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ADMA levels and arginine/ADMA ratios reflect severity of disease and extent of inflammation after subarachnoid hemorraghe
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
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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. Vol. 21, no 1, 91-101 p.
Keyword [en]
ADMA, subarachnoid hemorrage, inflammation, interleukin
National Category
Anesthesiology and Intensive Care Neurosciences Neurology
Research subject
Anaesthesiology
Identifiers
URN: urn:nbn:se:umu:diva-87531DOI: 10.1007/s12028-013-9945-8ISI: 000339350500014PubMedID: 24408146OAI: oai:DiVA.org:umu-87531DiVA: diva2:709672
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2017-05-10Bibliographically 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1623
Keyword
Subarachnoid haemorrhage, ADMA, Cortisol, EEG, inflammation, epidemiology, endothelium, arginine
National Category
Anesthesiology and Intensive Care Neurosciences
Research subject
Anaesthesiology; Neurosurgery; Epidemiology
Identifiers
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)
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

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