Cerebral Compliance Impairment in COVID-19

The gravity of the disease caused by the new coronavirus 2019 (COVID-19) is predominantly
harbored in severe acute respiratory syndrome (SARS), often requiring ventilatory support.
However, in some cases it has been observed that the involvement of this entity is not
restrict to the respiratory tract, but also to the central nervous system (CNS), heart,
kidneys, intestines and testicles, or even the cross-response of the immune system with
potential for Guillain-Barre and Miller-Fisher syndromes. It is not yet clear whether acute
respiratory failure in patients with COVID-19 is due exclusively to pulmonary invasion or
because of concurrent CNS disorders, however, as many of these patients have neurological
symptoms such as headache, anosmia, paresthesia, nausea, vomiting and consciousness level
alterations during the early stages of the disease, the hypothesis of this entity in
promoting cerebral compliance (CC) impairment directly (i.e. encephalitis, edema or focal
ischemia) or indirectly (i.e. hypoxic distress and linkage to angiotensin-converting enzyme)
becomes suitable.

Intracranial pressure (ICP) monitoring is relevant in several CNS diseases with risk for
critical intracranial hypertension (ICH)(10). Still, this parameter is considered in specific
situations, limiting its use in neurocritical settings, especially because of the invasive
nature of the monitoring techniques available. ICH has potential to compromise CC and,
consequently, promote brain tissue damage. Regarding COVID-19, unless a mass effect
structural damage documented by encephalic imaging is evident, there is no justification to
perform a trepanation to implant an ICP monitor, hence, noninvasive techniques such as
transcranial Doppler by means of cerebral hemodynamics evaluation and the novel cranial pulse
detector (B4C), by means of the quantitative evaluation of the ICP curves, may play a role in
this scenario.

The purpose of the present study was to evaluate CC in a set of COVID-19 patients, since
implementation until withdrawal of respiratory support in ICU, to evaluate the potential
persistence of CC impairment in this population. Prolonged CC impairment observation may aid
decision making and targeted therapy in this population. Study design A single center,
observational and prospective research was conducted including consecutive subjects in
intensive care units (ICU) of the Hospital das Clínicas, São Paulo University, Brazil, with
approval of local ethics committee. Our inclusion criteria regarded patients with SARS for
COVID-19, under ventilatory support of any age and gender. Exclusion criteria comprehended
the absence of legally authorized responsible (LAR) consent, patients without temporal
acoustic window for TCD assessment, patients unable to undergo monitoring with the NICC
sensor due to lesions and/or skin infections in the sensor application region, patients with
head circumference smaller than 47 cm. The study protocol followed the Standards for
Reporting of Diagnostic Accuracy Studies (STARD) statement.

Eligible subjects are selected by the ICU team (SF, BT, EB and LMSM) during the first three
days of orotracheal intubation for CC monitoring with B4C and TCD hemodynamics evaluation
once, marking the beginning of SARS. The same evaluations are repeated once again during the
first three days after extubating, as a sign of recovery stage. Clinical parameters were
controlled to avoid assessment bias, as systemic arterial pressure, hydric balance, presence
of CNS depressors with influence on cerebrovascular hemodynamics, laboratorial partial O2 and
CO2 pressures and hemoglobin, and temperature. One operator is performing TCD and B4C
evaluations. Overall sample clinical condition was quantified using the simplified acute
physiologic score (SAPS 3).

CC monitoring techniques Cerebral compliance was evaluated noninvasively by the cranial
deformation method developed by brain4care (B4C). The B4C sensor consists of a support for a
sensor bar for the detection of local cranial bone deformations adapted with deformation
sensors. The detection of these deformations is obtained by a cantilever bar modeled by
finite element calculations. For this bar, voltage meters are attached for deformation
detection. Noninvasive contact with the skull is obtained by adequate pressure directly into
the scalp by means of a pin. Variations in ICP cause deformations in the cranial bone
detected by the sensor bar. The device filters, amplifies, and scans the sensor signal and
sends the data to a mobile device. The method is completely non-invasive and painless. In
addition, it does not interfere with any routine monitoring.

Transcranial Doppler (TCD), because it is a technique for the study of CC influences on
cerebrovascular hemodynamics and vice-versa, was used to associate the information obtained
by the B4C sensor. The arteries of the right and left cerebral hemispheres and the brainstem
were evaluated, with Doppler colored technique with low frequency probe (2MHz) every 1 mm of
arterial extension, through the temporal, orbital, suboccipital, retromastoid and
submandibular windows. Arteries analyzed: proximal segments of middle, anterior and posterior
cerebral arteries, paraselar and supraclinoid carotid siphons, ophthalmic, vertebral and
basilar. Hemodynamic parameters of interest were mean flow velocities, peak systolic
velocities, final diastolic velocities and pulsatility indexes.

Data analysis methodology Data will be analyzed obtaining a correlation coefficient and
predictive ability (ROC curve) acceptable between measurements performed with the noninvasive
B4C technique compared to the clinical evaluation of the patient, TCD and other available
physiological parameters. To meet the objectives and goals of the study, appropriate
statistical techniques will be applied. All variables will be tested for normal distribution
and appropriate statistical analysis. The normality of the distribution was verified by using
the Kolmogorov-Smirnov or Shapiro-Wilk test. For the demographic and basic clinical
variables, descriptive data analysis was used.

The automated Brain4care Analytics system will verify all collected data by the sensor. ICP
pulse wave morphology parameters such as P2/P1 ratio (P2/P1 ratio and P1 and P2
classification: P1> P2 or P2> P1) and time to peak (TTP) were obtained and stored for
analysis. The calculations are performed using the mean pulse of the ICP, calculated by
identifying and extracting all ICP pulses, excluding possible artifacts. The mean pulse was
used to calculate the amplitudes of the P1 and P2 peaks, which were obtained by detecting the
highest point of these peaks and subtracting the base value of the ICP pulse. The P2/P1 ratio
was calculated by dividing the amplitude of these two points. TTP was calculated by means of
standardization of the mean pulse and temporal measurement from the beginning of the pulse to
its highest point (greatest amplitude).

By TCD, the first signal and elevation of ICP and CC impairment is the elevation of the
pulsatility index, calculated by the following formula: PI=Sv-Dv/Mv (Sv: systolic velocity,
Dv: diastolic velocity and Mv: mean flow velocity), since excluded confounding factors such
as distal stenosis of the cranial arteries, use of barbiturate in infusion pump, dehydration,
sepsis, aortic or microvascular cerebral valve failure (microangiopathy) for example. Later,
in situations of more severe intracranial hypertension, tissue tension is translated by TCD
as sharper systolic peaks, observed by the suppression of the second systolic peak (sys2).