PHARMACEUTICAL COMPOSITION COMPRISING L-TRIIODOTHYRONINE (T3) FOR USE IN THE TREATMENT OF TISSUE HYPOXIA AND SEPSIS

Abstract

The present invention relates to a composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory response and multi-organ dysfunction, including kidney, liver, brain, lung, heart, hematopoietic and / or gastrointestinal coagulation system, due to prolonged hypoxia and microvascular dysfunction, in patients with sepsis, coronavirus infection, cancer, severe trauma and / or in heart and / or other organ transplants.

Description

PHARMACEUTICAL COMPOSITION COMPRISING L-TRIIODOTHYRONINE (T3) FOR USE IN THE TREATMENT OF TISSUE HYPOXIA AND SEPSIS DESCRIPTIVE MEMORANDUM The present invention relates to a composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory response and multi-organ dysfunction, including kidney, liver, brain, lung, heart, hematopoietic and / or gastrointestinal coagulation system, due to prolonged hypoxia and microvascular dysfunction, in patients with sepsis, coronavirus infection, cancer, severe trauma and / or in heart and / or other organ transplants. Microvascular dysfunction is a common cause of tissue hypoxia that develops at the cellular level in several critical clinical conditions and has significant implications, resulting in dysfunction and failure of one or more vital organs (Dekker NAM, et al. Microvascular Alterations During Cardiac Surgery Using a Heparin or Phosphorylcholine-Coated Circuit. J. Cardiothorac. Vasc. Anesth. 2020, 34 (4): 912-919). Prolonged hypoxia, which frequently results in organ damage, occurs due to a systemic or local mismatch between oxygen supply and tissue demand despite normal organ blood flow. This response often occurs even after both cardiac output and blood oxygenation have been restored to normal levels (macro- to microcirculation decoupling). Prolonged microvascular dysfunction and tissue hypoxia, evidenced by elevated blood lactate levels, lead to multiple organ failure in patients with sepsis (renal, hepatic, and cardiac damage) and are associated with increased mortality in these patients (Sakr Y, et al. Persistent microcirculatory disturbances are associated with organ failure and death in patients with septic shock. Crit. Care Med. 2004, 32 (9): 1825-31). High lactate levels due to hypoxia are also associated with poor outcomes for patients in other critical conditions, such as after cardiac surgery (Maillet JM et al. Frequency, risk factors, and outcome of hyperlactatemia after cardiac surgery. Chest 2003, 123: 1361-6) and injury following multiple trauma (Abramson D et al. Lactate clearance and survival following injury. J. Trauma. 1993, 35: 5848). Tissue hypoxia also plays a fundamental role in the development of cancer cells. Hypoxia facilitates cell survival and tumor spread. The role of hypoxia is twofold: it promotes angiogenesis to provide oxygen and nutrients to the rapidly growing tumor and, at the same time, facilitates the survival and proliferation of cancer cells. However, the vessels resulting from this angiogenesis are frequently abnormal and Immature Q77P ίη / ZZΖΠZ / Β / YΙΛΙ cells frequently exhibit fluid extravasation resulting in edema and subsequent maintenance of hypoxia, thus creating a vicious cycle between hypoxia and tumor growth (Muz et al. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia 2015, 3: 83-92). These findings suggest that novel therapies targeting hypoxia may break this vicious cycle by targeting tumor growth as well as cancer cell metastasis. Cardiac surgery, such as coronary artery bypass grafting (CABG), is frequently associated with microvascular perfusion disturbances that persist for up to 72 hours post-surgery. This microvascular dysfunction creates tissue hypoxia and can play a significant role in the development of postoperative heart failure, resulting in prolonged hospital stays. The initiation of bypass surgery is also associated with an immediate decrease in microvascular perfusion due to an acute reduction in capillary density, primarily caused by the systemic inflammatory response and hemodialysis, resulting in endothelial dysfunction. Furthermore, the bypass itself promotes endothelial activation, leading to increased vascular permeability and leakage, which in turn leads to edema formation, tissue inflammation, and further exacerbation of hypoxia (Dekker NAM, et al.).Postoperative microcirculatory perfusion and endothelial glycocalyx shedding following cardiac surgery with cardiopulmonary bypass. Anesthesia 2019, 74:609-618). New treatments that aim to prevent and treat microvascular dysfunction and tissue hypoxia during cardiac surgery may be important for improving patient outcomes. Microvascular dysfunction and the development of tissue hypoxia, followed by subsequent long-term tissue damage, also play a significant role in cases requiring extracorporeal maintenance of vital organs, such as heart transplantation. In general, heart preservation in transplantation can be achieved through warm perfusion with specialized nutrient solutions, rather than using a cold preservation solution. Warm perfusion of the heart is a novel and promising approach; however, it frequently results in long-term microvascular dysfunction and tissue hypoxia despite successful maintenance of coronary perfusion, as well as left ventricular diastolic and systolic dysfunction.Recent technological advances have significantly improved the effects of continuous ex vivo warm blood perfusion by reducing the need for myocardial ischemia in graft and implant surgeries and cardiac surgery. Clinical trials with this pioneering technology indicate its safety and effectiveness; however, they are still significantly limited due to the development of microvascular dysfunction, tissue hypoxia, and consequent long-term tissue damage. Sepsis is a complex disorder that can be described as the body's extreme response to infection and is frequently associated with acute multiple organ dysfunction and high mortality. Sepsis causes more than 2.8 million deaths worldwide each year, accounting for 5–6% of total hospitalization costs in healthcare systems. The World Health Organization and the World Health Summit in 2017 established sepsis as a global health priority, adopting a series of proposals and measures to improve its prevention, diagnosis, and treatment. Following established guidelines, sepsis treatment should begin as soon as possible after diagnosis. Within the first hour, appropriate antibiotics should be administered, and relevant blood culture samples should be obtained. Hemodynamic stabilization should be achieved within the first hour through the administration of crystalloid solutions and, if necessary, the use of vasoactive inotropic agents (norepinephrine, dopamine, epinephrine). However, despite macrocirculatory stabilization and restoration of blood oxygen, sepsis frequently results in multiple organ failure due to microvascular disturbances and hypoxia at the cellular level. Lactate accumulation, despite macrocirculatory restoration, is strongly associated with mortality and has significant prognostic value.Lactate levels are an important indicator of both tissue ischemia at the cellular level and microcirculatory damage. Corticosteroids can inhibit the maladaptive inflammatory response associated with sepsis; however, recent data show no significant effect on survival. Thus, hydrocortisone is only recommended when sepsis-induced hemodynamic instability cannot be adequately treated with fluid and vasoactive agents. Sepsis can also cause secondary organ damage. Specifically, 40–50% of septic patients experience renal failure, 35% experience hepatic failure, 6–9% experience secondary respiratory failure, and 34% experience secondary leukopenia and immunosuppression, while the rates of secondary cardiac, cerebral, and gastrointestinal disorders can vary. Secondary damage to the coagulation system, which is responsible for increased rates of thrombosis, is also reported. Sepsis can be caused by a variety of infections, including bacterial (e.g., pneumococcus, meningococcus, Staphylococcus aureus, Haemophilus, Pseudomonas aeruginosa, etc.), viral (e.g., influenza, Ebola, Coxsackievirus, SARS-CoV-2, etc.), parasitic (e.g., Schistosoma, Amoeba, etc.), and fungal (e.g., Aspergillus, Cryptococcus, Histoplasma, etc.) (O'Brien JM et al. Sepsis. Am. J. Med. 2007, 120:1012-1022). Respiratory and intra-abdominal infections are the most common associated sites of infection, after the urinary system, the central nervous system, and soft tissues or bones. Sometimes, the infection may simply be found in the blood or involve injuries or burns (Klouwenberg, PK. Classification of sepsis, severe sepsis and septic shock: the impact of minor variations in data capture and definition of SIRS criteria. Intensive Care Med 2012, 38:811-819). The mechanisms involved in sepsis-induced cell damage and organ dysfunction are not fully understood and remain an active area of ​​scientific research. Tissue ischemia occurs due to either systemic or local disruption of the balance between oxygen transport and tissue demand. Therefore, the main causes of sepsis-induced multiple organ failure are reduced organ perfusion and oxygenation, and microvascular dysfunction, which lead to hypoxia at the cellular level even after an apparent restoration of stable systemic hemodynamics. It is important to note that even after aggressive restoration of circulation in septic patients, achieving normal or high cardiac output, tissue perfusion at the cellular level remains largely problematic. This indicates that sepsis-induced tissue hypoxia is essentially a microcirculatory problem. In fact, small vessel perfusion is strongly correlated with the prognosis of sepsis. Several studies have shown that tissue hypoxia, which manifests as insufficient lactate clearance in the blood during the first few hours of a patient's recovery, is associated with multiple organ failure and increased mortality (Nguyen, HB et al. Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock. J. Infami. 2010, 7:6). Another study demonstrated a strong correlation between improved lactate levels within the first 6 hours and subsequent improvements in blood biomarkers over 72 hours, as well as an improvement in multiple organ dysfunction. It is worth noting that lactate clearance has been strongly associated with improved microcirculation.These findings suggest that tissue hypoxia is a primary factor playing a critical role in the pathophysiological mechanisms of sepsis in multiple organ failure, rather than a terminal phenomenon. Interestingly, tissue hypoxia in severe sepsis is also associated with increased apoptosis. In particular, caspase-3, a key marker of the apoptosis pathway, is found to be significantly higher after 72 hours in septic patients with reduced lactate clearance compared to patients with increased lactate clearance. Furthermore, tissue hypoxia appears to be a precursor to the pre-thrombotic condition in severe sepsis; therefore, any treatment for tissue hypoxia may reverse hypercoagulability. Furthermore, sepsis places the body under severe stress and leads to a neurohormonal response with significant physiological consequences, such as changes in thyroid hormone metabolism. This results in low serum T3 levels with normal T4 levels in less severe cases, or low serum levels of both T3 and T4 in more severe cases. This response is known as Non-Thyroid Illness Syndrome (NTIS) and appears to be an important prognostic factor for the survival of septic patients. This dysregulation is known to occur in severe acute pathological conditions such as sepsis, myocardial infarction, etc. and is related to high mortality in sepsis (Padhi, R. et al. Prognostic significance of nonthyroidal disease syndrome in critically ill adult patients with sepsis. Int. J. Crít. IHn. Inj. Sd. 2018, 8:165-172).Furthermore, laboratory animals genetically modified to express reduced levels of deiodinase 2 (DIO2), which regulates the synthesis of biologically active T3, showed increased levels of respiratory failure in an experimental sepsis model (Ma, Shwu-Fan et al. Type 2 Deiodinase and Host Responses of Sepsis and Acute Lung Injury. Am. J. Respir. Ceii Moi. Bioi. 2011, 45 (6):1203-1211). In rat models of sepsis, administration of T3 was found to maintain lung function and surfactant synthesis, reduce the cytokine storm, and improve survival (Yokoe, T. et al. Triiodothyronine (T3) ameliorates the cytokine storm in rats with sepsis. Crít. CarelQQQ, 4:59). To date, there are no effective treatments against microvascular dysfunction and tissue hypoxia, aimed at limiting multi-organ damage due to sepsis or other pathological conditions. In particular, there are no effective treatments against microvascular dysfunction and tissue hypoxia resulting in the regulation of the inflammatory response and improvement of cardiovascular and coagulation system dysfunction in sepsis and other pathological conditions, and particularly in sepsis due to coronavirus infection. L-Triiodothyronine (T3) has been tested as a drug for critically ill patients by increasing cardiac output and supporting hemodynamics. However, due to the widely held belief that T3 can lead to increased oxygen consumption and worsen hypoxia, its use is limited to the treatment of hypothyroidism. Even in this case, it is used sparingly as a second-line treatment after levothyroxine (Kaptein, EM et al. Thyroid hormone therapy for postoperative nonthyroidal diseases: a systematic review and synthesis. J. CHn. Endocrinol. Metab. 2010, 95:4526-4534). In addition, it should be mentioned that the Summary of Product Characteristics (SmPC) for L-triiodothyronine solutions states that T3 is contraindicated in patients with cardiovascular disorders or angina, and may be used with extreme caution in patients with coronary heart disease (www.medicines.orq.Uk / emc / product / 2805 / smDc#qref). In other comments, the potential effect of early administration of high doses of TH (acute treatment) after a single event has already been investigated in experimental models of ischemia-reperfusion using isolated rat heart preparations. Thus, high-dose T3 administered after reperfusion improves post-ischemic recovery of function while limiting apoptosis [Pantos C, et al. Thyroid hormone improves post-ischemic recovery of function while limiting apoptosis: a new therapeutic approach to support hemodynamics in the setting of ischemia-reperfusion? Basic Res. Cardiol. (2009) 104, 69-77; QZZP ίη / ZZΖΠZ / E / YΙΛΙ ίΠ / ZZηZ / E / YΙΛΙ doi:10.1007 / s00395-008-0758-4]. In this study, the effects of T3 on reperfusion injury were investigated in a Langendorff rat heart model with 30 min of zero-flow perfusion (simulating acute ischemia) and 60 min of reperfusion with or without T3 (40 pg / L). In addition, phosphorylated levels of intracellular kinases were measured at 5, 15, and 60 min reperfusion intervals. T3 has been shown to significantly improve post-ischemic recovery of cardiac function, while simultaneously significantly reducing acute p38 MAPK activation during the first few minutes of reperfusion. Specifically, phospho-p38 MAPK levels were found to be 2.3 times lower in T3-treated rats after 5 minutes compared to matched control rats and 2.1 times lower after 15 minutes (P < 0.05).This may constitute a paradigm of a positive inotropic agent with adequate anti-apoptotic action to support hemodynamics in the clinical setting of ischemia-reperfusion. Furthermore, WO 2020 / 144073 reports the effects of high-dose T3 treatment initiated immediately after reperfusion and continued for 48 hours in patients with anterior or anterolateral ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). This study also explores the potential effects of T3 treatment on infarct size and cardiac remodeling by assessing changes in left ventricular (LV) volumes and geometry. Surprisingly, it has been recognized that administering high doses of T3, even over any consideration of thyroid replacement therapy, inhibits tissue hypoxia caused by microvascular dysfunction in various organs, including the kidneys, liver, heart, lungs, brain, gastrointestinal tract, and hematopoietic and coagulation systems, and reduces lactate levels. This contradicts the common belief that thyroid hormone is harmful in hypoxia due to increased oxygen consumption. In the present invention, strong, unprecedented evidence is provided showing that the active form of the thyroid hormone, L-triiodothyronine (T3), in high doses can treat tissue hypoxia related to microvascular dysfunction that occurs in various critical pathological conditions in vital organs and systems, especially those related to the cardiovascular system, the immune system, and the coagulation system, particularly when caused by a coronavirus infection. Priority Document GR 20200100200, which is incorporated herein by reference, indicates that the administration of high doses of T3 to critically ill patients with coronavirus is an effective treatment to reduce damage to hypoxic tissue and to maintain normal function of the patients' vital organs. Priority Document GR 20200100695, which is incorporated herein by reference, indicates that the administration of high doses of a pharmaceutical composition containing L-triiodothyronine is beneficial for treating one or more multiple organ failure in patients with tissue hypoxia and microvascular dysfunction due to sepsis, coronavirus infection, cancer, severe injury, or vital organ transplantation. Priority Document GR 20210100216, which is incorporated herein by reference, indicates that the administration of high doses of a pharmaceutical composition containing L-triiodothyronine is effective in the treatment of the inflammatory response and cardiovascular failure especially due to prolonged hypoxia and microvascular dysfunction caused by sepsis. The present invention is based on the surprising observation that administering a dosage regimen as considered herein (a high dose of T3 above any consideration of thyroid replacement therapy) effectively treats dysfunction of one or more vital organs in patients with sepsis. The present invention relates in particular to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, administered at doses of 5 pg per kg of body weight to 9 pg per kg of body weight, preferably 6 pg per kg of body weight to 8 pg per kg of body weight, more preferably 7 pg per kg of body weight total, for an initial period of 24 to 72 hours, preferably for 48 hours. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) effectively treats cancer in one or more organs. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) effectively treats dysfunction of one or more vital organs in patients with open or internal injuries. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) effectively treats dysfunction of one or more vital organs in patients following a heart and / or other organ transplant. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of a thyroid replacement therapy), effectively treats microvascular dysfunction and tissue hypoxia caused by sepsis. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy), effectively treats renal failure caused by tissue hypoxia due to microvascular dysfunction. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of a thyroid replacement therapy), effectively treats hepatic insufficiency caused by tissue hypoxia due to microvascular dysfunction. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) effectively treats brain damage caused by tissue hypoxia due to microvascular dysfunction. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of a thyroid replacement therapy), effectively treats hematopoietic system failure caused by tissue hypoxia due to microvascular dysfunction. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of a thyroid replacement therapy), effectively treats gastrointestinal tract failure caused by tissue hypoxia due to microvascular dysfunction. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of a thyroid replacement therapy), effectively treats respiratory system failure caused by tissue hypoxia due to microvascular dysfunction. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of a thyroid replacement therapy), effectively treats heart failure caused by tissue hypoxia due to microvascular dysfunction. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of a thyroid replacement therapy), is effective in treating tissue hypoxia due to microvascular dysfunction in a heart exposed to stress such as in transplants or heart surgeries. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) effectively treats microvascular dysfunction and tissue hypoxia caused by long-term ex vivo perfusion of the heart or QZZP ίη / ZZΖΠZ / E / YΙΛΙ another organ. This allows for the long-term preservation of an extracorporeal organ, thereby avoiding any significant tissue damage during transfer. Furthermore, it allows for the resuscitation of heart transplants that might otherwise be unsuitable for transplantation. This is also beneficial for the overall availability of transplants. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) is beneficial in the long-term extracorporeal maintenance of heart transplants in warm continuous perfusion devices, as well as in patients during cardiac surgery, thereby avoiding microvascular dysfunction and hypoxia of the myocardial tissue. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) effectively treats the inflammatory response and multi-organ failure in critically ill patients with sepsis and / or coronavirus infection. The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) effectively treats the impairment of left and right ventricular function in critically ill patients with sepsis and / or coronavirus infection. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) improves right ventricular systolic function in critically ill patients with sepsis and / or coronavirus infection. The present invention is based on the surprising observation that administering a dosage regimen as described herein (a high dose of T3 in addition to any consideration of thyroid replacement therapy) to critically ill patients diagnosed with single- or multiple-organ dysfunction due to coronavirus infection facilitates weaning from cardiopulmonary support. Successful weaning is defined as the absence of a requirement for mechanical ventilation support or extracorporeal membrane oxygenation (ECMO) support for 48 hours after extubation. The present invention further relates to the administration of a high dosage regimen of T3 to patients diagnosed with coronavirus disease in combination with parallel therapeutic treatment comprising other active agents selected from Chloroquine and / or Colchicine and / or Remdesivir and / or Ralimetinib and / or Losmapimod. qzzp ίη / ζζηζ / Ε / γίΛΐ So far, there is no previous technique that suggests a treatment for single-organ or multiple-organ damage from prolonged continuous hypoxia conditions, i.e., for more than 30 minutes, preferably more than 3 hours up to several days, for example, until successful disconnection or final monitoring and for a period of time of 30 days at most. Furthermore, there is not a single notion in the previous technique that suggests high-dose T3 treatment of a patient in intensive care units suffering from single-organ or multi-organ dysfunction induced by a coronavirus infection. Similarly, there is no reference in the previous technique to suggest high-dose T3 treatment for a patient in intensive care units suffering from single-organ or multi-organ dysfunction induced by COVID-19. Unexpectedly, high-dose administration of T3 to critically ill patients with coronavirus infection has been found to be an effective treatment for reducing hypoxic tissue damage and preserving organ function. Above all, the present invention relates to the surprising findings that the administration of T3 in high doses under prolonged conditions of hypoxic organ perfusion preserves organ function. Another objective of the invention is a high-dose L-triiodothyronine treatment that reduces excessive inflammation in critically ill patients with coronavirus infection. Another objective of the invention is a high-dose L-triiodothyronine treatment that reduces virus-induced tissue damage due to virus entry and replication in critically ill patients with coronavirus infection. Another objective of the invention is a high-dose L-triiodothyronine treatment to facilitate faster weaning from cardiorespiratory support in critically ill patients with coronavirus infection. One objective of the invention is a high-dose L-triiodothyronine treatment that reduces mortality in critically ill patients with coronavirus infection. The present invention in particular relates to a medicament comprising L-triiodothyronine administered to critically ill patients with coronavirus who require mechanical respiratory support or extracorporeal membrane oxygenation (ECMO). For example, one specific application is in the heart, where high-dose T3 administration prevents diastolic and microvascular dysfunction and improves contractile strength. Furthermore, these effects are related to the prolonged inhibition of p38 MAPK activation, which is associated with anti-apoptotic activity and tissue preservation from injury. The present invention is based on the surprising observation that the administration QZZP Ln / Zznz / E / YIAI ίΠ / ZZΖηZ / E / YILI of a dosing regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy), improves right ventricular systolic function in critically ill patients with sepsis and / or coronavirus infection, such that the Tricuspid Annular Plane Systolic Excursion (TAPSE) parameter is preferably between 16 and 30 mm, more preferably between 20 and 25 mm. TAPSE is easily measured by echocardiography from the annular plane of the tricuspid valve and assesses right ventricular function along the longitudinal axis. TAPSE correlates well with overall right ventricular function (Rudski LG et al.Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J. Am. Soc. Echocardiogr. 2010, 23: 685-713). The present invention is based on the surprising observation that administering a dosage regimen as considered herein (high dose of T3 above any consideration of thyroid replacement therapy) improves right ventricular systolic function in critically ill patients with sepsis and / or coronavirus infection, such that the central venous pressure value is preferably measured between 1 and 10 mm Hg, most preferably between 3.7 and 7.4 mm Hg. Central venous pressure reflects the pressure in the right atrium of the heart and is considered an efficient indicator of right ventricular function in combination with fluid status in patients with sepsis (Reems, MM et al. Central venous pressure: principles, measurement, and interpretation. Compend. Condn. Educ. Vet. 2012, 34(1):E1). The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) improves inflammation and coagulation system failure in critically ill patients with sepsis and / or coronavirus infection, such that the erythrocyte sedimentation rate is reduced by 50% within a 48-hour period and is preferably measured below 30 mm within the first hour, as calculated by the reference method described by the International Committee for Standardization in Hematology (ICSH recommendations for the measurement of the erythrocyte sedimentation rate. J. Clin. Pathol. 1993, 46 (3): 198-203).The erythrocyte sedimentation rate (ESR) is a simple blood test that measures how quickly red blood cells settle to the bottom of an elongated flask due to gravity. It is calculated by measuring the distance (in mm) covered by the red blood cells within 1 hour. It is a general indicator of inflammation and is directly affected by disorders of the coagulation system (Harisson, M. Erythrocyte sedimentation rate and C-reactive protein. Aust. Prescr. 2015, 38 (3): 93-4). The reduction in erythrocyte sedimentation rate (ESR) is also related to microcirculatory function. Blood flow in the microvessels depends on viscous shear forces due to low flow velocities. Consequently, when the attractive forces between erythrocytes (represented by the ESR) are greater than the shear force produced by microvascular flow, tissue perfusion alone cannot be sustained, leading to capillary leakage. Thus, a reduced ESR indicates improved blood viscosity and better microvascular flow (Cho Yi, et al. Hemorheology and microvascular disorders. Korean Circ J. 2011 Jun;41(6):287-95.) The present invention is based on the surprising observation that the administration of a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy), does not increase or even reduce the levels of D-dimers, which represent an indicator for diagnosing intravascular coagulopathy and thrombosis, in critically ill patients with coronavirus infection. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) reduces mortality in critically ill patients with tissue hypoxia and sepsis. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) facilitates faster weaning from cardiorespiratory support in critically ill patients with tissue hypoxia and sepsis. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) facilitates early discharge from the Intensive Care Unit in critically ill patients due to tissue hypoxia and sepsis. The present invention is based on the surprising observation that administering a dosage regimen as considered in the present invention (high dose of T3 above any consideration of thyroid replacement therapy) facilitates early hospital discharge in critically ill patients with tissue hypoxia and sepsis. The present invention relates to a composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory response and multi-organ dysfunction, including kidney, liver, brain, lung, heart, Q77P ίη / 77Π7 / E / YΙΛΙ ίΠ / ZZΖηZ / E / YΙΛΙ gastrointestinal hematopoietic and / or coagulatory system, due to prolonged tissue hypoxia and microvascular dysfunction, in patients with sepsis, coronavirus infection, cancer, severe trauma and / or in heart and / or other organ transplants. The present invention in particular relates to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, which is administered by any of the commonly used routes of administration, for example, orally, parenterally, intramuscularly, intravenously, rectally, by inhalation, most preferably administered intravenously. The present invention in particular relates to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, formulated either as an injectable solution for immediate administration or as a lyophilized powder for reconstitution just before use. The present invention in particular relates to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, administered intravenously as a solution with a concentration in the range of 2 to 20 pg of T3 / mL, preferably 5 to 15 pg of T3 / mL, more preferably 7 to 12 pg of T3 / mL, and more preferably 10 pg of T3 / mL. In a preferred embodiment, the pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, is in the form of a 10 pg / mL T3 solution for injection in a bottle containing 150 pg of T3 in a total volume of 15 mL. The present invention in particular relates to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, comprising the active substance and pharmaceutically acceptable excipients including sugars, pH regulators and solvents. In a preferred embodiment, the pharmaceutical composition comprising Ltriiodothyronine or a pharmaceutically acceptable salt thereof, comprises sodium liothyronine, dextran, sodium hydroxide solution IN and water for injection. In a preferred embodiment, the pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, is in the form of a lyophilized powder for reconstitution with water for injection or 0.9% sodium chloride solution, just before use. The present invention in particular relates to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, which is administered in much higher doses than in the normal treatment of patients with inadequate thyroid function (e.g., patients with hypothyroidism or myxedema). The present invention relates in particular to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, administered in doses of 5 pg per kg of body weight to 9 pg per kg of body weight, preferably 6 pg per kg of body weight to 8 pg per kg of body weight, more preferably 7 pg per kg of body weight in total, for 24 to 72 hours, optimally for 48 hours. Without supporting any theory, a period of 24 hours is considered the minimum time frame to achieve the beneficial effect of this treatment, while a period of more than 72 hours does not offer any additional beneficial effect. According to the present invention, subjects between 60 and 80 kg can receive intravenously from 420 pg to 560 pg of T3 in total. In a preferred modality, a 75 kg subject receives intravenously 375 pg to 675 pg of total T3, preferably 450 pg to 600 pg of T3, more preferably 525 pg of total T3. According to the present invention, the pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, is administered to a subject by continuous infusion at a rate of 0.08 to 0.20 pg / kg / h, preferably 0.12 to 0.16 pg / kg / h and more preferably 0.14 pg / kg / h for 48 hours. According to the present invention, the pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, is administered to a subject as an initial bolus on the scale of 0.6 pg / kg to 1.0 pg / kg of body weight, preferably as an initial bolus of 0.8 pg / kg of body weight, followed by continuous infusion at a rate of 0.1 to 0.2 pg / kg / h, preferably 0.1 to 0.12 pg / kg / h and more preferably at a rate of 0.112 pg / kg / h for 48 hours. According to the present invention, the pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof is administered to a subject preferably as an initial bolus followed by a continuous infusion, rather than as a continuous infusion from the outset, in order to achieve a rapid onset of action and therapeutic effects. If high T3 levels are not achieved in a timely manner, the beneficial effects of the pharmaceutical composition may be counteracted. The present invention in particular relates to a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, for use in the treatment of tissue hypoxia due to microvascular dysfunction, not only for short-term hypoxia, but also for long-term hypoxia, at least 30 minutes, or at least 3 hours, or at least 4, 6, 12, 18 or 24 hours of hypoxia. The present invention is further explained by means of the following non-limiting and illustrative examples. EXAMPLE 1 T3 v prevention of prolonged hypoxia-induced injury The isolated rat heart model was used to simulate non-ischemic conditions of tissue hypoxia ex vivo. In this study, rat hearts were perfused only with an oxygenated Krebs pH regulator containing electrolytes and glucose under normothermia. Despite normal perfusion, the organ gradually developed significant dysfunction over several hours due to the absence of erythrocytes and hemoglobin, creating hypoxic conditions. Thus, during a prolonged 4-hour period of hypoxic perfusion, normal hearts (control group) gradually developed diastolic dysfunction, and the left ventricular end-diastolic pressure (LVEDP) increased substantially above 20 mmHg (Figure 1). It should be noted that such an increase in LVEDP can lead to pulmonary edema in vivo.Furthermore, the force of contraction was reduced as evidenced by a 25% decrease in the pressure developed in the left ventricle (LVDP) in Control hearts (Figure 2). Interestingly, treatment with high-dose L-triiodothyronine (group T3) (40 pg / L) after the first 30 minutes of hypoxic perfusion attenuated diastolic dysfunction, maintained normal VEDP values, and improved contractile force at 4 hours. Furthermore, hypoxic perfusion resulted in microvascular dysfunction of the heart, monitored as a significant increase in coronary perfusion pressure over time in control hearts (Figure 3). However, treatment with triiodothyronine significantly inhibited microvascular dysfunction and resulted in lower perfusion pressure after 4 hours (Figure 3). More importantly, molecular analysis of intracellular kinase signaling activation revealed that the pro-apoptotic p38 MAPK was significantly activated after 4 hours of prolonged hypoxic perfusion and T3 administration prevented this activation by 3 times, p<0.05 (Figure 4).Specific p38 MAPK inhibitors exist and have been tested for other indications, but not for prolonged hypoxic tissue injury. Ralimetinib is a selective small-molecule p38 MAPK inhibitor. Preclinical studies have demonstrated antineoplastic activity in xenograft models as a single agent (non-small cell lung, multiple myeloma, breast, glioblastoma, and ovary) and in combination with other chemotherapeutic agents. [Vergote, I., et al, A randomized, double-blind, placebo-controlled phase lb / 2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer, Gynecologic Onco / ogy, ίΠ / ΖΖηΖ / Ε / ΥΙΛΙ https: / / doi.orq / 10· 1016 / i.yqyno.2019.11.0061.Losmapimod is another potential inhibitor of p38 MAPK in macrophages, myocardium, and endothelial cells and showed protective myocardial effects in patients with non-ST-segment elevation myocardial infarction [IK Newby et al. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial, Lancet(2014) 384, 1187-95]. The results indicated above are best understood with reference to figures 1 to 4. Figure 1 shows the left ventricular end-diastolic pressure (LVEDP) under hypoxic organ perfusion conditions in normal hearts (Control) and hearts treated with T3 (T3) for 4 hours. *p<0.05 vs. Control Figure 2 shows the reduction in left ventricular developed pressure (LVDP) under hypoxic organ perfusion conditions in normal hearts (Control) and hearts treated with T3 (T3) for 4 hours. *p<0.05 vs. Control Figure 3 shows the perfusion pressure under hypoxic organ perfusion conditions in normal hearts (Control) and hearts treated with T3 (T3) for 4 hours. *p<0.05 vs Control Figure 4 shows p38 MAPK activation under hypoxic organ perfusion conditions in normal (Control) and T3-treated (T3) hearts. *p<0.05 vs. Control EXAMPLE 2 L-Trivodothyronine v tissue hypoxia in sepsis occurring in the myocardium, kidneys and liver The effect of high-dose T3 administration in the treatment of tissue hypoxia due to microvascular dysfunction occurring in the myocardium, kidneys, and liver was evaluated in an experimental model of sepsis using 10- to 12-week-old male C57BL / 6N mice. Animal studies were conducted in accordance with all applicable regulations. The simulation of clinical conditions during sepsis that lead to tissue hypoxia and microvascular dysfunction is achieved by following the widely used clinical model of cecal ligation and puncture (CLP). In this experimental model, ligation distal to the ileocecal valve (25% of the total cecal length) and perforation via a single 21G needle puncture are performed under sevoflurane anesthesia, resulting in leakage of fecal contents into the peritoneum, with subsequent polymicrobial bacteremia and sepsis. Cecal perforation allows the release of fecal matter into the peritoneal cavity, generating an exacerbated immune response induced by polymicrobial infection. In this model, sepsis causes systemic activation of the inflammatory response, microvascular dysfunction, tissue hypoxia, multiorgan failure, and hemodynamic disturbance, resulting in death, as in clinical practice. The animals are maintained with subcutaneous fluid administration every 8 hours and the administration of buprenorphine 0.1 mg / kg and paracetamol 300 mg / kg, as is the case for septic patients in the Intensive Care Unit (ICU). All animals are closely monitored for their clinical status based on a modified scoring scale known as the Lipopolysaccharide (LPS) Score Sheet. The animals were divided into two groups: the first group received a placebo (placebo group), and the second group received an intraperitoneal dose of 0.3 pg of T3 / g of body weight immediately after surgery (T3 group). Based on guidelines for converting experimental animal doses to equivalent human doses (Nair, AB and Jacob S. A simple practice guide for dose conversion between animals and humans. J Basic Clin Pharma 2016, 7: 27-31), the dose of 0.3 pg of T3 / g of body weight corresponds approximately to the intravenous administration of 7 pg of T3 / kg of body weight, i.e., 400 to 600 pg of T3 for a patient weighing 60-80 kg. This dose is very high and beyond any T3 treatment in patients with hypothyroidism. This study was conducted in two separate experiments.In the first experimental protocol, the clinical condition of the animals and mortality after 72 hours were examined, while in the second experimental protocol, tissue hypoxia at the cellular level after euthanasia at 18 was studied. Initially, lactate levels in blood samples were measured (using the Sigma-Aldrich L-Lactate Assay Kit, MAK329) as a general indicator of hypoxia, which is also commonly used in clinical practice in patients with sepsis. Additionally, blood creatinine levels were measured as an indicator of renal function (using the Mouse Creatinine Kit Cat.80350, Crystal Chem). Finally, echocardiographic analysis was performed to assess end-diastolic and end-systolic volumes, ejection fraction, and pulse volume according to Simpson's rule. Echocardiographic analysis was performed after light anesthesia with sevoflurane (0.8%) and the animal was placed on a warming blanket. Echocardiographic images were then acquired along the longitudinal and transverse sternal axes using a Vivid 7 Pro version ultrasound system (GE Healthcare, Wauwatosa, Wisconsin), equipped with a 14.0 MHz probe (13L). Tissue hypoxia at the cellular level was determined in frozen, fixed tissues in 4% paraformaldehyde based on the standard method of pimonidazole administration using the Hypoxyprobe™ Plus kit. Pimonidazole was dissolved and administered intravenously to mice at a dose of 60 mg / kg, 2 hours prior to euthanasia. Following intracardiac infusion with paraformaldehyde, the organs were fixed, removed, and dehydrated for 5 days in 30% sucrose solution. The organs were then immersed in OCT (optimal cutting temperature compound), placed in a cryostat, and cut into 20 µm thick sections. Pimonidazole diffuses into cells and is reductively activated in hypoxic cells (pOz <10 mm Hg) by forming stable complexes with sulfhydryl groups of proteins, peptides, and amino acids.These complexes were then detected using immunohistochemical methods with specific antibodies and the dye DAB (3,3D-Diaminobenzidine), which imparts a characteristic brown color. Images were taken under a microscope (Zeiss Axiovert), and automated image analysis was performed using ImageJ software to quantify the hypoxic area. Sepsis resulted in a significant worsening of the clinical condition of the animals in the placebo group. Increased mortality was observed especially after 24 hours, while all animals died within 72 hours. However, in the T3 group, there was a significant improvement in mortality, with up to 20% of the animals surviving 72 hours (Figures 5A to 5C). Sepsis also causes elevated blood lactate levels in the placebo group at both 18 and 24 hours. Lactate is a known product of anaerobic metabolism and is therefore considered an important indicator of systemic hypoxia. Unexpectedly, T3 administration leads to a decrease in lactic acid levels at both 18 and 24 hours (Figures 6A and 6B). It is important to mention that the increase in lactate levels was observed despite normal cardiac function, as shown by echocardiography. Ejection fraction, pulse volume, and heart rate were found to be within normal limits, with no significant differences between the two groups studied, indicating that both cardiac output and macrocirculatory perfusion were normal (Figures 7A and 7B). The study of myocardial tissue hypoxia showed that in the placebo group of sepsis, positive tissue reached an average of 4% ± 0.5 of the total left ventricle tissue, whereas the administration of T3 resulted in a statistically significant reduction of tissue hypoxia to 1.5% ± 0.5, p = 0.028 (Figures 8A and 8B). Regarding renal tissue hypoxia, it was observed that only 18 hours after sepsis, there was a significant increase in tissue hypoxia in the placebo group, especially in the areas of the renal tubules (outer medullary fringe - OSOM, and inner medullary fringe - ISOM) and less in the cortex, while the administration of T3 significantly reduces tissue hypoxia in these areas (OSOM and ISOM) (Figures 9A and 9B). Furthermore, creatinine levels did not increase in either group at 18 hours, as damage to more than 50% of the kidney mass needs to occur to observe an increase in serum creatinine (Figure 10). qzzp ίη / ζζηζ / Ε / γίΛΐ Unexpected results were observed with respect to the study of liver tissue hypoxia. Specifically, 18 hours after sepsis, there was a significant increase in tissue hypoxia in the placebo group, selectively localized mainly around the hepatic venous regions, whereas administration of T3 according to the present invention led to a statistically significant reduction in hepatic hypoxia (Figures HA and 11B). The results above indicate that high-dose T3 treatment can prevent tissue hypoxia in cardiac, liver, and kidney samples occurring early in experimental sepsis (within 18 h) before cardiac output deteriorates. Pimonidazole staining was used to detect tissue pO2 <10 mmHg. Oxygen below this level results in the activation of hypoxia-inducible factor (HIFα)-dependent regulatory mechanisms that promote pathological angiogenesis, changes in the immune response, and determine the progression of sepsis-induced injury. Thus, T3 treatment could regulate HIFα-dependent pathways by restoring normal tissue oxygen levels. T3 treatment also significantly reduced circulating lactate levels, likely due to the prevention of tissue hypoxia and microvascular dysfunction.However, the beneficial effects of T3 on cellular metabolism may also explain this effect. T3 can enhance the coupling of glycolysis to glucose oxidation and decrease H+ production through its action on pyruvate dehydrogenase (PDH) activity. PDH has been found to be suppressed during sepsis (Nuzzo E, et al. Pyruvate dehydrogenase levels are low in sepsis. Cr / M^re2015, 19:P33.). The results indicated above are best understood with reference to figures 5A to 11B. Figures 5A to 5C show (Figure 5A) changes in body weight; (Figure 5B) changes in clinical condition (LPS scale) and (Figure 5C) animal survival after sepsis, in the placebo group and the T3 group. Figures 6A and 6B show lactic acid levels before surgery (Control) and after sepsis in the placebo group and the T3 group at (Figure 6A) 18 hours and (Figure 6B) 24 hours. Figures 7A and 7B illustrate (Figure 7A) the left ventricular ejection fraction and (Figure 7B) the pulse volume, 18 hours after induction of sepsis in the placebo group and in the T3 group, as shown in the echocardiogram analysis. Figures 8A and 8B show: (Figure 8A) representative microscope images showing myocardial tissue after tissue hypoxia induced by pimonidazole (brown, intense image). Presented are: normal tissue (Control - left side) as well as tissue from experimental animals that received placebo (center) and T3 (right side); (Figure 8B) the quantification of tissue hypoxia after image processing with specialized software. qzzp ίη / ζζηζ / Ε / γίΛΐ Figures 9A and 9B show (Figure 9A) representative microscope images of renal tissue after labeling of tissue hypoxia with pimonidazole (brown, intense images) in different areas of the kidney (Cortex, OSOM, ISOM). It shows normal tissue (Control - left side) as well as tissue from experimental animals that received placebo (center) and T3 (right side). (Figure 9B) Diagram illustrating the quantification of tissue hypoxia after image processing with specialized software. Figure 10 shows serum creatinine levels before surgery (Normal) as well as at 18 hours and 24 hours after sepsis in the placebo group and the T3 group. Figures 11A and 11B show (Figure 11A) representative microscope images of liver tissue after labeling of tissue hypoxia with pimonidazole (brown, bright image). Normal tissue: Control - left side; tissue from experimental animals that received placebo (center) and T3 (right side). (Figure 11B) the quantification of tissue hypoxia after image processing with special software. EXAMPLE 3 Effect of high-dose L-trivodothyronine administration in critically ill patients with COVID-19 infection This study (ThySupport, EudraCT: 2020-001623-13) is a phase II, parallel-group, prospective, randomized, double-blind, placebo-controlled study that aims to investigate the effect of intravenous T3 for the treatment of critically ill patients admitted to the intensive care unit (ICU) due to COVID-19 infection. Specifically, it refers to ICU patients diagnosed with lung infection due to COVID-19 who require mechanical ventilation or ECMO. Example 3 refers to the initial results of this study. Treatment begins with a relatively high dose immediately after the patient is intubated. This single dose (bolus) can range from 0.6 pg / kg to 1.0 pg / kg of body weight, and is preferably 0.8 pg / kg of body weight. Patients can then receive a dose of 4.0 to 8.0 mL of a T3 solution containing 10 pg of L-triiodothyronine per 1 mL over a period of 2 to 3 minutes. This bolus dose can be administered intravenously. Subsequently, patients receive a continuous infusion for 24 to 72 hours, preferably for 48 hours after the bolus administration. Typically, patients receive T3 by continuous infusion at a rate of 0.1 to 0.2 pg / kg / h, preferably 0.10 to 0.12 pg / kg / h, and more preferably 0.112 pg / kg / h for 48 hours. After the first continuous infusion, if necessary, patients Q77Ó ίη / 77Π7 / E / YΙΛΙ may receive a second continuous infusion of T3 on the scale of 0.025 to 0.08 pg / kg / h, preferably 0.056 gg / kg / h, until successful disconnection from mechanical support or final follow-up and for a maximum period of 30 days. Blood T3 levels increased as expected based on the dosage regimen and pharmacokinetic data as shown in Figure 12. However, the high doses of T3 administered according to the present invention do not cause adverse effects in patients, as shown, for example, by the d-dimer levels, which remained unchanged during the first 48 hours after administration of high-dose T3 (Figure 13). D-dimers are an indicator of activation of the coagulation system and are related to the inflammatory response in patients with sepsis. Effect of high-dose T3 administration on the heart High-dose T3 administration did not induce significant tachycardia, atrial fibrillation, or ventricular arrhythmias (Figure 14). High levels of thyroid hormones are associated with increased heart rate and can cause certain arrhythmias, such as atrial fibrillation. However, preliminary results from the ThySupport study do not support this effect in patients with severe COVID-19. High-dose T3 administration was not associated with an increase in myocardial damage as assessed by troponin levels. High-dose T3 administration to patients with COVID-19 tends to decrease troponin levels compared to patients receiving placebo (Figure 15). The cardioprotective effect of T3 in sepsis appears to be an important finding with significant therapeutic value regarding patient outcomes, as myocardial damage increases mortality in patients with COVID-19 according to recent studies. High-dose T3 administration is associated with improved troponin levels and maintenance of left ventricular function, as assessed by left ventricular ejection fraction (Figure 16). Left ventricular function is crucial for maintaining hemodynamic stability in these patients. High-dose T3 administration did not induce right ventricular (RV) function impairment but unexpectedly improved RV function (Figure 17). The RV, which maintains blood flow to the lungs, is affected by sepsis and COVID-19 infection due to tissue changes in the lung parenchyma that result in increased resistance encountered by the RV. Furthermore, mechanical ventilation during intubation can further increase pulmonary vascular resistance and impair right ventricular function. These conditions created in sepsis can lead to right ventricular dysfunction associated with the RV's inability to respond to the increased workload due to hypoxia (right ventricle QZZP ίη / ZZΠZ / E / YΙΛΙ arterial uncoupling). According to these data, pulmonary artery systolic pressure (PASP), an indicator of right ventricular workload, was found to be similar between the two groups, while right ventricular inotropic status, as assessed by measuring the tricuspid annular plane systolic excursion (TAPSE), showed an upward trend in patients after T3 administration. Furthermore, these patients exhibited low central venous pressure. The effect of T3 on right ventricular function in sepsis is an important finding, as right heart failure is associated with high mortality within the first 28 days. High-dose T3 administration was not accompanied by an increase in central venous pressure during the first 24 hours; in fact, it showed a tendency to decrease. (Figure 18). This finding is directly related to normal right ventricular function in patients in the T3 group. Effect of high-dose T3 administration on renal function Creatinine is an important indicator of renal function. An increase in creatinine in critically ill patients with COVID-19 indicates possible hypoxic kidney damage due to sepsis and is an indicator of poor prognosis. Laboratory tests have shown that high-dose T3 administration maintains normal renal function during the first 24 hours, as shown by creatinine levels (Figure 19). Effect of high-dose T3 administration on liver function Aspartate aminotransaminase (AST) is an important indicator of liver function. An increase in AST in critically ill patients with COVID-19 indicates possible hypoxic liver damage due to sepsis and is an indicator of poor prognosis. Laboratory tests show that high-dose T3 maintains good liver function in patients, as shown by AST measurements during the first 24 hours (Figure 20). Effect of high-dose T3 administration on the inflammatory response The administration of a high dose of T3 according to the present invention did not worsen, but unexpectedly improved the inflammatory response as shown by the erythrocyte sedimentation rate in the first 48 hours (Figure 21). The erythrocyte sedimentation rate (ESR) remains an informative parameter of inflammation and hemorheological abnormalities. The ESR reflects immune activation, altered plasma viscosity, increased red blood cell aggregation, and impaired microvascular blood flow. Interestingly, the ESR has been shown to be related to the severity of COVID-19, where vasculitis is one of the main underlying pathophysiological mechanisms (Lapic I, et al. Erythrocyte sedimentation rate is associated with severe coronavirus disease 2019 (COVID-19): a pooled analysis. Clin Chem Lab). QZZC Ln / Zznz / E / YIAI Med. 2020, 58(7):1146-1148). The erythrocyte sedimentation rate (ESR) has been a useful parameter in clinical practice for monitoring drug therapies in various diseases. Here, we provide data showing that T3 administration in ventilated COVID-19 patients results in an acute decrease in the ESR. Furthermore, the magnitude of the ESR decrease was strongly correlated with circulating T3 levels (Figure 22). The potential of T3 administration to acutely reduce the ESR has not been previously described. This may reflect novel actions of T3 in inflammation and hemorheological abnormalities. The latter may be physiologically relevant with respect to tissue hypoxia. The results indicated above are best understood with reference to Figures 12 to 22 where: Figure 12 shows the blood T3 levels for each patient in the first 48 hours after administration of high-dose T3. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 13 shows d-dimer levels for each patient during the first 48 hours after high-dose T3 administration. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 14 shows the heart rate (beats per minute) for each patient during the first 48 hours after administration of high-dose T3. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 15 shows the troponin I levels for each patient in the first 48 hours after administration of high-dose T3. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 16 shows the left ventricular ejection fraction for each patient in the first 48 hours after high-dose T3 administration. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 17 shows the systolic function of the right ventricle 48 hours after administration of high-dose T3. Figure 18 shows the central venous pressure for each patient in the first 24 hours after administration of high-dose T3. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 19 shows the creatinine levels for each patient in the first 24 hours after administration of high-dose T3. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 20 shows the liver enzyme levels for each patient in the first 24 hours after administration of high-dose T3. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 21 shows the erythrocyte sedimentation rate levels for each patient in the first 48 hours after high-dose T3 administration. (Patients A3 and A4 received T3, while A1, A2, and A5 received placebo.) Figure 22 shows the erythrocyte sedimentation rate between patients receiving a high dose of T3 and patients receiving a placebo. According to the present invention, the administration of high doses of T3 to intubated COVID-19 patients is safe, without serious side effects such as arrhythmias, pulmonary embolism, etc. According to the present invention, administering a high dose of T3 to patients with sepsis due to COVID-19 improves myocardial damage and right ventricular function while at the same time resulting in a reduction of the inflammatory response. EXAMPLE 4 A professional may refer to the following explanation and charts, which show an example of the T3 administration dosage schedule according to a subject's weight. TABLE 1 T3 Solution dosage schedule for injection at 10 uq / mL according to patient weight Patient Weight Bolus Administration over 2-3 min Continuous Infusion Pump Rate (first 48h) Pump Rate (from day 3 to end) 66Kg 5.5 mL (55pg) 18 mL (180pg) in 232 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h 70Kg 5.5 mL (55pg) 19 mL (190pg) in 231 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h 74Kg 6 mL (60pg) 20 mL (200pg) in 230 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h 77Kg 6 mL (60pg) 21 mL (210pg) in 229 mL of NaCl 0.9% 10.4 mL / h 5.2 mL / h 81 Kg 6.5 mL (65pg) 22 mL (220pg) in 228 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h 85 Kg 7.0mL (70pg) 23 mL (230pg) in 227 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h 89Kg 7.0mL (70pg) 24 mL (240pg) in 226 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h 92Kg 7.5 mL (75pg) 25 mL (250pg) in 225 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h >95Kg 7.5 mL (75pg) 26 mL (260pg) in 224 mL of 0.9% NaCl 10.4 mL / h 5.2 mL / h qzzp ίη / ζζηζ / Ε / γίΛΐ As a more specific example, the practitioner may consider the following. For a patient weighing 77 kg, a 6 mL dose (60 pg) will be administered as an intravenous bolus over 2–3 minutes within 60 minutes of initiating respiratory support. The patient will then receive 21 mL of the product (total 210 pg of T3) diluted in 0.9% NaCl and administered via pump at a steady flow rate of 10.4 mL / h for a total of 48 hours. From day 3 until successful weaning or the end of follow-up, the patient will receive 50% of this dose, 10.5 mL of the product (total 105 pg of T3) diluted in 0.9% NaCl and administered via pump at a steady flow rate of 5.2 mL / h. Triiodothyronine in the study was used in the form of a 10 pg / mL T3 Solution for Injection containing 150 pg of L-triiodothyronine in a total volume of 15 mL per vial. The drug is a solution containing the active substance liothyronine sodium and other ingredients, including dextran 70, 1 N NaOH, and water for injection. Liothyronine sodium is synthesized in vitro. The drug may also be supplied in lyophilized form and reconstituted with water for injection or saline solution immediately before use. Example of the T3 solution for injection NO. Name of ingredient(s) Amount / ImL Active ingredient: 1. Liothyronine sodium 10.0 pg Other ingredient(s): 1. Dextran 70 60.0 mg 2. NaOH 1 N ca. pH 10 3. Water for injection ca. 1.0 The administered dose is 0.8 pg / kg as an intravenous bolus starting immediately after the initiation of respiratory support, followed by an intravenous infusion of 0.112 pg / kg / h for 48 hours. From day 3 until successful weaning or the end of follow-up, the patient may receive 0.056 pg / kg / h intravenously, if necessary.

Claims

1. A pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory response or dysfunction of one or more organs in subjects with tissue hypoxia and microvascular dysfunction caused by sepsis, severe injury, cancer and / or extracorporeal organ protection comprising the treatment of kidneys, liver, brain, heart, gastrointestinal system, hematopoietic system or coagulation system, wherein said composition is adapted to be administered on the scale of 5 to 9 pg of L-triiodothyronine per kg of body weight, more preferably 6 to 8 pg of L-triiodothyronine per kg of body weight, more preferably 7 pg of L-triiodothyronine per kg of body weight.

2. The pharmaceutical composition for use according to claim 1, in the treatment of prolonged hypoxia due to sepsis for at least 30 minutes, or at least 3 hours, or at least 4, 6, 12, 18, or 24 hours.

3. The pharmaceutical composition for use according to claim 2, in the treatment of right ventricular systolic function, wherein the Tricuspid Annulus Plane Systolic Displacement (TAPSE) is between 16 and 30 mm, preferably between 20 and 25 mm.

4. The pharmaceutical composition for use according to claims 2 or 3, in the treatment of right ventricular systolic function, wherein the central venous pressure value is measured between 1 and 10 mm Hg, preferably between 3.7 and 7.4 mm Hg.

5. The pharmaceutical composition for use according to claim 2, in the treatment of an inflammatory response and dysfunction of the coagulation system, wherein the erythrocyte sedimentation rate is reduced by 50% during a period of 48 hours and is preferably measured below 30 mm within the first hour.

6. The pharmaceutical composition for use according to any of claims 1 to 5, wherein L-triiodothyronine or a pharmaceutically acceptable salt thereof is formulated either as a solution for injection or as a lyophilized powder for reconstitution.

7. The pharmaceutical composition for use according to claim 6, wherein the L-triiodothyronine or a pharmaceutically acceptable salt thereof is in the form of an injectable solution at a concentration of 2 to 20 pg / mL, preferably 5 to 15 pg / mL, more preferably at a concentration of 10 pg / mL.

8. The pharmaceutical composition for use according to claim 7, wherein the L-triiodothyronine or a pharmaceutically acceptable salt thereof is adapted to be administered as a continuous injection at a rate of 0.08 to 0.20 pg / kg / h, more preferably at a rate of 0.12 to 0.16 pg / kg / h, more preferably 0.14 pg / kg / h for 48 hours.

9. The pharmaceutical composition for use according to claim 7, wherein the L-triiodothyronine or a pharmaceutically acceptable salt thereof is adapted to be administered as an initial dose of 0.6 to 1.0 pg of L-triiodothyronine per kg of body weight, more preferably 0.7 to 0.9 pg of L-triiodothyronine per kg of body weight, more preferably 0.8 pg of L-triiodothyronine per kg of body weight, following continuous injection at a rate of 0.10 to 0.20 pg / kg / h, more preferably at a rate of 0.10 to 0.14 pg / kg / h, more preferably 0.112 pg / kg / h for 24 to 72 hours, preferably for 48 hours following bolus administration.

10. The pharmaceutical composition for use according to claims 7 to 9, wherein a 75 kg subject receives intravenously from 375 pg to 675 pg of T3 in total, preferably from 450 pg to 600 pg of T3, more preferably 525 pg of T3 in total.

11. The pharmaceutical composition for use in accordance with any of claims 1 to 10, comprising pharmaceutically acceptable excipients.

12. The pharmaceutical composition for use in accordance with any of claims 1 to 11, comprising one or more active substances.

13. The use of a pharmaceutical composition comprising L-triiodothyronine or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of an inflammatory response or dysfunction of one or more organs in subjects with tissue hypoxia and microvascular dysfunction caused by sepsis, severe injury, cancer and / or protection of extracorporeal organs comprising the treatment of kidneys, liver, brain, heart, gastrointestinal system, hematopoietic system or coagulation system, wherein said composition is adapted to be administered on a scale of 5 to 9 pg of L-triiodothyronine per kg of body weight, more preferably 6 to 8 pg of L-triiodothyronine per kg of body weight, more preferably 7 pg of L-triiodothyronine per kg of body weight.

14. The use as claimed in claim 13, in the treatment of prolonged hypoxia due to sepsis for at least 30 minutes, or at least 3 hours, or at least 4, 6, 12, 18, or 24 hours.

15. The use as claimed in claim 14, in the treatment of right ventricular systolic function, wherein the Tricuspid Ring Plane Systolic Displacement (TAPSE) is between 16 and 30 mm, preferably between 20 and 25 mm.

16. The use as claimed in claims 14 or 15, in the treatment of right ventricular systolic function, wherein the central venous pressure value is measured between 1 and 10 mm Hg, preferably between 3.7 and 7.4 mm Hg.

17. The use as claimed in claim 14, in the treatment of an inflammatory response and dysfunction of the coagulation system, wherein the erythrocyte sedimentation rate is reduced by 50% during a period of 48 hours and is preferably measured below 30 mm within the first hour.

18. The use as claimed in any of claims 13 to 17, wherein L-triiodothyronine or a pharmaceutically acceptable salt thereof is formulated either as a solution for injection or as a lyophilized powder for reconstitution.

19. The use as claimed in claim 18, wherein the L-triiodothyronine or a pharmaceutically acceptable salt thereof is in the form of an injectable solution in a concentration of 2 to 20 pg / mL, preferably 5 to 15 pg / mL, more preferably in a concentration of 10 pg / mL.

20. The use as claimed in claim 19, wherein L-triiodothyronine or a pharmaceutically acceptable salt thereof is adapted to be administered as a continuous injection at a rate of 0.08 to 0.20 pg / kg / h, more preferably at a rate of 0.12 to 0.16 pg / kg / h, more preferably 0.14 pg / kg / h for 48 hours.

21. The use as claimed in claim 19, wherein L-triiodothyronine or a pharmaceutically acceptable salt thereof is adapted to be administered as an initial bolus of 0.6 to 1.0 pg of L-triiodothyronine per kg of body weight, more preferably 0.7 to 0.9 pg of L-triiodothyronine per kg of body weight, more preferably 0.8 pg of L-triiodothyronine per kg of body weight, following continuous injection at a rate of 0.10 to 0.20 pg / kg / h, more preferably 0.10 to 0.14 pg / kg / h, more preferably 0.112 pg / kg / h for 24 to 72 hours, preferably for 48 hours following the bolus administration.

22. The use as claimed in claims 19 to 21, wherein a 75 kg subject receives intravenously from 375 pg to 675 pg of T3 in total, preferably from 450 pg to 600 pg of T3, more preferably 525 pg of T3 in total.

23. The use as claimed in any of claims 13 to 22, comprising pharmaceutically acceptable excipients.

24. The use as claimed in any of claims 13 to 23, comprising one or more active substances.