Randomized Control Trial For Transcranial Doppler monitoring in patients with Traumatic Brain Injury.

Traumatic Brain Injury is the leading cause of disability and mortality throughout the world. It temporarily or permanently impairs the brain function. Primary injury is induced by mechanical forces and occurs at the moment of injury while secondary brain damage may occurs hours or even days after the traumatic event. This injury may result from impairment or local decline in the cerebral blood ow. Decreases in cerebral blood ow are the result of local edema, hemorrhage or increased intracranial pressure. Although major progress has been made in understanding of the pathophysiology of this injury, this has not yet led to substantial improvements in outcome. Traumatic Brain Injury is associated with various complications including raised intracranial pressure, midline shift due to worsening of the volume of intracranial hematoma, cerebral vasospasm in traumatic sub arachnoid hemorrhage. Transcranial Doppler (TCD) has been utilized as a monitoring tool in the neurocritical care unit since it is noninvasive tool and that can be brought to bedside. However, its utility in using as a protocol in management of traumatic brain injury patients has not been studied. We hypothesized that daily TCD followed by early performance of Neuroimaging (CT scan) and Neurosurgical intervention will lead to improvement in clinical outcome. Our study’s design is Randomized Controlled Trial with neurosurgical intervention based upon the Intervention Group as the TCD-Monitoring/Neuroimaging vs Control Group as the Clinical Imaging/Neurological status. Our study’s outcome is 90 days’ clinical outcome (modied rankin scale) and Glasgow Coma Outcome Scale.


Introduction
Background Each year 200 per 100,000 people suffer from traumatic brain injury leading to mortality and morbidity worldwide. Early assessment and neurosurgical intervention can improve the clinical outcome of the patient and prevent long term morbidity. TCD is also called as "stethoscope for the brain." It is inexpensive, reproducible, and portable, which is particularly useful in a neurointensive care setting 2 .
The role of TCD in Trauma Unit: Transcranial Doppler ultrasound (TDU) is a tool that has been increasingly used in cerebrovascular haemodynamic monitoring since 1982 (1). It measure different haemodynamic parameters such as, 1) brain ow velocity, 2) estimation of vascular brain resistance, and 3) brain perfusion pressure 1 . The number one indication of TCD is for the detection and monitoring of vasospasm in patients with aneurysmal and traumatic subarachnoid hemorrhage. In addition, TCD is being studied as a non-invasive estimator of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with severe traumatic brain injury. TCD-based assessment of cerebral pressure autoregulation and CO 2 reactivity has been shown to have prognostic implications and holds the potential to allow for individualization of therapy. In addition, TCD is a non-invasive means of monitoring for vasospasm, stenosis, stroke, ICP or cerebral circulatory arrest 4 . Traumatic brain injury (TBI) may lead to hypoperfusion (day 0), hyperaemia (days 1-3), vasospasm (days 4-15), and raised ICP 14 . TCD can noninvasively identify such complications and provide prognostic information 15 The role of TCD in Monitoring Intracranial Pressure: TCD may be used as a noninvasive tool to screen for the development of elevated ICP in the rst 24 hours following injury 3 . TCD cannot replace invasive ICP monitoring 5 but may also be used to roughly predict ICP6 as well characterize the alterations in blood ow that occur during intra-cranial cerebral circulatory arrest from severely raised ICP 7 TCD can be used to give a rough estimate for ICP, to help rule-in high ICP, but not as a surrogate for accurate invasive ICP monitors. As ICP increases, ow in intra-cranial vessels changes. Initially, systolic velocity increases (i.e., systolic peak ows) as increased ICP causes cerebral vessels to narrow from external pressure in the MCA. During diastole, diastolic ow becomes decreased/blunted, as raised ICP becomes the predominant external pressure opposing forward MCA ow during diastole. Raised ICP can also exceed normal forward ow during diastole, leading to diastolic ow reversal 13 .
Raised ICP can be estimated using the Gosling's pulsatility index, which is a re ection of peripheral resistance, which is equal to the difference between the peak systolic velocity (PSV) and end-diastolic velocity (ESV), divided by the mean velocity (MV) 13  Gosling's pulsatility index (PI) provides information on downstream cerebral vascular resistance and is equal to (PSV-EDV)/MFV [27]. PI is normally 0.5 to 1.19 16 . Proximal stenosis or occlusion may lower the PI below 0.5 due to downstream arteriolar vasodilation whilst distal occlusion or constriction may increase the PI above 1.19 17 . A PI less than 0.5 may also indicate an arteriovenous malformation as vessel resistance in proximal vessels is reduced due to continuous distal venous ow 18 . PI positively correlates with ICP; a PI change of 2.4% is re ected by a 1 mmHg change in ICP 18 . Previous work with invasive 133Xe clearance methods has shown that the extent of hypoperfusion in the acute setting after TBI correlates with outcome at 6 months based on the Glasgow Outcome Scale (GOS) 19 . TCD can avoid use of invasive CBF measurement techniques and provide similar prognostic information. A low-ow velocity state de ned as an MCA MFV of <35 cm/s within 72 hours of head injury has been shown to predict unfavourable outcome at 6 months (GOS score 1-3: death, vegetative state, or severe disability) with an odds ratio of 3.9 (CI 1. [2][3][4][5][6][7][8][9][10][11][12][13] 20 . However, on multivariate analysis, this association was signi cantly less (OR 1.2 CI: 0.25-5.9), with initial GCS being a stronger predictor of outcome.
On TCD, raised ICP exhibits a sequential waveform, beginning with an increased PI and decreased MFV and EDV, followed by zero diastolic ow 21 . A signi cant correlation between PI and ICP (correlation coe cient 0.938) was demonstrated in a group of 81 patients who underwent TCD MCA PI measurements combined with invasive ICP measurements 6 . A regression line was derived as ICP = (11.1 PI) − 1.43, which could determine an ICP via the PI within ±4.2 mmHg of the actual ICP, which is reasonably accurate. Using this regression line, an ICP of >20 mmHg could also be determined with 89% sensitivity and 92% speci city 6 .
Furthermore, in a study of 125 patients with severe TBI, poor outcomes (GOS 1-3) were associated with a signi cant rise in MCA PI (1.56 versus 1,) within 24 hours of injury 22 . Additionally, a PI ≥1.56 predicted 83% of patients who had a poor outcome at 6 months, whereas a PI ≤1 identi ed 71% of patients with a good outcome (GOS 4-5) 22 .
The role of TCCD in determining the Midline shift: As ultrasound technology has improved, the same transcranial acoustic windows used for the Doppler assessment of the cerebral circulation may also be used to achieve two-dimensional (2D) images of the brain parenchyma. Though anatomic detail is inferior to CT imaging, resolution is su cient to answer emergent bedside questions such as mass effect leading to midline shift 8 Seidel et al. illustrated the use of ultrasonography for the measurement of midline shift. Reproducibility of MLS via ultrasound corresponded to 0.3 ± 0.2 mm in ten volunteers 9 . Measurements on ultrasound have correlated well with CT ndings10, and have been predictive of poor outcome from midline shift secondary to pathologies such as stroke, hemorrhage (subdural, epidural, subarachnoid), and traumatic brain injury 10 .
The role of TCD in deterring the Cerebral Vasospasm: Transcranial Doppler has been studied extensively as a validated screening tool for diagnosing vasospasm 11, aiding in the management of subarachnoid hemorrhage (SAH) patients. The severity of vasospasm may also predict outcome on the GOS; in a study of 116 SAH patients, moderate BA vasospasm (MFV >60 cm/s) was associated with permanent neurological de cit, and severe BA vasospasm (MFV >85 cm/s) was associated with vegetative state 23  In HMC, TCD is used for assessment of patients with brain aneurysm only. This study will help in determination of blood ow velocity, raised ICP and traumatic vasospasm at an early stage. Therefore, early diagnosis will lead to early management; thus improving the prognosis of patients with traumatic brain injury.
In addition, our study will help in global use of TCD in TBI, thus will be added as a protocol in the management of TBI.
Objectives OBJECTIVES:

Objectives of this study
The primary objectives of our study: Primary objectives: 1. Daily screening patients with TCD in traumatic brain injury will improve the clinical outcome by detecting early increase of ICP or VSP 2. Modi ed rankin scale at discharge Secondary objectives: 1. Modi ed rankin scale at 3 months 2. Length of Hospital stay

Number of interventions
Indicate if this is a retrospective data review Retrospective Chart/data Review (Retrospective means the data is already in existence when the project is submitted to the IRB for initial review. Provide the date range of the chart review (if this is a retrospective chart review, the end date must come before the submission date): mm/dd/yyyy to mm/dd/yyyy Patients And Methods However, there is no speci c rationale to do TCD in TBI. Therefore, we will continue it for 18 days as it the chances of traumatic vasospasm is very high till day 21 (max between 3-14 days)

Study Population and Study Setting/ Location
Patients who will be admitted with traumatic brain injury to HMC hospital will be enrolled in the study if willing to participate. This study will be conducted in the TRAUMA CENTER OF HAMAD GENERAL HOSPITAL; 1 Resident from Neurosurgery and 1 Senior Consultant from Neurology will be leading the research. TCD will be performed by sonologist, who has experience of TCD for more than 2 years. This will be double-checked by Dr. Maher Saqqur, who has certi cation in US and Sonology in Neurology. The hospital ethics review board will review and approve the study. Patient who is admitted to the hospital with moderate and severe Traumatic Brain Injury will be randomized by the block randomization method (300 patients in total) so equal number of 150 treatment and 150 control arms can be assured in 2 groups (moderate and severe Head Injury based upon the Glasgow Coma Scale) in Hamad General Hospital. The TCD arm will be assigned even number and the control odds ones in a randomization box in each block group.

Study procedures Study Duration and Timelines
Approximately 6 months for data collection and 2 months for manuscript writing. Ppatients/ relatives/ guardians will only be contacted by the consulting physician and if they agree, the research team can approach them to further explain the study and obtain consent. 3. Add that 3 copies of the ICF will be maintained 1 with the patient, 1 within medical records and 1 within the study site le Secondary outcome: three Investigators and the coordinator will have access to enter and monitor the data. The data will be stored on a password protected laptop which will be kept under lock and key at the Neurology o ce.

Subject Withdrawal/ Withdrawal of Consent
If a subject withdraws from the study, there electronic information will be erased. We will destroy their records immediately, we will not use the collected data for our nal analysis.

Statistical Consideration and Data Analysis
Demographic data will be calculated using descriptive analysis method. The sensitivity, speci city, positive predictive value (PPV), and Negative predictive value (NPV) will be calculated for screening TCD MFV/PI as compared to the ICP monitoring/serial CT scan head. The cut off for different criteria were selected based on the best accuracy parameters (P value > 0.001) and ROC curve analysis for each criteria (area under the curve ≥ 0.6).
Group sample sizes of 150 in TCD arm and 150 in the control one in order to achieve 80% power to detect a difference between the group proportions of -0.1000. The proportion in group one (the treatment group) is assumed to be 0.3000 under the null hypothesis and 0.2000 under the alternative hypothesis. The proportion in group two (the control group) is 0.3000. The test statistic used is the two-sided Z test with pooled variance. The signi cance level of the test was targeted at 0.0500.
We do expect to recruit 5 patients per month. For that reason, in order to complete the trial in 10 months period The study's analysis will be completed during the 3 months following completion of the study The Transcranial Doppler will be performed by one sonographer and the TCD reading will be done by MS and NA in blind fashion to other neuroimaging result. The neuroimaging test (CT) will be read by 2 neuroradiologists (AZ, PG) and ICP monitoring (PG, Nurse) in blind fashion to the randomization arm and TCD result.
The Head CT will be stored in archived PIN le.
The clinical TCD and neuroimaging variables are listed in the data form sheet.

Adverse Event Reporting
The study is not testing any new drugs. This is an observational study evaluating the progression and recurrence of Stroke and TIA.
Since we are not prescribing any new medication nor procedures for the purpose of our study, we do not anticipate any adverse events as such.If there is any adverse events, it WILL BE REPORTED FIRST TO THE HOSPITAL AND THEN MRC

Ethical Consideration
Page 11/14 "The study will only be conducted after review and approval from MRC"  RCT diagram