Transcranial Doppler Non-invasive Assessment of Intracranial Pressure, Autoregulation of Cerebral Blood Flow and Critical Closing Pressure during Orthotopic Liver Transplant

Abstract

Transcranial Doppler (TCD) ultrasonography allows continuous non-invasive monitoring of cerebral blood flow velocity in a variety of clinical conditions. Recently, signal processing of TCD signals has provided several comprehensive parameters for the assessment of cerebral haemodynamics. In this work, we applied a TCD multimodal approach in patients with acute liver failure undergoing orthotopic liver transplant (OLT) to assess the clinical feasibility of using TCD for cerebral haemodynamics assessment in this setting. We retrospectively studied six patients undergoing OLT with continuous monitoring of arterial blood pressure and blood flow velocity in the middle cerebral artery. The main cerebral haemodynamic parameters assessed were non-invasive intracranial pressure, cerebral perfusion pressure, cerebral autoregulation, pulsatility index, critical closing pressure and diastolic closing margin. TCD monitoring revealed marked alterations of these parameters in the OLT setting, which could provide relevant clinical information when there is imminent risk of neurologic impairment.

Full text

Original Contribution
TRANSCRANIAL DOPPLER NON-INVASIVE ASSESSMENT OF INTRACRANIAL
PRESSURE, AUTOREGULATION OF CEREBRAL BLOOD FLOW AND CRITICAL
CLOSING PRESSURE DURING ORTHOTOPIC LIVER TRANSPLANT
T
AGGEDPDANILO CARDIM,*
,y
CHIARA ROBBA,*
,z
ERIC SCHMIDT,
x
BERNHARD SCHMIDT,
{
JOSEPH DONNELLY,*
,║
JOHN KLINCK,
#
and MAREK CZOSNYKA*
,
**TAGGEDEND
* Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge,
United Kingdom;
y
Department of Anesthesiology, Pharmacology and Therapeutics, Vancouver General Hospital, University of British
Columbia, Vancouver, British Columbia, Canada;
z
Policlinico San Martino IRCCS, Genoa, Italy;
x
Service de Neurochirurgie, H^
opital
Universitaire ToulousePurpan, Toulouse, France;
{
Department of Neurology, University Hospital Chemnitz, Chemnitz, Germany;
║
Department of Anaesthesiology, University of Auckland, Auckland, New Zealand;
#
Department of Anaesthesia, Addenbrooke’s
Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; and **Institute of Electronic Systems,
Warsaw University of Technology, Warsaw, Poland
(Received 14 November 2018; revised 15 January 2019; in final from 5February 2019)
Abstract—Transcranial Doppler (TCD) ultrasonography allows continuous non-invasive monitoring of cerebral
blood flow velocity in a variety of clinical conditions. Recently, signal processing of TCD signals has provided sev-
eral comprehensive parameters for the assessment of cerebral haemodynamics. In this work, we applied a TCD
multimodal approach in patients with acute liver failure undergoing orthotopic liver transplant (OLT) to assess
the clinical feasibility of using TCD for cerebral haemodynamics assessment in this setting. We retrospectively
studied six patients undergoing OLT with continuous monitoring of arterial blood pressure and blood flow veloc-
ity in the middle cerebral artery. The main cerebral haemodynamic parameters assessed were non-invasive
intracranial pressure, cerebral perfusion pressure, cerebral autoregulation, pulsatility index, critical closing
pressure and diastolic closing margin. TCD monitoring revealed marked alterations of these parameters in the
OLT setting, which could provide relevant clinical information when there is imminent risk of neurologic
impairment. (E-mail: kiarobba@gmail.com)©2019 World Federation for Ultrasound in Medicine & Biology.
All rights reserved.
Key Words: Liver failure, Neuromonitoring, Transcranial Doppler, Cerebral oedema, Cerebral perfusion
pressure.
INTRODUCTION
The pathophysiology of hepatic encephalopathy is not
completely understood, but the development of cerebral
oedema resulting in intracranial hypertension and neuro-
logic deterioration is a well-known phenomenon of acute
liver failure (ALF) (Blei 2005, 2007).
Intracranial hypertension development may be
linked to both the systemic inflammatory state and effects
of neurotoxins in ALF. Cerebral hyperammonaemia
caused by compromised detoxification in the failing liver
results in the enzymatic conversion of ammonia to osmot-
ically active glutamine, with subsequent astrocyte
swelling and brain oedema (Ott and Vilstrup 2014).
Although the prevalence and mortality caused by these
complications have decreased in past years because of
advancements in treatment, the onset of oedema and intra-
cranial hypertension in ALF patients represents a leading
cause of death (mortality >50%) (Bernal et al. 2013)
and permanent neurologic damage (Chan et al. 2009; Tan
et al. 2012).
Patients with ALF are vulnerable to sudden relevant
changes in arterial blood pressure (ABP), causing
changes in cerebral blood flow in conditions of func-
tional loss of cerebral blood flow autoregulation. For the
same reason, they may be considered less suitable for
major surgery with large blood losses and fluid shifts,
such as orthotopic liver transplantation (OLT). Arterial
hypertensive or hypotensive episodes during OLT may
Address correspondence to: Chiara Robba, Anaesthesia and
Intensive Care, Ospedale Policlinico San Martino, Largo Rosanna
Benzi 8, 16131 Genoa, Italy. E-mail: kiarobba@gmail.com
1
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provoke cerebral hypoperfusion or hyperperfusion lead-
ing to either ischemia or aggravation of cerebral oedema
and even cerebral haemorrhage. Failure to regain con-
sciousness despite satisfactory graft function has also
been reported after OLT (Bismuth et al. 1987; Emond et
al. 1989; Iwatsuki et al. 1989; Vickers et al. 1988) and
may originate from episodes of intracranial hypertension
during transplantation.
In patients with ALF, the benefits of intracranial
pressure (ICP) monitoring include the precise and early
detection of intracranial hypertension; a correct evalua-
tion of response to therapies; the knowledge of current
cerebral perfusion pressure, which guides vasopressors
administration in the setting of loss of cerebral autoregu-
lation (Larsen et al. 1995); the procurement of prognos-
tic information, especially for deciding candidacy for
transplant; the lengthening of survival time, increasing
the chances for organ allocation (Keays et al. 1993) and
the improvement of anaesthetic management during
OLT, in which intracranial hypertension is common
(Lidofsky et al. 1992).
On the other hand, in patients with hepatic failure,
because of the risk of coagulopathy, the standard inva-
sive ICP monitoring may cause some complications,
such as haemorrhage (approximately 49% [Karvellas
et al. 2014]).
In this scenario, to avoid such complications and
broaden the knowledge of ICP and cerebral haemody-
namics monitoring of patients with ALF during OLT,
non-invasive procedures would be useful.
Transcranial Doppler (TCD) ultrasonography
allows continuous non-invasive monitoring of CBF
velocity. From TCD signal processing, several param-
eters describing cerebral haemodynamics have been
developed and applied in neurocritical care, including
non-invasive estimations of intracranial pressure
(nICP) and cerebral perfusion pressure (nCPP) (Car-
dim et al. 2016a), cerebral autoregulation indices
(Czosnyka et al. 2009) and determination of critical
closing pressure (CrCP) of the cerebral circulation
(Varsos et al. 2013). Considering these implications,
this study was aimed at testing the feasibility of nICP
monitoring in association with a TCD multiparameter
approach for cerebral haemodynamics assessment in
patients with ALF undergoing OLT. We applied a
multimodal approach in patients with ALF undergo-
ing OLT to assess the clinical feasibility of TCD for
cerebral haemodynamics assessment in this setting.
METHODS
Patient population
We retrospectively studied data from six prospec-
tively monitored patients undergoing OLT admitted to the
Transplant Unit at Addenbrooke’s Hospital, Cambridge,
United Kingdom, between December 2002 and March
2003. The median age was 56 y (range: 5165 y,
67% males). Inclusion criteria for this study were the
presence of chronic hepatic failure requiring OLT and
ALF requiring OLT. The exclusion criterion was contra-
indication to OLT. The long-time delay between monitor-
ing and retrospective data analysis was due to the fact that
many improved analytical procedures were introduced
only recently to the software we use for brain signal proc-
essing (Intensive Care Monitoring [ICM+], Cambridge
Enterprise, Cambridge, UK), including nICP (Schmidt
et al. 1997), modelled CrCP (Varsos et al. 2013)and
refined methods for cerebral autoregulation assessment
(Czosnyka et al. 2009).
General anaesthesia was maintained with intrave-
nous infusions of remifentanil and atracurium combined
with an air/oxygen/isoflurane mixture at sub-minimum
alveolar concentrations.
Monitoring and data analysis
During surgery, as a routine clinical procedure,
ABP was invasively monitored (Baxter Healthcare Corp.
Cardio Vascular Group, Irvine, CA, USA). Cerebral
blood flow velocity (FV) was assessed using TCD (TCD
Intraview, Rimed, Ra’anana, Israel) in the middle cere-
bral artery bilaterally. The probes were held in place dur-
ing the entire recording using a head band or frame
provided by the TCD device manufacturer. The experi-
mental protocol and informed consent were approved by
the institutional review board (REC 02/308, 2002).
Informed consent was obtained from all participants
included in the study.
During every surgery, we defined three time peri-
ods: the dissection phase (T0), that is, from the start of
surgery to clamping of portal vein; the anhepatic phase
(T1), when the portal vein is clamped; and lastly, the
reperfusion phase (T2), when the portal vein is released
until completion of the surgery. All haemodynamic
indices were calculated for each period and averaged.
The mean recording time was 6 h.
Raw signals were digitized using an analogue-to-
digital converter (DT 2814, Data Translation, Marlbor-
ough, CA, USA) sampled at a frequency of 50 Hz,
recorded using an in-house built software and post-
processed with ICM+. The recorded signals were sub-
jected to manual artefacts removal and analysed with
ICM+. All calculations were performed over a 10-s
long-sliding window. nICP estimation was performed
using a plugin developed for ICM+ software.
Analysis considered the calculations of left
sideright side mean values of each TCD-derived
parameter evaluated.
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TCD-derived multimodal assessment
Non-invasive estimation of ICP and cerebral perfu-
sion pressure (CPP). The nICP assessment was per-
formed using a “black-box” mathematical model
(Schmidt et al. 1997). In this model, the intracranial
compartment is considered a black-box system,
described in terms of a transfer function between ABP
and ICP. The transfer function is controlled by TCD-
and ABP-derived parameters, including ICP-related
parameters and an ABP-to-TCD transfer function
obtained from data sets of reference patients with trau-
matic brain injury (TBI) (Schmidt et al. 1997).
Cerebral autoregulation. Cerebral autoregulation
describes the intrinsic ability of the cerebral vasculature
to maintain a stable cerebral blood flow over a wide range
of ABPs (Czosnyka et al. 1996). Continuous indices of
cerebral autoregulation can be calculated from spontane-
ous fluctuations of ABP and FV. In this work, the correla-
tion coefficient between ABP and FV, termed Mxa (mean
flow index), was calculated (Czosnyka et al. 2009).
A Mxa close to +1 denotes that slow fluctuations in ABP
produce synchronized slow changes in FV indicating dys-
functional cerebral autoregulation. On the basis of previ-
ous studies considering TBI patients, negative values or
values <0.3 indicate intact cerebral autoregulation,
whereas positive values >0.3 indicate failure of cerebral
autoregulation (Czosnyka et al. 1996, 2001).
Pulsatility index. Pulsatility index describes the
quantitative and qualitative changes in the morphology
of the TCD waveform resulting from cerebral perfusion
pressure changes. It represents a ratio between pulsatile
and total cerebral blood flow.
Critical closing pressure. The concept of CrCP
was first introduced by Burton’s model, described as the
sum of ICP and vascular wall tension (WT) (Nichol et al.
1951). WT represents the active cerebral vasomotor tone
that, combined with ICP, determines the CrCP. Clinically,
CrCP represents the lower threshold of ABP below which
blood pressure in the brain microvasculature is inadequate
to prevent the collapse and cessation of blood flow
(Nichol et al. 1951). CrCP can be assessed non-invasively
using TCD, by utilising the pulsatile waveforms of FV
and ABP. The CrCP of the cerebral circulation was calcu-
lated according to Varsos et al. (2013).
Derived from CrCP and diastolic ABP (ABP
d
), the
diastolic closing margin (DCM = ABP
d
CrCP) of the
brain microvasculature was also calculated (Varsos et al.
2014). In this context, DCM represents an indication of
the pressure reserve available to avoid the cessation of
cerebral blood flow during the diastole part of heart cycle.
Optimal ABP. A method for individualization of
cerebral perfusion pressure-oriented management based
on determination of cerebrovascular reactivity (using the
pressure reactivity index [PRx]) has been proposed (Aries
et al. 2012; Steiner et al. 2002). PRx is the correlation
coefficient between ABP and invasive measurements of
ICP and describes how the cerebrovascular bed reacts in
the face of changes in systemic ABP (Czosnyka et al.
1997). Studies in TBI populations have indicated that a
PRx >0.25 is associated with impaired cerebral autoregu-
lation in patients with poor outcome, indicating that
changes in ABP are being directly transmitted to the cere-
brovascular bed, therefore altering cerebral perfusion
(Sorrentino et al. 2012). In the present work, an automated
curve-fitting method (OptimalValue function on ICM+
software) was applied to determine ABP at the minimum
value for the PRx (optimal ABP). Because only nICP was
available, we calculated the non-invasive pressure reactiv-
ity index (nPRx). For determination of optimal ABP in
individual patients, a 5-min median ABP time trend was
calculated alongside PRx. These PRx values were divided
and averaged into ABP bins spanning 5 mm Hg. An auto-
matic curve-fitting method was applied to the binned data
to determine the ABP value with the lowest associated
PRx value. A time trend of optimal ABP calculated in
this way was recorded from a moving 30-min time win-
dow updated every minute.
Statistical analysis
Statistical analysis was conducted with R Studio
software (R Version 3.3.1). Data were tested for normal
distribution using the ShapiroWilk test and are
expressed as the median (interquartile range [IQR]). Sta-
tistical measurements were performed with the Krus-
kalWallis rank sum test followed by pairwise
comparisons using the Wilcoxon rank sum test across
the different phases of OLT. The statistical significance
level was set at p<0.05.
RESULTS
Patient demographic characteristics and clinical
information are summarized in Table 1.Table 2 provides
the median IQR for different variables assessed at each
phase during OLT averaged by patient.
The variables undergoing statistically significant
changes between surgery phases were nCPP (T1T2,
mean decrease of 7 mm Hg [p= 0.03]) and DCM
(T0T1, mean decrease of 6.8 mm Hg [p= 0.03];
T0T2, mean decrease of 9.4 mm Hg [p= 0.03]). ABP
followed a reduction trend throughout OLT, as well as FV
from T0 to T1. CrCP and pulsatility index (PI) followed
an increasing trend, whereas nICP remained constant.
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With respect to the reference values for TCD
parameters in a healthy population (Tegeler et al. 2013),
patients had low FV in all phases during OLT (FV <60
cm/s). In an individualised analysis, patients 2, 3 and 6
had low-flow-velocity patterns in all phases; patient 4
had low flow only during T1 and patient 5 during T1 and
T2. PI values deviated from normal ranges in all patients
throughout OLT (PI >0.8 [Tegeler et al. 2013]).
Overall, nCPP values were low in all phases
(<60 mm Hg [Bratton et al. 2007]). Individually,
patients 2, 3 and 6 had low nCPP values in all phases;
patient 1 only from T1 to T2; patient 4 only during T2;
and patient 5 only during T0. Non-invasive ICP was
below the clinical threshold of 20 mm Hg for intracranial
hypertension throughout OLT in all patients.
The Mxa index exhibited impaired cerebral autore-
gulation throughout OLT (Mxa >0.3), with a gradual
worsening of autoregulation from T0 to T2.
CrCP was never close to ABP in any phases; conse-
quently, DCM did not reach critical values (0 mm Hg)
throughout OLT, remaining above a mean of 23 mm Hg.
Figure 1 illustrates an example of monitored ABP,
FV, nICP, nCPP, CrCP and Mxa throughout OLT for a
single patient. Figure 2 depicts individual and mean
changes for ABP, nICP and nCPP; Figure 3 for FV and
PI; Figure 4 for the autoregulation index Mxa; and
Figure 5 for CrCP and DCM. In Figures 6 and 7are
examples of optimal curves for ABP obtained from indi-
vidual patients, in which pressure reactivity (nPRx)
below levels associated with impairment of cerebral
autoregulation (>0.25) revealed optimal values for ABP
in certain cases (U-shaped curves).
DISCUSSION
In our study, we detected trends suggesting that:
Estimated ICP remains constant during OLT;
Estimated CPP gradually decreased (because of a
general trend of decreasing ABP);
Cerebral autoregulation was generally disturbed, and
worsened further during surgery;
Critical closing pressure was moderate, not disturbing
diastolic blood flow (the DCM remained above a
mean of 23 mm Hg).
Altogether, TCD monitoring revealed marked alter-
ations of cerebrovascular haemodynamics and, in partic-
ular, of cerebral autoregulation; this was probably
related to a decrease in CPP and ABP, which resulted in
cerebral vasodilation and progressive exhaustion of the
autoregulatory system. This means that TCD monitoring
in these patients could provide relevant clinical informa-
tion when there is an imminent risk of neurologic
impairment and brain injury, which could be recognized
early and treated by the clinician. TCD has proven to be
a valuable method in studies of cerebral haemodynamics
because of its high temporal resolution, non-invasive-
ness, portability, ability to monitor FV in real time and
low cost compared with other imaging techniques. In a
variety of clinical settings, multimodal applications of
TCD may provide an early detection of the onset of
Table 1. Patients’ demographic characteristics and acute liver
failure aetiology
Patient Age Sex ALF aetiology
1 51 M ArLD/HCV
2 60 M ArLD
3 51 M Cryptogenic cirrhosis
(likely NASH)
4 65 F HCV/HCC
5 53 F PSC
6 57 M PSC
ArLD = alcohol-related liver disease; HCV = hepatitis C virus;
HCC = hepatocellular carcinoma; NASH = non-alcoholic steatohepati-
tis; PSC = primary sclerosing cholangitis.
Table 2. Variables assessed at each phase during orthotopic liver transplant averaged by patient
Median (interquartile range)
T0 T1 T2
ABP (mm Hg) 72.16 (69.5577.91) 69.91 (66.3274.18) 63.34 (59.1966.62)
FV (cm/s) 53.94 (33.6658.74) 44.06 (38.5951.30) 52.89 (40.0565.76)
PI (a.u.) 1.16 (1.081.45) 1.19 (1.161.26) 1.29 (1.201.43)
nICP (mm Hg) 12.58 (10.8414.31) 12.32 (11.6713.07) 12.32 (8.8113.43)
nCPP (mm Hg) 58.12 (57.7863.31) 57.52 (55.6160.78)* 50.93 (50.3751.41)*
Mxa (a.u.) 0.56 (0.510.62) 0.67 (0.560.70) 0.72 (0.550.81)
CrCP (mm Hg) 18.17 (15.2921.34) 24.63 (22.8528.15) 22.50 (20.4322.80)
DCM (mm Hg) 34.56 (28.6136.10)*
,y
24.53 (21.5230.13)* 22.10 (20.3126.54)
y
T0 =dissection phase; T1= anhepatic phase; T2= reperfusion phase; ABP = arterial blood pressure; FV = cerebral blood flow velocity; PI= pulsatility
index; nICP = non-invasive intracranial pressure; nCPP = non-invasive cerebral perfusion pressure; Mxa = cerebral autoregulation index; CrCP = critical
closing pressure; DCM = diastolic closing margin; OLT = orthotopic liver transplant.
*
,y
Pairwise comparisons are statistically significant (p<0.05).
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Fig. 1. Representation of multimodal monitoring performed with transcranial Doppler during orthotopic liver transplant.
This figure depicts patient 5, for whom it is possible to observe the overall changes in cerebral haemodynamics among
different surgical phases. ABP = arterial blood pressure; FV = cerebral blood flow velocity; nICP = non-invasive intracra-
nial pressure; nCPP = non-invasive cerebral perfusion pressure; CrCP = critical closing pressure; Mxa = autoregulation
index; T0 = dissection phase; T1 = anhepatic phase; T2 = reperfusion phase.
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cerebrovascular derangements and facilitate their clini-
cal management. In previous studies on patients with
acute liver failure, TCD provided a repeatable and reli-
able non-invasive, bedside assessment of CBF changes,
allowing the evaluation of OLT feasibility (Bindi et al.
2008) and the identification of predominant haemody-
namic patterns (Abdo et al. 2015). In the present study,
different patterns of cerebral haemodynamics could be
identified non-invasively during OLT using a TCD-
derived multimodal approach encompassing nICP,
nCPP, cerebral autoregulation, CrCP and DCM.
The assessment of cerebral autoregulation with
TCD during OLT has been investigated previously. In
the study of Ardizzone et al (2004b), cerebral autoregu-
lation was evaluated by investigating parallel changes in
both ABP and FV during a slow phenylephrine infusion
at the beginning and end of OLT for 1 h at each period
compared with a baseline. Before OLT, cerebral autore-
gulation was impaired in all patients (n = 6). However, it
markedly improved at the end of surgery. In another
study from the same authors using a larger patient cohort
(n = 23) (Ardizzone et al. 2004a), cerebral autoregulation
Fig. 2. Longitudinal plots for (a) arterial blood pressure (ABP), (b) non-invasive intracranial pressure (nICP) and (c)
non-invasive cerebral perfusion pressure (nCPP) throughout OLT. Triangles on the plots represent the mean values for
each variable at a specific surgical phase. Thick black lines represent the linear fit of the data; grey-shadowed areas rep-
resent the 95% confidence interval of the linear model representative of the data. *Pairwise comparison is statistically
significant (p<0.05).
Fig. 3. Longitudinal plots for (a) cerebral blood flow velocity (FV) and (b) pulsatility index (PI) throughout orthotopic
liver transplant. Triangles on the plots represent the mean values for each variable at a specific surgical phase. Thick
black lines represent the linear fit of the data; grey-shadowed areas represent the 95% confidence interval of the linear
model representative of the data.
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and cerebrovascular resistance were increased in the
anhepatic versus post-reperfusion phase (within the first
hour) and versus recovery in the neohepatic phase (end
of surgery). Such results agree with ours, as throughout
OLT, cerebral autoregulation (Mxa, Fig. 4) values were
indicative of a non-reactive cerebrovascular bed.
The absence of optimal cerebral autoregulation may
explain the overall low-flow-velocity pattern presented
by patients. In addition, the overall estimated cerebral
perfusion pressure below 60 mm Hg may indicate that
patients were on the verge of the lower limit of autoregu-
lation, where FV decreases passively with decreasing
CPP (Czosnyka et al. 2001). PI, as an index describing
changes in TCD waveform resulting from changes in
CPP, deviated from normal range under these conditions.
However, PI values in our study did not increase as
reported by Abdo et al. in previous works assessing
cerebral haemodynamics in patients with ALF (PI = 2.4
[Abdo et al. 2003] or PI = 1.71 [Abdo et al. 2015]).
The driving force for such patterns could be related to
decreasing ABPs observed throughout the surgery. If left
unmanaged, significant reductions in cerebral blood flow
in the absence of functional cerebral autoregulation may
result in brain ischaemia and cerebral oedema with post-
operative neurologic damage associated with secondary
hypoxic ischaemic brain injury. These findings are
potentially aggravating in patients with history of cere-
brovascular disease, in whom the intrinsic disfunction in
cerebral autoregulation may lead to unsalvageable brain
ischaemia.
Although ICP monitoring is not an uncommon
practice in patients with ALF developing severe hepatic
encephalopathy (Maloney et al. 2016; Raschke et al.
2008), ICP behaviour during OLT has been reported
Fig. 4. Longitudinal plot for autoregulation index (Mxa). Triangles on the plots represent the mean values for each vari-
able at a specific surgical phase. Thick black line represents the linear fit of the data; grey-shadowed areas represent the
95% confidence interval of the linear model representative of the data.
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in only a few studies. In a study of six cases from
Keays et al. (1991), the mean ICP level was higher dur-
ing the “preclamp phase” and the “graft reperfusion”
phase than the “anhepatic phase.” Lidofsky et al. (1992)
found that ICP tends to vary significantly intra-opera-
tively during the surgery. It initially increases during the
dissection phase, then decreases in the anhepatic phase
and again increases during the reperfusion phase. Detry
et al.’s (1999) study suggested that in ALF patients, but
particularly in those who developed intracranial hyper-
tension before OLT, the dissection and reperfusion
phases were associated with a risk of brain injury sec-
ondary to elevated ICP and low CPP. The anhepatic
phase, similarly to the previous studies, seemed to be
associated with an ICP decrease. Lastly, a recent study
(Rajajee et al. 2018) comparing different TCD-derived
methods and measurement of the optic nerve sheath
diameter compared with invasive ICP reported that ICP
calculated from TCD flow velocities using a method for
estimating cerebral perfusion pressure could detect intra-
cranial hypertension with strong accuracy, with an area
under the receiver operating curve (AUC) of 0.90
(0.720.98, p<0.0001).
In our cohort, overall nICP behaviour was kept rela-
tively constant throughout OLT. An exception was
patient 5 (Fig. 1), who presented a similar pattern of ICP
decrease during the anhepatic phase and increase during
reperfusion, as previously described (Detry et al. 1999;
Keays et al. 1991; Lidofsky et al. 1992); however,
changes between phases were not significantly different,
and nICP mean values were not associated with intracra-
nial hypertension.
Overall, nCPP exhibited a stronger tendency of
decrease, particularly from the anhepatic to the reperfu-
sion phase, in which all patients had a decrease in nCPP.
As nICP remained relatively constant during this period,
the observed changes can be attributed to decreases in
ABP (Fig. 1).
Considering that cerebral autoregulation is subject
to haemodynamic changes such as in ABP, ICP and CPP
in pathologic conditions, the determination of optimal
thresholds for these parameters according to an optimal
state of cerebral autoregulation could provide more rea-
sonable, individualised management of cerebral haemo-
dynamics in critical situations, such as ICP surges. On
the basis of these assumptions, a previous study could
identify a narrow CPP target (optimal CPP [CPP
opt
]) by
defining the level of best cerebrovascular reactivity,
using PRx. In such study, the deviation from CPP
opt
was
associated with worse outcome in TBI patients
(Aries et al. 2012). In our study, we could obtain optimal
ABP values in certain patients, indicating the feasibility
of identifying these targets during OLT by means of
non-invasive monitoring using TCD (Figs. 6 and 7).
Critical closing pressure is another useful TCD-
derived parameter associated with the determination of a
Fig. 5. Longitudinal plots for (a) critical closing pressure (CrCP) and (b) diastolic closing margin (DCM). Triangles on
the plots represent the mean values for each variable at a specific surgical phase. Thick black lines represent the linear fit
of the data; grey-shadowed areas represent the 95% confidence interval of the linear model representative of the data.
*Pairwise comparisons are statistically significant (p<0.05).
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Fig. 6. Example of optimal curve for ABP throughout liver transplant. The lowest point on the “U-shaped” curve repre-
sents the optimal values for ABP, which in this case was close to 70 mm Hg. nPRx is expressed in arbitrary units (a.u.).
ABP = arterial blood pressure; nICP = non-invasive intracranial pressure; nCPP = non-invasive cerebral perfusion pres-
sure; nPRx = non-invasive pressure reactivity index.
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Assessment during orthotopic liver transplant D. CARDIM et al. 9

critical threshold for ABP. Through monitoring of CrCP,
the DCM can also be trended and may represent an
important clinical threshold in patients with arterial
hypotension, intracranial hypertension or pathologically
increased vascular WT (Varsos et al. 2014). In this sce-
nario, CrCP would provide information on which blood
pressure target the clinician should avoid to prevent a
circulatory arrest. Diastolic closing margin, on the other
hand, would indicate quantitatively a safety margin to
prevent such events from occurring. In a scenario where
neuromonitoring is essential to the management of
patients, these modelled parameters could provide preci-
sion to certain interventions and individualise the treat-
ment. In our six cases, we could not identify any cases in
which DCM decreased to 0 mm Hg, although it
decreased significantly throughout OLT (Fig. 4).
Limitations
This retrospective, observational study had a lim-
ited sample size (n = 6). Another potential limitation is
the absence of the gold standard invasive technique for
ICP monitoring, which would have allowed us to deter-
mine the degree of accuracy of TCD for estimating ICP
and CPP. In TBI patients, the nICP estimation method
used in this work had a 95% confidence interval for ICP
prediction of §9.94 mm Hg (Cardim et al. 2016b).
Although the accuracy of the method is not ideal at the
current stage of development, it has exhibited good pre-
diction ability for detection of ICP increases associated
with changes in cerebral blood volume (AUC of 0.82),
as well as good correlation with standard invasive meth-
ods to track changes of ICP in time non-invasively
(R= 0.80) (Cardim et al. 2017).
CONCLUSIONS
Our results indicated an alteration of cerebral autor-
egulation, normal ICP and decreasing CPP during OLT.
Transcranial Doppler appears to be a versatile tool
for assessment of cerebral haemodynamics in the OLT
setting and could provide clinically relevant information
for patient management in such conditions, where there
is a high risk of neurologic impairment.
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