Terapia de oxígeno hiperbárico para tratar el COVID-19 - Vía Orgánica

Terapia de oxígeno hiperbárico para tratar el COVID-19 - Vía Orgánica: Por Dr. Joseph Mercola, Mercola, 16 de mayo del 2020. HISTORIA EN BREVE El Hospital General Opelousas en Louisiana ha implementado el «uso compasivo y sin autorización» de la terapia de oxígeno hiperbárico (TOHB) para todos los pacientes que tienen COVID-19 con hipoxemia resistente al oxígeno Durante la TOHB, usted respira aire u oxígeno en […]

Hyperbaric oxygen therapy for COVID-19

Demonstration report on inclusion of hyperbaric oxygen therapy in treatment of COVID-19 severe cases

Demonstration report on inclusion of
hyperbaric oxygen therapy in treatment of
COVID-19 severe cases
Naval Specialty Medical Center Program Team
Clinical reports and pathologic anatomic findings shown,
progressive hypoxemia is the main cause of deterioration in patients with
COVID-19."The mortality rate of critical patients in WuHan is close to
60%, and we are trying to solve the problem of hypoxia," Zhong Nanshan
said on 27th Feb. HBOT is the strongest non-invasive oxygen therapy. In
the early stage, 5 cases of severe and critical patients with COVID-19 a
were clinically treated, which proved that the long-term excellent clinical
effect of using HBOT in treating hypoxia was also applicable to
COVID-19 patients. The effect of HBOT is better than breathing
atmospheric high flow oxygen and mechanical ventilation techniques. It
is suggested that promote HBOT as an oxygen therapy treatment for
critically ill patients with COVID-19, which is expected to significantly
improve the treatment efficiency, reduce the medical pressure and the risk
of infection, and decrease the mortality rate of critical patients. It has
practical significance for further accelerating the overall victory of this
epidemic, achieving the most effective treatment and realizing infection
prevention control.
I. Evaluation of the effectiveness of HBOT in oxygen
therapy for critical patients with COVID-19.
1) 5 critical patients showed consistent response to HBOT oxygen
therapy
Zhong Yangling, the director of the Department of Hyperbaric
Oxygen in Wuhan Yangtze River Shipping General Hospital, successfully
carried out HBOT treatment in 5 patients with COVID-19 (2 critical and
3 severe), which got significant results. Case reports of the first patient
have been published. 5 cases clinical analysis data shown:
a) Treatment effect of progressive hypoxemia in severe patients
-Rapid relief of hypoxic symptoms. 5 patients had obvious
symptoms of progressive hypoxia before. After the first session of HBOT,
symptoms such as dyspnea and chest pain are reduced. After the second
session HBOT, the symptoms are basically relieved, and the respiratory
rate decreases gradually, but the shortness of breath after the movement
relieved slowly.
-Rapid correction of hypoxemia. Arterial blood gas analysis of 5
patients under the condition of breathing oxygen with oxygen mask
（5~8L/min）before HBOT treatment showed PaO2 is 37, 65, 60, 78, and
68 mmHg, the trend of critical patients’ Blood oxygen saturation of artery
blood of finger(SO2)was reversed immediately. Since the 5th day,SO2
was up to 95% in daily average(1). Compare with the patients’ body data
before they do the HBOT treatment,which be regard as the last day data,
SO2 showed a significant upward trend day by day(2 left). After HBOT
treatment, SO2 is higher than 93%, and every treatment solved the
patient's problem of total hypoxia. Arterial blood gas index recovered
significantly(pic 2 right).
(pic 1)Changes of critical patients’ SO2 before and after HBOT (11/2)
(pic 2) SpO2 daily changes and Arterial blood gas analysis of 5 patients before and after HBOT
b) Comprehensive therapeutic effect of HBOT oxygen therapy
on severe patients
- General condition reversal. In addition to the relief of hypoxic
symptoms in all patients, the general state was significantly reversed.
Gastrointestinal symptoms are reduced and appetite is restored. Headache
disappeared and mental state improved.
- Clinical objective indicators improved. Except the significant
changes in artery blood of finger and Arterial blood gas, differential blood
count, which respond to immune function recovered gradually,
coagulation index of reactive peripheral circulation disorder improved,
Indexes reflecting liver function and myocardial injury improved(3).
- Improved lung pathology. Re-examination of the lung CT after
treatment showed that lung inflammation in all 5 patients was
significantly improved(4).
(pic 3) Changes of coagulation function and sacral hydration in 5 patients before and after HBOT
treatment
(pic 4) CT changes before and after 4-7 HBOT in 5 patients
2) The mechanism of HBOT oxygen therapy
The difference between HBOT oxygen therapy and normal pressure
oxygen therapy is, in general, the use of high pressure oxygen inhalation,
which fully and substantially improves the efficiency of oxygen transport
from the outside to the whole tissue cells. The mechanism of HBOT is to
take advantage of the physical characteristics of gas, to increase the
partial pressure of the oxygen in the environment through a large
amplitude, and to reduce the demand for oxygen exchange and
transportation in the body to achieve the best oxygen therapy effect. The
mechanism of HBOT is shown in pic 5. The advantages compared with
atmospheric pressure oxygen therapy technology are:
Firstly, more effectively than normal pressure oxygen inhalation to
overcome lung tissue inflammation.
The diffusion rate and distance of high pressure oxygen are several
times that of normal pressure oxygen, which overcome the gas exchange
obstacle caused by the thickening of the lung tissue inflammation.And
because of the higher solubility, the amount of oxygen dissolved in the
blood is several times that of atmospheric oxygen, which also further
overcomes the influence of the blood circulation gas ratio.
Secondly, it is more effective to increase oxygen partial pressure than
to increase oxygenation index by mechanical ventilation.
In respiratory and critical care medicine, oxygen efficiency in
clinical respiratory support uses oxygenation index (is the ratio of partial
pressure of oxygen in the artery to partial pressure of oxygen in the
inhaled gas [OI=PaO2/FiO2(air pressure /760)])) as the final evaluation
index. With partial arterial oxygen pressure as the therapeutic target, the
conversion formula[PaO2=OI × FiO2(air pressure /760)]. Mechanical
ventilation technique is to improve PaO2 by increasing OI. The FiO2 of
HBOT can be increased by 1.6~2.8 times. It can be predicted that PaO2
can be increased by 1.6~2.8 times with HBOT patients' OI unchanged,
which is the same as the effect of OI increased by 1.6~2.8 times. The
effects of OI and treatment before treatment in 5 patients have been fully
verified. In one case, HBOT was used to reverse hypoxia on the basis of
no effect of noninvasive mechanical ventilation for 2 days. HBOT
technology for patients with invasive mechanical ventilation is mature
and has been routinely used in clinical HBOT. Therefore suggested that
clinical selection principles are: (1) HBOT treatment is preferred when
patients' oxygenation index is significantly reduced and natural
respiration is clear, and mechanical ventilation is not expected to increase
oxygenation index by 1.5 times; (2) When the improvement of
oxygenation index under mechanical ventilation is less than twice that of
natural respiration, it is suggested to increase the daily HBOT treatment
on the basis of mechanical ventilation.
Thirdly, more effective than ECMO in improving tissue cell oxygen
uptake.
Although ECMO has surpassed the ventilation and gas exchange
functions of the lungs, and can make Hb completely saturated, it is not as
good as HBOT in tissue side oxygen supply. The dissolved oxygen in the
blood has exceeded the amount carried by Hb, and the diffusion distance
has been greatly increased, which can relatively overcome the peripheral
circulation obstacles caused by pre-hypoxic damage or / and infectious
inflammation, and improve the efficiency and absolute amount of tissue
cells to obtain oxygen.
Fourthly, there is no serious interference of mechanical ventilation to
the respiratory tract in natural breathing.
HBOT means that the patient is under high pressure. The common
metaphor of the difference between breathing mode and atmospheric
pressure is that breathing on the plateau is the same as breathing on the
plain, which is natural breathing. Different from mechanical ventilation, it
has a great effect on respiratory tract, need to be paid attention to and
dealt with by doctors and nurses at all times. Otherwise, it is easy to have
various complications such as airway injury.
Fifthly, there is no conflict with the current means of critical treatment,
and the +HBOT mode has a clear role in improving the treatment
effect.
COVID-19, in addition to antibodies and vaccines, there is no
specific drug. All clinical treatment is basically symptomatic treatment
and supportive treatment. HBOT is not the etiological treatment of
COVID-19, it is the symptomatic treatment of hypoxia in patients with
COVID-19, and it is a supplement to the existing oxygen treatment
technology. In addition to HBOT once a day for 95-120 minutes, the
patients also received the existing comprehensive treatment in ICU,
including mechanical ventilation. In addition to HBOT, ICU clinicians
are still responsible for the daily comprehensive treatment of the
above-mentioned severe patients. There is no conflict in treatment
technology. On the contrary, it can provide better support for other
supportive treatments.
(pic 5 The effect of different oxygen therapy on oxygen from the external environment to the
process of tissue and organ)
3) Clear indications of HBOT for the symptomatic treatment of
hypoxia
Firstly, hypoxia is the first indication of HBOT.
HBOT is a routine oxygen therapy for clinical refractory hypoxia.
HBOT has been widely used in the clinic for more than half a century
since it was first used in the supportive treatment of thoracic surgery in
1956. In China, grade A hospitals are generally equipped with oxygen
Chambers, and a large number of HBOT of various diseases are carried
out on a daily basis, especially for carbon monoxide poisoning -- a typical
acute anoxia, which has become a key treatment measure. From the
perspective of diseases, HBOT has a wide range of indications. As a
routine application of oxygen therapy, the indication is essentially a
"hypoxia", that is, generalized and local stubborn hypoxia problem.
Secondly, the diagnosis of anoxia in severe patients with COVID-19 is
clear.
The clinical manifestations of severe patients with hypoxia are
prominent, the indication of hypoxemia is obvious, and the existence of
hypoxia is obvious. In all the previous published clinical scientific
literature on COVID-19, it is clear that the continuous and progressive
development of hypoxemia is an important manifestation of disease
deterioration. In the severe treatment of COVID-19, HBOT is used for
the symptomatic treatment of anoxia correction with clear indications.
The therapeutic effect of 5 patients was very significant, and both
the subjective and objective clinical indexes showed that the deterioration
of hypoxia was interrupted immediately and then the whole body
recovered gradually after the first HBOT. Such a consistent treatment
response, according to the statistical law, cannot be explained by chance.
The above mechanism demonstrated that the efficacy of HBOT in 5
patients was not accidental. The therapeutic effect of HBOT on hypoxia is
a scientific summary of the effects of HBOT in the treatment of
intractable and refractory hypoxia in various diseases over a long period
of time. The relevant scientific papers, literature and works are endless.
The superiority of HBOT in solving severe hypoxia in patients with
COVID-19 is clearly scientific. Unlike the newly developed treatment
stage or the efficacy of medicine is still in the scientific hypothesis stage,
HBOT don't need clinical trial verification and other methods of oxygen
therapy that have been used clinically, such as mechanical ventilation or
ECMO, it can be reasonably used.
In summary, the use of HBOT can provide clear clinical benefits for
the pathophysiological problems encountered in the treatment of hypoxia
in severe critical diseases. HBOT can be used to treat severe hypoxia in
patients with COVID-19, which can more effectively and
comprehensively solve the problem of hypoxemia than normal pressure
oxygen therapy (high flow oxygen inhalation, mechanical ventilation),
make deep tissue hypoxia fully corrected and greatly relieve systemic
hypoxic inflammation, and also has practical clinical significance for the
effects of other treatment methods (such as medicine supportive
treatment).
II. Safety of HBOT for oxygen therapy in severe
patients with COVID-19
HBOT has been standardized and widely used clinically for nearly a
century. Its essential medical safety is not repeated here. The focus is on
disease prevention and control (CDC) risks posed by Class A infectious
diseases. HBOT treatment requires special equipment and procedures,
and patients need to be transferred back and forth from the ward to the
hyperbaric oxygen chamber. The transfer process is in an atmospheric
environment, and there are mature CDC measures without
insurmountable technical problems. Wuhan Changjiang General Hospital
has already formed a practicable method, which can be further improved,
and it will not be repeated here. This article focuses on the treatment
process of HBOT in the oxygen cabin and the risk of CDC in the
hyperbaric oxygen department.
1) . The risk of pathogenic microorganism infection in cabin is not
higher than the ward
Firstly, the risk of performing CDC in the hyperbaric oxygen chamber is
the same as the risk of CDC in the infection ward.
The difference between the micro-environment of the hyperbaric oxygen
chamber and the micro-environment of the infection ward is the radon
pressure.It is same as the difference between the plateau and sea level.
The medical staff is exposed to the oxygen chamber micro-environment
under a high pressure, the surface intensity of pressure is equal, and the
pressure difference cannot be felt. Protective equipment also does not
suffer from “compressive” deformation. The requirements for the
infection control of the hospital in plateau area are not different from
those in the plain area. There are no clear differences in CDC
requirements for different environmental pressures. The process of
medical treatment in the hyperbaric cabin did not significantly increase
the risk of CDC compared with the same operation in the infection ward.
Secondly, the hyperbaric oxygen cabin is a completely new wind
environment.
In the HBOT process, “ventilation” measures are usually adopted.
The pressure valve and the pressure relief valve are opened at the same
time.When the amount of air input is equal to the amount of air output,
the intensity of pressure in the cabin is guaranteed to be constant, and the
air purge inside cabin is continuously updated. The air inlet port and
output port are located on the opposite sides of the cabin. Under
continuous ventilation, the air flow in the cabin is generally unidirectional,
similar to a laminar flow operating room. The pressure of the air in the
pipeline decreases gradually from the source to the exhaust port. There is
no back flow of gas under the pressure gradient. The air sources are
filtered, pressurized, and depressurized by an oil-free air compressor
advanced purification device to ensure clean air sources.
Thirdly, air breathed by doctors and patients is relatively separated
inside the cabin.
The patient used a mask of the Bulding in breathing system (BIBS)
to breathe pure oxygen after entering the cabin. The exhaled gas of the
patient mainly exists in the oxygen exhaust line and flows
unidirectionally outward. Medical staff breathes air in the cabin, basically
does not cross the gas that the patient breathe. This is better than the
infection ward.
Medical staff pressurize independently. During the pressurization
process, the pressure on the body side of the protective equipment is low,
and the air in the cabin may enter the body side of the protective
equipment as the pressure increases. The hyperbaric oxygen chamber is
provided with a transition cabin (small cabin). The medical staff use
independent cabin to pressurize to avoid the possibility that a large
amount of air from the treatment cabin where the patient is regarded as a
contaminated area enters the body side of the protective equipment. The
decompression process is the opposite, so there is no risk of CDC.
Fourthly, Infection ward CDC measures are used in the hyperbaric
oxygen chamber and no additional evaluation is required.
The hyperbaric oxygen chamber is managed as a ward for patients
with new coronavirus. Disinfection process is performed under normal
pressure, and the disinfection technology method and effect are the same.
The pressurization process is with "full fresh air systems", the air that
doctors and patients breathe is relatively independent, and the possible
gas pollution is less than that of infected wards. In addition, the CDC
requirements for infection wards are applicable to infection-control
management after the pressure in the hyperbaric chamber is relatively
constant.
2). Hyperbaric Oxygen Department's measures to control infection
have been initially formed and practical
The Hyperbaric Oxygen Department is an area for the treatment of
infected patients. There are clear rules and regulations for the setting of
the ward isolation area and personnel protection under normal pressure,
which can a reference. It has also formed a set of effective practices,
which will not be repeated here. The focus of controlling infection is to
purify and sterilize the exhaust gas from the BIBS system oxygen outlet
and chamber decompression outlet of the patient's breathing. In this
regard, no products were found at home or abroad for hyperbaric chamber
exhaust gas purification and disinfection. We first adopted strict control
measures in the area of the exhaust port to avoid the possible impact of
the patient's exhaled gas on the outside activities in the effective area. At
the same time, non-standard disinfection measures were temporarily
adopted, and the exhaust gas was filtered by the disinfectant solution to
further prevent the pollution of the exhaust gas to the surrounding
environment and cause the virus to spread. At present, the hyperbaric
chamber supplier has purchased the medical gas purification equipment
certified by the relevant national authorities for modification. After
installation, it can meet the national standards.
To sum up, the hyperbaric oxygen chamber is a closed gas
management system with unidirectional air flow, full fresh air systems,
and separate air pipelines for medical staff and patients to breathe. There
are no insurmountable technical obstacles to the treatment of HBOT for
CDC. Hyperbaric Oxygen Department of Wuhan Changjiang Shipping
General Hospital has established a complete infection control procedures
and measures for HBOT treatment of patients with new coronavirus, and
has passed the evaluation of the infection control department. The HBOT
treatment for patients with severe disease has been carried out more than
20 times in the early stage, and none medical was infected. In general, the
risk of infection in the HBOT chamber is not as high as the ward. Early
intervention of HBOT can reduce the use of mechanical ventilation and
accelerate the cure of critically ill patients, and further reduce the risk of
infection for medical staff.
III. Feasibility Evaluation of HBOT Oxygen Therapy
at Huoshenshan Hospital for COVID-19
Huoshenshan Hospital will be the last line of defense for COVID-19.
The above discussion shows that it is obvious that HBOT can be used for
oxygen therapy in patients with COVID-19 if it can exert its clinical
significance. But Huoshenshan hospitals are not equipped with HBOT
equipment, which is the biggest problem with HBOT. Given that the
treatment of hypoxia is a key and difficult point in the current severe
treatment, it is of practical significance to strive for HBOT oxygen
therapy in Vulcan Hospital. The following preliminary suggestions are
made on the feasibility and progress of Huoshenshan Hospital's existing
treatment + HBOT.
Step1. Portable high-pressure oxygen equipment is used in a small
area, and a basic treatment process adapted to the actual
situation of Huoshenshan Hospital is formed.
In addition to the hyperbaric oxygen chamber, the equipment that
can inhale oxygen at high pressure also has a diving chamber for treating
decompression sickness. The military-equipped electric diving
pressurized chamber and portable High-pressure chamber can also treat
decompression sickness, and can be performed automatically in a good
oxygen environment in a short time(120min) without the help of medical
staff.
A military university in Wuhan is equipped with a mobile diving
chamber (for two people) and a portable hyperbaric oxygen chamber.
Therefore, hyperbaric oxygen therapy can be performed in the open area
of the hospital. This part of the area is controlled according to the
contaminated area and meets the CDC. It is recommended that the
equipment and operator be transferred to Huoshenshan Hospital together
to try HBOT treatment for 5 critically ill patients with similar conditions.
Basic treatment procedures and CDC procedures include:
(1) HBOT treatment: 1.6ATA / 120 minutes, continuous oxygen
inhalation. It is expected to achieve an oxygen therapy effect of 1.6 times
the oxygenation index, which is superior to mechanical ventilation, the
reasonable use of atmospheric oxygen, and the overall therapeutic effect
is significant.
(2) CDC process of HBOT treatment: The CDC process of hyperbaric
oxygen therapy in Wuhan Changjiang Shipping General Hospital has
been proven to be feasible in time, and can be optimized and adjusted
according to the actual layout of Huoshenshan Hospital.
(3) HBOT emergency treatment plan: HBOT uses 1.6ATA, diving
depth is about 6 meters, no decompression is needed. Once the patient's
condition has changed, it can be removed from the compression chamber
within 3 minutes. What you need to do is prepare first aid at atmospheric
pressure next to the oxygen chamber, and then take the patient back to the
ICU ward.
Step2. Concentrate portable hyperbaric oxygen equipment inside
and outside the army to popularize HBOT oxygen therapy as much
as possible
After researching the mobile high-pressure system capable of
treating decompression sickness and combining the number of military
equipment, preliminary estimates are that it can increase 144 times/day
HBOT.
Step3. Hyperbaric Oxygen Chamber Construction at Huoshenshan
Hospital Simultaneously Started
Construction of a new hyperbaric oxygen chamber system started at
Huoshenshan Hospital. After investigation, the supplier of hyperbaric
oxygen equipment of Wuhan Changjiang Shipping General Hospital can
complete the installation and commissioning and put it into use within 15
days. HBOT oxygen therapy for tracheal intubation mechanical
ventilation patients can be further developed and combined with portable
hyperbaric oxygen equipment, the overall effect will be very significant.
Conclusion
In general, HBOT oxygen therapy has clear indications for patients
with COVID-19, with obvious effects and no obvious uncontrollable
safety risks. Control measures and procedures have been developed to
meet the course of treatment for patients with Class A infectious diseases.
The risk of infection by medical staff is not greater than that of infected
wards. HBOT oxygen therapy is widely used, and some hospitals are also
equipped with a hyperbaric oxygen chamber. Therefore, we strongly
recommend including HBOT in the treatment of COVID-19 in order to
provide the treating physician with more effective oxygen therapy.
Huoshenshan Hospital, as the last line of defense for new serious
treatment, is gradually exploring and developing large-scale HBOT
oxygen therapy, which is expected to significantly improve treatment
efficiency, reduce medical and infection pressure and reduce mortality.

CORONAVIRUS & HYPERBARIC OXYGEN THERAPY

March 2020
A WHITE PAPER:

CORONAVIRUS & HYPERBARIC OXYGEN THERAPY

Barry Meuse, MA, Colonel, USAF, Ret, President & Chairman
Paul Hoffecker, CEO/Executive Director
Ray Cralle, PT, Director
Dom D’Agostino, PhD, Director
Daphne Denham, MD, Director
Xavier Figueroa, PhD, Director
Mike Flynn, Lt Gen, USA, Ret, Director
Ed Di Girolamo, Director
Julio Gonzalez, Director
Diane Levitan, VDM, Director
Gina Loudon, PhD, Director
Joe Maroon, MD, Director
Tami Peterson, PhD, Director
George Wolf, MD, Colonel, USAF, Ret, Director
CORONAVIRUS & RESPIRATORY FAILURE
“Amid the Coronavirus epidemic/pandemic it bears remembering the application of hyperbaric oxygen therapy to the last major pandemic that impacted the United States in 1918, the Spanish Flu Pandemic. Death was primarily by pulmonary infection and its attendant hypoxemia and respiratory failure.”
“The first application of hyperbaric medicine to a Spanish Flu victim was likely also the first application to a human being in the United States. In 1918 Dr. Orval Cunningham of Kansas City was brought a dying friend of a fellow physician.”
“The patient was moribund and blue. Dr. Cunningham was asked to treat this dying patient. With just a one-hour treatment with compressed air at 1.68 atmospheres absolute the patient experienced improvement. Combined with additional hyperbaric treatments over the next 3 days this patient’s life was saved. Others followed.”
“Today’s Coronavirus’ mortality is due to pulmonary infection and respiratory failure . . . the primary pathology is in the lungs, the first organ of contact with hyperbaric therapy beyond the skin.”
This not only allows adequate oxygen to reach the blood and therefore the whole rest of the body but hyperbaric oxygen therapy also inhibits the inflammatory process, allowing healing from the viral infection.
“Applied correctly, hyperbaric therapy may have utility in
Coronavirus patients like its life-saving history with the
Spanish Flu.” - Paul Harch, MD, Harch Hyperbarics Inc.
HYPERBARIC OXYGEN THERAPY
Hyperbaric Oxygen therapy (HBOT) is already used internationally to heal patients in the most-at-risk COVID-19 groups (heart disease, cancer, COPD, stroke, critical care, etc). it is a lifesaving therapy even without a virus present.
Treating high-risk Coronavirus patients – those who have the Coronavirus and who suffer from an underlying issue such as pulmonary disease, pneumonia, cardiac disease, diabetes, etc – with hyperbaric oxygen therapy will save lives. HBOT adds oxygen to hypoxic tissue, reduces inflammation, strengthens the immune system to defeat the Coronavirus – all the while improving the underlying medical condition which could otherwise be fatal.
INFLAMMATION
“The anti-inflammatory effects of oxygen, especially when increased in the body by hyperbaric oxygen therapy, are well documented. We know inflammation, even inflamasomes, cannot exist unless oxygen is low.
Hyper-oxygenation is a deterrent to the Coronavirus. Also, note that the 2019 Nobel Prize in Medicine was "Oxygen and the Cell" where Hypoxic inducible Factor 1-alpha was recognized as the precursor of all disease and tumor growth. Hyperbaric Oxygen Therapy saves lives by combating inflammation and hypoxia.”
- Ray Cralle, PT
WORLD HEALTH ORGANIZATION
Note that in March 2020, the World Health Organization said that “Oxygen therapy is the major treatment intervention for patients with severe COVID-19. All countries should work to optimize the availability of pulse oximeters and medical oxygen systems.”
HYPERBARIC MEDICINE INTERNATIONAL
Hyperbaric Medicine International (HMI) is a 501c4 nonprofit dedicated: 1/ to advocating hyperbaric oxygen therapy as the standard of care for a broad array of medical conditions worldwide including inflammation; and
2/ to certifying physicians, technicians and clinics to assure hyperbaric oxygen therapy is delivered under high medical standards and reaches all in need.
We encourage all healthcare practitioners consider hyperbaric oxygen therapy for high-risk Coronavirus patients.
FOR MORE INFORMATION, CONTACT
BARRY M MEUSE
President and Chairman of the Board
editor@hbotnews.org

COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism liu wenzhong, Li hualan

doi.org/10.26434/chemrxiv.11938173.v5
COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the
Porphyrin to Inhibit Human Heme Metabolism
liu wenzhong, Li hualan
Submitted date: 28/03/2020 • Posted date: 30/03/2020
Licence: CC BY-NC-ND 4.0
Citation information: wenzhong, liu; hualan, Li (2020): COVID-19: Attacks the 1-Beta Chain of Hemoglobin
and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv. Preprint.
https://doi.org/10.26434/chemrxiv.11938173.v5
The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel
coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. In this study,
conserved domain analysis, homology modeling, and molecular docking were used to compare the biological
roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein
could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could
coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The
attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have
extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen
frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the
normal heme anabolic pathway of the human body, is expected to result in human disease. According to the
validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to
form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent,
effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the envelope protein and
ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins.
Because the novel coronavirus is dependent on porphyrins, it may originate from an ancient virus. Therefore,
this research is of high value to contemporary biological experiments, disease prevention, and clinical
treatment.
File list (1)
covid19-202000328-EN-1.pdf (2.47 MiB) view on ChemRxiv download file
COVID-19: Attacks the 1-Beta Chain of Hemoglobin and
Captures the Porphyrin to Inhibit Human Heme Metabolism
Wenzhong Liu 1,2,*, Hualan Li2
1 School of Computer Science and Engineering, Sichuan University of Science & Engineering,
Zigong, 643002, China;
2 School of Life Science and Food Engineering, Yibin University, Yibin,644000, China;
* Correspondence: liuwz@suse.edu.cn;
Abstract
The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused
by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat
coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking
were used to compare the biological roles of certain proteins of the novel coronavirus. The results
showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time,
orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of
hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin
that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and
inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually
results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic
pathway of the human body, is expected to result in human disease. According to the validation
analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to
form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a
certain extent, effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the
envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and
catching free porphyrins. Because the novel coronavirus is dependent on porphyrins, it may originate
from an ancient virus. Therefore, this research is of high value to contemporary biological experiments,
disease prevention, and clinical treatment.
Keywords: Novel Coronavirus; Respiratory distress; Ground-glass-Like Lung; E2 glycoprotein;
ORF8; orf1ab; chloroquine; Blood; Diabetic; Fluorescence resonance energy transfer; Ancient virus;
Cytokine Storm
1 Introduction
The novel coronavirus pneumonia (COVID-19) is a contagious acute respiratory infectious
disease. Patients with the coronavirus pneumonia have a fever, and the temperature above 38 degrees
with symptoms such as dry cough, fatigue, dyspnea, difficulty breathing, and frost-glass-like symptoms
in the lungs1-3. A large amount of mucus can be discovered in the dissected tissue without obvious virus
inclusions. This pneumonia was first discovered in December 2019 in the South China Seafood Market
Hubei Province, China4. The disease is highly transmitted5,6. Now the number of infected people has
reached tens of thousands around the world, and the infected people are not restricted by race and
borders.
Researchers performed virus isolation tests and nucleic acid sequencing to confirm the disease
was caused by a novel coronavirus7,8. It is noted that the nucleic acid of the novel coronavirus is a
positive-stranded RNA8. Its structural proteins include: Spike Protein (S), envelope protein (E),
membrane protein (M), and nucleocapsid phosphoprotein. Transcribed non-structural proteins include:
orf1ab, ORF3a, ORF6, ORF7a, ORF10 and ORF8. The novel coronavirus is highly homologous to the
coronavirus in bats9,10, and has significant homology with SARS virus11,12. Researchers have studied
the function of novel coronavirus structural proteins and some non-structural proteins13,14. But, the
novel coronavirus has potential genomic characteristics, some of which are mainly the cause of human
outbreaks15,16. For example, CoV EIC (Coronavirus envelope protein ion channel) been implicated in
modulating virion release and CoV – host interaction17. Spike proteins, ORF8 and ORF3a proteins are
significantly different from other known SARS-like coronaviruses, and they may cause more serious
pathogenicity and transmission differences than SARS-CoV18. Earlier studies find that the novel
coronavirus enters epithelial cells through the spike protein interacting with the human ACE2 receptor
protein on the surface, causing human infection. However, structural analysis of the spike protein (S)
protein of the novel coronavirus reveals that the S protein only weakly binds to the ACE2 receptor
compared to SARS coronavirus19. Due to the limitations of existing experimental methods, the specific
functions of virual proteins such as ORF8 and surface glycoprotein are still unclear. The pathogenicity
mechanism of the novel coronavirus remains mysterious20.
Literature21 disclosed biochemical examination indexes of 99 patients with novel coronavirus
pneumonia, and the report also reflected the abnormal phenomenon of hemoglobin-related biochemical
indexes of patients. This report demonstrates that the hemoglobin and neutrophil counts of most
patients have decreased, and the index values of serum ferritin, erythrocyte sedimentation rate,
C-reactive protein, albumin, and lactate dehydrogenase of many patients increase significantly. This
trace implies that the patient's hemoglobin is decreasing, and the heme is increasing, and the body will
accumulate too many harmful iron ions, which will cause inflammation in the body and increase
C-reactive protein and albumin. Cells react to stress due to inflammation, producing large amounts of
serum ferritin to bind free iron ions to reduce damage. Hemoglobin consists of four subunits, 2-α and
2-β, and each subunit has an iron-bound heme22,23. Heme is an important component of hemoglobin. It
is a porphyrin containing iron. The structure without iron is called porphyrin. When iron is divalent,
hemoglobin can release carbon dioxide and capture oxygen atoms in alveolar cells, and iron is oxidized
to trivalent. When hemoglobin is made available to other cells in the body through the blood, it can
release oxygen atoms and capture carbon dioxide, and iron is reduced to divalent.
There are no particularly effective drugs and vaccines to control the disease against novel
coronaviruses24. However, there are several old drugs has found in the latest clinical treatments, which
can inhibit some functions of the virus, for example, cloroquine phosphate has a definite effect on the
novel coronavirus pneumonia25. chloroquine phosphate is an antimalarial drug that has been utilized
clinically for more than 70 years. Experiments show that erythrocytes infected by malaria can cause a
large amount of chloroquine to accumulate in it. The drug leads to the loss of hemoglobin enzyme, and
parasite death due to insufficient amino acids in the growth and development of the parasite. The
therapeutic effect of chloroquine phosphate on novel coronavirus pneumonia suggests that novel
coronavirus pneumonia might be closely related to abnormal hemoglobin metabolism in humans.
Meanwhile, one detail we can notice is that chloroquine is also a commonly used drug for treating
porphyria26,27.
Therefore, it is believed that combining viral proteins and porphyrins will cause a series of human
pathological reactions, such as a decrease in hemoglobin. Because of the severe epidemic, and the
existing conditions with limited experimental testing methods for the proteins’ functions, it is of great
scientific significance to analyze the proteins’ function of the novel coronavirus by bioinformatics
methods.
In this study, conserved domains prediction, homology modeling and molecular docking
techniques were used to analyze the functions of virus-related proteins. This study found that ORF8
and surface glycoprotein had a function to combine with porphyrin to form a complex, while orf1ab,
ORF10, ORF3a coordinately attack the heme on the 1-beta chain of hemoglobin to dissociate the iron
to form the porphyrin. This mechanism of the virus inhibited the normal metabolic pathway of heme,
and made people show symptoms of the disease. Built on the above research results, we also verified
the role of chloroquine phosphate and Favipiravir by molecular docking technology to assist clinical
treatment.
2 Materials and Methods
2.1 Data set
The protein sequences were downloaded from NCBI: All proteins of Wuhan novel coronavirus;
Heme-binding protein; Heme oxidase; Protein sequences were utilized to analyze conserved domain.
All proteins of Wuhan novel coronavirus were also used to construct three-dimensional structures by
homology modeling.
At the same time, the PDB files were downloaded from the PDB database: Crystal structure of
MERS-CoV nsp10_nsp16 complex--5yn5; HEM; Human Oxy-Hemoglobin 6bb5; DEOXY HUMAN
HEMOGLOBIN 1a3n; 0TX; RP. MERS-CoV nsp10_nsp16 complex--5yn5 was used to homology
modeling. HEM, 0TX and 1RP were used to molecular docking. Two Oxy-Hemoglobin were used to
protein docking
2.2 Flow view of bioinformatics analysis
A series of bioinformatics analysis was performed based on published biological protein
sequences in this study. The steps are illustrated in Figure 1: 1. Conserved Domains of Viral Proteins
are analyzed by MEME28-30 Online Server. Conserved domains were used to predict function
differences of viral proteins and human proteins. 2.The three-dimensional structure of viral proteins
was constructed by homology modeling of Swiss-model31,32. When the sequence length exceeded
5000nt, the homology modeling tool of Discovery-Studio 2016 was adopted. 3. Using molecular
docking technology (LibDock tool) of Discovery-Studio 201633, the receptor-ligand docking of viral
proteins with human heme (or porphyrins) was simulated. Depending on the results of bioinformatics
analysis, a life cycle modelof the virus was constructed, and the related molecular of the disease was
proposed.
Figure 1. Flow view of Bioinformatics Analysis
The workflow is based on evolutionary principles. Although the biological sequence characteristic
of advanced life forms and viral is different, molecules with similar structures can always achieve
similar biological roles. The homology modeling method uses the principle the similar primary
structure of protein sequences has a similar spatial structure. Molecular docking technology is built on
homology modeling or really three-dimensional molecular.
2.3 Analysis of conserved domain
MEME Suite is an online website that integrates many tools of predicting and annotation motif.
The maximum expectation (EM) algorithm is the basis for MEM's identification of the motif. The
motif is a conserved domain of a small sequence in a protein. Motif-based models could assess the
reliability of phylogenetic analysis. After opening the online tool MEME, the protein sequences of
interest are merged into a text file, and the file format remains fasta. Then select the number of motifs
you want to find, and click the "Go" button. At the end of the analysis, the conserved domains are
displayed after clicking the link.
2.4 Homology modeling
SWISS-MODEL is a fully automatic homology modeling server for protein structure, which can
be accessed through a web server. The first step is to enter the Swiss-model, enter the sequence, and
click "Search Template" to perform a simple template search. After the search is completed, you can
choose a template for modeling. A template search will be performed clicking "Build Model" and a
template model is chosen automatically. As can be seen, several templates were searched, and then
numerous models were built. Just a model is chosen here. The model in PDB format is downloaded and
visualized in VMD. SWISS-MODEL only models protein models with sequence lengths less than
5000nt. You can use Discovery-Studio's homology modeling tool to model where the protein sequence
exceeds 5000nt.
Before using Discovery-Studio to model homology of an unknown protein (such as orf1ab), the
pdb structure file of the template protein, such as MERS-CoVnsp10_nsp16 complex 5yn5, should be
downloaded from the PDB database. Next, the sequence alignment tool of Discovery-Studio is utilized
to align homologous sequences between 5yn5 and orf1ab. Then the spatial structure file of orf1ab was
constructed based on the template protein 5yn5.
2.5 Molecular docking technology
Molecular docking is the process of finding the best matching pattern between two or more
molecules through geometric matching and energy matching. The steps for using LibDock molecular
docking with Discovery-Studio are as follows:
1. Preparation of a ligand model. Open a ligand file such as HEM, and click “Prepare Ligands” in
the “Dock Ligands” submenu of the “Receptor-Ligand Interactions” menu to generate a heme ligand
model for docking. First delete FE (iron atom) in HEM, and then click the “Prepare Ligands” button,
then the porphyrin ligand model will be generated. With 0 XT is opened, click “Prepare Ligands” again
to get the chloroquine ligand model.
2. Prepare a protein receptor model. Open the protein's pdb file (generated by homology
modeling), and click “Prepare protein” in the “Dock Ligands” submenu of the “Receptor-Ligand
Interactions” menu to generate a protein receptor model for docking.
3. Set docking parameters to achieve docking. Select the generated protein receptor model. From
the “Define and Edit Binding Site” submenus in the “Receptor-Ligand Interactions” menu, click “From
receptor Cavities”. A red sphere appears on the protein receptor model diagram. After you right-click
the red ball, you can modify the radius of the red ball. Then, in the “Receptor-Ligand Interactions”
menu, select “Dock Ligands (LibDock)” in the “Dock Ligands” submenu. In the pop-up box, select the
ligand as the newly established ligand model-ALL, and select the receptor as the newly established
receptor model-ALL, and the sites sphere as the sphere coordinates just established. Finally click RUN
to start docking.
4. Calculate the binding energy and choose the pose with the largest binding energy. After docking
is complete, many locations of ligand will be displayed. Open the docked view, and click the “Caculate
Binding Energies” button in the “Dock Ligands” submenu of the “Receptor-Ligand Interactions” menu.
In the pop-up box, select the receptor as the default value, select ligand as the docked model -ALL, and
then start to calculate the binding energy. Finally, compare the binding energy and choose the pose with
the largest binding energy. The better the stability of the complex, the greater the binding energy.
5. Export the joint section view. For the docked view, after setting the display style of the binding
area, click the "Show 2D Map" button in the "View Interaction" submenu of the "Receptor-Ligand
Interaction" menu to pop up the view of the binding section. This view can be saved as a picture file.
2.6 Protein docking technology
Discovery-Studio's ZDOCK is another molecular docking tool for studying protein interactions.
We used it to study the attack of hemoglobin by viral non-structural proteins. The following is the
docking of orf1ab and hemoglobin, and other docking methods with virus non-structural proteins are
the same. After opening the PBD files of Human Oxy-Hemoglobin 6bb5 and orf1ab protein, click the
"Dock proteins (ZDOCK)" button of "Dock and Analyze Protein Comlexes" under the
"macromolecules" menu. In the pop-up interface, select Human Oxy-Hemoglobin 6bb5 as the receptor,
orf1a as the ligand, and then click the "Run" button. After the computer finishes computing, click on
the "proteinpose" interface and select the pose and cluster with the highest ZDOCK score. It could
obtain the position of orf1ab on Human Oxy-Hemoglobin 6bb5. Deloxy HUMAN HEMOGLOBIN
1a3n has a similar docking pattern with orf1ab protein.
3 RESULTS
3.1Virus structural proteins binding porphyrin
In humans, hemoglobin can be degraded into globin and heme. Heme is composed of a porphyrin
and an iron ion, and the iron ion is in the middle of the porphyrin. Heme is insoluble in water and can
be combined with heme-binding proteins to form a complex and be transported to the liver. The
porphyrin is degraded into bilirubin and excreted from the bile duct, and Iron in the molecule can be
reused by the body. If virus proteins can bind to the porphyrin of the heme, they should have the similar
binding ability to the human heme-binding protein, that is, the virus proteins and heme-binding
proteins should have the similar conserved domains. To examine the binding of virus structure proteins
and porphyrin, the following bioinformatics methods were applied in this paper.
First, MEME's online server was employed to search for conserved domains in each viral
structure protein and human heme-binding protein (ID:NP_057071.2 heme-binding protein 1, ID:
EAW47917.1 heme-binding protein 2). Figure 2 presents that three viral proteins (surface glycoprotein,
envelope protein and nucleocapsid phosphoprotein) and heme-binding proteins have conserved
domains, but membrane glycoprotein do not have any conserved domains. p-value values are small,
there were statistically significant. The domains in three viral proteins are different, suggesting the
structural protein's ability to bind porphyrin may be slightly different. Membrane glycoprotein could
not bind to theporphyrin.
Figure 2. Conserved domains between structure proteins and human heme-binding proteins. A.
Conserved domains of surface glycoprotein. B. Conserved domains of envelope protein. C. Conserved
domains of membrane glycoprotein. D. Conserved domains of nucleocapsid phosphoprotein.
Next, the Swiss-model online server modeled the surface glycoproteins to produce a
three-dimensional structure, and two kinds of files based on the Spike and E2 templates were selected.
The 3D-structural file of heme was downloaded from the PDB database.
In the end, Discovery-Studio realized molecular docking of surface glycoproteins and the
porphyrin. The docking of the Spike protein with heme (and porphyrin) failed first. E2 glycoprotein
(Figure 3.A) is derived from templates 1zva.1.A. The docking of E2 glycoprotein and heme was also
fruitless. When the iron ion was removed, the heme became a porphyrin, many kinds of docking were
finalized between the E2 glycoprotein and the porphyrin. Calculating the binding energy, the docking
pose with the highest binding energy (7,530,186,265.80kcal/mol) was accepted. The docking result is
exhibited in Figure 4.A-1, which is the molecular model of E2 glycoprotein binds to the porphyrin.
Figure 4.A-2 provides a two-dimensional view of the binding section, where 18 amino acids of the E2
glycoprotein interact with the porphyrin.
Analysis of envelope protein adopted the same methods. The template 5x29.1.A was selected as
the 3D structure template of envelope protein (Figure 3.B). Discovery-Studio found several kinds of
docking of the envelope protein and the porphyrin, where the docking pose with the highest binding
energy (219,317.76kcal/mol) was chosen. Figure 4.B-1 shows the docking result, which is the
molecular model of envelope protein binding to the porphyrin. Figure 4.B-2 is the two-dimensional
view of the binding section, where 18 amino acids of the envelope protein interact with the porphyrin.
Same methods were utilized to analyze the nucleocapsid phosphoprotein. The template of the
nucleocapsid phosphoprotein was 1ssk.1.A (Figure 3.C). Discovery-Studio provides the docking
between the nucleocapsid phosphoprotein and the porphyrin with the highest binding energy
(15,532,506.53kcal/mol). Figure 4.C-1 shows the docking result, which is the molecular model of the
nucleocapsid phosphoprotein bind to the porphyrin. Figure 4.C-2 is the two-dimensional view of the
binding section, where 22amino acids of thenucleocapsid phosphoprotein are bound to the porphyrin.
Membrane protein is derived from templates 1zva.1.A. The docking of membrane protein with heme
(and porphyrin) failed. These results signal the surface glycoprotein, envelope protein and nucleocapsid
phosphoprotein could bind to the porphyrin to form a complex.
It was found the binding energy of envelope protein was the lowest, the binding energy of E2
glycoprotein was the highest, and the binding energy of nucleocapsid phosphoprotein was medium. It
means that binding E2 glycoprotein to the porphyrin is the most stable, the binding of nucleocapsid
phosphoprotein to the porphyrin is unstable, and binding envelope protein to the porphyrin is the most
unstable.
After that, the following analysis was carried out to discover whether structural proteins attacked
the heme and dissociate the iron atom to form porphyrins. Heme has an oxidase called heme oxidase,
which oxidizes heme and dissociates the iron ion. If structural proteins could attack heme and
dissociate iron ions, it should have a similar conserved domain as a heme oxidase. MEME's online
server was manipulated to search for conserved domains of structural proteins and heme oxidase
proteins (NP_002124.1: heme oxygenase 1;BAA04789.1: heme oxygenase-2;AAB22110.2: heme
oxygenase-2). As a result, conserved domains of structural proteins were not found (Figure 5).
Combining the results of the previous analysis, that is, structural proteins could only combine with the
porphyrin. It can be possible to inferthe structural proteins did not attack heme and dissociate the iron
atom to form the porphyrin.
Figure 3.3D structure schematics of the novel coronavirus proteins by the homology modeling. A. E2
glycoprotein of the surface glycoprotein. B. Envelope protein. C.nucleocapsid phosphoprotein. D.
orf1ab protein. E. ORF8 protein. F. ORF7a protein
Figure 4. Molecular docking results of viral structure proteins and the porphyrin (red structure).
A.Molecular docking results of E2 glycoprotein and the porphyrin. B.Molecular docking results of the
envelope protein and the porphyrin. C.Molecular docking results of the nucleocapsid phosphoprotein
and the porphyrin. 1.Viral structure proteins. 2. View of the binding sections
Figure 5. Conserved domains between the structure proteins and human heme oxygenase proteins.
A. Conserved domains of surface glycoprotein. B. Conserved domains of envelope protein. C.
Conserved domains of membrane. D. Conserved domains of nucleocapsid phosphoprotein.
3.2 Virus non-structural proteins bind to the porphyrin
If the non-structure proteins (ID:YP_009724396.1) can bind to the porphyrin of heme, it should
have the similar binding ability to the human heme-binding protein. Then, HEME's online server was
used to search for conserved domains between the non-structure proteins and human heme-binding
proteins. Figure 6 shows that five viral proteins (orf1ab, ORF3a, ORF7a, ORF8 and ORF10) and
heme-binding proteins have conserved functional domains, but ORF6 and heme-binding proteins do
not have any conserved functional domains. p-value values are small, there were also statistically
significant. The domains in the five viral proteins are different, suggesting the non-structural protein's
ability to bind porphyrin may be slightly different. ORF6 protein dose not bind to porphyrin.
Figure 6. Conserved domains between non-structural proteins and human heme-binding proteins.
A. Conserved domains of orf1ab. B. Conserved domains of ORF3a. C. Conserved domains of ORF6. D.
Conserved domains of ORF7a. E. Conserved domains of ORF8. F. Conserved domains of ORF10.
Homology modeling and molecular docking technology were applied to study the characteristics
of orf1ab protein's ability to bind heme. Because swiss-model cannot model the 3D structure of orf1ab
protein sequence with a sequence length exceeding 5000nt, Discovery-Studio was used to homology
modeling. The crystal structure of MERS-CoV nsp10_nsp16 complex 5yn5 and heme were
downloaded from the PDB database. In this study, the crystal structure of MERS-CoV nsp10_nsp16
complex 5yn5 was set as a template to create a homologous structure of orf1ab protein. The default
homologous structure was selected as the orf1ab protein 3D-structure (Figure 3.D). Then molecular
docking of orf1ab protein and porphyrin was finished by Discovery-Studio. orf1ab protein and heme
could not complete the docking experiment, but by removing iron ions to make heme into a porphyrin,
and the radius of action increased, then several types of docking were completed. By calculating the
binding energy, a docking model with the highest binding energy (561,571.10kcal/mol) was selected.
The docking result is shown in Figure 7.A-1, where is the molecular model of the orf1ab protein
binding to the porphyrin. The binding part of the orf1ab protein acts like a clip. It was this clip that
grasps the porphyrin without the iron ion. Figure 7.A-2 shows a two-dimensional view of the binding
section. It can be seen that 18 amino acids of the orf1ab protein are bound to the porphyrin.
To study the binding properties of ORF8 protein to heme, the same analysis steps as the structural
protein method were used. The structure file was created based on the ORF7 template (Figure 3.E).
Several kinds of docking of the ORF8 protein and the porphyrin, where the docking pose with the
highest binding energy (12,804,859.25kcal/mol) was selected. The docking result (Figure 7.B-1)
represents the molecular model of ORF8 protein binding to the porphyrin. Figure 7.B-2 is the
two-dimensional view of the binding section, where 18 amino acids of the ORF8 are bound to the
porphyrin.
Same methods of ORF8 protein were used to analyze the ORF7a protein. The ORF7a’s template
is 1yo4.1.A (Figure 3.F). The ORF7a protein and the porphyrin had the highest binding energy
(37,123.79 kcal/mol). Figure 7.C-1 shows the molecular model of the ORF7a binds to the porphyrin.
Fifteen amino acids of the ORF7a are bound to the porphyrin (Figure 7.C-2). The binding part of the
ORF7a protein also acts like a clip.
Swiss-model could not provide the template for ORF10. ORF6a and ORF3a are derived from
templates 3h08.1.A and 2m6n.1.A, respectively, but the docking of ORF6a (ORF3a) with heme (and
porphyrin) failed.
Figure 7. Molecular docking results of viral non-structural proteins and the porphyrin (red).
A.Molecular docking results of the orf1ab protein and the porphyrin. B.Molecular docking results of
the ORF8 protein and the porphyrin. C.Molecular docking results of the ORF7a protein and the
porphyrin. 1.Viral non-structural proteins. 2. View of the binding sections
Finally, the following analysis was performed to find out whether non-structural proteins attacked
the heme and dissociated the iron atom to form porphyrins. Here, the same methods as previous
structural proteins, MEME's online server, were used to analyze the conserved domains of
non-structural proteins and heme oxidase proteins (NP_002124.1: heme oxygenase 1;BAA04789.1:
heme oxygenase-2;AAB22110.2: heme oxygenase-2). As shown in Figure 8, ORF10, orf1ab and
ORF3a have conserved domains. Combining the results of the previous analysis, it is showed,
non-structural proteins: ORF10, orf1ab and ORF3a could attack the heme and dissociate the iron atom
to form the porphyrin. However, the p-Value of orf1ab and ORF3a is great than 0.1%.Therefore ORF10
may be the primary protein to attack heme, orf1ab and ORF3a capture the heme or the porphyrin.
The results marked that orf1ab, ORF7a, and ORF8 could bind to the porphyrin, while ORF10,
ORF3a, and ORF6 could not bind to heme (and porphyrin). ORF10, ORF1ab and ORF3a also have the
ability to attack the heme to form a porphyrin. The binding energies of orf1ab, ORF7a, ORF8 and the
porphyrin were compared respectively. It was found the binding energy of ORF7a was the lowest, the
binding energy of ORF8 was the highest, and the binding energy of orf1ab was medium. This means
that binding ORF8 to the porphyrin is the most stable, the binding of orf1ab to the porphyrin is unstable,
and binding ORF7a to the porphyrin is the most unstable. The sequences of ORF10 and ORF6 are short,
so they should be short signal peptides. Therefore, the mechanism by which non-structural proteins
attack heme might be: ORF10, ORF1ab and ORF3a attacked heme and generatedthe porphyrin; ORF6
and ORF7a sentthe porphyrin to ORF8; and ORF8 and the porphyrin formed a stable complex.

Figure 8. Conserved domains between non-structure proteins and human heme oxygenase
proteins. A. Conserved domains of orf1ab. B. Conserved domains of ORF3a. C. Conserved domains of
ORF6. D. Conserved domains of ORF7a. E. Conserved domains of ORF8. F. Conserved domains of
ORF10.
3.3 Viral non-structural protein attacks the heme on the beta chain of the
hemoglobin
Porphyrins in the human body are mostly iron porphyrins, that is, heme. And a lot of heme is not
free, but bind to hemoglobin. There was a massive demand of porphyrins for viruses to survive.
Therefore, the novel coronavirus targeted hemoglobin, attacked heme and hunted porphyrins. The
previous analysis results showed that ORF1ab, ORF3a, and ORF10 have domains similar to heme
oxygenase, but only ORF1ab could bind to porphyrin. To study the attack behavior of orf1ab, ORF3a,
and ORF10 proteins, we used the ZDOCK molecular docking technology to examine these three
proteins. ZDOCK molecular docking technology can analyze protein interactions and find the
approximate positions of these three proteins on hemoglobin.
First, we downloaded heme oxygenase 2 (5UC8) from the PDB and used it as a template, and then
utilized the homology modeling tool of Discovery-Studio to generate the 3D structure of ORF10
(Figure 9). Since hemoglobin has two forms of oxidation and deoxygenation, the following analysis
also performs protein molecular docking in these two cases, taking the posture with the highest
ZDOCK score.
Figure 9. homology modeling of ORF10
For deoxyhemoglobin, orf1ab parked in the middle bottom of the 1-alpha and 2-alpha chain near
the 2-alpha chain (Figure 10.A). ORF3a parked in the middle bottom of the 1-alpha and 2-alpha chain
near the 2-alpha chain (Figure 10.B). ORF10 moored on the middle bottom of the 1-beta and 2-beta
chain near the 1-beta chain (Figure 10.C). The possible mechanism was that orf1ab hit the 2-alpha
chain, causing conformations changes in globin protein. ORF3A forced to the 2-alpha chain to attack
the 1-beta chain and exposed its heme. ORF10 quickly attached to the 1-beta chain and directly
impacted the heme of 1-beta chain. When the iron atom dissociated, the heme changed into porphyrin,
and orf1ab finally captured porphyrin. orf1ab played a vital role throughout the attack.
Figure 10. Viral non-structural protein attack hemoglobin. A. orf1ab attacks the deoxyhemoglobin.
B. ORF3a attacks the deoxyhemoglobin. C. ORF10 attacks the deoxyhemoglobin. D. orf1ab attacks the
oxidized hemoglobin. E. ORF10 attacks the oxidized hemoglobin. F. ORF3a attacks the oxidized
hemoglobin.
For oxidized hemoglobin, orf1ab parked in the middle bottom of the alpha and beta chain and
closed to the alpha chain (Figure 10.A). ORF10 parked below of the beta chain and neared to the outer
(Figure 10.B). ORF3a parked in the middle bottom of the alpha and beta chain and neared to the beta
chain (Figure 10.C). The possible mechanism was that orf1ab bound to the alpha chain and attacked the
beta chain, causing configurational changes in the alpha and beta chains; ORF3 attacked the beta chain
and exposed heme. ORF10 quickly attached the beta chain and directly impacted the iron atoms on the
heme of the beta chain. The heme was dissociated into porphyrin, and orf1ab finally captured
porphyrin. orf1ab played a vital role throughout the attack.
Attack of oxidized hemoglobin by viral proteins will lead to less and less hemoglobin that can
carry oxygen. The invasion of viral proteins on deoxidized hemoglobin will cause less and less
hemoglobin that can carry carbon dioxide and blood sugar. People with diabetes can have unstable
blood sugar. The patient is aggravated by carbon dioxide poisoning. The lung cells have extremely
intense inflammation due to the inability to exchange carbon dioxide and oxygen frequently, which
eventually results in ground-glass-like lung images. Patients with respiratory distress will be made
worse.
3.4 Validation for the effect of chloroquine phosphate
The chemical components in chloroquine phosphate compete with the porphyrin and bind to the
viral protein, thereby inhibiting the viral protein's attack on heme or binding to the porphyrin. To verify
the effect of chloroquine phosphate on the viral molecular mechanism of action, molecular docking
technology was accepted. The structure file of 0TX (chloroquine) was downloaded from the PDB
database. Then molecular docking technology of Discovery-Studio 2016 was used to test the effects of
viral proteins and chloroquine.
Figure 11.A-1 is a schematic diagram of binding chloroquine to a virus surface glycoprotein.
Figure 11.A-2 is the binding region of virus surface glycoprotein. 13 amino acids engaged in the
binding. The binding energy of chloroquine to the E2 glycoprotein of the virus is 3,325,322,829.64
kcal/mol, which is about half the binding energy of the E2 glycoprotein and the porphyrin. According
to the results of Figure 4.A-2, further analysis showed that some amino acids (for example VAL A:952,
ALA A:956, ALA B:956, ASN A:955 etc.) of the E2 glycoprotein could bind to not only chloroquine
phosphate, but also the porphyrins. In other words, the chloroquine has a one-third chance of inhibiting
viral E2 glycoprotein and reducing patient symptoms.
The binding view of the chloroquine and envelope protein is shown in Figure 11.B-1. The binding
energy of the chloroquine and envelope proteinis7,852.58 kcal/mol, which is only equivalent to 4% of
the binding energy of envelope protein and porphyrin. The binding region is shown in Figure 11.B-2.
Figure 4.B-2 and Figure 11.B-2representedsome amino acids (such as LEV E:28, PHE: D:20, VAL
E:25 ) of the envelope protein is not only bound to the chloroquine phosphate, but also to the
porphyrin.
Figure 11.C-1 is a schematic diagram of binding the chloroquine to the nucleocapsid
phosphoprotein. The binding energy of chloroquine to the nucleocapsid phosphoprotein is 198,815.22
kcal/mol, which is only equivalent to the 1.4% of the binding energy of the nucleocapsid
phosphoprotein and the porphyrin. ALA A:50 etc.of nucleocapsid phosphoprotein are involved in
binding (Figure 12.C-2). Figures 4.C-2 and Figures 11.C-2 declared that amino acids of nucleocapsid
phosphoprotein could bind the porphyrin, but could not bind chloroquine.
The docking of membrane protein with chloroquine failed.
Figure 11. Molecular docking results of viral structure proteins and the chloroquine (red).
A.Molecular docking results of the E2 glycoprotein and the porphyrin. B.Molecular docking results of
the envelope protein and the porphyrin. C.Molecular docking results of the nucleocapsid
phosphoprotein and the porphyrin. 1.Viral structure proteins. 2. View of the binding sections
A schematic diagram of binding chloroquine to the orf1ab protein is shown in Figure 12.A-1.
Binding section of the orf1ab protein is plotted in Figure 12.A-2. The binding energy of chloroquine
and the orf1ab protein is 4,584,302.64 kcal/mol, which equals 8-fold of the binding energy between the
orf1ab and the porphyrin. According to the results of Figure 7.A-2, it was shown that some amino acids
such as MET 7045, PHE 7043, LYS 6836 of orf1ab protein could be not only bound to chloroquine
phosphate, but also to porphyrin.
A schematic diagram of binding chloroquine to the ORF8 protein is shown in Figure 12.B-1.
Figure 12.B-2 shows the binding section of the ORF8. The binding energy of chloroquine to the ORF8
protein is 4,707,657.39 kcal/mol, which is only equivalent to 37% of the binding energy of the ORF8
protein to the porphyrin. According to the result of Figure 7.B-2, it showed the amino acids like as ILE
A:74, ASP A:75,LYS A:53 of ORF8 could not only bind to chloroquine phosphate, but also to the
porphyrin.
A schematic diagram of binding chloroquine to the ORF7a protein is shown in Figure 12.C-1.
Figure 12.C-2 is the view of the binding section. The binding energy of chloroquine to the ORF7a
protein is 497,154.45 kcal / mol, which equals 13-fold of the binding energy of the ORF7a protein to
the porphyrin. According to the results of Figure 7.C-2, it was shown the amino acids such as GLN
A:94, ARG A:78 and LEU A:96 of ORF7aprotein could be not only bound to chloroquine phosphate,
but also to the porphyrin.
The docking of ORF3a, ORF6 and ORF10 proteins with chloroquine failed.
These results marked the chloroquine could inhibit E2 and ORF8 bind to the porphyrin to form a
complex respectively to a certain extent. Meanwhile, chloroquine could prevent orf1ab, ORF3a and
ORF10 to attack the heme to form the porphyrin.
Figure 12. Molecular docking results of viral non-structural proteins and the chloroquine (red
structure). A.Molecular docking results of the orf1ab protein and the chloroquine. B.Molecular docking
results of the ORF8 protein and the chloroquine. C.Molecular docking results of the ORF7a protein and
the chloroquine. 1.Viral non-structural proteins. 2. View of the binding sections.
3.5 Validation for the effect of Favipiravir
Favipiravir is the latest anti-novel coronavirus drug with specific therapeutic effects. In
Favipiravir, the most critical ligand is 1RP, which is 6 - fluoro - 3 - oxo - 4 - (5 - O - phosphono - beta -
D - ribofuranosyl ) - 3, 4 - dihydropyrazine - 2 - carboxamide. Following the same method used to
examine chloroquine, we investigated the efficacy of Favipiravir. As can be seen from Table 1,
Favipiravir cannot be bind to E2 glycoprotein and Nucleocapsid, and its binding energy to Envelope
protein, ORF7a, orf1ab is higher than that to porphyrin. It is useful to note that the binding energy of
Envelope protein and Favipiravir is more than 2700 times the binding energy of porphyrin. The
primary function of Envelope protein is to help the virus enter host cells, which shows that Favipiravir
can effectively prevent the virus from infecting human cells. The binding energy of ORF7a to
Favisiravir is 450 times higher than that of porphyrin, indicating that it can effectively avoid the
non-structural protein of the virus capturing porphyrin. The binding energy of orf1ab and Favisiravir is
1.8 times higher than that of porphyrin, which shows that Faifiravir can prevent virus unstructured
protein from attacking heme on hemoglobin. According to previous studies, the binding energy of
orf1ab and Favisiravir is much smaller than that of chloroquine, so Favisiravir's ability to improve
respiratory distress is lower. In summary, the primary role of Favipiravir is to prevent the virus from
entering host cells and catching free porphyrins.
Table 1. Effect of Favipiravir
Virus potein
Porphyrin
(kcal/mol)
Favipiravir
(kcal/mol)
Has
Identical
residues
Target
Target Rate
(Favipiravir
/Porphyrin)
E2 glycoprotein 7,530,186,265.80 - - - -
Envelope protein 219,317.76 597,814,480.55 Yes Yes 2,725.79
Nucleocapsid 15,532,506.53 - - - -
orf1ab 561,571.10 1,052,489.88 Yes Yes 1.87
ORF8 12,804,859.25 348,589.80 Yes - -
ORF7a 37,123.79 17,034,560.60 Yes Yes 458.86
4 Discussion
4.1 The novel coronavirus originated from an ancient virus
For the most primitive-life viruses, it isn't very easy to see their role in binding the porphyrin. The
porphyrin compounds are widely present in photosynthetic or non-photosynthetic organisms, and they
are associated with critical physiological processes such as catalysis, oxygen transfer, and energy
transfer. The porphyrin is also an ancient compound widely present on the earth. The porphyrin is first
found in crude oil and asphalt rock in 1934. The porphyrin has unique photoelectronic properties and
excellent thermal stability and has broad application prospects in materials chemistry, medicine,
biochemistry, and analytical chemistry. It is excellent performance in two-photon absorption,
fluorescence effect, energy transfer, and other aspects. Fluorescence resonance energy transfer (FRET)
is a non-radiative process in which a donor in an excited state transfers energy to a receptor in the
ground state through a long-range dipole effect. The FRET characteristics of the porphyrin may be the
primary survival mode on which the original virus relied.
There are numerous theories about the origin of viruses, one of which is called co-evolution
theory, which viruses can evolve from complexes of the protein and the nucleic acid . Various methods
do not explain that a virus survived independently of non-appearing cells at the beginning of life, so the
origin of a virus remains a mystery. This paper proposes that a virus could be bind to the porphyrin,
which could explain the survival problem of an original virus. Because the porphyrin has the energy
transfer characteristic of fluorescence resonance, viruses that bind to porphyrins could obtain energy
through this light-induced method. A virus that gained power could achieve minimal displacement
movements, or wake itself from hibernation, or enter hibernation from an active state. Depending on
the research results in this study, the novel coronavirus was a life form dependent on the porphyrin.
Therefore, we could believe that the novel coronavirus originated from an ancient virus that may have
evolved over countless generations in bats.
4.2 Higher permeability of porphyrins into cell membranes leads to high
infections
Highly evolving of the novel coronavirus also displays some paradoxical characteristics. The
current theory suggests that the novel coronavirus binds to the human ACE2 receptor through a spike
protein. It enters human cells in the form of phagocytosis. Infectious disease models indicated that the
novel coronavirus pneumonia is highly contagious. Therefore, the spike protein and human ACE2
protein should have a strong binding ability, but there are reports in the literature that this binding
ability is weak. What causes the high infectivity of the novel coronavirus? We believe that in addition
to the invasive method of spike-ACE2, it should maintain the original invasive pattern.
Medical workers have detected the novel coronavirus from urine, saliva, feces, and blood. The
virus can also live in body fluids. In such media, porphyrin is a prevalent substance. Porphyrin
compounds are a class of nitrogen-containing polymers, and existing studies have found that they have
a strong ability to locate and penetrate cell membranes. At the beginning of life, virus molecules with
porphyrins directly moved into the original membrane structure by porphyrin permeability. This study
showed that the E2 glycoprotein and Envelope protein of the novel coronavirus could bind well to
porphyrins. Therefore, the coronavirus may also directly penetrate the human cell membrane through
porphyrin, so the infection is robust. Our validation analysis showed that Favipiravir could only
prevent the binding of Envelope protein and porphyrin. Meanwhile, chloroquine could effectively
prevent the binding of E2 glycoprotein to porphyrin to a certain extent. Therefore, the infectivity of the
novel coronavirus pneumonia was not completely prevented by the drugs, because of the the binding of
E2 glycoprotein and porphyrin was not inhibited.
4.3 Higher hemoglobin caused higher morbidity
The therapeutic effect of chloroquine phosphate on novel coronavirus pneumonia shows that
novel coronavirus pneumonia might be closely related to abnormal hemoglobin metabolism in humans.
The number of hemoglobin is a major blood biochemical indicator, and the content is different in
different genders. The number of normal men is significantly higher than that of normal women, which
might also be a reason why men are more likely to be infected with the novel coronavirus pneumonia
than women. Besides, patients of novel coronavirus pneumonia are most of the middle-aged and older
adults. Many of these patients have underlying diseases such as diabetes. Diabetic patients have higher
glycated hemoglobin. Glycated hemoglobin is deoxyhemoglobin. Glycated hemoglobin is a
combination of hemoglobin and blood glucose, which is another reason for the high infection rate for
older people.
This study has confirmed that orf1ab, ORF3a, and ORF10 could coordinately attack heme on the
beta chain of hemoglobin. Both oxygenated and deoxygenated hemoglobin are attacked. During the
attack, the positions of orf1ab, ORF3, and ORF10 are slightly different. It showed that the higher the
hemoglobin content, the higher the risk of disease. However, it is not sure that the disease rate caused
by abnormal hemoglobin (structural) is relatively low. The hemoglobin of patients and recoverers
should be detected for further research and treatment.
4.4 Inhibiting the heme anabolic pathway and causing the disease
This article considered the virus directly interfered with the assembly of human hemoglobin. The
main reason was the normal heme was too low. Heme joins in critical biological activities such as
regulation of gene expression and protein translation. Porphyrin is an important material for the
synthesis of heme. Because the existing traces show there is too much free iron in the body, it should be
that virus-producing molecule competes with iron for the porphyrin. Inhibiting the heme anabolic
pathway and causing symptoms in humans.
It is not clear whether the spatial molecular structure of heme and porphyrin in patients with
porphyria is the same as that in healthy people. If there is an abnormal structure, it is not clear whether
this porphyrin can bind to a viral protein to form a complex, or if a viral protein can attack this heme. It
should be proved by clinical and experimental research.
4.5 The complexity of individual immunity
Some theories suggest that an immune response occurs in the body after a patient becomes ill.
Some patients develop immune antibodies after recovery. According to this study, E2 glycoprotein,
envelope protein, nucleocapsid phosphoprotein, orf1ab, ORF7a, and ORF8 of the virus could bind to
porphyrin. But from the current research, it is unclear which immune antibodies have been raised
against viral proteins.
Besides, some patients may be killed by their cytokine storm. Comparing to patients with SARs,
the anatomical characteristics of the dead are different. The complex of virus proteins and the
porphyrin may be little soluble. Too much mucus in the tissues of the deceased patients was the cause
of too much mucin protein. Mucin could turn loosely connected cells into tightly adhered cells and
increases lubrication between cells. It suggests the compound leads to reduced cell connectivity, and
cells need mucin to consolidate tissue-cell connectivity and lubricity. Also, when a patient enters a
severe infection period, viral structural proteins were mainly used for virus assembly. Therefore, we
cannot find noticeable virus inclusions in tissue cells of the dissected patient.
5 Conclusions
Since the emergency epidemic, it is of high scientific significance to use bioinformatics to analyze
the roles of novel coronavirus proteins (such as ORF8 and surface glycoproteins). In this study, domain
prediction methods were applied to search for conserved domains. The structure of protein molecules
such as ORF8 and surface glycoproteins were obtained using homology modeling methods. Molecular
docking technology was used to analyze the binding part of viral proteins to the heme and the
porphyrin. The study results show that ORF8 and surface glycoproteins could combine to the porphyrin
to form a complex, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could
coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the
porphyrin. The attack will lead to less hemoglobin to carry oxygen and carbon dioxide. The lung cells
have extremely intense inflammation due to the inability to exchange carbon dioxide and oxygen
frequently, which eventually results in ground-glass-like lung images. Patients with respiratory distress
will be made worse. Diabetic patients and older people have higher glycated hemoglobin. Glycated
hemoglobin was reduced by the attack, which made patients' blood sugar unstable. Since the porphyrin
complexes of the virus produced in the human body inhibited the heme anabolic pathway, they caused
a wide range of infection and disease.
With these findings in mind, further analysis revealed that chloroquine could prevent orf1ab,
ORF3a, and ORF10 from attacking the heme to form the porphyrin, and inhibit the binding of ORF8
and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of
respiratory distress. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin,
prevent the virus from entering host cells, and catching free porphyrins. Because the novel coronavirus
is dependent on porphyrins, it may originate from an ancient virus. Given the current epidemic, it is
believed the results of this study are of high value in preventing the spread of novel coronavirus
pneumonia, developing drugs and vaccines, and clinical treatment.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and materials
The datasets and results supporting the conclusions of this article are available at
https://pan.baidu.com/s/1YQNGoN6L9rPU8K5Bnh3EuQ, code: ry25.
Competing interests
The authors declare that they have no competing interests.
Author Contributions:
Design, analysis, writing: Wenzhong Liu. Data curation, check manuscript: Hualan Li. All
authors have read and agreed to the published version of the manuscript.
Funding
This work was partially supported by the Natural Science Foundation for Talent Introduction
Project of Sichuan University of Science & Engineering (No. 2018RCL20).
Acknowledgements
Not applicable.
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Demonstration report on inclusion of hyperbaric oxygen therapy in treatment of COVID-19 severe cases

Demonstration report on inclusion of
hyperbaric oxygen therapy in treatment of
COVID-19 severe cases

Naval Specialty Medical Center Program Team
Clinical reports and pathologic anatomic findings shown,
progressive hypoxemia is the main cause of deterioration in patients with
COVID-19."The mortality rate of critical patients in WuHan is close to
60%, and we are trying to solve the problem of hypoxia," Zhong Nanshan
said on 27th Feb. HBOT is the strongest non-invasive oxygen therapy. In
the early stage, 5 cases of severe and critical patients with COVID-19 a
were clinically treated, which proved that the long-term excellent clinical
effect of using HBOT in treating hypoxia was also applicable to
COVID-19 patients. The effect of HBOT is better than breathing
atmospheric high flow oxygen and mechanical ventilation techniques. It
is suggested that promote HBOT as an oxygen therapy treatment for
critically ill patients with COVID-19, which is expected to significantly
improve the treatment efficiency, reduce the medical pressure and the risk
of infection, and decrease the mortality rate of critical patients. It has
practical significance for further accelerating the overall victory of this
epidemic, achieving the most effective treatment and realizing infection
prevention control.
I. Evaluation of the effectiveness of HBOT in oxygen
therapy for critical patients with COVID-19.
1) 5 critical patients showed consistent response to HBOT oxygen
therapy
Zhong Yangling, the director of the Department of Hyperbaric
Oxygen in Wuhan Yangtze River Shipping General Hospital, successfully
carried out HBOT treatment in 5 patients with COVID-19 (2 critical and
3 severe), which got significant results. Case reports of the first patient
have been published. 5 cases clinical analysis data shown:
a) Treatment effect of progressive hypoxemia in severe patients
-Rapid relief of hypoxic symptoms. 5 patients had obvious
symptoms of progressive hypoxia before. After the first session of HBOT,
symptoms such as dyspnea and chest pain are reduced. After the second
session HBOT, the symptoms are basically relieved, and the respiratory
rate decreases gradually, but the shortness of breath after the movement
relieved slowly.
-Rapid correction of hypoxemia. Arterial blood gas analysis of 5
patients under the condition of breathing oxygen with oxygen mask
（5~8L/min）before HBOT treatment showed PaO2 is 37, 65, 60, 78, and
68 mmHg, the trend of critical patients’ Blood oxygen saturation of artery
blood of finger(SO2)was reversed immediately. Since the 5th day,SO2
was up to 95% in daily average(1). Compare with the patients’ body data
before they do the HBOT treatment,which be regard as the last day data,
SO2 showed a significant upward trend day by day(2 left). After HBOT
treatment, SO2 is higher than 93%, and every treatment solved the
patient's problem of total hypoxia. Arterial blood gas index recovered
significantly(pic 2 right).
(pic 1)Changes of critical patients’ SO2 before and after HBOT (11/2)
(pic 2) SpO2 daily changes and Arterial blood gas analysis of 5 patients before and after HBOT
b) Comprehensive therapeutic effect of HBOT oxygen therapy
on severe patients
- General condition reversal. In addition to the relief of hypoxic
symptoms in all patients, the general state was significantly reversed.
Gastrointestinal symptoms are reduced and appetite is restored. Headache
disappeared and mental state improved.
- Clinical objective indicators improved. Except the significant
changes in artery blood of finger and Arterial blood gas, differential blood
count, which respond to immune function recovered gradually,
coagulation index of reactive peripheral circulation disorder improved,
Indexes reflecting liver function and myocardial injury improved(3).
- Improved lung pathology. Re-examination of the lung CT after
treatment showed that lung inflammation in all 5 patients was
significantly improved(4).
(pic 3) Changes of coagulation function and sacral hydration in 5 patients before and after HBOT
treatment
(pic 4) CT changes before and after 4-7 HBOT in 5 patients
2) The mechanism of HBOT oxygen therapy
The difference between HBOT oxygen therapy and normal pressure
oxygen therapy is, in general, the use of high pressure oxygen inhalation,
which fully and substantially improves the efficiency of oxygen transport
from the outside to the whole tissue cells. The mechanism of HBOT is to
take advantage of the physical characteristics of gas, to increase the
partial pressure of the oxygen in the environment through a large
amplitude, and to reduce the demand for oxygen exchange and
transportation in the body to achieve the best oxygen therapy effect. The
mechanism of HBOT is shown in pic 5. The advantages compared with
atmospheric pressure oxygen therapy technology are:
Firstly, more effectively than normal pressure oxygen inhalation to
overcome lung tissue inflammation.
The diffusion rate and distance of high pressure oxygen are several
times that of normal pressure oxygen, which overcome the gas exchange
obstacle caused by the thickening of the lung tissue inflammation.And
because of the higher solubility, the amount of oxygen dissolved in the
blood is several times that of atmospheric oxygen, which also further
overcomes the influence of the blood circulation gas ratio.
Secondly, it is more effective to increase oxygen partial pressure than
to increase oxygenation index by mechanical ventilation.
In respiratory and critical care medicine, oxygen efficiency in
clinical respiratory support uses oxygenation index (is the ratio of partial
pressure of oxygen in the artery to partial pressure of oxygen in the
inhaled gas [OI=PaO2/FiO2(air pressure /760)])) as the final evaluation
index. With partial arterial oxygen pressure as the therapeutic target, the
conversion formula[PaO2=OI × FiO2(air pressure /760)]. Mechanical
ventilation technique is to improve PaO2 by increasing OI. The FiO2 of
HBOT can be increased by 1.6~2.8 times. It can be predicted that PaO2
can be increased by 1.6~2.8 times with HBOT patients' OI unchanged,
which is the same as the effect of OI increased by 1.6~2.8 times. The
effects of OI and treatment before treatment in 5 patients have been fully
verified. In one case, HBOT was used to reverse hypoxia on the basis of
no effect of noninvasive mechanical ventilation for 2 days. HBOT
technology for patients with invasive mechanical ventilation is mature
and has been routinely used in clinical HBOT. Therefore suggested that
clinical selection principles are: (1) HBOT treatment is preferred when
patients' oxygenation index is significantly reduced and natural
respiration is clear, and mechanical ventilation is not expected to increase
oxygenation index by 1.5 times; (2) When the improvement of
oxygenation index under mechanical ventilation is less than twice that of
natural respiration, it is suggested to increase the daily HBOT treatment
on the basis of mechanical ventilation.
Thirdly, more effective than ECMO in improving tissue cell oxygen
uptake.
Although ECMO has surpassed the ventilation and gas exchange
functions of the lungs, and can make Hb completely saturated, it is not as
good as HBOT in tissue side oxygen supply. The dissolved oxygen in the
blood has exceeded the amount carried by Hb, and the diffusion distance
has been greatly increased, which can relatively overcome the peripheral
circulation obstacles caused by pre-hypoxic damage or / and infectious
inflammation, and improve the efficiency and absolute amount of tissue
cells to obtain oxygen.
Fourthly, there is no serious interference of mechanical ventilation to
the respiratory tract in natural breathing.
HBOT means that the patient is under high pressure. The common
metaphor of the difference between breathing mode and atmospheric
pressure is that breathing on the plateau is the same as breathing on the
plain, which is natural breathing. Different from mechanical ventilation, it
has a great effect on respiratory tract, need to be paid attention to and
dealt with by doctors and nurses at all times. Otherwise, it is easy to have
various complications such as airway injury.
Fifthly, there is no conflict with the current means of critical treatment,
and the +HBOT mode has a clear role in improving the treatment
effect.
COVID-19, in addition to antibodies and vaccines, there is no
specific drug. All clinical treatment is basically symptomatic treatment
and supportive treatment. HBOT is not the etiological treatment of
COVID-19, it is the symptomatic treatment of hypoxia in patients with
COVID-19, and it is a supplement to the existing oxygen treatment
technology. In addition to HBOT once a day for 95-120 minutes, the
patients also received the existing comprehensive treatment in ICU,
including mechanical ventilation. In addition to HBOT, ICU clinicians
are still responsible for the daily comprehensive treatment of the
above-mentioned severe patients. There is no conflict in treatment
technology. On the contrary, it can provide better support for other
supportive treatments.
(pic 5 The effect of different oxygen therapy on oxygen from the external environment to the
process of tissue and organ)
3) Clear indications of HBOT for the symptomatic treatment of
hypoxia
Firstly, hypoxia is the first indication of HBOT.
HBOT is a routine oxygen therapy for clinical refractory hypoxia.
HBOT has been widely used in the clinic for more than half a century
since it was first used in the supportive treatment of thoracic surgery in
1956. In China, grade A hospitals are generally equipped with oxygen
Chambers, and a large number of HBOT of various diseases are carried
out on a daily basis, especially for carbon monoxide poisoning -- a typical
acute anoxia, which has become a key treatment measure. From the
perspective of diseases, HBOT has a wide range of indications. As a
routine application of oxygen therapy, the indication is essentially a
"hypoxia", that is, generalized and local stubborn hypoxia problem.
Secondly, the diagnosis of anoxia in severe patients with COVID-19 is
clear.
The clinical manifestations of severe patients with hypoxia are
prominent, the indication of hypoxemia is obvious, and the existence of
hypoxia is obvious. In all the previous published clinical scientific
literature on COVID-19, it is clear that the continuous and progressive
development of hypoxemia is an important manifestation of disease
deterioration. In the severe treatment of COVID-19, HBOT is used for
the symptomatic treatment of anoxia correction with clear indications.
The therapeutic effect of 5 patients was very significant, and both
the subjective and objective clinical indexes showed that the deterioration
of hypoxia was interrupted immediately and then the whole body
recovered gradually after the first HBOT. Such a consistent treatment
response, according to the statistical law, cannot be explained by chance.
The above mechanism demonstrated that the efficacy of HBOT in 5
patients was not accidental. The therapeutic effect of HBOT on hypoxia is
a scientific summary of the effects of HBOT in the treatment of
intractable and refractory hypoxia in various diseases over a long period
of time. The relevant scientific papers, literature and works are endless.
The superiority of HBOT in solving severe hypoxia in patients with
COVID-19 is clearly scientific. Unlike the newly developed treatment
stage or the efficacy of medicine is still in the scientific hypothesis stage,
HBOT don't need clinical trial verification and other methods of oxygen
therapy that have been used clinically, such as mechanical ventilation or
ECMO, it can be reasonably used.
In summary, the use of HBOT can provide clear clinical benefits for
the pathophysiological problems encountered in the treatment of hypoxia
in severe critical diseases. HBOT can be used to treat severe hypoxia in
patients with COVID-19, which can more effectively and
comprehensively solve the problem of hypoxemia than normal pressure
oxygen therapy (high flow oxygen inhalation, mechanical ventilation),
make deep tissue hypoxia fully corrected and greatly relieve systemic
hypoxic inflammation, and also has practical clinical significance for the
effects of other treatment methods (such as medicine supportive
treatment).
II. Safety of HBOT for oxygen therapy in severe
patients with COVID-19
HBOT has been standardized and widely used clinically for nearly a
century. Its essential medical safety is not repeated here. The focus is on
disease prevention and control (CDC) risks posed by Class A infectious
diseases. HBOT treatment requires special equipment and procedures,
and patients need to be transferred back and forth from the ward to the
hyperbaric oxygen chamber. The transfer process is in an atmospheric
environment, and there are mature CDC measures without
insurmountable technical problems. Wuhan Changjiang General Hospital
has already formed a practicable method, which can be further improved,
and it will not be repeated here. This article focuses on the treatment
process of HBOT in the oxygen cabin and the risk of CDC in the
hyperbaric oxygen department.
1) . The risk of pathogenic microorganism infection in cabin is not
higher than the ward
Firstly, the risk of performing CDC in the hyperbaric oxygen chamber is
the same as the risk of CDC in the infection ward.
The difference between the micro-environment of the hyperbaric oxygen
chamber and the micro-environment of the infection ward is the radon
pressure.It is same as the difference between the plateau and sea level.
The medical staff is exposed to the oxygen chamber micro-environment
under a high pressure, the surface intensity of pressure is equal, and the
pressure difference cannot be felt. Protective equipment also does not
suffer from “compressive” deformation. The requirements for the
infection control of the hospital in plateau area are not different from
those in the plain area. There are no clear differences in CDC
requirements for different environmental pressures. The process of
medical treatment in the hyperbaric cabin did not significantly increase
the risk of CDC compared with the same operation in the infection ward.
Secondly, the hyperbaric oxygen cabin is a completely new wind
environment.
In the HBOT process, “ventilation” measures are usually adopted.
The pressure valve and the pressure relief valve are opened at the same
time.When the amount of air input is equal to the amount of air output,
the intensity of pressure in the cabin is guaranteed to be constant, and the
air purge inside cabin is continuously updated. The air inlet port and
output port are located on the opposite sides of the cabin. Under
continuous ventilation, the air flow in the cabin is generally unidirectional,
similar to a laminar flow operating room. The pressure of the air in the
pipeline decreases gradually from the source to the exhaust port. There is
no back flow of gas under the pressure gradient. The air sources are
filtered, pressurized, and depressurized by an oil-free air compressor
advanced purification device to ensure clean air sources.
Thirdly, air breathed by doctors and patients is relatively separated
inside the cabin.
The patient used a mask of the Bulding in breathing system (BIBS)
to breathe pure oxygen after entering the cabin. The exhaled gas of the
patient mainly exists in the oxygen exhaust line and flows
unidirectionally outward. Medical staff breathes air in the cabin, basically
does not cross the gas that the patient breathe. This is better than the
infection ward.
Medical staff pressurize independently. During the pressurization
process, the pressure on the body side of the protective equipment is low,
and the air in the cabin may enter the body side of the protective
equipment as the pressure increases. The hyperbaric oxygen chamber is
provided with a transition cabin (small cabin). The medical staff use
independent cabin to pressurize to avoid the possibility that a large
amount of air from the treatment cabin where the patient is regarded as a
contaminated area enters the body side of the protective equipment. The
decompression process is the opposite, so there is no risk of CDC.
Fourthly, Infection ward CDC measures are used in the hyperbaric
oxygen chamber and no additional evaluation is required.
The hyperbaric oxygen chamber is managed as a ward for patients
with new coronavirus. Disinfection process is performed under normal
pressure, and the disinfection technology method and effect are the same.
The pressurization process is with "full fresh air systems", the air that
doctors and patients breathe is relatively independent, and the possible
gas pollution is less than that of infected wards. In addition, the CDC
requirements for infection wards are applicable to infection-control
management after the pressure in the hyperbaric chamber is relatively
constant.
2). Hyperbaric Oxygen Department's measures to control infection
have been initially formed and practical
The Hyperbaric Oxygen Department is an area for the treatment of
infected patients. There are clear rules and regulations for the setting of
the ward isolation area and personnel protection under normal pressure,
which can a reference. It has also formed a set of effective practices,
which will not be repeated here. The focus of controlling infection is to
purify and sterilize the exhaust gas from the BIBS system oxygen outlet
and chamber decompression outlet of the patient's breathing. In this
regard, no products were found at home or abroad for hyperbaric chamber
exhaust gas purification and disinfection. We first adopted strict control
measures in the area of the exhaust port to avoid the possible impact of
the patient's exhaled gas on the outside activities in the effective area. At
the same time, non-standard disinfection measures were temporarily
adopted, and the exhaust gas was filtered by the disinfectant solution to
further prevent the pollution of the exhaust gas to the surrounding
environment and cause the virus to spread. At present, the hyperbaric
chamber supplier has purchased the medical gas purification equipment
certified by the relevant national authorities for modification. After
installation, it can meet the national standards.
To sum up, the hyperbaric oxygen chamber is a closed gas
management system with unidirectional air flow, full fresh air systems,
and separate air pipelines for medical staff and patients to breathe. There
are no insurmountable technical obstacles to the treatment of HBOT for
CDC. Hyperbaric Oxygen Department of Wuhan Changjiang Shipping
General Hospital has established a complete infection control procedures
and measures for HBOT treatment of patients with new coronavirus, and
has passed the evaluation of the infection control department. The HBOT
treatment for patients with severe disease has been carried out more than
20 times in the early stage, and none medical was infected. In general, the
risk of infection in the HBOT chamber is not as high as the ward. Early
intervention of HBOT can reduce the use of mechanical ventilation and
accelerate the cure of critically ill patients, and further reduce the risk of
infection for medical staff.
III. Feasibility Evaluation of HBOT Oxygen Therapy
at Huoshenshan Hospital for COVID-19
Huoshenshan Hospital will be the last line of defense for COVID-19.
The above discussion shows that it is obvious that HBOT can be used for
oxygen therapy in patients with COVID-19 if it can exert its clinical
significance. But Huoshenshan hospitals are not equipped with HBOT
equipment, which is the biggest problem with HBOT. Given that the
treatment of hypoxia is a key and difficult point in the current severe
treatment, it is of practical significance to strive for HBOT oxygen
therapy in Vulcan Hospital. The following preliminary suggestions are
made on the feasibility and progress of Huoshenshan Hospital's existing
treatment + HBOT.
Step1. Portable high-pressure oxygen equipment is used in a small
area, and a basic treatment process adapted to the actual
situation of Huoshenshan Hospital is formed.
In addition to the hyperbaric oxygen chamber, the equipment that
can inhale oxygen at high pressure also has a diving chamber for treating
decompression sickness. The military-equipped electric diving
pressurized chamber and portable High-pressure chamber can also treat
decompression sickness, and can be performed automatically in a good
oxygen environment in a short time(120min) without the help of medical
staff.
A military university in Wuhan is equipped with a mobile diving
chamber (for two people) and a portable hyperbaric oxygen chamber.
Therefore, hyperbaric oxygen therapy can be performed in the open area
of the hospital. This part of the area is controlled according to the
contaminated area and meets the CDC. It is recommended that the
equipment and operator be transferred to Huoshenshan Hospital together
to try HBOT treatment for 5 critically ill patients with similar conditions.
Basic treatment procedures and CDC procedures include:
(1) HBOT treatment: 1.6ATA / 120 minutes, continuous oxygen
inhalation. It is expected to achieve an oxygen therapy effect of 1.6 times
the oxygenation index, which is superior to mechanical ventilation, the
reasonable use of atmospheric oxygen, and the overall therapeutic effect
is significant.
(2) CDC process of HBOT treatment: The CDC process of hyperbaric
oxygen therapy in Wuhan Changjiang Shipping General Hospital has
been proven to be feasible in time, and can be optimized and adjusted
according to the actual layout of Huoshenshan Hospital.
(3) HBOT emergency treatment plan: HBOT uses 1.6ATA, diving
depth is about 6 meters, no decompression is needed. Once the patient's
condition has changed, it can be removed from the compression chamber
within 3 minutes. What you need to do is prepare first aid at atmospheric
pressure next to the oxygen chamber, and then take the patient back to the
ICU ward.
Step2. Concentrate portable hyperbaric oxygen equipment inside
and outside the army to popularize HBOT oxygen therapy as much
as possible
After researching the mobile high-pressure system capable of
treating decompression sickness and combining the number of military
equipment, preliminary estimates are that it can increase 144 times/day
HBOT.
Step3. Hyperbaric Oxygen Chamber Construction at Huoshenshan
Hospital Simultaneously Started
Construction of a new hyperbaric oxygen chamber system started at
Huoshenshan Hospital. After investigation, the supplier of hyperbaric
oxygen equipment of Wuhan Changjiang Shipping General Hospital can
complete the installation and commissioning and put it into use within 15
days. HBOT oxygen therapy for tracheal intubation mechanical
ventilation patients can be further developed and combined with portable
hyperbaric oxygen equipment, the overall effect will be very significant.
Conclusion
In general, HBOT oxygen therapy has clear indications for patients
with COVID-19, with obvious effects and no obvious uncontrollable
safety risks. Control measures and procedures have been developed to
meet the course of treatment for patients with Class A infectious diseases.
The risk of infection by medical staff is not greater than that of infected
wards. HBOT oxygen therapy is widely used, and some hospitals are also
equipped with a hyperbaric oxygen chamber. Therefore, we strongly
recommend including HBOT in the treatment of COVID-19 in order to
provide the treating physician with more effective oxygen therapy.
Huoshenshan Hospital, as the last line of defense for new serious
treatment, is gradually exploring and developing large-scale HBOT
oxygen therapy, which is expected to significantly improve treatment
efficiency, reduce medical and infection pressure and reduce mortality.