Developed and updated by Paul Marik, MD Chief of Pulmonary and Critical Care Medicine Eastern Virginia Medical School, Norfolk, VA August 1st, 2020
This is our recommended approach to COVID-19 based on the best (and most recent) literature. This is a very dynamic situation; therefore, we will be updating the guideline as new information emerges. Please check on the EVMS website for updated versions of this protocol.
EVMS COVID website: https://www.evms.edu/covid-19/medical_information_resources/
Short url: evms.edu/covidcare
Disclaimer: The information provided in this protocol is primarily to educate physicians on a protocol that we found to be highly effective in damping down the hyper-inflammatory cytokine “storm” that is the cause of mortality and morbidity in COVID-19. Our guidance should only be used by medical professionals in formulating their approach to COVID19. Patients should always consult with their physician before starting any medical treatment
FLCC website: https://covid19criticalcare.com/
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Prophylaxis
While there is extremely limited data, the following “cocktail” may have a role in the prevention/mitigation of COVID-19 disease. It should however be noted that a recent publication suggests that melatonin my reduce the risk of COVID-19 infection.[1] This cocktail is cheap, safe, and widely available.
• Vitamin C 500 mg BID (twice daily) and Quercetin 250-500 mg BID [2-8]
• Zinc 50-75 mg/day (elemental zinc). Zinc lozenges are preferred. After 1 month, reduce the dose to 30-50 mg/day. [2,9-13]
• Melatonin (slow release): Begin with 0.3mg and increase as tolerated to 2 mg at night [1,14-17]
• Vitamin D3 2000-4000 u/day [18-25]
• Optional: Famotidine 20-40 mg/day [26]
Symptomatic patients (at home):
• Vitamin C 500 mg BID and Quercetin 250-500 mg BID
• Zinc 75-100 mg/day (elemental zinc)
• Melatonin 6-12 mg at night (the optimal dose is unknown)
• Vitamin D3 2000-4000 u/day
• ASA 81 -325 mg/day (unless contraindicated)
• Optional: Famotidine 20-40 mg/day
• Optional: Ivermectin 150-200 ug/kg orally (dose can be repeated on day 2) [27-31]
• In symptomatic patients, monitoring with home pulse oximetry is recommended. Baseline or ambulatory desaturation < 94% should prompt hospital admission. [32]
• Not recommended: Hydroxychloroquine (HCQ). The use of HCQ is extremely controversial.[33] The best scientific evidence to date suggest that HCQ has no proven benefit for post exposure prophylaxis, for the early symptomatic phase and in hospitalized patients. [34-39] It should be noted that these studies did not include Zinc, and it is possible that the efficacy of HCQ requires the co-administration of Zinc. [40,41] However, considering the unique pharmacokinetics of HCQ, it is unlikely that HCQ is of benefit (takes about 10 days to achieve adequate plasma and lung concentrations).[42-44] The benefit derived from the co-administration of Zinc may be due to the effects of zinc alone. This is however, a very “volatile” situation, so stay tuned.
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
• Melatonin 6-12 mg at night (the optimal dose is unknown)
• Vitamin D3 4000 u/day
• Enoxaparin 60 mg daily [31,45-54] Consider increasing the dose to 1mg/kg q 12 hourly in those with a high D-Dimer or an increasing D-Dimer (see Xa monitoring below).
• Methylprednisolone 40 mg q 12 hourly ; increase to 80 mg q 12 hourly in patients with progressive symptoms and increasing CRP. [55-61] The role of inhaled corticosteroids (budesonide) is unclear and appears to be rather limited.
• Famotidine 40 mg daily (20 mg in renal impairment)
• Optional: Ivermectin 150-200 ug/kg (dose can be repeated on day 2)
• Optional: Vascepa (Ethyl eicosapentaenoic acid) 4g daily or Lovaza (EPA/DHA) 4g daily; alternative DHA/EPA 4g daily. Vascepa and Lovaza tablets must be swallowed and cannot be crushed, dissolved or chewed.
• Optional: Remdesivir, 200 mg IV loading dose D1, followed by 100mg day IV for 9 days. [62,63] This agent has been reported to reduce time to recovery (based on an ordinal scale). [63] The benefit of this agent on patient centered outcomes is unclear.
• 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 “Spinhaler” or MDI and spacer if required.
• T/f EARLY to the ICU for increasing respiratory signs/symptoms, increasing oxygen requirements and arterial desaturation
Progressive Respiratory symptoms (hypoxia- requiring N/C ≥ 4 L min: admit to ICU):
Essential Treatment (dampening the STORM); MATH +
1. Methylprednisolone 80 mg loading dose then 40 mg 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 125mg q 12 hourly), then titrate down as appropriate. [55-61]
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 (see below). [64-72]. Oral absorption is limited by saturable transport and it is difficult to achieve adequate levels with PO administration. However, unfortunately, IV Vitamin C is not available in many hospitals; in this situation attempts should be made to administer PO vitamin C at a dose of 1g every 4-6 hours.
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). [45-54] Heparin is suggested with CrCl < 15 ml/min. Due to augmented renal clearance patients may have reduced anti-Xa activity despite standard dosages of LMWH.[73] We therefore recommend monitoring anti-Xa activity in underweight and obese patients, those with chronic renal failure and in those patients with an increasing D-dimer, aiming for an anti-Xa activity of 0.6-1.1 IU.ml.
Note: A falling SaO2 despite respiratory symptoms should be a trigger to start anti-inflammatory treatment (see Figure 2).
Note: Early termination of ascorbic acid and corticosteroids will likely result in a rebound effect with clinical deterioration (see Figure 3).
Additional Treatment Components (the Full Monty)
4. Melatonin 6-12 mg at night (the optimal dose is unknown).
5. Famotidine 40 mg daily (20 mg in renal impairment)
6. Vitamin D 4000 u PO daily
7. Thiamine 200 mg IV q 12 hourly [74-78]
8. 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). [79-81]
9. Atorvastatin 80 mg/day. Statins have pleotropic anti-inflammatory, immunomodulatory, antibacterial, and antiviral effects. In addition, statins decrease expression of PAI-1. Simvastatin has Page 6 of 25 | EVMS Critical Care COVID-19 Management Protocol 08-01-2020 | evms.edu/covidcare been demonstrated to reduce mortality in the hyper-inflammatory ARDS phenotype. [82] Preliminary data suggests atorvastatin may improve outcome in patients with COVID-19.[83,84] Due to numerous drug-drug interactions simvastatin should be avoided.
10. Optional: Vascepa, Lovaza or DHA/EPA 4g day (see above).
11. Optional: Azithromycin 500 mg day 1 then 250 mg for 4 days (has immunomodulating properties including downregulating IL-6; has anti-viral properties and in addition, Rx of concomitant bacterial pneumonia). [31,85] The benefit of azithromycin in COVID-19 is however unproven.
12. Optional: Remdesivir. The role of this agent in patients with more advanced pulmonary involvement appears to be limited.
13. 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.
14. Maintain EUVOLEMIA (this is not non-cardiogenic pulmonary edema). 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 noninvasive hemodynamic monitoring. Diuretics should be avoided unless the patient has obvious intravascular volume overload. Avoid hypovolemia.
15. Early norepinephrine for hypotension. It should however be appreciated that despite the cytokine storm vasodilatory shock is distinctly uncommon in uncomplicated COVID-19 (not complicated by bacterial sepsis). This appears to be due to the fact TNF-α which is only moderately elevated in COVID-19, is “necessary” for vasodilatory shock.
16. Escalation of respiratory support (steps); Try to avoid intubation if at all possible, (see Figure 4)
• Accept “permissive hypoxemia” (keep O2 Saturation > 84%); follow venous lactate and Central Venous O2 saturations (ScvO2) in patents with low arterial O2 saturations
• N/C 1-6 L/min
• High Flow Nasal canula (HFNC) up to 60-80 L/min
• Trial of inhaled Flolan (epoprostenol)
• Attempt proning (cooperative repositioning-proning) [86,87]
• 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 Flolan (epoprostenol)
• Prone positioning.
There is widespread concern that using HFNC could increase the risk of viral transmission. There is however, no evidence to support this fear. HFNC is a better option for the patient and the health care system than intubation and mechanical ventilation. CPAP/BiPAP may be used in select patients, 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.
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