RU2735797C1 - Method for improving oxygenating pulmonary function in the patients with a new coronaviral infection (covid-19) with respiratory failure who are on respiratory support - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to intensive care and resuscitation, and can be used for treating patients with a new coronavirus infection (COVID-19). Method involves intravenous introduction of a serotonin adipinate solution at rate of 10–30 mg/h to the patients with a new coronaviral infection COVID-19 with respiratory failure on respiratory support. Respiratory support is non-invasive lung ventilation, oxygen therapy; additionally, calcium nandroparin or enoxaparine are administered.

EFFECT: using the invention enables improving the oxygenating function of the lungs by normalizing smooth muscle function of the microcirculatory bed of the lungs and other organs, and thereby increasing gas exchange.

1 cl, 3 tbl, 3 ex

Description

The invention relates to medicine, in particular to intensive care and resuscitation, and for the treatment of patients with a new coronavirus infection (COVID-19).

The primary task in critical conditions is the elimination of total (hypoxemia) and local hypoxia, followed by the normalization of metabolism in human organs and tissues.

Violation of the oxygenating function of the lungs, as the main process in the work of the external respiration apparatus, leads to the development of respiratory failure, which leads to hypoxia, metabolic disorders, organ dysfunction, mono-multiple organ failure and death. The efficiency of gas exchange in the lungs is evidenced mainly by a laboratory indicator - the partial pressure (tension) of oxygen in arterial blood (PaO2), and the indicator measured by a pulse oximeter - the degree of saturation of hemoglobin of arterial blood with oxygen (SpO2) [1].

A number of authors during COVID-19 have noted the direct cytotoxic effect of the virus on type 2 alveolocytes, leading to the collapse of the alveoli and disruption of gas exchange with the development of a "shock lung", called in the literature - acute respiratory distress syndrome (ARDS). They also note the importance of alveolar damage to the endothelium with microvascular thrombosis, which indicates atypical ARDS in COVID-19, and gave it its own name - MicroCLOTS - microvascular COVID-19 of pulmonary vessels with obstructive thromboinflammatory syndrome [2].

ARDS in COVID-19, according to them, includes increasing hypoxemia with microvascular pulmonary thrombosis, which are detected not only in the lungs, but also transfer to the microvascular bed of the brain, heart, kidneys and other organs [3]. Pneumonia in COVID-19 leads to a complete loss of vascular tone due to vasoconstrictor or vasodilating agents [4].

It was previously thought that in the case of ARDS and severe pneumonia, early intubation and mechanical ventilation (ALV) would improve patient survival [5]. However, according to studies conducted in the UK and the USA, with COVID-19, the lethality of patients on mechanical ventilation is very high and amounts to 65-88% [6]. Therefore, in the treatment of hypoxemia in COVID-19, respiratory support techniques have begun to be used, which make it possible to delay or completely reduce the frequency of patient transfers to mechanical ventilation and, as a result, reduce mortality. These include the following: oxygen therapy, high-flow oxygenation and non-invasive ventilation (NVL) [7]. Respiratory support techniques are ineffective in critically ill patients. For example, in the intensive care unit (RO) of China, up to 56% of patients were on NVL, but 76% of them were subsequently transferred to mechanical ventilation. The mortality rate among patients receiving NVL before mechanical ventilation was 78% [8].

Thus, an urgent and large scientific and practical task is the development of new pathogenetically substantiated methods for the prevention and treatment of impaired lung oxygenation in patients with COVID-19, which will allow to delay or avoid mechanical ventilation and, accordingly, improve the results of treatment of these patients and reduce the cost of efforts and resources for their treatment.

There are known reports, which can be taken as an analogue when writing a patent, on the use of inhaled nitric oxide (NO) to correct hypoxemia in non-intubated patients with COVID-19, allowing to delay mechanical ventilation [9].

This analogue, in our opinion, has the following disadvantages:

1. According to the Italian School of Respiratory Therapy, NO inhalation is indicated not for all patients.

2. Determination of the detailed indications for ARDS in non-intubated patients with COVID-19 is technically difficult, since the condition of the patients does not always allow for CT (computed tomography) examination.

3. Inhaled NO is not universal for all types of COVID-19 patients, since it only plays the role of a vasodilator [10], and it is known that impaired vascular smooth muscle tone in ARDS is mosaic in nature and is accompanied by both vasospasm and vasodilation.

4. Conducting NO inhalation requires additional expenditures of manpower and resources, which limits the application of the technique in the context of the COVID-19 pandemic.

The closest analogue for us is a method for improving the oxygenating function of the lungs in patients with respiratory failure who are on mechanical ventilation [11]. The patent description provides data that patients with respiratory failure and who are on mechanical ventilation are injected intravenously with 10-500 mg of a 1% solution of serotonin adipate (CA) at a rate of 10-30 mg / h, dissolved in physiological solution. The introduction is repeated for 10-14 days. In patients, the function of smooth muscles (GM) of the microvasculature of the lungs and other organs improves, as a result of which gas exchange improves with an increase in PaO2 and the elimination or decrease of the severity of total hypoxia (hypoxemia), which improves metabolism in tissues and leads to recovery. At the same time, the increase in PaO2 is 40-42% on average. Similar results of improving the oxygenating function of the lungs when using SA were obtained by independent researchers from the Russian Federation and Kazakhstan [12, 13, 14].

However, this method has not yet been tested in patients with COVID-19, who have features from other previously known infections, as well as in patients on respiratory support, in addition, this analogue does not reflect the role of anticoagulants that can improve the rheological properties of blood and, accordingly , have a possible synergistic effect on improving impaired oxygenating lung function.

The technical problem to be solved by the present invention is to improve the impaired oxygenating function of the lungs by intravenous administration of CA and direct anticoagulants to patients who are on respiratory support, which will lead to a decrease in the number of their transfers to mechanical ventilation, to improve treatment results and, accordingly, to reduce the time hospitalization of patients with COVID-19 and reducing the cost of their treatment.

The problem is solved in the claimed method for improving the oxygenating function of the lungs in patients with COVID-19 by normalizing the function of the GM of the vascular bed, improving microcirculation and gas exchange in the lungs, for this a solution of serotonin adipinate is injected intravenously at a rate of 10-30 mg / h, characterized in that the patient COVID-19 is provided with respiratory support and additionally, direct anticoagulants are administered in a therapeutic dose.

The human body contains serotonin (20-300 μg / l), which is necessary for normal life. In 1991, the "Syndrome of serotonin deficiency in humans and animals" was described, which was recognized by the RAMS as a discovery. Serotonin deficiency syndrome occurs in various diseases. Normally, serotonin, interacting with serotonin receptors of smooth muscles (GM), provides intestinal peristalsis and endogenous vasomotor activity in the body. Endo- and / or exotoxins, by binding to the serotonin receptors of GM instead of serotonin, cause spasm or paralysis of the GM. The serotonin circulating in the blood is no longer sufficient to maintain the normal function of both GM and platelets, i.e. in the body there is a relative deficiency of serotonin. Depending on the number of disturbed myocytes, the clinical picture will manifest itself in the form of functional intestinal obstruction and / or vascular insufficiency, impaired oxygenating function of the lungs, and in case of local microcirculation disorders - tissue hypoxia, tissue damage and necrosis in various organs (myocardial and brain infarction, necrosis foot tissues, etc.).

Serotonin adipinate (CA) is a dosage form of natural (endogenous) serotonin, and therefore only it, being a specific mediator for serotonin receptors of GM, is able to eliminate serotonin deficiency and restore the impaired function of GM, regardless of whether its dysfunction was caused by paralysis or spasm ... This also explains the fact that CA is the only drug that improves gas exchange in the lungs in critically ill patients; in addition, CA eliminates thrombocytopenia and increases nonspecific immunity. The daily dose of CA has an individual character and depends on the duration of the clinical effect obtained and can reach 900 mg of CA per day. The letalis50 dose for CA is 164 mg / kg [15].

Human aging is accompanied by the degradation of serotonin receptors in the body, which, in our opinion, explains the high mortality rate of elderly patients from COV1D-19. Abroad, serotonin is not used in clinical practice. Thus, the use of exogenous serotonin is pathogenetically justified and is an additional and necessary component in the treatment of ARDS in patients with COVID-19.

The proposed method is based on the elimination of GM dysfunction and impaired endogenous vasomotor (vascular peristalsis, vasomotion), on the normalization of microcirculation in the lungs and restoration of impaired oxygenating function of the lungs, which leads to the elimination of hypoxemia and normalization of metabolism in tissues and the recovery of patients.

Improvement of oxygenating lung function in patients with COVID-19 using only direct anticoagulants is justified, but at the same time, as practice shows, it is ineffective, despite its positive effect on blood rheology [16].

We believe that the combined use of CA and direct anticoagulants can synergistically improve impaired lung oxygenation in the treatment of ARDS in patients with COVID-19.

Thus, the combined method developed by us, including the use of CA and direct anticoagulants in patients with COVID-19, is pathogenetically justified.

The following are clinical examples of the application of the claimed method.

Example # 1.

Patient G. is a 63-year-old man, weight 112 kg, height 184 cm. Doctor, got sick at the workplace. He was undergoing treatment from 06.06.2020 to 26.06.20 in the infectious diseases hospital of the Tula Regional Center for the Prevention and Control of AIDS and Infectious Diseases, providing assistance to patients with COVID-19 (hereinafter the infectious diseases hospital). Ill for 2 weeks: cold symptoms, fever up to 38.0 ° C, complaints of shortness of breath during the last 5 days, fever up to 39.0 ° C. He was treated symptomatically on his own. At home, there was shortness of breath at rest, called an ambulance. CT scan of the chest organs (CT) was performed - the picture corresponds to bilateral polysegmental pneumonia, of a viral nature, the volume of the lesion is 75%, CT-3. Hospitalized for the severity of the condition in the RO with a diagnosis of coronavirus infection caused by the COVID-19 virus, no virus identified (U07.2). At admission, respiratory support was started - oxygen therapy with a flow of 10 l / min. Standard therapy COVID-19 [1], the dose of nadroparin calcium "prophylactic" - 0.6 ml once a day. Within 2 days, respiratory failure was growing, the patient was transferred to NLV, oxygen demand increased to 70%, NLV parameters were “toughened up”, in addition, from the moment of admission to the RO, there is no stool for 3 days, insomnia and anxiety are worried. Transferred to titration of non-fractional heparin IV in an "intermediate dose" - 1000 units / hour with a dispenser. 06/08/2020 increased the dose of non-fractional heparin to "therapeutic" - 2200 units / hour. Before the introduction of CA - PaO2 82.4 mm Hg, SpO2 94%. Ventilation parameters and oxygen fraction (FiO2) in the inhaled mixture did not change during administration. After intravenous administration of CA 30 mg diluted in 500 ml NaCL 0.9% for 3 hours, there is an improvement in the oxygenating function of the lungs, manifested in the form of an increase in PaO2 to 137 mm Hg, and SpO2 to 96-98%). This indicates the normalization of endogenous vasomotor and microcirculation in the lungs. As a result, tissue hypoxia is eliminated, which leads to an improvement in hemodynamics, stabilization of blood pressure (BP) and heart rate (HR), a decrease in respiratory rate (RR), an increase in urine output, the appearance of stool and physiological sleep. After sleep, the normalization of the neuropsychological status is noted. On 09.06.20 at 08.00, the NLV parameters were “softened”, against this background, the target values were achieved - SpO2 equal to 94% and NPV equal to 20 per min, coagulogram: APTT 45 seconds, MHO 1.2 (Table No. 1).

06/12/2020 nadroparin calcium was prescribed in a "therapeutic dose" 1.2 ml n / a 2 times a day, CA was re-administered at a dose of 20 mg. After the introduction, there is an improvement in the oxygenating function of the lungs in the form of an increase in Sp02 by 4% from the initial values, a decrease in the compensatory function of external respiration in the form of normalization of respiratory rate, the appearance of stools 2 hours after administration. I slept at night, by the morning of 08.00 on 06/13/2020, the NLV parameters were "softened", against this background, NPV and SpO2 were without negative dynamics. Coagulogram: APTT 44 sec, MHO 1.18, fibrinogen 4.5 g / l. Further state with positive dynamics, on June 16, 20, he was removed from NVL and transferred to oxygen therapy, the flow of 3-5 l / min, taking into account the stabilization of the state, was transferred to the infectious diseases department. 06/26/2020 was discharged from the infectious diseases hospital in a satisfactory condition. The diagnosis at discharge is the same - U07.2 due to receiving three negative swabs from the throat and nose by polymerase chain reaction (HYDR) for COVID-19. After discharge, he independently passed a blood test for immunoglobulins (Ig), according to the results of which a high titer of IgG and IgM was noted, indicating a confirmed case of COVID-19.

Example # 2.

Patient K. is a 52-year-old man, weight 118 kg, height 182 cm. Head of Regional Department of the Central District Hospital, fell ill at the workplace. Was being treated at the infectious diseases hospital from 07/03/2020 to 07/20/2020. Ill since 07/01/2020: cold symptoms, fever up to 37.5 ° C. 07/03/2020 there was shortness of breath at rest, cough, CT scan was performed: the picture corresponds to bilateral polysegmental pneumonia, of a viral nature, the volume of the lesion is 80%, CT-4. He lives with his wife, the wife fell ill with symptoms of respiratory failure and was diagnosed with U07.2, was admitted to the infectious diseases hospital. According to the severity of the condition, the patient was admitted immediately to the RO with a diagnosis of U07.2. At admission, respiratory support was started - NLV, FiO2 40%. The standard therapy for COVID-19 has been started [1]. Dose of enoxaparin sodium "intermediate" 0.8 ml 1 time per day. Within 2 days, an increase in the phenomena of respiratory failure, an increase in FiO2 up to 70%, a "tightening" of NLV parameters, in addition, from the moment of admission to the RO, there is no chair for 3 days, insomnia and anxiety.

07/05/20 at 08.00 the dose of enoxaparin sodium was increased to the "therapeutic" 0.8 ml sc 2 times a day, a blood test was taken before the introduction of CA: PaO2 48.9 mm Hg, SpO2 90%, CA 30 was introduced mg dissolved in 200 ml of 0.9% NaCL solution, 10 mg / h. After CA PaO2 86.1 mm Hg, SpO2 96 - 98%. In a dream on 06.07.20 at 04.00, a drop in SpO2 is noted, an increase in NPV, it was decided to re-inject 20 mg intravenous CA at a rate of 10 mg / h (Table No. 2).

Clinically, an improvement is noted in the form of a decrease in NPV, an increase in urine output, the appearance of stool and sleep, and after sleep, a normalization of the neuropsychological status is noted, as well as an increase in SpO2 88 to 94%.

07/09/2020 was removed from NVL, further respiratory support was carried out in the form of oxygen therapy (flow 8 l / min), taking into account the stabilization of the state, he was transferred to the infectious diseases department. 07/20/2020 was discharged from the hospital in satisfactory condition. The diagnosis at discharge is the same -U07.2, due to the receipt of three negative swabs from the throat and nose by PCR for COVID-19. At the same time, it is known that the sensitivity of swabs from the throat and nose by PCR for COVID-19 is no more than 68% [17]. However, given the profession, severity and typical clinical and laboratory manifestations of the patient's disease, as well as similar manifestations of the disease in the spouse of the treated patient, according to WHO criteria, there is a high probability that the patient has COVID-19 [18].

Example No. 3

Patient L. A 60-year-old man, weight 82 kg, height 176 cm. He was undergoing treatment since 28.07.2020 in an infectious diseases hospital. Ill since 18.07.20: symptoms of a cold, an increase in body temperature to 37.5 ° C. 07/21/2020 was prescribed treatment by a local therapist, a smear from the pharynx and nose by PCR method to determine COVID-19 is positive. Repeated visit of the doctor on 07/28/20, there was shortness of breath at rest, an increase in body temperature to 39.9 ° C, was directed to hospitalization in an infectious diseases hospital, CT scan was performed: the picture corresponds to bilateral polysegmental pneumonia, of a viral nature, the lesion volume is 40%, CT-3 ... He was admitted to the infectious diseases department of the infectious diseases hospital with a diagnosis of coronavirus infection caused by the COVID-19 virus, the virus was identified (U07.1). Upon admission, the patient started standard COVID-19 therapy [1], respiratory support in the form of oxygen therapy with a flow of 6 l / min, a dose of nadroparin calcium "intermediate" 0.6 ml 2 times a day. During the day, the increase in the phenomena of respiratory failure: NPV up to 35 per minute, SpO2 78% against the background of respiratory support in the form of oxygen therapy - 15 l / min, insomnia, anxiety and no stool for 3 days. Due to the severity of his condition, he entered the RO at 19.00. The dose of nadroparin calcium was increased to the therapeutic 0.9 ml 2 times a day, respiratory support in the form of NVL, FiO2 90%, SpO2 96%, at 20.00 FiO2 reduced to 70%, SpO2 97%), at 00.00 the ventilation parameters were the same, FiO2 70 %, SpO2 97%). Given the high demand for oxygen, the presence of signs of a compensatory reaction of the body in response to hypoxia of the cardiovascular system in the form of tachycardia (heart rate 118 per minute) and hypertension (blood pressure 150/100 mm Hg), the respiratory system (increased respiratory rate up to 30 min), absence of stool for three days, CA 20 mg in dilution per 200 ml of 0.9% NaCL solution was introduced at a rate of 10 mg / h. After the introduction of CA, there is an increase in the oxygenating capacity of the lungs in the form of an increase in PaO2 by 39%, SpO2 by 3% from the initial values, a decrease in NPV, stabilization of blood pressure and heart rate, and also after the introduction of the appearance of stool, a decrease in anxiety and sleep (Table 3).

On August 1, 20, the patient complained of the absence of stool for 2 days, CA was re-administered at a dose of 30 mg per 200 ml of 0.9% NaCL solution at a rate of 30 mg / h. After the introduction of CA, there is an increase in the oxygenating capacity of the lungs in the form of an increase in PaO2 by 23%, SpO2 by 3% from the initial values and the appearance of stools (Table 3). At 20.00 he was removed from the NLV and further respiratory support in the form of oxygen therapy (flow 8 l / min) Sp02 98% was carried out. 08/03/2020 transferred to the infectious diseases department. Discharged from the hospital in satisfactory condition with the same diagnosis - U07.1.

Our data are pathogenetically substantiated and do not contradict previously obtained scientific data, but only expand and supplement them.

The method is based on new data revealed in the study of the effect of CA and direct anticoagulants on the oxygenating function of the lungs in patients with COVID-19, it provides a high clinical effect and can be recommended for implementation into wide clinical practice in the treatment of patients with respiratory failure who are on respiratory support.

Literature

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Claims (1)

A method for improving the oxygenating function of the lungs in patients with a new coronavirus infection COVID-19 with respiratory failure, who are on respiratory support, characterized in that patients are injected intravenously with a solution of serotonin adipate at a rate of 10-30 mg / h, as respiratory support, non-invasive ventilation of the lungs is carried out, oxygen therapy, additionally administer calcium nandroparin or enoxaparin.