Omega 3 and Ischemic Stroke; Fish Oil as an Option
Omega 3 and Ischemic Stroke; Fish Oil as an Option
In this trial, The investigators are going to investigate the improvement of neurological
 functions and infarced area of the brain in ischemic stroke patients after ingestion of omega
 3 products that have high concentrations of DHA and EPA in comparison to control group. The
 study will assess the improvement by computerized calculation of the size of the infarcted
 area before and after the intervention and neurological assessment tools. The researchers
 will follow the scientific and ethical regulations prevent any harmful effect on recruited
 subjects.
Introduction and Background According to the Center of Disease Control and Prevention, stroke
 is the 5th leading cause of mortality in the US, and a leading cause of significant long-term
 disability where almost 50% of stroke survivors, age 65 and above, suffer from disabling
 decrease in mobility. In its simplest form, an ischemic stroke is a decrease in the blood
 flow to a certain area in the brain, due to a clot, stenosis or other cause, which lasts long
 enough to cause permanent cellular injury and death and by extension, disability [1].
 However, much more goes into that process.

 The decreased blood flow to the tissue leads to the primary insult caused by ischemia which
 leads to direct and immediate cell death. Meanwhile, the tissue surrounding this ischemic
 area gets affected by the inflammation in the ischemic area, but maintains its viability and
 is called the penumbra. Later on, this penumbra gets affected by the immune response and
 toxic inflammatory mediators released in the ischemic area. Which ultimately results in
 axonal structural changes and subsequent neuronal damage (secondary insult.) The main
 attention of this paper is looking into the prevention of secondary insult and preserving the
 penumbra which carries a neurorestorative capacity that is diminished by the inflammatory
 response and the possibility of restoring the damaged area by neurogenesis as will be
 explained later. As a result, improving the disability caused by the ischemic event [2].

 Currently, the only FDA approved treatments of stroke are Tissue Plasminogen Activator (tPA)
 and Trevo which is a clot removal device, introduced in 2012. However, the group harvesting
 the benefits of those treatments are fairly limited. For example, tPA has many
 contraindications in addition to a narrow window of application of 4.5 hours from the start
 of symptoms. Trevo can only be used within 6 hours as well (extended to 24h in certain cases)
 [3]. Furthermore, a major downside that plagues these interventions is the
 ischemia/reperfusion injury. I/R injury is characterized by reduced vascular relaxation and
 perfusion, increased macromolecular permeability and an intense inflammatory response derived
 by reactive oxygen species (ROS) from the ischemic area [2].

 Other interventions are being currently studied in the preclinical setting which is aimed at
 enhancing and supporting the activity of neurons and neural progenitor cells and promoting
 long-term functional recovery. Rather than concentrating on restoring blood flow, these
 interventions are aimed towards inducing neuroprotection and saving brain function in the
 long term. One such example, is omega-3 essential polyunsaturated fatty acids (PUFA n3)
 specifically docosahexaenoic acid (DHA, 22:6, n-3) and eicosapentaenoic acid (EPA, 20:5,
 n-3), to a lesser extent. They have been shown to have a profound effect on decreasing the
 neuroinflammation in the brain tissue of animal models after an acute stroke in addition to
 its positive effects on cognitive function and neurodevelopment [4,5]. Furthermore, studies
 conducted on mice such as the one conducted by José Pedro De La Cruz et al has shown great
 neuroprotective qualities and a significant reduction in post-stroke neuroinflammation using
 olive oil and acetylsalicylic acid [6].

 Considering all that which have been mentioned in our introduction, the investigators have
 set several objectives for this paper. First of all, studying the effects of using * omega-3*
 as a safe and effective measures to prevent neuroinflammation after an ischemic event and how
 can this affect the process of neurogenesis and subsequently and effect on patient disability
 by using olive oil as one of the resources of omega-3.

 Research Design :

 The study will be an open-labelled two-armed randomized control trial, phase 4. One arm will
 receive the intervention (fish oil). The other arm will be the control.

 Population and Sample:

 The setting of our study will be the KFMC ASU and NCCU. Our target population will be an
 ischemic stroke, non-hemorrhagic, reperfused, and non-complicated stabilized patients
 admitted to the NCCU/ASU at KFMC stroke unit located in Riyadh, Saudi Arabia. Regarding the
 sample size, it will consist of 60 stroke patients /year compiled of 5 patients each month.
 The investigators will put into consideration having a confidence level of 95% with a power
 of 80%. So, the number of the sample might be changed slightly according to the rate of
 encountered eligible patients.

 Plan of Subject's recruitment:

 The investigators are going to recruit confirmed admitted ischemic stroke patients from the
 emergency department then referred to the stroke unit (NCCU/ASU) who need to follow up or
 close monitoring. Patients will be eligible after stabilization and reperfusion to minimize
 any risks to our intervention. This process will be monitored by the ICU specialist and a
 neurologist. The intervention will not be started until the specialists approve to start.
 More importantly, the subject will not be recruited until they or their responsible relative
 gives informed consent. Participants can withdraw at any time during the trial.

 Plan of data collectors' recruitment:

 Data collectors will be from health-care-related specialities

 Randomization :

 Patients will be randomized by the order of their arrival to the NCCU/ASU alternating between
 intervention and control groups with every patient. A research team member will be assigned
 to put patients that arrive at the NCCU/ASU in either of the 2 groups using a computer
 program which randomly selects between A or B. The fact of which letter is assigned to which
 group will also be chosen by the same researcher and stored on an excel sheet which only
 he\she has access to.

 Blinding :

 The study will be an open-label randomized trial due to the difficulty of blinding the
 patients and physicians from the odour, taste and colour between the intervention and
 control.

 Intervention Details:

 Generally, the supplement (but not the placebo) will come in the form of an encapsulated soft
 gel which will be administered through the nasogastric or orogastric tube by injecting it in
 the nutrition bag and dividing the dose throughout the number of bags per day.

 The average length of stay in ischemic stroke patients is 28 days, thus, the intervention
 group will receive fish oil for 1 month starting from the incidence of the stroke. [13] The
 chosen product of intervention is OMACOR from Abbott brand. This product is registered in the
 Saudi FDA and is available in the market.

 The investigators will administer 4g per day of fish oil three times with meals for one month
 with monitoring the health status regularly. According to the European Food Safety Authority
 in 2012, long-term consumption of EPA and DHA supplements at combined doses of up to about 5
 g/day, or EPA alone up to 1.8 g/day appears to be safe for the adult population and does not
 increase the risk of spontaneous bleeding episodes, or affect glucose homeostasis, immune
 function or lipid peroxidation. [18]

 Mechanism:

 Until the time of this study, the full mechanism of action of omega 3 is not well understood
 to explain all of its effects. However, some theories to how it lowered blood triglyceride
 levels propose that it reduces the hepatic production of triglyceride-rich very-low-density
 lipoproteins. It also suppresses adipose tissue inflammation and increases FA uptake in
 adipose, heart, and skeletal muscle. On the cellular level, it inhibits the action of acyl
 CoA:1,2 diacylglycerol acyltransferase, increase hepatic mitochondrial and peroxisomal
 beta-oxidation and thus result in a reduction in the hepatic synthesis of triglycerides
 lowering their blood levels1. Furthermore, its cardiovascular effects are considered
 multifactorial. It inhibits platelet aggregation, increases circulating EPA/arachidonic acid
 ratio, and increases EPA composition from carotid plaques. [14]

 Safety :

 From a safety standpoint, omega 3 is a very safe drug with mild or no symptoms at all. The
 only serious dangerous side effect is an allergic reaction to the drug. some side effects
 include headache, unpleasant taste, bad-smelling sweat, bad breath, and gastrointestinal
 symptoms such as heartburn, nausea, and diarrhoea. [15] Besides, omega 3 being a mild
 platelet aggregation inhibitor, it potentiates the effects of antiplatelet like low dose
 (baby) aspirin. The interaction was reported in a case report

 paper. Thus, after administering omega 3 or changing the dose for a patient on baby aspirin
 or warfarin, the INR should be checked. [14]

 Monitoring :

 While administering omega 3, some parameters should be monitored at baseline and
 periodically. In patients with hepatic impairment monitor liver function tests and enzymes
 particularly ALT. Signs or symptoms of bleeding and perform an INR both at baseline and
 periodically. [14]

 Drug Administration :

 In our study, the investigators expect that some patients might be fully dependent on feeding
 tubes. However, the omega 3 pills could still be administered through NGT or through feeding
 formulas that contain EPA and DHA. In the study by Julie M. [15] Martin et al. found no
 difference in the clinical outcome in critically ill patients when administering the drug
 through NGT vs feeding formulas. However, administering pills instead of feeding formulas is
 more convenient regarding training the staff and determining doses in addition to being
 cost-effective. [16]

 Data collection, Follow-up and Communication :

 The neurology consultant (the principal investigator) will directly supervise the data
 collection, intervention, follow-up and communication with the help of medical professionals
 co-investigators and nurses. Meanwhile, entering the data and monitoring adverse effects will
 be assessed by clinical pharmacists and other co-investigators. The participants will have
 the contact number of the principal investigator to report any news or adverse reactions

 Criteria for stopping follow-up and intervention in the subject:

 Some events will cause stopping and loss of follow-up such as :

 1. Enlarging stroke area

 2. Deterioration of the case condition (e.g. loss more neurological functions and
 consciousness or other systematic organs)

 3. New onset of stroke in the same or different areas

 4. Participant withdrawing

 5. Death or brain death

 Analysis :

 The investigators will analyze the data using the SPSS software program (version 25).
 Descriptive analysis and statistical Drop-outs from the study will be excluded from the
 analysis, so the analysis type will be "per protocol analysis".
Inclusion Criteria:

 -  Admitted ischemic occlusive stroke after successful reperfusion therapy - Stabilized
 in ICU or the inward

 -  Attack started 48 hours or less

 -  Can be fed by nasogastric tube or by himself

 -  MRI imaging was taken in the first 24 hours and CT [10]

 Exclusion Criteria:

 -  Hemorrhagic stroke

 -  Non-occlusive hypoxic brain

 -  Global cerebral ischemia

 -  Transient ischemic attack

 -  Non-scanned by MRI or CT in the first 48 hours of onset

 -  Non-reperfused stroke patient or non-successful reperfusion therapy

 -  Deteriorating cases and not stabilised patients

 -  Attack exceeded 48 hours since onset

 -  Non-tolerated patients to feeding (NPO)

 -  Unstable source of thrombi (e.g. vegetation heart valves, unstable carotid
 atherosclerosis..etc)

 -  Presence of any coagulopathy

 -  Sickle cell anaemia

 -  Risk for shock ( e.g. septic shock, hypovolemic shock, cardiogenic shock...etc) - Time
 of onset is not reliably known

 -  Suspected non-stroke diagnosis

 -  Significant concurrent medical condition

 -  Significant pre-existing disability ( will be excluded from neurological scoring
 assessment not CT MRI assessment)

 -  Liver disease