A Novel Non-invasive Technique of Cerebral Compliance and Auto-regulation Assessment

• ClinicalTrials.gov Identifier: NCT03144219
• Recruitment Status: Recruiting
• First Posted: May 8, 2017
• Last Update Posted: September 30, 2022
• Sponsor: University of Sao Paulo
• Collaborator: Brain4Care USA Corp.
• Information provided by (Responsible Party): Sergio Brasil, MD, University of Sao Paulo

Tracking Information

• First Submitted Date: May 4, 2017
• First Posted Date: May 8, 2017
• Last Update Posted Date: September 30, 2022
• Actual Study Start Date: May 1, 2017
• Estimated Primary Completion Date: December 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 5, 2017)

Impaired cerebral compliance [ Time Frame: 10 minutes ]

Performing ICP and TCD monitoring simultaneously during jugular compression, matching waveform behavior through computer software QL Online

Original Primary Outcome Measures (submitted: May 4, 2017)

Elevation of TCD pulsatility index during jugular compression as the ICP values [ Time Frame: 10 minutes ]

Impaired cerebral compliance

Current Secondary Outcome Measures (submitted: July 18, 2019)

• Impaired cerebral auto-regulation [ Time Frame: 10 minutes ]
  The same procedure detailed above, matching mean arterial pressure and CBFv in the computer software QL Online
• Non-invasive intracranial compliance monitoring [ Time Frame: 10 minutes ]
  The same approaches described above, using the non-invasive Brain4Care system concomitantly.

Original Secondary Outcome Measures (submitted: May 4, 2017)

CBF velocities fluctuating as the AMP values [ Time Frame: 10 minutes ]

Impaired cerebral auto-regulation

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Novel Non-invasive Technique of Cerebral Compliance and Auto-regulation Assessment
• Official Title: A Novel Non-invasive Technique of Cerebral Compliance and Auto-regulation Assessment

Brief Summary

Introduction: Intracranial pressure (ICP) monitoring is essential in several medical situations, however, currently there is an invasive technique, costly, not widely available and sometimes contraindicated. Transcranial Doppler (TCD) pulsatility index (PI) measure can provide indirect information on the cerebrovascular resistance (CVR) augmentation, which is present concomitantly with intracranial hypertension (ICH). The hypothesis that PI measure accurately indicates cerebral compliance impairment (CCI) has been not assessed by large studies currently, and would be of value as a non invasive technique to denote earlier installing of therapeutics to prevent the effects of ICH. Likewise, a novel technique of intracranial compliance assessment by means of an external sensor has been developed, still in need of being prospectively studied.

Objective: The present study aims to assess PI accuracy indicating CCI, and dynamic cerebral auto regulation (dCAR) during internal jugular veins (IJVs) compression observed by both invasive and non-invasive techniques.

Methods: A prospective, observational controlled study, including critical neurological patients with ICP monitoring in normal range (under 20 mmHg). Initially, dCAR is monitored, then, the IJVs are compressed for 60 seconds with ultrasound guidance. We evaluate optic nerve sheath prior to intervention, and dCAR, ICP values, ICP waveforms and PI variation at different times, correlating results.

Detailed Description

Introduction

Multimodal monitoring in neurocritical care is essential in current practice. It aims to early Identify treats occurring in the brain of comatose patients and implement targeted therapies to avoid further complications and poorer outcomes.

Some of the methods used for monitoring require invasive procedures, such as the assessment of intracranial pressure (ICP) with intracranial catheter. However, these techniques can raise morbidity, are costly, and are not available or contraindicated1. In addition, the invasive ICP method is not perfectly accurate with cases in which, intracranial hypertension (ICH) may be present despite normal screen ICP values2.

Transcranial Doppler (TCD) is a noninvasive bedside ultrasound technique which could be implemented in the monitoring of raised ICP3-4 and in the identification of impaired intracranial compliance by the compression of the internal jugular veins (IJVs)1. However, such application of the method has not been validate with large prospective studies. Validation of this technique would be of value for screening patients prior to suffer the consequences of ICH.

Recently, a non-invasive cranial strain gauge sensor has been developed, able to provide the curves of cardiac beat by beat cranial dilation. The sensor registers have been demonstrated to be similar to those obtained by the invasive ICP catheters, although large series comparing both techniques are lacking.

Objectives

1) Evaluate the reliability of TCD during the IJVs compression in the assessment of intracranial compliance; 2) evaluate dynamic cerebral auto regulation (dCAR) during IJVs compression. 3) Evaluate the suitability of novel non-invasive intracranial compliance system.

Methods

This is a prospective observational study which will be performed at "Hospital das Clinicas" (São Paulo University School of Medicine). The sample desired is of 50 consecutive subjects, as a pilot study based in recommendations of the literature5. After ethics committee approval, neurological patients of any cause, gender or age, whose underwent ICP monitoring displaying both ICP curves and values will be included. The non-invasive system of intracranial compliance monitoring (Brain4Care Brasil, São Carlos, Brazil) will be used concomitantly. We will exclude patients without insonation window.

The control group will be of healthy subjects, to evaluate PI and cerebral auto-regulation during IJVs compression.

Initially, the study of dynamic cerebral auto regulation through the relationship of spontaneous fluctuations of cerebral blood flow velocity in the middle cerebral arteries (MCAs) and arterial blood pressure, will be done using TCD (DWL Doppler Box 2 MHz, Germany) for five minutes, plus the optic nerve sheath measure (Sonosite Micromaxx 13 MHz, USA), then, ultrasound guided (Sonosite Micromaxx 13 MHz, USA) IJVs compression will be performed for 60 seconds in the included patients, and the following variables will be registered prior and after intervention: blood pressure, mean arterial blood pressure, heart rate, breathing rate, hemoglobin, hematocrit, carbon dioxide pressure (pCO2), oxygen saturation, systolic flow velocity, diastolic flow velocity, mean velocity, pulsatility index, ICP values and changes in the ICP relation P1-P2 (waveform behavior).

One researcher (SB) will perform TCD examinations and obtain patients data, while two blinded researchers (RN and MLO) the offline analysis.

Data will be presented as mean ± standard error of the mean or median and interquartile ranges depending on the nature of the variable. The Chi-square test (χ2) will be used to assess the difference in sex distribution and etiology between groups. To evaluate the homogeneity of the sample we will use the Lèvene test. And, we will use the Kolmogorov-Smirnov test to evaluate the normality of distribution of each variable studied. According to the homogeneity and normality of distribution (Gaussian) of the studied variable will be used the appropriate statistical test (parametric or non-parametric) for each variable. In the homogeneous and Gaussian variables during rest, the analysis of variance (ANOVA) of a factor will be used to test the differences between the groups. In cases of significant F, the Scheffé post-hoc test will be performed for multiple comparisons. In non-homogeneous and / or non-Gaussian variables during rest, the Kruskal-Wallis test will be used, followed by the Dunn's test between the groups. On the other hand, in the homogeneous and Gaussian variables analyzed during the physiological maneuvers, the analysis of variance (ANOVA) of two factors will be used to test the differences between groups. In cases of significant F, the Scheffé post-hoc test will be performed for multiple comparisons. However, in non-homogeneous and / or non-Gaussian variables analyzed during physiological maneuvers, the Wilcoxon (paired data) and Mann-Whitney (unpaired data) tests, when appropriate, will be used. Will be considered as statistically significant to differences with P values <0.05.

• Study Type: Observational
• Study Design: Observational Model: Case-Control; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: Neurological patients (GCS 5 and under) of any cause, gender or age.
• Condition: Intracranial Hypertension

Intervention

• Diagnostic Test: Transcranial Doppler (TCD) ultrasound monitoring
  TCD monitoring comatose patients in ICU looking for signs of impaired cerebral compliance
• Diagnostic Test: Non invasive intracranial compliance monitoring
  A sensor of cardiac beat by beat cranial dilation will be used for monitoring intracranial compliance, in non-invasive fashion.

• Study Groups/Cohorts: Not Provided

Publications *

• Dahlqvist MB, Andres RH, Raabe A, Jakob SM, Takala J, Dunser MW. Brain herniation in a patient with apparently normal intracranial pressure: a case report. J Med Case Rep. 2010 Aug 31;4:297. doi: 10.1186/1752-1947-4-297.
• Bellner J, Romner B, Reinstrup P, Kristiansson KA, Ryding E, Brandt L. Transcranial Doppler sonography pulsatility index (PI) reflects intracranial pressure (ICP). Surg Neurol. 2004 Jul;62(1):45-51; discussion 51. doi: 10.1016/j.surneu.2003.12.007.
• O'Brien NF, Maa T, Reuter-Rice K. Noninvasive screening for intracranial hypertension in children with acute, severe traumatic brain injury. J Neurosurg Pediatr. 2015 Oct;16(4):420-5. doi: 10.3171/2015.3.PEDS14521. Epub 2015 Jul 3.
• Hertzog MA. Considerations in determining sample size for pilot studies. Res Nurs Health. 2008 Apr;31(2):180-91. doi: 10.1002/nur.20247.
• Paschoal FM Jr, Bor-Seng-Shu E, Teixeira MJ. Transcranial Doppler ultrasonography with jugular vein compression can detect impairment of intracranial compliance. Clin Neurol Neurosurg. 2013 Jul;115(7):1196-8. doi: 10.1016/j.clineuro.2012.09.028. Epub 2012 Nov 3. No abstract available.
• Brasil S, Frigieri G, Taccone FS, Robba C, Solla DJF, de Carvalho Nogueira R, Yoshikawa MH, Teixeira MJ, Malbouisson LMS, Paiva WS. Noninvasive intracranial pressure waveforms for estimation of intracranial hypertension and outcome prediction in acute brain-injured patients. J Clin Monit Comput. 2022 Nov 18:1-8. doi: 10.1007/s10877-022-00941-y. Online ahead of print.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 29, 2022): 133
• Original Estimated Enrollment (submitted: May 4, 2017): 40
• Estimated Study Completion Date: December 31, 2023
• Estimated Primary Completion Date: December 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Patients whose underwent ICP monitoring displaying both ICP curves and values.

Exclusion Criteria:

Patients whose display absence of insonation window

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Sergio Brasil, MDMSc; +5511981210990; sbrasil@usp.br

• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT03144219
• Other Study ID Numbers: 66721217.0.0000.0068
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Sergio Brasil, MD, University of Sao Paulo
• Original Responsible Party: Sergio Brasil, University of Sao Paulo
• Current Study Sponsor: University of Sao Paulo
• Original Study Sponsor: Same as current
• Collaborators: Brain4Care USA Corp.
• Investigators: Not Provided
• PRS Account: University of Sao Paulo
• Verification Date: September 2022