<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04429477</url>
  </required_header>
  <id_info>
    <org_study_id>31750820.1.0000.0068</org_study_id>
    <nct_id>NCT04429477</nct_id>
  </id_info>
  <brief_title>Cerebral Compliance Impairment in COVID-19</brief_title>
  <official_title>Assessment of Cerebral Compliance and Hemodynamics in Severe COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sao Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Sao Paulo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Several recent studies point to the possibility of the new coronavirus (SARS-Cov2), which&#xD;
      currently causes pandemic COVID-19, to infiltrate the central nervous system (CNS) and cause&#xD;
      primary damage to neural tissues, increasing the morbidity and mortality of these patients. A&#xD;
      pathophysiological hypothesis for insulting the CNS would be the impairment of cerebral&#xD;
      compliance (CC), because elevation of intracranial pressure (ICP), but due to the invasive&#xD;
      nature of the methods available for ICP evaluation, this hypothesis has so far not been&#xD;
      verified. Recently, a noninvasive technique was developed to evaluate CC (B4C sensor), making&#xD;
      it possible to analyse CC in patients outside the neurosurgical environment. Therefore, the&#xD;
      main objective of this study was to assess the presence of CC impairment in patients with&#xD;
      COVID-19, and observe potential influences of this syndrome on cerebral hemodynamics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The gravity of the disease caused by the new coronavirus 2019 (COVID-19) is predominantly&#xD;
      harbored in severe acute respiratory syndrome (SARS), often requiring ventilatory support.&#xD;
      However, in some cases it has been observed that the involvement of this entity is not&#xD;
      restrict to the respiratory tract, but also to the central nervous system (CNS), heart,&#xD;
      kidneys, intestines and testicles, or even the cross-response of the immune system with&#xD;
      potential for Guillain-Barre and Miller-Fisher syndromes. It is not yet clear whether acute&#xD;
      respiratory failure in patients with COVID-19 is due exclusively to pulmonary invasion or&#xD;
      because of concurrent CNS disorders, however, as many of these patients have neurological&#xD;
      symptoms such as headache, anosmia, paresthesia, nausea, vomiting and consciousness level&#xD;
      alterations during the early stages of the disease, the hypothesis of this entity in&#xD;
      promoting cerebral compliance (CC) impairment directly (i.e. encephalitis, edema or focal&#xD;
      ischemia) or indirectly (i.e. hypoxic distress and linkage to angiotensin-converting enzyme)&#xD;
      becomes suitable.&#xD;
&#xD;
      Intracranial pressure (ICP) monitoring is relevant in several CNS diseases with risk for&#xD;
      critical intracranial hypertension (ICH)(10). Still, this parameter is considered in specific&#xD;
      situations, limiting its use in neurocritical settings, especially because of the invasive&#xD;
      nature of the monitoring techniques available. ICH has potential to compromise CC and,&#xD;
      consequently, promote brain tissue damage. Regarding COVID-19, unless a mass effect&#xD;
      structural damage documented by encephalic imaging is evident, there is no justification to&#xD;
      perform a trepanation to implant an ICP monitor, hence, noninvasive techniques such as&#xD;
      transcranial Doppler by means of cerebral hemodynamics evaluation and the novel cranial pulse&#xD;
      detector (B4C), by means of the quantitative evaluation of the ICP curves, may play a role in&#xD;
      this scenario.&#xD;
&#xD;
      The purpose of the present study was to evaluate CC in a set of COVID-19 patients, since&#xD;
      implementation until withdrawal of respiratory support in ICU, to evaluate the potential&#xD;
      persistence of CC impairment in this population. Prolonged CC impairment observation may aid&#xD;
      decision making and targeted therapy in this population. Study design A single center,&#xD;
      observational and prospective research was conducted including consecutive subjects in&#xD;
      intensive care units (ICU) of the Hospital das Clínicas, São Paulo University, Brazil, with&#xD;
      approval of local ethics committee. Our inclusion criteria regarded patients with SARS for&#xD;
      COVID-19, under ventilatory support of any age and gender. Exclusion criteria comprehended&#xD;
      the absence of legally authorized responsible (LAR) consent, patients without temporal&#xD;
      acoustic window for TCD assessment, patients unable to undergo monitoring with the NICC&#xD;
      sensor due to lesions and/or skin infections in the sensor application region, patients with&#xD;
      head circumference smaller than 47 cm. The study protocol followed the Standards for&#xD;
      Reporting of Diagnostic Accuracy Studies (STARD) statement.&#xD;
&#xD;
      Eligible subjects are selected by the ICU team (SF, BT, EB and LMSM) during the first three&#xD;
      days of orotracheal intubation for CC monitoring with B4C and TCD hemodynamics evaluation&#xD;
      once, marking the beginning of SARS. The same evaluations are repeated once again during the&#xD;
      first three days after extubating, as a sign of recovery stage. Clinical parameters were&#xD;
      controlled to avoid assessment bias, as systemic arterial pressure, hydric balance, presence&#xD;
      of CNS depressors with influence on cerebrovascular hemodynamics, laboratorial partial O2 and&#xD;
      CO2 pressures and hemoglobin, and temperature. One operator is performing TCD and B4C&#xD;
      evaluations. Overall sample clinical condition was quantified using the simplified acute&#xD;
      physiologic score (SAPS 3).&#xD;
&#xD;
      CC monitoring techniques Cerebral compliance was evaluated noninvasively by the cranial&#xD;
      deformation method developed by brain4care (B4C). The B4C sensor consists of a support for a&#xD;
      sensor bar for the detection of local cranial bone deformations adapted with deformation&#xD;
      sensors. The detection of these deformations is obtained by a cantilever bar modeled by&#xD;
      finite element calculations. For this bar, voltage meters are attached for deformation&#xD;
      detection. Noninvasive contact with the skull is obtained by adequate pressure directly into&#xD;
      the scalp by means of a pin. Variations in ICP cause deformations in the cranial bone&#xD;
      detected by the sensor bar. The device filters, amplifies, and scans the sensor signal and&#xD;
      sends the data to a mobile device. The method is completely non-invasive and painless. In&#xD;
      addition, it does not interfere with any routine monitoring.&#xD;
&#xD;
      Transcranial Doppler (TCD), because it is a technique for the study of CC influences on&#xD;
      cerebrovascular hemodynamics and vice-versa, was used to associate the information obtained&#xD;
      by the B4C sensor. The arteries of the right and left cerebral hemispheres and the brainstem&#xD;
      were evaluated, with Doppler colored technique with low frequency probe (2MHz) every 1 mm of&#xD;
      arterial extension, through the temporal, orbital, suboccipital, retromastoid and&#xD;
      submandibular windows. Arteries analyzed: proximal segments of middle, anterior and posterior&#xD;
      cerebral arteries, paraselar and supraclinoid carotid siphons, ophthalmic, vertebral and&#xD;
      basilar. Hemodynamic parameters of interest were mean flow velocities, peak systolic&#xD;
      velocities, final diastolic velocities and pulsatility indexes.&#xD;
&#xD;
      Data analysis methodology Data will be analyzed obtaining a correlation coefficient and&#xD;
      predictive ability (ROC curve) acceptable between measurements performed with the noninvasive&#xD;
      B4C technique compared to the clinical evaluation of the patient, TCD and other available&#xD;
      physiological parameters. To meet the objectives and goals of the study, appropriate&#xD;
      statistical techniques will be applied. All variables will be tested for normal distribution&#xD;
      and appropriate statistical analysis. The normality of the distribution was verified by using&#xD;
      the Kolmogorov-Smirnov or Shapiro-Wilk test. For the demographic and basic clinical&#xD;
      variables, descriptive data analysis was used.&#xD;
&#xD;
      The automated Brain4care Analytics system will verify all collected data by the sensor. ICP&#xD;
      pulse wave morphology parameters such as P2/P1 ratio (P2/P1 ratio and P1 and P2&#xD;
      classification: P1&gt; P2 or P2&gt; P1) and time to peak (TTP) were obtained and stored for&#xD;
      analysis. The calculations are performed using the mean pulse of the ICP, calculated by&#xD;
      identifying and extracting all ICP pulses, excluding possible artifacts. The mean pulse was&#xD;
      used to calculate the amplitudes of the P1 and P2 peaks, which were obtained by detecting the&#xD;
      highest point of these peaks and subtracting the base value of the ICP pulse. The P2/P1 ratio&#xD;
      was calculated by dividing the amplitude of these two points. TTP was calculated by means of&#xD;
      standardization of the mean pulse and temporal measurement from the beginning of the pulse to&#xD;
      its highest point (greatest amplitude).&#xD;
&#xD;
      By TCD, the first signal and elevation of ICP and CC impairment is the elevation of the&#xD;
      pulsatility index, calculated by the following formula: PI=Sv-Dv/Mv (Sv: systolic velocity,&#xD;
      Dv: diastolic velocity and Mv: mean flow velocity), since excluded confounding factors such&#xD;
      as distal stenosis of the cranial arteries, use of barbiturate in infusion pump, dehydration,&#xD;
      sepsis, aortic or microvascular cerebral valve failure (microangiopathy) for example. Later,&#xD;
      in situations of more severe intracranial hypertension, tissue tension is translated by TCD&#xD;
      as sharper systolic peaks, observed by the suppression of the second systolic peak (sys2).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 1, 2020</start_date>
  <completion_date type="Actual">July 31, 2020</completion_date>
  <primary_completion_date type="Actual">July 15, 2020</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>6 Months</target_duration>
  <primary_outcome>
    <measure>Detection of cerebral compliance impairment by the B4C sensor</measure>
    <time_frame>During critical care, around 15 days/patient</time_frame>
    <description>Observe alteration in cerebral compliance due to potential intracranial hypertension during severe COVID-19. This situation is indicated when the relation P2/P1 given by the B4C sensor is &gt;1.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Detection of cerebral hemodynamics impairment by transcranial Doppler</measure>
    <time_frame>During critical care, around 15 days/patient</time_frame>
    <description>Observe disturbances in cerebral circulation during severe COVID-19, given by blood flow velocities in middle cerebral arteries (with normal range 40-70 cm/s) and the pulsatility index (normal &lt;1.2) calculated by transcranial Doppler.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Calculate mortality in this population</measure>
    <time_frame>3 months</time_frame>
    <description>Observe whether disturbances in cerebral compliance and hemodynamics assessed in this population is significantly associated with higher mortality.</description>
  </secondary_outcome>
  <enrollment type="Actual">50</enrollment>
  <condition>Intracranial Hypertension</condition>
  <condition>Cerebral Circulatory Failure</condition>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Cerebral compliance and hemodynamics monitoring</intervention_name>
    <description>Noninvasive devices are been used to assess cerebral circulation and compliance.</description>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Eligible subjects were selected by the ICU team during the first three days of orotracheal&#xD;
        intubation for CC monitoring with B4C and TCD hemodynamics evaluation once, marking the&#xD;
        beginning of SARS. The same evaluations were repeated once again during the first three&#xD;
        days after orotracheal tube withdrawal, as a sign of recovery stage. Clinical parameters&#xD;
        were controlled to avoid assessment bias, as systemic arterial pressure, hydric balance,&#xD;
        presence of CNS depressors with influence on cerebrovascular hemodynamics, laboratorial&#xD;
        partial O2 and CO2 pressures and hemoglobin, and temperature. One operator is performing&#xD;
        TCD and B4C evaluations. Overall sample clinical condition is quantified using the&#xD;
        simplified acute physiologic score (SAPS 3). Each subject undergone a skull CT scan in&#xD;
        order to exclude a mass effect lesion not related to COVID-19.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients with SARS for COVID-19, under ventilatory support of any age and gender&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  the absence of legally authorized responsible (LAR) consent,&#xD;
&#xD;
          -  patients without temporal acoustic window for TCD assessment,&#xD;
&#xD;
          -  patients unable to undergo monitoring with the NICC sensor due to lesions and/or skin&#xD;
             infections in the sensor application region,&#xD;
&#xD;
          -  patients with head circumference smaller than 47 cm.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hospital das Clínicas da Faculdade de Medicina da USP.</name>
      <address>
        <city>São Paulo</city>
        <zip>05403000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <reference>
    <citation>Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020 Jun;92(6):552-555. doi: 10.1002/jmv.25728. Epub 2020 Mar 11.</citation>
    <PMID>32104915</PMID>
  </reference>
  <reference>
    <citation>Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020 Apr 1;11(7):995-998. doi: 10.1021/acschemneuro.0c00122. Epub 2020 Mar 13.</citation>
    <PMID>32167747</PMID>
  </reference>
  <reference>
    <citation>Needham EJ, Chou SH, Coles AJ, Menon DK. Neurological Implications of COVID-19 Infections. Neurocrit Care. 2020 Jun;32(3):667-671. doi: 10.1007/s12028-020-00978-4.</citation>
    <PMID>32346843</PMID>
  </reference>
  <reference>
    <citation>Bridwell R, Long B, Gottlieb M. Neurologic complications of COVID-19. Am J Emerg Med. 2020 Jul;38(7):1549.e3-1549.e7. doi: 10.1016/j.ajem.2020.05.024. Epub 2020 May 16.</citation>
    <PMID>32425321</PMID>
  </reference>
  <reference>
    <citation>Niazkar HR, Zibaee B, Nasimi A, Bahri N. The neurological manifestations of COVID-19: a review article. Neurol Sci. 2020 Jul;41(7):1667-1671. doi: 10.1007/s10072-020-04486-3. Epub 2020 Jun 1.</citation>
    <PMID>32483687</PMID>
  </reference>
  <reference>
    <citation>Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, Liu C, Yang C. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020 Jul;87:18-22. doi: 10.1016/j.bbi.2020.03.031. Epub 2020 Mar 30.</citation>
    <PMID>32240762</PMID>
  </reference>
  <reference>
    <citation>Delanghe JR, Speeckaert MM, De Buyzere ML. The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections. Clin Chim Acta. 2020 Jun;505:192-193. doi: 10.1016/j.cca.2020.03.031. Epub 2020 Mar 24. No abstract available.</citation>
    <PMID>32220422</PMID>
  </reference>
  <reference>
    <citation>Kochanek PM, Tasker RC, Carney N, Totten AM, Adelson PD, Selden NR, Davis-O'Reilly C, Hart EL, Bell MJ, Bratton SL, Grant GA, Kissoon N, Reuter-Rice KE, Vavilala MS, Wainwright MS. Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary. Neurosurgery. 2019 Jun 1;84(6):1169-1178. doi: 10.1093/neuros/nyz051.</citation>
    <PMID>30822776</PMID>
  </reference>
  <reference>
    <citation>Frigieri G, Andrade RAP, Dias C, Spavieri DL Jr, Brunelli R, Cardim DA, Wang CC, Verzola RMM, Mascarenhas S. Analysis of a Non-invasive Intracranial Pressure Monitoring Method in Patients with Traumatic Brain Injury. Acta Neurochir Suppl. 2018;126:107-110. doi: 10.1007/978-3-319-65798-1_23.</citation>
    <PMID>29492543</PMID>
  </reference>
  <reference>
    <citation>Vilela GH, Cabella B, Mascarenhas S, Czosnyka M, Smielewski P, Dias C, Cardim DA, Mascarenhas YM, Wang CC, Andrade R, Tanaka K, Lopes LS, Colli BO. Validation of a New Minimally Invasive Intracranial Pressure Monitoring Method by Direct Comparison with an Invasive Technique. Acta Neurochir Suppl. 2016;122:97-100. doi: 10.1007/978-3-319-22533-3_19.</citation>
    <PMID>27165885</PMID>
  </reference>
  <reference>
    <citation>Cabella B, Vilela GH, Mascarenhas S, Czosnyka M, Smielewski P, Dias C, Cardim DA, Wang CC, Mascarenhas P, Andrade R, Tanaka K, Silva Lopes L, Colli BO. Validation of a New Noninvasive Intracranial Pressure Monitoring Method by Direct Comparison with an Invasive Technique. Acta Neurochir Suppl. 2016;122:93-6. doi: 10.1007/978-3-319-22533-3_18.</citation>
    <PMID>27165884</PMID>
  </reference>
  <reference>
    <citation>Schaafsma A. A new method for correcting middle cerebral artery flow velocity for age by calculating Z-scores. J Neurosci Methods. 2018 Sep 1;307:1-7. doi: 10.1016/j.jneumeth.2018.06.009. Epub 2018 Jun 18.</citation>
    <PMID>29920296</PMID>
  </reference>
  <reference>
    <citation>Schaafsma A. Improved parameterization of the transcranial Doppler signal. Ultrasound Med Biol. 2012 Aug;38(8):1451-9. doi: 10.1016/j.ultrasmedbio.2012.03.016. Epub 2012 May 12.</citation>
    <PMID>22579541</PMID>
  </reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>June 9, 2020</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>September 19, 2020</last_update_submitted>
  <last_update_submitted_qc>September 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sao Paulo</investigator_affiliation>
    <investigator_full_name>Sergio Brasil, MD</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Intracranial Hypertension</mesh_term>
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>July 4, 2021</submitted>
    <returned>July 7, 2021</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04429477
org study id: 31750820.1.0000.0068
nct id: NCT04429477
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
Several recent studies point to the possibility of the new coronavirus (SARS-Cov2), which
      currently causes pandemic COVID-19, to infiltrate the central nervous system (CNS) and cause
      primary damage to neural tissues, increasing the morbidity and mortality of these patients. A
      pathophysiological hypothesis for insulting the CNS would be the impairment of cerebral
      compliance (CC), because elevation of intracranial pressure (ICP), but due to the invasive
      nature of the methods available for ICP evaluation, this hypothesis has so far not been
      verified. Recently, a noninvasive technique was developed to evaluate CC (B4C sensor), making
      it possible to analyse CC in patients outside the neurosurgical environment. Therefore, the
      main objective of this study was to assess the presence of CC impairment in patients with
      COVID-19, and observe potential influences of this syndrome on cerebral hemodynamics.
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).
observational model: Cohort
time perspective: Prospective
measure: Detection of cerebral compliance impairment by the B4C sensor
time frame: During critical care, around 15 days/patient
description: Observe alteration in cerebral compliance due to potential intracranial hypertension during severe COVID-19. This situation is indicated when the relation P2/P1 given by the B4C sensor is >1.
measure: Detection of cerebral hemodynamics impairment by transcranial Doppler
time frame: During critical care, around 15 days/patient
description: Observe disturbances in cerebral circulation during severe COVID-19, given by blood flow velocities in middle cerebral arteries (with normal range 40-70 cm/s) and the pulsatility index (normal <1.2) calculated by transcranial Doppler.
measure: Calculate mortality in this population
time frame: 3 months
description: Observe whether disturbances in cerebral compliance and hemodynamics assessed in this population is significantly associated with higher mortality.
intervention type: Device
intervention name: Cerebral compliance and hemodynamics monitoring
description: Noninvasive devices are been used to assess cerebral circulation and compliance.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 1 Year
maximum age: N/A
healthy volunteers: No
facility: 
country: Brazil
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responsible party type: Principal Investigator
investigator affiliation: University of Sao Paulo
investigator full name: Sergio Brasil, MD
investigator title: Principal investigator
mesh term: Intracranial Hypertension
mesh term: Shock
sharing ipd: No
submitted: July 4, 2021
returned: July 7, 2021