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Cortisol levels are influenced by sedation in the acute phase after subarachnoid haemorrhage
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
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2013 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 57, no 4, 452-460 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Subarachnoid haemorrhage (SAH) is a life-threatening condition that may be aggravated by acute pituitary damage and cortisol insufficiency. Robust diagnostic criteria for critical illness-related corticosteroid insufficiency (CIRCI) are lacking. The aim of this study was to assess the frequency of CIRCI in the acute phase (0-240 h) after SAH and to evaluate associations between cortisol levels and clinical parameters (sedation, circulatory failure, gender, age, severity of disease, treatment). CIRCI was defined as a single morning serum cortisol (mSC) < 200 nmol/L. The lower limit for calculated free cortisol (cFC) was set at < 22 nmol/L, and for saliva cortisol at < 7.7 nmol/L.

METHODS: Fifty patients were included. Serum/saliva cortisol and corticosteroid-binding globulin were obtained every second morning. A logistic regression model was used for multivariate analysis comparing cortisol levels with clinical parameters.

RESULTS: Of the patients, 21/50 (42%) had an mSC < 200 nmol/L and 30/50 (60%) had a cFC < 22 nmol/L. In patients with continuous intravenous sedation, the odds ratio for a mSC to be < 200 nmol/L was 18 times higher (95% confidence interval 4.2-85.0, P < 0.001), and the odds ratio for a cFC to be < 22 nmol/L was 2.4 times higher (95% confidence interval 1.2-4.7, P < 0.05) compared with patients with no continuous intravenous sedation.

CONCLUSIONS: Continuous intravenous sedation was significantly associated with cortisol values under defined limits (mSC < 200, cFC < 22 nmol/L). The possibility that sedating drugs per se may influence cortisol levels should be taken into consideration before CIRCI is diagnosed.

Place, publisher, year, edition, pages
2013. Vol. 57, no 4, 452-460 p.
National Category
Anesthesiology and Intensive Care
URN: urn:nbn:se:umu:diva-64100DOI: 10.1111/aas.12014OAI: diva2:588180
Available from: 2013-01-15 Created: 2013-01-15 Last updated: 2015-01-21Bibliographically approved
In thesis
1. Subarachnoid haemorrhage: clinical and epidemiological studies
Open this publication in new window or tab >>Subarachnoid haemorrhage: clinical and epidemiological studies
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Subarachnoid haemorrhage (SAH) is a severe stroke that in 85% of all cases is caused by the rupture of a cerebral aneurysm. The median age at onset is 50-55 years and the overall mortality is approximately 45%.Sufficient cortisol levels are important for survival. After SAH hypothalamic/pituitary blood flow may be hampered this could result in inadequate secretion of cortisol. SAH is also associated with a substantial inflammatory response. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, mediates vasoconstriction and increased ADMA levels may be involved in inflammation and endothelial dysfunction. Continuous electroencephalogram (EEG) monitoring can be used to detect non-convulsive seizures, leading to ischemic insults in sedated SAH patients. Elevated ADMA levels are risk factors for vascular diseases. Vascular disease has been linked to stress, inflammation and endothelial dysfunction. SAH possesses all those clinical features and theoretically SAH could thus induce vascular disease.

Aims: 1. Assess cortisol levels after SAH, and evaluate associations between cortisol and clinical parameters. 2. Assess ADMA levels and arginine/ADMA ratios after SAH and evaluate associations between ADMA levels and arginine/ADMA ratios with severity of disease, co-morbidities, sex, age and clinical parameters. 3. Investigate occurrence of subclinical seizures in sedated SAH patients. 4. Evaluate if patients that survive a SAH ≥ one year have an increased risk of vascular causes of death compared to a normal population.

Results: Continuous infusion of sedative drugs was the strongest predictor for a low (<200 nmol/L) serum cortisol. The odds ratio for a sedated patient to have a serum cortisol < 200 nmol/L was 18.0 times higher compared to an un-sedated patient (p < 0.001). Compared to admission values, 0-48 hours after SAH, CRP increased significantly already in the time-interval 49-72 hours (p<0.05), peaked in the time-interval 97-120 hours after SAH and thereafter decreased. ADMA started to increase in the time-interval 97-120 hours (p<0.05). ADMA and CRP levels were significantly higher, and arginine/ADMA ratios were significantly lower in patients with a more severe condition (p<0.05). Epileptic seizure activity, in sedated SAH patients, was recorded in 2/28 (7.1%) patients during 5/5468 (0.09%) hours of continuous EEG monitoring. Cerebrovascular disease was significantly more common as a cause of death in patients that had survived a SAH ≥ one year, compared to the population from the same area (p<0.0001).

Conclusions: Continuous infusion of sedative drugs was associated with low (<200 nmol/L) cortisol levels. ADMA increased significantly after SAH, after CRP had peaked, indicating that endothelial dysfunction, with ADMA as a marker, is induced by a systemic inflammation. Patients with a more severe condition had significantly higher ADMA and CRP levels, and significantly lower arginine/ADMA ratio. Continuous sedation in sedated SAH patients seems to be beneficial in protecting from subclinical seizures. Cerebrovascular causes of death are more common in SAH survivors.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 74 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1623
Subarachnoid haemorrhage, ADMA, Cortisol, EEG, inflammation, epidemiology, endothelium, arginine
National Category
Anesthesiology and Intensive Care Neurosciences
Research subject
Anaesthesiology; Neurosurgery; Epidemiology
urn:nbn:se:umu:diva-87553 (URN)978-91-7459-791-2 (ISBN)
Public defence
2014-04-25, Sal D, T9, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)

Funding: The Swedish Society of Medicine, the Faculty of Medicine at Umeå University, The Kempe Foundations and The Stroke Foundation of Northern Sweden supported this study financially.

Available from: 2014-04-03 Created: 2014-04-02 Last updated: 2014-04-03Bibliographically approved

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Lindgren, CeciliaDahlqvist, PerLindvall, PeterNilsson, LeifKoskinen, Lars-OweNaredi, Silvana
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