umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Hormones, biomarkers, genetics and prognostication of patients suffering severe traumatic brain injury
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

 

 

 

 

 

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2014. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1624
National Category
Surgery
Research subject
Neurosurgery
Identifiers
URN: urn:nbn:se:umu:diva-85845ISBN: 978-91-7459-790-5 (print)OAI: oai:DiVA.org:umu-85845DiVA: diva2:695534
Public defence
2014-03-07, sal E04, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-02-14 Created: 2014-02-11 Last updated: 2014-02-14Bibliographically approved
List of papers
1. The apolipoprotein E epsilon4 allele and outcome in severe traumatic brain injury treated by an intracranial pressure-targeted therapy
Open this publication in new window or tab >>The apolipoprotein E epsilon4 allele and outcome in severe traumatic brain injury treated by an intracranial pressure-targeted therapy
2010 (English)In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 112, no 5, 1113-1119 p.Article in journal (Refereed) Published
Abstract [en]

The presence of epsilon4 is not associated with long-term clinical outcome in patients with severe TBI treated with an ICP targeted therapy, based on the Lund concept.

Keyword
apolipoprotein E; ε4 allele; severe traumatic brain injury; outcome; prediction
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-42318 (URN)10.3171/2009.8.JNS09636 (DOI)19747047 (PubMedID)
Available from: 2011-04-07 Created: 2011-04-07 Last updated: 2017-12-11Bibliographically approved
2. The release of S-100B and NSE in severe traumatic head injury is associated with APOE epsilon 4
Open this publication in new window or tab >>The release of S-100B and NSE in severe traumatic head injury is associated with APOE epsilon 4
2012 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 154, no 4, 675-680 p.Article in journal (Refereed) Published
Abstract [en]

In this article we tested the hypothesis that the level of two biochemical markers of brain injury may be associated with the apolipoprotein E (APOE) epsilon 4 allele. In this prospective consecutive study patients with sTBI were included (n = 48). Inclusion criteria were Glasgow Coma Scale (GCS) score a parts per thousand currency signaEuro parts per thousand 8 at the time of intubation and sedation, patient age between 15 and 70 years, an initial cerebral perfusion pressure > 10 mmHg, and arrival to our level-one trauma university hospital within 24 h after trauma. Blood samples for neuron-specific enolase (NSE) and S-100B were collected as soon as possibly after arrival, and then twice daily (12-h intervals) for 5 consecutive days. Venous blood was used for APOE genotype determination. Clinical outcome at 3 months after injury was assessed with the Extended Glasgow Outcome Scale (GOSE). Significantly higher levels of the maximal S-100B (S-100B(max)) and area under the curve (S-100B(AUC)) were found in subjects with the APOE epsilon 4 allele compared to those with non-epsilon 4. A similar tendency was observed for NSEmax and NSEAUC, though not statistically significant. Our data indicate that there might be a gene-induced susceptibility to severe traumatic brain injury and that patients with the APOE epsilon 4 allele may be more predisposed to brain cellular damage measured as S-100B and NSE. Thus, it seems to be of importance to consider the APOE genotype in interpreting the levels of the biomarkers.

Place, publisher, year, edition, pages
Wien: Springer, 2012
Keyword
Severe traumatic brain injury, APOE epsilon 4, S-100B, NSE
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-54120 (URN)10.1007/s00701-012-1292-6 (DOI)000301788900017 ()
Available from: 2012-04-23 Created: 2012-04-17 Last updated: 2017-12-07Bibliographically approved
3. The association of ICP, CPP, CT findings and the levels of S-100B and NSE in severe traumatic head injury. Prognostic value of the biomarkers.
Open this publication in new window or tab >>The association of ICP, CPP, CT findings and the levels of S-100B and NSE in severe traumatic head injury. Prognostic value of the biomarkers.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The first hypothesis was that biochemical markers of brain injury might be influenced by the intracranial pressure (ICP) and cerebral perfusion pressure (CPP) after severe traumatic brain injury (sTBI), in patients treated by an ICP targeted therapy. A second hypothesis was that there is a relationship between the biomarker levels and a systematic classification of the CT-scan of the brain. We also hypothesized that clinical outcome can be related to biomarker levels and that mortality may be predicted by the biomarkers. In this prospective consecutive study patients with sTBI were included. Inclusion criteria were Glasgow Coma Scale (GCS) score ≤ 8, age between 15 and 70 years, an initial cerebral perfusion pressure >10 mm Hg. Blood samples for neuron specific enolase (NSE) and S-100B were collected twice daily during five consecutive days. The initial (CTinit) and follow-up CT-scans (CT24h) were classified according to the Marshall, Rotterdam and Morris-Marshall classifications. Outcome was evaluated with extended Glasgow outcome scale (GOSE) at 3 months. There was a clear correlation of the maximal ICP (ICPmax) and minimal CPP (CPPmin) with the S-100B and NSE levels. A complex relation between biomarkers and the CT classifications were observed. Generally, the Marshall scores were correlated to the biomarker levels at 72 hrs and the Rotterdam scores correlated to the total (bulk) release. The Morris-Marshall scores correlated to all S-100B values, but not to any of the NSE values. A ROC curve analysis showed that the biomarkers had a moderate predictive value of mortality. S-100B bulk release and NSE at 72 hrs had the highest power in this prediction. A combination of the CT classification according to Morris-Marshall and the bulk release of S-100B further improved the prediction of clinical outcome.

National Category
Surgery
Research subject
Neurosurgery
Identifiers
urn:nbn:se:umu:diva-85843 (URN)
Available from: 2014-02-11 Created: 2014-02-11 Last updated: 2014-02-14Bibliographically approved
4. Acute neuro-endocrine profile and prediction of outcome after severe brain injury
Open this publication in new window or tab >>Acute neuro-endocrine profile and prediction of outcome after severe brain injury
2013 (English)In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 21, no 33Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
Severe traumatic brain injury, Hypopituitarism, Outcome, ICP targeted therapy, Hypothalamic-pituitary dysfunction, Prostacyclin
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-73085 (URN)10.1186/1757-7241-21-33 (DOI)000318597100002 ()
Available from: 2013-06-17 Created: 2013-06-17 Last updated: 2017-12-06Bibliographically approved

Open Access in DiVA

fulltext(1746 kB)699 downloads
File information
File name FULLTEXT02.pdfFile size 1746 kBChecksum SHA-512
8b9efc7587c26a86bd385b82f7c937e05bf4bed2be839e2ddd627d4a077f26f5b5ade0f23903ef32d8bf6402d9292e266bb7aee4d89c8d0e473998f4f20f18ee
Type fulltextMimetype application/pdf
omslag(75 kB)82 downloads
File information
File name COVER01.pdfFile size 75 kBChecksum SHA-512
911651145cc1f5de00dd64bfb61211bf4af083629b47f8d6e9d3ac5b3a27f445185cda39f9af8da40043535d0130a13c159f95b5a8decda7f6c51bb71b4c51b5
Type coverMimetype application/pdf

Search in DiVA

By author/editor
Olivecrona, Zandra
By organisation
Clinical Neuroscience
Surgery

Search outside of DiVA

GoogleGoogle Scholar
Total: 699 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 367 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf