Critical Care Covid-19 Management Protocol

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Salient features:

This article focuses on:

  • Prophylaxis
  • Mildly Symptomatic patients (at home)
  • Mildly Symptomatic patients (on floor)
  • Respiratory symptoms (SOB; hypoxia- requiring N/C ≥ 4 L min: admit to ICU):
  • Essential Treatment (dampening the STORM)
  • Additional Treatment Components (the Full Monty)
  • Treatment of secondary HLH
  • Monitoring
  • Post ICU management
  • General thoughts

Detailed summary:

Prophylaxis:

  • Vitamin C 500 mg BID and Quercetin 250-500 mg BID
  • Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1-2 months, reduce the dose to 30-50 mg/day.
  • Melatonin (slow release): Begin with 0.3mg and increase as tolerated to 1-2 mg at night
  • Vitamin D3 1000-4000 u/day

Mildly Symptomatic patients (at home)

  • Vitamin C 500mg BID and Quercetin 250-500 mg BID
  • Zinc 75-100 mg/day
  • Melatonin 6-12 mg at night
  • Vitamin D3 1000-4000 u/day
  • Optional: Hydroxychloroquine 400mg BID day 1 followed by 200mg BID for 4 days

Mildly Symptomatic patients (on floor):

  • Vitamin C 500mg BID and Quercetin 250-500 mg BID
  • Zinc 75-100 mg/day
  • Melatonin 6-12 mg at night
  • Vitamin D3 1000-4000 u/day
  • Methylprednisolone 40 mg daily
  • Enoxaparin 40-60 mg daily
  • Optional: Hydroxychloroquine 400mg BID day 1 followed by 200mg BID for 4 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 “Spinhaler” or MDI and spacer if required.
  • Avoid non-invasive ventilation
  • T/f EARLY to the ICU for increasing respiratory signs/symptoms.

Respiratory symptoms (SOB; hypoxia- requiring N/C ≥ 4 L min: admit to ICU):

Essential Treatment (dampening the STORM)

  1. Methylprednisolone 80 mg loading dose then 40mg q 12 hourly for at least 7 days and until transferred out of ICU.

Alterative approach: Hydrocortisone 50 mg q 6 hourly.

  1. Ascorbic acid (Vitamin C) 3g IV q 6 hourly for at least 7 days and/or until transferred out of ICU.
  2. Full anticoagulation: Unless contraindicated 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). Heparin is suggested with CrCl < 15 ml/min.

Alternative approach: Half-dose rTPA: 25mg of tPA over 2 hours followed by a 25mg tPA infusion administered over the subsequent 22 hours, with a dose not to exceed 0.9 mg/kg followed by full anticoagulation. On transfer to floor, consider reducing enoxaparin to 40-60 mg /day.

Note: Early termination of ascorbic acid and corticosteroids will result in a rebound effect

Additional Treatment Components (the Full Monty)

  1. Melatonin 6-12 mg at night
  2. Magnesium: 2 g stat IV. Keep Mg between 2.0 and 2.4 mmol/l. Prevent hypomagnesemia
  3. Optional: Azithromycin 500 mg day 1 then 250 mg for 4 days
  4. Optional: Atorvastatin 40-80 mg/day.
  • Statins reduce mortality in the hyper-inflammatory ARDS phenotype.
  • Statins have pleotropic anti-inflammatory, immunomodulatory, antibacterial and antiviral effects.
  • Statins decrease expression of PAI-1
  1. Broad-spectrum antibiotics if superadded bacterial pneumonia is suspected based on procalcitonin levels and resp. culture.
  2. Maintain EUVOLEMIA. Cautious rehydration with 500 ml boluses of Lactate Ringers may be warranted. Diuretics should be avoided unless the patient has obvious intravascular volume overload.
  3. Early norepinephrine for hypotension.
  4. Escalation of respiratory support (steps); Try to avoid intubation if at all possible
  • Accept “permissive hypoxemia” (keep O2 Saturation > 84%)
  • N/C 1-6 L/min
  • High Flow Nasal canula (HFNC) up to 60-80 L/min
  • Trial of inhaled Flolan (epoprostenol)
  • Attempt 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 Flolan (epoprostenol)
  • Prone positioning
  • ECMO < 60 yrs. and no severe commodities/organ failure.

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.

  1. Treatment of secondary HLH (increasing Ferritin, CRP and transaminases)
  • “High dose corticosteroids.” Methylprednisolone 120 mg q 8 hourly for at least 3 days, then wean accruing to CRP, IL-6, Ferritin etc.
  • Tocilizumab (IL-6 inhibitor) as per dosing guideline.
  • Consider plasma exchange
  1. Monitoring
  • Daily: PCT, CRP, IL-6, BNP, Troponins, Ferritin, Neutrophil-Lymphocyte ratio, D-dimer, Mg, CRP and Ferritin are good biomarkers and track disease severity. Thromboelastogram (TEG) on admission and repeated as indicated.
  • 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/hydrochloroquine and azithromycin and monitor Mg++
  • No routine CT scans, follow CXR and chest ultrasound.
  • Follow ECHO closely; Pts develop a severe cardiomyopathy.
  1. Post ICU management
  • Enoxaparin 40-60 mg s/c daily
  • Methylprednisone 40 mg day, the wean slowly
  • Vitamin C 500 mg PO BID d. Melatonin 3-6 mg at night

General thoughts

  • Severe COVID-19 disease results in a dysregulated immune response with aberrant CD4+ T cell activation.
  • Patients have significantly elevated levels of IL-6, IL-10 and TNFα.
  • Downregulating the cytokine storm is an essential component of the treatment of severe COVID-19 disease.
  • COVID-19 patients developed a severe hypercoagulable state.This likely results in pulmonary micro- and macrovascular disease which may lead to hypoxia/pulmonary shunting.
  • These patients have a markedly increased risk of pulmonary and cerebral emboli.
  • Chest CT shows bilateral, discreet, irregular, multilobar “ground-glass” infiltrates
  • Physiologically in “COVID-19 lung water (EVLWI) is normal or only marginally increased
  • Lung compliance is quite good yet there is severe hypoxia (due to shunting).
  • This suggest microvascular disease and pulmonary vasoplegic resulting in marked V/Q mismatching (shunt).
  • Pulmonary embolism appears to be very common in these patients and may be the cause of sudden death .
  • The typical ARDS that develops over time is due mechanical ventilator induced lung injury and/or superadded bacterial pneumonia.
  • Sice there is no proper cure for it, we should be using multiple drugs/interventions that have synergistic and overlapping biological effects that are safe, cheap and “readily” available.
  • Good medical practice and the best interests of the patient require that physicians use legally available drugs according to their best knowledge and judgement.
  • Zinc (Zn++) inhibits viral RNA dependent RNA polymerase (replicase).
  • Chloroquine and hydroxychloroquine have broad antiviral properties.
  • These drugs are potent Zn ionophores and have favorable immunomodulating properties including inhibition of PAI-1 expression. These drugs may have a role in the EARLY viral replicative phase.
  • Ascorbic acid has numerous proven biological properties (anti-inflammatory, anti-oxidant, immune enhancing, antiviral) that are likely to be of benefit in patients with COVID-19 disease.
  • Ascorbic acid has synergistic effects when combined with corticosteroids.
  • Melatonin may have direct antiviral effects against COVID-19. In healthy people, melatonin levels plummet after the age of 40 years. This may partly explain the increased risk of death in patients with COVID-19 who are over the age of 40. Melatonin may therefore have a role in both the prevention and treatment of COVID-19.
  • Vitamin D has important immune-enhancing effects.
  • Low vitamin D levels have been shown to increase the risk of developing viral upper respiratory tract infections.
  • Therefore, prophylactic vitamin D should be considered especially in the elderly.
  • Quercetin is a plant phytochemical.
  • This compound has broad antiviral properties and acting at various steps in the viral life cycle.

Quercetin is a potent inhibitor of heat shock proteins (HSP 40 and 70) which are required for viral assembly. This readily available and cheap plant-derived compound may play a role in the prophylaxis of COVID-19 in high-risk populations.

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