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Subarachnoid haemorrhage: clinical and epidemiological studies
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1623
Keyword [en]
Subarachnoid haemorrhage, ADMA, Cortisol, EEG, inflammation, epidemiology, endothelium, arginine
National Category
Anesthesiology and Intensive Care Neurosciences
Research subject
Anaesthesiology; Neurosurgery; Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-87553ISBN: 978-91-7459-791-2 (print)OAI: oai:DiVA.org:umu-87553DiVA: diva2:709718
Public defence
2014-04-25, Sal D, T9, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Note

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
List of papers
1. Cortisol levels are influenced by sedation in the acute phase after subarachnoid haemorrhage
Open this publication in new window or tab >>Cortisol levels are influenced by sedation in the acute phase after subarachnoid haemorrhage
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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.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-64100 (URN)10.1111/aas.12014 (DOI)
Available from: 2013-01-15 Created: 2013-01-15 Last updated: 2017-12-06Bibliographically approved
2. ADMA levels and arginine/ADMA ratios reflect severity of disease and extent of inflammation after subarachnoid hemorraghe
Open this publication in new window or tab >>ADMA levels and arginine/ADMA ratios reflect severity of disease and extent of inflammation after subarachnoid hemorraghe
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2014 (English)In: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 21, no 1, 91-101 p.Article in journal (Refereed) Published
Abstract [en]

Background: Subarachnoid hemorrhage (SAH) is characterized by an inflammatory response that might induce endothelial dysfunction. The aim of this study was to evaluate if ADMA and arginine/ADMA ratios after SAH (indicators of endothelial dysfunction) are related to clinical parameters, inflammatory response, and outcome.

Methods: Prospective observational study. ADMA, arginine, C-reactive protein (CRP), and cytokines were obtained 0–240 h (h) after SAH. Definition of severe clinical condition was Hunt&Hess (H&H) 3–5 and less severe clinical condition H&H 1–2. Impaired cerebral circulation was assessed by clinical examination, transcranial doppler, CT-scan, and angiography. Glasgow outcome scale (GOS) evaluated the outcome.

Results: Compared to admission, 0–48 h after SAH, the following was observed 49–240 h after SAH; (a) ADMA was significantly increased at 97–240 h (highest 217–240 h), (b) CRP was significantly increased at 49–240 h (highest 73–96 h), (c) interleukin-6 (IL-6) was significantly lower at 97–240 h (highest 49–96 h), p < 0.05. ADMA, CRP, and IL-6 were significantly lower and peak arginine/ADMA ratio was significantly higher in patients with H&H 1–2 compared to patients with H&H 3–5, p < 0.05. The peak ADMA or the nadir arginine/ADMA ratio did not differ significantly between patients with (55 %) or without (45 %) signs of impaired cerebral circulation. The peak ADMA or the nadir arginine/ADMA ratio did not differ significantly between patients with GOS 1–3 and patients with GOS 4–5.

Conclusions: ADMA increased significantly after SAH, and the increase in ADMA started after the pro-inflammatory markers (CRP and IL-6) had peaked. This might indicate that endothelial dysfunction, with ADMA as a marker, is induced by a systemic inflammation.

Place, publisher, year, edition, pages
Humana Press, 2014
Keyword
ADMA, subarachnoid hemorrage, inflammation, interleukin
National Category
Anesthesiology and Intensive Care Neurosciences Neurology
Research subject
Anaesthesiology
Identifiers
urn:nbn:se:umu:diva-87531 (URN)10.1007/s12028-013-9945-8 (DOI)000339350500014 ()24408146 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2017-05-10Bibliographically approved
3. Frequency of non-convulsive Seizures and non-convulsive status Epilepticus in Subarachnoid Hemorrhage patients in need of controlled ventilation and sedation
Open this publication in new window or tab >>Frequency of non-convulsive Seizures and non-convulsive status Epilepticus in Subarachnoid Hemorrhage patients in need of controlled ventilation and sedation
2012 (English)In: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 17, no 3, 367-373 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Non-convulsive seizures (NCSZ) can be more prevalent than previously recognized among comatose neuro-intensive care patients. The aim of this study was to evaluate the frequency of NCSZ and non-convulsive status epilepticus (NCSE) in sedated and ventilated subarachnoid hemorrhage (SAH) patients.

METHODS: Retrospective study at a university hospital neuro-intensive care unit, from January 2008 until June 2010. Patients were treated according to a local protocol, and were initially sedated with midazolam or propofol or combinations of these sedative agents. Thiopental was added for treatment of intracranial hypertension. No wake-up tests were performed. Using NicoletOne((R)) equipment (VIASYS Healthcare Inc., USA), continuous EEG recordings based on four electrodes and a reference electrode was inspected at full length both in a two electrode bipolar and a four-channel referential montage.

RESULTS: Approximately 5,500 h of continuous EEG were registered in 28 SAH patients (33 % of the patients eligible for inclusion). The median Glasgow Coma scale was 8 (range 3-14) and the median Hunt and Hess score was 4 (range 1-4). During EEG registration, no clinical seizures were observed. In none of the patients inter ictal epileptiform activity was seen. EEG seizures were recorded only in 2/28 (7 %) patients. One of the patients experienced 4 min of an NCSZ and one had a 5 h episode of an NCSE.

CONCLUSION: Continuous EEG monitoring is important in detecting NCSZ in sedated patients. Continuous sedation, without wake-up tests, was associated with a low frequency of subclinical seizures in SAH patients in need of controlled ventilation.

Place, publisher, year, edition, pages
Totowa, NJ, USA: Humana Press, 2012
Keyword
Epilepsy, Seizures, Non-convulsive seizures, Continuous electroencephalogram, Subarachnoid hemorrhage
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-59419 (URN)10.1007/s12028-012-9771-4 (DOI)1556-0961 (Electronic) 1541-6933 (Linking) (ISBN)
Available from: 2012-09-13 Created: 2012-09-13 Last updated: 2017-12-07Bibliographically approved
4. Long term survivors of subarachnoid haemorrhage have an increased risk of death due to cerebrovascular causes
Open this publication in new window or tab >>Long term survivors of subarachnoid haemorrhage have an increased risk of death due to cerebrovascular causes
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(English)Manuscript (preprint) (Other academic)
Keyword
epidemiology, subarachnoid haemorrhage, cerebrovascular disease, cardiovascular disease
National Category
Anesthesiology and Intensive Care
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-87551 (URN)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2014-04-14Bibliographically approved

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