Neurocritical Care

, Volume 21, Issue 1, pp 91–101 | Cite as

ADMA Levels and Arginine/ADMA Ratios Reflect Severity of Disease and Extent of Inflammation After Subarachnoid Hemorrhage

  • Cecilia Lindgren
  • Magnus Hultin
  • Lars-Owe D. Koskinen
  • Peter Lindvall
  • Ljubisa Borota
  • Silvana Naredi
Original Article

Abstract

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.

Keywords

Subarachnoid hemorrhage ADMA Arginine Inflammation Interleukin-1beta Interleukin-6 Interleukin-8 Interleukin-10 Tumor necrosis factor-alpha 

Notes

Acknowledgments

We would like to thank the staff at our high dependency and intensive care units. Without their dedicated work, this study could not have been performed. We also extend a special thanks to our research nurses for their invaluable help and support. The Swedish Society of Medicine, the Faculty of Medicine at Umeå University, and The Stroke Foundation of Northern Sweden supported this study.

Conflict of interest

Cecilia Lindgren, Magnus Hultin, Lars-Owe Koskinen, Peter Lindvall, Ljubisa Borota, and Silvana Naredi declare that they have no conflict of interests.

References

  1. 1.
    van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369:306–18.PubMedCrossRefGoogle Scholar
  2. 2.
    Rinkel GJ, Algra A. Long-term outcomes of patients with aneurysmal subarachnoid haemorrhage. Lancet Neurol. 2011;10:349–56.PubMedCrossRefGoogle Scholar
  3. 3.
    Macmillan CS, Grant IS, Andrews PJ. Pulmonary and cardiac sequelae of subarachnoid haemorrhage: time for active management? Intensive Care Med. 2002;28:1012–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Muroi C, Hugelshofer M, Seule M, et al. Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2013;72:367–75 discussion 75.PubMedCrossRefGoogle Scholar
  5. 5.
    Vespa PM, Bleck TP. Neurogenic pulmonary edema and other mechanisms of impaired oxygenation after aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2004;1:157–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Boger RH. Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond. Ann Med. 2006;38:126–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Rodling-Wahlstrom M, Olivecrona M, Koskinen LO, Naredi S, Hultin M. Subarachnoid haemorrhage induces an inflammatory response followed by a delayed persisting increase in asymmetric dimethylarginine. Scand J Clin Lab Invest. 2012;72:484–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Palmer R, Ashton D, Moncada S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature. 1988;333:664–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Pluta RM, Oldfield EH. Analysis of nitric oxide (NO) in cerebral vasospasm after aneurysmal bleeding. Rev Recent Clin Trials. 2007;2:59–67.PubMedCrossRefGoogle Scholar
  10. 10.
    Nanayakkara PW, Teerlink T, Stehouwer CD, et al. Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima-media thickness and plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration in patients with mild-to-moderate renal failure. Kidney Int. 2005;68:2230–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Siroen MP, Teerlink T, Nijveldt RJ, Prins HA, Richir MC, van Leeuwen PA. The clinical significance of asymmetric dimethylarginine. Annu Rev Nutr. 2006;26:203–28.PubMedCrossRefGoogle Scholar
  12. 12.
    Visser M, Vermeulen MA, Richir MC, et al. Imbalance of arginine and asymmetric dimethylarginine is associated with markers of circulatory failure, organ failure and mortality in shock patients. Br J Nutr. 2012;107:1458–65 Epub 2011 Dec 1.PubMedCrossRefGoogle Scholar
  13. 13.
    Diringer MN, Bleck TP, Claude Hemphill J 3rd, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit care. 2011;15:211–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Bederson JB, Connolly ES Jr, Batjer HH, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009;40:994–1025.PubMedCrossRefGoogle Scholar
  15. 15.
    Vergouwen MD, Vermeulen M, van Gijn J, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010;41:2391–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Carrera E, Schmidt JM, Oddo M, et al. Transcranial Doppler for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Neurosurgery. 2009;65:316–23 discussion 23–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Wagner M, Steinbeis P, Guresir E, et al. Beyond delayed cerebral vasospasm: infarct patterns in patients with subarachnoid hemorrhage. Clin Neuroradiol. 2013;23:87–95.PubMedCrossRefGoogle Scholar
  18. 18.
    Mills JN, Mehta V, Russin J, Amar AP, Rajamohan A, Mack WJ. Advanced imaging modalities in the detection of cerebral vasospasm. Neurol Res Int. 2013;2013:415960.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2:81–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg. 1968;28:14–20.PubMedCrossRefGoogle Scholar
  21. 21.
    Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery. 1980;6:1–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Vincent JL, Moreno R, Takala J, et al. The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Stegmayr B, Lundberg V, Asplund K. The events registration and survey procedures in the Northern Sweden MONICA Project. Scand J Public Health Suppl. 2003;61:9–17.PubMedCrossRefGoogle Scholar
  25. 25.
    World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2000;284:3043–5.CrossRefGoogle Scholar
  26. 26.
    Sibal L, Agarwal SC, Home PD, Boger RH. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Current Cardiol Rev. 2010;6:82–90.CrossRefGoogle Scholar
  27. 27.
    Chen S, Li N, Deb-Chatterji M, et al. Asymmetric dimethyarginine as marker and mediator in ischemic stroke. Int J Mol Sci. 2012;13:15983–6004.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Boger RH. Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials. Vasc Med. 2005;10:19–25.CrossRefGoogle Scholar
  29. 29.
    Juvela S, Kuhmonen J, Siironen J. C-reactive protein as predictor for poor outcome after aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien). 2012;154:397–404.CrossRefGoogle Scholar
  30. 30.
    Mellergard P, Aneman O, Sjogren F, Saberg C, Hillman J. Differences in cerebral extracellular response of interleukin-1beta, interleukin-6, and interleukin-10 after subarachnoid hemorrhage or severe head trauma in humans. Neurosurgery. 2011;68:12–9 discussion 9.PubMedCrossRefGoogle Scholar
  31. 31.
    Sarrafzadeh A, Schlenk F, Gericke C, Vajkoczy P. Relevance of cerebral interleukin-6 after aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2010;13:339–46.PubMedCrossRefGoogle Scholar
  32. 32.
    Kielstein J, Donnerstag F, Gasper S, et al. ADMA increases arterial stiffness and decreases cerebral blood flow in humans. Stroke. 2006;37:2024–9 Epub 06 Jun 29.PubMedCrossRefGoogle Scholar
  33. 33.
    Boger R. Association of asymmetric dimethylarginine and endothelial dysfunction. Clin Chem Lab Med. 2003;41:1467–72.PubMedCrossRefGoogle Scholar
  34. 34.
    McMahon CJ, Hopkins S, Vail A, et al. Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J Neurointerv Surg. 2013;5(6):512–7.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Boger RH, Maas R, Schulze F, Schwedhelm E. Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality: an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res. 2009;60:481–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Achan V, Broadhead M, Malaki M, et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol. 2003;23:1455–9.PubMedCrossRefGoogle Scholar
  37. 37.
    van der Bilt IA, Hasan D, Vandertop WP, et al. Impact of cardiac complications on outcome after aneurysmal subarachnoid hemorrhage: a meta-analysis. Neurology. 2009;72:635–42.PubMedCrossRefGoogle Scholar
  38. 38.
    Naredi S, Lambert G, Eden E, et al. Increased sympathetic nervous activity in patients with nontraumatic subarachnoid hemorrhage. Stroke. 2000;31:901–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Banki NM, Kopelnik A, Dae MW, et al. Acute neurocardiogenic injury after subarachnoid hemorrhage. Circulation. 2005;112:3314–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Nijveldt RJ, Teerlink T, Van Der Hoven B, et al. Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr. 2003;22:23–30.PubMedCrossRefGoogle Scholar
  41. 41.
    Jung CS, Lange B, Zimmermann M, Seifert V. The CSF concentration of ADMA, but not of ET-1, is correlated with the occurrence and severity of cerebral vasospasm after subarachnoid hemorrhage. Neurosci Lett. 2012;524:20–4.PubMedCrossRefGoogle Scholar
  42. 42.
    Pikula A, Boger RH, Beiser AS, et al. Association of plasma ADMA levels with MRI markers of vascular brain injury: Framingham offspring study. Stroke. 2009;40:2959–64.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Worthmann H, Chen S, Martens-Lobenhoffer J, et al. High plasma dimethylarginine levels are associated with adverse clinical outcome after stroke. J Atheroscler Thromb. 2011;18:753–61.PubMedCrossRefGoogle Scholar
  44. 44.
    Staalso JM, Bergstrom A, Edsen T, Weikop P, Romner B, Olsen NV. Low plasma arginine: asymmetric dimethyl arginine ratios predict mortality after intracranial aneurysm rupture. Stroke. 2013;44:1273–81.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Cecilia Lindgren
    • 1
  • Magnus Hultin
    • 1
  • Lars-Owe D. Koskinen
    • 2
  • Peter Lindvall
    • 2
  • Ljubisa Borota
    • 3
  • Silvana Naredi
    • 1
  1. 1.Department of Surgical and Perioperative Sciences, Anesthesiology and Intensive CareUmeå UniversityUmeåSweden
  2. 2.Department of Pharmacology and Clinical Neuroscience, NeurosurgeryUmeå UniversityUmeåSweden
  3. 3.Department of Radiology, Oncology and Radiation ScienceUppsala UniversityUppsalaSweden

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