Cerebrovascular Autoregulation Monitoring in the Management of Adult Severe Traumatic Brain Injury: A Delphi Consensus of Clinicians

Background Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. Aim To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. Methods A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. Results Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. Conclusion The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies. Supplementary Information The online version contains supplementary material available at. 10.1007/s12028-020-01185-x.

The observed dynamic impairment of CA could be a plausible explanation for the failure to identify a fixed and universal CPP threshold associated with poor outcome. Moreover, the association of CPP and outcome may be better conceptualized by an intensity-duration concept, rather than by the crossing of a certain threshold alone (2). These concepts are likely to be valid for too low as well as too high CPP.
The incorporation of monitoring the CA status in the management of severe TBI is a hot topic, and is mentioned in the BTF guidelines. BTF 2016 extract: "Level IIB: The recommended target CPP value for survival and favorable outcomes is between 60 and 70 mmHg. Whether 60 or 70 mmHg is the minimum optimal CPP threshold is unclear and may depend on the patient's autoregulatory status." It is plausible that monitoring the status of CA, or determining the CPP zone in which CA is preserved, could help in determining safe CPP zones (3,4). However, the current evidence is mainly retrospective, and prospective trials are lacking to support more specific guidelines on how CA could be monitored or how TBI management could be optimized when the CA status is known.
In the absence of such evidence, a RAND-based Delphi consensus methodology will be used, and questionnaires will be sent to a panel of experts, with the aim to identify valid statements representing current knowledge, as well as to guide the direction of future research.
In the next pages, you will find a set of statements on static as well as dynamic assessment of CA for the management of severe TBI. All statements relate to the setting of adult patients with severe TBI. Please either choose a statement in case of a multiple choice question or give the statement a score when requested. In the latter case, an 8-point Likert scale is used (1 Very strongly disagree; 2 Strongly disagree; 3 Disagree; 4 Slightly disagree; 5 Slightly agree; 6 Agree; 7 Strongly agree; 8 5. An episode of low CPP has a certain intensity (depth), and a certain duration. Please indicate which of both you rate as most determinant in terms of association with poor outcome. * For episodes of low CPP, the intensity (depth) is more determinant than the duration in terms of association with poor outcome.
For episodes of low CPP, the duration is more determinant than the intensity (depth) in terms of association with poor outcome.
For episodes of low CPP, the intensity (depth) AND duration are equally determinant in terms of association with poor outcome.
Impossible to answer N/A (not within my expertise) 6. An episode of high CPP has a certain intensity (level of elevation), and a certain duration. Please indicate which of both you rate as most determinant in terms of association with poor outcome. * For episodes of high CPP, the intensity (level of elevation) is more determinant than the duration in terms of association with poor outcome.
For episodes of high CPP, the duration is more determinant than the intensity (height) in terms of association with poor outcome.
For episodes of high CPP, the intensity (level of elevation) AND duration are equally determinant in terms of association with poor outcome. Impossible to answer N/A (not within my expertise) 7. Association with poor outcome has been reported for both low and high CPP. Please indicate which insult is most detrimental. * Episodes of too low CPP are more detrimental than episodes of too high CPP.
Episodes of too low CPP are equally detrimental than episodes of too high CPP.
Episodes of too low CPP are less detrimental than episodes of too high CPP. Impossible to answer N/A (not within my expertise) 8. Randomized studies on protocols to target CPP above a fixed threshold failed to demonstrate benefit. Meanwhile, low CPP protocols in some centers were not associated with worse outcomes. Please choose which statement is most accurate. * Because of potential dynamic CA impairment, absolute and universal CPP targets do not exist. The safe CPP zone can differ between individuals and can change within individuals.
Absolute and universal CPP targets do exist regardless of intact/deficient CA. Failures to identify a universal safe CPP zone in clinical trials on severe TBI only reflect technical/methodological issues. Impossible to answer N/A (not within my expertise) As your reply to this question may depend on the clinical definition of CA you scored in question 1, you are free to comment. 9. Please indicate which statement on the relation between CA status and CPP target zone is most accurate.

*
The CPP target zone does not depend on CA status.
The CPP target zone corresponds to the area between the lower and upper limit of CA. As CA can be dynamically impaired in severe TBI, CPP targets will depend on CA status.
The CPP target zone depends on CA status as well as on other variables and is/can be narrower than the area between the lower and upper limit of CA. 11. It is safe to increase CPP all the way to the upper limit of CA, if this value could be reliably detected. * Role of autoregulatory (CA) status in management protocols in adult severe TBI.
Delphi consensus round 1 on the use of cerebrovascular autoregulation monitoring in adult severe TBI management Please note that all questions relate to the setting of adult severe TBI.
12. Please indicate which statement is most accurate on the potential role of CA status in CPP management protocols. * CA status helps in choosing between primarily ICP targeted therapy (in case of deficient CA) or primarily CPP targeted therapy (in case of intact CA).
CA status helps/could help in dynamically determining the safest CPP zone, applying so-called 'CPP opt' algorithms. 25. Information on CA status may be helpful, but is subordinate to ICP, CPP and PbO2 signals. * Association of autoregulatory (CA) status with outcome independent from perfusion variables Delphi consensus round 1 on the use of cerebrovascular autoregulation monitoring in adult severe TBI management All questions concern the setting of adult severe TBI. 28. Impaired autoregulation worsens overall tolerability for secondary insults (i.e. unfavorably shifts the thresholds associated with worse outcome 29. Whether overall CA status is intact or deficient, has an independent association with outcome (regardless of actual CPP).

Research agenda on cerebrovascular autoregulation (CA)
Delphi consensus round 1 on the use of cerebrovascular autoregulation monitoring in adult severe TBI management All questions concern the setting of adult severe TBI.