CPPopt Guided Therapy: Assessment of Target Effectiveness

Traumatic brain injury (TBI) is a global health problem. Despite improvements
in Intensive Care management, one-fourth of the patients will not survive, or
survives with major handicaps (60%). Many severe TBI patients develop
life-threatening brain swelling. Medical/surgical interventions aim to control
the swelling and maintain adequate brain perfusion. Continuous monitoring of
intracranial pressure (ICP) and cerebral perfusion pressure (CPP = arterial
blood pressure (ABP) minus ICP) is therefore widely practised. However,
treatment failure, apparent from ischemia or
oedema, is common. Novel strategies are thus urgently needed to optimize
perfusion and improve patient outcome.

Currently, clinicians apply just one brain perfusion target for all patients
during their whole admission. It is becoming increasingly clear that this *one
size fits all* guideline is inadequate, because perfusion varies between
individuals and changes over time. Moreover, the self-protective autoregulation
mechanism of the brain is impaired after severe TBI, which further affects
perfusion. Cerebral autoregulation is an unique and complex mechanism of the
cerebral arterioles.

Together with the well-known brain physics monitoring group in Cambridge an
advanced TBI monitoring algorithm was developed that calculates the CPP level
at which individual autoregulation works best (CPPopt), allowing optimal
perfusion. Importantly, retrospective data showed that deviation from the
calculated CPPopt value (relative hypo- or hyperperfusion) was related to poor
outcome. Patients with perfusion levels close to the individual and flexibleCPP
had a more favourable outcome. However there is no prospective evidence to
support its use and observational data is insufficient to draw firm conclusions
as to how to operationalize the use of autoregulation measurements as part of
daily treatment. Despite this, the concept of individual and flexible CPP is
already being used clinically in two European centres.

The physiological effect of targeting individual and flexible CPP has not been
prospectively established. Optimal autoregulation often occurs at CPPs somewhat
higher than the (recent adjusted) recommended range of 60-70 mmHg given by the
brain trauma foundation (BTF) guidelines, although these are based on weak
evidence. It is unknown whether augmenting CPP to benefit cerebral perfusion
may instead drive further oedema or contusion expansion over the next days or
lead to excess respiratory, renal or myocardial injury.

The bottom line is that the physiological effect of targeting individual and
flexible CPP must first be established as a prerequisite for any future
clinical outcome study. At the same time, a feasibility study employing
randomisation would also have the benefit of providing information on the
down-stream physiological effects of targeting CPPopt and the feasibility of
doing this.

Main aim: We will assess whether the new intervention protocol provides a
greater percentage of time during which CPP is within 5 mmHg of calculated
individual and flexible CPP (CPPopt). This window has been chosen based on past
studies which show significant impacts on outcome with greater variation from
CPPopt, and on an initial feasibility study across participating centres.
Therefore, the major endpoint of this study is to evaluate whether a CPPopt
monitor, along with a CPP targeting protocol, is effective in reducing the
difference between patient*s CPP and target *optimal* CPPopt (mainly by
changing the patient*s blood pressure).

Secondary aim: Worsening of ICP is likely to be a poor primary endpoint for a
safety study, as neuro-intensive care will attempt to control this and keep it
constant with escalating levels of (potentially harmful) therapeutically
intense interventions. Thus one of the secondary endpoints for this proposed
study will be a change in daily TBI Therapeutic Intensity Level (TIL) score.
The TIL score is a global summary measure of therapy intensity for control of
intracranial pressure. We know that increasing TIL score involves therapies
with increasing risk of harm. We will assess if targeting individual and
flexible CPP in TBI patients causes a significant increase in daily TIL score.

Randomized, controlled, non-blinded, multicentre, intervention study

Control group: Standard care.
This means: Patients are managed according to recent international trauma
foundation guidelines with keeping CPP between 60 and 70 mmHg. Individual and
flexible CPP information is recorded but hidden for the treating clinicians.

Intervention group: Patients are managed according to recent trauma foundation
guidelines, except for CPP where the individual and flexible CPP is targeted.
Individual and flexible CPP is calculated by an algorithm published in the
literature since 2012 and already applied (of label) in 2 intensive care units
in Europe (adult patients).

Benefit: Severe TBI patients have a high risk of not surviving the ICU
admission or survive with major handicaps. Individual and flexible CPP guided
management might decrease the changes of secondary brain damage during the ICU
admission and eventually improve the functional patient outcome.

Risks: Individual and flexible CPP guided management might cause increased
swelling of cerebral parenchyma, enlargements of cerebral contusions and areas
with cerebral ischemia. Due to changes in arterial blood pressure levels and
use of vaso-active medications damage to other organs like the lungs, heart and
kidneys might occur. The potential role of improving neurological outcome is
large enough to accept these risks.

Burden: During the research period the patients are comatose or sedated and not
expected to suffer from changes in CPP management. ICU and hospital admission
is not expected to be extended by inclusion in this study.