Appendix VIII 20200314_Program for the Diagnosis and Treatment of Severe and Critical Cases of Novel

Guidance Group of The Central Government to Hubei and other severe epidemic areas Guidance Group Medicine [2020] No.19

Notice on further improving diagnosis and treatment program for severe and critical cases of novel coronavirus pneumonia Hubei Health Committee: In order to further guide the treatment of severe and critical patients with novel coronavirus pneumonia, the National Expert Group on Medical Treatment of Novel Coronavirus Pneumonia has revised the diagnosis and treatment plan of the severe and critical cases based on the characteristics of the disease and the experience of clinical diagnosis and treatment. And Program for the Diagnosis and Treatment of Severe and Critical Cases of novel coronavirus pneumonia (trial version 3rd) has been formed. It is hereby printed and distributed to you for your reference.

Please issue this program to the whole province as soon as possible, and immediately organize the training work to guide the medical institutions to strengthen the management of severe and critical patients of novel coronavirus pneumonia, and continuously improve the level of medical treatment, strive to improve the cure rate and reduce fatality.

Medical Treatment Group of Central Guidance Group March 14, 2020 (Form of information disclosure: Active Disclosure)

Program for the Diagnosis and Treatment of Severe and Critical Cases of Novel Coronavirus Pneumonia (trial version 3rd) A novel coronavirus infection often involves respiratory system, leading to pneumonia. The heart, kidneys, intestines and other organs can also be affected in patients with severe or critical illness. Therefore, the novel coronavirus pneumonia needs comprehensive prevention and treatment for multiple organs.

I. Applicable population Patients who are diagnosed as severe or critical in accordance with the National Health Committee of China's Program for the Diagnosis and Treatment of novel coronavirus pneumonia (trial version 7rd) .

(I) Severe case Any of the following: 1. Respiratory distress, respiratory rate (RR) ≥ 30 times per minute; 2. Finger pulse oxygen saturation ≤93% at rest and without oxygen inhalation; 3. Arterial partial pressure of oxygen(PaO2)/fraction of inspired oxygen(FiO2) ≤ 300mmHg; 4. If any of the above criteria is met, the patient should be managed as a severe case; or, although it has not reached the above-mentioned diagnostic criteria for severe cases, the following cases are also managed according to the severe cases: the patients with significant progression of lesions > 50% within 24-48 hours as shown by pulmonary imaging; age > 70 years old, with severe chronic diseases including hypertension, diabetes, coronary heart disease, malignant tumors, structural lung disease, pulmonary heart disease and immunosuppressive population.

(II) Critical case Any of the following: 1. Respiratory failure requiring mechanical ventilation; 2. Shock; 3. Patients with other organ failure requiring to be treated in ICU.

II. Diagnosis and treatment of severe cases (I) Clinical early warning indicators In severe cases, vital signs, oxygen saturation of blood (SpO2), state of consciousness and clinical routine organ function should be evaluated. Monitoring contents according to the state of the disease: blood routine, urine routine, biochemical parameters (liver and kidney function, lactic acid, blood glucose, electrolyte, lactate dehydrogenase, etc.) , myocardial injury markers, 2

c-reactive protein, procalcitonin, coagulation function, arterial blood gas analysis, electrocardiogram and chest imaging.

In addition, changes of the following indicators should be alert to the deterioration of the disease: 1. A progressive decrease in peripheral blood lymphocyte counts; 2. Peripheral blood inflammatory factors such as IL-6 and C-reactive protein increase progressively; 3. Deterioration of tissue oxygenation index or progressive increase of lactate; 4. Chest CT shows significant progression of pulmonary lesions.

(II) Treatment 1. Treatment principles Patients should rest in bed and are provided with support treatment, ensuring adequate heat; water, electrolyte and acid-base balance should be maintained; timely oxygen therapy and mechanical ventilation as well as other life support measures should be provided to prevent and treat complications; basic diseases should be treated and secondary infection need to be prevented. In short, make sure the patients can go through the severe course of disease in the most possible effective state of life support.

2. Antiviral treatment At present, there is no specific antiviral drug. Within 10 days of onset, lopinavir/ritonavir, ribavirin, chloroquine phosphate, abidol, etc may be tried. Adverse drug reactions and interactions with other drugs should be closely monitored during administration.

3. Oxygen therapy and respiratory support (1) Patients with hypoxemia, PaO2/FiO2 in 200 - 300mmHg ① Oxygen inhalation should be adopted nasal cannula or mask, and whether respiratory distress and/or hypoxemia are relieved or not should be timely assessed. It is recommended that the oxygen flow rate of nasal catheter should not exceed 5L/min, and that of mask oxygen therapy should be 5-10L/min. ②High-flow nasal cannula oxygen therapy (HFNC): When the patients receive nasal catheter or mask oxygen inhalation for 2 hours, and no improvement is seen in the respiratory distress and/or hypoxemia, high-flow nasal cannula oxygen therapy should be applied.

During HFNC treatment, the symptoms and signs of the patients need to be closely observed. If the hypoxemia of the patients can not be improved (SpO2 < 93%), or with RR ≥ 35 times/min, evident inspiratory effort and so on, it is suggested that the therapeutic effect of HFNC is poor, and respiratory support therapy should be timely switched. Those with conditions can be treated with inhalation of a Hydrogen-Oxygen mixture gas (H2/O2: 66.7%/33.3%) to improve respiratory distress.

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(2) Patients with hypoxemia, PaO2/FiO2 in 150 - 200mmHg. Non-invasive mechanical ventilation (NIV) should be the first choice. Such patients have a high failure rate with non-invasive mechanical ventilation and should be monitored closely. If the condition does not improve or even worsen in a short period of time (1 - 2 hours), invasive mechanical ventilation should be performed in time.

During the treatment of NIV, the symptoms and signs of the patients need to be closely observed. If the hypoxemia of the patients cannot be improved (SpO2 < 93%), or with RR ≥ 35 times/min, excessive tidal volume or inspiratory negative pressure, etc., it is often suggested that the therapeutic effect of NIV is poor, and invasive mechanical ventilation should be timely switched.

(3) Patients with hypoxemia, PaO2/FiO2 is less than 150mmHg ① Invasive mechanical ventilation Early and appropriate invasive mechanical ventilation is an important treatment for critical patients. Lung protective mechanical ventilation should be performed with an initial tidal volume of 6 ml/kg ideal body weight. If the plateau pressure exceeds 30cmH2O or the driving pressure exceeds 15cmH2O, the tidal volume should be further decreased to reduce the risk of ventilator-associated lung injury; When setting PEEP, plateau pressure and/or driving pressure shall be both considered. When the PEEP is set according to the FIO2 - PEEP corresponding table (the low PEEP setting method of ARDSnet), the platform pressure or driving pressure is often too high, and the PEEP can be set according to the optimum oxygenation method or the optimum adaptation method. ②Lung recruitment For patients with moderate to severe ARDS, or with invasive mechanical ventilation with FIO2 above 0.5, can be treated with lung recruitment maneuver. And according to the responsiveness of lung recruitment, it is decided whether to repeatedly implement the lung recruitment maneuver. ③ Prone position ventilation The oxygenation of most patients with moderate and severe ARDS was significantly improved when they were ventilated in prone position. If PaO2/FiO2 is lower than 150mmhg continuously, it was recommended to adopt prone position ventilation (more than 12 hours per day). Some patients may consider using both prone position ventilation and lung recruitment maneuver. ④ Weaning of invasive mechanical ventilation After treatment, if the oxygenation of the patients is improved (PaO2/FiO2 is more than 200mmhg continuously), and the patients are conscious and their circulation is stable, they may consider initiating an evaluation weaning procedure.

(4) Extracorporeal membrane oxygenation (ECMO) ① Starting time of ECMO

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Evaluation and Implementation of ECMO should be considered as early as possible when protective ventilation and prone ventilation are not effective and the following conditions are met: Under the optimal ventilation conditions (FIO2 ≥ 0.8, tidal volume is 6ml/kg ideal body weight, PEEP ≥ 10cmH2O, and no contraindications), prone position ventilation has been performed, and one of the following is met: (a) PaO2/FiO2 < 50 mmHg for more than 3 hours; (b) PaO2/FiO2 < 80mmHg for more than 6 hours; (c) FiO2 1.0，PaO2/FiO2 < 100 mmHg； (d) Arterial blood pH < 7.25 and PaCO2 > 60 mmHg for more than 6 hours, and RR > 35 times/min; (e) When RR > 35 times/min, the arterial blood pH < 7.2 and the plateau pressure > 30 cmH2O; (f) Combined with cardiogenic shock or cardiac arrest. ② ECMO contraindications Combined with irrecoverable primary diseases; anticoagulation contraindications; mechanical ventilation for more than 7 days under higher mechanical ventilation settings (FiO2 > 0.9, plateau pressure > 30 cmH2O); age greater than 70 years; immunosuppression; anatomical malformations of large peripheral vessels or vascular lesions. ③Selection of ECMO treatment mode VV-ECMO mode is recommended. When circulatory failure occurs, determine whether there is cardiogenic shock, so as to determine whether VA-ECMO is required.

4. Airway secretion drainage Airway secretion drainage is an important treatment for patients with pneumonia. Enhancement of airway humidification and addition of expectorant drugs (ambroxol, N-acetylcysteine, etc.) should be adopted on the basis of the conventional treatment measures.

5. Cycle monitoring and support (1) Close monitoring of cardiac function is required when patients are associated with significant elevation of cardiac enzymes (especially troponin) and (or) BNP. Acute cor pulmonale (ACP) is easy to occur in patients with severe disease, therefore right heart function should be closely monitored.

(2) Follow the principle of tissue perfusion-oriented hemodynamics therapy and closely monitor patients' circulatory status. In case of hemodynamic instability (shock, systolic blood pressure < 90mmHg or 40mmHg lower than basic blood pressure, or need to use vasoconstrictor drugs, serious arrhythmia, etc.), it is necessary to carefully identify the causes, correctly deal with different types of shock, improve tissue perfusion, and actively deal with serious arrhythmia.

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(3) Hemodynamic monitoring techniques that are simple and easy to maintain and manage should be selected. Technically sophisticated invasive hemodynamic monitoring at the bedside is not recommended. When conditions permit, ultrasonic Doppler monitoring, a non-invasive, convenient means of monitoring method, should be actively applied.

(4) When the Hemodynamics is unstable, the first step is to assess the volume state, maintain effective tissue perfusion, avoid volume overload, and use vasoactive drugs such as noradrenaline if necessary.

6. Nutritional support treatment Patients with severe and severe novel coronavirus pneumonia often have inadequate nutritional intake and hypercatabolic state, resulting in rapid consumption, anemia and hypoproteinemia.

Malnutrition becomes a prominent problem in these patients. Early nutritional support can reverse the malnutrition state.

(1) Nutritional risk assessment should be performed in patients with severe novel coronavirus pneumonia.

(2) Initiate nutrition (EN) as early as possible. Early use of parenteral nutrition (PN) alone or complementary PN in combination with EN is not recommended.

(3) For patients with hemodynamic instability, nutritional support should be initiated as early as possible after the completion of fluid resuscitation and the basic stability of hemodynamics. In the non-life-threatening, controlled hypoxemia or compensatory/permissive hypercapnia, delayed initiation of nutritional support therapy is not recommended even during prone ventilation or ECMO. (4) It is recommended that nasogastric tube should be retained for gastric nutrition in severe patients. For patients who are not suitable for transgastric nutrition, a postpyloric feeding route, such as a nasogastric tube, is used.

(5) For severe patients, the target feeding amount is 25 - 30kcal//kg/d, starting at a low dose. If feeding intolerance occurs, nourishing feeding (infusion speed 10-20kcal/h or 10-30ml/h) can be considered.

(6) To enhance protein supply, target protein requirement is 1.5 - 2.0g/kg/d. When the protein intake is insufficient, it is recommended to add additional protein powder to the standard whole protein preparation.

(7) Patients with severe novel coronavirus pneumonia can be treated with enteral nutrition rich in Ί-3 fatty acids. Fat emulsion rich in EPA and DHA can be added to parenteral nutrition.

(8) Corresponding measures shall be taken for the patients with EN to prevent vomiting and reflux.

(9) In the case of feeding-related diarrhea, it is recommended to change the infusion mode or formula composition.

7. Glucocorticoid 6

There is no evidence-based medicine to support the use of glucocorticoid can improve the prognosis of severe novel coronavirus pneumonia, thus the routine use of glucocorticoid is not recommended. For the patients with progressive deterioration of oxygenation index, rapid progression of imaging and over activation of inflammatory reaction, methylprednisolone 40mg q12h for 5 days can be considered for short-term treatment. Before use, we should analyze whether the patients have contraindications of hormone administration.

8. Antimicrobial therapy Routine use of antibiotics is not recommended without clear evidence of bacterial infection. It should be noted that severe patients often have a course of more than 5 - 7 days, and most of them have manifestations of cellular immunosuppression, especially those admitted to the ICU requiring invasive mechanical ventilation, requiring attention to secondary bacterial or fungal infections.

If conditions permit, respiratory pathogens should be actively monitored and targeted antiinfection treatment should be carried out. If there is a history of antibacterial drug use, the length of hospital stay is more than 72 hours, or there is previous structural lung disease, the selection of antibacterial drugs should consider covering resistant bacteria.

9. Anticoagulant therapy There are obvious endothelial cell damage, microthrombosis and focal necrosis in lung tissue and other organs. Therefore it is indicated that anticoagulant therapy may be beneficial. When patients have DIC with hypercoagulable state, they should be treated with therapeutic dose of unfractionated heparin or low molecular weight heparin. The coagulation function and bleeding should be monitored during the course of treatment.

10. Prevention and treatment of venous thromboembolism (VTE) Because patients remain in bed for a long time and are often associated with coagulation abnormalities, it is necessary to assess the risk of VTE in severe and critical patients. For patients with high risk of VTE, DVT ultrasound screening can be carried out if conditions permit. Encourage early activity of patients to prevent DVT. In the absence of contraindications to anticoagulation, such as severe active bleeding or bleeding in important areas, it is recommended to use unfractionated heparin or low molecular weight heparin for preventive treatment. Patients with anticoagulant contraindications should be treated with limb compression.

11. Analgesia and sedation Patients with severe mechanical ventilation should be given appropriate analgesic and sedative treatment. If the patient has high respiratory rate, excessive tidal volume or obvious manmachine confrontation, short-term use of muscle relaxant should be considered. According to the patient's condition and treatment measures, set the goals of analgesia and sedation; humanistic care for patients with severe novel coronavirus pneumonia must be emphasized.

12. Acute kidney injury (AKI) and renal replacement therapy 7

If AKI occurs in some severe patients, the patient's volume status and renal function should be fully assessed. In general, in the second stage of the KDIGO standard, namely, 2 - 2.9 times the baseline value of creatinine increment, urine output lasts more than 12 hours and less than 0.5ml/kg/h, renal replacement therapy should be adopted.

13. Other medication (1) Human immunoglobulin (IVIG): At present, there is insufficient evidence-based medical evidence to support the clinical efficacy of IVIG for coronaviruses, which can be applied as appropriate in critical patients.

(2) Convalescent plasma: The use of human convalescent plasma containing novel coronavirus antibodies in patients with early new coronary pneumonia can be used as an option for specific treatment. If the convalescent plasma is adopted, the titer of protective antibodies in the plasma should be measured. Plasma should be infused slowly during the recovery period and closely observed for transfusion reactions and changes in respiratory function.

(3) Thymosin Îą 1: the usage of thymosin Îą 1 may be considered in severe patients with significantly reduced lymphocyte count.

(4) Intestinal microecological regulators: Intestinal microecological regulators can be adopted to maintain the intestinal microecological balance; (5) Xuebijing injection: the traditional Chinese medicine Xuebijing injection can be used.

14. Traditional Chinese medicine treatment According to patients' conditions, local climate characteristics and different physical conditions, the following schemes can be used for syndrome differentiation and treatment. When superpharmacopoeia dosage is involved, it should be used under the guidance of a physician.

(1) Qingfei Paidu Decoction It is applicable to severe patients and can be reasonably used in combination with the actual situation of patients in the treatment of critical patients.

Basic prescription: Ephedra 9g, prepared Glycyrrhizae 6g, almond 9g, raw Gypsum 15-30g (decocted first), cassia twig 9g, Rhizoma Alismatis 9g, Polyporus umbellatus 9g, Atractylodes macrocephala 9g, Poria cocos 15g, bupleuri 16g, scutellariae 6g, Pinellia rhizoma 9g, ginger 9g, aster 9g, Flos farfarae 9g, Belamcanda chinecsis 9g, asarum 6g, Chinese yam 12g, Fructus Aurantii 6g, dried tangerine peel 6g, Patchouli 9g.

Method of administration: traditional Chinese herb pieces (decocted in water). One dose a day, twice in the morning and twice in the evening (40 minutes after meals), warm taking, three dose for a course.

If conditions permits, half a bowl of rice soup can be added after taking the medicine each time, and one more bowl can be taken for those whose tongue is dry and body fluid is deficient.

(Note: if the patient does not have fever, the dosage of raw gypsum should be small, and the dosage of raw gypsum can be increased for patients with fever or strong fever). Take the second course of treatment if the symptoms are improved but not cured. If the patient has special 8

conditions or other basic diseases, the prescription can be modified in the second course according to the actual situation. Stop administration if symptoms disappear.

(2) Syndrome of epidemic toxin blocking lung Clinical manifestations: Fever, blushing, coughing, less yellow sticky phlegm, or blood seen in phlegm, wheezing and suffocating, tiredness, dry bitter sticky mouth, nausea and anorexia, inhibited defecation, short red urine. Red tongue with yellow sticky coating, rolling and rapid pulse.

Recommended prescription: Huashi Baidu Prescription Basic prescription: raw ephedra 6g, almond 9g, raw gypsum 15 - 30g (decocted first), licorice 3g, Patchouli 10g (decocted later), Magnolia officinalis 10g, Atractylodes macrocephala 15g, Rhizoma Pinellinae Praeparata 9g, Poria cocos 15g, raw rhubarb 5g (decocted later), raw Astragalus 10g, lespedeza 10g, red peony root 10g.

Method of administration: 1-2 doses per day (decocted in water), 100ml-200ml each time, 24 times a day, oral or nasal feeding.

(3) Syndrome of flaring heat in Qifen and Yingfen Clinical manifestations: excessive heat, thirst, shortness of breath, delirium, wrong vision, or rash, or limb convulsion. Red tongue with little or no coating, deep and rapid pulse, or superficial, large and rapid pulse.

Recommended prescription: Antipyretic and Antitoxic Decoction Basic prescription: raw gypsum 30 ~ 60g (decocted first), Rhizoma anemarrhenae 30g, dried rehmannia root 30 ~ 60g, Cornu bubali 30g, red peony root 30g, scrophulariae 30g, forsythia 15g, Cortex Moutan 15g, Coptis chinensis 6g, lespedeza 15g, licorice 6g.

Method of administration: 1 dose per day (decocted in water), 100ml-200ml each time, 2-4 times a day, oral or nasal feeding.

(4) Syndrome of internal block and external collapse Clinical manifestations: shortness of breath, accompanied by dizziness, irritability, sweating, cold limbs, dark purple tongue with thick greasy or dry coating, superficial, large and rootless pulse.

Recommended prescription: Ginseng and Aconiti Decoction Basic prescription: ginseng 15g, monkshood 10g (decocted first), fructus corni 15g. Take Suhexiang Pill or Angong Niuhuang Pill.

Method of administration: 1 - 2 doses per day (decocted in water), 100-200ml per time, 2-4 times per day, oral or nasal feeding.

(5) Traditional Chinese medicine injections Recommended prescriptions: Xuebijing injection, Xiyanping injection, Reduning injection, Tanreqing injection, Xingnaojing injection, Shenfu injection, Shengmai injection and Shenmai 9

injection. One drug can be selected among those with similar efficacy according to individual conditions, or two drugs can be used in combination according to clinical symptoms.

Traditional Chinese medicine injection can be combined with traditional Chinese medicine decoction.

Recommended usage: The use of traditional Chinese medicine injections follows the package insert, as follows: ① Basic administration: 0.9% sodium chloride injection 250ml plus Xuebijing injection 100ml bid; 5% glucose injection 250ml plus Shenmai injection 100ml or Shengmai injection 20~60ml bid. ② Continuing fever: 0.9% sodium chloride injection 250ml plus Xiyanping injection 100mg bid, or 0.9% sodium chloride injection 250ml plus Reduning injection 20ml, or 0.9% sodium chloride injection 250ml plus Tanreqing Injection 40ml bid. ③ Consciousness disturbance: 0.9% sodium chloride injection 250ml and Xingnaojing injection 20ml bid. ④ Shock: 5% glucose injection 250ml and Shenfu injection 40~100ml bid.

(6) Others ① Unstable oxygen saturation: ginseng 30g, decocted in water 200ml, taken in small doses at short intervals. ② Abdominal distension and constipation or man-machine asynchrony: raw rhubarb 5 - 10g, decocted in water 200ml, taken in small doses at short intervals; or add mirabilite 15g retention enema, twice a day. ③ Continuing high fever: 1 pill of Angong Niuhuang Pill, 2 times a day or Zixue Powder 3g, 2 times a day, nasal feeding.

III. Criteria for transfer out of intensive care units Patients with severe novel coronavirus pneumonia should be transferred out of the ICU as soon as possible when their condition is stable, oxygenation improves and life support is not required.

Discharge criteria (to be fully met): (I) Conscious. Analgesic sedatives and/or muscle relaxants have been discontinued as instructed.

(II) Mechanical ventilation has been weaned. RR < 30 times/min and SpO2 > 93% when inhaled air or low flow oxygen (through nasal catheter or ordinary mask).

(III) Stable circulation. There is no need for vasopressin and fluid resuscitation.

(IV) There is no other acute progressive organ dysfunction. No supportive treatment measures, such as blood purification, etc., are needed.

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CC: Health Committee of all provinces, autonomous regions, municipalities and Xinjiang Production and Construction Corps.

Medical Treatment Group of Central Guidance Group

Issued on March 14, 2020 Checked by: Ma Xudong

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