CPPopt Guided Therapy: Assessment of Target Effectiveness

Study Overview
=================
Brief Summary
-----------------
Despite improvements in management, mortality in severe traumatic brain injury (TBI) remains 25% and only 40% of patients survive without major handicap. Medical/surgical interventions aim to maintain adequate brain perfusion, which is critically dependent on cerebral perfusion pressure (CPP); calculated as the difference between mean arterial pressure (MAP) and intracranial pressure (ICP). Current guidelines aim for a CPP above 50 mmHg, based on population means. However, this 'one size fits all' approach is flawed, because the relation between CPP and brain perfusion varies between individuals. Further, this approach takes no account of autoregulation, a key protective mechanism that maintains cerebral perfusion despite CPP fluctuations. Autoregulation is variably preserved following TBI, and there are large between patient variances in the 'optimal' CPP (CPPopt) at which autoregulation operates best. Individual CPPopt can be retrieved automatically by plotting autoregulation data against the CPP over a certain time window. The investigators have shown that maintenance of CPP close to CPPopt is associated with improved outcomes. These data pose the hypothesis that optimisation of management in individuals may be achieved by using the zone of optimal autoregulation as a basis for defining individualised CPP targets. The investigators propose, together with collaborators in the CPPopt study group (Maastricht, Cambridge, Leuven and Aachen) to set up a pilot (multicenter) feasibility study to develop a protocol for a definitive outcome randomized controlled trial (RCT). This study aims to develop protocols for CPPopt guided critical care, and show that they maintain patients closer to their optimum perfusion levels than standard protocols which keep above a population CPP threshold of 60 mmHg. Hence, the main objective is to offer clinicians monitoring and therapy algorithms that achieve individualized optimal CPPopt targets and potentially improve TBI outcome.

Official Title
-----------------
A Randomized Clinical Trial Assessing the Effect of Optimal Cerebral Perfusion Pressure Monitoring in the Management of Severe Traumatic Brain Injury

Conditions
-----------------
Brain Injuries, Traumatic, Cerebrovascular Circulation, Homeostasis

Intervention / Treatment
-----------------
* Other: For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Any adult severe TBI patient requiring multimodality monitoring and ICP-directed therapy for at least 24 hrs on the assessment of the recruiting team. Start randomization within 24 hrs after ICU admission. Deferred informed consent or deferred proxy assent from relatives/legal representative (consultee). Exception for enrolling a patient past the 24 hour window: A patient who is admitted to the hospital and later experiences neuro-worsening that is not due to a systemic insult, (e.g. myocardial infarction, arrhythmia, pulmonary embolus, systemic hemorrhage) but due to a presumptive intracranial cause, and subsequently requires an ICP monitor, may be screened for enrolment. Consent, randomization, and monitor placement must be done within 48 hours from injury in order for the patient to qualify. Exclusion Criteria: Patients < 18 years old. Known pregnancy. Moribund at presentation (e.g. bilaterally absent pupillary responses) Patients with primary decompressive craniectomy. Patients already enrolled in > 1 other research studies.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CPPopt intervention group<br>Patients are managed according to Brain Trauma Foundation guidelines, except for CPP where the CPPopt is targeted. | Other: For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.<br>* For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.<br>|
| Active Comparator: CPP control group<br>Patients are managed according to Brain Trauma Foundation guidelines with CPP between 60 and 70 mmHg. CPPopt information is recorded but hidden for the treating clinicians. | Other: For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.<br>* For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of monitoring time with measured CPP within 5 mmHg of calculated CPPopt | Main feasible endpoint: In pilot studies, we showed that, on average, patients spent a mean (+SD) of 30% ( 8%) of their monitored time with measured CPP within 5 mmHg of CPPopt. The study will be powered to target an increase in this metric to 50% of monitored time. | First 5 days during intensive care unit admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Intensity Level (TIL) score | Main safety secondary endpoint: A change in daily TIL score of > 3 is representative of a clinical significant escalation of TBI treatment from basic ICP management to second tier therapies known to carry risk of harm and therefore is expected to represent a clinically significant potentially harmful effect of CPPopt guided management. | First 5 days during intensive care unit admission |