Pressure Autoregulation Measurement Techniques in Adult Traumatic Brain Injury,Part II: A Scoping Review of Continuous Methods

Abstract

A scoping review of the literature was performed systematically on commonly described continuous autoregulation measurement techniques in adult traumatic brain injury (TBI) to provide an overview of methodology and comprehensive reference library of the available literature for each technique. Five separate small systematic reviews were conducted for each of the continuous techniques: pressure reactivity index (PRx), laser Doppler flowmetry (LDF), near infrared spectroscopy (NIRS) techniques, brain tissue oxygen tension (PbtO₂), and thermal diffusion (TD) techniques. Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to December 2016), and reference lists of relevant articles were searched. A two-tier filter of references was conducted. The literature base identified from the individual searches was limited, except for PRx. The total number of articles using each of the five searched techniques for continuous autoregulation in adult TBI were: PRx (28), LDF (4), NIRS (9), PbtO₂ (10), and TD (8). All continuous techniques described in adult TBI are based on moving correlation coefficients. The premise behind the calculation of these moving correlation coefficients focuses on the impact of slow fluctuations in either mean arterial pressure (MAP) or cerebral perfusion pressure (CPP) on some indirect measure of cerebral blood flow (CBF), such as: intracranial pressure (ICP), LDF, NIRS signals, PbtO₂, or TD CBF. The thought is the correlation between a hemodynamic driving factor, such as MAP or CPP, and a surrogate for CBF or cerebral perfusion sheds insight on the state of cerebral autoregulation. Both PRx and NIRS indices were validated experimentally against the “gold standard” static autoregulatory curve (Lassen curve) at least around the lower threshold of autoregulation. The PRx has the largest literature base supporting the association with patient outcome. Various methods of continuous autoregulation assessment are described within the adult TBI literature. Many studies exist on these various indices, suggesting an association between their values and patient morbidity/death.

Introduction

Methods for continuously measuring cerebral autoregulation provide real-time information on autoregulatory capacity and reserve in the critically injured brain and present attractive means of monitoring the critically ill patient. Currently, continuous monitoring of autoregulatory assessment has received support in multidisciplinary consensus statements from experts in neurosurgery, neurocritical care, and brain physics.^1,2 Autoregulation is, more on the basis of knowledge rather than evidence, understood as an important autoprotective mechanism. Traumatic brain injury (TBI) has been the neuropathological state in which autoregulation often fails, and its continuous evaluation should assist neurocritical care management¹ because it facilitates detection of patients at risk of impending insufficient cerebral perfusion and its consequences.^3
–5

To date, numerous studies have been published on various “reactivity” indices in TBI, based on a physiological neuromonitoring modality response to changes in mean arterial pressure (MAP) or cerebral perfusion pressure (CPP).^6
–8 The most frequently used of those is the pressure reactivity index (PRx), derived using a moving correlation coefficient between slow waves of intracranial pressure (ICP) and MAP.^6,8 The literature reports an association between PRx values and patient morbidity and death^1,2 and suggests that PRx monitoring may be able to define optimal CPP targets that are patient-specific, allowing precision medicine approaches to clinical management, rather than using a one size fits all strategy based on population-derived CPP targets.⁹ There are numerous other such indices that have appeared within the literature over the last 10 to 15 years.

The literature on continuous methods of autoregulation assessment in TBI is vast, however, and, at times, is difficult to interpret given the number of monitoring techniques. Our goal was to collect the available literature on pressure autoregulatory measurement techniques (both intermittent and continuous) in adult TBI, with two main intentions: (1) to outline the commonly described techniques, and (2) to provide a comprehensive reference library of the available literature describing the use of these measurement techniques in adult TBI. It was not our intention to describe in detail the individual studies and their findings. Given the large amount of literature, this review is split into two related but self-contained articles. This article forms Part II of a two-part series and focuses solely on continuous pressure autoregulatory measurement techniques in adult TBI.

Methods

Multiple small systematic reviews were conducted (five in total), using the methodology outlined in the Cochrane Handbook for Systematic Reviews of Interventions. ¹⁰ Each continuous technique of pressure autoregulation measurement was searched separately. The methodology outline below is similar for this article (Part II) and the other article in the series.

Search question, population, inclusion and exclusion criteria

The question posed for each individual systematic review was: what literature is available on “x” pressure autoregulation measurement technique in adult TBI? The following continuous pressure techniques were searched individually within their own individual systematic review: PRx (including variations such as Long-PRx (LPRx) or LAx), near infrared spectroscopy (NIRS) indices, oxygen reactivity index (ORx) based on brain tissue oxygenation (PbtO₂), laser Doppler flowmetry (LDF), and thermal diffusion (TD) catheters. Other less common indices such as pulse amplitude index (PAx), were not searched individually, because these are not commonly used indices for continuous autoregulation measurement in TBI and still require further evaluation.

As with Part I of this series, cerebrovascular reactivity (CVR) studied via blood gases manipulation (such as with CO₂ testing, response to acetazolamide, etc.) was excluded specifically from this review, because these methods test chemical reactivity of the cerebral vasculature and not autoregulation as it is classically understood, which denotes the vascular response to variations in blood pressure.

Given that the main goal of this article was to produce a scoping review describing these continuous measurement techniques and provide a comprehensive reference library of the available studies in adult TBI, we did not define primary/secondary outcomes of interest. Further, the individual studies were not discussed in detail within the body of the article, because the goal of the comprehensive searching was to provide a reference library for interested readers.

Inclusion/exclusion criteria

Inclusion criteria were: all studies including human subjects with TBI (any severity), studies with five or more patients, adults only (age 18 or older), the use of an continuous autoregulation measurement technique (as listed above), and focus on pressure autoregulation (i.e., not chemical, metabolic, or neurogenic modulation of CVR). Exclusion criteria were: non-English studies, animal studies, pediatric patients, and studies of fewer than five patients. Non-English studies were excluded given the small number identified.

The only exception to the above-mentioned criteria was for PRx. We focused on studies documenting the association between PRx and patient outcome within the body of the article. The reason for stricter inclusion criteria for the PRx search is that there is a large volume of literature for this technique (∼100 articles in TBI alone). In addition, we wanted to highlight the core studies within the article for the reader (i.e., the literature documenting association between PRx and a clinically relevant parameter, patient outcome).

There are many smaller studies on PRx documenting various associations between these indices other outcomes, such as neurophysiology. These are not reviewed within the body of the article. We have tabulated, however, all the relevant studies related to PRx and other outcomes within Supplementary Appendix D (Part I—Study Characteristics, Part II—“Other” PRx Study Outcomes), with a separate reference list found within (see online supplementary material at ftp.liebertpub.com). In addition, the relation of PRx to other continuous techniques (i.e., such as NIRS, ORx, etc.) can be seen in the individual tables/appendices for those continuous techniques. Finally, the relation of PRx to other intermittent/semi-intermittent techniques can be found in Part I of this series, within the respective subsections for those techniques. Thus, the hope was to provide a comprehensive appendix as a reference library on PRx (across the two articles and through all of the tables/appendices), given this index is the most commonly quoted continuous autoregulatory measurement technique.

Search strategy

Each continuous technique was searched separately through individual systematic reviews of the literature. In total, there were five separate systematic reviews conducted, one for each continuous technique. The strategy described below was conducted for each technique:

MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2016 were searched using individualized search strategies. The search strategy for MEDLINE can be seen in Appendix A of the supplementary material for each continuous technique (see online supplementary material at ftp.liebertpub.com), with a similar search strategy used for the other databases. Finally, reference lists of any review articles on autoregulation techniques were reviewed for relevant studies on continuous techniques in adult TBI.

Study selection

A two-step review of all articles returned by our search strategies was performed. First, the reviewer independently screened titles and abstracts of the returned articles to decide whether they met the inclusion criteria. Second, full texts of the chosen articles were then assessed to confirm whether they met the inclusion criteria.

Any meeting abstracts identified within the database search results were cross-checked with MEDLINE to determine whether any full articles were published subsequently based on these abstract results. If a full article was identified, the meeting abstract was discarded from the final review with the formal article included in its place.

Data collection

Data were extracted from the selected articles and stored in an electronic database. Data fields included: patient demographics, type of study, article location, number of patients, autoregulation technique described, autoregulation based outcomes described, and complications associated with the technique. Basic study characteristics can be seen in Tables 1, 2, and 3. All data on specific study outcomes can be seen in Supplementary Appendices C, D, E, and F (see online supplementary material at ftp.liebertpub.com).

Table 1.

Pressure Reactivity Index Study Characteristics and Patient Demographics: Patient Outcome Studies

Reference	Number of patients	Study type	Article location	Mean age (years)	Patient characteristics	Primary and secondary goal of study
Patient 0utcome—studies with 50 or more patients
Adams et al.¹¹	573	Retrospective cohort	Meeting abstract	Unknown “adults”	Moderate–severe TBI	Primary: to assess if changes in ICP and PRx are associated with patient outcome. Secondary: none mentioned.
Aries et al.¹²	327	Retrospective cohort	Manuscript	36 years (range: 15–87 years)	Moderate–severe TBI	Primary: to assess the association between PAx and PRx. Secondary: assess the association with patient outcome.
Balestreri et al.¹³	96	Retrospective cohort	Manuscript	32 years (range: unknown)	Moderate–severe TBI with ICP elevations >25 mm Hg for at least 4 h	Primary: to assess the association between ICP, PRx, and RAP during sustained ICP elevations. Secondary: assess the association with patient outcome.
Budohoski et al.¹⁴	345	Retrospective Cohort	Manuscript	23 years (range: 11–78 years)	Moderate – Severe TBI	Primary: Assess the correlation between TCD based indices and PRx. Secondary: assess the association with patient outcome.
Czosnyka et al.¹⁵	82	Retrospective cohort	Manuscript	36 years (range: 6–75 years)	Moderate–severe TBI	Primary: to describe PRx and its association with TCD indices. Secondary: assess the association with patient outcome.
Czosnyka et al.¹⁶	188	Retrospective cohort	Manuscript	Unknown	Moderate–severe TBI	Primary: to evaluate Mx and PRx and their associations with patient outcome. Secondary: none mentioned.
Eide et al.¹⁷	76	Retrospective cohort	Manuscript	27.5 years (range: 3–75 years)	Moderate–severe TBI	Primary: to assess if ICP pulse pressure amplitude relates to various indices (including PRx, Mx, and Sx). Secondary: to assess the association of various indices with patient outcome.
Gao et al.¹⁸	174	Prospective observational	Manuscript	37.7 years (range: unknown)	Moderate–severe TBI	Primary: to evaluate ABP and ICP signal entropy as it relates to PRx. Secondary: to assess the association of these indices with patient outcome.
Hiler et al.¹⁹	126	Retrospective cohort	Manuscript	Unknown	Moderate–severe TBI	Primary: to assess if initial CT findings are associated with ICP and PRx. Secondary: to assess the association with patient outcome.
Howells et al.²⁰	131	Prospective observational	Manuscript	42 years (range: unknown)	Moderate–severe TBI	Primary: to identify the optimal frequency range to calculate PRx. Secondary: to assess the association of PRx with patient outcome.
Johnson et al.²¹	107	Retrospective cohort	Manuscript	40.6 years (range: unknown)	Moderate–severe TBI	Primary: to assess the impact of PRx on patient outcome. Secondary: assess CT define imaging pattern and the association with PRx and CPP.
Lang et al.²²	307	Retrospective cohort	Manuscript	36 years (range: unknown)	Moderate–severe TBI	Primary: to assess the association between PRx and L-PRx. Secondary: to assess the association between PRx indices and patient outcome.
Lazaridis et al.²³	327	Retrospective cohort	Manuscript	36 years (range: 15–87 years)	Moderate–severe TBI	Primary: to assess ICP thresholds and the association with outcome. Secondary: to assess PRx association with outcome.
Sorrentino et al.²⁴	459	Retrospective cohort	Manuscript	34 years (range: 14–79 years)	Moderate–severe TBI	Primary: to determine PRx thresholds associated with patient outcome. Secondary: none mentioned.
Steiner et al.²⁵	114	Retrospective cohort	Manuscript	34 years (range: 14–77 years)	Moderate–severe TBI	Primary: to evaluate CPPopt and its association with outcome. Secondary: to evaluate the association of PRx with patient outcome.
Sykora et al.²⁶	327	Retrospective cohort	Manuscript	36 years (range: 16–76.4 years)	Moderate–severe TBI	Primary: to evaluate HRV and BRS in TBI patients. Secondary: to assess the association of various indices with patient outcome (including PRx).
Timofeev et al.²⁷	223	Retrospective cohort	Manuscript	35 years (range: 22–49 years)	Moderate–severe TBI	Primary: Determine the relationship between CMD markers and neurological outcome. Secondary: association between CMD markers and ICP/PRx
Zweifel et al.²⁸	398	Retrospective cohort	Manuscript	33 years (range: 16–79 years)	Moderate–severe TBI	Primary: to evaluate the association between PRx and outcomes. Secondary: none mentioned.
Patient outcome—studies with fewer than 50 patients
Czosnyka et al.²⁹	20	Retrospective cohort	Manuscript	Unknown	Moderate–severe TBI	Primary: to describe PRx patterns during refractory ICP episodes. Secondary: to describe relation to outcome.
De La Cerda et al.³⁰	38	Prospective observational	Meeting abstract	Unknown	Moderate–severe TBI	Primary: to compare PRx and RAP with CT findings on admission. Secondary: to determine association between indices and outcome.
Jaeger et al.³¹	27	Retrospective cohort	Manuscript	42.1 years (range: 18–72 years)	Severe TBI	Primary: to evaluate ORx as a surrogate for autoregulatory assessment by comparing with PRx. Secondary: To evaluate the association between these indices and outcome.
Kirkness et al.³²	27	Retrospective cohort	Manuscript	Unknown	Moderate–severe TBI	Primary: to determine the association between PRx and patient outcome. Secondary: none mentioned.
Nikouei et al.³³	40	Prospective RCT	Meeting abstract	Unknown (range: 20–70 years)	Severe TBI	Primary: to investigate the efficacy of intravenous erythropoietin on autoregulation. Secondary: to measure to impact on patient outcome.
Oshorov et al.³⁴	40 with PRx monitoring	Prospective observational	Meeting abstract	Unknown	Moderate–severe TBI	Primary: to evaluate PRx monitoring and its relation to patient outcome. Secondary: none mentioned.
Preiksaitis et al.⁷	33	Prospective observational	Manuscript	36.7 years (range: 18–66 years)	Severe TBI	Primary: to measure duration of PRx impairments and association with patient outcome. Secondary: none mentioned.
Sanchez-Porrez et al.⁶	29	Retrospective cohort	Manuscript	37.2 years (range: unknown)	Severe TBI	Primary: to evaluate L-PRx and its association with outcome Secondary: none mentioned.
Schmidt et al.³⁵	15 with TBI	Retrospective cohort	Manuscript	53 years (range: 18–77 years)	Moderate–severe TBI	Primary: to evaluate the association between PRx or Mx and patient outcome. Secondary: none mentioned.
Schmidt et al.³⁶	41	Retrospective cohort	Manuscript	52 years (range: 18–77 years)	Severe TBI	Primary: to compare PRx and Mx in outcome prediction Secondary: none mentioned.

TBI, traumatic brain injury; ICP, intracranial pressure; PRx, pressure reactivity index; PAx, reactivity index between pulse amplitude of ICP and ABP; RAP, moving correlation coefficient between pulse amplitude of ICP and ICP; TCD, transcranial Doppler; Mx, reactivity index between mean flow velocity via TCD and ABP; Sx, reactivity index between systolic TCD flow velocity and ABP; ABP, arterial blood pressure; CT, computed tomography; CPP, cerebral perfusion pressure; L-PRx, long PRx; CPPopt, optimal CPP; HRV, heart rat e variability; BRS, baroreceptor response; CMD, cerebral micordialysis; ORx, oxygen reactivity index; RCT, randomized controlled trial.

Table 2.

Study Characteristics and Patient Demographics

Reference	Number of patients	Study type	Article location	Mean age (years)	Patient characteristics	Primary and secondary goal of study
LDF studies
Kirkpatrick et al.³⁷	22	Prospective observational	Manuscript	Unknown (range: 19–69 years)	Moderate–severe TBI	Primary: to evaluate the application of LDF probes in TBI patients. Secondary: none mentioned.
Lam et al.³⁸	31	Prospective observational	Manuscript	Unknown (range: 5–65 years)	Moderate–severe TBI	Primary: to assess the relationship between LDF-based CBF and CPP. Secondary: none mentioned.
Lang et al.³⁹	3 with TBI	Prospective observational	Meeting abstract	Unknown	Severe TBI	Primary: to assess the correlation between LDF, TCD, and ABP Secondary: none mentioned.
Zweifel et al.⁴⁰	29	Prospective observational	Manuscript	27 years (range: 16–69 years)	Moderate–severe TBI	Primary: To compare Lx with Mx. Secondary: none mentioned.
NIRS studies
Bindra et al.⁴¹	2 with TBI	Prospective observational	Manuscript	62.2 years (range: 28–87 years)	Severe TBI	Primary: to assess NIRS-based autoregulation measures with invasive and noninvasive ABP. Secondary: none mentioned.
^*Dias et al.⁴²	18	Prospective observational	Manuscript	42 years (range: 20– to 66 years)	Severe TBI	Primary: to assess autoregulatory status during plateau waves. Secondary: none mentioned.
^*Dias et al.⁴³	18	Retrospective cohort	Manuscript	42 years (range: 20 66 years)	Severe TBI	Primary: to evaluate CPP guided therapy. Secondary: to assess agreement between various autoregulatory indices (PRx, ORx, COx, CBFx)
Diedler et al.⁴⁴	37	Prospective observational	Manuscript	34 years (range: 16–78 years)	Moderate–severe TBI	Primary: to assess NIRS derived THx and compare it with PRx Secondary: to assess if there is a difference between sides with NIRS-based THx measurement.
Highton et al.⁴⁵	13	Prospective ubservational	Meeting abstract	Unknown	Unknown severity	Primary: to compare NIRS-derived TOx, HHbx with Mx and ORx. Secondary: none mentioned.
Highton et al.⁴⁶	11 with TBI	Prospective observational	Manuscript	50 years (range: 39–63 years)	Unknown severity	Primary: to assess slow waves between NIRS, TCD, and ICP. Secondary: none mentioned.
Highton et al.⁴⁷	14	Prospective observational	Meeting Abstract	Unknown	Unknown severity	Primary: to compare NIRS-based reactivity indices with Mx and PRx. Secondary: none mentioned.
Smielewski et al.⁴⁸	34 adult TBI	Retrospective cohort	Meeting Abstract	Unknown “Adults”	Unknown severity	Primary: to compared NIRS- based autoregulatory measures (COx, THx, TOx) with PRx and Mx. Secondary: none mentione.
Zweifel et al.⁴⁹	40	Prospective observational	Manuscript	34 years (range: 24–53 years)	Moderate–severe TBI	Primary: to assess NIRS-based THx compared with PRx Secondary: none mentioned.
TD probe studies
^*Dias et al.⁵⁶	18	Prospective observational	Manuscript	40 years (range: 21–64 years)	Severe TBI	Primary: to examine the effect of 20% HTS bolus on cerebral physiology (including CBFx). Secondary: none mentioned.
^*Dias et al.⁴³	18	Retrospective cohort	Manuscript	42 years (range: 20–66 years)	Severe TBI	Primary: to evaluate CPP guided therapy. Secondary: to assess agreement between various autoregulatory indices (PRx, ORx, COx, CBFx)
^*Dias et al.⁵¹	18	Prospective observational	Manuscript	42 years (range: unknown)	Severe TBI	Primary: to study the physiological characteristics (including CBFx) of plateau waves in patient with severe TBI. Secondary: none mentioned.
Hinzman et al.⁵⁷	24	Prospective observational	Manuscript	48.1 years (range: 23–79 years)	Moderate – Severe TBI requiring craniotomy	Primary: to evaluate neurovascular coupling is involved in secondary injury. Spreading depolarizations monitoring via subdural electrodes were correlated with CBF via TD catheters. Secondary: none mentioned.
Oshorov et al.⁵⁸	5	Prospective observational	Meeting abstract	Unknown	Severe TBI	Primary: to evaluate the influence of hyperthermia on cerebral indices, including CBFx. Secondary: none mentioned.
Rosenthal et al.⁵⁹ ^*	14	Prospective observational	Manuscript	37 years (range: 15–65 years)	Moderate–severe TBI	Primary: to evaluate the association of PbtO₂ with other indices (including CBF during MAP challenge). Secondary: none mentioned.
Rosenthal et al.⁶⁰ ^*	20	Prospective observational	Manuscript	37 years (range: 15–65 years)	Moderate–severe TBI	Primary: to evaluate a CBF probe in the assessment of autoregulatory status during MAP manipulation. Secondary: none mentioned.
Tackla et al.⁶¹	7	Prospective observational	Manuscript	41 years – 61 years)	Moderate–severe TBI	Primary: to assess TD-based assessment of autoregulation in TBI patients requiring surgery. Secondary: none mentioned.

TBI, traumatic brain injury; LDF, laser Doppler flowmetry; CPP, cerebral perfusion pressure; TCD, transcranial Doppler; ABP, arterial blood pressure; Lx, index based on LDF; Mx = reactivity index between mean flow velocity via TCD and ABP; NIRS, nears infrared spectroscopy; Prx, pressure reactivity index; ORx, oxygen reactivity index; COx, cerebral oxygenation index; CBFx, correlation coefficient between thermal diffusion cerebral blood flow and CPP; THx, total hemoglobin index (HbO + HHb) correlation coefficient with CPP; TOx, total oxygenated hemoglobin index (HbO/HbT) correlation coefficient with CPP; HHbx = deoxyhemoglobin index; ICP, intracranial pressure; HTS, hypertonic saline; CBF, cerebral blood flow; TD, thermal diffusion; PbtO2, brain tissue oxygen level; MAP, mean arterial pressure.

Results

Search results

Five separate systematic reviews were conducted based on the five individual continuous techniques for autoregulatory measurement that were selected. The flow diagrams of the search/filtering results for each individual technique can be seen in Figures 1 through 5 in Supplementary Appendix B (see online supplementary material at ftp.liebertpub.com). The results of the five searches were as follows:

1. The PRx search yielded 515 references, reduced to 232 after the first filters, once duplicates were removed. Ninety-seven made it through to the second filter, with one added from the reference sections of the selected articles. After application of the inclusion/exclusion criteria to the full articles, 28 articles were deemed eligible for inclusion in the final body of the manuscript (i.e., documenting relation to patient outcome).^{5,6,11

–36}

2. Searching for LDF-based studies produced 218 references, with 135 for first filter after removal of duplicates. Eleven references made it to the second filter stage, with an additional four articles added from the reference sections. After the second filter stage, four articles were deemed eligible for inclusion in the final review.^37

–40

3. The NIRS search produced 337 references, with 159 remaining after removal of duplicates. After passing through the first and second filtering stages, with the addition of one article from the reference sections, a total of nine articles were deemed eligible for inclusion in the final review.^{41

–49}

4. The PbtO₂-based ORx search yielded 200 references, of which 170 remained after removal of the duplicate references. Through application of the first and second filters, and the addition of one article from reference sections of articles, a total of 10 articles were deemed eligible for final inclusion.^{31,42,43,45,50

–55}

5. The TD technique search produced 49 references, with 27 remaining after duplicate removal. Three were added from reference sections of relevant articles. Eight articles were included in the final review.^{43,51,56

–61}

Technique overview and selected literature commentary

PRx

The use of continuously updating PRx monitoring started in the mid to late 1990s, and that technique is currently one of the most common forms of continuous autoregulation assessment used within the intensive care unit (ICU). The concept behind this index of autoregulatory capacity is that the continuous relationship between slow wave changes in MAP and ICP is an indirect measure of the cerebrovascular response to slow changes in blood pressure.

To obtain this value, a moving correlation coefficient is calculated between ICP and MAP. First, continuous, full waveform quality signals of MAP (typically from a radial artery line) and ICP (typically from any invasive ICP monitoring device) are recorded. Processing these signals to determine PRx may be conducted off-line or in real time. Next, a 10-sec moving average is calculated for both ICP and MAP and decimated to 0.1Hz, using 10-sec nonoverlapping data windows averages (to remove the influence of cardiac cycle and respiration). The Pearson correlation coefficient is then calculated using 30 consecutive average ICP and MAP values, essentially spanning 5 min of data. This calculation is then repeated every 60 sec (thus introducing 80% overlap, 4 min), producing a minute-by-minute update to the PRx value.

The concept behind PRx is that changes in ICP within the 5-min window in this calculation represent a surrogate for changes in intracerebral blood volume that in turn represent most likely arteriolar vasodilation or constriction. Thus PRx can be considered a measure of vascular reactivity. A single value of PRx is difficult to interpret. Averaging over a minimal period of 30 min is suggested, unless transient responses of PRx to deep and sudden events are being explored (such as a change in ICP during plateau waves, response to change in PaCO₂, etc). Other calculation window lengths have been described.⁶²

The PRx values produced from the above described calculation range from −1 to +1, given that they are correlation coefficients. A positive value indicates a strong positive correlation between MAP and ICP such that any increase in MAP leads to an increase in ICP (i.e., no phase shift between the ICP and MAP waveforms), and thus represents “impaired” autoregulation. Conversely, a negative PRx indicates a negative correlation between MAP and ICP, indicating “intact” autoregulation. While the physiological significance of these extreme PRx values are self-evident, the threshold value of PRx that represents a transition from functioning autoregulation to impaired autoregulation is, as yet, not clear.

Various thresholds of PRx have been identified within the literature. The most commonly quoted are those by Sorrentino and associates.²⁴ Within this study, various thresholds of PRx (mean value over the entire monitoring period) were assessed by their association with death and good versus poor functional outcome as assessed by the Glasgow Outcome Scale (GOS) at six months post-TBI. Two thresholds were identified: 1. PRx of 0 or lower was associated with better six month GOS; 2. PRx >0.25 was associated with death.²⁴ Thus, to date, the threshold of 0.25 for PRx is the value many clinicians use to identify those patients with impaired autoregulation. When PRx is negative, autoregulation is good. The “intermediate” range of 0 to 0.25 for PRx, based on the two thresholds identified by Sorrentino and associates,²⁴ may provide warning of imperfect autoregulation or impending autoregulatory dysfunction.

The use of PRx has led to the development of patient tailored therapy for CPP targets. By plotting PRx versus CPP, one can identify the CPP with the lowest PRx values (i.e., “best” autoregulatory state). A recent systematic review of CPP optimum, as derived from PRx, displayed trends to improved outcomes when CPP was within the “optimum range.”⁹ This has sparked some interest in a trial of CPP optimum guided therapy versus conventional CPP targets in TBI, which is planned for the near future.⁴³

Through our search strategy, we identified 28 articles that described the association of PRx to patient outcome in adult TBI.^{6,7,11

–36} Eighteen of these studies had 50 or more patients, with an average of 243 patients per study. The remaining 10 studies had fewer than 50 patients per study.^{6,7,29

–36} The patients studied had moderate to severe TBI, with almost all patients within the included studies being of adult age. A small number of pediatric patients (age <18 years) were embedded within the large data sets, making it impossible to extract the pediatric information. Thus, the number of pediatric patients is quite small.

Of note, of the 18 articles with 50 or more patients describing patient outcome, only two studies originated from outside Addenbrooke's Hospital, University of Cambridge.^20,21 The remaining 16 studies from Cambridge are derived from a prospectively maintained database of patients with continuous monitoring. Thus, the studies referenced from Cambridge have overlap in the patients included.^{11

–19,22

–28} Many of the studies with fewer than 50 patients originated from outside of Cambridge.^{6,7,29

–36} These smaller studies, despite having smaller numbers of patients, were more likely to be prospective in nature and displayed results confirming the associations seen in larger retrospective cohorts produced by the Cambridge database. The majority of the studies referenced in Table 1 and Supplementary Appendix C report strong associations between PRx and outcomes at various time points, regardless of study size. PRx is also noted to correlate with the TCD-based intermittently monitored indices of autoregulation.¹⁴ Further, correlation with NIRS-based indices has also been confirmed.⁵¹ For further details on specific study design and outcomes, see Table 1 and Supplementary Appendix C (see online supplementary material at ftp.liebertpub.com).

As mentioned within the Methods section, we have also compiled the “other” articles on PRx (and its variants) in Supplementary Appendix D, Part I and II (see online supplementary material at ftp.liebertpub.com). Part I of Supplementary Appendix D focuses on those studies discussing PRx as it is related to other commonly measured neurophysiological variables and tissue outcomes. Part II of Supplementary Appendix D focuses on other PRx methodology studies. The purpose of Supplementary Appendix D is to provide a comprehensive reference library for those interested in more reading on PRx. Further, the association between PRx and other intermittent/semi-intermittent or continuous techniques can be found within the respective subsections/tables/appendices in the two articles (Parts I and II) that compose this series.

LDF-based techniques

The use of LDF monitoring in TBI has ceased in the clinical setting, with only a few studies documenting its use. We decided to include LDF monitoring to be thorough and describe a technique based on the assessment of cortical small arteriolar/microvasculature.

The LDF probe is placed in the subdural space, overlying the cortical surface of the brain. A low power solid-state laser diode would then emit infrared light onto the cortical surface.^39,40 Photons are scattered and subsequently Doppler shifted as a function of moving blood in the area. The reflected infrared signal is detected by the probe, with blood flow determined by the product of blood volume and velocity (derived from the recorded infrared signal).³⁸ The resultant cerebral blood flow (CBF) is reported in arbitrary units and recorded as a continuous signal. To derive an index of autoregulatory capacity, the same moving Pearson correlation coefficient (as with PRx) can be determined, using 10-sec mean values for CBF and CPP (updated every 10 sec), with the correlation coefficient based on 30 consecutive values from a moving window. This autoregulatory index based on LDF is called Lx. The premise here is that the impact of slow changes in CPP on LDF derived CBF are an indirect measure of autoregulatory capacity.

Given the small literature base on LDF in TBI, the exact values of Lx that denote intact versus impaired autoregulatory capacity are unclear. Values above an Lx of 0 likely indicated some degree of impairment of autoregulatory capacity, while those less than 0 likely indicated intact autoregulation.

Our search of the adult TBI literature produced only four studies on the use of LDF for autoregulatory assessment.^37

–40 All of these studies have originated from Addenbrooke's Hospital in Cambridge. The populations studied were patients with moderate to severe TBI. Conclusions regarding the technique are limited given small patient numbers. Persistently positive Lx values, however, were associated with poor GOS at 6 months.³⁸ For further details on LDF-based autoregulation studies in adult TBI, please refer to Table 2 and Supplementary Appendix E (see online supplementary material at ftp.liebertpub.com).

NIRS techniques

The use of NIRS has generated numerous new indices of cerebral autoregulatory capacity. The application of NIRS involves placing adhesive optodes on the patient's scalp (typically with a bifrontal distribution, because optodes require placement on a hairless area). The NIRS device, depending on the manufacturer, uses two or more wavelengths of infrared light via typically a single emitter, with two to four detector photodiodes placed in line with the emitter at the distance of min 2.5 cm.^47
–49

Based on the diffusion characteristics of infrared light, various measures can be mathematically derived from the signal using the modified Beer Lambert law. Typically, indices measured include uncalibrated changes in oxyhemoglobin (HbO₂ or Co₂Hb), deoxyhemoglobin (HHb or CHb), and total hemoglobin (Hb) concentration (HbT = HbO + Hb), Hb difference (Hbdiff = HbO – HHb).⁴⁹ Different indices (total Hb - THI and total oxygenation index - TOI, sometimes branded CO or rSO₂, depending on manufacturer) are derived from the spatially resolved spectroscopy, a technique designed to overcome the problem of calibration because of unknown scattering coefficient and absorption path length, and at the same time attempt to minimize the influence of scalp blood flow on NIRS based measures.

The Hb and HbO₂ are believed to represent venous and predominantly arterial compartment, respectively. Indices derived from both the oxygenated and deoxygenated NIRS measures are believed to represent blood transit from arterial to venous systems. In addition to the NIRS monitoring, continuous MAP or CPP are required for continuous autoregulatory assessment. The change in NIRS-based measures with respect to CPP is believed to represent autoregulatory function.

Autoregulatory assessment with NIRS applied in patients with TBI is all based on moving Pearson correlation coefficients between the various NIRS measures (HbO, HHb, HbT, TOI, THI, and Hbdiff) and CPP or MAP. The method of calculation is the same as that for PRx or Mx. The indices introduced in the literature include TOx (or COx), based on TOI (or rSO2) and THx (HVx), based on THI, or HbT, respectively.⁴⁹ Thresholds for autoregulatory impairment have not been determined, given a small number of studies available in adult TBI, evaluating a small number of patients. Similar to PRx, positive index values may represent impaired autoregulation, while negative values may denote intact status.

Our literature search identified nine articles describing NIRS based autoregulatory indices in adult TBI.^{41

–49} A total of 187 patients with TBI were described across the nine studies, with an average of 21 patients per study. Within these studies, various NIRS-based autoregulatory indices were compared with existing indices (such as PRx and Mx) and patient outcomes. THx and TOx were found to be correlated to PRx and Mx.⁴⁷ For further details regarding the individual study on NIRS-based autoregulatory indices in adult TBI, please refer to Table 2 and Supplementary Appendix E (see online supplementary material at ftp.liebertpub.com).

PbtO₂-based ORx

The PbtO₂ can be used to derive a continuous index of autoregulation (ORx). The PbtO₂ probe is situated within the brain parenchyma, where diffusible oxygen is measured by the catheter tip continuously. This generates a value for the partial pressure of brain tissue oxygen (PbtO₂). With continuous MAP and ICP recording, one can calculate a moving Pearson correlation coefficient between CPP and PbtO₂. The thought is that the slow correlation between CPP and PbtO₂ provides an indirect measure of autoregulatory function. One must be cautioned, however, given that PbtO₂ levels can fluctuate in response to many local and systemic factors. The Pearson correlation coefficient is calculated in a similar manner to PRx, but over much longer windows (over 30 or 60 min in duration).³¹ The ORx, however, has also been described using 5 min moving windows as well.^43,56

As with the less common indices (i.e., Lx and NIRS), threshold-based studies do not exist for ORx. Thus, the exact point where autoregulation becomes impaired is unclear currently. Positive ORx values are believed to represent an impairment of the autoregulatory capacity, however, while negative ORx values are believed to represent an intact state.

Our search of the adult TBI literature produced 10 studies on ORx.^{31,42,43,45,50

–55} A total of 159 patients were described across these studies, with an average of 17 patients per study. The main purpose of the individual studies was quite varied, with some reporting correlations with other indices (such as NIRS or PRx)^42,45,51 while other were reporting CPP optimal-based targets derived from ORx.⁵² ORx displayed some correlation to NIRS-based HHbx⁴⁵ and PRx.⁵¹ Further, some agreement between CPP optimum derived from ORx and that from PRx has been noted.⁴² To date, this index is not routinely utilized for autoregulatory assessment, given the PbtO₂ signals propensity to be influence by various factors unrelated to the central nervous system. For further information on the ORx studies in adult TBI, please refer to Table 3 and Supplementary Appendix F (see online supplementary material at ftp.liebertpub.com).

Table 3.

Oxygen Reactivity Index Study Characteristics and Patient Demographics

Reference	Number of patients	Study type	Article location	Mean age (years)	Patient characteristics	Primary and secondary goal of study
ORx-based studies
Dengler et al.⁵⁰	6 with TBI	Prospective observational	Manuscript	53 years (range: unknown)	Severe TBI	Primary: to determine if ORx values were different using different PbtO₂ probes. Secondary: to determine if CPPopt could be determined from ORx recordings.
^*Dias et al.⁴²	18	Prospective observational	Manuscript	42 years (range: unknown)	Severe TBI	Primary: to study the physiological characteristics of plateau waves in patients with severe TBI. Secondary: none mentioned.
^*Dias et al.⁴³	18	Retrospective cohort	Manuscript	42 years (range: 20–66 years)	Severe TBI	Primary: to evaluate CPP guided therapy. Secondary: to assess agreement between various autoregulatory indices (PRx, ORx, COx, CBFx)
^*Dias et al.⁵⁶	18	Prospective observational	Manuscript	42 years (range: 20–66 years)	Severe TBI	Primary: to assess autoregulatory status during plateau waves. Secondary: none mentioned.
Highton et al.⁴⁵	13	Prospective observational	Meeting Abstract	Unknown	Unknown severity	Primary: to compare NIRS- derived TOx, HHbx with Mx and ORx. Secondary: none mentioned.
Jaeger et al.³¹	27	Retrospective cohort	Manuscript	42.1 years (range: 18–72 years)	Severe TBI	Primary: to evaluate ORx as a surrogate for autoregulatory assessment by comparing with PRx. Secondary: none mentioned.
^*Lang et al.⁵²	20	Retrospective cohort	Manuscript	Unknown “Adults”	Severe TBI	Primary: to compared ORx and PRx during plateau waves. Secondary: none mentioned.
Menzel et al.⁵³	7	Prospective observational	Manuscript	49 years (range: unknown)	Severe TBI	Primary: to measure ORx and assess CPPopt as derived via ORx. Secondary: none mentioned.
Radolovich et al.⁵⁴	32	Retrospective cohort	Manuscript	Unknown “Adults”	Severe TBI	Primary: to compare ORx and PRx in severe TBI patients.
Soehle et al.⁵⁵	Unknown number of TBI (mixed study)	Prospective observational	Manuscript	Unknown “Adults”	Severe TBI	Primary: to assess the association between PbtO₂ and blood pressure. Secondary: none mentioned.

TBI, traumatic brain injury; ORx, oxygen reactivity index; PbtO₂, brain tissue oxygen level; CPPopt, CPP optimum; CPP, cerebral perfusion pressure; PRx, pressure reactivity index; ORx, oxygen reactivity index; COx, cerebral oxygenation index; CBFx, correlation coefficient between thermal diffusion cerebral blood flow and cerebral perfusion pressure; TOx, total oxygenated hemoglobin index (HbO/HbT) correlation coefficient with CPP; HHbx = deoxyhemoglobin index; Mx = reactivity index between mean flow velocity via transcranial Doppler and arterial blood pressure.

TD technique

The use of TD probes affords the ability to comment on regional CBF and perfusion. This device consists of a dual thermistor probe that is inserted directly into the brain parenchyma. The distal thermistor generates heat at ∼2°C above tissue temperature, while the proximal thermosensor (5 mm proximal) records the brain temperature outside of the distal thermistor's heat field.⁶⁵ Thus, the relative changes in brain temperature related to blood transit regionally can be measured and correlated with CBF. The issue with this device is that it regularly recalibrates, interrupting the constant data stream, and can be influenced by systemic factors, such as pyrexia.⁶² Thus, the reliability of CBF measurement has been drawn into question.

Regardless of limitations of the device, autoregulation measurement has been conducted with the TD catheter. Two methods have been described. The first is intermittent and will be mentioned only in passing. It involves the measurement of CBF via the catheter during active manipulation of the MAP using vasopressor agents.^58,59 Only two studies to date have described this approach in adult TBI and are included here for completeness on TD-based autoregulation. Their details can be found in Table 3 and Supplementary Appendix E (see online supplementary material at ftp.liebertpub.com).

The second technique of autoregulation measurement is continuously updating, assuming an uninterrupted TD-based CBF signal. This technique is again based on a moving Pearson correlation coefficient between CBF and CPP, called CBFx. The method of calculation is similar to PRx, Mx, and Lx. The premise behind its association with autoregulation is similar to the concept for LDF-based Lx measurement. As with the other less utilized indices, there are no guidelines as to thresholds for CBFx during particular states of autoregulatory capacity. Thus, positive CBFx values are believed to denote impairment of autoregulation, while negative CBFx values are believe to represent intact states.

Our search of the adult TBI literature yielded eight articles on TD-based autoregulatory assessment.^{43,51,56

–61} As mentioned, two studies were intermittent^58,59 and only mentioned here for completeness. These were not included within the intermittent part of this article series, because it is not a “commonly” described technique of intermittent autoregulation assessment. The remaining six studies focused on CBFx calculation in adult TBI. Various physiological outcomes were described in relation to CBFx. Optimal CPP was even derived from CBFx in one study.⁶⁰ Very small patient numbers were found in these studies, so the conclusions drawn are limited. For further details on the TD-based autoregulation techniques in adult TBI, please refer to Table 2 and Supplementary Appendix E (see online supplementary material at ftp.liebertpub.com).

Discussion

Through Part II of this article series on autoregulatory measures in adult TBI, we have been able to highlight the main continuous methods of autoregulation assessment. Further to this, we believe that through the five separately conducted systematic searches, we have provided a valuable resource of a reference library for the main literature on each technique in adult TBI. Further, with the addition of Supplementary Appendix D, where “other” studies on PRx are catalogued, we hope this article and its online supplementary files will serve as a comprehensive source for continuous autoregulatory techniques, which may be updated periodically as new literature emerges.

Aside from PRx, a small literature base exists for the other continuous autoregulation measurement techniques in adult TBI. The non-PRx studies, however, were only based on small patient populations in the moderate to severe TBI cohort. Of note, the literature with large patient cohorts highlighted for PRx stems from a single center, Addenbrooke's Hospital at the University of Cambridge, with a small number of articles on PRx (with more than 50 patients) arising outside of this center. Thus, despite the seemingly large number of large studies on PRx, one must understand that many of these studies are reporting overlapping patient cohorts. Several smaller (fewer than 50 patients) studies that emerged from centers outside of Cambridge displayed confirmatory results. This highlights the need for multi-center collaboration in this field. With growing understanding of the importance of collecting high resolution data in the neurocritical care community and commercial availability of tools that could be used to that effect, development of a “brain physic consortia” allowing for multi-center sharing of high resolution monitoring data is now easily achievable and required for robust validation of those indices.

The techniques described for continuous autoregulation measurement (PRx, Lx, NIRS-based, ORx, CBFx) are based on the determination of a moving Pearson correlation coefficient that is typically updated every minute. Given the relative ease of calculation and many studies documenting strong correlations between PRx with patient outcome, these continuous indices are increasingly calculated within the ICU setting,¹ either in the form of off-line analysis or real-time analysis with CPP optimum derivations.⁹ The premise behind the calculation of these moving correlation coefficients focuses on the impact of slow fluctuations in either MAP or CPP on some indirect measure of CBF (or cerebral blood volume) such as: ICP, LDF, NIRS signals, PbtO₂ or TD CBF. The thought is the correlation between a hemodynamic driving factor, such as MAP or CPP, and a surrogate for CBF or cerebral perfusion sheds insight on the state of cerebral autoregulation. This is in contrast to the intermittent/semi-intermittent techniques, seen in Part I of this series, where the autoregulatory capacity is determined via direct manipulations in the patient's systemic physiology, as a means to “probe” the cerebrovascular system.

Of all indices, only PRx and COx (equivalent of TOx) were validated against the “gold standard” Lassen autoregulation curve. Validation studies have been conducted experimentally^64,65 and as such do not belong to the scope of this review. The rest of the indices have been cross-validated against each other.

Other less known correlation indices for autoregulatory capacity have been described, namely: PAx, RAC, LAx, LPRx. These indices were not described in detail within this review, because they are just emerging within the literature. It is currently unclear as to where these indices will fit in the overall scheme of autoregulation assessment. Based on preliminary work, PAx (a moving correlation coefficient between pulse amplitude of ICP and MAP) has demonstrated strong positive correlation with PRx and is potentially a better discriminator of patient outcome in those with mean ICP values under 20 mm Hg.¹² The RAC is a moving correlation coefficient between pulse amplitude of ICP and CPP, with literature on its association to outcome being very preliminary at this point.⁶⁶ Low resolution PRx, termed LAx, is calculated via a moving correlation coefficient based on minute-by-minute measures of ICP and MAP, calculated over various intervals ranging from 3 min up to 120 min. It has been described, sparingly, as an alternative method for optimal CPP calculations.⁶⁷ Finally, LPRx was only mentioned briefly within the tables for PRx, because this is another variatiant of PRx.^22,36 The calculation is described typically as a moving correlation between minute-by-minute ICP and MAP values, over a 20 min window. Small study cohorts display a statistically significant correlation between LPRx and six month patient outcomes (r = −0.556, p = 0.002).⁶

The use of these “newer” ICP-derived continuous autoregulatory indices is still emerging, with their current role in the assessment and management of autoregulatory failure in adult TBI being unclear. Their main attraction, and the sole reason for their introduction, was that they could take advantage of the low resolution physiological data routinely collected by electronic medical record systems and offer some sort of measure of autoregulation to centers without high-resolution data collection capabilities.

Limitations of current literature on continuous autoregulation indices

Despite the potential ease of measurement and wide applicability of continuous measures of autoregulation, there are some deficits in the literature that require further study. First, as mentioned previously, it is believed that positive index values denote impaired autoregulation, and negative values denote intact autoregulation. This is only an assumption. What we know from the current literature is that positive values are more consistently associated with increased death and worse morbidity. It is assumed that this is secondary to impaired autoregulation, although this has yet to be proven definitively.

Second, only two continuous indices have been validated in animal models against the classic Lassen curve of autoregulation, PRx and COx (or TOx).⁶⁷ In short, this animal model was based on piglets, under a general anesthetic with maintenance of eucarbia. Using an inflatable balloon within the inferior vena cava, systemic venous return was gradually slowed to produce systemic hypotension. The ICP, MAP, LDF, and NIRS-based CO were measured during controlled hypotension. Because CPP was reduced with systemic hypotension, LDF-based CBF was monitored and plotted against CPP to visualize the lower limit of autoregulation. The PRx, COx, and Lx were then calculated during the entire study, updating every 60 sec.

These autoregulation indices were plotted versus CPP, using 5 mm Hg bins of CPP and mean index values for PRx, COx, and Lx in those CPP bins. Across the lower limit of autoregulation, as identified by plotting CPP versus CBF, the index values were subsequently split into two groups, “above” and “below” the lower limit of autoregulation. A receiver operating curve analysis was then conducted. The results displayed that PRx and COx both respect the lower limit of autoregulation. Thus, all other continuous indices described have not been validated in this manner. It is only assumed that they measure autoregulatory function, as they are derived based on a similar concept to PRx and COx. Further animal model work is required to validate these other indices.

Finally, the majority of clinical studies on continuous autoregulation indices focus on morbidity/death associated with large blocked averages of these indices—for example, the average PRx over the entire recording period in the ICU. Thus, the frequency at which patients “flip in and out” of a preserved autoregulatory state has yet to be adequately outlined. Further, the time frame post-injury in which patients are found to display impaired autoregulation is also not well characterized. Thus, in both of these areas, much further work is required beyond “block averaging” of signals and derived indices, to better delineate incidence of autoregulatory dysfunction, frequency of autoregulation status change, most “at risk” period for autoregulation failure, and the time course over which one's autoregulatory status changes.

Conclusions

Various methods of continuous autoregulation assessment are described within the adult TBI literature. These measures are rooted in the calculation of a continuously updating moving Pearson correlation coefficient, such as PRx, with large positive values signifying impaired vascular reactivity. Many studies have been published using one or a combination of two or more of those indices suggesting an association between positive values and patient morbidity/death. Some of those studies also promote individualizing CPP management targets using the relationship between the studied autoregulation indices and CPP. The body of evidence, however, can be still classified as weak, calling for larger multi-center validation efforts.

Footnotes

Acknowledgments

This work was made possible through salary support through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean's Fellowship Fund.

JD is supported by a Woolf Fisher Scholarship (Woolf Fisher Trust, NZ).

These studies were also supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150).

Author Disclosure Statement

FAZ has received salary support for dedicated research time, during which this project was partially completed. Such salary support came from: the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba—Faculty of Medicine Dean's Fellowship Fund. MC and PS have financial interest in a part of licensing fee for ICM+ software (Cambridge Enterprise Ltd, UK). MC is an honorary co-Director of Technicam Ltd- producer of Cranial Access Device used for CMD insertion. For the remaining authors, no competing financial interests exist.

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Supplementary Material

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Pressure Autoregulation Measurement Techniques in Adult Traumatic Brain Injury,Part II: A Scoping Review of Continuous Methods

Abstract

Introduction

Methods

Search question, population, inclusion and exclusion criteria

Inclusion/exclusion criteria

Search strategy

Study selection

Data collection

Results

Search results

Technique overview and selected literature commentary

PRx

LDF-based techniques

NIRS techniques

PbtO2-based ORx

TD technique

Discussion

Limitations of current literature on continuous autoregulation indices

Conclusions

Footnotes

Acknowledgments

Author Disclosure Statement

References

Supplementary Material

PbtO₂-based ORx