Clinical management of COVID-19.pptx

Clinical management of COVID-19.pptx

1. toolkit COVID-19 Clinical Management

2. Directed by Dr.Karar. Abid. Ali [email protected]

3. Anticoagulation

4. Anticoagulation in COVID-19

5. disseminated intravascular coagulation

6. Patients with D-dimer >1,000 at admission are twenty times more likely to die than patients with lower D-dimer values Fibrinogen : In clinical practice, fibrinogen is generally elevated or normal. However, in extremely severe and late-stage disease, consumption of fibrinogen may occur leading to hypofibrinogenemia

7. Thrombocytopenia can occur, but this is less common than in other forms of DIC . PT and INR is often slightly elevated aPTT (activated partial thromboplastin time) may be reduced slightly. Thromboelastography (TEG) ( Panigada et al. ) Reduced R-time indicating enzymatic hypercoagulability in 50% of patients (but it may rarely be increased in some patients). Increased maximal amplitude (MA) indicating excess platelet/fibrinogen function in 83% of patients. Reduced Lys-30 is extremely common. Antithrombin levels may be slightly diminished. Factor VIII and von Willebrand factor are considerably increased

8. Antivirals

9. Remdesivir Remdesivir is to be administered via IV infusion in a total volume of up to 250 mL of 0.9% saline over 30 minutes

10. Remdesivir Optimal treatment duration is unknown; for this EUA, dosing is as follows Dosage (weight 40 kg or more) Requires mechanical ventilation and/or ECMO Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN Days 2-10 maintenance dose: 100 mg IV qDay Does not require mechanical ventilation and/or ECMO Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN Days 2-5 maintenance dose: 100 mg IV qDay If clinical improvement not demonstrated, treatment may be extended for up to 5 additional days ( ie , up to 10 days total)

11. Reports have documented serious dysrhythmias in patients with COVID-19 who were treated with chloroquine or hydroxychloroquine , often in combination with azithromycin and other medicines that prolong the QTc interval. Given the risk of dysrhythmias, the Food and Drug Administration (FDA) cautions against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19 outside of a hospital or clinical trial

12. dose High-dose chloroquine (600 mg twice daily for 10 days) has been associated with more severe toxicities than lower-dose chloroquine (450 mg twice daily for 1 day, followed by 450 mg once daily for 4 days).

13. ADVERSE EVENTS The most common adverse events of hydroxychloroquine and chloroquine are gastrointestinal upset along with nausea, vomiting, and diarrhea Retinopathy is one of the most frequently observed, severe, and irreversible side effect associated with high-dose (>5 mg/kg) and long-term use (>5 years ) The most severe and life-threatening complications from use of hydroxychloroquine and chloroquine include QTc prolongation and the resultant risk of ventricular arrhythmias

14. Kaletra ( lopinavir /ritonavir) Administer 400/100 mg of twice daily

15. combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group) FDA Approved, but FDA Approved, but NOT for COVID-19 NOT for COVID-19

16. atazanavir Adults—300 milligrams (mg) with 100 mg of ritonavir ( Norvir ®) once a day.

17. Research Highlights 1. Atazanavir binds to and inhibits the cysteine protease activity of the major protease of SARS-CoV-2. 2. Atazanavir , alone or with Ritonavir, inhibits SARS-CoV-2 viral replication in a human lung epithelial cell line. with a high CC50/EC50 level. 3. Atazanavir , alone or with Ritonavir, inhibits SARS-CoV-2 viral replication and secretion of pro-inflammatory cytokines in primary human monocytes.

18. ribavirin

19. Triple combination of interferon beta-1b, lopinavir –ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19

20. ( lopinavir 400 mg and ritonavir 100 mg) every 12 h for 14 days. For patients who had no history of prolonged QTc syndrome, but were found to have prolonged QTc less than 480 ms , first-degree heart block or bundle branch block, or bradycardia upon ECG examination, and those who developed increased alanine transaminase of three times the upper limit of normal (ULN), the lopinavir –ritonavir treatment was reduced to once per day. Lopinavir –ritonavir would be stopped if alanine transaminase levels exceeded six times the ULN. The randomisation window from symptom onset was extended from 10 to 14 days after trial commencement after knowing that the incubation period could go beyond 14 days. Because a placebo group was generally not accepted in Chinese culture, and our previous study showed that interferon beta-1b and lopinavir –ritonavir are active against SARS- CoV and MERS- CoV , lopinavir –ritonavir was used in the control group whereas interferon beta-1b, lopinavir –ritonavir, and ribavirin were used in the combination group for patients admitted less than 7 days from symptom onset. The intervention treatment had to be started within 48 h after hospital admission. Standard of care included oxygen, non-invasive and invasive ventilatory support, extracorporeal membrane oxygenation support, dialysis support, and antimicrobial treatment for secondary bacterial infection as indicated clinically. Stress doses of corticosteroid (50 mg hydrocortisone every 8 h intravenously, tapering over 7 days) were given to patients who developed oxygen desaturation and required oxygen support. Non-invasive or invasive ventilatory support beyond day 7 from symptom onset was at the discretion of the consultants.

21. Favipiravir in covid

22. CONCLUSION Favipiravir provides a substitute for compassionate use in COVID-19 based on its mechanism of action inhibiting virus RdRp and safety data in previous clinical studies. Data obtained from inf luenza treatment and proof-of-concept clinical trial in EVD aids the determination of dose regimen in clinical trials or experimental use of the drug in COVID-19. However, the exact efficacy of favipiravir awaits further clinical confirmation. Potential DDIs due to AO inhibition should not be ignored in the clinical setting.

23. immunomodulators

24. Intravenous Immunoglobulin Immunotherapy with IVIg could be employed to neutralize COVID-19. However, the efficacy of IVIg would be better if the immune IgG antibodies were collected from patients who have recovered from COVID-19 in the same city, or the surrounding area, in order to increase the chance of neutralizing the virus. These immune IgG antibodies will be specific against COVID-19 by boosting the immune response in newly infected patients. Different procedures may be used to remove or inactivate any possible pathogens from the plasma of recovered coronavirus patient derived immune IgG, including solvent/detergent, 60 °C heat-treatment, and nanofiltration. Overall, immunotherapy with immune IgG antibodies combined with antiviral drugs may be an alternative treatment against COVID-19 until stronger options such as vaccines are available. human polyclonal immunoglobulin G (SAB-300) IVIg was administered immediately at a dose of 25 g/d for 5 days

25. As a result, high-dose IVIg at 0.3–0.5 g per kg weight per day for five days was used in our patients as a potent and safe immune modulator.

26. Bevacizumab Bevacizumab is a drug that is currently used to treat cancer (colorectal, lung, breast, renal, brain, and ovarian), as well as age-related macular degeneration and diabetic retinopathy. This drug has been used as an anti- tumour treatment for almost 20 years, so the safety of the drug is already known. Some of the most common adverse reactions to bevacizumab include hypertension, fatigue, diarrhea, and abdominal pain. Bevacizumab is a human monoclonal antibody that works by attaching to a growth factor called vascular endothelial growth factor A (VEGF-A). By blocking the activity of this growth factor, the drug is able to inhibit the process of angiogenesis (formation of new blood vessels), which is an important process in cancer development.

27. Clinical trials assessing the effectiveness of bevacizumab for the treatment of COVID-19 An interventional clinical trial is underway at the Qilu Hospital of Shandong University in Jinan, China. The trial aims to assess the safety of bevacizumab and its effectiveness in treating severe and severe new crown pneumonia and dyspnea (shortness of breath) and diffuse pulmonary lesions in patients with COVID-19. The trial aims to enroll over 100 participants and its estimated completion date is May 31, 2020.

28. What’s the evidence to support using bevacizumab for the treatment of COVID-19? The basis for using bevacizumab to treat COVID-19 comes from research that has identified elevated levels of VEGF in the blood of patients with COVID-19. It has been suggested that the increase in levels of VEGF is due to hypoxia (low oxygen) and severe inflammation, with evidence that VEGF plays a key role, and is therefore a prime treatment target, in acute lung injury and acute respiratory distress syndrome. Prior research suggests that suppression of VEGF could suppress pulmonary edema (accumulation of fluid in the lungs leading to respiratory failure), thereby reducing overall mortality in patients with severe COVID-19 infection.

29. Bevacizumab 7.5mg/kg body weight + 0.9% NaCl 100ml, intravenous drip

30. Eculizumab eculizumab 900mg IV over 35 minutes for each dose

31. ( Actemra ) Tocilizumab Chinese investigators conducted a retrospective, uncontrolled study of 21 patients (average age, 57) with severe COVID-19 symptoms (as defined by prespecified criteria) who received treatment with the IL-6 blocker tocilizumab ( Actemra ; approved in the U.S. to treat rheumatoid arthritis and juvenile idiopathic arthritis). All patients required supplemental oxygen (2 were on ventilators), had worsening ground-glass opacities on chest computed tomography, and showed deterioration of other clinical and laboratory measures. Within 24 hours of starting tocilizumab therapy, fevers and elevated C-reactive protein levels resolved, and levels of IL-6 and other proinflammatory cytokines declined. Use of supplemental oxygen dropped in 15 patients, oxygen saturation levels stabilized or improved in all patients, the 2 ventilated patients were weaned, and all patients subsequently were discharged alive.

32. Cytokine Release Syndrome adult Indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS) 8 mg/kg IV once; may be administered as alone or in combination with corticosteroids If no clinical improvement in the signs and symptoms of CRS occurs after initial dose, may administer up to 3 additional doses; allow 8-hr interval between consecutive doses

33. Cytokine Release Syndrome (CRS) Indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS) in adults and pediatric patients aged ≥2 years SC is not approved for CRS <2 years: Safety and efficacy not established ≥2 years <30 kg: 12 mg/kg IV once ≥30 kg: 8 mg/kg IV once May be administered as monotherapy or with corticosteroids If no clinical improvement in the signs and symptoms of CRS occurs after initial dose, may administer up to 3 additional doses; allow 8-hr interval between consecutive doses Not to exceed 800 mg/dose Not approved for SC administration

34. Coronavirus disease 2019 (COVID-19), cytokine release syndrome (off-label use): IV: Limited data available; dosing used in clinical trials includes the following: 8 mg/kg (maximum: 800 mg/dose) as a single dose; may repeat dose in 8 to 12 hours if signs/symptoms worsen or do not improve (Genentech 2020). 8 mg/kg (maximum: 800 mg/dose) every 12 hours for 2 doses (NIH 2020a). 8 mg/kg as a single dose (NIH 2020b; NIH 2020e). 4 to 8 mg/kg (usual dose: 400 mg/dose; maximum: 800 mg/dose) as a single dose; may repeat dose in ≥12 hours in patients who remain febrile within 24 hours of initial dose (NIH 2020c).

35. Cytokine release syndrome (due to bi-specific T-cell engaging therapy), severe or life-threatening (off-label use): IV: 4 mg/kg once; may repeat the dose if clinical improvement does not occur within 24 to 48 hours (Lee 2014). Cytokine release syndrome (due to chimeric antigen receptor-T cell therapy), severe or life-threatening: Note: If clinical improvement does not occur after the first dose, up to 3 additional doses may be administered (with at least an 8-hour interval between consecutive doses). Tocilizumab may be administered as monotherapy or in combination with corticosteroids. IV: Maximum dose: 800 mg per dose. <30 kg: 12 mg/kg. ≥30 kg: 8 mg/kg.

36. no enough studies Fingolimod Contraindications Hypersensitivity; observed reactions include rash, urticaria , and angioedema upon treatment initiation History within past 6 months of MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker Baseline QTc interval ≥500 ms Coadministration with Class Ia or Class III antiarrhythmic drugs 0.5 mg PO qDay

37. Interferon- α2 b Treatment for COVID-19

38. In total, 20 eligible patients with confirmed COVID-19 were assigned to receive IFN-β-1a ( ReciGen ®, CinnaGen , Iran) subcutaneously. Simultaneously, the patients received conventional antiviral regimen of hydroxychloroquine (200 mg P.O. BID) and lopinavir /ritonavir (200/50 mg P.O.; two tablets QID) for 5 days. Oxygenation with nasal cannula, high-flow therapy, noninvasive strategies, or mechanical ventilation was considered for all patients. Subcutaneous administration of IFN-β-1a at a dose of 44 µg (equivalent to 12 million international units) was initiated on day 1 of hospitalization and continued every other day until day 10. Injections were administered in the peri -umbilical area of the abdomen, and injection sites were changed for each administration.

39. Fig. 2. Lung computed tomography and chest X-ray showing ground glass opacity and bilateral infiltration, respectively, at admission (left pictures). The images on the right reveal recovery after 14 days of treatment with IFN-β-1a.

40. Nitazoxanide Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum antiviral drug that is used in medicine for the treatment of various helminthic, protozoal , and viral infections Dosing If nitazoxanide were to be used, the most likely dose regimen would be 600 mg twice daily of extended release tablets, which was the dosing used for influenza without major safety concerns

41. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro Ivermectin 150-200 ug /kg (single dose)

42. antifibrotic therapy

43. Pirfenidone Initial dose titration Take with food Days 1-7: 267 mg PO TID (801 mg/day) Days 8-14: 534 mg PO TID (1602 mg/day) Day 15 and thereafter (maintenance): 801 mg PO TID; not to exceed 2403 mg/day is a medication used for the treatment of idiopathic pulmonary fibrosis.

44. Summary In December, 2019, reports emerged from Wuhan, China, of a severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the end of April, 2020, over 3 million people had been confirmed infected, with over 1 million in the USA alone, and over 215 000 deaths. The symptoms associated with COVID-19 are diverse, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome. The major risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male sex, and comorbidities such as hypertension and diabetes. However, the role of antifibrotic therapy in patients with IPF who contract SARS-CoV-2 infection, and the scientific rationale for their continuation or cessation, is poorly defined. Furthermore, several licensed and potential antifibrotic compounds have been assessed in models of acute lung injury and viral pneumonia. Data from previous coronavirus infections such as severe acute respiratory syndrome and Middle East respiratory syndrome, as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection. Antifibrotic therapies that are available or in development could have value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and might have a role in preventing fibrosis after SARS-CoV-2 infection.

45. Idiopathic Pulmonary Fibrosis Indicated for idiopathic pulmonary fibrosis 150 mg PO q12hr for 8 weeks antifibrotic therapy

46. Table Potential link between antiviral mechanisms and antifibrotic drugs

47. Antibiotic

48. Secondary Infections The most common reported infections were pneumonia (32%), bacteremia (24%), and urinary tract infections (22%) (He et al, Infect Control Hosp Epidemiol , 2020 ) Organisms reported included those commonly seen with hospital-acquired infections Fungal pathogens such as Candida albicans , Aspergillus species, Pneumocystis jirovecii , and Mucor species have been described in a small subset of patients Bacterial pathogens include drug-resistant Pseudomonas aeruginosa , Acinetobacter species, extended spectrum beta-lactamase (ESBL) Klebsiella sp. and E.coli , and vancomycin -resistant Enterococcus sp.

49. Risk factors for secondary bacterial and fungal infections In a single center study of 65 COVID-19 patients, invasive devices (OR 4.28, 95% CI: 2.47–8.61), diabetes (OR 3.06, 95% CI: 1.41–7.22), and the use of one or more class of antibiotic (OR 1.84, 95% CI: 1.31–4.59) were significant predictors of nosocomial infection (He et al, Infect Control Hosp Epidemiol , 2020 Glucocorticoid treatment (38% in He et al, Infect Control Hosp Epidemiol , 2020) was also found to be positively associated with secondary infection There is a disproportionate high use of antibiotics despite paucity of evidence for bacterial secondary infection (He et al, Infect Control Hosp Epidemiol , 2020; Zhou et al, Infect Control Hosp Epidemiol , 2020; Rawson et al, Clin Infect Dis, 2020)

50. Nebulization

51. Nebulized Heparin for the Treatment of COVID-19 Induced Lung Injury Nebulized heparin (10,000 IU/4 h) Nebulized Heparin Heparin 5,000 units/mL IV formulation diluted with 3 mL of 0.9% sodium chloride Dose: 10,000 units Frequency: every 4 hours Duration: 10 days

52. What is hypertonic saline (HTS) nebulization Hypertonic saline belongs to a class of drugs called mucolytics . It is a salty solution that helps to hydrate the airways and thin the mucus in the lungs. Hydrating the airways helps the respiratory tract move the mucus from the lungs. This may help keep your lungs healthy and decrease the number of respiratory infections. NOTE: Hypertonic saline is known to irritate the airways. A bronchodilator may be given either before or with the hypertonic saline therapy

53. Albuterol asthma

54. Inhaled corticosteroids and COVID-19

55. Potential steps in the development and evolution of SARS-CoV-2 infection that may be affected beneficially or adversely by inhaled corticosteroids (ICS): 1: infection with SARS-CoV-2; 2: development of COVID-19 disease; 3: progression of COVID-19.

56. lidocaine nebulizer for cough Successful cough suppression has also been demonstrated in several studies with the use of nebulized lidocaine . Lidocaine toxicity is a serious concern, and concentrations of serum lidocaine over 5 mg/L can lead to lightheadedness, tremors, hallucinations, and cardiac arrest . A generally accepted safe range of nebulized lidocaine is between 100 and 200 mg per dose.[23] Some research has suggested that higher doses may be tolerable, with one study recommending up to 600 mg of lidocaine in asthma patients undergoing experimental bronchoscopy.

57. Pulmonary Vasodilators

58. Inhaled nitric oxide ( iNO ) (at BWH, iNO is supplied by Respiratory Dept via INO Vent Device): Exclude contraindications: LV systolic or diastolic CHF (see epoprostenol above). Measure baseline ABG for PaO2 Initiate iNO at 20ppm. Do not change ventilator settings, sedation, paralysis, patient position or other care that could affect oxygenation. Re-check ABG 2 hrs after initiation of iNO . If PaO2 increased by >10% from baseline, continue iNO . If PaO2 has not increased by >10%, increase iNO to 80ppm. Re-check ABG 2 hrs later; if PaO2 increased >10% from baseline, continue iNO at 80ppm. If PaO2 increased less than 10% from baseline, wean iNO to off. NO can cause methemoglobinemia (↑ risk if on nitroglycerin or nitroprusside ). Monitor methemoglobin on ABG Q6 hr for the first 24 hr , Q12 hr for the second 24 hr , daily thereafter, or PRN if new clinical deterioration or SpO2-PaO2 dissociation.

59. Systemic Corticosteroids

60. WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients Coronavirus breakthrough: dexamethasone is first drug shown to save lives Inflammation dose 0.75-9 mg/day IV/IM/PO divided q6-12hr

61. Comparison of the clinical outcomes between severe COVID-19 pneumonia patients with and without methylprednisolone treatment. a Dynamic change of SpO2 at rest; b length of ICU hospitalization; c length of hospitalization; d images of chest CT scan on day 1, 7, and 14 after hospitalization

62. In conclusion, early, low-dose and short-term application of methylprednisolone was associated with better clinical outcomes in severe patients with COVID-19 pneumonia, and should be considered before the occurrence of ARDS. low-dose methylprednisolone treatment with the dosage of 1–2 mg/kg/day for 5–7 days via intravenous injection.

63. Usual standard of care plus Methylprednisolone (MP) 80 mg/kg IV bolus, followed by MP infusion of 80 mg/day in 240 mL normal saline at 10 mL/h. The infusion is continued for at least eight days and until achieving either a PaO2:FiO2 > 350 mmHg or a CRP < 20 mg/L. Treatment is then switched to oral administration of Methylprednisolone 16 mg or 20 mg IV twice daily until CRP returns to < 20% of normal range and/or PaO2:FiO2 > 400 or SatHbO2 ≥ 95%

64. supplement

65. Zinc 75-100 mg/day Zinc

66. Vitamin C Vitamin C 500 mg BID

67. Quercetin 250-500 mg BID

68. Melatonin (slow release): Begin with 0.3mg and increase as tolerated to 2 mg at night

69. Vitamin D3 1000-4000 u/day

70. The Endocrine Society and The Institute of Medicine have suggested recommended daily allowances (RDA) for vitamin D and calcium, as well as maximum daily consumption amounts that you should not exceed for your safety :

71. famotidine SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. histamine-2 receptor antagonist 80 mg three times daily Famotidine 20-40mg/day or

72. thymosin 1.6 mg (900 µg/m2) administered subcutaneously twice a week

73. Hypertonic mannitol in the therapy of the acute respiratory distress syndrome. 1.25 g/kg IV infused over 30-60 minutes; may repeat q6-8hr

74. Medications for Respiratory Disorders may needed Bronchospasm (Off-label) 25-50 mg/kg IV over 10-20 minutes Acute Bronchospasm Loading Patients not currently taking theophylline: 5-7 mg/kg IV/PO; not to exceed 25 mg/min IV Aminophylline: 6-7 mg/kg IV infused over 20 minutes Maintenance 0.4-0.6 mg/kg/ hr IV or 4.8-7.2 mg/kg PO (extended release) q12hr to maintain levels 10-15 mg/L Smokers: 0.79 mg/kg/ hr IV for next 12 hours after loading dose, then 0.63 mg/kg/ hr or 5 mg/kg PO (extended release) q8hr

75. N- acetylcysteine Pulmonary Disease Facilitation of expectoration via mucolysis Solution (10 and 20%) may be used undiluted; 3-5 mL of 20% solution or 6-10 mL of 10% solution; administer 1 to 10 mL of 20% solution every 6-8 hours or 2 to 20 mL of 10% every 2 to 6 hours 600 mg PO q12hr N- acetylcysteine can cause bronchoconstriction. Pre-treat with albuterol 2.5mg just prior to delivery.

76. Paracetamol to treat the symptoms of COVID-19, says NHS England

77. Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS) Low-dose radiotherapy polarizes macrophages to an M-2 anti-inflammatory phenotype. • Recommend a single dose of 0.3–0.5 Gy to patients experiencing cytokine storm.

78. Convalescent plasma

79. Convalescent plasma therapy 400ml The vast majority of patients who recover from COVID-19 illness develop some level of circulating neutralizing antibodies to various SARS-CoV-2 proteins 2-3 weeks following infection, detectable by ELISA or other quantitative assays. This has been demonstrated in at least two cohorts of rhesus macaques infected with SARS-CoV-2 who generated antibody responses and could not be re-infected with the virus weeks to months later.

80. potential risks of convalescent plasma for COVID-19? Convalescent plasma transfusion appears safe as over 7000 units have been transfused to over 5000 patients to date in the US (uscovidplasma.org). Known risks of plasma transfusion include allergic reactions, transfusion-associated circulatory overload (TACO), and transfusion-associated acute lung injury (TRALI) as with any plasma or blood transfusion. Additional concerns include potential worsening of immune-mediated tissue damage via the poorly understood phenomenon of antibody-dependent enhancement (ADE), and blunting of endogenous immunity to the virus. However, ADE has not been documented to date, so likely is not a major issue for COVID-19 convalescent plasma infusions. Importantly, blood product transmission of the SARS-CoV-2 virus has not been documented and is extremely unlikely via transfusion from a recovered donor with a documented antibody response, even if viral spread to tissues outside the lung may have occurred earlier in the donor’s illness.

81. Transfusion-related acute lung injury (TRALI) Clinical presentation Symptoms of TRALI typically develop during or within six hours of a transfusion. Patients present with the rapid onset of dyspnea and tachypnea. There may be associated fever, cyanosis and hypotension. Clinical examination reveals hypoxic respiratory distress, and pulmonary crackles may be present without signs of congestive heart failure or volume overload. In general, however, chest findings on auscultation tend to be minimal. Chest x-ray (CXR) shows evidence of bilateral pulmonary edema unassociated with heart failure (non-cardiogenic pulmonary edema), with bilateral patchy infiltrates, which may rapidly progress to complete "white out" indistinguishable from acute respiratory distress syndrome (ARDS). Physiologic findings include acute hypoxemia with normal cardiac function on echocardiogram. Up to a third of patients exhibit transient leukopenia and patients may have a low level of brain natriuretic peptide (BNP).

82. Treatment Supportive care is the mainstay of therapy in TRALI. Oxygen supplementation is employed in all reported cases of TRALI and aggressive respiratory support is needed in 72 percent of patients. Intravenous administration of fluids, as well as vasopressors, are essential for blood pressure support. Use of diuretics, which are indicated in the management of transfusion associated circulatory overload (TACO), should be avoided in TRALI. Corticosteroids can be beneficial

83. (albumin IV) Adult Respiratory Distress Syndrome Indicated for adult respiratory distress syndrome (ARDS) in conjunction with diuretics to correct fluid volume overload associated with ARDS 25 g IV over 30 minutes; repeat q8hr PRN

84. Albumin downregulates the expression of the ACE2 receptors (3) and has been shown to improve the ratio of arterial partial pressure of oxygen/fraction of inspired oxygen in patients with acute respiratory distress syndrome as soon as 24 hours after treatment and with an effect that persisted for at least seven days (4). Moreover, researchers who have studied the clinical characteristics of Covid-19 patients have reported again and again that lower serum albumin levels were associated with an increased risk of death, even to suggest that “albumin therapy might be a potential remedy

85. COVID-19 in Pregnancy

86. The recommended dose of acetaminophen for pregnant women is the same as the recommended dose in adults: up to 1,000 mg in a single dose, not-to-exceed 3,000 mg in a 24-hour period . Aspirin Low-dose aspirin is used in pregnancy for several indications, most commonly in preventing preeclampsia (ACOG Guidance on Low-Dose Aspirin Use During Pregnancy) We support continued use of low-dose aspirin after discussion with maternal-fetal-medicine and other relevant consultative services (e.g. cardiology)

87. Hydroxychloroquine HCQ Use in Pregnancy HCQ crosses the placenta HCQ is considered safe to continue for the management of rheumatologic diseases, such as systemic lupus erythematosus (SLE), in pregnancy Several studies of women in whom HCQ therapy was continued in pregnancy revealed no adverse fetal outcomes (Parke, J Rheumatol, 1996; Clowse et al, Arthritis Rheum, 2006, Costedoat-Chalumeau, Arthritis Rheum, 2003) HCQ Use in Lactation HCQ levels in breastmilk are low and it’s considered safe to use in lactating mothers. Evidence for HCQ for COVID-19 in Pregnancy HCQ is an investigational agent for the treatment of COVID-19 and has not yet been demonstrated to be effective. Recent data have suggested against the use of hydroxychloroquine for COVID-19 outside of the context of a clinical trial. Recommendations Hydroxychloroquine use in COVID-19 is not recommended outside of the context of a clinical trial There are currently no enrolling hydroxychloroquine trials for pregnant patients at BWH

88. Immunomodulators Anti-IL6 Agents (Tocilizumab, Siltuximab, Sarilumab ) We do not recommend the routine use of anti-IL-6 agents in COVID-19 or in pregnancy unless part of a clinical trial Tocilizumab in Pregnancy Tocilizumab crosses the placenta Post-marketing data analysis of pregnancy outcomes in 288 evaluable women out of 399 who were exposed to tocilizumab shortly before or during pregnancy revealed no substantial increase in adverse pregnancy outcomes. However, this series is too small and diverse to demonstrate the safety of this agent in pregnancy (Hoeltzenbein M et al. Semin Arthritis Rheum, 2016) Outcome data during pregnancy are limited Tocilizumab may only be considered for use in pregnant women who have severe or critical COVID-19 AND suspicion of cytokine activation syndrome with elevated IL-6 levels in conjunction with Infectious Diseases consultation

89. Systemic Corticosteroids We do not recommend the routine use of systemic corticosteroids for COVID-19 except as part of a clinical trial or if treating another indication There are no data to inform on the risks and benefits of the use of steroids for fetal maturation in women with suspected or confirmed COVID-19 Systemic Antibiotics Information on treatment of bacterial infections that may be associated with COVID-19 can be found in the Infectious Disease chapter There is no sufficient supporting evidence to recommend the use azithromycin in combination with hydroxychloroquine for the indication of COVID-19 treatment Concomitant treatment of community-acquired bacterial pneumonia, if suspected, and typical coverage is desired, should be considered with an infectious diseases consultation, after weighing cardiac risks and benefits Suspected or confirmed COVID-19 should not delay treatment with antibiotics that would usually be given for a non-COVID-19 indication (for example treatment of bacteriuria, or evaluation or treatment of fever with prolonged rupture of membranes or postpartum fever)

90. Acute Kidney Injury

91. Work up: Monitor serum creatinine and electrolytes at least daily Studies find variable onset of AKI, from 7 days (Cheng et al, medRxiv, 2020 preprint) to 15 days after illness onset (Zhou et al, Lancet, 2020). Onset of AKI more rapid and severe in patients with underlying CKD (Cheng et al, medRxiv, 2020 preprint) In patients with AKI, order urine electrolytes (urine Na, urea and Cr) and urinalysis with sediment Patients may present with proteinuria (44%), hematuria (26.9%) (Cheng et al, medRxiv, 2020 preprint) For patients with proteinuria, quantify proteinuria with spot urine protein-to-creatinine and albumin-to-creatinine ratios Consider other common etiologies of AKI that can occur in patients who do not have COVID-19 (e.g. volume depletion, ATN from hypotension, contrast-associated nephropathy, acute interstitial nephritis and urinary tract obstruction)

92. Management: Discontinue all medications that can contribute to AKI (e.g. NSAIDs, ACE inhibitors, ARBs, and diuretics in volume depleted patients) and avoid using iodinated contrast with CT imaging as much as possible Consider a gentle fluid challenge (e.g. 1 liter of isotonic crystalloid fluid) to determine if there is a pre-renal component to AKI, especially in patients with clinical or laboratory signs suggestive of intravascular volume depletion (e.g. hypotension, tachycardia, dry mucous membranes, FENa<1% and/or FEurea<35%). Be cautious with fluid administration in patients with severe hypoxemia Consult nephrology for patients with any of the following: Creatinine clearance <30 ml/min/1.73m2 Oliguria: urine output <500cc/day or <0.5cc/Kg/hour Volume overload not improving with diuretics Hyperkalemia (>5.5) not responsive to dietary K restriction and diuretics

93. Renal Replacement Therapy (RRT) Estimates for RRT range from 0.8 to 5% of hospitalized patients (Guan et al, NEJM, 2020, Zhou et al, Lancet, 2020) in studies including floor patients. Among critically ill patients in the ICU, need for CRRT has been reported as high as 39% (Chen et al, Lancet, 2020). Few studies have reported outcomes of RRT. One case series reported that out of 191 patients, 10 received CRRT, and all 10 died (Zhou et al, Lancet, 2020). The nephrology consult service will determine the need, timing, and modality of renal replacement on a case-by-case basis. Indications for RRT in COVID-19 patients are the same as the indications for all patients.

94. Prognosis Increased serum creatine, BUN, AKI, proteinuria, or hematuria are each independent risk factors for in-hospital death (Cheng et al, medRxiv, 2020 preprint) In two other studies, non-survivors had higher BUN and creatinine and higher rates of AKI (Wang et al, JAMA, 2020; Yang et al, Lancet Respir Med, 2020). Another study found that higher BUN and creatinine are associated with progression to ARDS, and higher BUN (though not creatinine) is associated with death (HR 1.06-1.20) (Wu et al, JAMA Intern Med, 2020). Based on previous data from SARS, AKI was associated with poor prognosis as 91.7% of patients with AKI died (vs 8.8% without AKI, p < 0.0001) (Chu et al, Kidney Int, 2005).

95. Cardiology in COVID

96. Cardiology Consultation The following clinical scenarios should prompt cardiology consultation: Malignant and unstable arrhythmias A marked rise in cardiac biomarkers (including hsTnT >200 ng/L) Concern for myocarditis Concern for ACS New heart failure or new reduction in LVEF Undifferentiated or suspected mixed or cardiogenic shock

97. Arrhythmias Incidence Case series report the occurrence of unspecified arrhythmias in 17% of hospitalized patients with COVID-19 (n=23 of 138), with higher rate in ICU patients (44%, n=16) compared to non-ICU patients (7%, n=7)

98. Management Atrial fibrillation/atrial flutter Beta blockade if no evidence of heart failure or shock If significant heart failure or borderline BPs, use amiodarone. There is no known increased concern for amiodarone lung toxicity If unstable, synchronized DCCV with 200 Joules biphasic Ventricular tachycardia (VT) Unstable/pulseless: initiate ACLS Stable: Cardiology consult (may represent evolving myocardial involvement) Amiodarone 150mg IV x 1 or lidocaine 100mg IV x 1

99. Acute Coronary Syndromes Incidence There is no current available data on the incidence of ACS in COVID. However, we presume that due to the presence of ACE2 receptors on the endothelium, and the known increased risk of ACS in influenza that there is a possible increased incidence of ACS among COVID-19 patients. The incidence of ACS is about 6 times as high within seven days of an influenza diagnosis than during the control interval - incidence ratio 6.05 (95% CI, 3.86 to 9.50) (Kwong et al, NEJM, 2018).

100. Workup Elevated troponin/ECG changes alone may not be able to discriminate between: Coronary thrombosis Demand-related ischemia Myocarditis Toxic myocardial injury (e.g. sepsis) Determination of ACS will rely on all evidence available: Symptoms (if able to communicate): New dyspnea, chest pain, anginal equivalents Regional ECG changes Rate of change of Troponin changes (i.e., steep rise suggests ACS) Echo findings (e.g., new RWMA): When in doubt, request a cardiology consult.

101. Critical Care

102. Shock Definition: Acute onset of new and sustained hypotension (MAP < 65 or SBP < 90) with signs of hypoperfusion requiring IVF or vasopressors to maintain adequate blood pressure Patients rarely present in shock on admission Natural history seems to favor the development of shock after multiple days of critical illness. Etiology: The range of reasons for shock is wide and more variable than for most patients and may includes: Myocardial dysfunction Secondary bacterial infection Cytokine storm

103. Workup Assess for severity of end organ damage: UOP, mental status, lactate, BUN/creatinine, electrolytes, LFTs Obtain a FULL infectious/ septic workup, which includes all of the following: Labs: CBC with differential. Note that most COVID patients are lymphopenic (83%). However, new leukocytosis can occur and left-shift can be used as a part of clinical picture (Guan et al, N Engl J Med, 2020). Two sets of blood cultures, LFTs (for cholangitis/acalculous cholecystitis), urinalysis (with reflex to culture), sputum culture (if safely obtained via inline suctioning, do not perform bronchoscopy or sputum induction), procalcitonin at 0 and 48h (do not withhold early antibiotics on the basis of procalcitonin alone), urine Strep and legionella antigens Portable CXR (avoid CT unless absolutely necessary) Full skin exam Assess for cardiogenic shock Assess extremities: warm or cool on exam Assess patient volume status: JVP, CVP, edema, CXR

104. Assess for other causes of shock: Vasoplegia: Run medication list for recent cardiosuppressive medications, vasodilatory agents, antihypertensives Adrenal insufficiency: Unless high pretest probability of adrenal insufficiency, we recommend against routine cortisone stimulation testing Obstruction: PE (given the elevated risk of thrombosis) Tamponade (given elevated risk of pericarditis) Obstruction from PEEP Cytokine storm (see “Cytokine Storm” below) Allergic reactions to recent medications Neurogenic shock is uncommon in this context Hypovolemia: Bleeding Insensible losses from fever Diarrhea/vomiting

105. Sepsis Incidence The reported rates of sepsis and septic shock are not reported consistently in currently available case series Secondary bacterial infections are reported: 20% of non-survivors (Zhou et al, Lancet, 2020) 16% of non-survivors (Ruan et al, Intensive Care Med, 2020) 12-19% In H1N1 epidemic (MacIntyre et al, BMC Infect Dis, 2018) Concurrent Pneumocystis pneumonia has been reported in at least one case (possibly due to lymphopenia)

106. Management Antibiosis: Early empiric antibiotics should be initiated within 1 hour (see “Antibiotics”) Pressors and Fluid Management: Goal MAP > 65mmHg While there is emerging data that lower MAP thresholds may be beneficial, we recommend following this threshold for now. Pressors Start Norepinephrine while determining the etiology of undifferentiated shock Unless new evidence emerges, standard choices for distributive shock (i.e., norepinephrine then vasopressin) are recommended, with high vigilance for the development of cardiogenic shock

107. onservative fluid management: Do not give conventional 30cc/kg resuscitation COVID-19 clinical reports indicate the majority of patients present with respiratory failure without shock. ARDS is mediated in part by pulmonary capillary leak, and randomized controlled trials of ARDS indicate that a conservative fluid strategy is protective in this setting (Grissom et al, Crit Care Med, 2015; Famous et al, Am J Respir Crit Care Med, 2017; Silversides et al, Int Care Med, 2017) Conservative fluid management is also part of the most recent WHO guidelines. WHO, COVID-19 Interim guidance, March 2020). Instead, give 250-500cc IVF and assess in 15-30 minutes for: Increase > 2 in CVP Increase in MAP or decrease in pressor requirement Use isotonic crystalloids; Lactated Ringer’s solution is preferred where possible. Avoid hypotonic fluids, starches, or colloids

108. Repeat 250-500cc IVF boluses; Use dynamic measures of fluid responsiveness Pulse Pressure Variation: can be calculated in mechanically ventilated patients without arrhythmia; PPV >12% is sensitive and specific for volume responsiveness Straight Leg Raise: raise legs to 45° w/ supine torso for at least one minute. A change in pulse pressure of > 12% has sensitivity of 60% & specificity of 85% for fluid responsiveness in mechanically ventilated patients; less accurate if spontaneously breathing Ultrasound evaluation of IVC collapsibility should only be undertaken by trained personnel to avoid contamination of ultrasound For further guidance, Conservative Fluid Management protocols are available from from FACCT Lite trial (Grissom et al, Crit Care Med, 2015). Corticosteroids See “Systemic Corticosteroids” section Stress dose hydrocortisone should still be considered in patients on > 2 pressors.

109. Cardiogenic Shock Incidence and clinical course Mechanism is unknown, potentially direct viral toxicity, ACS, stress or inflammatory cardiomyopathy Incidence: Heart failure or cardiogenic shock was observed In 23% (n=44 of 191) of hospitalized patients in one case series (Zhou et al, Lancet, 2020). There were higher rates in non-survivors (52%, n=28) compared to survivors (12%, n=16), In 33% of patients admitted to an ICU in Washington State 33% (n=7 of 21) (Arentz et al, JAMA, 2020). These patients tended to be older with more comorbidities and had a high mortality (11 of the 21 died).

110. Nutrition in ICU Patients

111. Consult nutrition services if not already done. While awaiting nutrition input, start enteral nutrition: In most patients: Osmolite 1.5 @10mL/hr., advance by 20mL Q6h to goal 50mL/hr. If renal failure and high K or phosphorus: Nepro @ 10mL/hr, advance by 10mL Q6h to goal 40mL/hr. If on pressor support: Hold tube feeds for elevated pressors requirements d/t risk of intestinal ischemia including: Hold tube feeds if on two escalating pressors Epinephrine > 5 mcg/min Norepinephrine > 10 mcg/min Phenylephrine >60 mcg/min Vasopressin >0.04 units/min If unable to tolerate enteral nutrition support given escalating or multiple vasopressors TPN should be considered.

112. If paralyzed: It is safe to feed while patients are on paralytic agents such as cisatracurium If prone: Patients requiring proning may continue to receive tube feeding. The tube feeds should be held for one hour prior to turning the patient. Prokinetic agents may be beneficial during proning to enhance gastric emptying and decrease risk of vomiting as per ICU nursing procedure ICU-31. Other: Famotidine 20mg IV BID in intubated patients; Pantoprazole 20-40mg IV daily if history of GERD or GI bleed MVI with minerals daily Thiamine 100mg daily and Folate 1mg daily x3 days Goal glucose range is 70-180.

113. Hypoxemia Management

114. Definition of Acute Respiratory Distress Syndrome (ARDS) Most patients with COVID-19 who require ICU level of care will develop ARDS. The Berlin definition of ARDS requires the following four criteria: Acute (onset over 1 week or less) Bilateral opacities detected on CT or chest radiograph PF ratio <300mmHg with a minimum of 5 cmH20 PEEP (or CPAP) Must not be fully explained by cardiac failure or fluid overload

115. Time course Anecdotally, many report that progression of hypoxemic respiratory failure occurs rapidly (within ~12-24 hours). From onset of symptoms, the median time to: Development of ARDS: 8-12 days (Wang et al, JAMA, 2020; Zhou et al, Lancet, 2020; Huang et al, Lancet, 2020) Mechanical ventilation: 10.5-14.5 days (Huang et al, Lancet, 2020; Zhou et al, Lancet, 2020)

116. Supplemental Oxygen Support Goals of therapy: Maintain target SpO2 92-96% Target SpO2 88-94% in patients with oxygen-dependent COPD Maintain stable work of breathing Goal respiratory rate < 24 Target normal respiratory effort (no signs of accessory muscle use or obvious increased respiratory work)

117. Supplemental oxygen support: Initial oxygen delivery should be humidified nasal cannula (NC) titrated from 1 to 6 LPM to meet goals of therapy. If goals of therapy are not met at 6 LPM NC then advance to either: Oxymizer mustache: Initiate at 6 LPM Titrate to maximum of 12 LPM to meet goals of therapy Venturi mask Initiate at FiO2 40% (check device’s instructions to determine minimum flow rate needed to achieve 40%) Titrate to maximum of FiO2 60% to meet goals of therapy (some devices are not able to achieve Fi02 of 60%,

118. If appropriate, consult ICU for triage and evaluation : If SpO2 < 92% (<88% in COPD) or unstable work of breathing at Oxymizer at 10 LPM or Venturi mask at FiO2 50%

119. Top 10 Must-Dos in ICU in COVID-19 Include Prone Ventilation

120. Potential benefits of self-proning Proning is thought to provide physiologic benefits for patients with COVID infection: it improves recruitment of alveoli in dependent areas of the lungs and it may improve perfusion to ventilated areas, improving V/Q mismatching. Typically proning is used in ventilated ICU patients, however the same benefits may accrue to non-ventilated patients. Intubated proning: Proning is one of the mainstays of ARDS therapy for intubated patients, showing both 28 day and 90 day mortality benefit in the PROSEVA 2013 trial. Self-proning (non-intubated) in non-Covid-19 patient cohorts: ARDS, after lung transplant, and post-surgery. These small studies showed that self-proning was associated with lab, radiographic, or clinical improvement

121. Use in COVID-19: In one study (N=24), Covid-19 patients tolerated self-proning for 1 hr (17%, all required intubation within 72 hours), 1 to 3 hrs (21%) or more than 3 hrs (63%). Only 1 of the patients who tolerated proning for more than 1 hr was intubated in 10d follow-up. The only patients with a significant increase in PaO2 were the patients who self-proned for at least 3 hours (74 mmHg to 95 mmHg). This increase in PaO2 was not sustained after re-supination. Back pain was a limiting factor to self-proning

122. Non-invasive Positive Pressure Ventilation (NIPPV) cpap mask Risk mitigation BiPAP/CPAP transmission risk

123. High-Flow Nasal Cannula (HFNC) Risk mitigation transmission risk

124. For patients already on NIPPV/HFNC, transition to Venturi mask or non-rebreather mask if possible, ideally 45 minutes prior to intubation

125. METHOD OF DELIVERY select appropriate cannulae and circuit for patient size connect bag of sterile water to heater/ humdifier the water bag must run freely and be placed as high as possible above the humidifier to achieve flow of water into the humidifier chamber turn on heater/ humdifier and allow to warm up before use select non-invasive mode and set temperature (T37C) always use a blender, never use flow meter off wall delivering FiO2 100% set oxygen flow rate (up to 8 L/min on pediatric tubing, up to 60L/min in adults) — <10Kg 2 L per kg per minute — >10Kg 2 L per kg per minute (max flow 60 L/min) — start off at 6L/min and increase up to goal flow rate over a few minutes to allow patient to adjust to high flow set FiO2 (from 21% to 100%) place nasal cannulae on patient — ensure cannulae sit snugly in the patient’s nares Prongs should not totally occlude nares Titrate FiO2 and flow rate as required

126. THER INFORMATION Performance HFNC can generate FiO2 1.0 and PEEP of up to 7.4 cmH20 at 60 L/min, but this is reduced at lower flow rates and if the nasal cannulae do not have a snug fit in the nares more comfortable and better compliance than a face mask observational data suggests that HFNC outperform face masks for relieving respiratory distress, improving oxygenation and preventing the need for NIV or intubation traditional unheated low-flow (≤ 6 L/min) diffuser humidifiers (“bubblers”) are much less effective Disadvantages PEEP drops to ~2 cmH20 when the patient’s mouth is open PEEP is variable and not measurable more costly and requires more technology than standard nasal cannula critically ill patients may not be perceived as being so sick if they only have nasal cannulae on!

127. ARDS = acute respiratory distress syndrome; PaO2 = partial pressure of arterial oxygen; FiO2 = percentage of inspired oxygen. *—A normal person breathing room air (FiO2 = 0.21), whose PaO2 is approxi- mately 100 mm Hg, would have a PaO2/FiO2 ratio of approximately 500.

128. Hypotension and cardiac arrest during and after tracheal intubation Hypotension occurred in 18% of patients during and 28% ofpatients after tracheal intubation. Four patients developedcardiac arrest. These data are consistent with estimates ofperi-intubation hypotension incidence reported previ-ously54,55and cardiac arrest of 2e3% in the critically ill, withthe latter associated with increased mortality.56,57Predictorsof cardiac arrest in the critically ill at the time of trachealintubation include both hypotension and hypoxaemia beforeintubation (odds ratio: 3.4 and 4.0, respectively).57As withhypoxaemia, tracheal intubation earlier in the course of thedisease may reduce the risk of cardiovascular collapse. Allcases of cardiac arrest occurred in Hospital B. In Hospital A,prophylactic use of cardiovascular-stimulating agents wasadministered at the time of intubation.Recommendations: Where possible, tracheal intubation should beperformed earlier in the phase of the illness to avoid increased risk ofcardiovascular collapse during anaesthesia and intubation. Despite alack of clear evidence, we recommend consideration of the followingmeasures to minimise hypotension: (i) a250 mlcrystalloid bolus i.v.if not contraindicated (heart failure, kidney failure with volumeoverload, or similar), (ii) reduction in the use or dose of propofol as aninduction agent, and (iii) prophylactic use of cardiovascular-stimulating agents (e.g. phenylephrine, epinephrine, ornorepinephrine )

129. Recommendations: Early intubation is expected to reduce the risk of pneumothorax. Noninvasive ventilation before intubation shouldbe used with great caution. Large volume ventilation and recruitmentmanoeuvres to correct hypoxaemia immediately after tracheal intu-bation should be avoided. A protective ventilation strategy withsmall tidal volumes (e.g.6mlkg1ideal body weight) maintaininglower airway pressures is recommended. Early prone ventilationshould be considered, especially where peak pressure or drivingpressure is high. Methods to identify or exclude pneumothorax (e.g.chest radiography and point-of-care ultrasound) should be availableimmediately after tracheal intubation to enable prompt diagnosis

130. Hypoxaemia was defined as oxygen saturation(SaO2)<90% orPaO2/FIO2<150 mm Hg, tachypnoea with venti-latory frequency>30 bpm, arterial hypotension with blood pressure<90/60 mm Hg, tachycardia with HR>120 beats min 1, and unconsciousness with a negative response topurposeful physical stimulation (likely equivalent to Glasgow coma score <8 )

131. Clinical characteristics during Tracheal intubation Before induction of general anaesthesia, preoxygenation wasperformed for 5 min in all patients either using a face mask supplying 100% oxygen (47%) or by continuing the previous oxygen therapy (53%). Propofol was used for induction in 194(96%) cases with rocuronium for neuromuscular block in 200(99%); other drugs used at induction are shown inTable 2.Mask ventilation after induction and before intubation wasundertaken in 93% of intubations.

132. Rapid-Sequence Intubation Protocol 1. Preoxygenate (denitrogenate) the lungs by providing 100% oxygen by mask. 2. Assemble the equipment required: • Bag-valve-mask device connected to an oxygen delivery system • Suction with a Yankauer tip • ET tube with an intact cuff, stylet, syringe, and tape • Laryngoscope and blades, in working order • Back up airway equipment 3. Check to be sure that a functioning, secure intravenous line is in place. 4. Continuously monitor cardiac rhythm and oxygen saturation. 5. Premedicate as appropriate: • Fentanyl: 2 to 3 µg/kg given at a rate of 1 to 2 µg/kg/min intravenously for analgesia in awake patients • Atropine: 0.01 mg/kg by intravenous push for children or adolescents (minimum dose of 0.1 mg recommended)

133. Lidocaine: 1.5 to 2 mg/kg intravenously over a period of 30 to 60 seconds 6. Induce anesthesia with one of the following agents administered intravenously: thiopental, methohexital, fentanyl, ketamine, etomidate, or propofol. Apply cricoid pressure. 7. Give succinylcholine, 1.5 mg/kg by intravenous push (use 2 mg/kg for infants and small children). 8. Apnea, jaw relaxation, and/or decreased resistance to bag-mask ventilation (use only when oxygenation before rapid-sequence intubation cannot be optimized by spontaneous ventilation) indicates that the patient is sufficiently relaxed to proceed with intubation. 9. Perform ET intubation. If unable to intubate during the first 20-second attempt, stop and ventilate the patient with the bag-mask device for 30 to 60 seconds. Monitor pulse oximetry readings as a guide. 10. Treat bradycardia occurring during intubation with atropine, 0.5 mg by intravenous push (smaller dose for children; see item 5). 11. Once intubation is completed, inflate the cuff and confirm ET tube placement by auscultating for bilateral breath sounds and checking the pulse oximetry and capnography readings. 12. Release cricoid pressure and secure the ET tube. ET, endotracheal.

134. Indications for early intubation of the COVID-19 patient Significant hypoxemia refractory to non-rebreathing mask at flows < 15 lpm in conjunction with one or more of the following: Clinical signs of the patient tiring: Dyspnea; Tachypnea with RR > 30-35 (adult); Tachycardia; Agitation; Accessory muscle use; paradoxical chest/abdomen movement Worsening PaO2/FiO2; Increasing PaCO2; Rapidly progressive disease trajectory or other clinical judgement. Other standard indications for tracheal indication, e.g., failure to protect the airway or obstructing airway pathology, hemodynamic instability, sepsis, multi-organ failure.

135. Mechanical Ventilation - COVID-19

136. CPAP &BiPAP via a face mask CPAP. CPAP stands for Continued Positive Airway Pressure Biphasic Positive Airway Pressure (BIPAP)

137. CPAP

138. BIPAP

139. Protocol: Start BIPAP settings

140. The mechanical ventilation strategy from the ARDS

141. Parameters Tidal Volume (TV) Ventilator Tidal Volume: 6-8 ml/kg of Ideal Body Weight Prior levels of 10 to 15 ml/kg were too high ARDS: Start at 6 ml/kg based on Ideal Body Weight (lung protective strategy) Indications to Reduce Tidal Volume Lung Resection history (reduce Tidal Volume by percent loss in lung) Plateau pressure >30 cmH2O In Obstructive Lung Disease, decrease RR first (indicates Breath Stacking) Indications to Increase Tidal Volume Neuromuscular disease Stiff Lungs (e.g. Pulmonary edema) High Peak Inflation Pressure (>20-40 cm H2O) Results in large loss of Tidal Volume in tubing

142. Respiratory Rate (RR, "Ventilation") Set at 12 to 14 breaths per minute (many patients may require 16-18, esp. lung injury) Set Respiratory Rate closest to patient rate prior to intubation (especially in Metabolic Acidosis) Ensures adequate carbon dioxide removal Keep to a minimum to avoid Respiratory Alkalosis Increased Respiratory Rate needed in Metabolic Acidosis Observe patient's own Respiratory Rate prior to intubation and use as a guide Recheck Arterial Blood Gas (ABG) at 20 minutes after initial settings Indications to decrease Respiratory Rate Obstructive Lung Disease with Breath Stacking

143. Minute ventilation (Alveolar Minute Ventilation) Reflects gas exchanged per minute and determines CO2 clearance Typically 7 to 8 L/min, but up to twice as much may be needed in certain conditions Minute Ventilation = (Vt - Vd) * RR Where Vt is Tidal Volume, Vd is dead space and RR is Respiratory Rate

144. Fraction of Inspired Oxygen (FIO2) Start: 80% or higher Titrate: decrease in 10-20% steps Goal: Keep FIO2 <60% (<50% in the first 24 hours if possible) Higher FIO2 is associated with Oxygen Toxicity Target Oxygen Saturations 90-94% (>88% may be used as target in severe ARDS) Increasing PEEP can reduce FIO2 requirements (see below) Monitoring: Arterial Blood Gas Wait 20 minutes after each change in FIO2 Keep PaO2 60 to 80 mm Hg (90-95% O2 Sat)

145. Inspiratory flow rate (IFR) Describes how quickly a breath is delivered (anologous to Peak Flow) Faster breaths tend to be more comfortable, and result in less Air Hunger sensation for patient Adjust for patient comfort

146. Positive End-Expiratory Pressure (PEEP) Prevents distal airspace collapse (especially dependent lung fields) Most important in shunting of blood past collapsed alveoli (e.g. Pneumonia, Atelectasis) Start PEEP at 5 cm H2O (minimum) Higher PEEP Indications Extensive alveolar collapse (8-10 cm H2O) Obesity or pregnancy High FIO2 (esp. >60%) required or Hypoxemia refractory to oxygenation Goal Oxygen Saturation 88-95% (PaO2 55-80 mmHg) FIO2 30%: Set PEEP 5 cmH2O (high PEEP to FIO2: 5-8-10-12-14 cmH2O) FIO2 40%: Set PEEP 5-8 cmH2O (high PEEP to FIO2: 14-16 cmH2O) FIO2 50%: Set PEEP 8-10 cmH2O (high PEEP to FIO2: 16-18-20 cmH2O) FIO2 60-80%: Set PEEP 10-14 cmH2O (high PEEP to FIO2: 20 cmH2O) FIO2 90%: Set PEEP 14-18 cmH2O (high PEEP to FIO2: 22 cmH2O) FIO2 100%: Set PEEP 18-24 cmH2O (high PEEP to FIO2: 22-24 cmH2O) http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf

147. Precautions: Excessive PEEP PEEP Levels >15 cm H2O are rarely required and are associated with complications Lung injury risk (alveolar over-distention) Hypotension risk (increased intrathoracic pressure decreases venous return) Decrease PEEP if hypotensive response to increasing PEEP

148. Adverse Effects Mechanical Ventilation Barotrauma (Tension Pneumothorax, Auto-PEEP) Ventilator-Associated Pneumonia Myocardial Infarction Consider serial Electrocardiogram and Troponin Severe Respiratory Alkalosis Occurs with high Respiratory Rates Consider IMV ventilation mode or patient sedation Venous Thromboembolism See Venous Thromboembolism Prevention Anticoagulation or if contraindicated, pneumatic compression device Gastric Stress Ulcer Empiric intravenous Proton Pump Inhibitor (e.g. Pantoprazole) or H2 Blocker (e.g. Famotidine) Nosocomial Pneumonia Head of bed to 30 degrees Oral Hygiene

149. weaning criteria from mechanical ventilation

150. Sedation and Analgesia

151. ABG Interpretation

152. Causes: Acute Respiratory Acidosis Central Nervous System Depression Sedative Medications (e.g. Benzodiazepines) Cerebrovascular Accident Head Trauma Neuromuscular Disease Myasthenia Gravis Guillain-Barre Polio Muscular Dystrophy Hypokalemia Impaired lung motion Pleural Effusion Pneumothorax Crush injury Acute airway obstruction Foreign Body Aspiration Tumor Laryngospasm (e.g. Croup, Epiglottitis) Bronchospasm (e.g. Asthma) Acute Respiratory Disease Severe Pneumonia Pulmonary edema

153. Respiratory Acidosis Treatment & Management Pharmacologic Therapy Bronchodilators Bronchodilators such as beta agonists (eg, albuterol and salmeterol), anticholinergic agents (eg, ipratropium bromide and tiotropium), and methylxanthines (eg, theophylline) are helpful in treating patients with obstructive airway disease and severe bronchospasm. Theophylline may improve diaphragm muscle contractility and may stimulate the respiratory center.

154. Respiratory stimulants Medroxyprogesterone increases central respiratory drive and may be effective in treating obesity-hypoventilation syndrome (OHS). Medroxyprogesterone has also been shown to stimulate ventilation is some patients with COPD and alveolar hypoventilation. Acetazolamide is a diuretic that increases bicarbonate excretion and induces a metabolic acidosis, which subsequently stimulates ventilation. However, acetazolamide must be used with caution in this setting. Inducing a metabolic acidosis in a patient with a respiratory acidosis could result in a severely low pH. If the patient's respiratory system cannot compensate for the metabolic acidosis it induces, the patient may suffer hyperkalemia and potentially a life-threatening cardiac arrhythmia.

155. Drug antagonists Drug therapy aimed at reversing the effects of certain sedative drugs may be helpful in the event of an accidental or intentional overdosage. Naloxone may be used to reverse the effects of narcotics. Flumazenil may be used to reverse the effects of benzodiazepines. However, care must be taken in reversing the effects of benzodiazepines because patients may have seizures if benzodiazepine reversal is accomplished too vigorously

156. Oxygen Therapy Because many patients with hypercapnia are also hypoxemic, oxygen therapy may be indicated. Oxygen therapy is employed to prevent the sequelae of long-standing hypoxemia. Patients with COPD who meet the criteria for oxygen therapy have been shown to have decreased mortality when treated with continuous oxygen therapy. Oxygen therapy has also been shown to reduce pulmonary hypertension in some patients. Oxygen therapy should be used with caution because it may worsen hypercapnia in some situations. For example, patients with COPD may experience exacerbation of hypercapnia during oxygen therapy. This observation is thought by many to be primarily a consequence of ventilation-perfusion mismatching, in opposition to the commonly accepted concept of a reduction in hypoxic ventilatory drive. The exact pathophysiology, however, remains controversial. Hypercapnia is best avoided by titrating oxygen delivery to maintain oxygen saturation in the low 90% range and partial arterial pressure of oxygen (PaO2) in the range of 60-65 mm Hg

157. The treatment of respiratory alkalosis is primarily directed at correcting the underlying disorder. Respiratory alkalosis itself is rarely life threatening. Therefore, emergent treatment is usually not indicated unless the pH level is greater than 7.5. Because respiratory alkalosis usually occurs in response to some stimulus, treatment is usually unsuccessful unless the stimulus is controlled. If the PaCO2 is corrected rapidly in patients with chronic respiratory alkalosis, metabolic acidosis may develop due to the renal compensatory drop in serum bicarbonate. In mechanically ventilated patients who have respiratory alkalosis, the tidal volume and/or respiratory rate may need to be decreased. Inadequate sedation and pain control may contribute to respiratory alkalosis in patients breathing over the set ventilator rate. In hyperventilation syndrome, patients benefit from reassurance, rebreathing into a paper bag during acute episodes, and treatment for underlying psychological stress. Sedatives and/or antidepressants should be reserved for patients who have not responded to conservative treatment. Beta-adrenergic blockers may help control the manifestations of the hyperadrenergic state that can lead to hyperventilation syndrome in some patients. [4] In patients presenting with hyperventilation, a systematic approach should be used to rule out potentially life-threatening, organic causes first before considering less serious disorders.