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Subarachnoid haemorrhage induces a long-lasting increase of asymmetric dimethylarginine, ADMA, in serum
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Anesthesiology and Intensive Care.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Anesthesiology and Intensive Care.
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Background and Purpose: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), inhibiting nitric oxide (NO) production and thus induces vasoconstriction and endothelial dysfunction. ADMA might therefore be involved in the cerebral vasospasm and cardiovascular complications observed after subarachnoid haemorrhage (SAH). The aim of this study was to evaluate whether ADMA was increased in subjects during the acute phase (first week) and non-acute phase (three months later) after SAH.

Methods: Prospective clinical study of 20 subjects with SAH. ADMA in serum (ADMA/s) at admission was compared to sex and age matched controls. ADMA/s and ADMA in cerebrospinal fluid (ADMA/csf, from subjects with ventriculostomy) were determined by HPLC-based separation and detection.

Results: There was no significant difference in ADMA/s the day after SAH (day 2) between SAH subjects and controls (0.22±0.10 vs. 0.25±0.12 µmol/L). ADMA/s increased by 68% during the first week after SAH (day 2; 0.22±0.10 vs. day 7; 0.37±0.34 µmol/L, p<0.05) and remained elevated at a three-month follow-up (0.36±0.10 µmol/L). ADMA/csf was significantly lower than ADMA/s throughout the study period.

Conclusion; ADMA/s in SAH subjects increased significantly during the first week after SAH and remained elevated at a three-month follow-up. This might indicate that reduction of the available NO is involved in long-term effects after SAH.

Keyword [en]
asymmetric dimethylarginine
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
URN: urn:nbn:se:umu:diva-21057OAI: oai:DiVA.org:umu-21057DiVA: diva2:210553
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2010-02-10Bibliographically approved
In thesis
1. Severe cerebral emergency: aspects of treatment and outcome in the intensive care patient
Open this publication in new window or tab >>Severe cerebral emergency: aspects of treatment and outcome in the intensive care patient
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Severe Traumatic Brain Injury (TBI) and aneurysmal Subarachnoid Hemorrhage (SAH) are severe cerebral emergencies. They are common reasons for extensive morbidity and mortality in young people and adults in the western world. This thesis, based on five clinical studies in patients with severe TBI (I-IV) and SAH (V), is concentrated on examination of pathophysiological developments and of evaluation of therapeutic approaches in order to improve outcome after cerebral emergency.

The treatment for severe TBI patients at Umeå University Hospital, Sweden is an intracranial pressure (ICP)-targeted therapy according to “the Lund-concept”. This therapy is based on physiological principles for cerebral volume regulation, in order to preserve a normal cerebral microcirculation and a normal ICP. The main goal is to avoid development of secondary brain injuries, thus avoiding brain oedema and worsened microcirculation.

Study I is evaluating retrospectively 41 children with severe TBI, from 1993 to 2002. The boundaries of the ICP-targeted protocol were obtained in 90%. Survival rate was 93%, and favourable outcome (Glasgow Outcome Scale, score 4+5) was 80%.

Study II is retrospectively analysing fluid administration and fluid balance in 93 adult patients with severe TBI, from 1998 to 2001.The ICP-targeted therapy used, have defined fluid strategies. The total fluid balance was positive day one to three, and negative day four to ten. Colloids constituted 40-60% of total fluids given/day. Severe organ failure was evident for respiratory insufficiency and observed in 29%. Mortality within 28 days was 11%.

Study III is a prospective, randomised, double-blind, placebo-controlled clinical trial in 48 patients with severe TBI. In order to improve microcirculation and prevent oedema formation, prostacyclin treatment was added to the ICP-targeted therapy. Prostacyclin is endogenously produced, by the vascular endothelium, and has the ability to decrease capillary permeability and vasodilate cerebral capillaries. Prostacyclin is an inhibitor of leukocyte adhesion and platelet aggregation. There was no significant difference between prostacyclin or placebo groups in clinical outcome or in cerebral microdialysis markers such as lactatepyruvate ratio and brain glucose levels.

Study IV is part of the third trial and focus on the systemic release of pro-inflammatory mediators that are rapidly activated by trauma. The systemically released pro-inflammatory mediators, interleukin-6 and CRP were significantly decreased in the prostacyclin group versus the placebo group.

Study V is a prospective pilot study which analyses asymmetric dimethylarginine (ADMA) concentrations in serum from SAH patients. Acute SAH patients have cerebral vascular, systemic circulatory and inflammatory complications. ADMA is a marker in vascular diseases which is correlated to endothelial dysfunction. ADMA concentrations in serum were significantly elevated seven days after the SAH compared to admission and were still elevated at the three months follow-up.

Our results show overall low mortality and high favourable outcome compared to international reports on outcome in severe TBI patients. Prostacyclin administration does not improve cerebral metabolism or outcome but significantly decreases the levels of pro-inflammatory mediators. SAH seems to induce long-lasting elevations of ADMA in serum, which indicates persistent endothelial dysfunction. Endothelial dysfunction may influence outcome after severe cerebral emergencies.

Place, publisher, year, edition, pages
Umeå: , 2009. 83 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1244
Keyword
severe traumatic brain injury, intracranial pressure-targeted therapy, albumin, prostacyclin, endothelial dysfunction, pro-inflammatory cytokines, subarachnoid haemorrhage, asymmetric dimethylarginine
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
urn:nbn:se:umu:diva-21065 (URN)978-91-7264-725-1 (ISBN)
Distributor:
Anestesiologi och intensivvård, 901 87, Umeå
Public defence
2009-04-24, Sal B 9tr, Tandläkarhögskolan, Norrlands Universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-04-09 Created: 2009-04-02 Last updated: 2010-01-18Bibliographically approved

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