
==== Front
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Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

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10.1038/s41598-024-71843-z
Article
The association of acute and chronic phase cerebrovascular reactivity with patient reported quality of life following moderate-to-severe traumatic brain injury
http://orcid.org/0000-0002-3737-2065
Gomez Alwyn gomeza35@myumanitoba.ca

12
Marquez Izabella 3
http://orcid.org/0000-0002-6076-0189
Froese Logan 45
Bergmann Tobias 3
http://orcid.org/0000-0003-3231-5683
Sainbhi Amanjyot Singh 4
http://orcid.org/0000-0003-2764-145X
Vakitbilir Nuray 4
http://orcid.org/0009-0006-6669-3374
Islam Abrar 4
http://orcid.org/0000-0002-5983-008X
Stein Kevin Y. 46
http://orcid.org/0000-0003-1737-0510
Zeiler Frederick A. 1457
1 https://ror.org/02gfys938 grid.21613.37 0000 0004 1936 9609 Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB Canada
2 https://ror.org/02gfys938 grid.21613.37 0000 0004 1936 9609 Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
3 https://ror.org/02gfys938 grid.21613.37 0000 0004 1936 9609 Department of Biosystems Engineering, Price Faculty of Engineering, University of Manitoba, Winnipeg, MB Canada
4 https://ror.org/02gfys938 grid.21613.37 0000 0004 1936 9609 Department of Biomedical Engineering, Price Faculty of Engineering, University of Manitoba, Winnipeg, MB Canada
5 https://ror.org/056d84691 grid.4714.6 0000 0004 1937 0626 Department of Clinical Neurosciences, Karolinksa Institutet, Stockholm, Sweden
6 https://ror.org/02gfys938 grid.21613.37 0000 0004 1936 9609 Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
7 grid.490345.f 0000 0004 0467 0538 Pan Am Clinic Foundation, Winnipeg, MB Canada
5 9 2024
5 9 2024
2024
14 2073721 5 2024
31 8 2024
© The Author(s) 2024
2024
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Global outcomes have been reported to be associated with cerebrovascular reactivity (CVR) in the acute phase following moderate and severe traumatic brain injury (TBI). The association of CVR in the acute and chronic phase of injury with patient-reported health-related quality of life metrics (HRQOL) metrics has never been explored. The aim of this study is to examine the association of CVR, as measured by the cerebral oxygen indices (COx and COx_a), in the acute and chronic phase following moderate and severe TBI, with patient reported HRQOL. In this prospective cohort study, performed in a Canadian quaternary care center, the association between continuous acute and chronic phase CVR with patient reported HRQOL outcomes following moderate and severe TBI was examined. The main outcomes of interest of this study were validated measures of patient-reported HRQOL over various domains as measured by both the 12-Item Short-Form Health Survey (SF-12) and a Quality of Life after Brain Injury (QOLIBRI) questionnaire. In the 29 subjects of this cohort, acute phase CVR was found to be significantly more active in those with a favorable Mental Component Summary (MCS) scores of the SF-12 at early follow-up when measured by COx (-0.015 [IQR: -0.067 to 0.032] vs 0.040 [IQR: 0.019 to 0.137] for Favorable first MCS vs Unfavorable respectively; Mann–Whitney U test p-value = 0.046) and COx_a (0.038 [IQR: 0.009 to 0.062] vs 0.112 [IQR: 0.065 to 0.167] for Favorable first MCS vs Unfavorable respectively; Mann–Whitney U test p-value = 0.014). Further, multivariable logistic regression analysis found acute phase COx and COx_a to improve model performance when predicting favorable versus unfavorable early MCS scores over established parameters such as age and measures of injury severity. Associations between outcomes and chronic phase CVR were limited, potentially due to short recording periods. This is the first ever pilot study to identify a relationship between acute phase CVR following moderate-to-severe TBI with mental and cognitive outcomes as experienced by patients. Given the small cohort, these findings will need to be confirmed in a larger multicenter study. This highlights the need for additional examination of the role dysfunctional CVR may play in mental and cognitive outcomes, as well as patient-reported outcomes more generally following TBI.

Keywords

Traumatic brain injury
Cerebrovascular reactivity
Near infrared spectroscopy
Patient reported outcomes
Subject terms

Brain injuries
Neuro-vascular interactions
Canadian Institutes of Health ResearchGrant #: 472286 Natural Sciences and Engineering Research Council of CanadaDGECR-2022-00260 RGPIN-2022-03621 ALLRP-578524-22 ALLRP-576386-22 ALLRP 586244-23 Canada Foundation for InnovationProject #: 38583 Zeiler Frederick A. Research ManitobaGrant #: 3906 Grant #: 5429 Zeiler Frederick A. issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Cerebrovascular reactivity (CVR) describes the ability of the brain to maintain cerebral blood flow (CBF) over a range of arterial blood pressures (ABP)1,2. Disruption in CVR in the acute phase following traumatic brain injury (TBI) has been found to be associated with global outcomes, such as the Glasgow Outcome Scale (GOS) or it’s extended variant (GOSE), at follow up3–7. However, the relationship between acute or chronic phase CVR with validated patient-reported outcome measures following TBI has not been explored.

Contemporary methods of continuously measuring CVR examine the correlation between a surrogate for cerebral blood volume (CBV)/CBF and a surrogate for driving pressure such as ABP or cerebral perfusion pressure (CPP)8. The most widely used metric is the pressure reactivity index (PRx), which utilizes invasively derived intracranial pressure (ICP) as a surrogate of CBV and ABP as a surrogate for driving pressure3,4,6,7,9–17. This need for invasively derived ICP limits its use to the acute phase of TBI where ICP monitoring is already indicated.

Non-invasive imaging-based methods do exist for the measurement of CVR, however, these are costly and resource intensive18,19. Fortunately, methods that leverage near-infrared spectroscopy (NIRS)-based regional cerebral oxygen saturation (rSO2) as a surrogate for CBV have been developed to measure CVR continuously20. These rSO2-based indices of CVR are the only indices other than PRx that have been shown to detect the lower limit of CVR in large animal models20. Additionally, they have been shown to share statistical properties with ICP-based indices of CVR21,22. rSO2-based indices can also provide an entirely non-invasive continuous measure of CVR, extending evaluation into the chronic phase of injury23,24.

This study aims to examine the relationship between CVR, in both the acute and chronic phase, with patient reported health related quality of life (HRQOL) outcomes following moderate-to-severe TBI. The association of chronic phase CVR with global outcomes will also be examined.

Methods

Study design

A prospective cohort study of TBI patients at the Winnipeg Health Sciences Centre, Manitoba, Canada was performed as previously proposed24. Subjects were considered for enrollment if they were at least 18 years of age and admitted to the intensive care unit (ICU) having sustained a moderate-to-severe TBI (Glasgow coma scale [GCS] of 12 or less) requiring ICP monitoring. Concurrent NIRS-based rSO2 was also monitored on all included subjects as part of the study protocol. All patients were cared for utilizing ICP- and CPP-based Brain Trauma Foundation guidelines25. Data collection occurred in two distinct phases. First during the acute phase following injury while admitted to ICU and secondly during the chronic phase at standard outpatient follow-up at 3-, 6- and 12- months post-injury. Subjects were enrolled between February 2020 and December 2022 with the last follow-up data collection completed in June 2023. Due to the nature of the study, only those subjects that survived and who attended at least one follow-up visit were included.

Ethical considerations

Full approval was received for this study from the University of Manitoba Biomedical Research Ethics Board (BREB; B2018:103) as well as the Health Science Centre Impact Committee (RI2020:016). Deferral of consent was approved by the BREB given the nature of the included study population. This allowed for rapid initiation of data collection shortly after admission to ICU. However, as soon as reasonably possible, informed consent for study participation was obtained from either the subject or an appropriate substitute decision maker. Informed consent for study participation was reobtained at all follow-up visits and participants were able to withdraw from the study at any time. All research methods were performed in accordance with the Declaration of Helsinki.

Data collection

During the acute phase ABP, ICP, as well as left and right frontal rSO2 were collected as high-resolution data streams as previously reported21,22. During follow-up visits in the chronic phase, right and left frontal rSO2was also collected and ABP was collected continuously and non-invasively. Recording sessions lasted 30 min at each visit. This setup has been previously described in detail23,26,27. In both phases Intensive Care Monitoring (ICM+) software (Cambridge Enterprise Ltd, Cambridge, UK) was utilized to store, and time link the digitized physiologic signals.

During each follow-up visit a GOSE was determined for each subject by a qualified clinician28. Additionally, when possible (i.e. as patient communication allowed), patients completed validated measures of patient reported HRQOL including a 12-Item Short-Form Health Survey (SF-12)29 and a Quality of Life after Brain Injury (QOLIBRI)30 questionnaire31–33.

Data processing

High-resolution physiologic data from both the acute and chronic period was manually artifact cleared and processed utilizing ICM+. For the acute phase data, minute-by-minute measures of CVR were calculated in a standard fashion as previously described9,12,13,34,35. PRx utilized ICP as surrogate for CBV and ABP for a surrogate of driving pressure. Two variants of rSO2-based indices of CVR were also derived utilizing rSO2 as a surrogate for CBV. The cerebral perfusion pressure (CPP)-based cerebral oxygen index (COx) utilizes CPP as a surrogate for driving pressure while the ABP-based cerebral oxygen index (COx_a) utilizes ABP as a surrogate for driving pressure. Both COx and COx_a were calculated for the right and left side when rSO2 signals were available. All continuous measures of CVR are based on a moving Pearson correlation between a surrogate for CBV and driving pressure. As such, they range from − 1 to + 1 with values closer to + 1 indicating a vasopassive state and values closer to − 1 indicating a vasoactive state9,36.

For the chronic phase data, due to the lack of availability of invasive ICP monitoring in this phase, right and left COx_a were only calculated for each 30-min recording as previously described27.

Patient-reported HRQOL questionnaires were scored by domain as standardly reported and dichotomized as favorable or unfavorable. For each SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were calculated and were deemed unfavorable if they fell below the 25th percentile for biologic sex matched norms in a U.S. general population37. Each QOLIBRI questionnaire was scored over the six standard domains (cognition, self, daily life and autonomy, social relationships, emotions, and physical problems) and in total32. Domain scores were deemed unfavorable if they fell below one standard deviation less than the mean of a U.K. general population38. The GOSE score were dichotomized, with values less than or equal to 4 being characterized as unfavorable28.

Statistical analysis

Overview

Statistical analysis was performed utilizing R statistical software (Version 4.3.0, R Foundation for Statistical Computing, Vienna, Austria) and the tidyverse, pROC, and lmtest packages. An alpha of 0.05 was utilized for the threshold for statistical significance without correction for multiple comparisons due to the exploratory nature of this study. Shapiro–Wilk Testing for normality indicated that most of the HRQOL outcomes were not normally distributed so non-parametric statistical analysis was utilized unless otherwise specified.

For the acute period, measures of CVR were averaged over the entire recording. In the case of COx and COx_a, side of signal was selected to avoid possible interference from extravascular blood (scalp, epidural, and subdural hematomas as well as cerebral contusions) based on radiographic data. If no hematoma was present, the side of longest duration of rSO2 recording was utilized, similar to previous studies5. Additionally, the percentage of time over previously determined outcome-based thresholds for PRx (+ 0.25), COx (− 0.05), and COx_a (− 0.05) were calculated for each subject5,10. For chronic phase physiological data, COx_a was averaged over the recording period and over both sides due to the short duration of recording to provide a point measurement at each visit.

Since all subjects were not present for every follow-up visit, COx_a values and outcome data were dichotomized into first available and last available time periods. For subjects only present at one follow-up visit, data from that visit was utilized as both the first and last available value.

CVR and patient outcomes

To identify parameters of interest, non-parametric statistical testing (Mann–Whitney U test) was performed to see if there existed significant differences in acute or chronic phase CVR values between those with favorable versus unfavorable outcomes in each SF-12 and QOLIBRI domain. CVR parameters that were significantly different between those with a favorable versus unfavorable outcome in a particular domain were examined for their ability to augment outcome prediction.

Multivariable logistic regression analysis was performed to examine the prognostic utility of these identified CVR parameters, in the specified domain, over and above a standard TBI-IMPACT model (International Mission for Prognosis and Analysis or Clinical Trials in Traumatic Brain Injury Model; age at admission, admission GCS motor score, and admission pupil exam). Given that these are patient reported HRQOL metrics, the presence of severe extracranial injury (SEI, defined as having at least one extracranial AIS greater than or equal to 3) was thought to potentially influence outcomes significantly39. As such, SEI was added as an additional parameter to the baseline model. Model performance was quantified utilizing area under the receiver operating characteristic (ROC) curve (AUC; an aggregate measure of performance across all possible model classification thresholds), Akaike information criterion (AIC; a means of evaluating model fit that penalizes model complexity), and Nagelkerke R2 (a measure of the proportion of data variance explained by the model)40–42. The performance of models were directly compared utilizing the likelihood ratio test of nested models.

Additionally, Spearman correlation analysis was performed to identify any monotonic relationships between CVR parameters and patient reported HRQOL outcome domain percentiles. This was done for both acute and chronic phase CVR measurements.

Non-parametric statistical testing (Mann–Whitney U test) was also used to determine if there was a statistically significant difference in chronic CVR measures between those with a favorable versus unfavorable GOSE. This was done for GOSE at the first and last available follow-up. The relationship between acute phase CVR and global outcomes was the subject of a recent publication with an overlapping cohort and was therefor not repeated in this study5.

Results

Study population

Through the acute phase of recruitment 66 patients were identified to meet inclusion criteria. Of these, 25 did not survive past the acute phase, 2 subjects declined to participate in the chronic phase of data collection and 10 subjects were lost to follow-up. Ultimately, 29 patients had at least one follow-up recording at either 3-, 6-, or 12-months and were included in the study. For seven of these subjects only one visit was available. However, most of the first available data was from the 3-month visit (23 of 29) while the majority of the last available data was from the 12-month visit (18 of 29). In total 174,845 min (median 5445, IQR: 3095 to 8779) of acute physiologic data was recorded while 65 30-min recordings were performed at follow-up. In four subjects, no HRQOL data was available due to inability to complete the questionnaire. Full demographic data for the study cohort can be found in Table 1.Table 1 Demographic data of the chronic traumatic brain injury patients.

Demographic parameter	Median or number of patients, N = 29	
Age (IQR)	40 (25–50)	
Biological sex	Male (%)	24 (82.8)	
Female (%)	5 (17.2)	
Admission GCS (IQR)	7 (4–8)	
Admission pupils	Bilaterally reactive (%)	22 (75.9)	
Unilaterally reactive (%)	5 (17.2)	
Bilaterally unreactive (%)	2 (6.9)	
Admission Marshall CT classification	I (%)	0 (0)	
II (%)	1 (3.4)	
III (%)	11 (37.9)	
IV (%)	6 (20.7)	
V (%)	11 (37.9)	
VI (%)	0 (0)	
Severe extracranial injury	Yes	14	
No	15	
Acute phase rSO2 side	Right	25	
Left	4	
Acute phase CVR (IQR)	PRx	0.088 (−0.061 to 0.270)	
COx	0.019 (−0.011 to 0.073)	
COx_a	0.064 (0.019 to 0.122)	
% Time PRx >  + 0.25	33.2 (21.6 to 55.3)	
% Time COx > − 0.05	60.9 (56.5 to 68.5))	
% Time COx_a > − 0.05	66.4 (61.8 to 71.0)	
Follow-up GOSE	3-month	6 (5 to 6)	
6-month	7 (5 to 7)	
12-month	7 (6 to 8)	
Recording sessions	3-month	23	
6-month	24	
12-month	18	
Subject average chronic COx_a (IQR)	3-month	−0.02 (−0.04 to 0.06)	
6-month	0.05 (−0.06 to 0.17)	
12-month	0.02 (−0.04 to 0.11)	
Used as first available COx_a	3-month (%)	23 (79.3)	
6-month (%)	5 (17.2)	
12-month (%)	1 (3.4)	
Used as last available COx_a	3-month (%)	4 (13.7)	
6-month (%)	7 (24.1)	
12-month (%)	18 (62.1)	
Favorable PCS	At first available visit (%)	5 (17.2)	
At last available visit (%)	4 (13.7)	
Favorable MCS	At first available visit (%)	12 (41.4)	
At last available visit (%)	14 (48.3)	
COx  cerebral oxygen index based on cerebral perfusion pressure, COx_a cerebral oxygen index based on arterial blood pressure, CT computed tomography, CVR cerebrovascular reactivity, GCS Glasgow Coma Scale, GOSE Extended Glasgow Outcome Scale, IQR interquartile range, MCS Mental Component Summary of Short Form-12, PCS Physical Component Summary of Short Form-12, PRx pressure reactivity index, rSO2 regional cerebral oxygen saturation.

CVR and patient reported outcomes

When examining the relationship between acute phase CVR and patient reported HRQOL as determined by the SF-12, several interesting findings were identified. Acute CVR as measured by average COx was found to be significantly lower in those with a favorable MCS at first available follow-up as compared to those with an unfavorable one (−0.015 [IQR: −0.067 to 0.032] vs 0.040 [IQR: 0.019 to 0.137] for Favorable vs Unfavorable respectively; Mann–Whitney U test p-value = 0.046). A similar finding was seen for average acute COx_a (0.038 [IQR: 0.009 to 0.062] vs 0.112 [IQR: 0.065 to 0.167] for Favorable vs Unfavorable respectively; Mann–Whitney U test p-value = 0.014). Additionally, the percentage of time above the COx_a threshold of −0.05 was significantly lower in those with a favorable MCS at first follow-up than those with an unfavorable MCS (62.3% [IQR: 60.8 to 68.5] vs 69.8% [IQR: 66.4 to 75.1] for favorable first MCS vs unfavorable respectively; Mann–Whitney U test p-value = 0.040). Notably, this difference did not persist when favorable MCS was determined at the last available follow-up. Acute phase CVR was no different in those with a favorable PCS as compared to those with an unfavorable PCS. Further, no significant differences in chronic CVR were found between those with favorable and unfavorable outcomes as determined by the SF-12. The full results of this analysis can be seen in Additional File 1.

The addition of acute phase (1) average COx, (2) average COx_a, as well as (3) time above COx_a threshold to the baseline TBI-IMPACT model with SEI greatly improved performance at predicting a favorable MCS outcome at first follow-up, as measured by AUC, AIC and Nagelkerke R2 values. Additionally, likelihood ratio testing found that each of the models that incorporated these CVR parameters performed significantly better than the baseline model with SEI. These findings can be seen in Table 2. Notably, the inclusion of average COx_a in the acute phase produced the greatest model improvement.Table 2 Multivariable logistic regression analysis for favorable Mental Component Summary Score of the Short Form-12 (SF-12) Questionnaire at first available follow-up.

Model	AUC (95% CI)	AIC	Nagelkerke R2	Likelihood ratio test VS TBI-IMPACT model	Likelihood ratio test VS TBI-IMPACT + SEI model	
TBI-IMPACT	0.859 (0.707 to 1.00)	32.5	0.514	NA	NA	
TBI-IMPACT + SEI	0.849 (0.692 to 1.00)	34.2	0.523	0.290 (p = 0.590)	NA	
TBI-IMPACT + SEI + average acute COx	0.923 (0.811 to 1.00)	29.4	0.716	NA	6.79 (p = 0.009)	
TBI-IMPACT + SEI + acute phase COx_a	0.936 (0.8451 to 1.00)	28.8	0.729	NA	7.34 (p = 0.007)	
TBI-IMPACT + SEI + % time COx_a > − 0.05 during acute phase	0.923 (0.823 to 1.00)	32.3	0.640	NA	3.89 (p = 0.048)	
AIC Akaike Information Criterion, AUC area under the receiver operating characteristic curve, COx cerebral oxygen index based on cerebral perfusion pressure, COx_a cerebral oxygen index based on arterial blood pressure, SEI severe extracranial injury, TBI-IMPACT Internation Mission for Prognosis and Analysis or Clinical Trials in Traumatic Brain Injury Model (age at admission, admission Glasgow coma scale motor score, and admission pupil exam).

Prediction of favorable first MCS was not improved by the addition of SEI to the TBI-IMPACT baseline model. However, it should be noted that the addition of SEI to the TBI-IMPACT model of favorable first PCS did result in a significant improvement in model performance. The full results of this analysis can be found in Additional File 2.

Spearman correlation analysis between acute CVR parameters and SF-12 based outcomes only found a statistically significant correlation between average COx_a in the acute phase and MCS at the first available visit (r = −0.469 p = 0.019). There were no other significant correlations between acute or chronic CVR parameters and SF-12 based outcomes. The remainder of this analysis can be found in Additional File 3.

When examining outcome relationships utilizing the QOLIBRI instrument, first available daily life and autonomy (Qadl) scale and social relationships (Qsoc) scale were the only domains to have any identifiable relationship with CVR parameters. Average COx_a in the acute phase was significantly lower in those with a favorable first available Qadl than those with an unfavorable one (0.015 [IQR: 0.008 to 0.047] vs 0.115 [IQR: 0.065 to 0.116] for Favorable vs Unfavorable respectively; Mann–Whitney U test p-value = 0.006). Similarly, the percentage of time over COx_a threshold in the acute phase was lower in those with a favorable first available Qadl than those with an unfavorable one (61.8% [IQR: 60.5 to 66.3] vs 69.8 [IQR: 66.4 to 74.9] for Favorable vs Unfavorable respectively; Mann–Whitney U test p-value = 0.011). Unexpectedly, last available COx_a at follow-up was higher in those with a favorable first Qadl than those with an unfavorable one (0.114 [IQR: 0.022 to 0.196] vs 0.011 [IQR: 0.062 to 0.086] for Favorable vs Unfavorable respectively; Mann–Whitney U test p-value = 0.041). Finally, first available COx_a at follow-up was significantly lower in those with favorable first available Qsoc than those with an unfavorable one (−0.028 [IQR: −0.052 to 0.065] vs 0.172 [IQR: 0.039 to 0.276] for Favorable vs Unfavorable respectively; Mann–Whitney U test p-value = 0.035). The remainder of this analysis can be found in Additional File 4.

The results of the multivariable logistic regression analysis of the prognostic value of these parameters for favorable first available Qadl and Qsoc can be seen in Tables 3 and 4 respectively. Notably, while the addition of average COx_a and percent time over the COx_a threshold in the acute phase each significantly improved model performance, the inclusion of last available COx_a in the chronic phase did not. However, first available chronic phase COx_a did markedly improve model performance for the determination of favorable first Qsoc.Table 3 Multivariable logistic regression analysis for favorable daily life and autonomy domain (Qadl) of the Quality of Life After Brain Injury (QOLIBRI) Questionnaire at first available follow-up.

Model	AUC (95% CI)	AIC	Nagelkerke R2	Likelihood ratio test VS TBI-IMPACT model	Likelihood ratio test VS TBI-IMPACT + SEI model	
TBI-IMPACT	0.821 (0.658 to 0.985)	37.3	0.362	NA	NA	
TBI-IMPACT + SEI	0.885 (0.755 to 1.00)	31.0	0.631	8.31 (p = 0.004)	NA	
TBI-IMPACT + SEI + acute phase Cox	0.958 (0.892 to 1.00)	26.1	0.795	NA	6.83 (p = 0.009)	
TBI-IMPACT + SEI + % time COx_a > − 0.05 during acute phase	0.988 (0.959 to 1.00)	23.6	0.847	NA	9.38 (p = 0.002)	
TBI-IMPACT + SEI + last available COx_a in the chronic phase	0.927 (0.832 to 1.00)	31.0	0.682	NA	1.95 (p = 0.162)	
AIC Akaike information criterion, AUC area under the receiver operating characteristic curve, COx cerebral oxygen index based on cerebral perfusion pressure, COx_a cerebral oxygen index based on arterial blood pressure, SEI severe extracranial injury, TBI-IMPACT International Mission for Prognosis and Analysis or Clinical Trials in Traumatic Brain Injury Model (age at admission, admission Glasgow coma scale motor score, and admission pupil exam).

Table 4 Multivariable logistic regression analysis for favorable social relationships domain (Qsoc) of the Quality of Life After Brain Injury (QOLIBRI) Questionnaire at first available follow-up.

Model	AUC (95% CI)	AIC	Nagelkerke R2	Likelihood ratio test vs TBI-IMPACT Model	Likelihood ratio test VS TBI-IMPACT + SEI Model	
TBI-IMPACT	0.700 (0.414 to 0.986)	32.7	0.140	NA	NA	
TBI-IMPACT + SEI	0.775 (0.580 to 0.970)	33.7	0.195	0.98 (p = 0.323)	NA	
TBI-IMPACT + SEI + first available chronic phase COx_a	0.970 (0.907 to 1.00)	22.4	0.767	NA	13.30 (p < 0.001)	
AIC Akaike information criterion, AUC area under the receiver operating characteristic curve, COx cerebral oxygen index based on cerebral perfusion pressure, COx_a cerebral oxygen index based on arterial blood pressure, SEI  severe extracranial injury, TBI-IMPACT International Mission for Prognosis and Analysis or Clinical Trials in Traumatic Brain Injury Model (age at admission, admission Glasgow coma scale motor score, and admission pupil exam).

Finally, correlation between acute and chronic phase CVR parameters with QOLIBRI domains did not yield any statistically significant relationships. The full results of this analysis can be found in Additional File 5.

Chronic phase CVR and global outcomes

No statistically significant difference was found in the first or last available COx_a in those with a favorable GOSE as compared to those with an unfavorable GOSE. This was the case for both outcomes at either the first or last available follow-up. The detailed results of this analysis can be found in Additional File 6.

Discussion

In this prospective cohort pilot study, the relationship between acute and chronic phase CVR with patient reported HRQOL metrics was examined, to the best of our knowledge, for the first time. Additionally, the relationship between chronic phase CVR and global outcomes was examined.

A significant relationship was identified between acute measures of CVR and early mental health and cognitive outcomes. Specifically, acute phase (1) average COx, (2) average COx_a as well as (3) percent time over COx_a threshold were all found to be significant predictors of favorable MCS scores at the first available follow-up. COx and COx_a values were significantly lower in the acute phase in those with a favorable outcome as compared to those with an unfavorable outcome. Concordant with this, the percentage of time over the COx_a threshold during the acute phase was slightly but significantly lower in those with a favorable MCS score at early follow-up. Of the three metrics of acute phase CVR, acute phase COx_a seemed to have the strongest relationship with mental health and cognitive outcomes.

Acute phase COx_a was also found to be significantly related to the daily life and autonomy domain of the QOLIBRI instrument. Lower acute phase COx_a values and lower percentages of time over threshold were both related to favorable outcomes in this domain.

These findings are consistent with the previously held notion that a vasopassive state, indicative of dysfunctional CVR, in the acute phase negatively impacts patient outcomes following moderate and severe TBI3,4,6,7,10,12,13,43–45. This is the first study, to the best of our knowledge, to ever identify an association between acute phase CVR and patient reported HRQOL outcomes. It is also the first to identify a link between dysfunctional CVR and poor metal health/cognitive patient reported outcomes. This finding, while novel, is not entirely surprising as ongoing secondary injury in the acute phase, attributable to dysfunctional CVR, would likely disproportionately affect these outcome domains. It should be emphasized, however, that while the findings of this study are consistent with past work, it was not designed to assess the causality of this relationship.

Interestingly, acute and chronic phase CVR metrics were unrelated to the PCS of the SF-12. However, SEI was found to be strongly influential in these components of the SF-12. This has implications for future studies in TBI that hope to use patient-reported HRQOL outcomes as extracranial injury will need to be factored in as a strong contributor to variance in physical-related outcomes.

The multivariable regression models highlighted the added strength of acute phase CVR and SEI as parameters when added to current prognostic TBI models. The performance of the augmented models indicates that these are parameters that are of significant prognostic importance.

Chronic phase CVR was not found to have a significant relationship to global outcomes or patient reported HRQOL outcomes. The only exception to this was a relationship found between early COx_a values in the chronic phase and the social relationships domain of the QOLIBRI instrument. This paucity of findings may be due to the limited recording duration in the chronic phase. A recent study examining the relationship between various CVR metrics found that continuous CVR indices needed to be averaged over at least 30 min to be consistent with one another22. The recordings of this study, at 30 min in duration, would have only just met this requirement.

Limitations

While this study has numerous strengths, including its prospective nature and rich data, it does have limitations that need to be considered when interpreting its findings. First, this was a single center small pilot study. While the cohort was well characterized and practice patterns were consistent with contemporary management of moderate and severe TBI, this still reduces the generalizability of these findings. As such, the findings of this study must be interpreted with measured enthusiasm prior to further validation.

Secondly, while this is the largest cohort to examine these relationships, it is relatively small compared to other CVR studies in TBI46. This is in strong part due to the need to collect high-quality chronic phase data. In fact, even within this cohort, 4 of the subjects did not complete any of the HRQOL questionnaires. This also had the effect of narrowing the range of global outcomes experienced by members of this cohort as, by the nature of the study, they needed to be able to participate in the questionnaire. At the first available follow-up 26 out of 29 patients had a favorable GOSE. This also may contribute to the underpowering of the logistic regression models utilized for analysis.

Further, given that follow-up was not complete for all subjects, there was a need to dichotomize follow-up data points into the first and last available. While this was done to improve the power of the study, it does limit the ability to identify precisely when acute and chronic phase CVR might be associated with patient-reported HRQOL outcomes.

Finally, because of the analysis techniques leveraged for this study there was a need to dichotomize patient reported outcomes. While best practices were followed for quantification and dichotomization, these are ultimately arbitrary “lines in the sand”47. One example of this is the use of dichotomized GOSE, with values less than or equal to 4 being characterized as unfavorable. This was done to be consistent with literature focused on moderate-to-severe TBI. However, some studies of mild TBI utilize GOSE less than 8 to define an unfavorable outcome. This approach was not taken for this study given the degree of injury sustained by the study patients.

Future direction

The findings of this study lay the foundation for multiple areas of future research. However, prior to this, these findings will need to be validated in a larger multi-institutional cohort given the small pilot nature of this study. Due to the quality of data required for such a study, it would be a significant undertaking, especially considering the difficulties associated with obtaining consistent follow-up. Additionally, considering the findings of this study regarding the role of dysfunctional CVR in patient reported cognitive and mental health outcomes, future work may aim to assess these associations with objective measures of cognition and mental health. Any future work examining the role of CVR in patient reported HRQOL outcomes following TBI will also need to control for the severity of extracranial injury.

Conclusion

In this prospective cohort study the relationship between CVR following moderate-to-severe TBI with patient reported HRQOL metrics was examined. Acute phase CVR, especially as measure by COx_a, seemed to have a strong association with early mental and cognitive outcome domains. This study links acute phase CVR with patient reported HRQOL outcomes, and particularly in the domains of mental health and cognition.

Prior to widespread acceptance of these relationships, future research will need to validate these findings in a large multi-institutional cohort. Consideration will need to be made to include objective testing of cognition and mental health considering the findings of the present study.

Supplementary Information

Supplementary Information 1.

Supplementary Information 2.

Supplementary Information 3.

Supplementary Information 4.

Supplementary Information 5.

Supplementary Information 6.

Supplementary Information 7.

Abbreviations

ABP Arterial blood pressure

AIC Akaike information criterion

AUC Area under the receiver operating characteristic curve

BREB Biomedical Research Ethics Board

CBF Cerebral blood flow

CBV Cerebral blood volume

CI Confidence interval

COx Cerebral oxygen index with cerebral perfusion pressure

COx_a Cerebral oxygen index with arterial blood pressure

CPP Cerebral perfusion pressure

.csv Comma-separated values

CT Computed tomography

CVR Cerebrovascular reactivity

GCS Glasgow Coma Scale

GOS Glasgow Outcome Scale

GOSE Extended Glasgow Outcome Scale

HRQOL Health related quality of life

ICM+ Intensive care monitoring software

ICP Intracranial pressure

ICU Intensive care units

IQR Interquartile ranges

MCS Mental Component Summary of SF-12

NIRS Near-infrared spectroscopy

PCS Physical Component Summary of SF-12

PRx Pressure reactivity index

Qadl QOLIBRI daily life and autonomy domain

Qcog QOLIBRI cognition domain

Qemo QOLIBRI emotions domain

QOLIBRI Quality of Life after Brain Injury Questionnaire

Qphys QOLIBRI physical problems domain

Qself QOLIBRI self domain

Qsoc QOLIBRI social relationships domain

ROC Receiver operating characteristic

rSO2 Regional cerebral oxygen saturation

SEI Severe extracranial injury

SF-12 12-Item Short-Form Health Survey

TBI Traumatic brain injury

TBI-IMPACT International Mission for Prognosis and Analysis or Clinical Trials in Traumatic Brain Injury

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-71843-z.

Acknowledgements

We would like to acknowledge the patients and staff of the Health Sciences Centre Winnipeg, without which the data from this study would not be possible.

Author contributions

Study conception and design was done by AG and FAZ. Data collection was performed by AG, LF, KS, and FAZ. Data analysis and preparation of the first draft of the manuscript performed by ATG. All authors contributed to editing and revising the manuscript. All authors read an approved the final manuscript.

Funding

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under Award Number R03NS114335. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also directly supported by the University of Manitoba Endowed Manitoba Public Insurance (MPI) Chair in Neuroscience, and the Natural Sciences and Engineering Research Council of Canada (NSERC) (ALLRP-578524-22). FAZ is supported through the University of Manitoba Endowed Manitoba Public Insurance (MPI) Chair in Neuroscience/TBI Research Endowment, the Natural Sciences and Engineering Research Council of Canada (NSERC) (DGECR-2022-00260, RGPIN-2022-03621, ALLRP-578524-22, ALLRP-576386-22, ALLRP 586244-23), Canadian Institutes of Health Research (CIHR), the MPI Neuroscience Research Operating Fund, the Health Sciences Centre Foundation Winnipeg, the Canada Foundation for Innovation (CFI) (Project #: 38583), and Research Manitoba (Grant #: 3906 and 5429). AG is supported through a CIHR Fellowship (Grant #: 472286). LF is supported through an NSERC Post-Doctoral Fellowship. KYS is supported through the University of Manitoba R.G. and E.M. Graduate Fellowship (Doctoral) in Biomedical Engineering, and the University of Manitoba MD/PhD program, and NSERC CGS-D (CGS D-579021-2023).

Data availability

The datasets analyzed and code utilized during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Full approval was received for this study from the University of Manitoba Biomedical Research Ethics Board (BREB; B2018:103) as well as the Health Science Centre Impact Committee (RI2020:016). Deferral of consent was approved by the BREB given the nature of the included study population allowing for rapid initiation of data collection shortly after admission to ICU. However, as soon as reasonably possible, informed consent for study participation was obtained from either the subject or an appropriate substitute decision maker. Informed consent for study participation was reobtained at all follow-up visits and participants were able to withdraw from the study at any time.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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