**9.3 Safety considerations**

Evidence obtained over more than two decades in other clinical fields indicates omega-3 FAs interventions are unlikely to lead to serious clinical harm in SAH patients [25, 59]. Nevertheless, parenteral administration of omega-3 FAs may raise some safety concerns. Total parenteral nutrition is associated with an increased risk of complications in critically ill patients [9]. Furthermore, administration of lipid emulsions (LEs) may cause fat overload syndrome; the amount of fat administered and LE infusion rate are the primary risk factors. In this regard, it should be emphasized that the therapeutic dose of FO (0.1–0.2 g of FO/kg/day) is about one order of magnitude lower than that of regular LE (0.7–1.5 g of fat/kg/day) [59]. Additionally, the plasma clearance rate is faster for FAs administered in FOLE than soybean oil-based LEs. These unique features contribute to the good safety profile of FOLE. Fish oil has been widely used as a component of total parenteral nutrition and is associated with reduced rates of infection, shorter hospital stay, and decreased mortality, particularly in surgically treated patients [59].

Furthermore, isolated parenteral administration of FO has increasingly been used in pediatric patients with parenteral nutrition-associated liver disease (PNALD). Several case series published since 2006 have reported parenteral FO monotherapy (PFOM) remarkably improved clinical outcome of patients with PNALD [75]. Importantly, PFOM has demonstrated a good safety profile in these


**247**

*Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation*

critically ill patients, even at FO doses up to 1.5 g FO/kg/day and overextended treatments beyond 4 weeks, well beyond the manufacturer's recommendations. The aim of replacement FO therapy in PNALD is obviously different to SAH patients. Parenteral administration of FO is intended to address key nutrient deficiencies during the acute stage after SAH, and thus only short-term administration of a regular FO dose should be necessary. In fact, a 5-day parenteral perioperative regimen did not increase the occurrence of major postoperative complications in 19 surgically treated SAH patients [13]. Thus, there is good quality evidence to warrant further clinical trials of parenteral pharmaconutrition as an integral component of

**10. Role of inflammation resolution in the growth and rupture** 

eicosanoids from ARA and also downregulates the activity of NF-kB [25].

Atherosclerotic plaques readily incorporate omega-3 FAs, and a higher plaque EPA content is associated with a reduced number of foam cells and macrophages, as well as increased plaque stability, as determined by a well-formed fibrous cap [80]. Additionally, signs of defective resolution of inflammation have been identified in atherosclerotic plaques [81]. One major function of SPMs (particularly maresins) is to induce phenotypic conversion of macrophages, which decrease inflammation and promote tissue regeneration [16]. In animal models of atherosclerosis, a traditional Western high-fat diet disrupts the homeostasis of inflammation resolution by nutrigenetic modulation of the 12/15-LOX pathways, thereby inhibiting the generation of protective SPMs [81, 82]. These recent findings in atherosclerosis, particularly the involvement of docosanoids in vascular inflammation, provide biological plausibility that defective resolution of inflammation is implicated in the

Human beings evolved, and their genetic patterns were established on a diet with an omega-6/omega-3 FAs ratio of 1/1, whereas in current Western diets, this ratio is around 16/1 [83]. Thus, this extreme nutritional imbalance in current Western diets should be seriously considered as a potential aggravating factor for the growth and rupture of IAs [48, 82]. This suggestion may appear somewhat counterintuitive considering the high prevalence of IAs with increased risk of rupture in the Japanese population, which has one of the highest dietary intakes of omega-3 FAs worldwide [48, 84]. However, nutritional deficiency of long-chain omega-3 FAs may not be the only factor associated with defective resolution of inflammation. Inter-individual and ethnic variations in the susceptibility to IA growth and rupture could be related to tissue-specific enzymatic deficiencies in the biosynthetic routes that regulate the resolution of inflammation. However, while defective resolution has already been associated with other chronic

The role of inflammation in the growth and rupture of intracranial aneurysms (IAs) has been increasingly recognized over the last few decades; however, the specific role of resolution of inflammation in IAs has not yet been considered [76]. Although the pathophysiology of atherosclerosis and the growth and rupture of IAs are distinct, both conditions are mediated by an underlying inflammatory process [77]. The progression of atherosclerotic plaques determines plaque morphology and the risk of rupture. The degree of macrophage infiltration plays a crucial role in the progression of atherosclerotic plaques. Interestingly, IAs have also been recently regarded as a macrophage-mediated inflammatory disease in which prostaglandin E2 and the master transcription factor NF-kB may be crucial drivers of inflammatory signals [78, 79]. It should be remembered that prostaglandin E2 is derived from the long-chain omega-6 FAs ARA and that EPA can inhibit the generation of

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

interventions with omega-3 FAs in SAH patients.

**of intracranial aneurysms**

pathogenesis of IA growth and rupture.

**Table 1.** *Summary of the features and outcomes of clinical interventional studies in SAH patients.*

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

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

decreased mortality, particularly in surgically treated patients [59].

*n* = 101 EPA = 73

EPA = 81

*n* = 100 EPA + DHA = 55

EPA + DHA = 20

*Summary of the features and outcomes of clinical interventional studies in SAH patients.*

**9.3 Safety considerations**

are summarized in **Table 1**. Two studies utilized EPA and DHA, and only one study included a parenteral regimen. In total, 229 patients with SAH have received an omega-3 FAs intervention; most patients were surgically treated (*n* = 223). Although two studies were published as RCTs, one study had significant methodological shortcomings in the randomization process that conferred a high risk of selection bias [74]. While these preliminary clinical studies reported encouraging results (see **Table 1**), high-quality RCTs are needed to confirm the benefits of omega-3 FAs in SAH patients.

Evidence obtained over more than two decades in other clinical fields indicates omega-3 FAs interventions are unlikely to lead to serious clinical harm in SAH patients [25, 59]. Nevertheless, parenteral administration of omega-3 FAs may raise some safety concerns. Total parenteral nutrition is associated with an increased risk of complications in critically ill patients [9]. Furthermore, administration of lipid emulsions (LEs) may cause fat overload syndrome; the amount of fat administered and LE infusion rate are the primary risk factors. In this regard, it should be emphasized that the therapeutic dose of FO (0.1–0.2 g of FO/kg/day) is about one order of magnitude lower than that of regular LE (0.7–1.5 g of fat/kg/day) [59]. Additionally, the plasma clearance rate is faster for FAs administered in FOLE than soybean oil-based LEs. These unique features contribute to the good safety profile of FOLE. Fish oil has been widely used as a component of total parenteral nutrition and is associated with reduced rates of infection, shorter hospital stay, and

Furthermore, isolated parenteral administration of FO has increasingly been

**Reference Type of study Population,** *n* **Intervention Main result**

Oral EPA: 1800 mg/ day × 10 postoperative

Oral EPA: 2700 mg/ day × 30 PO days

Oral EPA: 1860 mg/ day + oral DHA: 750 mg/ day × 90 PO days

Parenteral perioperative:

Oral EPA: 1840 mg/ day + oral DHA: 1520 mg/

day × 8 weeks

Reduction in vasospasm and cerebral infarction

Reduction in vasospasm and cerebral infarction

Reduction in vasospasm and cerebral infarction

No postoperative intracranial bleeding complications Easy-toimplement intervention

(PO) days

5 days

used in pediatric patients with parenteral nutrition-associated liver disease (PNALD). Several case series published since 2006 have reported parenteral FO monotherapy (PFOM) remarkably improved clinical outcome of patients with PNALD [75]. Importantly, PFOM has demonstrated a good safety profile in these

**246**

**Table 1.**

Yoneda et al. [73]

Yoneda et al. [74]

Nakagawa et al. [72]

Saito et al. [13]

Prospective, nonrandomized

Retrospective study

RCT *n* = 162

Pilot RCT *n* = 41

critically ill patients, even at FO doses up to 1.5 g FO/kg/day and overextended treatments beyond 4 weeks, well beyond the manufacturer's recommendations.

The aim of replacement FO therapy in PNALD is obviously different to SAH patients. Parenteral administration of FO is intended to address key nutrient deficiencies during the acute stage after SAH, and thus only short-term administration of a regular FO dose should be necessary. In fact, a 5-day parenteral perioperative regimen did not increase the occurrence of major postoperative complications in 19 surgically treated SAH patients [13]. Thus, there is good quality evidence to warrant further clinical trials of parenteral pharmaconutrition as an integral component of interventions with omega-3 FAs in SAH patients.
