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Publications (10 of 92) Show all publications
Bader, S. E., Brorsson, C., Löfgren, N., Löfgren, F., Blind, P.-J., Sundström, N., . . . Olivecrona, M. (2024). Cerebral haemodynamics and intracranial pressure during haemorrhagic shock and resuscitation with total endovascular balloon occlusion of the aorta in an animal model. European Journal of Trauma and Emergency Surgery, 50(6), 3069-3082
Open this publication in new window or tab >>Cerebral haemodynamics and intracranial pressure during haemorrhagic shock and resuscitation with total endovascular balloon occlusion of the aorta in an animal model
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2024 (English)In: European Journal of Trauma and Emergency Surgery, ISSN 1863-9933, E-ISSN 1863-9941, Vol. 50, no 6, p. 3069-3082Article in journal (Refereed) Published
Abstract [en]

Purpose: To assess changes of cerebral haemodynamic and intracranial pressure (ICP) in animals, with or without elevated ICP, during controlled haemorrhagic shock and resuscitation with Total REBOA (tREBOA).

Method: In 22 anaesthetized and normoventilated pigs, after placement of catheters for monitoring invasive proximal blood pressure (pMAP), ICP, and vital parameters, and 60 min stabilisation phase, a controlled haemorrhagic shock (HS), was conducted. In 11 pigs (EICPG), an elevated ICP of 25–30 mmHg at the end HS was achieved by simulating an epidural mass. In 11 pigs (NICPG), the ICP was normal. tREBOA was then applied for 120 min. The changes of pMAP and ICP were followed, and cerebral perfusion pressure (CPP) calculated. The integrity of the autoregulation was estimated using a calculated Modified-Long Pressure Reactivity Index (mL-PRx).

Results: After stabilisation, hemodynamics and physiological parameters were similar and normal in both groups. At the end of the HS, ICP was 16 mmHg in NICPG vs. 32 in EICPG (p = 0.0010). CPP was 30 mmHg in NICPG vs. 6 mmHg in EICPG (p = 0.0254). After aorta occlusion CPP increased immediately in both groups reaching after 15 min up to104 mmHg in NICPG vs. 126 mmHg in EICPG. Cerebrovascular reactivity seems to be altered during bleeding and occlusion phases in both groups with positive mL-PRx. The alteration was more pronounced in EICPG, but reversible in both groups.

Conclusion: tREBOA is lifesaving by restoration the cerebral circulation defined as CPP in animals with HS with normal or elevated ICP. Despite the observation of short episodes of cerebral autoregulation impairment during the occlusion, mainly in EICPG, tREBOA seems to be an effective tool for improving cerebral perfusion in HS that extends the crucial early window sometimes known as the “golden hour” for resuscitation even after a traumatic brain injury.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Cerebral autoregulation, Haemorrhagic shock, ICP, REBOA, Resuscitative endovascular balloon occlusion of the aorta
National Category
Anesthesiology and Intensive Care Surgery
Identifiers
urn:nbn:se:umu:diva-231382 (URN)10.1007/s00068-024-02646-0 (DOI)001341139300001 ()39453469 (PubMedID)2-s2.0-85207360385 (Scopus ID)
Funder
Region Västerbotten, RV969834 (2021-10-11)Region Västerbotten, RV- 941769 (2020-10-10)Region Västerbotten, RV-849041 (2018- 10-07)
Available from: 2024-11-12 Created: 2024-11-12 Last updated: 2025-03-20Bibliographically approved
Qvarlander, S., Sundström, N., Malm, J. & Eklund, A. (2024). CSF formation rate: a potential glymphatic flow parameter in hydrocephalus?. Fluids and Barriers of the CNS, 21(1), Article ID 55.
Open this publication in new window or tab >>CSF formation rate: a potential glymphatic flow parameter in hydrocephalus?
2024 (English)In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 21, no 1, article id 55Article in journal (Refereed) Published
Abstract [en]

Background: Studies indicate that brain clearance via the glymphatic system is impaired in idiopathic normal pressure hydrocephalus (INPH). This has been suggested to result from reduced cerebrospinal fluid (CSF) turnover, which could be caused by a reduced CSF formation rate. The aim of this study was to determine the formation rate of CSF in a cohort of patients investigated for INPH and compare this to a historical control cohort.

Methods: CSF formation rate was estimated in 135 (75 ± 6 years old, 64/71 men/women) patients undergoing investigation for INPH. A semiautomatic CSF infusion investigation (via lumbar puncture) was performed. CSF formation rate was assessed by downregulating and steadily maintaining CSF pressure at a zero level. During the last 10 min, the required outflow to maintain zero pressure, i.e., CSF formation rate, was continuously measured. The values were compared to those of a historical reference cohort from a study by Ekstedt in 1978.

Results: Mean CSF formation rate was 0.45 ± 0.15 ml/min (N = 135), equivalent to 27 ± 9 ml/hour. There was no difference in the mean (p = 0.362) or variance (p = 0.498) of CSF formation rate between the subjects that were diagnosed as INPH (N = 86) and those who were not (N = 43). The CSF formation rate in INPH was statistically higher than in the reference cohort (0.46 ± 0.15 vs. 0.40 ± 0.08 ml/min, p = 0.005), but the small difference was probably not physiologically relevant. There was no correlation between CSF formation rate and baseline CSF pressure (r = 0.136, p = 0.115, N = 135) or age (-0.02, p = 0.803, N = 135).

Conclusions: The average CSF formation rate in INPH was not decreased compared to the healthy reference cohort, which does not support reduced CSF turnover. This emphasizes the need to further investigate the source and routes of the flow in the glymphatic system and the cause of the suggested impaired glymphatic clearance in INPH.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
CSF dynamics, CSF production, Glymphatic system, Idiopathic normal pressure hydrocephalus
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-227922 (URN)10.1186/s12987-024-00560-6 (DOI)001268928000001 ()38987813 (PubMedID)2-s2.0-85198121726 (Scopus ID)
Funder
Swedish Foundation for Strategic Research, RMX18-0152Swedish Research Council, 2021-00711
Available from: 2024-07-19 Created: 2024-07-19 Last updated: 2025-04-24Bibliographically approved
Liljegren, A. R., Brorsson, C., Karlsson, M., Koskinen, L.-O. D. & Sundström, N. (2023). Cerebrovascular pressure reactivity measures: index comparison and clinical outcome in patients with traumatic brain injury treated according to an intracranial pressure–focused management. Neurotrauma Reports, 4(1), 848-856
Open this publication in new window or tab >>Cerebrovascular pressure reactivity measures: index comparison and clinical outcome in patients with traumatic brain injury treated according to an intracranial pressure–focused management
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2023 (English)In: Neurotrauma Reports, E-ISSN 2689-288X, Vol. 4, no 1, p. 848-856Article in journal (Refereed) Published
Abstract [en]

The aim was to investigate whether the pressure reactivity indices PRx, long-PRx (L-PRx), and pressure reactivity (PR) are interchangeable as measures of vascular reactivity, and whether they correlate with clinical outcome when an intracranial pressure (ICP)-targeted treatment regimen is applied in patients with traumatic brain injury (TBI). Patients with TBI (n = 29) that arrived at the hospital within 24 h of injury were included. PRx and L-PRx were derived from Pearson correlations between mean arterial pressure (MAP) and ICP over a short- and long-time interval. PR was the regression coefficient between the hourly mean values of ICP and MAP. Indices were compared to each other, parameters at admission, and outcome assessed by the extended Glasgow Outcome Scale-Extended (GOSE) at 6 and 12 months. PRx and L-PRx had the strongest correlation with each other (R = 0.536, p < 0.01). A correlation was also noted between L-PRx and PR (R = 0.475, p < 0.01), but not between PRx and PR. A correlation was found between age and PRx (R = 0.482, p = 0.01). No association with outcome for any of the indices was found. PRx/L-PRx and L-PRx/PR were moderately correlated with each other. Age was associated with PRx. None of the indices correlated with outcome when our ICP treatment regime was applied. Part of our null hypothesis, that the three indices are associated with outcome, must be rejected. There was, however, an association between some of the indices. To further understand the relation of treatment regimes and pressure reactivity indices, a larger, randomized study is warranted.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2023
Keywords
neurointensive care, neurosurgery, pressure reactivity indices, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-219526 (URN)10.1089/neur.2023.0074 (DOI)001145547200001 ()2-s2.0-85181575401 (Scopus ID)
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2025-04-24Bibliographically approved
van Essen, T. A., van Erp, I. A., Lingsma, H. F., Pisică, D., Yue, J. K., Singh, R. D., . . . Peul, W. C. (2023). Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study. eClinicalMedicine, 63, Article ID 102161.
Open this publication in new window or tab >>Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study
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2023 (English)In: eClinicalMedicine, E-ISSN 2589-5370, Vol. 63, article id 102161Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy.

METHODS: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582).

FINDINGS: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]).

INTERPRETATION: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling.

FUNDING: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Acute subdural hematoma, Comparative effectiveness research, Craniotomy, Decompressive craniectomy, Instrumental variable analysis, Practice variation
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-221574 (URN)10.1016/j.eclinm.2023.102161 (DOI)001063167900001 ()37600483 (PubMedID)2-s2.0-85167581191 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 602150
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
Riemann, L., Mikolic, A., Maas, A., Unterberg, A. & Younsi, A. (2023). Computed tomography lesions and their association with global outcome in young people with mild traumatic brain injury. Journal of Neurotrauma, 40(11-12), 1243-1254
Open this publication in new window or tab >>Computed tomography lesions and their association with global outcome in young people with mild traumatic brain injury
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2023 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 40, no 11-12, p. 1243-1254Article in journal (Refereed) Published
Abstract [en]

Mild traumatic brain injury (mTBI) can be accompanied by structural damage to the brain. Here, we investigated how the presence of intracranial traumatic computed tomography (CT) pathologies relates to the global functional outcome in young patients one year after mTBI. All patients with mTBI (Glasgow Coma Scale: 13-15) ≤24 years in the multi-center, prospective, observational Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study were included. Patient demographics and CT findings were assessed at admission, and the Glasgow Outcome Scale Extended (GOSE) was evaluated at 12 months follow-up. The association between a "positive CT" (at least one of the following: epidural hematoma, subdural hematoma, traumatic subarachnoid hemorrhage (tSAH), intraventricular hemorrhage, subdural collection mixed density, contusion, traumatic axonal injury) and functional outcome (GOSE) was assessed using multi-variable mixed ordinal and logistic regression models. A total of 462 patients with mTBI and initial brain CT from 46 study centers were included. The median age was 19 (17-22) years, and 322 (70%) were males. CT imaging showed a traumatic intracranial pathology in 171 patients (37%), most commonly tSAH (48%), contusions (40%), and epidural hematomas (37%). Patients with a positive CT scan were less likely to achieve a complete recovery 12 months post-injury. The presence of any CT abnormality was associated with both lower GOSE scores (odds ratio [OR]: 0.39 [0.24-0.63]) and incomplete recovery (GOSE <8; OR: 0.41 [0.25-0.68]), also when adjusted for demographical and clinical baseline factors. The presence of intracranial traumatic CT pathologies was predictive of outcome 12 months after mTBI in young patients, which might help to identify candidates for early follow-up and additional care.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2023
Keywords
CT findings, adolescents, children, intracranial lesions, mild TBI, outcome
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-221575 (URN)10.1089/neu.2022.0055 (DOI)000938494700001 ()36578216 (PubMedID)2-s2.0-85160968721 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 602150
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
Erelund, S., Södergren, A., Wiklund, U. & Sundström, N. (2023). Heart rate variability and cardiovascular risk factors in patients with rheumatoid arthritis: a longitudinal study. Autonomic Neuroscience: Basic & Clinical, 249, Article ID 103119.
Open this publication in new window or tab >>Heart rate variability and cardiovascular risk factors in patients with rheumatoid arthritis: a longitudinal study
2023 (English)In: Autonomic Neuroscience: Basic & Clinical, ISSN 1566-0702, E-ISSN 1872-7484, Vol. 249, article id 103119Article in journal (Refereed) Published
Abstract [en]

Background: It is established that the risk of cardiovascular disease (CVD) is increased in patients with Rheumatoid Arthritis (RA). Heart rate variability (HRV) is a method for evaluating the activity in the cardiac autonomic nervous system. Our aim was to assess the longitudinal development of HRV in patients with RA and compare with healthy controls. Furthermore, we wanted to investigate associations between HRV, inflammatory disease activity and cardiovascular complications in patients with RA over time.

Method: HRV was assessed with frequency-domain analysis at baseline and after five years in 50 patients with early RA, all being younger than 60 years. HRV indices were age-adjusted based on the estimated age-dependency in 100 age and sex matched healthy controls. Additionally, clinical data including serological markers, disease activity, and blood pressure were collected from the patients. Eleven years after inclusion CVD was assessed.

Results: At baseline, patients with RA presented with lower HRV compared to controls during deep breathing (6 breaths/min), paced normal breathing (12 breaths/min) and after passive tilt to the upright position. No significant change in HRV was observed at the five-year follow-up. A significant negative correlation was found between HRV parameters and systolic blood pressure (SBP) at baseline. A significant positive correlation was found between heart rate and inflammatory markers at baseline but not after five years. Nine patients had developed CVD after 11 years, but no significant association was found with baseline HRV data.

Conclusion: This study showed that patients with RA have autonomic imbalance both at an early stage of the disease and after five years, despite anti-rheumatic medication, but no correlation between HRV and inflammation markers were observed. Reduced HRV was also significantly negatively correlated with increased SBP. Hypertension is a common finding in patients with RA. Thus, significant decline of HRV could be a useful early marker for development of hypertension in patients with RA.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Autonomic nervous system, Clinical physiology, Heart rate variability, Rheumatoid arthritis
National Category
Cardiology and Cardiovascular Disease Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-214502 (URN)10.1016/j.autneu.2023.103119 (DOI)001077844100001 ()37703773 (PubMedID)2-s2.0-85170415207 (Scopus ID)
Funder
Region VästerbottenSwedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Rheumatism AssociationVisare NorrSwedish Heart Lung FoundationStiftelsen Konung Gustaf V:s 80-årsfondSwedish Society of Medicine
Available from: 2023-09-21 Created: 2023-09-21 Last updated: 2025-04-24Bibliographically approved
Andersen, L., Appelblad, M., Wiklund, U., Sundström, N. & Svenmarker, S. (2023). Our initial experience of monitoring the autoregulation of cerebral blood flow during cardiopulmonary bypass. The journal of extra-corporeal technology, 55(4), 209-217
Open this publication in new window or tab >>Our initial experience of monitoring the autoregulation of cerebral blood flow during cardiopulmonary bypass
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2023 (English)In: The journal of extra-corporeal technology, ISSN 0022-1058, Vol. 55, no 4, p. 209-217Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Cerebral blood flow (CBF) is believed to be relatively constant within an upper and lower blood pressure limit. Different methods are available to monitor CBF autoregulation during surgery. This study aims to critically analyze the application of the cerebral oxygenation index (COx), one of the commonly used techniques, using a reference to data from a series of clinical registrations.

METHOD: CBF was monitored using near-infrared spectroscopy, while cerebral blood pressure was estimated by recordings obtained from either the radial or femoral artery in 10 patients undergoing cardiopulmonary bypass. The association between CBF and blood pressure was calculated as a moving continuous correlation coefficient. A COx index > 0.4 was regarded as a sign of abnormal cerebral autoregulation (CA). Recordings were examined to discuss reliability measures and clinical feasibility of the measurements, followed by interpretation of individual results, identification of possible pitfalls, and suggestions of alternative methods.

RESULTS AND CONCLUSION: Monitoring of CA during cardiopulmonary bypass is intriguing and complex. A series of challenges and limitations should be considered before introducing this method into clinical practice.

Place, publisher, year, edition, pages
EDP Sciences, 2023
Keywords
Autoregulation, Cardiopulmonary bypass, Cerebral blood flow, Monitoring, Near-infrared spectroscopy
National Category
Cardiology and Cardiovascular Disease
Identifiers
urn:nbn:se:umu:diva-218633 (URN)10.1051/ject/2023032 (DOI)38099638 (PubMedID)2-s2.0-85179772071 (Scopus ID)
Available from: 2023-12-27 Created: 2023-12-27 Last updated: 2025-02-10Bibliographically approved
Erelund, S., Karp, K., Arvidsson, S., Johansson, B., Sundström, N. & Wiklund, U. (2023). Pulmonary function in a cohort of heart-healthy individuals from Northern Sweden: a comparison with discordant reference values. BMC Pulmonary Medicine, 23(1), Article ID 110.
Open this publication in new window or tab >>Pulmonary function in a cohort of heart-healthy individuals from Northern Sweden: a comparison with discordant reference values
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2023 (English)In: BMC Pulmonary Medicine, E-ISSN 1471-2466, Vol. 23, no 1, article id 110Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Dynamic spirometry is an important investigation to differentiate between impaired and normal lung function. This study aimed to evaluate the results of lung function testing in a cohort of subjects from Northern Sweden without any known heart or pulmonary disease. Our focus was to compare with two reference materials that have showed differences in the age-dependency of lung function in Swedish subjects.

METHODS: The study population consisted of 285 healthy adults (148 males, 52%) between 20-90 years of age. The subjects had been randomly selected from the population register for inclusion in a study investigating cardiac function in heart-healthy subjects, but were also assessed with dynamic spirometry. At least seven percent reported smoking. Sixteen subjects presented with pulmonary functional impairments and were excluded from the current study. The sex-specific age-dependency in lung volumes was estimated using the LMS model, where non-linear equations were derived for the mean value (M), the location (L) or skewness, and the scatter (S) or coefficient of variation. This model of the observed lung function data was compared with reference values given by the original LMS model published by the Global Lung Initiative (GLI), and with the model from the recent Obstructive Lung Disease In Norrbotten (OLIN) study, where higher reference values were presented for Swedish subjects than those given by the GLI model.

RESULTS: No differences were found in the age-dependency of pulmonary function between the LMS model developed in the study and the OLIN model. Although the study group included smokers, the original GLI reference values suggested significantly lower normal values of FEV1 (forced expiratory volume) and FVC (forced vital capacity), and consequently fewer subjects below the lower limit of normality, than both the rederived LMS and OLIN models.

CONCLUSIONS: Our results are in line with previous reports and support that the original GLI reference values underestimate pulmonary function in the adult Swedish population. This underestimation could be reduced by updating the coefficients in the underlying LMS model based on a larger cohort of Swedish citizens than was available in this study.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Clinical physiology, Linear regression, Lung function, Reference values, Spirometry
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-206770 (URN)10.1186/s12890-023-02403-w (DOI)000963360400001 ()37020237 (PubMedID)2-s2.0-85151789612 (Scopus ID)
Available from: 2023-04-26 Created: 2023-04-26 Last updated: 2024-01-17Bibliographically approved
Kals, M., Kunzmann, K., Parodi, L., Radmanesh, F., Wilson, L., Izzy, S., . . . Menon, D. K. (2022). A genome-wide association study of outcome from traumatic brain injury. EBioMedicine, 77, Article ID 103933.
Open this publication in new window or tab >>A genome-wide association study of outcome from traumatic brain injury
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2022 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 77, article id 103933Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Factors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias.

METHODS: We performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography.

FINDINGS: The estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10-8), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10-5). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10-4).

INTERPRETATION: While multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available.

FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Consortia, Genome-Wide association study, Outcome, Recovery, Traumatic brain injury
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-215813 (URN)10.1016/j.ebiom.2022.103933 (DOI)000795901400017 ()35301180 (PubMedID)2-s2.0-85126327411 (Scopus ID)
Available from: 2023-10-26 Created: 2023-10-26 Last updated: 2023-10-27Bibliographically approved
Åkerlund, C. A. I., Holst, A., Stocchetti, N., Steyerberg, E. W., Menon, D. K., Ercole, A. & Nelson, D. W. (2022). Clustering identifies endotypes of traumatic brain injury in an intensive care cohort: a CENTER-TBI study. Critical Care, 26(1), Article ID 228.
Open this publication in new window or tab >>Clustering identifies endotypes of traumatic brain injury in an intensive care cohort: a CENTER-TBI study
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2022 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 26, no 1, article id 228Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: While the Glasgow coma scale (GCS) is one of the strongest outcome predictors, the current classification of traumatic brain injury (TBI) as 'mild', 'moderate' or 'severe' based on this fails to capture enormous heterogeneity in pathophysiology and treatment response. We hypothesized that data-driven characterization of TBI could identify distinct endotypes and give mechanistic insights.

METHODS: We developed an unsupervised statistical clustering model based on a mixture of probabilistic graphs for presentation (< 24 h) demographic, clinical, physiological, laboratory and imaging data to identify subgroups of TBI patients admitted to the intensive care unit in the CENTER-TBI dataset (N = 1,728). A cluster similarity index was used for robust determination of optimal cluster number. Mutual information was used to quantify feature importance and for cluster interpretation.

RESULTS: Six stable endotypes were identified with distinct GCS and composite systemic metabolic stress profiles, distinguished by GCS, blood lactate, oxygen saturation, serum creatinine, glucose, base excess, pH, arterial partial pressure of carbon dioxide, and body temperature. Notably, a cluster with 'moderate' TBI (by traditional classification) and deranged metabolic profile, had a worse outcome than a cluster with 'severe' GCS and a normal metabolic profile. Addition of cluster labels significantly improved the prognostic precision of the IMPACT (International Mission for Prognosis and Analysis of Clinical trials in TBI) extended model, for prediction of both unfavourable outcome and mortality (both p < 0.001).

CONCLUSIONS: Six stable and clinically distinct TBI endotypes were identified by probabilistic unsupervised clustering. In addition to presenting neurology, a profile of biochemical derangement was found to be an important distinguishing feature that was both biologically plausible and associated with outcome. Our work motivates refining current TBI classifications with factors describing metabolic stress. Such data-driven clusters suggest TBI endotypes that merit investigation to identify bespoke treatment strategies to improve care. 

Place, publisher, year, edition, pages
BioMed Central (BMC), 2022
Keywords
Critical care, Endotypes, Intensive care unit, Machine learning, Traumatic brain injury, Unsupervised clustering
National Category
Anesthesiology and Intensive Care Neurology
Identifiers
urn:nbn:se:umu:diva-221583 (URN)10.1186/s13054-022-04079-w (DOI)000831208500002 ()35897070 (PubMedID)2-s2.0-85135370588 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-02-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3486-5251

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