Following practice recommendations have been compiled by cardiologists Dr Yashpaul Sharma and Dr Prem Aggarwal

These recommendations regarding the approach to COVID-19 treatment are based upon the most recent literature. These are general guidelines for physicians confronting the COVID-19 patient across the country. The recommendations so proposed are likely to change as new information emerges. We shall be constantly updating the recommendations in time to time.

• COVID-19 (coronavirus disease 2019) is respiratory tract infection due to a novel coronavirus, SARS-COV-2 (initially called 2019-NCOV); as of March 11, 2020, extent of infection was declared a pandemic by WHO. The pathogen is a beta coronavirus, similar to the agents of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) and Classified as a member of the species. Severe acute respiratory syndrome-related coronavirus.
• About 5% of diagnosed cases require critical care to manage severe manifestations and complications. Among patients with COVID-19 who are critically ill, mortality rates of 39% to 72% are reported
• Due to the sudden onset and rapid spread large number of hospitals who have not be exposed this disease are now facing the responsibility of treating these very seriously ill patients with no evidence based treatment.

• We have tried to create an clinical overview these can work as the ready help of the literature till to date regarding the management of this disease.

CLINICAL PRESENTATION

History

When the patient starts having symptoms, an illness may evolve over the course of a week or longer, beginning with mild symptoms. The syndrome is usually dominated by respiratory complaints, but it may include alterations in taste and smell, gastrointestinal symptoms, myalgia's, and fatigue (often profound)

CLINICAL PRESENTATION

The Median time from symptom onset to Pulmonary involvement is 5 days; time to severe hypoxemia is 7 to 12 days

The patients with progression to severe disease, deterioration is typically rapid and characterized by progressive hypoxemia which may or may not be associated with symptoms of dyspnoea

Cardiac, vascular, and neurologic manifestations may accompany pulmonary disease, resulting in localized symptoms (e.g., pain, including headache) and alterations in cognition and level of consciousness.

Physical Examination

• In the recent epidemic the reported case series have not fully detailed all the physical findings, but clinicians should be particularly attuned to pulmonary, haematological and hemodynamic indicators of critical illness.
• Patients in apparent distress require immediate assessment of airway, breathing, and circulation (e.g., pulses, blood pressure) Oxygenation should be assessed promptly by
• peripheral saturation (e.g., pulse oximetry) and ABG.
• Fever is typical, often exceeding 39 °C. Patients in the extremes of age or with immunodeficiency may not develop fever
• Patients with severe disease may appear quite ill, with tachypnoea and laboured respirations Tachyarrhythmia's may be noted on auscultation or cardiac monitor signs of arterial or deep venous thrombosis may be detected large-vessel stroke and associated neurologic deficit has been described as the presenting clinical event 11 . Patients may be agitated, confused, or poorly responsive
• A variety of skin changes have been described, including purpura [13] and petechial [14] as well as the vesicular [15] and nonspecific erythematous exanthemas [16] typical of viral infections. Typical viral eruptions generally occur early in the disease, but remnants may be apparent in patients presenting with severe disease.
• Hypotension, tachycardia, and cool/clammy extremities suggest shock.

RISK FACTORS AND / OR ASSOCIATIONS AGE

• Risk of severe disease increases with age; severe illness is rare in children and adolescents. Male sex may be a risk factor for severe disease
• Various comorbidities (especially if not well controlled) have been associated with moresevere disease [5,17] like Heart Disease, Hypertension, Previous Stroke, Diabetes, Chronic lung disease, including moderate or severe asthma, chronic liver or kidney disease, Immunocompromised, BMI of 40 or more.

DIAGNOSIS

• Polymerase chain reaction tests are the standard for diagnosis. Collection of specimens from the upper respiratory tract or lower respiratory tract is recommended for polymerase chain reaction testing.
• Routine blood work is not diagnostic, but a pattern of typical abnormalities has emerged, particularly in patients with severe illness:
• Leukopenia may be observed and relative lymphopenia is common, especially in patients with more severe illness
• Anaemia was noted in about half of patients in one series
• Both elevated and low platelet counts have been seen
• Prolonged prothrombin time has been reported
• Levels of D-dimer and fibrinogen may be elevated
• Elevated levels of lactate dehydrogenase and liver enzymes (ALT and AST) are common
• Serum procalcitonin levels are usually within reference range; elevated levels have been seen in patients with secondary infection
• Serum levels of some other acute phase reactants (e.g., C-reactive protein, ferritin) are elevated in most patients, as is the erythrocyte sedimentation rate 20 especially with cytokinin crisis
• Troponin level is commonly elevated, but it does not necessarily signify myocardial infarction in the absence of other indicators (e.g., ECG changes); similarly, B-type natriuretic peptide level may be elevated without necessarily indicating presence of heart failure

• Some experts caution against measuring these biomarkers in the absence of suggestive clinical findings, [22] whereas others note the possibility that elevations suggest non coronary myocardial involvement that may benefit from early use of vasopressors and inotropes
• Lactate level of 2 mmol/L or higher suggests the presence of septic shock [9]

IMAGING

Chest imaging (e.g., plain radiography, CT, ultrasonography) has shown abnormalities in most reported patients. It usually shows bilateral involvement, varying from consolidation in more severely ill patients, to ground-glass opacities in less severe and recovering pneumonia [2,6,19,20,23]

CT appears to be more sensitive 24,25 than plain radiographs, CT abnormalities are usually detected from Day 3-4 from the day of symptoms and persist at least till Day 22-24 from the initial symptoms CT can detect Resolution or worsening of lung abnormalities, helping in prognostication.

Negative Predictive Value (NPV) Of Chest CT is 95-99% Positive Predictive Value (PPV) Of Chest CT is 65-84 %. CT Chest Done after 4-5 days of initiation of symptoms (and with negative PCR), is Positive in 94-99 % of COVID patients

There may be residual changes on CT up to 22 days after initial symptoms. So YOU may see some residual changes if YOU discharge the patient before 3 weeks. That's why It has been recommended for Quarantine of 3 weeks for optimal recovery. So CT will be helpful to decide whether the patient needs further quarantine for another week or 10 days.

It is safer to obtain Chest CT in all high-risk patients (if PCR not done or if PCR is negative) like Immunocompromised PTs, Comorbidities, Invasive procedures, Obesity, Age above 65.

Bedside ultrasonography is widely used to monitor the progression of pulmonary infiltrates, and to assess cardiac function and fluid status; it may also be used to detect deep vein or vascular catheter thrombosis, which appear to be common in patients with COVID-19 [7,26]

TREATMENT

PROPHYLAXIS

While there is very limited data (and none specific for COVID-19), the following "cocktail" may have a role in the prevention/mitigation of COVID-19 disease. While there is no high-level evidence that this cocktail is effective; it is cheap, safe and widely available.

• Vitamin C 500 mg BID [27-31]
• Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1 month, reduce the dose to 30-50 mg/day [27, 32-35]
• Vitamin D3 1000-4000 u/day [36-42]
• Famotidine 20-40mg/day [43]
• Once weekly chloroquine / Hydroxychloroquine may have a role in prophylaxis in high-risk subgroups i.e. health care workers, residents of nursing homes, etc. Ongoing studies are testing this hypothesis.

SYMPTOMATIC PATIENTS (AT HOME)

• Vitamin C 500 mg BID and Quercetin 250-500 mg BID
  
• Zinc 75-100 mg/day
• Vitamin D3 2000-4000 u/day
• Optional: ASA 81 -325 mg/day
• Optional: Famotidine 20-40mg/day
• Optional: Hydroxychloroquine 400mg BID day 1 followed by 200mg BID for 4 days [44] Recent evidence suggests that HCQ has a doubtful role in the treatment of COVID-19 in hospitalized patients.
• Ivermectin 150-200 ug/kg (single dose) [45,46]
• In symptomatic patients, monitoring with home pulse oximetry is recommended.

CRITERIA FOR ADMISSION

1. Ambulatory desaturation < 94% should prompt hospital admission.

2. Risk of severe disease increases with age and patients with more than 70 age are preferred in a hospital setting.

3. Various comorbidities (especially if not well controlled) have been associated with a more severe disease like Heart Disease Hypertension Previous Stroke Diabetes, Chronic lung disease, including moderate or severe asthma Chronic liver or kidney disease, Immunocompromised, BMI of 40 or more. These patients are also better treated in hospital setting.

MILDLY SYMPTOMATIC PATIENTS (ON FLOOR)

• Vitamin C 500 mg q 6 hourly and Quercetin 250-500 mg BID (if available)
  
• Zinc 75-100 mg/day
• Vitamin D3 2000-4000 u/day
• Enoxaparin 60 mg daily [47-51]
• Methylprednisolone 40 mg q 12 hourly; increase to 80 mg q 12 hourly in patients with progressive symptoms and increasing CRP [52-56]
• Famotidine 40mg daily (20 mg in renal impairment)
• If available Remdesivir, 200 mg IV loading dose D1, followed by 100mg day IV for5 TO 9 days. [57,58] This agent has been reported to reduce time to recovery [58] The benefit of this agent on patient-centred outcomes is unclear. Ivermectin 150-200 ug/kg (Single Dose) [45,46]
• Recently Favipiravir (Fabi Flu) also be approved in India but still not available till today. It is likely to be available within a fort might this drug was used in Japan and was found to be effective. Doses of Favipiravir are 1600 mg twice a day on the first day and 1600 mg twice a day for 14 days.
• N/C 2L /min if required (max 4 L/min; consider early t/f to ICU for escalation of care).
• Avoid Nebulization and Respiratory treatments. Use a spacer if required.
• Avoid CPAP or BiPAP
• Transfer EARLY to the ICU for increasing respiratory signs/symptoms and arterial desaturation.

ADMIT TO INTENSIVE CARE UNIT (ICU) SERIOUSLY ILL PATIENTS

Respiratory symptoms (SOB; Hypoxia- requiring N/C ≥ 4 L min:

1. Methylprednisolone 80 mg loading dose then 40mg q 12 hourly for at least 7 days and until transferred out of ICU. In patients with an increasing CRP or worsening clinical status increase the dose to 80 mg q 12 hourly, then titrate down as appropriate [52,56]

2. Ascorbic acid (Vitamin C) 3g IV q 6 hourly for at least 7 days and/or until transferred out of ICU. Note caution with POC glucose testing [59-67]

3. Full anticoagulation: Unless contraindicated we suggest full anticoagulation (on admission to the ICU) with enoxaparin, i.e. 1 mg kg s/c q 12 hourly (dose adjust with Cr Cl < 30mls/min). [47-51] Heparin is suggested with CrCl < 15 ml/min with a dose not to exceed 0.9 mg/kg followed by full anticoagulation.

4. COVID Awake Repositioning/Proning Protocol (CARP)

1. Prone positioning improves oxygenation in spontaneously breathing non-intubated patients with hypoxemic acute respiratory failure
2. Indications for Awake Proning:
3. Isolated hypoxemic respiratory failure without substantial dyspnea (the "paradoxically well appearing" hypoxemic patient). A reasonable candidate might meet the following criteria: 7
1. not in multi-organ failure
2. expectation that patient has a fairly reversible lung injury and may avoid intubation
3. no hypercapnia or substantial dyspnea
4. normal mental status, able to communicate distress
5. no anticipation of difficult airway

4. Patients who do not wish to be intubated. The main risk of awake proning is that it could cause excessive delays in intubation. In the patient who do not give consent for

intubation, there is little to be lost by trial of awake proning.

5. Patients with a PF Ratio (po2/Fio2) of < 100 on Non-Invasive Ventilation (NIV) are not suitable candidates and this may delay unavoidable intubation. Patients should prone, as tolerated for 2-4 hours/session for 2-4/days. Patients may receive light sedation in order to tolerate pronation. While the evidence is far from robust, this technique is currently being used and has both physiological and laboratory basis. More importantly, it has a demonstrated anecdotal benefit to avoid intubation.

CARP Protocol

Timed Position Changes

Every 2 hrs, ask the patient to switch between the following positions. Bed adjustments will be required between positions

1. Left Lateral Recumbent

2. Right Lateral Recumbent

3. Sitting Upright 60-90 degrees

4. Lying Prone in bed

If these 4 positions are not raising the Oxygen Saturation, a 5th position can be tried:

5. Trendelenburg position (Supine, Bed 30 degrees Head Down)

10-15 Minutes after each position change, check to make sure that Oxygen Saturation has not decreased. If it has, try another position.

Position Changes to Counter Hypoxemia

If the patient has a significant drop in Oxygen saturation, follow these steps:

1. Ensure that the source of the patient's Oxygen is still hooked up to the wall and is properly placed on the patient (this is a common cause of desaturation)

2. Ask the patient to move to a different position as below.

TIMING OF THE INITIATION OF ANTI-INFLAMMATORY THERAPY

Figure 1

ADOPTED AND CURTSEY EVMS CRITICAL CARE COVID-19 MANAGEMENT PROTOCOL BY PAUL MARIK, MD.

ADDITIONAL TREATMENT COMPONENTS

1. Famotidine 40mg daily (20 mg in renal impairment)

2. Vitamin D 2000-4000 u PO daily

3. Thiamine 200 mg IV q 12 hourly

4. Magnesium: 2 g stat IV. Keep Mg between 2.0 and 2.4 mmol/l. Prevent hypomagnesemia (which increases the cytokine storm and prolongs Qtc) [68-70]

5. Azithromycin 500mg day 1 then 250 mg for 4 days (has immunomodulating properties including downregulating IL-6; in addition, Rx of concomitant bacterial pneumonia)

6. Atorvastatin 80 mg/day. Of theoretical but unproven benefit. Atorvastatin has been demonstrated to reduce mortality in the hyper-inflammatory ARDS phenotype. 72 Statins have pleotropic anti-inflammatory, immunomodulatory, antibacterial and antiviral effects. In addition, statins decrease expression of PAI-1.

7. Remdesivir - Patients hospitalized for severe Covid-19 who were treated with compassionate-use Remdesivir, clinical improvement was observed in 36 of 53 patients (68%).While useful in early stages, The role of this agent in patients with more advanced pulmonary involvement appears to be limited.

8. Recently Favipiravir (Fabi Flu) also be approved in India but still not available till today. It is likely to be available within a fort might this drug was used in Japan

and was found to be effective. Doses of Favipiravir are 1600 mg twice a day on a first day and 1600 mg twice a day for 14 days.

9. Broad-spectrum antibiotics if superadded bacterial pneumonia is suspected based on procalcitonin levels and resp. culture (no bronchoscopy). Due to the paradox of hyper-inflammation and immune suppression (a major decrease of HLA-DR on CD14 monocytes) secondary bacterial infection is not uncommon.

10. Maintain EUVOLEMIA (this is not non-cardiogenic pulmonary oedema). Due to the prolonged "symptomatic phase" with flu-like symptoms (6-8 days) patients may be volume depleted. Cautious rehydration with 500 ml boluses of Lactate Ringers may be warranted, ideally guided by non- invasive hemodynamic monitoring. Diuretics should be avoided unless the patient has obvious intravascular volume overload.

Avoid hypovolemia

11. Blood - Judicious use of blood transfusion and Plasma therapy in some patients on ventilator.

12. Early norepinephrine for hypotension.

13. Escalation of respiratory support (steps);

TRY TO AVOID INTUBATION IF AT ALL POSSIBLE

• Accept "permissive hypoxemia" (keep O2 Saturation > 84%); follow venous lactate and Central Venous O2 saturation (ScvO2) in patients with low arterial O2 saturations
• N/C 1-6 L/min
• High Flow Nasal cannula (HFNC) up to 60-80 L/min
• Trial of inhaled (epoprostenol)
• Attempt proning (cooperative repositioning-proning)
• Intubation … by Expert intubator; Rapid sequence. No Bagging; Full PPE. Crash/emergency intubations should be avoided.
• Volume protective ventilation; Lowest driving pressure and lowest PEEP as possible. Keep driving pressures < 15 cmH2O.
• Moderate sedation to prevent self-extubation
• Trial of inhaled (epoprostenol)
• Prone positioning.

HFNC is a better option for the patient and the health care system than intubation and mechanical ventilation. CPAP/Bipap should be used early notably those with COPD exacerbation or heart failure.

A sub-group of patients with COVID-19 deteriorates very rapidly. Intubation and mechanical ventilation may be required in these patients.

"Across the world, there has been very little success of survival for patients who were intubated and put on invasive mechanical ventilation. The thinking is changing to postpone intubation to as long as possible and to prevent mechanical engineering injury from the ventilator. These patients tolerate arterial hypoxia surprisingly well. The natural course seems to be the best."

SALVAGE TREATMENTS

• Plasma exchange Should be considered in patients with progressive oxygenation failure despite corticosteroid therapy. Patients may require up to 5 exchanges
• High dose corticosteroids; 120mg methylprednisolone q 6-8 hourly
• Tocilizumab (IL-6 inhibitors) An observational study in New Jersey showed an improved survival rate among patients who received tocilizumab. Among 547 ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend toward an improved survival rate of 54% who received tocilizumab compared with 44% who did not receive the therapy
• Convalescent serum; the role and timing of convalescent serum are uncertain [78-80]

" Convalescent plasma is an experimental procedure for COVID-19 patients. Hospitals and institutions planning to provide this modality of treatment should do so in a clinical trial with protocols which are cleared by the Institutional Ethics Committee (IEC)," ICMR stated. In this experimental treatment, plasma of a treated COVID-19 patient is indicated to an existing patient. Theoretically, plasma from a cured patient is assumed to have antibodies against the virus and this can then be used to cure another patient.

TREATMENT OF MACROPHAGE ACTIVATION SYNDROME (MAS)

• A sub-group of patients will develop MAS. This appears to be driven by SARS-CoV- 2 induced inflammation activation and increased IL-1 β production (see Figure 3) [83,84]
• A ferritin > 4400 ng/ml is considered diagnostic of MAS. Other diagnostic features include increasing AST/ALT and increasing CRP. [85]
• "High dose corticosteroids." Methylprednisolone 120 mg q 6-8 hourly for at least 3 days, then wean according to Ferritin, CRP, AST/ALT (see Figure 4). Ferritin should decrease by at least 15% before weaning corticosteroids.

MONITORING

• Daily: PCT, CRP, IL-6, BNP, Troponins, Ferritin, Neutrophil-Lymphocyte ratio, D- dimer and Mg. CRP, IL-6 and Ferritin track disease severity closely (although ferritin tends to lag behind CRP). Early CRP levels are closely associated with the degree of pulmonary involvement and the CT score [86]
• In patients receiving IV vitamin C, the Accu-Chek™ POC glucose monitor will result in spuriously high blood glucose values. Therefore, a laboratory glucose is recommended to confirm the blood glucose levels.
• Monitor QTc interval if using chloroquine/hydro chloroquine and azithromycin and monitor Mg++ (torsade's is uncommon in monitored ICU patients)
• No routine CT scans, follow CXR and chest ultrasound.
• Follow ECHO closely; Pts develop severe cardiomyopathy.

POST ICU MANAGEMENT

a) Enoxaparin 40-60 mg s/c daily

b) Methylprednisolone 40 mg day, then wean slowly

c) Vitamin C 500 mg PO BID

FIGURE - 2

ADOPTED AND CURTSEY EVMS CRITICAL CARE COVID-19

MANAGEMENT PROTOCOL BY PAUL MARIK, MD.

Figure - 3

ADOPTED AND CURTSEY EVMS CRITICAL CARE COVID-19

MANAGEMENT PROTOCOL BY PAUL MARIK, MD.

Figure – 4

ADOPTED AND CURTSEY EVMS CRITICAL CARE COVID-19 MANAGEMENT PROTOCOL BY PAUL MARIK, MD.

TREATMENT

Figure - 5

ADOPTED AND CURTSEY EVMS CRITICAL CARE COVID-19 MANAGEMENT PROTOCOL BY PAUL MARIK,

SCIENTIFIC RATIONALE FOR TREATMENT PROTOCOL

Three core pathologic processes lead to multi-organ failure and death in COVID-19

1. Hyper-inflammation ("Cytokine storm") – A dysregulated immune system whose cells infiltrate and damage multiple organs, namely the lungs, kidneys, and heart. It is now widely accepted that SARS-CoV-2 causes aberrant T lymphocyte and macrophage activation resulting in a "cytokine storm." [77,83,84,87-95]

2. Hyper-coagulability (increased clotting) – The dysregulated immune system damages the endothelium and activates blood clotting, causing the formation of micro and macro blood clots. These blood clots impair blood flow [47,48,50,96-100]

3. Severe Hypoxemia (low blood oxygen levels) – Lung inflammation caused by the cytokine storm, together with micro thrombosis in the pulmonary circulation severely impairs oxygen absorption resulting in oxygenation failure.

• The above pathologies are not novel, although the combined severity in COVID-19 disease is considerable. Our long-standing and more recent experiences show consistently successful treatment if traditional therapeutic principles of early and aggressive intervention is achieved, before the onset of advanced organ failure. It is our collective opinion that the historically high levels of morbidity and mortality from COVID-19 is due to a single factor: the widespread and inappropriate reluctance amongst intensivists to employ anti-inflammatory and anticoagulant treatments, including corticosteroid therapy early in the course of a patient's hospitalization. It is essential to recognize that it is not the virus that is killing the patient, rather it is the patient's overactive immune system [92] The flames of the "cytokine fire" are out of control and need to be extinguished. Providing supportive care (with ventilators that themselves stoke the fire) and waiting for the cytokine fire to burn itself out simply does not work… this approach has FAILED and has led to the death of tens of thousands of patients.

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Dr Yash Paul Sharma, MD Medicine DM Cardiology FCSI is the Professor & Head Department of Cardiology, Advanced Cardiac center PGIMER, Chandigarh

Dr Prem Aggarwal, MD Med, DNB Med, DNB Card,, Fellow Phd. Cardiology is a Consultant Cardiologist & Intensivist Managing Director Sanjeevan Hospital and a co-founder Medical Dialogues