| 1. |
- Bartek, Jiri, Jr., et al.
(author)
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Scandinavian Multicenter Acute Subdural Hematoma (SMASH) Study : Study Protocol for a Multinational Population-Based Consecutive Cohort
- 2019
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In: Neurosurgery. - : Ovid Technologies (Wolters Kluwer Health). - 0148-396X .- 1524-4040. ; 84:3, s. 799-803
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Journal article (peer-reviewed)abstract
- BACKGROUNDTraumatic acute subdural hematomas (ASDHs) are associated with high rate of morbidity and mortality, especially in elderly individuals. However, recent reports indicate that the morbidity and mortality rates might have improved.OBJECTIVETo evaluate postoperative (30-d) mortality in younger vs elderly (70 yr) patients with ASDH. Comparing younger and elderly patients, the secondary objectives are morbidity patterns of care and 6 mo outcome according to Glasgow outcome scale (GOS). Finally, in patients with traumatic ASDH, we aim to provide prognostic variables.METHODS This is a large-scale population-based Scandinavian study including all neurosurgical departments in Denmark and Sweden. All adult (18 yr) patients surgically treated between 2010 and 2014 for a traumatic ASDH in Denmark and Sweden will be included. Identification at clinicaltrials.gov is NCT03284190.EXPECTED OUTCOMESWe expect to provide data on potential differences between younger vs elderly patients in terms of mortality and morbidity. We hypothesize that elderly patients selected for surgery have a similar pattern of care as compared with younger patients. We will provide functional outcome in terms of GOS at 6 mo in younger vs elderly patients undergoing ASDH evacuation. Finally, clinical useful prognostic factors for favorable (GOS 4-5) vs unfavorable (GOS 1-3) will be identified.DISCUSSION An improved understanding of the clinical outcome, treatment and resource allocation, clinical course, and the prognostic factors of traumatic ASDH will allow neurosurgeons to make better treatment decisions.
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| 2. |
- Krakau, Karolina, 1968-, et al.
(author)
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Energy balance and metabolism after severe traumatic brain injury : A pilot study using doubly labelled water
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Other publication (other academic/artistic)abstract
- Objective: To explore the course of energy balance in patients with severe traumatic brain injury, from time of injury until twelve weeks post injury. Method: This prospective desriptive study included six patients with isolated, closed severe traumatic brain injury and an expected hospital stay of ≥2-3 months. Energy balance was calculated from energy intake compared to total energy expenditure measured by continuous indirect calorimetry and doubly labelled water. Clinical and laboratory variables with possible influence on metabolism and nutritional delivery were recorded simultaneously. Intermittent indirect calorimetry measurements were used to differentiate components of the energy expended. Results: Patients were roughly in energy balance while on mechanical ventilation, but in negative energy balance from the 3rd week post injury. The total energy expenditure then increased while the daily energy intake declined. Concurrent with this period were difficulties in retaining enteral and/or parenteral nutrition delivery routes until oral feeding was satisfactory. Nitrogen balance was back to normal at about 1.5 months and the inflammatory period with increased C-reactive protein levels continued for 12 to 58 days from time of injury. During the first and second month post injury, patients lost 8-19% of their initial body weight. Conclusion: Data suggests that negative energy balance after a severe TBI could not only be explained by the elevated metabolic rate and catabolism induced by the trauma, but also by difficulties in securing alternative nutritional routes in the distressed patient.
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| 3. |
- Nelson, David W., et al.
(author)
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Multivariate outcome prediction in traumatic brain injury with focus on laboratory values
- 2012
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 29:17, s. 2613-2624
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is a major cause of morbidity and mortality. Identifying factors relevant to outcome can provide a better understanding of TBI pathophysiology, in addition to aiding prognostication. Many common laboratory variables have been related to outcome but may not be independent predictors in a multivariate setting. In this study, 757 patients were identified in the Karolinska TBI database who had retrievable early laboratory variables. These were analyzed towards a dichotomized Glasgow Outcome Scale (GOS) with logistic regression and relevance vector machines, a non-linear machine learning method, univariately and controlled for the known important predictors in TBI outcome: age, Glasgow Coma Score (GCS), pupil response, and computed tomography (CT) score. Accuracy was assessed with Nagelkerke's pseudo R2. Of the 18 investigated laboratory variables, 15 were found significant (p<0.05) towards outcome in univariate analyses. In contrast, when adjusting for other predictors, few remained significant. Creatinine was found an independent predictor of TBI outcome. Glucose, albumin, and osmolarity levels were also identified as predictors, depending on analysis method. A worse outcome related to increasing osmolarity may warrant further study. Importantly, hemoglobin was not found significant when adjusted for post-resuscitation GCS as opposed to an admission GCS, and timing of GCS can thus have a major impact on conclusions. In total, laboratory variables added an additional 1.3-4.4% to pseudo R2.
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| 4. |
- Ahl, Rebecka, 1987-, et al.
(author)
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β-Blocker after severe traumatic brain injury is associated with better long-term functional outcome : a matched case control study
- 2017
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In: European Journal of Trauma and Emergency Surgery. - : Springer Berlin/Heidelberg. - 1863-9933 .- 1863-9941. ; 43:6, s. 783-789
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Journal article (peer-reviewed)abstract
- PURPOSE: Severe traumatic brain injury (TBI) is the predominant cause of death and disability following trauma. Several studies have observed improved survival in TBI patients exposed to β-blockers, however, the effect on functional outcome is poorly documented.METHODS: Adult patients with severe TBI (head AIS ≥ 3) were identified from a prospectively collected TBI database over a 5-year period. Patients with neurosurgical ICU length of stay <48 h and those dying within 48 h of admission were excluded. Patients exposed to β-blockers ≤ 48 h after admission and who continued with treatment until discharge constituted β-blocked cases and were matched to non β-blocked controls using propensity score matching. The outcome of interest was Glasgow Outcome Scores (GOS), as a measure of functional outcome up to 12 months after injury. GOS ≤ 3 was considered a poor outcome. Bivariate analysis was deployed to determine differences between groups. Odds ratio and 95% CI were used to assess the effect of β-blockers on GOS.RESULTS: 362 patients met the inclusion criteria with 21% receiving β-blockers during admission. After propensity matching, 76 matched pairs were available for analysis. There were no statistical differences in any variables included in the analysis. Mean hospital length of stay was shorter in the β-blocked cases (18.0 vs. 26.8 days, p < 0.01). The risk of poor long-term functional outcome was more than doubled in non-β-blocked controls (OR 2.44, 95% CI 1.01-6.03, p = 0.03).CONCLUSION: Exposure to β-blockers in patients with severe TBI appears to improve functional outcome. Further prospective randomized trials are warranted.
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| 5. |
- Al Nimer, Faiez, et al.
(author)
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Comparative Assessment of the Prognostic Value of Biomarkers in Traumatic Brain Injury Reveals an Independent Role for Serum Levels of Neurofilament Light
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is a common cause of death and disability, worldwide. Early determination of injury severity is essential to improve care. Neurofilament light (NF-L) has been introduced as a marker of neuroaxonal injury in neuroinflammatory/-degenerative diseases. In this study we determined the predictive power of serum (s-) and cerebrospinal fluid (CSF-) NF-L levels towards outcome, and explored their potential correlation to diffuse axonal injury (DAI). A total of 182 patients suffering from TBI admitted to the neurointensive care unit at a level 1 trauma center were included. S-NF-L levels were acquired, together with S100B and neuron-specific enolase (NSE). CSF-NF-L was measured in a subcohort (n = 84) with ventriculostomies. Clinical and neuro-radiological parameters, including computerized tomography (CT) and magnetic resonance imaging, were included in the analyses. Outcome was assessed 6 to 12 months after injury using the Glasgow Outcome Score (1-5). In univariate proportional odds analyses mean s-NF-L, -S100B and -NSE levels presented a pseudo-R-2 Nagelkerke of 0.062, 0.214 and 0.074 in correlation to outcome, respectively. In a multivariate analysis, in addition to a model including core parameters (pseudo-R-2 0.33 towards outcome; Age, Glasgow Coma Scale, pupil response, Stockholm CT score, abbreviated injury severity score, S100B), S-NF-L yielded an extra 0.023 pseudo-R-2 and a significantly better model (p = 0.006) No correlation between DAI or CT assessed-intracranial damage and NF-L was found. Our study thus demonstrates that SNF-L correlates to TBI outcome, even if used in models with S100B, indicating an independent contribution to the prediction, perhaps by reflecting different pathophysiological processes, not possible to monitor using conventional neuroradiology. Although we did not find a predictive value of NF-L for DAI, this cannot be completely excluded. We suggest further
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| 6. |
- Bellander, Bo-Michael
(author)
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On the role of complement activation following traumatic brain injury
- 2004
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Doctoral thesis (other academic/artistic)abstract
- Traumatic brain injury (TBI) is one of the leading causes of early death and disability among young people in the industrial world. The final clinical outcome in terms of morbidity/mortality is not only related to the "primary brain injury", but also seems to be dependent on the potential development of so called "secondary injuries", that may occur in the brain the days after the initial impact. Several biochemical mechanisms have been suggested to be involved in these secondary events, like release of free radicals, glutamate, proteases and nitric oxide. During recent years neuroinflammation has gained a growing interest as a mediator of such secondary injuries. One important immunological entity is the complement system, which when activated results in a cascade of events leading to increased vascular permeability, induction of cytokine production which further triggers the inflammatory response, facilitation of phagocytosis by chemotactical recruitment of macrophages and opsonization. The terminal pathway of the complement cascade results in formation of the membrane attack complex (MAC), a protein complex, with capacity to damage basically any target cell by creating pores in the cell membrane, which in turn allows intracellular influx of water and ions, e.g. calcium, that eventually may cause cell death. In this thesis we have shown that the complement cascade is activated in the border zone ("penumbra") of a brain contusion in the adult rat as well as in the human brain. Clusters of MAC, the cytolytic end-product of the complement cascade, were shown to accumulate at membrane surfaces of viable neurons located in the immediate vicinity to the primary brain injury and may thus contribute to additional damages, so called secondary brain injuries. Reactive microglia/macrophages seem to have a key role in complement activation by synthesis of at least complement factor C3. Resident microglial cells which in vivo are difficult to distinguish from peripherally derived monocytes/macrophages were shown in this thesis to contribute to the pool of reactive macrophages surrounding the lesion using an experimental blood/serum free brain slice model. The subsequent neuronal degeneration that follows TBI was found to be more severe in a rat strain that, based on its genetic features, presents a more pronounced neuroinflammatory response, including complement activation, supporting the hypothesis that this biological cascade is involved in the development of secondary brain injuries. Furthermore, in humans suffering from severe traumatic brain injuries, the occurrences of hypoxia, hypotension and other so called "secondary insults" is followed by higher levels of MAC as well as higher levels of the tissue damage marker S100B, in the cerebrospinal fluid, suggesting that secondary insults further enhance complement activation resulting in more and perhaps avoidable secondary injuries, provided that a thorough and systematic monitoring of these patients are undertaken as they are being treated in the neurointensive care unit. In summary, a traumatic brain injury causes a primary necrotic area surrounded by a "penumbra like" border zone where reactive microglial cells accumulate and transform into macrophages. These macrophages synthesize complement factor C3 and thus contribute to the activation of the complement cascade in the immediate vicinity to the contusion. The cytolytic end product of the complement system, MAC, may in turn induce secondary neuronal injuries by its membrane destructive effects, a process that is further enhanced by secondary insults. Future neuroprotective therapies might be based not only on avoiding secondary insults by careful monitoring, but also on specific regulatory compounds acting selectively on specific parts of the neuroinflammatory process, e.g. the terminal pathway of the complement systern.
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| 7. |
- Cacciani, Nicola, et al.
(author)
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A prospective clinical study on the mechanisms underlying critical illness myopathy : A time-course approach
- 2022
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In: Journal of Cachexia, Sarcopenia and Muscle. - : John Wiley & Sons. - 2190-5991 .- 2190-6009. ; 13:6, s. 2669-2682
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Journal article (peer-reviewed)abstract
- Background: Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive.Methods: Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points.Results: (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma.Conclusions: The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.
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| 8. |
- Fletcher-Sandersjöö, Alexander, et al.
(author)
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Absolute Contusion Expansion Is Superior to Relative Expansion in Predicting Traumatic Brain Injury Outcomes : A Multi-Center Observational Cohort Study
- 2024
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 41:5-6, s. 705-713
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Journal article (peer-reviewed)abstract
- Contusion expansion (CE) is a potentially treatable outcome predictor in traumatic brain injury (TBI), and a suitable end-point for hemostatic therapy trials. However, there is no consensus on the definition of clinically relevant CE, both in terms of measurement criteria (absolute vs. relative volume increase) and cutoff values. In light of this, the aim of this study was to assess the predictive abilities of different CE definitions on outcome. We performed a multi-center observational cohort study of adults with moderate-to-severe TBI treated in an intensive care unit. The exposure of interest was CE, defined as the absolute and relative volume change between the first and second computed tomography scan. The primary outcome was the Glasgow Outcome Scale (GOS) at 6–12 months post-injury, dichotomized into unfavorable (GOS ≤3) or favorable (GOS ≥4). The secondary outcome was all-cause mortality. In total, 798 patients were included, with a median duration of 7.0 h between the first and second CT scan. The median absolute and relative CE was 1.5 mL (interquartile range [IQR] 0.1–8.3 mL) and 100% (IQR 10–530%), respectively. Both CE forms were independently associated with unfavorable GOS. Absolute CE outperformed relative CE in predicting both unfavorable GOS (area under the curve [AUC]: 0.65 vs. 0.60, p = 0.002) and all-cause mortality (AUC: 0.66 vs. 0.60, p = 0.003). For dichotomized CE, absolute cutoffs of 1–10 mL yielded the best results. We conclude that absolute CE demonstrates stronger outcome correlation than relative CE. In studies focusing on lesion progression in TBI, it may be advantageous to use absolute CE as the primary outcome metric. For dichotomized outcomes, cutoffs between 1 and 10 mL are suggested, depending on the desired sensitivity-specificity balance.
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| 9. |
- Forssten, Maximilian Peter, 1996-, et al.
(author)
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The Role of Glycerol-Containing Drugs in Cerebral Microdialysis : A Retrospective Study on the Effects of Intravenously Administered Glycerol
- 2019
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In: Neurocritical Care. - : Humana Press. - 1541-6933 .- 1556-0961. ; 30:3, s. 590-600
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cerebral microdialysis (CMD) is a valuable tool for monitoring compounds in the cerebral extracellular fluid (ECF). Glycerol is one such compound which is regarded as a marker of cell membrane decomposition. Notably, in some acutely brain-injured patients, CMD-glycerol levels rise without any other apparent indication of cerebral deterioration. The aim of this study was to investigate whether this could be due to an association between CMD-glycerol levels and the administration of glycerol-containing drugs.METHODS: Microdialysis data were retrospectively retrieved from the hospital's intensive care unit patient data management system (PDMS). All patients who were monitored with CMD for ≥ 96 h were included. Administered drug doses were retrieved from the PDMS and converted to exact doses of glycerol. Cross-correlation analyses were performed between the free, metabolized as well as total administered dose of glycerol and the detrended and differenced CMD-glycerol concentration. These analyses were repeated for two sets of subgroups based upon the individual catheter's graphical trend and its location in relation to the lesion.RESULTS: There was no significant correlation between the differenced CMD-glycerol levels and drug-administered glycerol. Furthermore, there was no significant correlation between CMD-glycerol and catheter location or graphical trend. However, if the CMD-glycerol levels were detrended, significant but clinically non-relevant correlations were identified (maximum correlation coefficient of 0.1 (0.04-0.15, 95% CI) at a lag of 7 h using the total administered dose of glycerol).CONCLUSIONS: Glycerol-containing drugs routinely administered intravenously in the clinical setting appear to have a minimal and clinically insignificant effect on levels of glycerol in the cerebral ECF.
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| 10. |
- Hutchinson, Peter J, et al.
(author)
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Consensus statement from the 2014 International Microdialysis Forum
- 2015
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In: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 41:9, s. 1517-1528
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Journal article (peer-reviewed)abstract
- Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.
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| 11. |
- Krakau, Karolina, 1968-, et al.
(author)
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Prediction of energy expenditure in patients with severe traumatic brain injury : A validation study by use of continuous indirect calorimetry and doubly labelled water
-
Other publication (other academic/artistic)abstract
- Objective: The aim was to evaluate the accuracy of methods to predict energy expenditure (EE) in patients with severe traumatic brain injury (TBI). Method: To this prospective descriptive study, a small cohort of patients (n6) with isolated, severe TBI and an expected hospital stay of ≥2-3 months were included. The EE was measured at two intervals: by continuous indirect calorimetry during mechanical ventilation and by doubly labelled water from 3rd to 5th week post injury. Different equations for prediction of EE and a portable monitor, the SenseWear Armband were compared to the measured EE. Result: The majority of methods for predicting EE agreed poorly with the measured EE during indirect calorimetry period. A good agreement was found only with the three Penn-State equations, but two were biased according to Bland Altman analysis. The Penn-State equation from 1998 was the only valid predictive method, with a mean difference per day close to zero (+22 kcal), an excellent agreement (ICC 0.82) with 72% (n54/75) accurately assessed days (±10% of the measured EE) and with all patients within clinically acceptable levels, i.e. ±15% of the measured EE. During doubly labelled water period, observations were too few for any conclusive statement. Conclusion: These data support use of the Penn-State equation from 1998 to estimate EE in patients with severe TBI while on mechanical ventilation.
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| 12. |
- Lilford, Robert D., et al.
(author)
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Increased Incidence and Mortality of Civilian Penetrating Traumatic Brain Injury in Sweden : A Single-Center Registry-Based Study
- 2024
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In: World Neurosurgery. - : Elsevier. - 1878-8750 .- 1878-8769. ; 182, s. e493-e505
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Journal article (peer-reviewed)abstract
- BackgroundPenetrating trauma to the head and neck has increased during the past decade in Sweden. The aim of this study was to characterize these injuries and evaluate the outcomes for patients treated at a tertiary trauma center.MethodsSwedish trauma registry data were extracted on patients with head and neck injuries admitted to Karolinska University Hospital (Stockholm, Sweden) between 2011 and 2019. Outcome information was extracted from hospital records, with the primary endpoints focusing on the physiological outcome measures and the secondary endpoints on the surgical and radiological outcomes.ResultsOf 1436 patients with penetrating trauma, 329 with penetrating head and neck injuries were identified. Of the 329 patients, 66 (20%) had suffered a gunshot wound (GSW), 240 (73%) a stab wound (SW), and 23 (7%) an injury from other trauma mechanisms (OTMs). The median age for the corresponding 3 groups of patients was 25, 33, and 21 years, respectively. Assault was the primary intent, with 54 patients experiencing GSWs (81.8%) and 158 SWs (65.8%). Patients with GSWs had more severe injuries, worse admission Glasgow coma scale, motor, scores, and a higher intubation rate at the injury site. Most GSW patients underwent major surgery (59.1%) as the initial procedure and were more likely to have intracranial hemorrhage (21.2%). The 30-day mortality was 45.5% (n = 30) for GSWs, 5.4% (n = 13) for SWs, and 0% (n = 0) for OTMs. There was an annual increase in the incidence and mortality for GSWs and SWs.ConclusionsBetween 2011 and 2019, an increasing annual trend was found in the incidence and mortality from penetrating head and neck trauma in Stockholm, Sweden. GSW patients experienced more severe injuries and intracranial hemorrhage and underwent more surgical interventions compared with patients with SWs and OTMs.
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| 13. |
- Lindblad, Caroline, et al.
(author)
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Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood-brain barrier disruption and outcome prediction following severe traumatic brain injury : a prospective, observational study
- 2021
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In: Critical Care. - : Springer Nature. - 1364-8535 .- 1466-609X. ; 25:1
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Journal article (peer-reviewed)abstract
- Background: Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls. Methods: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6-12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (Q(A)), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort. Results: TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with Q(A), among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained similar to 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, Delta R-2 = 7.4%) and complement factor B in serum (p = 0.003, Delta R-2 = 9.2%) were independent outcome predictors also following step-down modelling. Conclusions: This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.
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| 14. |
- Marrero, Humberto D. J. Gonzalez, et al.
(author)
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Neurogenic vs. Myogenic Origin of Acquired Muscle Paralysis in Intensive Care Unit (ICU) Patients : Evaluation of Different Diagnostic Methods
- 2020
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In: Diagnostics (Basel). - : MDPI. - 2075-4418. ; 10:11
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Journal article (peer-reviewed)abstract
- Introduction. The acquired muscle paralysis associated with modern critical care can be of neurogenic or myogenic origin, yet the distinction between these origins is hampered by the precision of current diagnostic methods. This has resulted in the pooling of all acquired muscle paralyses, independent of their origin, into the term Intensive Care Unit Acquired Muscle Weakness (ICUAW). This is unfortunate since the acquired neuropathy (critical illness polyneuropathy, CIP) has a slower recovery than the myopathy (critical illness myopathy, CIM); therapies need to target underlying mechanisms and every patient deserves as accurate a diagnosis as possible. This study aims at evaluating different diagnostic methods in the diagnosis of CIP and CIM in critically ill, immobilized and mechanically ventilated intensive care unit (ICU) patients. Methods. ICU patients with acquired quadriplegia in response to critical care were included in the study. A total of 142 patients were examined with routine electrophysiological methods, together with biochemical analyses of myosin:actin (M:A) ratios of muscle biopsies. In addition, comparisons of evoked electromyographic (EMG) responses in direct vs. indirect muscle stimulation and histopathological analyses of muscle biopsies were performed in a subset of the patients. Results. ICU patients with quadriplegia were stratified into five groups based on the hallmark of CIM, i.e., preferential myosin loss (myosin:actin ratio, M:A) and classified as severe (M:A < 0.5; n = 12), moderate (0.5 <= M:A < 1; n = 40), mildly moderate (1 <= M:A < 1.5; n = 49), mild (1.5 <= M:A < 1.7; n = 24) and normal (1.7 <= M:A; n = 19). Identical M:A ratios were obtained in the small (4-15 mg) muscle samples, using a disposable semiautomatic microbiopsy needle instrument, and the larger (>80 mg) samples, obtained with a conchotome instrument. Compound muscle action potential (CMAP) duration was increased and amplitude decreased in patients with preferential myosin loss, but deviations from this relationship were observed in numerous patients, resulting in only weak correlations between CMAP properties and M:A. Advanced electrophysiological methods measuring refractoriness and comparing CMAP amplitude after indirect nerve vs. direct muscle stimulation are time consuming and did not increase precision compared with conventional electrophysiological measurements in the diagnosis of CIM. Low CMAP amplitude upon indirect vs. direct stimulation strongly suggest a neurogenic lesion, i.e., CIP, but this was rarely observed among the patients in this study. Histopathological diagnosis of CIM/CIP based on enzyme histochemical mATPase stainings were hampered by poor quantitative precision of myosin loss and the impact of pathological findings unrelated to acute quadriplegia. Conclusion. Conventional electrophysiological methods are valuable in identifying the peripheral origin of quadriplegia in ICU patients, but do not reliably separate between neurogenic vs. myogenic origins of paralysis. The hallmark of CIM, preferential myosin loss, can be reliably evaluated in the small samples obtained with the microbiopsy instrument. The major advantage of this method is that it is less invasive than conventional muscle biopsies, reducing the risk of bleeding in ICU patients, who are frequently receiving anticoagulant treatment, and it can be repeated multiple times during follow up for monitoring purposes.
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| 15. |
- Nyholm, Lena
(author)
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Quality systems to avoid secondary brain injury in neurointensive care
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Outcome after traumatic brain injury (TBI) depends on the extent of primary cell death and on the development of secondary brain injury. The general aim of this thesis was to find strategies and quality systems to minimize the extent of secondary insults in neurointensive care (NIC).An established standardized management protocol system, multimodality monitoring and computerized data collection, and analysis systems were used.The Uppsala TBI register was established for regular monitoring of NIC quality indexes. For 2008-2010 the proportion of patients improving during NIC was 60-80%, whereas 10% deteriorated. The percentage of ‘talk and die’ cases was < 1%. The occurrences of secondary insults were less than 5% of good monitoring time (GMT) for intracranial pressure (ICP) > 25 mmHg, cerebral perfusion pressure (CPP) < 50 mmHg and systolic blood pressure < 100 mmHg. Favorable outcome was achieved by 64% of adults.Nurse checklists of secondary insult occurrence were introduced. Evaluation of the use of nursing checklists showed that the nurses documented their assessments in 84-85% of the shifts and duration of monitoring time at insult level was significantly longer when secondary insults were reported regarding ICP, CPP and temperature. The use of nurse checklist was found to be feasible and accurate. A clinical tool to avoid secondary insults related to nursing interventions was developed. Secondary brain insults occurred in about 10% of nursing interventions. There were substantial variations between patients. The risk ratios of developing an ICP insult were 4.7 when baseline ICP ≥ 15 mmHg, 2.9 when ICP amplitude ≥ 6 mmHg and 1.7 when pressure autoregulation ≥ 0.3.Hyperthermia, which is a known frequent secondary insult, was studied. Hyperthermia was most common on Day 7 after admission and 90% of the TBI patients had hyperthermia during the first 10 days at the NIC unit. The effects of hyperthermia on intracranial dynamics (ICP, brain energy metabolism and BtipO2) were small but individual differences were observed. Hyperthermia increased ICP slightly more when temperature increased in the groups with low compliance and impaired pressure autoregulation. Ischemic pattern was never observed in the microdialysis samples. The treatment of hyperthermia may be individualized and guided by multimodality monitoring.
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| 16. |
- Rostami, Elham, 1979-, et al.
(author)
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A Model for Mild Traumatic Brain Injury that Induces Limited Transient Memory Impairment and Increased Levels of Axon Related Serum Biomarkers
- 2012
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 3, s. 115-
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Journal article (peer-reviewed)abstract
- Mild traumatic brain injury (mTBI) is one of the most common neuronal insults and can lead to long-term disabilities. mTBI occurs when the head is exposed to a rapid acceleration-deceleration movement triggering axonal injuries. Our limited understanding of the underlying pathological changes makes it difficult to predict the outcome of mTBI. In this study we used a scalable rat model for rotational acceleration TBI, previously characterized for the threshold of axonal pathology. We have analyzed whether a TBI just above the defined threshold would induce any detectable behavioral changes and/or changes in serum biomarkers. The effect of injury on sensory motor functions, memory and anxiety were assessed by beam walking, radial arms maze and elevated plus maze at 3–7 days following TBI. The only behavioral deficits found were transient impairments in working and reference memory. Blood serum was analyzed at 1, 3, and 14 days after injury for changes in selected protein biomarkers. Serum levels of neurofilament heavy chain and Tau, as well as S100B and myelin basic protein showed significant increases in the injured animals at all time points. No signs of macroscopic injuries such as intracerebral hematomas or contusions were found. Amyloid precursor protein immunostaining indicated axonal injuries at all time points analyzed. In summary, this model mimics some of the key symptoms of mTBI, such as transient memory impairment, which is paralleled by an increase in serum biomarkers. Our findings suggest that serum biomarkers may be used to detect mTBI. The model provides a suitable foundation for further investigation of the underlying pathology of mTBI.
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| 17. |
- Rostami, Elham, et al.
(author)
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Modern handläggning minimerar följder av traumatisk hjärnskada : [Treatment of traumatic brain injury in the acute setting - An overview]
- 2023
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In: Läkartidningen. - : Sveriges Lakarforbund. - 0023-7205 .- 1652-7518. ; 120
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Research review (peer-reviewed)abstract
- Traumatic brain injury (TBI) is the leading cause of death among the young, and has an increasing incidence among the elderly. In Sweden there are 20 000 new TBI cases each year, of which most are mild. The primary impact can lead to different types of brain hemorrhages, fractures and diffuse axonal injuries. The level of consciousness is used to define injury severity. Of all TBIs, 4-5 percent require surgical intervention. The primary impact initiates injury processes exacerbating the initial brain injury, and the goal of the acute management and neurointensive care treatment is to prevent these secondary insults. Among unconscious TBI patients, monitoring of intracranial pressure and cerebral perfusion pressure (CPP, defined as the difference between the mean arterial pressure and intracranial pressure) is routine. In this article we present an overview on different types of TBI, and describe the treatment of patients in the acute setting.
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| 18. |
- Rostami, Elham, et al.
(author)
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Modern handläggning minimerar följder av traumatisk hjärnskada: behandlingsriktlinjer har tydligt reducerat mortaliteten : [Treatment of traumatic brain injury in the acute setting - an overview]
- 2023
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In: Läkartidningen. - : Läkartidningen Förlag. - 0023-7205 .- 1652-7518. ; 120:4-5
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is the leading cause of death among the young, and has an increasing incidence among the elderly. In Sweden there are 20 000 new TBI cases each year, of which most are mild. The primary impact can lead to different types of brain hemorrhages, fractures and diffuse axonal injuries. The level of consciousness is used to define injury severity. Of all TBIs, 4-5 percent require surgical intervention. The primary impact initiates injury processes exacerbating the initial brain injury, and the goal of the acute management and neurointensive care treatment is to prevent these secondary insults. Among unconscious TBI patients, monitoring of intracranial pressure and cerebral perfusion pressure (CPP, defined as the difference between the mean arterial pressure and intracranial pressure) is routine. In this article we present an overview on different types of TBI, and describe the treatment of patients in the acute setting.
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| 19. |
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| 20. |
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| 21. |
- Rostami, Elham, 1979-, et al.
(author)
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Time-Dependent Changes in Serum Level of Protein Biomarkers after Focal Traumatic Brain Injury
- 2015
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In: International Journal of Neurorehabilitation. - : OMICS Publishing Group. - 2376-0281. ; 2:3, s. 1-6
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Journal article (peer-reviewed)abstract
- Serum biomarkers could indicate the pathological changes during the secondary injury process after traumatic brain injury (TBI). Furthermore, they could reflect specific pathological processes following different types of TBI. Here we analyzed time-dependent changes of select protein biomarkers in serum samples collected from a rodent model of penetrating type of injury (pen-TBI). The model is a controlled penetration of a 2 mm thick needle-shaped object, which is accelerated into the brain tissue with a bullet from an air gun. The results obtained in the current study were compared to previously reported results of levels of serum biomarker following a rotational acceleration injury that mimics mild TBI. A total of 24 animals were used, grouped in normal controls, sham-operated and injured animals. The rats were sacrificed at day 1, day 3 and day 14 post-injury and serum samples were analyzed for Tau, neurofilament heavy chain (NF-H), myelin basic protein (MBP), N-cadherin and S100B. We found that all markers but MBP showing a bi-phasic response to injury. Their serum levels significantly increased at day 1, dropped at 3 and increased again at day 14 post-injury. This was in contrast to rotational TBI model where the peak of biomarkers was found at day 3. Our study suggests that pen-TBI results in both acute axonal and neuronal damages as well as delayed changes likely part of the ongoing secondary injury process. These findings illustrate the dynamics of the injury process in pen-TBI and underline the importance of monitoring changes in serum biomarker levels for more accurate assessment of injury severity and outcome. In addition, comparison to rotational TBI model revealed distinctive temporal pattern of serum biomarker expression dependent on the type of injury.
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| 22. |
- Taxiarchis, Apostolos, et al.
(author)
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Extracellular vesicles in plasma and cerebrospinal fluid in patients with COVID-19 and neurological symptoms
- 2024
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In: International Journal of Laboratory Hematology. - : John Wiley & Sons. - 1751-5521 .- 1751-553X. ; 46:1, s. 42-49
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Journal article (peer-reviewed)abstract
- Introduction:Increased levels of extracellular vesicles (EVs) are associated with haemostatic disturbances in various clinical settings. However, their role in COVID-19 patients is still not fully clear. In the present study we investigated EVs in plasma from patients with COVID-19 and neurological symptoms in relation to the activation of coagulation.Methods:Nineteen COVID-19 patients with neurological symptoms and twenty-three aged-matched healthy individuals were included. Global coagulation assays were performed and levels of EVs were determined by flow-cytometry in plasma and cerebrospinal fluid (CSF).Results:A procoagulant state characterized by significantly increased overall coagulation- (OCP) and overall haemostatic potential (OHP), diminished overall fibrinolytic potential (OFP) together with a denser fibrin structure was found in patients with COVID-19. Flow cytometry revealed elevated levels of plasma circulating EVs derived from neutrophils (MPO+) and platelets (CD61+), as well as EVs expressing phosphatidylserine (PS+) and complement component C5b-9 (TCC+) in patients with COVID-19 compared with controls. The concentrations of PS+, CD61+ and TCC+ EVs were positively correlated with OCP and OHP in COVID-19 patients. Moreover, we identified CD61+, MPO+ and endothelial cell-derived EVs, as well as EVs exposing PS and TCC in the CSF of patients suffering from neurological symptoms during COVID-19.Conclusion:The unique finding in this study was the presence of EVs in the CSF of COVID-19 patients with neurologic manifestations as well as higher expression of complement protein on circulating plasma EVs. EVs may indicate blood-brain barrier damage during SARS-COV-2 infection.
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| 23. |
- Thelin, Eric Peter, et al.
(author)
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Protein profiling in serum after traumatic brain injury in rats reveals potential injury markers
- 2018
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In: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 340, s. 71-80
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Journal article (peer-reviewed)abstract
- Introduction: The serum proteome following traumatic brain injury (TBI) could provide information for outcome prediction and injury monitoring. The aim with this affinity proteomic study was to identify serum proteins over time and between normoxic and hypoxic conditions in focal TBI. Material and methods: Sprague Dawley rats (n = 73) received a 3 mm deep controlled cortical impact ("severe injury"). Following injury, the rats inhaled either a normoxic (22% O-2) or hypoxic (11% O-2) air mixture for 30 min before resuscitation. The rats were sacrificed at day 1, 3, 7, 14 and 28 after trauma. A total of 204 antibodies targeting 143 unique proteins of interest in TBI research, were selected. The sample proteome was analyzed in a suspension bead array set-up. Comparative statistics and factor analysis were used to detect differences as well as variance in the data. Results: We found that complement factor 9 (C9), complement factor B (CFB) and aldolase c (ALDOC) were detected at higher levels the first days after trauma. In contrast, hypoxia inducing factor (HIF)1 alpha, amyloid precursor protein (APP) and WBSCR17 increased over the subsequent weeks. S100A9 levels were higher in hypoxic-compared to normoxic rats, together with a majority of the analyzed proteins, albeit few reached statistical significance. The principal component analysis revealed a variance in the data, highlighting clusters of proteins. Conclusions: Protein profiling of serum following TBI using an antibody based microarray revealed temporal changes of several proteins over an extended period of up to four weeks. Further studies are warranted to confirm our findings.
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| 24. |
- Thelin, Eric Peter, et al.
(author)
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S100B Is an Important Outcome Predictor in Traumatic Brain Injury
- 2013
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 30:7, s. 519-528
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Journal article (peer-reviewed)abstract
- The objective of the study was to examine how S100B, a biomarker of traumatic brain injury (TBI), contributes to outcome prediction after adjusting for known parameters, including age, Glasgow Coma Scale (GCS), pupil reaction, and computed tomography (CT) variables; to examine which parameters have the best correlation to elevated serum levels of S100B; and to investigate when to sample S100B to achieve the strongest association to outcome. This retrospective study included 265 patients with TBI admitted to the neurointensive care unit, Karolinska University Hospital Solna, Stockholm, Sweden. Univariate and multivariate proportional odds regressions were performed to determine parameters most closely related to outcome, and how S100B adds to prediction accuracy. Age (p < 0.0001), pupil reaction (p < 0.0001), and levels of S100B (p < 0.0001) had the strongest statistical correlation to outcome. The area under curve of S100B, the first 48 h after trauma, yielded an additional explained variance of 6.6% in excess of known outcome parameters, including age, GCS, pupil reaction, and CT variables, themselves exhibiting an explained variance of 29.3%. S100B adds substantial information regarding patient outcome, in excess of that provided by known parameters. Only CT variables were found to be significant predictors of increased levels of S100B in uni- and multivariate analysis. Early samples of S100B, within 12 h after trauma, appear to have little prognostic value, and S100B should likely be sampled 12-36 h following trauma to best enhance TBI outcome prediction.
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| 25. |
- Thelin, Eric Peter, et al.
(author)
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Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics : A systematic review
- 2017
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In: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 8
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Research review (peer-reviewed)abstract
- Background: The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" (t1/2) in order to describe the "fall" rate in serum.Materials and methods: Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations.Results: Following screening (10,389 papers), n = 122 papers were included. The proteins S100B (n = 66) and NSE (n = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1-2 h) though possibly of non-cerebral origin. In contrast, the t1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18) appears to have t1/2 of about 24-48 h in severe TBI. The protein UCH-L1 (n = 9) presents a t1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use.Conclusion: Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI.
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| 26. |
- Thelin, Eric, et al.
(author)
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THE SENSITIVITY AND ROLE OF PROTEIN S100B IN DETECTING SECONDARY INJURIES AFTER TRAUMATIC BRAIN INJURY IN HUMANS
- 2011
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 28:6, s. a55-A55
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Journal article (peer-reviewed)abstract
- BACKGROUND: Patients suffering from traumatic brain injury (TBI) are often treated in specialized neuro-intensive care units (NICU) using multi-modal monitoring to detect harmful secondary insults such as increased intra cranial pressure. In addition to different monitoring devices. serum biomarkers have been shown to provide additional important information regarding the patient. Elevated serum levels of S100B have been detected following TBI. cerebral ischemia. spontaneous intra-cerebral hematomas and edema formation. S100B is known to correlate to outcome. Severe secondary cerebral injuries have been shown to correlate to secondary peaks in serum levels of S100B. Increases of more than 0.1mug/L are considered pathological. METHOD: 267 patients treated in the NICU for TBI with S100B samples obtained every 12 hours during a minimum of a 96-hour time period were included. Secondary increases of S100B after 48 hours following trauma were noted. All patients had at least 2 CT-scans and/or MRI scans performed. RESULTS: 67 secondary injuries during the NICU stay were detected using MRI or CT-scans. The most common lesions were diffuse is- chemic injuries (29). edema (13). cerebral infarctions (11) and intracerebral hematoma (5). Looking at secondary peaks of S100B in detecting radiological verifiable cerebral lesions during the NICU stay. a cut-off level of more than 0.5mug/L the specificity was 100% and sensitivity 8.9%. Decreasing the cut-off level to 0.1mug/L a specificity of 95.9% and sensitivity of 64.2% was obtained. while a cut-off level of 0.05mug/L presented a specificity of 92.7% and sensitivity of 92.5%. CONCLUSIONS: S100B is a sensitive marker for secondary cerebral injuries occurring in the NICU after TBI. A low cut-off point for the secondary peak of S100B (0.05 mug/L) increases sensitivity without any major deficit of specificity in detecting secondary injuries during the NICU stay.
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| 27. |
- Thelin, Eric, et al.
(author)
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The temporal profiles in serum concentrations of the biomarker S100B in the first 48 hours after traumatic brain injury correspond to outcome
- 2011
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 28:5, s. A20-A20
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Journal article (peer-reviewed)abstract
- Background: Traumatic brain injury (TBI) is one of the leading causes of death and disability. An early and accurate assessment of the affected patient suffering from TBI is important to promptly decide upon treatment strategies. Serum levels of the protein S100B are elevated in patients suffering from TBI, and has been proposed as a good addition to other clinical variables when calculating outcome. Different temporal patterns of the serum levels of S100B have been shown. The aim of this study was to analyze the different patterns, with a focus on outcome and other factors related to co-morbidity in patients suffering from TBI.Methods: In all, 265 patients suffering from TBI admitted to the neuro-intensive care unit, having three consecutive serum samples of S100B within the first 72 h after trauma were included.Results: S100B AUC, S100 peak serum level, and increasing serum levels of S100B significantly presence of traumatic subarachnoid hemorrhage, early cerebral ischemia and signs of increasing intracranial hematomas are statistically significant (p<0.05) to high and increasing levels of S100B. Using a multi-nomial logit regression analysis, increased age (p<0.01), early cerebral ischemia (p<0.05), and increased S100B AUC statistically significantly affected mortality (p<0.01).Conclusion: The temporal profile of S100B is unique for every patient after TBI, and statistically correlates with S100B AUC, one of the factors that correlates strongly with mortality and morbidity, and thereby may promptly provide the physician with an important tool in clinical decision-making.
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| 28. |
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| 29. |
- Vlachogiannis, Pavlos
(author)
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Studies on inflammation in the acute phase of aneurysmal Subarachnoid Hemorrhage
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Spontaneous subarachnoid hemorrhage (SAH) accounts for 5% of all strokes and is associated with high morbidity and mortality. Rupture of intracranial aneurysm is the cause in 85% of cases. After aneurysm repair to prevent rebleeding, patients are treated at Neuro-Intensive Care Units for multimodal monitoring and interventions aiming to treat the primary injury and prevent/treat secondary complications. The acute phase after SAH can roughly be divided in the periods of Early Brain Injury (EBI) and Delayed Cerebral Ischemia (DCI). EBI refers to the events occurring within the first 72h from SAH and includes the primary injury and its direct consequences. DCI occurs in 30-40% of SAH patients between days 4-14 after SAH and leads usually to neurologic deterioration. The term Delayed Ischemic Neurologic Deficit (DIND) is used almost synonymously. Cerebral vasospasm was earlier considered to be the main (if not the sole) contributor to DCI. It is now widely accepted that DCI is a multifactorial phenomenon where inflammation plays a pivotal role. Numerous molecular, cellular, and genetic aspects of inflammation have been analyzed in both clinical and preclinical experimental studies in different compartments, such as plasma, cerebrospinal fluid (CSF) and cerebral extracellular fluid (through microdialysis).The aim of the studies included in this thesis was to analyze different molecular and clinical aspects of the inflammatory response in the acute phase of SAH and provide new insights in understanding the complex pathophysiology of SAH. In Paper I, a pilot study of intrathecal and systemic inflammation was conducted by measuring levels of Interlukin-6 in CSF and plasma of 44 patients. In Paper II, a comprehensive inflammatory profile of SAH was illustrated by simultaneously measuring 92 inflammation-related proteins in CSF of 29 patients using multiplex Proximity Extension Assay technology for the first time in SAH research. Twenty chemokines included in the same panel as in Paper II were further analyzed regarding their associations with clinical parameters and outcome in Paper III. Finally, in Paper IV two common inflammatory markers, C-reactive protein (CRP) and leukocytes, were analyzed in blood of 552 patients regarding their temporal trajectories and correlations with factors reflecting EBI and SAH complications. In general, the results support the notion that more severe bleeding is associated with stronger cerebral and systemic inflammatory response. Some molecules have also emerged as potential predictors of complications and outcome.
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