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Neurocrit Care
https://doi.org/10.1007/s12028-019-00763-y
ORIGINAL WORK
Clinical Usefulness ofTranscranial Doppler
asa Screening Tool forEarly Cerebral Hypoxic
Episodes inPatients withModerate andSevere
Traumatic Brain Injury
C. Sokoloff1, D. Williamson2,3, K. Serri1,2,4, M. Albert1,2,4, C. Odier5,6, E. Charbonney1,2,4 and F. Bernard1,2,4* on
behalf of for the ÉRESI Reseach Group (Équipe de Recherche En Soins Intensifs)
© 2019 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society
Abstract
Background: Brain tissue oxygenation (PbtO2) in traumatic brain injury (TBI) is known to be dependent on cerebral
blood flow (CBF) which remains difficult to assess during the very early phase of TBI management. This study evalu-
ates if blood flow velocity measurement with 2D color-coded transcranial Doppler (TCD) can predict cerebral hypoxic
episodes in moderate-to-severe TBI measured with a PbtO2 probe.
Methods: This is a prospective observational study of serial TCD measurements to assess blood flow velocity and
its association with PbtO2. Measurements were done bilaterally on the middle cerebral artery (MCA) early after the
insertion of PbtO2 monitoring, daily for 5 days and during dynamic challenge tests. Physiological parameters affecting
PbtO2 and Doppler velocities were collected simultaneously (PaO2, PaCO2, hemoglobin [Hb] level, intracranial pres-
sure, and cerebral perfusion pressure [CPP]).
Results: We enrolled 17 consecutive patients with a total of 85 TCD studies. Using 2D color-coded TCD, signal
acquisition was successful in 96% of the cases. Twenty-nine (34%) TCD measures were performed during an epi-
sode of cerebral hypoxia (PbtO2 ≤ 20 mmHg). For early episodes of cerebral hypoxia (occurring ≤ 24 h from trauma),
all Vmean < 40 cm/s were associated with an ipsilateral PbtO2 ≤ 20 mmHg (positive predictive value 100%). How-
ever, when considering all readings over the course of the study, however, we found no correlation between PbtO2
and MCA’s mean blood flow velocity (Vmean). Vmean is also positively correlated with PaCO2, whereas PbtO2 is also
correlated with PaO2, CPP, and Hb level.
Conclusions: Early TCD measurements compatible with low CBF (mean velocity < 40 cm/s) detect brain tissue
hypoxia early after TBI (≤ 24 h) and could potentially be used as a screening tool before invasive monitoring inser-
tion to help minimize time-sensitive secondary injury. Various factors influence the relationship between Vmean and
PbtO2, affecting interpretation of their interaction after 24 h.
Keywords: Traumatic brain injury, Transcranial Doppler, Brain oxygenation
*Correspondence: bernard.francis@gmail.com
1 Department of Medicine, Hôpital du Sacré-Coeur de Montréal, Centre
intégré universitaire de santé et de services sociaux (CIUSSS) du Nord-de-
l’Ile-de-Montréal, 5400 Boul Gouin O, Montréal, Québec H4J 1C5, Canada
Full list of author information is available at the end of the article
Introduction
Substantial improvement in severe traumatic brain injury
(TBI) outcomes has been achieved in the last 40years
due to a better understanding of the pathophysiology of
head injury and the introduction of multimodal moni-
toring (MMM) [1–3]. Among modalities, brain tissue
oxygen (PbtO2) monitoring is increasingly used to guide
optimal brain perfusion and oxygenation [4–6]. In fact,
PbtO2 has been independently associated with short-
term outcomes and represents a better indicator of poor
outcome than intracranial pressure (ICP) or cerebral
perfusion pressure (CPP) [4]. However, MMM is often
invasive and requires neurosurgical expertise for inser-
tion, which involves potential delays before information
is available for clinical use.
Studies have shown that 60–80% of TBI patients go
through an initial phase ofcerebral hypoperfusion dur-
ing the early post-traumatic period, termed «early low-
flow» [5–8]. e pathophysiology of this phenomenon
is not fully understood, but ICP and CPP may be within
normal limits. Microcirculatory vasoconstriction and
misdistribution of regional cerebral blood flow (CBF)
may be responsible for this low-flow state [7, 9]. us,
clinicians could be falsely reassured by arterial pres-
sure measurements. Monitoring PbtO2 avoids indirect
assumptions of O2 delivery, while ICP and CPP remain in
the normal range [4] but isnot available in the emergency
department.
Transcranial Doppler (TCD) can be used in the emer-
gency department and has been shown to detect elevated
ICP and low CPP [10, 11]. In particular, the mean blood
flow velocity (Vmean) of the middle cerebral artery
(MCA) has been shown to detect changes in ICP [12],
PbtO2 [9, 12] and early low-flow states [7]. To our knowl-
edge, only two studies have adequately investigated the
relation between Vmean and PbtO2 [9, 12]. One focused
on the early post-traumatic period and showed a strong
correlation between PbtO2 and Vmean within 8h of the
trauma [9]. However, this observation was a secondary
outcome of the study. Furthermore, other determinants
of PbtO2 or factors influencing TCD measurements were
not taken into account such as PaCO2 or PaO2. e sec-
ond studied the reactivity of cerebral oxygen monitors
and Doppler indices in response to fluctuations of arte-
rial blood pressure without correlating them directly or
identifying absolute Doppler values associated with cer-
ebral hypoxia [12]. Finally, TCD used in these studies did
not rely on 2D color-coded Doppler to identify MCAs.
In an attempt to assess the usefulness of TCD as a
screening tool for early hypoxic episodes, we evaluated
the association between mean velocities measured by
2D color-coded TCD in the MCA and PbtO2 in patients
with moderate-to-severe TBI. We hypothesized that
time-averaged Vmean measured in the MCA would
detect early brain hypoxic episodes after TBI, particularly
in the first 24h after TBI. Our main objective was to eval-
uate the association of Vmean with PbtO2. e secondary
objective was to evaluate factors influencing Vmean and
PbtO2 measurement.
Methods
Subjects
is prospective observational study was conducted at
the Neuro-Critical Care Unit of Hôpital du Sacré-Coeur
de Montréal, an adult academic Level 1 trauma cen-
tre. We consecutively recruited every patient with non-
penetrating TBI who required the insertion of a PbtO2
monitor between May 2015 and December 2015. PbtO2
and ICP monitors were inserted simultaneously. Patients
were excluded if they had a penetrating brain injury or
a diagnosis of brain death on arrival. e research ethics
committee approved the study protocol, and written con-
sent was obtained from the patient’s next of kin (REB#
2015-1134).
Standard Monitoring andCare
As part of standard of care, invasive mean arterial pres-
sure (MAP) leveled at the foramen of Monroe, ICP, CPP,
and PbtO2 weremonitored continuously. ICP was moni-
tored with an intraparenchymal probe (Camino®, San
Diego, USA) or with an external ventricular drain. PbtO2
was monitored with a Clark-type electrode (Licox®,
Integra Lifesciences, USA) inserted according to manu-
facturer’s recommendation. All probes were adequately
positioned in normal appearing white matter as con-
firmed with a brain computed tomography (CT) scan
or FiO2 challenge. Two hours were added for calibration
before the readings were considered reliable (equilibra-
tion time). When possible, a pulse contour analysis sys-
tem (Flotrac®, Vigileo®, Edward Lifesciences™, USA) was
added to the arterial line to monitor the cardiac output
and stroke volume. In accordance with our local protocol
[13] and 2007 Brain Trauma Foundation guidelines [14],
systematic therapeutic measures were undertaken every
time ICP was ≥ 20 mmHg, PbtO2 was ≤ 20 mmHg , or
CPP was < 60mmHg. Patients with mass lesions under-
went surgical intervention for decompression or hema-
toma removal as judged necessary by the neurosurgical
team.
2D Color‑Coded Transcranial Doppler Measurements
Every patient had serial 2D color-coded TCD ultra-
sonography performed by one investigator (C. Sokoloff)
to assess blood flow velocity of the MCA through the
temporal window as described by Aaslid et al. [15]
while the patient was in the ED or intensive care. Color
duplex images were first recorded using an echo-Doppler
1–5MHz transducer. After identifying the M1 segment
of the MCA at a depth of 4.5–6cm and making an angle
adjustment, the artery was interrogated with pulse-wave
Doppler. For every MCA insonation, we recorded maxi-
mal (Vmax), minimal (Vmin), and Vmean, as well as
the pulsatility index (PI) calculated as (Vmax − Vmin)/
Vmean ipsilateral to PbtO2. At least three measurements
on the same vessel segment were taken, and the signal
with the highest value was recorded. Measurements were
taken bilaterally as soon as possible after the insertion
of PbtO2, daily for a total of 5days, and during dynamic
challenge tests. Dynamic challenge tests evaluated cer-
ebral vascular autoregulation, PbtO2 reactivity to 100%
oxygen, and cerebrovascular reactivity to CO2 (see sup-
plements for details). We defined a low-flow velocity state
as a Vmean < 40cm/s and a high flow state as > 100cm/s
as previously reported in the literature, the normal range
being 43–67cm/s [9]. When the Vmean was ≥ 120cm/s ,
the internal carotid artery was insonated to calculate
a Lindegaard ratio (ratio of MCAVmean/ICAVmean), to dif-
ferentiate vasospasm from hyperemia. Vasospasm was
defined by a Vmean ≥ 120cm/s associated with a Linde-
gaard ratio > 3, whereas hyperemia was defined as
Vmean ≥ 120cm/s associated with a Lindegaard ratio ≤ 3.
We collected the following data: demographic informa-
tion (age and sex) and trauma characteristics (date and
time of trauma, initial Glasgow Coma Scale [GCS], Injury
Severity Score, Marshall and Rotterdam scores on the
initial cerebral scan, and need for surgical intervention
and craniectomy). Location of the PbtO2 monitor (left
or right) was recorded. Simultaneously to every TCD,
we recorded variables that could affect TCD velocities or
PbtO2 values including: time since injury, pulse rate, sys-
tolic, diastolic, and MAP, oxygen saturation (SaO2), tem-
perature, blood gas result (PaO2 and PaCO2), hemoglobin
level (Hb), inspired oxygen fraction delivered (FiO2), car-
diac index (CI), and vasoactive medications. An Extended
Glasgow Outcome Scale (GOS-E) was assessed 6months
after injury. e cause of death and the reason for with-
drawal of life-sustaining therapy, if applicable, were also
collected.
Statistical Analysis
e sample size was calculated to verify the association
between PbtO2 and Vmean, derived from the data from
Van Santbrink which showed a correlation of r = 0.73 [9].
Eleven patients were required to establish a simple corre-
lation considering a set error of 0.05 and a desired power
of 80% (G*Power 3.1) [16]. In order to detect a correla-
tion of r = 0.70, we recruited 17 patients.
TCD values used for analysis were always the ones
acquired on the same side as the PbtO2 measurements.
Descriptive values are reported as means with stand-
ard deviations or medians with inter-quartiles range,
as appropriate. Normal distribution of variables was
assessed through visual inspection, Kolmogorov, and
Shapiro tests. Correlations were established using a sim-
ple Pearson coefficient for normally distributed variables
and with Spearman correlation for nonparametric values
(SPSS v.24).
Results
We included 17 patients (14 males and three females), of
which 16 had a severe TBI and one had a moderate TBI
(initial GCS of 10). Eleven patients (65%) had diffuse cer-
ebral injury and six lateralized injury. Fifteen patients
(88%) had a subarachnoid hemorrhage reported on the
admission CT scan. Eight patients (47%) underwent a
surgical intervention, of which seven were initial, primary
decompressive hemicraniectomies and one a secondary
intervention for persistently elevated ICP and low PbtO2
after an attempt at medical management. e 30-day and
6-month mortality rates in our population were 53% and
65%, respectively. Patient characteristics can be found in
Table1.
All patients had continuous ICP and PbtO2 monitor-
ing inserted within a median of 7h (IQR 5–14.5h) from
the trauma. e majority of PbtO2 probes (n = 15, 82%)
were inserted on the right side according to local prac-
tice, except for three patients who had PbtO2 device
Table 1 Patient characteristics
GCS Glasgow Coma Scale, IQR interquartile range, SAH subarachnoid
hemorrhage, SD standard deviation
Variables N = 17
Mean age, years (SD) 44 (± 15)
Gender, female/male 3/14
Mean admission GCS (SD) 5 (± 2)
Trauma characteristics
Concomitant extracranial trauma (%) 10 (59)
Diffuse cerebral injury (%) 11 (65)
Traumatic SAH (%) 15 (88)
Median Rotterdam Score (IQR) 4 (2–4)
Median Marshall Score (IQR) 5(2–5)
Injury Severity Score (IQR) 27 (19)
Surgical characteristics
Surgical intervention (%) 8 (47)
Decompressive hemicraniectomy (%) 7 (41)
Extended Glasgow Outcome Scale at 6 months
1 (death) 11
2–4 (vegetative state or severe disability) 2
5–6 (moderate disability) 3
7–8 (good recovery) 1
positioned under direct vision during craniectomy
(tunneled catheter). Of the six patients with unilateral
injury, four had surgery and the PbtO2 probe inserted
on the side of injury; the other two did not have sur-
gery with the probe inserted on the contralateral side.
Twelve patients (71%) had cardiac output monitored.
A total of 85 TCD examinations were performed
(mean of five TCD/patient). Doppler signal with 2D
color-coded Doppler was obtained in 96% of patients.
e first TCD values were obtained at a median of
19.5h (IQR 13.2–26.3h) after TBI and were obtained
within 8h in two (12%) and < 24h in ten patients (59%).
When considering all TCD readings, we found no cor-
relation between PbtO2 and ipsilateral Vmean (Fig.1).
However, a correlation was shown in readings collected
within 24 h of trauma (r2 = 0.41; p = 0.035, Fig. 2).
All TCD Vmean below 40cm/s in the first 24h after
TBI (n = 6) were associated with PbtO2 values below
20mmHg (positive predictive value 100%).
Twenty-four (28%) TCD measures were done during
an episode of cerebral hypoxia (PbtO2 < 20 mmHg) and
Vmean varied from 15 to 164cm/s, mean 71 ± 38cm/s
(Figs. 1, 2). Sensitivity and specificity of Vmean
of < 40cm/s to detect PbtO2 below 20mmHg were 38%
and 58%, respectively. According to predefined criteria,
we observed vasospasm in only one patient. Excluding
the Vmean obtained from this patient, episodes of low
PbtO2 corresponded to a mean Vmean of 48 ± 27 cm/s.
No correlation was seen between Vmean values and Hb,
temperature, PaO2, ICP, MAP, CPP, or CI (all p > 0.05).
A correlation was seen between Vmean and PCO2 (R2
0.351, p = 0.003).
A correlation was also found between PbtO2 and PaO2
(R2 0.429, p < 0.001), CPP (R2 0.450, p < 0.001), and Hb
(R2 0.272, p = 0.027) but not temperature, PI, PCO2, ICP,
or CI (all p > 0.05). Nine patients had dynamic challenge
tests performed (total of 20 challenges). All had pre-
served autoregulation, reactivity to O2 and CO2. ere
was no correlation between Vmean and PbtO2 during
dynamic challenge tests (all p > 0.05).
Discussion
Our findings suggest that measurements compatible with
low CBF velocity (Vmean < 40cm/s) collected in the first
24h after TBI are associated with brain tissue hypoxia
(PbtO2 < 20 mmHg). However, there is no correlation
between PbtO2 and Vmean when all measurements are
considered. We were able to obtain a good TCD signal
with 2D color-guided ultrasound in 96% of insonation
attempts.
is association is clinically important for two reasons.
First, considering it takes a mean of 7h for the PbtO2
monitoring system to be inserted, it was important to
confirm that TCD measures can be used as a surrogate
marker of cerebral ischemia. Our results confirm the
association between the early low velocities and paren-
chymal hypoxia, which in turn is known to be associated
with a poor outcome [17]. Second, our results suggest the
24h time frame following TBI in which the ultrasound
might be of interest in detecting cerebral hypoxia. Simi-
larly, van Santbrink etal. [9] evaluated the evolution of
TCD measurements in the early post-traumatic period.
ey found a stronger correlation between Vmean and
PbtO2 (r = 0.73). is correlation was limited to the first
8h after TBI and could not be replicated beyond that
time frame. Our study confirms these previous findings
and suggests that despite improvement in the manage-
ment in TBI patients in neuro-critical care, there is a
need to focus on improving very early management.
Our results indicate that episodes of early low-flow
detected by TCD are associated with brain hypoxia as
measured by PbtO2 [7]. It must be appreciated that more
Fig. 1 Relationship between PbtO2 and Vmean for all readings
Fig. 2 Relationship between PbtO2 and ipsilateral Vmean for meas-
ures at ≤ 24 h of trauma. Gray zone showing results associated with a
Vmean ≤ 40 cm/s and PbtO2 ≤ 20 mmHg
than a third of patients with severe TBI may have early
brain ischemia detected by SjvO2 on the initial invasive
cerebral monitoring after resuscitation despite MAP of
80mmHg or higher [18]. Since TCD is noninvasive and
readily available at the bedside, it might identify patients
with cerebral hypoxia before invasive monitoring is avail-
able to prevent secondary injuries. is strategy has been
investigated in two small pilot observational studies
[19, 20]. In both studies, a specific therapy (increase in
MAP and administration of osmotic agents) was adjusted
depending on TCD results collected during the initial
emergency evaluation and before any invasive intrac-
ranial monitoring was inserted. Following the observa-
tion that initially abnormal TCD results improved after
treatment, the authors concluded that TCD was useful
in detecting patients with an impaired cerebral perfu-
sion. However, both studies were performed in centers
where early use of TCD was a standard of care and their
results were not correlated with direct CBF or PbtO2
measurements.
e usefulness of TCD to predict cerebral hypoxia
seems to diminish as time after trauma increases and
despite a statistically significant correlation between
PbtO2 and Vmean, this association does not seem to be
clinically relevant. is is probably explained by the com-
plex interaction of pathophysiological conditions at play
in an injured brain during the first few days after TBI.
Various determinants of Vmean and PbtO2 can alter
the relationship between these two variables [13]. For
example, increasing PaO2 can correct cerebral hypoxia
measured by PbtO2 even in the presence of decreased
CBF [16, 21]. Also, diffusion being the rate limiting step
of oxygen delivery to the brain, cerebral hypoxia can be
observed despite adequate CBF and Vmean as diffusion
conditions can deteriorate over a few days after TBI [22].
Microvascular collapse, endothelial swelling, and perivas-
cular edema play a role in the increased diffusion gradi-
ent following head injury [22, 23]. Not surprisingly and
in line with these pathophysiological considerations, we
observed a strong correlation between PaO2 and PbtO2
in our study. Finally, various situations can occur where
Vmean can be increased, while CBF is actually reduced,
the best example of this being cerebral vasospasm.
Hyperventilation can potentially have the same effect on
cerebral hemodynamics and occurs frequently after TBI
[21]. Accordingly, PaCO2 was positively correlated with
Vmean in our study. It must be emphasized that normal
TCD values do not mean that there is no brain hypoxia.
It is worth mentioning that using 2D color-coded TCD,
we were able to obtain reliable measurements 96% of the
time. is is in line with a recent trial using the same
technique in mild-to-moderate TBI reporting a 99%
acquisition rate [24]. e fact that anatomical structures
(clinoid process, temporal lobe, brain stem, etc.) can ini-
tially be identified coupled with colored visualization of
the circle of Willis probably explains this very low rate
of “no acoustic window available.” at being said, TCD
interpretation requires skill and expertise. An abnormal
TCD detected in the emergency department would war-
rant confirmation by an experienced sonographer.
Limitations
Our study has several limitations and important fac-
tors to consider when interpreting the results. First, this
is a small single-center study in which we considered
all measures obtained in our patients for our statistical
analyses. As some of these data are non-independent,
this may have influenced our correlation results. It should
also be noted that our population represents very severe
TBI since mortality rate was 53% and five patients had
moderate disability (GOS-E 5–6). Most patients died
following withdrawal of care (6/11) and because of cat-
astrophic neurologic injury leading to organ donation
(2/11). e reason for this high mortality rate is prob-
ably circumstantial and associated with family wishes in
a shared decision making process. A 50% mortality rate
has been reported after severe TBI [25]. Also, we were
unable to get the first measurements within 8h of the
trauma because of delays in PbtO2 probe insertion due to
patient transfer from a referral center or urgent surgery.
However, it is conceivable that low Vmean (< 40 cm/s)
at earlier time point would also be associated with cer-
ebral hypoxia. e fact that the ultrasonographer was not
blinded from the PbtO2 value could have introduced a
reporting bias although a rigorous methodology was used
to perform the examination. Finally, despite treatment
management being protocolized, we cannot exclude that
confounding variables affected TCD and PbtO2 meas-
urements. is seems unlikely since we collected mul-
tiple determinants of these two measures at the same
time. at being said, it should be noted that we did not
have the power to conduct multivariate analysis to fully
explore this matter.
Conclusion
TCD measurements compatible with low CBF veloc-
ity (Vmean < 40cm/s) collected in the first 24h seem to
correlate with brain tissue hypoxia. Interpreting Doppler
and PbtO2 values, one should take into consideration that
Vmean seems to be influenced by PaCO2 and that PbtO2
is influenced by PaO2, CPP, and Hb in this study. Further
studies are needed to verify if this modality can be used
as a screening tool to help minimize time-sensitive sec-
ondary injuries.
Electronic supplementary material
The online version of this article (https ://doi.org/10.1007/s1202 8-019-00763 -y)
contains supplementary material, which is available to authorized users.
Author details
1 Department of Medicine, Hôpital du Sacré-Coeur de Montréal, Centre
intégré universitaire de santé et de services sociaux (CIUSSS) du Nord-de-
l’Ile-de-Montréal, 5400 Boul Gouin O, Montréal, Québec H4J 1C5, Canada.
2 Research Center, Hôpital du Sacré-Coeur de Montréal, Centre intégré
universitaire de santé et de services sociaux (CIUSSS) du Nord-de-l’Ile-de-
Montréal, Montréal, Canada. 3 Pharmacy Faculty, Université de Montréal,
Montréal, Canada. 4 Faculty of Medicine, Université de Montréal, Montréal,
Canada. 5 Department of Medicine, Centre Hospitalier de l’Université de Mon-
tréal, Montréal, Canada. 6 Faculty of Neurosciences, Université de Montréal,
Montréal, Canada.
Author Contributions
CS, DW, and FB design the study. KS, MA, CO, and EC provided significant
feedback on study design. CS collected the data, and FB vouches for the
accurateness of it. All authors participated in interpreting the data. CS and FB
drafted the article. DW, KS, MA, CO, and EC read the papers and provided criti-
cal feedback and suggestions to improve the manuscript. The final manuscript
was approved by all authors.
Source of Support
There was no financial support for this work.
Conflicts of Interest
All authors have nothing to disclose.
Ethical Approval
This work was approved by our local ethics committee.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
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