Hormones, biomarkers, genetics and prognostication of patients suffering severe traumatic brain injury

Severe traumatic brain injury (sTBI) is a significant cause of mortality and mobidity worldwide. In Umeå University Hospital, at the department of Neurosurgery, patients with sTBI are treated by the Lund concept, which can be characterized as an intracranial pressure (ICP) targeted therapy. In recent decades, there has been an increasing interest in trying to understand why some patients recover better and survive after sTBI, and why some do not. Also, improving the instruments of prognostication is becoming increasingly important both for relocating health resources and for the benefit of patients and relatives. The main goal of the work described in this thesis was to explore factors influencing clinical outcome and improve the prognostication of outcome after sTBI. The ultimate goal is to improve the clinical outcome in patients suffering sTBI. It has been proposed that the outcome after sTBI is influenced by genetic variability, including variability in apolipoprotein E (APOE). We therefore examined the relationship between the presence of APOE ε4 allele and the outcome. Except for 1 dichotomization of Glasgow outcome scale (GOS) at 3 months, the presence of the allele did not influence the outcome. The biochemical markers of brain injury, S-100B and NSE, can be used to quantify the tissue lesion in sTBI. We investigated whether the levels of the biomarkers were associated with the APOE ε4 allele. Patients expressing the APOEε4 allele had significantly higher levels of S-100B than non-ε4 subjects. The temporal course of S-100B differed between the APOE groups. Similar, but not statistically significant results were observed for NSE. The results suggest that variations in genetics have to be considered when interpreting the biochemical markers. We also found that serum levels of S-100B and NSE were correlated with ICPmax, CPPmin and radiological findings on brain CT quanttified by CT scoring systems and that S-100B and NSE (max and bulk release) may predict mortality. The pituitary gland is vulnerable for traumatic events. This may be reflected in acute hormonal deviations, which can influence the clinical outcome. We found dynamic changes in hormone levels after sTBI. A large number of the patients had low cortisol levels, which were not however associated with an unfavourable outcome. We also found that a preserved capacity to a mutable hormonal response, i.e. fast and strong repression of the pituitary-gonadal axis and a capacity to re-establish activity in the pituitary-thyroid axis, was associated with less severe injury according to CT-findings and to a more favourable outcome after sTBI. It is concluded that the presence of the APOEε4 allele did not indicate worse long-term outcome in our patient group. Patients expressing the APOEε4 allele, had significantly higher levels of S-100B than non-ε4 subjects, indicating that in some cases the genetics have to be considered when interpreting the biochemical markers. The biomarkers were also correlated to intracranial pressure and radiological findings, and may predict for mortality at 3 months. Profound hormonal changes in the acute phase occur. However, low levels of cortisol are not associated with a worse clinical outcome.        

Acute neuro-endocrine profile and prediction of outcome after severe brain injury

Object: The aim of the study was to evaluate the early changes in pituitary hormone levels after severe traumatic brain injury (sTBI) and compare hormone levels to basic neuro-intensive care data, a systematic scoring of the CT-findings and to evaluate whether hormone changes are related to outcome. Methods: Prospective study, including consecutive patients, 15-70 years, with sTBI, Glasgow Coma Scale (GCS) score <= 8, initial cerebral perfusion pressure > 10 mm Hg, and arrival to our level one trauma university hospital within 24 hours after head trauma (n = 48). Serum samples were collected in the morning (08-10 am) day 1 and day 4 after sTBI for analysis of cortisol, growth hormone (GH), prolactin, insulin-like growth factor 1 (IGF-1), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), follicular stimulating hormone (FSH), luteinizing hormone (LH), testosterone and sex hormone-binding globulin (SHBG) (men). Serum for cortisol and GH was also obtained in the evening (17-19 pm) at day 1 and day 4. The first CT of the brain was classified according to Marshall. Independent staff evaluated outcome at 3 months using GOS-E. Results: Profound changes were found for most pituitary-dependent hormones in the acute phase after sTBI, i.e. low levels of thyroid hormones, strong suppression of the pituitary-gonadal axis and increased levels of prolactin. The main findings of this study were: 1) A large proportion (54% day 1 and 70% day 4) of the patients showed morning s-cortisol levels below the proposed cut-off levels for critical illness related corticosteroid insufficiency (CIRCI), i.e. < 276 nmol/L (= 10 ug/dL), 2) Low s-cortisol was not associated with higher mortality or worse outcome at 3 months, 3) There was a significant association between early (day 1) and strong suppression of the pituitary-gonadal axis and improved survival and favorable functional outcome 3 months after sTBI, 4) Significantly lower levels of fT3 and TSH at day 4 in patients with a poor outcome at 3 months. 5) A higher Marshall CT score was associated with higher day 1 LH/FSH-and lower day 4 TSH levels 6) In general no significant correlation between GCS, ICP or CPP and hormone levels were detected. Only ICPmax and LH day 1 in men was significantly correlated. Conclusion: Profound dynamic changes in hormone levels are found in the acute phase of sTBI. This is consistent with previous findings in different groups of critically ill patients, most of which are likely to be attributed to physiological adaptation to acute illness. Low cortisol levels were a common finding, and not associated with unfavorable outcome. A retained ability to a dynamic hormonal response, i.e. fast and strong suppression of the pituitary-gonadal axis (day 1) and ability to restore activity in the pituitary-thyroid axis (day 4) was associated with less severe injury according to CT-findings and favorable outcome

Management of paediatric traumatic brain injury in Sweden : a national cross-sectional survey

Background: Previous studies have shown variations in management routines for children with traumatic brain injury (TBI) in Sweden. It is unknown if this management has changed after the publication of the Scandinavian Neurotrauma Committee guidelines in 2016 (SNC16). Also, knowledge of current practice routines may guide development of an efficient implementation strategy for the guidelines. The aim of this study is therefore to describe current management routines in paediatric TBI on a hospital/organizational level in Sweden. Secondary aims are to analyse differences in management over time, to assess the current dissemination status of the SNC16 guideline and to analyse possible variations between hospitals. Methods: This is a sequential, cross-sectional, structured survey in five sections, covering initial management routines for paediatric TBI in Sweden. Respondents, with profound knowledge of local management routines and recommendations, were identified for all Swedish hospitals with an emergency department managing children (age 0–17 year) via phone/mail before distribution of the survey. Responses were collected via an on-line survey system during June 2020–March 2021. Data are presented as descriptive statistics and comparisons were made using Fisher exact test, when applicable. Results: 71 of the 76 identified hospitals managed patients with TBI of all ages and 66 responded (response rate 93%). 56 of these managed children and were selected for further analysis. 76% (42/55) of hospitals have an established guideline to aid in clinical decision making. Children with TBI are predominately managed by inexperienced doctors (84%; 47/56), primarily from non-paediatric specialities (75%; 42/56). Most hospitals (75%; 42/56) have the possibility to admit and observe children with TBI of varying degrees and almost all centres have complete access to neuroradiology (96%; 54/56). In larger hospitals, it was more common for nurses to discharge patients without doctor assessment when compared to smaller hospitals (6/9 vs. 9/47; p < 0.001). Presence of established guidelines (14/51 vs. 42/55; p < 0.001) and written observation routines (16/51 vs. 29/42; p < 0.001) in hospitals have increased significantly since 2006. Conclusions: TBI management routines for children in Sweden still vary, with some differences occurring over time. Use of established guidelines, written observation routines and information for patients/guardians have all improved. These results form a baseline for current management and may also aid in guideline implementation

Best practice guidelines for blunt cerebrovascular injury (BCVI)

Blunt cerebrovascular injury (BCVI) is a non-penetrating injury to the carotid and/or vertebral artery that may cause stroke in trauma patients. Historically BCVI has been considered rare but more recent publications indicate an overall incidence of 1–2% in the in-hospital trauma population and as high as 9% in patients with severe head injury. The indications for screening, treatment and follow-up of these patients have been controversial for years with few clear recommendations. In an attempt to provide a clinically oriented guideline for the handling of BCVI patients a working committee was created. The current guideline is the end result of this committees work. It is based on a systematic literature search and critical review of all available publications in addition to a standardized consensus process. We recommend using the expanded Denver screening criteria and CT angiography (CTA) for the detection of BCVI. Early antithrombotic treatment should be commenced as soon as considered safe and continued for at least 3 months. A CTA at 7 days to confirm or discard the diagnosis as well as a final imaging control at 3 months should be performed

Best practice guidelines for blunt cerebrovascular injury (BCVI) :

Blunt cerebrovascular injury (BCVI) is a non-penetrating injury to the carotid and/or vertebral artery that may cause stroke in trauma patients. Historically BCVI has been considered rare but more recent publications indicate an overall incidence of 1–2% in the in-hospital trauma population and as high as 9% in patients with severe head injury. The indications for screening, treatment and follow-up of these patients have been controversial for years with few clear recommendations. In an attempt to provide a clinically oriented guideline for the handling of BCVI patients a working committee was created. The current guideline is the end result of this committees work. It is based on a systematic literature search and critical review of all available publications in addition to a standardized consensus process. We recommend using the expanded Denver screening criteria and CT angiography (CTA) for the detection of BCVI. Early antithrombotic treatment should be commenced as soon as considered safe and continued for at least 3 months. A CTA at 7 days to confirm or discard the diagnosis as well as a final imaging control at 3 months should be performed

Best practice guidelines for blunt cerebrovascular injury (BCVI)

Blunt cerebrovascular injury (BCVI) is a non-penetrating injury to the carotid and/or vertebral artery that may cause stroke in trauma patients. Historically BCVI has been considered rare but more recent publications indicate an overall incidence of 1–2% in the in-hospital trauma population and as high as 9% in patients with severe head injury. The indications for screening, treatment and follow-up of these patients have been controversial for years with few clear recommendations. In an attempt to provide a clinically oriented guideline for the handling of BCVI patients a working committee was created. The current guideline is the end result of this committees work. It is based on a systematic literature search and critical review of all available publications in addition to a standardized consensus process. We recommend using the expanded Denver screening criteria and CT angiography (CTA) for the detection of BCVI. Early antithrombotic treatment should be commenced as soon as considered safe and continued for at least 3 months. A CTA at 7 days to confirm or discard the diagnosis as well as a final imaging control at 3 months should be performed