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      Inhaled Milrinone for sick COVID-19 cohort: a pathophysiology driven hypothesis!

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          Abstract

          Dear Editor, COVID-19 has essentially emerged as a multi-systemic disease with endotheliitis at the heart of resultant organ dysfunction. The pulmonary endothelial cells substantially contribute to the progression of COVID-related acute respiratory distress syndrome (ARDS) associated with the breach of the vascular integrity accompanied by the inexorable widespread endothelial dysfunction leading to the pulmonary and systemic micro-circulatory alterations, perpetuation of the inflammatory cascade and cytokine release syndrome (CRS) and, the promotion of a procoagulant environment [1], [2]. The recognition of vascular and coagulation pathophysiological networks of an ongoing endothelial disease in the sick COVID-19 cohort doubtlessly calls for a more endothelium-centric treatment approach. Moreover, amidst the ardent discussions on the role of nitric oxide (NO) deficiency in accentuating the endothelial dysfunction in COVID-19, the whole NO and closely related downstream pathways have presented viable therapeutic opportunities to the fraternity [3]. In this context, phosphodiesterase enzyme (PDE) inhibition has captivated attention [4]. Within the purview of PDE inhibitors, we present a perspective on the therapeutic potential of inhaled Milrinone (iMil) in COVID-19, under the following heads: A mechanistic-pathway of significance While NO (endothelium derived relaxation factor) mediated vasodilatation is in itself intricately linked to an augmented cyclic monophosphates level in the vascular smooth muscle cells (v-SMCs), the contribution of PDE inhibition in preventing the enzymatic hydrolysis and subsequent termination of vasodilatory effects of cyclic adenosine and guanosine monophosphates (cAMP and cGMP) cannot be overlooked, particularly in a scenario of COVID-associated vasculopathy [3], [4], [5]. Herein, Mil classifies as a PDE3 inhibiting member of the PDE family and presents a rather familiar therapeutic option. Wide biological target expression Mil biological targets: PDE3A and 3B subtypes are widely expressed across the v-SMCs (cardiovascular system), airway SMCs, bronchial epithelial cells, fibroblasts, T-lymphocytes, megakaryocytes and macrophages. The cardiovascular and pulmonary expression profile of the drug endorse unique clinical promises pertinent to COVID-19 [4], [5]. An exclusive therapeutic stance for iMil An intravenous Mil infusion has been reported to assist a successful management of a spectrum of isolated COVID-19 adult and pediatric cases, for instance, in an adult setting of fulminant myocarditis and multisystem inflammatory syndrome in children (MIS-C) [6], [7]. Despite the combination of inotropic and pulmonary artery dilatation (inodilator) and, lung endothelial function preservation properties of Mil being pivotal to the amelioration of pulmonary hypertension, deteriorating myocardial pump function and endotheliitis in COVID-19, the often associated enhanced vasopressor requirement owing to the systemic vasodilatory effects of intravenous Mil present peculiar management challenges [2], [8], [9]. Quite understandably, avoiding the untoward systemic effects, iMil can achieve the other drug benefits relevant to a COVID-19 setting. Nevertheless, the platelet counts should be closely monitored in patients receiving Mil through any of the administration routes. Furthermore, cAMP (potentiated by PDE inhibition) is a key secondary messenger in modulating the CRS through involvement in the protein kinase A and nuclear factor kB (NF-kB) inflammatory pathways. Enhanced intracellular cAMP levels shift the tenuously balanced inflammatory milieu in favour of the anti-inflammatory mediators such as interleukin-10 in addition to suppressing the major pro-inflammatory cytokines like tumour necrosis factor alpha (TNF-α) [4], [5]. At the same time, an increased intracellular cAMP concentration reinforces the microvascular barrier, stimulates alveolar fluid clearance and inhibits neutrophil chemotaxis [10]. The description of a potential anti-remodelling, immunomodulatory and bronchodilator role of PDE inhibition also add to the contextual significance [5]. Encouraging literature While Albert and colleagues demonstrate the safety and feasibility alongside a debatable efficacy of iMil administration in their small prospective study in adult ARDS patients [11], the Lamarche and colleagues description of a superior post-cardiopulmonary bypass (CPB) preservation of endothelial function heralded by a better postoperative hemodynamic and oxygenation profile of iMil compared to an intravenous infusion in a porcine model, merits elucidation [9]. Lamarche et al administered iMil bolus of 60-90 µg/Kg nebulised through the endotracheal tube over the 15 minutes preceding the CPB initiation followed by a maintenance iMil (a preparation of 200 µg/mL in normal saline, 2 mg drug diluted in 8 mg saline) employing a traditional in-line nebulizer (connected to the inspiratory ventilatory limb) at a continuous rate of 0.08-0.11 µg/Kg/minute throughout the CPB [9]. Their study findings stand particular relevance in consideration of the endothelial dysfunctional consequences of COVID-associated CRS which is in many ways related to the endotheliitis owing to a systemic inflammatory response to CPB [1,2,9]. Bueltmann and colleagues reveal an attenuated experimental acute lung injury with iMil in two separate animal models [10]. Their elaboration of a retarded elevation of wet-dry lung weight ratio, systemic hypoxemia and, bronchoalveolar lavage myeloperoxide activity, neutrophils and TNF-α levels in the animal groups receiving iMil, is certainly noteworthy [10]. Beute and colleagues also highlight the anti-inflammatory potential of iMil in house dust mite inflicted allergic airway inflammation in mice [12]. Conclusion An improved comprehension of the COVID-19 pathobiophysiology should be closely backed by the meticulous investigation of the mechanistically related and specific drug therapies aimed at ameliorating the root cause of the disease process. Amidst the intensifying research challenges in the ongoing pandemic where a part of fraternity is impressing upon the fact that the plural of anecdotes does not classify as data [13], [14], the importance of rapidly responding to the dynamic challenging clinical landscape cannot be overemphasized wherein a judicious application of more familiar medications such as iMil can be helpful in mitigating the ever growing concerns of COVID-19 attributable morbidity and mortality.

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          Most cited references12

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          Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children

          Background A recent increase in children admitted with hypotensive shock and fever in the context of the COVID-19 outbreak requires an urgent characterization and assessment of the involvement of SARS-CoV-2 infection. This is a case series performed at 4 academic tertiary care centers in Paris of all the children admitted to the pediatric intensive care unit (PICU) with shock, fever and suspected SARS-CoV-2 infection between April 15th and April 27th, 2020. Results 20 critically ill children admitted for shock had an acute myocarditis (left ventricular ejection fraction, 35% (25–55); troponin, 269 ng/mL (31–4607)), and arterial hypotension with mainly vasoplegic clinical presentation. The first symptoms before PICU admission were intense abdominal pain and fever for 6 days (1–10). All children had highly elevated C-reactive protein (> 94 mg/L) and procalcitonin (> 1.6 ng/mL) without microbial cause. At least one feature of Kawasaki disease was found in all children (fever, n = 20, skin rash, n = 10; conjunctivitis, n = 6; cheilitis, n = 5; adenitis, n = 2), but none had the typical form. SARS-CoV-2 PCR and serology were positive for 10 and 15 children, respectively. One child had both negative SARS-CoV-2 PCR and serology, but had a typical SARS-CoV-2 chest tomography scan. All children but one needed an inotropic/vasoactive drug support (epinephrine, n = 12; milrinone, n = 10; dobutamine, n = 6, norepinephrine, n = 4) and 8 were intubated. All children received intravenous immunoglobulin (2 g per kilogram) with adjuvant corticosteroids (n = 2), IL 1 receptor antagonist (n = 1) or a monoclonal antibody against IL-6 receptor (n = 1). All children survived and were afebrile with a full left ventricular function recovery at PICU discharge. Conclusions Acute myocarditis with intense systemic inflammation and atypical Kawasaki disease is an emerging severe pediatric disease following SARS-CoV-2 infection. Early recognition of this disease is needed and referral to an expert center is recommended. A delayed and inappropriate host immunological response is suspected. While underlying mechanisms remain unclear, further investigations are required to target an optimal treatment.
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            Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency

            Martel and colleagues provide a thoughtful review on strategies to increase airway nitric oxide to treat and possibly prevent Covid-19 [1]. However, it is becoming apparent that the clinical presentation of Covid-19 begins with acute respiratory distress in the lungs that moves quickly to vascular networks throughout the gut, kidney, heart, and brain with associated platelet-endothelial dysfunction and abnormally rapid life-threatening blood clotting [2]. SARS-CoV-2 is emerging as a thrombotic and vascular disease targeting endothelial cells throughout the body and is particularly evident in patients with cardiometabolic comorbidities, in particular hypertension, with associated endothelial dysfunction [3]. A hallmark of endothelial dysfunction and thrombotic events is suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency. In healthy vessels, the endothelium releases the vasodilator and antithrombotic factor, nitric oxide. Whereas in injured vessels, nitric oxide is impaired contributing hypertension and thrombus formation [4]. Restoring nitric oxide, independent of eNOS, may counter endotheliitis and contribute to pulmonary vasodilatation, antithrombotic, and direct antiviral activity [5]. As to the later, nitric oxide reportedly interferes with the interaction between coronavirus viral S-protein and its cognate host receptor, ACE-2. Nitric oxide-mediated S-nitrosylation of viral cysteine proteases and serine protease, TMPRSS2, which are critical in viral cellular entry and also appear to be nitric oxide sensitive [6,7,8,9,10]. Based on a report of improved lung function during the 2003 SARS outbreak, FDA’s emergency expanded use of nitric oxide gas is now underway for treating Covid-19 [1]. Alternatively, dietary inorganic nitrate has been shown in multiple studies to be effective at restoring endothelial function, reducing pulmonary and arterial hypertension, and promoting antimicrobial activity [5]. It is well understood that dietary inorganic nitrates is bio-converted to nitric oxide through a series of well-defined steps beginning with the friendly microflora on the tongue reducing nitrate to nitrite, which is subsequently reduced to nitric oxide in the gut, blood stream, and various organs, including the lung. The formation of inorganic nitrite and S-nitrosothiols is absorbed into the circulation where it acts as a transitory storage pool for subsequent nitric oxide production [11]. The conversion of inorganic nitrite to nitric oxide is expedited in conditions of acidosis or hypoxemia which occurs in regions of the pulmonary vasculature in lungs of COPD patients and those that exhibit acute respiratory distress syndrome as observed in coronavirus infected lungs. Reportedly, consumption of inorganic nitrate for 8 days in COPD population increased lung nitric oxide by 200% and reduced respiratory symptoms [12]. Restoring nitric oxide through dietary inorganic nitrate may be a consideration for prevention and early treatment which would operate at two-levels: reverse platelet-endothelial dysfunction and associated thrombosis as well as lower viral burden [1,5,11,14]. Uncited References 13.
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              Phosphodiesterases as therapeutic targets for respiratory diseases

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                Author and article information

                Journal
                Med Hypotheses
                Med Hypotheses
                Medical Hypotheses
                Elsevier Ltd.
                0306-9877
                1532-2777
                29 November 2020
                29 November 2020
                : 110441
                Affiliations
                Department of Cardiac Anaesthesia, Atal Bihari Vajpayee Institute of Medical Sciences (ABVIMS) and Dr. Ram Manohar Lohia Hospital, Baba Kharak Singh Marg, New Delhi-110001, India
                Author notes
                [* ]Corresponding author.
                Article
                S0306-9877(20)33332-6 110441
                10.1016/j.mehy.2020.110441
                7700763
                33308938
                b8676ef6-1e10-4136-be88-00e3febedeb5
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 19 November 2020
                : 26 November 2020
                Categories
                Letter to Editors

                Medicine
                acute respiratory distress syndrome,covid-19,endothelial dysfunction,hypothesis,inhaled milrinone,pathophysiology,systemic inflammation

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