**11. Final remarks**

The vital roles of EPA and DHA in the human body emphasize the evolutionary importance of maintaining efficient functional couplings between chemical and biological systems as well as between the vasculature and the brain [87]. Resolution of inflammation and endogenous neuroprotective signaling are interrelated processes that largely depend on EPA and DHA derivatives. This novel concept may open new avenues for public health interventions and innovative research in IAs and SAH.

Although nutrition has been traditionally viewed as a supportive measure, increasing evidence strongly suggests that a more balanced dietary intake of omega-6 and omega-3 FAs may represent the most efficient means of improving the status of inflammation resolution at the population level [48, 82, 83]. This specific dietary recommendation could contribute to decrease the risk of IAs growth and rupture and the devastating consequences of SAH, along with other important health benefits.

The pathological significance of the loss of brain DHA after SAH has been widely ignored, even though strong preclinical evidence supports the hypothesis that the integrity of the neurovascular unit largely depends on high DHA enrichment. This previously unrecognized pathophysiological process may significantly increase the risk of secondary brain injury following SAH.

The robust demonstration of the clinical efficacy of EPA in patients with chronic CV disease supports the encouraging results obtained in preliminary clinical studies of omega-3 FAs in SAH and warrants a large-scale RCT. It needs to be emphasized that DHA should always be included in neuroprotective interventions, as DHA plays an essential role in neural tissue and is the cornerstone for docosanoid generation. Parenteral pharmaconutrition with FO offers major clinical advantages for the treatment of SAH patients and should also be an integral component of omega-3 FAs interventions during the acute stage of the disease.

The design of future RCTs of omega-3 FAs in SAH should bear in mind a potentially important factor. Clinical approaches that mainly focus on large-artery vasospasm may actually counteract the beneficial effects of omega-3 FAs and other neuroprotective interventions. The main rationale behind this seemingly paradoxical notion is based on both theoretical models and clinical perspectives [3, 31]. An unpublished subgroup analysis of our pilot pharmaconutrition trial of omega-3 FAs showed unexpected differences in the occurrence of cerebral infarction due to DCI between study centers, each of which had different clinical approaches to large-artery vasospasm [13]. In addition, a recently published observational study performed in the UK showed centers that screened for large-artery vasospasm using transcranial Doppler ultrasound (TCD) had poorer inhospital outcomes and similar rates of DCI diagnosis compared to centers that did not [88]. These results support the dissociation between large-artery vasospasm and clinical outcome that has been observed in major phase 3 RCTs in SAH [8]. Therefore, reliance on a surrogate clinical endpoint such as large-artery vasospasm may lead to the adoption of useless or even harmful clinical approaches [88–91]. Indeed, some research centers in Europe do not include TCD ultrasound or endovascular rescue therapy in their treatment protocols for SAH patients [92].

Moreover, it would be clinically meaningful to determine if correlations exist between the omega-3 index and the concentrations of EPA and DHA as well as the status of inflammation resolution in the wall of ruptured and non-ruptured IAs. There may be a real opportunity for a readily implementable and low-cost therapy if the walls of IAs are as responsive to omega-3 FAs as atherosclerotic plaques.

**249**

*Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation*

implement therapeutic strategy for patients with unruptured IAs.

enzymatic deficiencies in the resolution pathways [93].

The authors have no conflicts of interest to declare.

The interplay between omega-3 FAs and widely used drugs (aspirin and statins) that lead to the generation of longer-acting SPM R-epimers provides ample opportunities for future translational approaches in IAs and SAH. Indeed, combined therapies with omega-3 FAs and aspirin or statins could represent a viable, easy-to-

Parenteral pharmaconutrition with FO could also be a clinically effective intervention for perioperative neuroprotection for patients subjected to other surgeries at high risk of neurological injury, such as carotid endarterectomy, cardiac surgery,

In the future, new drug delivery systems capable of carrying synthetic analogues of SPMs could become a viable therapeutic strategy for patients with tissue-specific

We express our appreciation to our patients from whom we have learned so much.

*DOI: http://dx.doi.org/10.5772/intechopen.88297*

or diverse neurosurgical procedures.

**Notes/thanks/other declarations**

and Rodrigo Zapata2

Libertador Bernardo O'Higgins, Rancagua, Chile

provided the original work is properly cited.

\*Address all correspondence to: rzapata.barra@gmail.com

\*

1 Department of Anaesthesiology, Asenjo Neurosurgery Institute, Santiago, Chile

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Neurosurgery Service, Regional Hospital of Rancagua, Hospital Regional

**Conflict of interest**

**Author details**

Geisi Saito1

*Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation DOI: http://dx.doi.org/10.5772/intechopen.88297*

The interplay between omega-3 FAs and widely used drugs (aspirin and statins) that lead to the generation of longer-acting SPM R-epimers provides ample opportunities for future translational approaches in IAs and SAH. Indeed, combined therapies with omega-3 FAs and aspirin or statins could represent a viable, easy-toimplement therapeutic strategy for patients with unruptured IAs.

Parenteral pharmaconutrition with FO could also be a clinically effective intervention for perioperative neuroprotection for patients subjected to other surgeries at high risk of neurological injury, such as carotid endarterectomy, cardiac surgery, or diverse neurosurgical procedures.

In the future, new drug delivery systems capable of carrying synthetic analogues of SPMs could become a viable therapeutic strategy for patients with tissue-specific enzymatic deficiencies in the resolution pathways [93].
