VI. Antiviral Treatment for Timely Elimination of Pathogens
An early antiviral treatment can reduce the incidence of severe and critical cases. Although
there is no clinical evidence for effective antiviral drugs, currently the antiviral strategies based
on the characteristics of SAR-CoV-2 are adopted according to Protocols for Diagnosis and
Treatment of COVID-19: Prevention, Control, Diagnosis and Management.
Antiviral Treatment
At FAHZU, lopinavir/ritonavir (2 capsules, po q12h} combined with arbidol (200 mg po
ql 2h) were applied as the basic regimen. From the treatment experience of 49 patients
in our hospital, the average time to achieve negative viral nucleic acid test for the first
time was 12 days (95% Cl: 8-15 days). The duration of negative nucleic acid test result
(negative for more than 2 times consecutively with interval<! 24h} was 13.5 days (95% Cl:
9.5 - 17.5 days).
If the basic regimen is not effective, chloroquine phosphate can be used on adults
between 18-65 years old (weight<! so kg: 500 mg bid; weight ~so kg: 500 mg bid for first
two days, 500 mg qd for following five days).
Interferon nebulization is recommended in Protocols for Diagnosis and Treatment of
COVID-19. We recommend that it should be performed in negative-pressure wards
rather than general wards due to the possibility of aerosol transmission.
Darunavir/cobicistat has some degree of antiviral activity in viral suppression test in
vitro, based on the treatment experience of AIDS patients, and the adverse events are
relatively mild. For patients who are intolerant to lopinavir/ritonavir, darunavir/ cobici
stat (1 tablet qd) or favipiravir (starting dose of 1600 mg by 600 mg tid) is an
alternative option after the ethical review. Simultaneous use of three or more antiviral
drugs is not recommended.
Course of Treatment
The treatment course of chloroquine phosphate should be no more than 7 days. The
treatment course of other regimens has not been determined and are usually around 2
weeks. Antiviral drugs should be stopped if nucleic acid test results from sputum
specimens remain negative for more than 3 times.
VII. Anti-shock and Anti-hypoxemia Treatment
During the progression from the severe to critically ill stage, patients may develop severe
hypoxemia, cytokine cascade and severe infections that might develop into shock, tissue
perfusion disorders, and even multiple organ failure. Treatment is aimed at incentive removal
and fluid recovery. The artificial liver support system (ALSS} and blood purification can
effectively diminish inflammatory mediators and cytokine cascade and prevent the incidence
of shock, hypoxemia and respiratory distress syndrome.
Usage of Glucocorticoids when Necessary
Appropriate and short-term use of corticosteroids to inhibit cytokine cascade and to
prevent disease progression should be considered for patients with severe COVID-19
pneumonia as early as possible. However, a high dose of glucocorticoids should be
avoided due to adverse events and complications.
1.1 Indication for Corticosteroids
(D for those in severe and critically ill stage;
al for those with persistent high fever (temperature above 39°C};
@for those whose computerized tomography (CT) demonstrated patchy ground-glass
attenuation or more than 30% area of the lungs are involved;
@for those whose CT demonstrated rapid progression (more than 50% area involved in
pulmonary CT images within 48 hours);
® for those whose IL-6 is above;;, 5 ULN.
1.2 Application of Corticosteroids
Initial routine methylprednisolone at a dose of 0.75-1.5 mg/kg intravenously once a day
(nearly 40 mg once or twice a day) is recommended. However, methylprednisolone at a
dose of 40 mg ql2h can be considered for patients with falling body temperature or for
patients with significantly increased cytokines under routine doses of steroid. Even
methylprednisolone at a dose of 40 mg-80 mg ql2h can be considered for critical cases.
Closely monitor body temperature, blood oxygen saturation, blood routine, c-reactive
protein, cytokines, biochemical profile and lung CT every 2 to 3 days during the
treatment as necessary. The dosage of methylprednisolone should be halved every 3 to
5 days if medical conditions of patients are improved, the body temperature normaliz
es, or involved lesions on CT are significantly absorbed. Oral methylprednisolone
(Medrol) once a day is recommended when the intravenous dose is reduced to 20 mg
per day. The course of corticosteroids in not defined; some experts have suggesting
ceasing corticosteroids treatment when patients are nearly recovered.
1.3 Special Consideration during Treatment
G) screening of TB by T-SPOT assay, HBV and HCV by antibody assay should be
performed before corticosteroid therapy;
al proton pump inhibitors could be considered to prevent complications;
@ blood glucose should be monitored. High blood glucose should be treated with
insulin when necessary;
@ low serum potassium should be corrected;
® liver function should be monitored closely;
® traditional Chinese herbal medicine may be considered for patients who are sweat
ing;
(J) sedative-hypnotics can be administered temporarily for patients with sleep disorder.
2
Artificial Liver Treatment for Suppression of Cytokine Cascade
The artificial liver support system (ALSS) can conduct plasma exchange, adsorption,
perfusion, and filtration of inflammatory mediators such as endotoxins and harmful
metabolic substances of small or medium molecular weight. It can also provide serum
albumin, coagulation factors, balance fluid volume, electrolytes and acid-base ratio,
and manifest anti-cytokine storms, shock, lung inflammation, et al. In doing so it can
also help to improve multiple organ functions including the liver and kidney. Thus, it can
increase treatment success and reduce the mortality of severe patients.
2.1 Indication for ALSS
G) serum inflammatory indicator (such as IL-6) level rises to;;, 5 ULN, or rising rate is ;;el
time per day;
al involved area of pulmonary CT or X-ray images ;;,10% progression per day;
@ artificial liver support system is required for the treatment of underlying diseases.
Patients meeting G) + al, or patients meeting@.
2.2 Contraindications
There is no absolute contraindication in the treatment of critically ill patients. However,
ALSS should be avoided in the following situations:
G) Severe bleeding disease or disseminated intravascular coagulation;
@ Those who are highly allergic to blood components or drugs used in the treatment
process such as plasma, heparin and protamine;
® Acute cerebrovascular diseases or severe head injury;
@) Chronic cardiac failure, cardiac functional classification;;, grade Ill;
® Uncontrolled hypotension and shock;
® Severe arrhythmia.
Plasma exchange combined with plasma adsorption or dual plasma molecular
adsorption, perfusion, and filtration is recommended according to the patients'
situation. 2000 ml of plasma should be exchanged when ALSS is performed. Detailed
operating procedures can be found in the Expert Consensus on the Application of
Artificial Liver Blood Purification System in the Treatment of Severe and Critical Novel
Coronavirus Pneumonia.
ALSS significantly reduces the time that critically ill patients stay in the ICU in our
hospital. Typically, the levels of serum cytokines such as IL-2/IL-4/IL-6/TNF-a are
remarkably decreased, and oxygen saturation is significantly improved after ALSS.
Oxygen Therapy for Hypoxemia
Hypoxemia can present due to impaired respiratory functions by COVID-19. Oxygen
supplementation treatment can correct hypoxemia, relieving secondary organ damage
caused by respiratory distress and hypoxemia.
3.1 Oxygen therapy
{1) Continual oxygen saturation monitoring during oxygen therapy
Some patients do not necessarily have impaired oxygenation functions at the onset of
infection but may manifest rapid deterioration in oxygenation over time. Therefore,
continual monitoring of oxygen saturation is recommended, before and during oxygen
therapy.
{2) Oxygen therapy as soon as possible
Oxygen therapy is not necessary for patients with oxygen saturation (SpO2) of more than
93% or for patients without obvious symptoms of respiratory distress without oxygen
treatment. Oxygen therapy is strongly recommended to the patients with symptoms of
respiratory distress. It should be noted that some severe patients with PaO/FiO2 < 300
had no obvious symptoms of respiratory distress.
{3) Treatment goal of oxygen therapy
The treatment goal of oxygen therapy is to maintain the oxygen saturation {SpO2) at
93%-96% for patients without chronic pulmonary disease and at 88%-92% for patients
with chronic type II respiratory failure. Specially, the oxygen concentration should be
increased to 92%-95% for patients whose SpO2 drops below 85% frequently during daily
activities.
(4) Control oxygen therapy
PaO/FiO2 is a sensitive and accurate indicator of oxygenation function. The stability and
monitorability of FiO2 are very important for patients with disease progression and PaO/FiO2
below 300 mmHg. Controlled oxygen therapy is the preferred treatment.
High-flow nasal cannula (HFNC) oxygen therapy is recommended for patients with the
following conditions: SpO2 < 93%; PaO/FiO2 < 300 mmHg (1 mmHg = 0.133 kPa); respiratory
rate> 25 times per min at bed; or remarkable progression on X-ray imaging. Patients should
wear a surgical mask during HFNC treatment. The airflow of HFNC oxygen therapy should
start at a low level and gradually increased up to 40-60 L/min when PaO/FiO2 is between
200-300 mm Hg so that patients do not feel obvious chest tightness and shortness of breath.
An initial flow of at least 60 L/min should be given immediately for patients with obvious
respiratory distress.
Tracheal intubation for patients is dependent on disease progression, systemic status and
complication of patients for those with stable situation but with a low oxygenation index
(<l 00 mmHg). Thus, detailed evaluations of the clinical condition of patients is very important
before decision making. Tracheal intubation should be performed as early as possible for
patients with an oxygenation index less than 150 mm Hg, worsening symptoms of respiratory
distress or multiple organ dysfunction within 1-2 hours after high-flow (60 L/min) and
high-concentration(> 60%) HFNC oxygen therapy.
Older patients (> 60 years old) with more complications or PaO,/FiO, less than 200 mmHg
should be treated in ICU.
3.2 Mechanical Ventilation
(1) Noninvasive Ventilation (NIV)
NIV is not strongly recommended in COVID-19 patients who fail HFNC treatment. Some severe
patients progress to ARDS rapidly. Excessive inflation pressure may cause gastric distension
and intolerance which contribute to aspiration and worsen lung injury. A short-term (less than
2 hours) use of NIV can be closely monitored if the patient has acute left heart failure, chronic
obstructive pulmonary disease or is immunocompromised. Intubation should be performed
as early as possible if improvement of respiratory distress symptoms or PaO/FiO2 is not
observed.
NIV with a double circuit is recommended. A virus filter should be installed between the mask
and the exhalation valve when applying NIV with a single tube. Suitable masks should be
chosen to reduce the risk of virus spread through air leakage.
(2) Invasive Mechanical Ventilation
G) Principles of invasive mechanical ventilation in critically ill patients
It is important to balance the ventilation and oxygenation demands and the risk of
mechanical ventilation-related lung injury in the treatment of COVID-19.
• Strictly set the tidal volume to 4 - 8 ml/kg. In general, the lower the lung compliance, the
smaller the preset tidal volume should be.
• Maintain the platform pressure< 30 cmH,O (1 cmH,O = 0.098 kPa) and driving pressure <15
cmH,O.
• Set PEEP according to the ARDS's protocol.
• Ventilation frequency: 18-25 times per minute. Moderate hypercapnia is allowed.
• Administer sedation, analgesia, or muscle relaxant if the tidal volume, platform pressure
and driving pressure are too high.
@ Lung Recruitment
Lung recruitment improves the heterogeneous distribution of lesions in patients with
ARDS. However, it may result in severe respiratory and circulatory complications and
therefore, the lung recruitment maneuver is not routinely recommended. The assessment
of lung expandability should be performed prior to the application.
(3) Prone Position Ventilation
Most critically ill patients with COVID-19 respond well to prone ventilation, with a rapid
improvement of oxygenation and lung mechanics. Prone ventilation is recommended as
a routine strategy for patients with PaO/FiO2 < 150 mmHg or with obvious imaging
manifestations without contraindications. Time course recommended for prone
ventilation is more than 16 hours each time. The prone ventilation can be ceased once
PaO/FiO2 is greater than 150 mm Hg for more than 4 hours in the supine position.
Prone ventilation while awake may be attempted for patients who have not been
intubated or have no obvious respiratory distress but with impaired oxygenation or have
consolidation in gravity-dependent lung zones on lung images. Procedures for at least 4
hours each time is recommended. Prone position can be considered several times per
day depending on the effects and tolerance.
(4) Prevention of Regurgitation and Aspiration
Gastric residual volume and gastrointestinal function should be routinely evaluated.
Appropriate enteral nutrition is recommended to be given as earlier as possible.
Nasointestinal feeding and continuous nasogastric decompression are recommended.
Enteral nutrition should be suspended and aspiration with so ml syringe be done before
transfer. If no contraindication exists, a 30° semi-sitting position is recommended.
(5) Fluid Management
Excessive fluid burden worsens hypoxemia in COVID-19 patients. To reduce pulmonary
exudation and improve oxygenation, the amount of fluid should be strictly controlled
while ensuring the patient's perfusion.
{6) Strategies to Prevent Ventilator-Associated Pneumonia (VAP)
VAP bundled strategies should be strictly implemented:
CD Select appropriate type of endotracheal tube;
@ Use a endotracheal tube with subglottic suction (once every 2 hours, aspirated with 20
ml empty syringe each time);
® Place the endotracheal tube at the right position and correct depth, fix properly and
avoid pulling
@) Maintain the airbag pressure at 30 - 35 cmH,O (1 cmH,O = 0.098 kPa) and monitor
every 4 hours;
® Monitor the airbag pressure and deal with water condensates when the position
changes (two people cooperate in dumping and pouring the water condensates into a
capped container containing a pre-made disinfectant chlorine solution); deal with
secretions accumulated in the airbag;
@ Clean up secretions from the mouth and nose timely.
(7) Weaning of Ventilation
Sedatives is reduced and discontinued before awakening when the patient's PaO2'FiO2 is
more than 150 mmHg. Intubation withdrawal should be performed as earlier as possible
if permitted. HFNC or NIV is used for sequential respiratory support after withdrawal.
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