Managing Endothelial Dysfunction in Critically Ill COVID-19 Patients at LAUMCRH
Managing Endothelial Dysfunction in Critically Ill COVID-19 Patients at LAUMCRH
COVID-19 Infection has been found to cause endothelial dysfunction and most of the adverse
 events stem to this mechanism. So we seek to target endothelial dysfunction in critically Ill
 patients with covid by giving them an endothelial protocol ( L-arginine, Folic Acid, Statin,
 Nicorandil, Vitamin B complex) and monitor clinical outcome in those patients.
Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the novel pathogen
 responsible for coronavirus disease 2019 (COVID-19) first discovered in Wuhan, China [1].
 Since its emergence in late December 2019, many pathophysiological mechanisms have been
 proposed with multiple pathways that involve various organ systems [2, 3]. Although
 considered at its emergence as a respiratory infection with manifestations ranging from lower
 respiratory tract infection to pneumonia and advancing to acute respiratory disease syndrome
 (ARDS) in its final stages, recent evidence has highlighted how disseminated the virus can be
 affecting almost every organ be it the heart, kidneys, or blood vessels . Recent trends in
 research have focused on elucidating the cardiovascular dysfunction in COVID-19 patients
 especially following studies showing that cardiovascular risk factors are among the most
 common presenting comorbidities and that cardiovascular complications of SARS-CoV-2 are among
 the most lethal [4-11] . Initial research revealed that the virus makes use of the
 angiotensin-converting enzyme 2 (ACE-2) receptor, a widely expressed receptor found in
 multiple cells lining the lung, heart, gastrointestinal tract, kidneys and endothelial cells
 to infiltrate host cells. Another prominent mechanism of infection is immune system
 dysregulation manifesting as a cytokine storm and inflammatory response over-activation [12,
 13].

 Attempts at laying out a comprehensive or unifying pathogenesis of a COVID-19 infection have
 singled out endothelial dysfunction as a core pathway [14]. The endothelium is a monolayer of
 squamous endothelial cells lining the inner surface of arteries, veins and microvasculature.
 The endothelium hence plays a major role in homeostasis with interactive roles in blood
 pressure regulation, anti-coagulation and immune protection. Moreover, it is relevant to note
 that the most common comorbidities that present with COVID-19 such as hypertension, diabetes,
 obesity and old age are all underlined by pre-existing endothelial damage or dysfunction. As
 such, endothelial dysfunction and oxidative stress and their relation to the manifestation
 and progression of COVID-19 infections has gained significant traction in recent publications
 [15]. This breakthrough exposes several causes of endothelial dysfunction which include
 direct lining attack, hypoxia, cytokine storm and suppressed endothelial nitric oxide
 synthase (eNOS) with concomitant nitric oxide deficiency [15]. Several studies have
 emphasized the role of Nitric Oxide (NO) signaling as a major regulator of vascular tone with
 its antioxidant, anti-inflammatory and antithrombotic activity. For example, augmenting the
 production of NO and its bioavailability by Nicorandil has been proposed as a potential
 treatment in patients with COVID 19. Nicorandil is a vasodilatory agent composed of
 N-[2-hydroxyethyl]-Nicotinamide Nitrate) used among patients with acute heart failure
 emergencies. However, it has never been tested in patients with cardiovascular complications
 resulting from COVID 19 [16]. Moreover, statins are cardio-protective in nature with recent
 reports showing that they can be beneficial in COVID-19 [17]. An important mechanism via
 which Statins may improve endothelial function include increasing the production of NO and
 subsequent vasodilation effect, along with its established major anti-inflammatory and
 anti-oxidant properties [17]. Vitamin B complex will be used because of the role it plays in
 cell functioning, energy metabolism, and proper immune function. In addition of its
 assistance in proper activation of the immune response, reducing pro-inflammatory cytokine
 levels, improving respiratory function, maintaining endothelial integrity, preventing
 hypercoagulability and reducing the length of stay in hospital. [18-19-20] Furthermore, eNOS
 overexpression leads to an increase in NO formation only when the BH4 synthase
 GTP-cyclohydrolase 1 (GCH-1) is also up-regulated. So, Folic Acid and L-arginine will be
 given to supplement our patients with BH4 (Tetrahydrobiopterin) [21]. We hypothesize that its
 administration along with the other previously mentioned agents would improve endothelial
 function in patients suffering from COVID 19 via a cumulative increase in the bioavailability
 of NO, and thus improving patients' outcomes
Inclusion Criteria:

 -  Participants must be 18 years of age or older

 -  Participants must have a PCR confirming COVID 19 status

 -  Participants must be classified as critical as per the FDA evidence of critical
 illness, which is defined as respiratory failure requiring at least one of the
 following: Endotracheal intubation and mechanical ventilation, oxygen delivered by
 high- flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal
 cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5), noninvasive
 positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure
 (i.e., clinical need for one of the preceding therapies, but preceding therapies not
 able to be administered in setting of resource limitation)

 -  Eligible for or already taking Statin

 Exclusion Criteria:

 -  Patients who are already on statins or Nicorandil.

 -  Patients labeled as having mild, moderate or severe COVID-19 infection as per the FDA
 definitions.

 -  Patients with shock as defined by SBP<90 for more than 30 minutes not responding to IV
 fluids with evidence of end organ damage.

 -  Severe hepatic impairment (Child-Pugh class C) or active liver disease are absolute
 reasons not to be included especially those with unexplained persistent elevations of
 serum transaminases.

 -  Pregnancy or breastfeeding

 -  Hypersensitivity to any of the above-mentioned medications

 -  On Levodopa.

 -  Patients on PDE5 inhibitors, Riociguat

 -  Acute pulmonary edema

 -  Hypovolemia

 -  Leber's disease