DETAILS OF THE RESEARCH PROJECT

TITLE OF THE PROJECT: Optimal versus standard cerebral perfusion pressure targets for the management of severe traumatic brain injury- A randomised controlled clinical trial  (OPT-STAND- CPP trial)

INTRODUCTION & REVIEW OF LITERATURE:

Among various injuries, traumatic brain injury (TBI) is a leading cause of morbidity, mortality, disability, socioeconomic losses and poor quality of life among survivors. It is estimated that nearly one million persons suffer serious head injuries and 100,000 lives are lost every year in India. In the city of Bangalore alone, nearly 10,000 individuals sustain brain injury and more than 1,000 die every year¹. Investigators’ hospital which is located in Bangalore, is a tertiary level neurotrauma centre and caters to 60 to 70% of these head injured patients. 65% of the patients with traumatic brain injury (TBI) are due to road traffic accidents, 35% due to fall from height and 10% due to assault. In total, 71% of TBIs were mild, 15% moderate and 13% severe in nature based on Glasgow Coma Scale. Measurement of outcome based on Glasgow outcome scale (GOS) at hospital discharge time revealed that 5.5% died in hospital and 4% were discharged in a persistent vegetative state. Severe and extremely severe disabilities at discharge from hospital were observed in upto 49% of patients with severe head injury in our hospital². Disabilities were measured using disability rating scale. These disabilities have a major socio economic burden on patients, families and society to meet costs of rehabilitation. The indirect costs due to loss of work and income are substantial and are not routinely included in costing calculations. Thus, the total costs are huge and phenomenal for developing societies. Any interventions that reduce disabilities among patients with TBI will have humongous benefits to patients and society. Apart from prevention of road traffic accidents, clinical management strategies make a huge difference to patient outcome. Several clinical trials have been conducted and brain trauma foundation has recommended guidelines to manage patients with TBI which are followed in several hospitals across the world including ours. However, till date, no specific treatment has been identified that makes a dependable and measurable difference in outcome to patients with TBI. A key challenge is that each patient with TBI has a unique set of factors that may influence patient outcome. They are location and severity of the injury, patient’s age and overall heath, and the time between the injury and the initiation of treatment. These factors, along with differences in care across treatment centres, highlight the importance potential new treatments which can be easily measured and applied clinically. One such patient management strategy is identifying the optimal cerebral perfusion pressure where the pressure autoregulation is best maintained. Thus a patient with head injury is maintained at normal or near normal autoregulation most of the time during the clinical management. 

Rationale for the Study: 

One of the parameter that is recommended by brain trauma foundation (BTF) is a target cerebral perfusion pressure (CPP) value of 60 to 70 mm Hg (CPPstd) for management of patients with head injury. The guideline does not take into consideration the cerebral autoregulatory status of the patients after TBI when recommending this range for CPP maintenance. However, this target CPP of 60-70 mmHg may not be optimal to every patient with TBI as cerebral autoregulation may be impaired to different extents. In such a scenario, brain is likely to suffer cerebral edema if CPP is above optimal CPP level for that particular patient or brain may suffer cerebral ischemia if CPP is below the optimal level for that patient. Thus, optimal CPP (CPPopt) is a dynamic value for an individual patient (not fixed at 60-70 mm. of Hg for all patients at all time-points) and changes as the intracranial compliance and pressure reactivity index varies. Retrospective data demonstrated an association between improved outcomes in patients who had a CPP value concordant with the CPPopt value. 

Currently, most centres managing TBI including ours follow the BTF guidelines and maintain a standard CPP of 60 to 70 mm Hg for all patients with TBI in the operating rooms and intensive care unit (ICU). Considering the limitation of this method of managing CPP in patients with TBI, we hypothesis that CPPopt method may be superior to CPPstd method in patients with TBI for outcome at discharge. Hence, we plan to conduct a randomized controlled trial comparing the two methods for CPP management in patients with TBI with regards to clinical outcomes. 

Hypothesis: 

We hypothesize that managing patients with CPPopt (individualized approach) will reduce severe disability on Disability rating Scale at hospital discharge to 29% as compared to 49% of severe disability with CPPstd (standardized approach) management.  

AIMS AND OBJECTIVES: 

Primary objective: 

To compare the disability rating scale (DRS) (Appendix 1) at hospital discharge between patients with acute severe TBI managed with CPPopt and CPPstd methods in the ICU

Secondary objectives: 

1)     To compare in hospital mortality, Glasgow Outcome scale Extended (GOSE) (Appendix 2) at 3 months and 6 months after discharge

2)     To compare length of ICU stay, sudden adverse events, pulmonary and cardiovascular complications. 

3)     To correlate PRx values derived from ICM+ monitor with outcome in both groups

METHODOLOGY:

1. Study design 

This will be a multicentric, prospective double blind randomised controlled study.

2. Study site 

Study will be conducted in the ICUs of two large trauma centres of Bangalore, India. a) National Institute of Mental Health and Neurosciences b) St. John’s Medical College Hospital

3. Methods (e.g. PICO)

         Study Population: Patients with severe TBI identified using Glasgow coma scale (GCS)      </=8 or if intubated motor score </=5

Inclusion criteria:

1)     Admission to study hospital within 24 to 48 hours of injury

2)     GCS <= 8 or if intubated, GCS Motor <=5 on admission to intensive care unit

3)     Patients deteriorating in the hospital to GCS <=8 within 48 hours of injury

4)     Age >/= 18 years

Exclusion criteria: 

1)     GCS of 3 with fixed and dilated pupils

2)     Non-ICU patients

3)     Pregnancy

4)     No consent

Randomization: Within 24 hours of injury or in hospital deterioration to GCS ≤8 within 48 hours of injury

Proposed study procedure: 

After the local institutional Ethics committee approval in the two study centres, primary and co-investigators will screen eligible patients. Flow of study subjects into the study will be as depicted in Figure 1. 

Figure 1 study flow: 

Randomization:

Computer generated randomization will be done in both the study sites. Randomization will be stratified based on site, age </=vs >40) and GCS (3-5 or if intubated motor score 1-2 vs GCS 6-8 or if intubated motor score 3-5). 

Blinding: This will be a double blinded study. Study patients, outcome assessor  and data analyst will be blinded to reduce bias. However, the treating intensive care physician will be aware of the management plan for study patients. Treating physician will not have access to CPPopt data when the patient is being managed with CPPstd. 

Study groups: 

Intervention group (CPPopt group) vs Control group (CPPstd group)

Treatment protocol in both groups: 

Clinical Management in ICU:

1)     Mechanical ventilation with PCV mode to begin with and weaning modes later

2)     Head end elevation to 30 degree

3)     Avoid hyperthermia and maintain normothermia

4)     Anti-edema measures using mannitol or equiosmolar 3% saline will be used if ICP is >20 cm H2O 

5)     Seizure prophylaxis 

6)     Gastric ulcer prophylaxis

7)     Deep Vein thrombosis prophylaxis as per BTF recommendation

8)     Early enteral nutrition support

9)     Administration of antibiotics as and when needed

10)  Injection Propofol and morphine will be used for sedation and analgesia as required

11)  Surgical decompression if not already done and when medical management fails

12)  Serious adverse events and complications will be noted (in hospital death, cardiovascular and pulmonary complications)

Monitoring

1)     Continuous SpO2 monitoring

2)     Urine output monitoring

3)     Electrocardiography

4)     Intracranial pressure monitoring by codman subdural/intraparenchymal sensor on the side ipsilateral to the injury as decided by neurosurgeon in CPPopt group and when available in CPPstd group. When invasive ICP monitoring is not available in CPPstd group, non invasive ICP will be measured using trans cranial doppler or optic nerve sheath diameter in CPPstd group.

5)     Brain Imaging as per clinical indication

Intervention:

CPPopt group: CPPopt will be observed as displayed on the ICM + monitor. 

Nurses will be trained to observe and target CPPopt for patient management. CPPopt will be recorded and maintained for atleast 72 hours in the intensive care unit and later the patient management will be similar to CPPstd group. Mean arterial pressure (MAP) of patients in CPPopt group will be CPPopt + ICP. ICP will be displayed on codman monitor. CPPopt will be will be recorded every 2^nd hourly and maintained for the next two hours. 

CPPstd group: Patients will have ICP monitored. ICP will be displayed on codman monitor. MAP of patients in CPPstd group will be 60 to 70 + ICP. CPPstd will be will be recorded every 2^nd hourly and maintained for the next two hours. 

Injection noradrenaline will be used to increase CPP and analgosedation or injection dexmedetomidine or antihypertensive as appropriate will be used to lower CPP.  

Definitions: 

Increased ICP: ICP > 20 mm Hg for > 5mins

Neuro-worsening: 

Decrease in by GCS ≥2 scores

A new pupillary asymmetry or loss of reaction

A new onset focal neurological deficit

Complications: Infections, sepsis, neuro-worsening, cardiac events, acute kidney injury, coagulopathy, deep venous thrombosis, pulmonary embolism, death and any other complications during hospital stay

Treatment escalation when ICP is >20 cm H2O for > 5 mins: 

Brief hyperventilation with target PaCO2 ≥28 mmHg

Propofol sedation with or without muscle relaxation and mechanical ventilation 

Hyperosmolar therapy with mannitol or 3% hypertonic saline

EVD insertion if feasible

Hypothermia upto 35.5 degrees for 24 hours 

Decompressive craniectomy if not already done

CPPopt measurement: 

CPPopt is measured using intensive care monitoring (ICM+) software. ICM+ software program is developed by the Clinical Neuroscience Department in Cambridge, UK. In this software, CPPopt function is mainly applied using the ICP and arterial blood pressure (ABP). The CPPopt mathematical algorithm displays CPPopt U shaped curve plotted over time and CPPopt values are automatically displayed. Bedside nurse will maintain mean arterial pressure derived from real time CPPopt+ realtime ICP.   

CPPstd: CPP is maintained at 60 to 70 mmHg as per BTF guideline. MAP=60 to 70+ICP

Outcome assessment will be done by the investigators as follows:

A] Primary outcome: - Disability rating scale assessment in study subjects at discharge from hospital

B] Secondary outcomes: -Glasgow outcome scale assessment at 3 and 6 months post discharge through a telephonic follow up

Sample Size

Sample size is calculated using Clincalc sample size calculator. There are no previous similar Randomized control studies to calculate sample size for this proposed project. From our hospital data we are aware that the incidence of severe disabilities in patients with severe head injury after management as per conventional BTF guidelines is 49%. Disabilities are measured at discharge using disability rating scale. We hypothesized that severe disabilities would reduce to 29% (about 40% reduction) when they are managed with CPP opt. As per this assumption, the total sample size would be 184 with 92 in exposed (CPPopt group) and 92 (CPPstd) in unexposed. Considering 10% attrition of study subjects, we will inflate the sample size to 206.

Statistical Analysis

The null hypothesis is that, managing patients with CPP opt will reduce severe disability by 20%. Data will be presented as mean and standard deviation for continuous variables, and as frequency/percent for categorical variables, stratified by treatment and outcome classifications. Descriptive statistics and unadjusted univariate comparisons will be carried out using Student t-tests for continuous measures, and chi2 tests for independence for categorical. Data violating assumptions of normality will be compared using nonparametric test analogs— Wilcoxon rank-sum or Fisher exact tests—as appropriate. A modified logistic regression analysis will be used to produce multivariate-adjusted estimates of the relative risk of worst disability rating scale. Interaction and confounding will be assessed through stratification and relevant expansion covariates. P values 0.05 were considered statistically significant. 

Ethical issues 

There will not be any ethical issues with this study. The present standard of care in most of the Indian hospitals, including ours is same as that of CPPstd group. However, invasive ICP monitoring in severe head injury patients is standard of care and is strongly recommended as per brain trauma foundation guidelines. CPPopt is derived from ICM+ software incorporating arterial waveform and ICP values. We will explain in detail and take consent about the benefits and complications of invasive ICP monitoring before recruiting patients. And study subjects are covered by insurance. 

REFERENCES:

1.     Gururaj G, Kolluri S.V.R, Chandramouli B.A, Subbakrishna D.K and Kraus JF, “Traumatic brain injury” National Institute of Mental Health & Neuro. Sciences, Publication no 61, Bangalore-560029, India, 2005

2.     Deepika A, Devi BI, Shukla D. Predictive validity of disability rating scale in determining functional outcome in patients with severe traumatic brain injury. Neurol India. 2017 Jan-Feb;65(1):83-86.doi: 10.4103/0028-3886.198228. PMID:28084245

3.     Tas J, Beqiri E, van Kaam RC, Czosnyka M, Donnelly J, Haeren RH, van der Horst ICC, Hutchinson PJ, van Kuijk SMJ, Liberti AL, Menon DK, Hoedemaekers CWE, Depreitere B, Smielewski P, Meyfroidt G, Ercole A, Aries MJH. Targeting Autoregulation-Guided Cerebral Perfusion Pressure after Traumatic Brain Injury (COGiTATE): A Feasibility Randomized Controlled Clinical Trial. J Neurotrauma. 2021 Oct 15;38(20):2790-2800. doi: 10.1089/neu.2021.0197. Epub 2021 Aug 16. PMID: 34407385Stegmayr B, Eriksson M, Asplund K. Declining Mortality From Subarachnoid Hemorrhage. Stroke 2004;35(9):2059–63.

          INFORMED CONSENT DOCUMENT

Participant Information Sheet (PIS)

“Optimal versus standard cerebral perfusion pressure targets for the management of severe traumatic brain injury- A randomised controlled clinical trial  (OPT-STAND- CPP trial)”

Type of participant: Patient

a) Introduction

The study ““Optimal versus standard cerebral perfusion pressure targets for the management of severe traumatic brain injury- A randomised controlled clinical trial  (OPT-STAND- CPP trial)” is conducted by Dr Suparna Bharadwaj, Associate Professor, Department of Neuroanesthesia and Neurocritical Care, NIMHANS, Bengaluru. 

You/your relative is being invited to take part in a research study. Before you decide on your/your relative’s participation, it is important for you to understand why the research is being carried out and your relative’s role in the project. Please take time to read the following information carefully and discuss it with friends, other relatives, and your treating physician/family doctor if you wish, before you take a decision. Ask us if there is anything that is not clear or if you would like more information.

b) What is purpose of this study?

Forty nine percent of the patients suffer severe disabilities after traumatic brain injury. Severe brain injury results in increased pressure inside the skull with consequent damage to functional areas of brain. Maintaining optimal brain blood circulation is necessary to prevent or to reduce brain damage. Conventional management includes a. fixed values of pressure parameters to be maintained within brain. A new monitor from Cambridge University will help titrate more suitable circulatory pressures within brain for a given patient. The purpose of this research is to investigate if brain circulatory pressures derived from the Cambridge monitor did better than conventional management in terms of patient recovery at discharge from the hospital and a few months later.   

c) Why I am being invited?

The purview of this study is to include patients with severe traumatic brain injury and who require intracranial pressure monitoring and ICU admission. Since you fulfill our study inclusion criteria, we invite you to participate in this study. 

d) Do I have to take part?

Your decision to participate in the study is purely voluntary.

e) What will happen to me if I take part in this study?

Your decision to participate in this study will permit us to evaluate the usefulness of optimal cerebral perfusion pressure in the management of severe traumatic brain injury.  If you do decide to take part in the study, you will be asked to sign a consent form regarding the same. At any time-point during the study, you are free to withdraw from the same without giving a reason. Such a decision will not affect you or your relative’s routine medical care in anyway. Participation in this study will not pose an extra monetary burden in anyways.

b)             What investigations or treatments will be conducted in this study?

If you give consent to enrol in this study, you or your relative will get all the necessary steps for management of head injury. You or your relative will have an intracranial pressure (ICP) sensor inserted into the skull to monitor ICP. Based on ICP and your arterial blood pressure you will either receive therapy with optimal or standard brain circulation pressures. Insertion of ICP sensor is a minimally invasive procedure. Risks involve bleeding and infection. Bleeding risks are minimal as the sensor will be inserted in the operating room or ICU with due precautions. Infection will be rare as strict asepsis will be followed. You will be enrolled in the study for three days and after that you will receive similar treatment as with any other patient with head injury at NIMHANS. We will contact you or your relative at discharge to assess diability. We will also call up you or your relative at 3 months to assess residual disability. 

g) Will I benefit from this study?

By participating in the study, there may or may not be any direct benefit to you/your relative, but your/your relative’s participation is likely to help us in finding the answer to our research question and it will help us in modifying our management in future so that we can prevent or reduce disability after severe traumatic brain injury. However, if RIPC results in reduction of brain blood vessel narrowing, you/your relative is likely to directly benefit from this study.

h) Risks – What are the risks that I am likely to face if I participate in this study?

What if something goes wrong?

By participating in the study, it is possible that you/your relative may rarely experience some complications like bleeding and infection directly related to the study. However, skull pressure monitoring is a standard of care and is recommended by brain trauma foundation.  

Participation in this study will not interfere in the routine treatment. However, any unanticipated untoward events will be covered under the health insurance scheme as deemed appropriate.

i) How will my confidentiality be protected?

The information that we are going to collect during this study will be kept confidential. We may publish the results of the study in order that other interested people will learn from our study. However, your/your relative’s personal information would not be divulged to anyone.

j) What if I don’t want to participate in this study, or I want to withdraw later?

If you decline to give consent for participation in this study or withdraw consent at any stage of the study your/your relative’s medical treatment will not be affected and the Principal Investigator will not use your/your relative’s data for any analysis or report. 

k) What happens with the data collected / results / my samples?

The data collected will be analyzed and published. The confidentiality about your/your relative’s medical data will be ensured, and the results published will not in any way be linked to you/your relative. 

l) Who is organizing the study?

This study is conducted by Dr Suparna Bharadwaj, Additional Professor, Department of Neuroanesthesia and Neurocritical Care, NIMHANS, Bengaluru. This study is funded by Indian Council of Medical Research.

m) Who has reviewed this study?

This study is being conducted with approval by the Institutional Ethics Committee, which is a committee whose task is to make sure that research participants are protected from harm.

n) Whom should I contact for more information?

If you have any questions, you/your relative may ask them now or later, even after the study has been conducted. If you/your relative wish to ask questions later, you may contact any of the following:

Dr Suparna Bharadwaj, Additional Professor, Department of Neuroanesthesia and Neurocritical Care, NIMHANS, Bengaluru, 9483458514; acharya.suparna@gmail.com

Dr. Sriganesh K, Professor and Head, Dept. of Neuroanesthesia and Neurocritical Care(9480829727)

Dr. Rohini M Surve, Additional Professor, Dept. of Neuroanesthesia and Neurocritical Care (9620216654)

Dr. Subhas Konar, Additional Professor, Dept. of Neurosurgery (9986438181)

Dr. Bharath Srinivasaiah, Associate Professor, Dept. of Neuroanesthesia and Neurocritical Care (9945965202)

Dr. Rajeeb Mishra, Associate Professor and head, Dept. of Neuroanesthesia and Neurocritical Care (9968961339)

Dr. Dhaval Shukla, Professor and Head, Dept. of Neurosurgery (9898073843)

Dr. Vikas V, Professor, Dept. of Neurosurgery (8277125998)