome, ICP, CPP, etc. To check

whether averaging changed the character of the relation-

ship between Mx and Mxa, data from individual re-

cordings (n¼ 495) were compared qualitatively (Fig. 2a

and b).

Results

Both Mx and Mxa were well associated with each

other (r2 ¼ 0.71; see Fig. 2a). There was no visual and

quantitative difference when the association between

individual recordings was compared to values of auto-

regulation indices averaged from multiple recordings

in each patient (r2 ¼ 0.72; Fig. 2b). The average value

of Mxa was higher than Mx (Mxa¼ 0.22 � 0.22;

Mx¼ 0.062 � 0.28; p<0.000001; t-test for dependent

samples, n¼ 151). A Bland-Altman plot (Fig. 3) indi-

cated a decreasing difference between Mxa and Mx as

autoregulation deteriorated. This has been confirmed

considering the same relationship for individual patients

(r¼�0.39; p<0.000001; n¼ 151). 95% limit of agree-

ment between Mx and Mxa was �0.32.

Indices of autoregulation were compared to outcome.

After outcome dichotomizing (GOS 4–5¼ favourable,

GOS 1–3¼ unfavourable), Mx showed a significant dif-

ference between means, whereas Mxa did not (Fig. 4:

Mxa: 0.23 � 0.21 for unfavourable outcome and 0.16 �0.24 for favourable outcome; p¼ 0.08. Mx: 0.12 � 0.24

for unfavourable outcome and for �0.072 � 0.21 for fa-

vourable outcome, p¼ 0.007).

Fig. 2. (a) Relationship between Mxa and Mx in individual mea-

surements (median – 3 per patient). (b) Relationship between Mxa and

Mx in individual patients Point A denotes an obvious outlier. This was

a patient who was admitted and developed refractory intracranial

hypertension (ICP>70 mmHg) with CPP still around 50–60 mmHg.

He died two days after injury

552 P. M. Lewis et al.

Our previous study [5] has suggested that autoregu-

lation is impaired at low CPP (<90 mmHg) and at high

ICP. In our material a significant negative correla-

tion between CPP and Mx was found (r¼�0.24;

p¼ 0.001; n¼ 151) while the correlation between Mxa

and CPP was weaker (r¼�0.15; p¼ 0.043; n¼ 151).

Similarly, the correlation between Mx and ICP was

stronger (r¼ 0.27; p<0.0004) than between Mxa and

ICP (r¼ 0.15; p¼ 0.043; n¼ 151).

Discussion

We have compared two different indices of dynamic

cerebral autoregulation. One measures the strength of

correlation between slow waves (�0.05 Hz) in ABP

and cerebral blood velocity (Mxa), whilst the other mea-

sures the correlation between slow waves in CPP and

cerebral blood velocity (Mx).

Validation of Mx and Mxa as indices of autoregula-

tion has been highlighted in previous studies; Mxa was

in good agreement with the leg-cuff test and CO2 reac-

tivity [19] and Mx with the transient hyperemic response

test [21] and static rate of regulation (SRoR), in head

injured patients. Theoretically, Mx and Mxa can mea-

sure autoregulation if the magnitude of slow ABP or CPP

fluctuations is large enough to activate an autoregulatory

response (approx. >5 mmHg). This was the case in all of

our patients.

We have demonstrated that the two indices correlate

with each other decently. However, the 95% confidence

limit of agreement is wide (�0.32, decreasing to �0.23

Fig. 4. (a) Mean � standard error of Mxa vs outcome, after grouping into

favourable and unfavourable outcome. (b) Mean � standard error of Mx

vs outcome, after grouping into favourable and unfavourable outcome

Fig. 3. Bland-Altman plot showing the dif-

ference between Mx and Mxa vs the average

of Mx and Mxa. Dashed line represents 95%

confidence limits for accordance between

variables (�0.32)

Dynamic cerebral autoregulation 553

after excluding obvious outliers). This may encourage

the use of Mxa in circumstances where ICP monitoring

is not clinically indicated.

However, analysing the association between these indi-

ces and outcome revealed substantial differences. A sig-

nificant association was noted between Mx and outcome,

whilst Mxa only showed a trend towards significance. This

result implies that when ICP is considered in the analysis

of autoregulation, the clinical implications of the result-

ing index are stronger. This is in agreement with previous

findings, wherein the profile of intracranial hypertension

was found to contribute meaningfully to outcome [5].

A Bland-Altman plot showing the difference between

the two indices plotted against their average shows that

as CA tends to deteriorate, the indices themselves con-

verge. Drawing upon the link between phase shift (or

time lag) and the correlation coefficient between mon-

itored variables [23], it is possible to explain this in

terms of the phase relationships between ABP, FV and

ICP and how they affect the correlation coefficient in-

dices. When autoregulation is impaired, slow waves in

ABP and ICP are mostly in phase, meaning fluctuations

in ABP and CPP are relatively coherent. In this situation,

the indices Mx and Mxa will produce similar results.

When autoregulation is functioning however, the phase

relationship (or time lag) between ABP and ICP may be

highly variable, with time constants of between 0.3 and

approximately 8 s [23]. This relationship has been ex-

amined in previous work wherein the correlation be-

tween ABP and ICP was also shown to describe CA

and have prognostic value in head injury [4].

Previous analyses of relationships between ICP and

FV have reported high correlations or coherence (low

time lag) between slow fluctuations in these two vari-

ables [17, 23]. Whilst many researchers have reported

that the origin of ICP slow waves is predominantly in the

cerebral vasculature and therefore waves in ICP and FV

are highly correlated [15, 17], there is also evidence to

indicate that in some cases, slow waves in ICP may be

independent of ABP or precede slow waves in ABP [6,

7, 23]. Under such circumstances, the difference (or

rather, phase shift) between CPP slow waves and ABP

slow waves may be substantial, giving rise to a discre-

pancy between Mx and Mxa.

The implications of using CPP vs ABP in the calcula-

tion of indices of dynamic autoregulation remain unre-

solved from a formal, mathematical perspective [17].

However, it seems clear that, based on this study, the cli-

nical value to be derived from including CPP in the as-

sessment of dynamic autoregulation cannot be dismissed.

Limitations and methodological issues

In focal head injury, particularly with midline brain

shift, autoregulation is worse at the side of expansion of

the brain [21]. Placement of the TCD probe at the side of

ICP monitoring may under describe cases with asymmet-

rical autoregulation, but from the point of view of this

comparison between Mx and Mxa this seems not to be a

serious limitation.

Approximately 75% of patients were on vasopressors.

The use of vasopressors seems to influence Mx in an

indirect way as it has been described in [5]. Mx is a

U-shape function of CPP. There was no significant re-

lationship in the difference between Mxa and Mx and

cerebral perfusion pressure.

No differences between an index of autoregulation

assessed using ICP microtransducers vs ventriculostomy

can be expected. Unfortunately we do not have clinical

material to prove this, but since autoregulation indices

are assessed from slow waves of ICP (0.005 Hz), slower

than the limit for bandwidth of ventriculostomy transdu-

cers (8–10 Hz or more), this point seems to be not rele-

vant in clinical practice.

There is no indication that the radial or dorsalis pedis

artery may be better in providing an ABP waveform for

calculation of autoregulatory indices. Even non-invasive

ABP (Finapres) seems to be acceptable [19].

The calculation has been performed from re-sampled

(0.33 Hz), filtered and moving averaged signals (6 s

period). The influence of all faster components was

sufficiently reduced. Therefore, using different types of

ICP monitors seems to have negligible influence on the

results.

Conclusion

We have shown that the indices Mx and Mxa are re-

latively well associated, however the limit of agreement

between them is large. Association with outcome shows

that Mx has clear prognostic value whereas Mxa shows

much less correlation with outcome following head injury.

Acknowledgements

– Mr. Lewis was supported by a Trauma Practice Scholarship from the

Victorian Trauma Foundation, Victoria, Australia.

– Professor Pickard and Drs. Czosnyka & Smielewski are supported by

MRC Grant No.: G9439390, ID 65883.

– Dr. Czosnyka is on leave from the Warsaw University of Technology,

Poland.

– ICMþ (http:==www.neurosurg.cam.ac.uk=icmplus) is licensed by the

University of Cambridge. PS and MC have a financial interest in the

software.

554 P. M. Lewis et al.

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Comment

The development of the Mx index as a measure assessing autoregula-

tion has gained considerable interest over the last ten years. The associa-

tion between Mx and Mxa are expected given that they are related

variables and it would be surprising if there were any substantial intra

or inter recording variability. The evidence from retrospectively analysed

data shows that although both cerebral perfusion pressure (CPP) and

intracranial pressure (ICP) are strongly related to long term outcome from

severe head injury it is CPP that is a slightly more reliable measure.

However the analysis of this data is not done simultaneously with clinical

management so the advantage of the Mx indices is the ability to provide,

in real time, a measure that is related to the status of autoregulation.

Given the improvements in the relationship to outcome in models

that include CPP rather than just ICP Lewis et al. have shown a similar

feature with this correlation index. It may further support the use of

ICP monitoring in these patients with the advantage of a bedside mea-

sure that can inform clinical management to optimise the care of these

patients.

Further work, with more contemporaneous data may support and

advance the use of this methodology.

Iain Chambers

Middlesbrough

Correspondence: Marek Czosnyka, Department of Neurosurgery,

University of Cambridge, Box 167 Addenbrooke’s Hospital, Cambridge

CB2 2QQ, UK. e-mail: mc141@medschl.cam.ac.uk

Dynamic cerebral autoregulation 555